U.S. patent application number 12/229891 was filed with the patent office on 2009-11-12 for benzoimidazole compounds.
Invention is credited to Kristen L. Arienti, James G. Breitenbucher, Daniel J. Buzard, James P. Edwards, Michael D. Hack, Haripada Khatuya, Alice Lee-Dutra.
Application Number | 20090281307 12/229891 |
Document ID | / |
Family ID | 38952593 |
Filed Date | 2009-11-12 |
United States Patent
Application |
20090281307 |
Kind Code |
A1 |
Arienti; Kristen L. ; et
al. |
November 12, 2009 |
Benzoimidazole compounds
Abstract
Benzoimidazole compounds, compositions, and methods of using
them in leukocyte recruitment inhibition, in modulating H.sub.4
receptor, and in treating conditions such as inflammation, H.sub.4
receptor-mediated conditions, and related conditions.
Inventors: |
Arienti; Kristen L.; (La
Mesa, CA) ; Breitenbucher; James G.; (Escondido,
CA) ; Buzard; Daniel J.; (San Diego, CA) ;
Edwards; James P.; (San Diego, CA) ; Hack; Michael
D.; (San Diego, CA) ; Lee-Dutra; Alice; (San
Diego, CA) ; Khatuya; Haripada; (San Diego,
CA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
38952593 |
Appl. No.: |
12/229891 |
Filed: |
August 26, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10952989 |
Sep 29, 2004 |
7432378 |
|
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12229891 |
|
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60507236 |
Sep 30, 2003 |
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Current U.S.
Class: |
540/575 ;
544/370; 546/194; 546/199 |
Current CPC
Class: |
C07K 2317/50 20130101;
A61P 35/02 20180101; C07K 2318/10 20130101; A61P 37/08 20180101;
A61P 29/00 20180101; C07K 16/00 20130101; C07D 401/04 20130101;
C04B 35/632 20130101; A61P 37/04 20180101; C07D 403/12 20130101;
C07K 2317/53 20130101; C07D 235/18 20130101; C07D 401/14 20130101;
C07D 401/12 20130101 |
Class at
Publication: |
540/575 ;
544/370; 546/199; 546/194 |
International
Class: |
C07D 403/12 20060101
C07D403/12; C07D 401/12 20060101 C07D401/12; C07D 401/14 20060101
C07D401/14 |
Claims
1. A compound of formula (I): ##STR00186## wherein W is CR.sup.7; Y
is CR.sup.12R.sup.13; Z is N; n is 1; each of R.sup.1-4 is,
independently from other substituent assignments, H,
C.sub.1-4alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.3-6cycloalkyl, --C.sub.1-4alkoxy, --C.sub.1-4alkylamino,
--C.sub.1-4alkylthio, --C.sub.1-4alkylsulfonyl,
--OC.sub.3-6cycloalkyl, --OCH.sub.2Ph, cyano, --CF.sub.3, F, Cl,
Br, I, nitro, --OCF.sub.3, --SCF.sub.3, --OR.sup.c, --SR.sup.c,
--S(O)R.sup.c, --SO.sub.2R.sup.c, --C(O)R.sup.c, phenyl, benzyl,
phenethyl, --C(O)NR.sup.aR.sup.b, --C(O)OR.sup.c,
--NR.sup.aR.sup.b, CH.sub.2NR.sup.aR.sup.b or --CH.sub.2OR.sup.c;
wherein each of R.sup.a, R.sup.b and R.sup.c is, independently from
other substituent assignments, selected from H, C.sub.1-4alkyl,
C.sub.3-6cycloalkyl, phenyl, (C.sub.3-6cycloalkyl)C.sub.1-2alkyl-,
benzyl and phenethyl, or R.sup.a and R.sup.b taken together with
the nitrogen to which they are attached, form a 4-7 membered
heterocyclic ring HetCycl, wherein said ring HetCyc1 has 0 or 1
additional heteroatoms selected from O, S, >NH and
>NC.sub.1-6alkyl, and wherein any phenyl, phenethyl, benzyl,
alkyl or cycloalkyl moiety in any of said R.sup.1-4, R.sup.a,
R.sup.b, R.sup.c, and said ring HetCyc1 is optionally, and
independently from other substituent assignments, substituted with
1, 2 or 3 substituents selected from C.sub.1-3alkyl, halo, hydroxy,
amino, and C.sub.1-3alkoxy; each of R.sup.5-7 is, independently
from other substituent assignments, H, C.sub.1-6alkyl, F, Cl, Br,
I, CF.sub.3, --OCF.sub.3, --OR.sup.c, --SR.sup.c, --S(O)R.sup.c,
--SO.sub.2R.sup.c, C.sub.1-4alkoxy, cyano, nitro,
--C(O)NR.sup.aR.sup.b, --C(O)phenyl, --C(O)C.sub.1-6alkyl,
--S(O)C.sub.1-4alkyl, or --SO.sub.2C.sub.1-4alkyl; or, R.sup.5 and
R.sup.6 for a compound of formula (I) taken together with the
carbon atoms to which they are attached form a cyclic structure
Cyc1 selected from aryl, heteroaryl, 5- or 6-membered carbocycle,
and 5- or 6-membered heterocycle with 1 or 2 heteroatoms, wherein
said cyclic structure Cyc1 is, independently from other substituent
assignments, substituted with 0, 1, or 2 substituents selected from
C.sub.1-3alkyl, halo, hydroxy, amino, and C.sub.1-3alkoxy; R.sup.8
is H, C.sub.1-6alkyl, C.sub.1-4alkoxy, or OH; each of R.sup.9 and
R.sup.10 is, independently from other substituent assignments, H or
C.sub.1-6alkyl, or R.sup.9 and R.sup.10 taken together form a 5-6
membered cyclic structure Cyc3, wherein said cyclic structure Cyc3
is a 5- or 6-membered carbocycle or a 5- or 6-membered heterocycle
with 1 or 2 heteroatoms, and wherein said cyclic structure Cyc3 is,
independently from other substituent assignments, substituted with
0, 1, or 2 substituents selected from C.sub.1-3alkyl, halo,
hydroxy, amino, and C.sub.1-3alkoxy; R.sup.11 is H, C.sub.1-4alkyl;
each of R.sup.12 and R.sup.13 is, independently from other
substituent assignments, H or C.sub.1-4alkyl; or, R.sup.12 and
R.sup.13 taken together with the carbon member to which they are
attached form an optionally substituted cyclic structure Cyc4,
wherein said cyclic structure Cyc4 is a 3- to 6-membered carbocycle
or a 3- to 6-membered heterocycle with 0 or 1 additional
heteroatoms, or CR.sup.12R.sup.13 is C.dbd.O; an enantiomer,
diastereomer, racemate thereof, or a pharmaceutically acceptable
salt, amide or ester thereof; provided that: neither R.sup.1 nor
R.sup.4 is C(O)NH.sub.2; and when R.sup.11 is methyl, then at least
one of R.sup.1-10 and R.sup.12-13 is not H.
2. A compound as in claim 1, wherein Y is CH.sub.2.
3. A compound as in claim 1, wherein R.sup.1 is selected from the
group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, F,
Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido, and
CH.sub.2OMe.
4. A compound as in claim 1, wherein R.sup.1 is H, methyl, F, or
Cl.
5. A compound as in claim 1, wherein R.sup.2 is selected from the
group consisting of H, methyl, ethyl, isopropyl, t-butyl,
cyclopropyl, CF.sub.3, OCF.sub.3, F, Cl, Br, cyano, phenyl,
carboxymethyl, dimethylcarboxamido, and benzoyl.
6. A compound as in claim 1, wherein R.sup.2 is H, F, Cl, methyl,
CF.sub.3, OCF.sub.3, or t-butyl.
7. A compound as in claim 1, wherein R.sup.3 is selected from the
group consisting of H, methyl, ethyl, isopropyl, t-butyl,
cyclopropyl, CF.sub.3, OCF.sub.3, F, Cl, Br, cyano, phenyl,
carboxymethyl, dimethylcarboxamido, and benzoyl.
8. A compound as in claim 1, wherein R.sup.3 is H, F, Cl, methyl,
CF.sub.3, OCF.sub.3, or t-butyl.
9. A compound as in claim 1, wherein R.sup.4 is selected from the
group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, R,
Cl, Br, cyano, phenyl, carboxymethyl, dimethylcarboxamido, and
CH.sub.2OMe.
10. A compound as in claim 1, wherein R.sup.4 is H, methyl, F, or
Cl.
11. A compound as in claim 1, wherein one or two of R.sup.1-4 are
not H.
12. A compound as in claim 1, wherein R.sup.5 is H, F, Cl, methyl,
or ethyl.
13. A compound as in claim 1, wherein R.sup.5 is F, Cl, or
methyl.
14. A compound as in claim 1, wherein R.sup.5 is H, F, Cl, or
methyl.
15. A compound as in claim 1, wherein R.sup.7 is H, F, Cl, or
methyl.
16. A compound as in claim 1, wherein R.sup.8 is H, methyl, or
OH.
17. A compound as in claim 1, wherein R.sup.8 is H.
18. A compound as in claim 1, wherein R.sup.9 and R.sup.10 are,
independently, selected from the group consisting of: H, methyl,
ethyl, propyl, and isopropyl.
19. A compound as in claim 1, wherein each of R.sup.9 and R.sup.10
is, independently, H or methyl.
20. A compound as in claim 1, wherein R.sup.11 is H. methyl, or
ethyl.
21. A compound as in claim 1, wherein R.sup.11 is methyl.
22. A compound selected from the group consisting of:
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl--
1H-benzoimidazole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorome-
thoxy-1H-benzoimidazole;
4,5-Dimethyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-b-
enzoimidazole;
5-Methyl-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalen-1-yl}-1H-b-
enzoimidazole;
5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro-1H-ben-
zoimidazole;
5-tert-Butyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
2-{2-Chloro-4-[2-methyl-3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-me-
thyl-1H-benzoimidazole;
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-me-
thyl-1H-benzoimidazole;
6-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-me-
thyl-1H-benzoimidazole;
5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
5-Chloro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole;
5-Chloro-6-fluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole;
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-b-
enzoimidazole;
5,6-Difluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,6-dime-
thyl-1H-benzoimidazole;
5-tert-Butyl-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
2-{3-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorom-
ethyl-1H-benzoimidazole;
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fl-
uoro-1H-benzoimidazole;
5,6-Dichloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole;
5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fl-
uoro-1H-benzoimidazole;
5-Chloro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole;
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-b-
enzoimidazole;
5,6-Dichloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
5-Chloro-6-methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-b-
enzoimidazole;
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole;
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorome-
thyl-1H-benzoimidazole;
5-Chloro-6-fluoro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole;
5-Methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole;
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole;
2-{3-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzo-
imidazole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H--
benzoimidazole;
5-Chloro-6-fluoro-2-{3-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole;
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methoxy-1H--
benzoimidazole;
5-tert-Butyl-2-{3,5-dibromo-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-pheny-
l}-1H-benzoimidazole;
2-{2-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorom-
ethyl-1H-benzoimidazole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorome-
thyl-1H-benzoimidazole;
4,6-Dimethyl-2-{2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-b-
enzoimidazole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-fluoro-4-me-
thyl-1H-benzoimidazole;
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-3H-naphtho[1,-
2-d]imidazole;
6-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5H-[1,3]dioxo-
lo[4',5':4,5]benzo[1,2-d]imidazole;
5-Chloro-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole;
5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole;
5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; and pharmaceutically acceptable salts of said
compounds.
Description
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/952,989, filed on Sep. 29, 2004, which in turn claims
the benefit of U.S. provisional patent application Ser. No.
60/507,236, filed on Sep. 30, 2003 each of which is incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to novel, pharmaceutically active,
fused heterocyclic compounds, more particularly benzoimidazole
compounds, and methods of using them to treat or prevent disorders
and conditions mediated by the histamine H.sub.4 receptor.
BACKGROUND OF THE INVENTION
[0003] Histamine was first identified as a hormone (G. Barger and
H. H. Dale, J. Physiol. (London) 1910, 41:19-59) and has since been
demonstrated to play a major role in a variety of physiological
processes, including the inflammatory "triple response" via H.sub.1
receptors (A. S. F. Ash and H. O, Schild, Br. J. Pharmac.
Chemother. 1966, 27:427-439), gastric acid secretion via H.sub.2
receptors (J. W. Black et al., Nature 1972, 236:385-390), and
neurotransmitter release in the central nervous system via H.sub.3
receptors (J.-M. Arrang et al., Nature 1983, 302:832-837) (for
review see S. J. Hill et al., Pharmacol. Rev. 1997, 49(3):253-278).
All three histamine receptor subtypes have been demonstrated to be
members of the superfamily of G protein-coupled receptors (I. Gantz
et al., Proc. Natl. Acad. Sci. U.S.A. 1991, 88:429-433; T. W.
Lovenberg et al., Mol. Pharmacol. 1999, 55(6):1101-1107; M.
Yamashita et al. Proc. Natl. Acad. Sci. U.S.A. 1991,
88:11515-11519). There are, however, additional functions of
histamine that have been reported, for which no receptor has been
identified. For example, in 1994, Raible et al., demonstrated that
histamine and R-.alpha.-methylhistamine could activate calcium
mobilization in human eosinophils (D. G. Raible et al., Am. J.
Respir. Crit. Care Med. 1994, 149:1506-1511). These responses were
blocked by the H.sub.3-receptor antagonist thioperamide. However,
R-.alpha.-methylhistamine was significantly less potent than
histamine, which was not consistent with the involvement of known
H.sub.3 receptor subtypes. Therefore, Raible et al. hypothesized
the existence of a novel histamine receptor on eosinophils that was
non-H.sub.1, non-H.sub.2, and non-H.sub.3. Most recently several
groups (T. Oda et al., J. Biol. Chem. 2000, 275(47):36781-36786; C.
Liu et al., Mol. Pharmacol. 2001, 59(3):420-426; T. Nguyen et al.,
Mol. Pharmacol. 2001, 59(3):427-433; Y. Zhu et al., Mol. Pharmacol.
2001, 59(3):434-441; K. L. Morse et al., J. Pharmacol. Exp. Ther.
2001, 296(3):1058-1066) have identified and characterized a fourth
histamine receptor subtype, the H.sub.4 receptor. This receptor is
a 390 amino acid, seven-transmembrane, G protein-coupled receptor
with approximately 40% homology to the histamine H.sub.3 receptor.
In contrast to the H.sub.3 receptor, which is primarily located in
the brain, the H.sub.4 receptor is expressed at greater levels in
eosinophils and mast cells, among other cells, as reported by Liu
et al. (see above) and C. L. Hofstra et al. (J. Pharmacol. Exp.
Ther. 2003, 305(3):1212-1221). Because of its preferential
expression on immunocompetent cells, this H.sub.4 receptor is
closely related with the regulatory functions of histamine during
the immune response.
[0004] A biological activity of histamine in the context of
immunology and autoimmune diseases is closely related with the
allergic response and its deleterious effects, such as
inflammation. Events that elicit the inflammatory response include
physical stimulation (including trauma), chemical stimulation,
infection, and invasion by a foreign body. The inflammatory
response is characterized by pain, increased temperature, redness,
swelling, reduced function, or a combination of these.
[0005] Mast-cell de-granulation (exocytosis) releases histamine and
leads to an inflammatory response that may be initially
characterized by a histamine-modulated wheal and flare reaction. A
wide variety of immunological stimuli (e.g., allergens or
antibodies) and non-immunological (e.g., chemical) stimuli may
cause the activation, recruitment, and de-granulation of mast
cells. Mast-cell activation initiates allergic (H.sub.1)
inflammatory responses, which in turn cause the recruitment of
other effector cells that further contribute to the inflammatory
response. The histamine H.sub.2 receptors modulate gastric acid
secretion, and the histamine H.sub.3 receptors affect
neurotransmitter release in the central nervous system.
[0006] Modulation of H.sub.4 receptors controls the release of
inflammatory mediators and inhibits leukocyte recruitment, thus
providing the ability to prevent and/or treat H.sub.4-mediated
diseases and conditions, including the deleterious effects of
allergic responses such as inflammation. Compounds according to the
present invention have H.sub.4 receptor modulating properties.
Compounds according to the present invention have leukocyte
recruitment inhibiting properties. Compounds according to the
present invention have anti-inflammatory properties.
[0007] Examples of textbooks on the subject of inflammation include
J. I. Gallin and R. Snyderman, Inflammation: Basic Principles and
Clinical Correlates, 3.sup.rd Edition, (Lippincott Williams &
Wilkins, Philadelphia, 1999); V. Stvrtinova, J. Jakubovsky and I.
Hulin, "Inflammation and Fever", Pathophysiology Principles of
Diseases (Textbook for Medical Students, Academic Press, 1995);
Cecil et al., Textbook Of Medicine, 18.sup.th Edition (W.B.
Saunders Company, 1988); and Steadmans Medical Dictionary.
[0008] Background and review material on inflammation and
conditions related with inflammation can be found in articles such
as the following: C. Nathan, Points of control in inflammation,
Nature 2002, 420:846-852; K. J. Tracey, The inflammatory reflex,
Nature 2002, 420:853-859; L. M. Coussens and Z. Werb, Inflammation
and cancer, Nature 2002, 420:860-867; P. Libby, Inflammation in
atherosclerosis, Nature 2002, 420:868-874; C. Benoist and D.
Mathis, Mast cells in autoimmune disease, Nature 2002, 420:875-878;
H. L. Weiner and D. J. Selkoe, Inflammation and therapeutic
vaccination in CNS diseases, Nature 2002, 420:879-884; J. Cohen,
The immunopathogenesis of sepsis, Nature 2002, 420:885-891; D.
Steinberg, Atherogenesis in perspective: Hypercholesterolemia and
inflammation as partners in crime, Nature Medicine 2002,
8(11):1211-1217.
[0009] Inflammation herein refers to the response that develops as
a consequence of histamine release, which in turn is caused by at
least one stimulus. Examples of such stimuli are immunological
stimuli and non-immunological stimuli.
[0010] Inflammation is due to any one of a plurality of conditions
such as allergy, asthma, chronic obstructed pulmonary disease
(COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis,
inflammatory bowel diseases (including Crohn's disease and
ulcerative colitis), psoriasis, allergic rhinitis, scleroderma,
autoimmune thyroid diseases, immune-mediated (also known as type 1)
diabetes mellitus and lupus, which are characterized by excessive
or prolonged inflammation at some stage of the disease. Other
autoimmune diseases that lead to inflammation include Myasthenia
gravis, autoimmune neuropathies, such as Guillain-Barre, autoimmune
uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune
thrombocytopenia, temporal arteritis, anti-phospholipid syndrome,
vasculitides, such as Wegener's granulomatosis, Behcet's disease,
dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary
biliary cirrhosis, autoimmune hepatitis, autoimmune oophoritis and
orchitis, autoimmune disease of the adrenal gland, polymyositis,
dermatomyositis, spondyloarthropathies, such as ankylosing
spondylitis, and Sjogren's syndrome. Regarding the onset and
evolution of inflammation, inflammatory diseases or
inflammation-mediated diseases or conditions include, but are not
limited to, acute inflammation, allergic inflammation, and chronic
inflammation.
[0011] Cited references are incorporated herein by reference.
SUMMARY OF THE INVENTION
[0012] The invention features a compound of formula (I) or
(II):
##STR00001##
wherein [0013] W is, independently from other member and
substituent assignments, N or CR.sup.7; [0014] X is, independently
from other member and substituent assignments, N or CH; [0015] Y
is, independently from other member and substituent assignments, O,
NR.sup.12, or CR.sup.12R.sup.13; [0016] Z is, independently from
other member and substituent assignments, N or CR.sup.14, in which
case the solid/dash feature () in any one of formulae (I) and (II)
is a single bond; or Z is C, in which case the solid/dash feature
() in any one of formulae (I) and (II) is a double bond; [0017] n
is, independently from member and substituent assignments, 0, 1, or
2; [0018] each of R.sup.1-4 is, independently from other member and
substituent assignments, H, C.sub.1-4alkyl, C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.3-6cycloalkyl, --C.sub.1-4alkoxy,
--C.sub.1-4alkylamino, --C.sub.1-4alkylthio,
--C.sub.1-4alkylsulfonyl, --OC.sub.3-6cycloalkyl, --OCH.sub.2Ph,
cyano, --CF.sub.3, F, Cl, Br, I, nitro, --OCF.sub.3, --SCF.sub.3,
--OR.sup.c, --SR.sup.c, --S(O)R.sup.c, --SO.sub.2R.sup.c,
--C(O)R.sup.c, phenyl, benzyl, phenethyl, --C(O)NR.sup.aR.sup.b,
--C(O)OR.sup.c, --NR.sup.aR.sup.b, --CH.sub.2NR.sup.aR.sup.b or
--CH.sub.2OR.sup.c; wherein each of R.sup.a, R.sup.b and R.sup.c
is, independently from other substituent assignments, selected from
H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, phenyl,
(C.sub.3-6cycloalkyl)C.sub.1-2alkyl-, benzyl and phenethyl, or
R.sup.a and R.sup.b taken together with the nitrogen to which they
are attached, form a 4-7 membered heterocyclic ring HetCyc1,
wherein said ring HetCyc1 has 0 or 1 additional heteroatoms
selected from O, S, >NH and >NC.sub.1-6alkyl, and wherein any
phenyl, phenethyl, benzyl, alkyl or cycloalkyl moiety in any of
said R.sup.1-4, R.sup.a, R.sup.b, R.sup.c, and said ring HetCyc1 is
optionally, and independently from other substituent assignments,
substituted with 1, 2 or 3 substituents selected from
C.sub.1-3alkyl, halo, hydroxy, amino, and C.sub.1-3alkoxy; [0019]
each of R.sup.5-7 is, independently from other member and
substituent assignments, H, C.sub.1-6alkyl, F, Cl, Br, I, CF.sub.3,
--OCF.sub.3, --OR.sup.c, --C.sub.1-3alkylOR.sup.c,
--C.sub.1-3alkylSR.sup.c, --SR.sup.c, --S(O)R.sup.c,
--SO.sub.2R.sup.c, C.sub.1-4alkoxy, cyano, nitro,
--C(O)NR.sup.aR.sup.b, --NR.sup.aR.sup.b,
--C.sub.1-3alkylNR.sup.aR.sup.b, --C(O)phenyl,
--C(O)C.sub.1-16alkyl, --S(O)C.sub.1-4alkyl, or
--SO.sub.2C.sub.1-4alkyl; or, R.sup.5 and R.sup.6 for a compound of
formula (I) taken together with the carbon atoms to which they are
attached form a cyclic structure Cyc1 selected from aryl,
heteroaryl, 5- or 6-membered carbocycle, and 5- or 6-membered
heterocycle with 1 or 2 heteroatoms, wherein said cyclic structure
Cyc1 is, independently from other substituent assignments,
substituted with 0, 1, or 2 substituents selected from
C.sub.1-3alkyl, halo, hydroxy, amino, and C.sub.1-3alkoxy; or,
R.sup.7 and R.sup.6 for a compound of formula (II) taken together
with the carbon atoms to which they are attached form a cyclic
structure Cyc2 selected from aryl, heteroaryl, 5- or 6-membered
carbocycle, and 5- or 6-membered heterocycle with 1 or 2
heteroatoms, wherein said cyclic structure Cyc2 is, independently
from other substituent assignments, substituted with 0, 1, or 2
substituents selected from C.sub.1-3alkyl, halo, hydroxy, amino,
and C.sub.1-3alkoxy; [0020] R.sup.8 is, independently from other
member and substituent assignments, H, C.sub.1-6alkyl,
C.sub.1-4alkoxy, or OH; [0021] each of R.sup.9 and R.sup.10 is,
independently from other member and substituent assignments, H or
C.sub.1-6alkyl, or R.sup.9 and R.sup.10 taken together form a 5-6
membered cyclic structure Cyc3, wherein said cyclic structure Cyc3
is a 5- or 6-membered carbocycle or a 5- or 6-membered heterocycle
with 1 or 2 heteroatoms, and wherein said cyclic structure Cyc3 is,
independently from other substituent assignments, substituted with
0, 1, or 2 substituents selected from C.sub.1-3alkyl, halo,
hydroxy, amino, and C.sub.1-3alkoxy; [0022] R.sup.11 is,
independently from other member and substituent assignments, H or
C.sub.1-4alkyl; [0023] each of R.sup.12 and R.sup.13 is,
independently from other member and substituent assignments, H or
C.sub.1-4alkyl; or, when Y is CR.sup.12R.sup.13, R.sup.12 and
R.sup.13 taken together with the carbon member to which they are
attached form an optionally substituted cyclic structure Cyc4,
wherein said cyclic structure Cyc4 is a 3- to 6-membered carbocycle
or a 3- to 6-membered heterocycle with 0 or 1 additional
heteroatoms, or CR.sup.12R.sup.13 is C.dbd.O; [0024] R.sup.14 is,
independently from other member and substituent assignments, H,
C.sub.1-4alkyl, OH, or C.sub.1-4alkoxy; an enantiomer,
diastereomer, racemate thereof, or a pharmaceutically acceptable
salt, amide or ester thereof; with the following provisos: [0025]
when Y is O or NR.sup.12, then Z is CR.sup.14 and R.sup.8 is not OH
or C.sub.1-4alkoxy; [0026] when Z is N, Y is CR.sup.12R.sup.13; and
[0027] none of R.sup.1-4 is C(O)NH.sub.2.
[0028] Isomeric forms of the compounds of formulae (I) and (II),
and of their pharmaceutically acceptable salts, amides and esters,
are encompassed within the present invention, and reference herein
to one of such isomeric forms is meant to refer to at least one of
such isomeric forms. One of ordinary skill in the art will
recognize that compounds according to this invention may exist, for
example, in a single isomeric form whereas other compounds may
exist in the form of a regioisomeric mixture.
[0029] Whether stated explicitly or not in any part of the written
description and claims, it is understood that each substituent and
member assignment in the context of this invention is made
independently of any other member and substituent assignment,
unless stated otherwise. By way of a first example on substituent
terminology, if substituent S.sup.1.sub.example is one of S.sub.1
and S.sub.2, and substituent S.sup.2.sub.example is one of S.sub.3
and S.sub.4, then these assignments refer to embodiments of this
invention given according to the choices S.sup.1.sub.example is
S.sub.1 and S.sup.2.sub.example is S.sub.3; S.sup.1.sub.example is
S.sub.1 and S.sup.2.sub.example is S.sub.4; S.sup.1.sub.example is
S.sub.2 and S.sup.2.sub.example is S.sub.3; S.sup.1.sub.example is
S.sub.2 and S.sup.2.sub.example is S.sub.4; and equivalents of each
one of such choices. The shorter terminology "S.sup.1.sub.example
is one of S.sub.1 and S.sub.2, and S.sup.2.sub.example is one of
S.sub.3 and S.sub.4" is accordingly used herein for the sake of
brevity, but not by way of limitation. The foregoing first example
on substituent terminology, which is stated in generic terms, is
meant to illustrate the various substituent R assignments described
herein. The foregoing convention given herein for substituents
extends, when applicable, to members such as X, Y, Z, and W, and
the index n.
[0030] Furthermore, when more than one assignment is given for any
member or substituent, embodiments of this invention comprise the
various groupings that can be made from the listed assignments and
equivalents thereof. By way of a second example on substituent
terminology, if it is herein described that substituent
S.sub.example is one of S.sub.1, S.sub.2, and S.sub.3, this listing
refers to embodiments of this invention for which S.sub.example is
S.sub.1; S.sub.example is S.sub.2; S.sub.example is S.sub.3;
S.sub.example is one of S.sub.1 and S.sub.2; S.sub.example is one
of S.sub.1 and S.sub.3; S.sub.example is one of S.sub.2 and
S.sub.3; S.sub.example is one of S.sub.1, S.sub.2 and S.sub.3; and
S.sub.example is any equivalent of each one of these choices. The
shorter terminology "S.sub.example is one of S.sub.1, S.sub.2, and
S.sub.3" is accordingly used herein for the sake of brevity, but
not by way of limitation. The foregoing second example on
substituent terminology, which is stated in generic terms, is meant
to illustrate the various substituent R assignments described
herein. The foregoing convention given herein for substituents
extends, when applicable, to members such as X, Y, Z, and W, and
the index n.
[0031] The nomenclature "C.sub.i-j" with j>i, when applied
herein to a class of substituents, is meant to refer to embodiments
of this invention for which each and every one of the number of
carbon members, from i to j including i and j, is realized. By way
of example, the term C.sub.1-3 refers independently to embodiments
that have one carbon member (C.sub.1), embodiments that have two
carbon members (C.sub.2), and embodiments that have three carbon
members (C.sub.3).
[0032] When any variable referring to a substituent, compound
member or index, occurs more than once, the full range of
assignments is meant to apply to each occurrence, independently of
the specific assignment(s) to any other occurrence of such
variable.
[0033] According to the foregoing interpretive considerations on
assignments and nomenclature, it is understood that explicit
reference herein to a set implies, where chemically meaningful and
unless indicated otherwise, independent reference to embodiments of
such set, and reference to each and every one of the possible
embodiments of subsets of the set referred to explicitly.
[0034] The invention also features a pharmaceutical composition for
treating or preventing an H.sub.4 receptor-mediated condition in a
subject, comprising a therapeutically effective amount of at least
one H.sub.4 receptor modulator selected from compounds of formulae
(I) and (II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof. In
addition, the invention features a pharmaceutical composition for
inhibiting leukocyte recruitment in a subject, comprising a
therapeutically effective amount of at least one leukocyte
recruitment inhibitor selected from compounds of formulae (I) and
(II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof. The
invention additionally features an anti-inflammatory composition,
comprising a therapeutically effective amount of at least one
anti-inflammatory compound selected from compounds of formulae (I)
and (II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof.
[0035] The invention features methods for treating or preventing
inflammation in a subject, comprising administering to the subject
in connection with an inflammatory response a pharmaceutical
composition that comprises a therapeutically effective amount of at
least one anti-inflammatory compound selected from compounds of
formulae (I) and (II), enantiomers, diastereomers, racemates
thereof, pharmaceutically acceptable salts, amides and esters
thereof. The invention also features methods for treating or
preventing an H.sub.4 receptor-mediated condition in a subject,
comprising administering to the subject a pharmaceutical
composition that comprises a therapeutically effective amount of at
least one H.sub.4 receptor modulator selected from compounds of
formulae (I) and (II), enantiomers, diastereomers, racemates
thereof, pharmaceutically acceptable salts, amides and esters
thereof. In addition, the invention features methods for modulating
an H.sub.4 receptor, comprising exposing an H.sub.4 receptor to at
least one compound selected from compounds of formulae (I) and
(II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof.
Furthermore, the invention features methods for inhibiting
leukocyte recruitment in a subject, comprising administering to the
subject a pharmaceutical composition that comprises a
therapeutically effective amount of at least one leukocyte
recruitment inhibitor selected from compounds of formulae (I) and
(II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof.
DETAILED DESCRIPTION
[0036] The present invention is directed to compounds of formula
(I) or (II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof, as
herein defined, pharmaceutical compositions that contain at least
one of such compounds, methods of using, including treatment and/or
prevention of conditions such as those that are mediated by the
H.sub.4 receptor, and methods of making such pharmaceutical
compositions.
[0037] The following terms are defined below, and by their usage
throughout the disclosure.
[0038] "Alkyl" includes straight chain and branched hydrocarbons
with at least one hydrogen removed to form a radical group. Alkyl
groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl,
heptyl, octyl, and so on. Alkyl does not include cycloalkyl.
[0039] "Alkenyl" includes straight chain and branched hydrocarbon
radicals as above with at least one carbon-carbon double bond
(sp.sup.2). Unless indicated otherwise by the prefix that indicates
the number of carbon members, alkenyls include ethenyl (or vinyl),
prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or
1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls,
hexa-2,4-dienyl, and so on.
[0040] "Alkynyl" includes straight chain and branched hydrocarbon
radicals as above with at least one carbon-carbon triple bond (sp).
Unless indicated otherwise by the prefix that indicates the number
of carbon members, alkynyls include ethynyl, propynyls, butynyls,
and pentynyls. Hydrocarbon radicals having a mixture of double
bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as
alkynyls herein.
[0041] "Alkoxy" includes a straight chain or branched alkyl group
with a terminal oxygen linking the alkyl group to the rest of the
molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy,
butoxy, t-butoxy, pentoxy and so on.
[0042] "Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are analogous
to alkoxy, replacing the terminal oxygen atom of alkoxy with,
respectively, NH (or NR), S, and SO.sub.2.
[0043] Unless indicated otherwise by the prefix that indicates the
number of carbon members, "cycloalkyl" includes cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and
so on.
[0044] Unless indicated otherwise by the prefix that indicates the
number of members in the cyclic structure, "heterocyclyl",
"heterocyclic" or "heterocycle" is a 3- to 8-member aromatic,
saturated, or partially saturated single or fused ring system that
comprises carbon atoms wherein the heteroatoms are selected from N,
O, and S. Examples of heterocyclyls include thiazoylyl, furyl,
pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl,
isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl,
quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
indolinyl, and morpholinyl. For example, preferred heterocyclyls or
heterocyclic radicals include morpholinyl, piperazinyl,
pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino, and more
preferably, piperidyl.
[0045] Carbocycle is a cycloalkyl or a partially saturated
cycloalkyl that is not benzo
##STR00002##
[0046] "Aryl" includes phenyl, naphthyl, biphenylyl,
tetrahydronaphthyl, and so on, any of which may be optionally
substituted. Aryl also includes arylalkyl groups such as benzyl,
phenethyl, and phenylpropyl. Aryl includes a ring system containing
an optionally substituted 6-membered carbocyclic aromatic ring,
said system may be bicyclic, bridged, and/or fused. The system may
include rings that are aromatic, or partially or completely
saturated. Examples of ring systems include indenyl, pentalenyl,
1-4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl,
indolyl, benzofuranyl, isoquinolinyl, and so on. Examples
illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl,
oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl.
[0047] "Halo" includes fluoro, chloro, bromo, and iodo, and is
preferably fluoro or chloro.
[0048] As in standard chemical nomenclature, the group phenyl is
herein referred to as "phenyl" or as "Ph".
[0049] "Patient" or "subject" includes mammals such as human beings
and animals (e.g., dogs, cats, horses, rats, rabbits, mice,
non-human primates) in need of observation, experiment, treatment
or prevention in connection with the relevant disease or condition.
Preferably, the patient is a human being.
[0050] "Composition" includes a product comprising the specified
ingredients in the specified amounts, including in the effective
amounts, as well as any product that results directly or indirectly
from combinations of the specified ingredients in the specified
amounts.
[0051] "Therapeutically effective amount" or "effective amount" and
grammatically related terms mean that amount of active compound or
pharmaceutical agent that elicits the biological or medicinal
response in a tissue system, animal or human that is being sought
by a researcher, veterinarian, medical doctor or other clinician,
which includes alleviation of the symptoms of the disease or
disorder being treated.
TABLE-US-00001 Table of Acronyms Term Acronym Tetrahydrofuran THF
N,N-Dimethylformamide DMF N,N-Dimethylacetamide DMA Dimethyl
sulfoxide DMSO tert-Butylcarbamoyl BOC Bovine serum albumin BSA
High-pressure liquid chromatography HPLC Thin layer chromatography
TLC
[0052] Particular preferred compounds of the invention comprise a
benzoimidazole compound of formula (I) or (II), or an enantiomer,
diastereomer, racemate thereof, or a pharmaceutically acceptable
salt, amide or ester thereof, wherein R.sup.1-14, X, Y, Z, W, and n
have any of the meanings defined hereinabove and equivalents
thereof, or at least one of the following assignments and
equivalents thereof. Such assignments may be used where appropriate
with any of the definitions, claims or embodiments defined
herein:
[0053] Preferably, W is N or CR.sup.7.
[0054] Preferably, X is N or CH.
[0055] Preferably, Y is CR.sup.12R.sup.13.
[0056] More preferably, Y is CH.sub.2.
[0057] Preferably, Z is N or CH.
[0058] Preferably, n=1 or 2.
[0059] More preferably, n=1.
[0060] Preferably, R.sup.1 is selected from the group consisting of
H, methyl, ethyl, isopropyl, cyclopropyl, F, Cl, Br, cyano, phenyl,
carboxymethyl, dimethylcarboxamido, or CH.sub.2OMe.
[0061] More preferably, R.sup.1 is H, methyl, F, or Cl.
[0062] Preferably, R.sup.2 is independently selected from the group
consisting of H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl,
CF.sub.3, OCF.sub.3, F, Cl, Br, cyano, phenyl, carboxymethyl,
dimethylcarboxamido, or benzoyl.
[0063] More preferably, R.sup.2 is H, F, Cl, methyl, CF.sub.3,
OCF.sub.3, or t-butyl.
[0064] Preferably, R.sup.3 is independently selected from the group
consisting of H, methyl, ethyl, isopropyl, t-butyl, cyclopropyl,
CF.sub.3, OCF.sub.3, F, Cl, Br, cyano, phenyl, carboxymethyl,
dimethylcarboxamido, or benzoyl.
[0065] More preferably, R.sup.3 is H, F, Cl, methyl, CF.sub.3,
OCF.sub.3, or t-butyl.
[0066] Preferably, R.sup.4 is selected from the group consisting of
H, methyl, ethyl, isopropyl, cyclopropyl, R, Cl, Br, cyano, phenyl,
carboxymethyl, dimethylcarboxamido, or CH.sub.2OMe.
[0067] More preferably, R.sup.4 is H, methyl, F, or Cl.
[0068] Most preferably, one or two of R.sup.1-4 are not H.
[0069] Preferably, R.sup.5 is H, F, Cl, methyl, or ethyl.
[0070] More preferably, R.sup.5 is F, Cl, methyl, hydroxymethyl,
hydroxyethyl, pyrrolidinylmethyl, or diethylaminomethyl.
[0071] More preferably, R.sup.6 is H, F, Cl, or methyl.
[0072] More preferably, R.sup.7 is H, F, Cl, or methyl.
[0073] Most preferably, R.sup.5 is Cl, methyl, or
hydroxymethyl.
[0074] Preferably, R.sup.8 is H, methyl, or OH.
[0075] More preferably, R.sup.8 is H.
[0076] Preferably, R.sup.9 and R.sup.10 are, independently,
selected from the group consisting of
[0077] a) H,
[0078] b) methyl, ethyl, propyl, isopropyl, and
[0079] c) trifluoromethyl.
[0080] Most preferably, R.sup.9 and R.sup.10 are, independently, H
or methyl.
[0081] Preferably, R.sup.11 is H, methyl, or ethyl.
[0082] More preferably, R.sup.11 is methyl.
[0083] Compounds of formula (I) or (II) also comprise compounds
that satisfy any one of the combinations of definitions given
herein and equivalents thereof.
[0084] It is understood that some compounds referred to herein are
chiral and/or have geometric isomeric centers, for example E- and
Z-isomers. The present invention encompasses all such optical,
including stereoisomers and racemic mixtures, diastereomers, and
geometric isomers that possess the activity that characterizes the
compounds of this invention. In addition, certain compounds
referred to herein can exist in solvated as well as unsolvated
forms. It is understood that this invention encompasses all such
solvated and unsolvated forms that possess the activity that
characterizes the compounds of this invention. Compounds according
to the present invention that have been modified to be detectable
by some analytic technique are also within the scope of this
invention. An example of such compounds is an isotopically labeled
compound, such as an .sup.18F isotopically labeled compound that
may be used as a probe in detection and/or imaging techniques, such
as positron emission tomography (PET) and single-photon emission
computed tomography (SPECT). Another example of such compounds is
an isotopically labeled compound, such as a deuterium and/or
tritium labeled compound that may be used in reaction kinetic
studies.
[0085] It is understood that substitutions and combinations of
substitutions recited herein, whether stated explicitly or not,
refer to substitutions that are consistent with the valency of the
member being substituted. For example, a substitution applied to a
carbon member refers to the tetravalency of C; it refers to the
trivalency of N when applied to a nitrogen member; and it refers to
the tetravalency of a nitrogen member that is conventionally
characterized with a positive electric charge. Valence allowed
options are part of the ordinary skill in the art.
[0086] The "pharmaceutically acceptable salts, amides and/or esters
thereof" refer to those salts, amides and ester forms of the
compounds of the present invention that would be apparent to the
pharmaceutical chemist, i.e., those that are non-toxic and that
would favorably affect the pharmacological properties of said
compounds of the present invention. Those compounds having
favorable pharmacological properties would be apparent to the
pharmaceutical chemist, i.e., those that are non-toxic and that
possess such pharmacological properties to provide sufficient
palatability, absorption, distribution, metabolism and excretion.
Other factors, more practical in nature, that are also important in
the selection are cost of raw materials, ease of crystallization,
yield, stability, hygroscopicity, and flowability of the resulting
bulk drug.
[0087] Representative acids and bases that may be used in the
preparation of pharmaceutically acceptable salts include the
following:
[0088] acids including acetic acid, 2,2-dichlorolactic acid,
acylated amino acids, adipic acid, alginic acid, ascorbic acid,
L-aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, x-oxo-glutaric acid,
glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid,
(+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid, maleic
acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic acid,
methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid;
and
[0089] bases including ammonia, L-arginine, benethamine,
benzathine, calcium hydroxide, choline, deanol, diethanolamine,
diethylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole,
L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,
piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine,
secondary amine, sodium hydroxide, triethanolamine, tromethamine
and zinc hydroxide.
[0090] See, for example, S. M. Berge, et al., "Pharmaceutical
Salts", J. Pharm. Sci. 1977, 66:1-19, which is incorporated herein
by reference. Examples of suitable esters include C.sub.1-7alkyl,
C.sub.5-7cycloalkyl, phenyl, substituted phenyl, and
phenylC.sub.1-6alkyl-esters. Preferred esters include methyl
esters.
[0091] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound that may not be specifically disclosed, but that
converts to the specified compound in vivo after administration to
the patient. Analogously, the term "compound", when applied to
compounds within the scope of this invention, shall encompass in
addition to a specific compound of formula (I) or (II), a compound
(or prodrug) that converts to the specifically disclosed compound
in vivo after administration, even if such prodrug is not
explicitly disclosed herein. Conventional procedures for the
selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard,
Elsevier, 1985.
[0092] Compounds where W is CR.sup.7 were made according to the
synthetic methods outlined in Schemes 1 and 2 and examples of such
compounds are provided in the group:
[0093] EX Compound [0094] 1
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl--
1H-benzoimidazole; [0095] 2
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-b-
enzoimidazole; [0096] 3
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorome-
thoxy-1H-benzoimidazole; [0097] 4
5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phen-
yl}-1H-benzoimidazole; [0098]
5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0099] 6
4,5-Dimethyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0100] 7
5-tert-Butyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoim-
idazole; [0101] 8
5-tert-Butyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-ben-
zoimidazole; [0102] 9
(1-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-2-chloro-phenoxy]-propyl}-p-
yrrolidin-3-yl)-dimethylamine; [0103] 10
5-Chloro-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}--
6-methyl-1H-benzoimidazole; [0104] 11
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-b-
enzoimidazole; [0105] 12
5-Methyl-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalen-1-yl}-1H-b-
enzoimidazole; [0106] 13
4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-piperazin--
1-yl)-butan-1-one; [0107] 14
5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro-1H-ben-
zoimidazole; [0108] 15
5-tert-Butyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0109] 16
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,6-dimethyl--
1H-benzoimidazole; [0110] 17
2-{2-Chloro-4-[2-methyl-3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-me-
thyl-1H-benzoimidazole; [0111] 18
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-me-
thyl-1H-benzoimidazole; [0112] 19
6-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-me-
thyl-1H-benzoimidazole; [0113] 20
5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0114] 21
5-Chloro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0115] 22
2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,6-dimet-
hyl-1H-benzoimidazole; [0116] 23
5-Chloro-6-methyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-be-
nzoimidazole; [0117] 24
5-Chloro-6-fluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole; [0118] 25
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-b-
enzoimidazole; [0119] 26
5,6-Difluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0120] 27
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole; [0121] 28
2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5-dimet-
hyl-1H-benzoimidazole; [0122] 29
5,6-Dimethyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoim-
idazole; [0123] 30
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,6-dimethyl--
1H-benzoimidazole; [0124] 31
2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl--
1H-benzoimidazole; [0125] 32
5-tert-Butyl-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0126] 33
2-{3-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorom-
ethyl-1H-benzoimidazole; [0127] 34
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fl-
uoro-1H-benzoimidazole; [0128] 35
5,6-Dichloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0129] 36
5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0130] 37
5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fl-
uoro-1H-benzoimidazole; [0131] 38
5-Chloro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0132] 39
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-b-
enzoimidazole; [0133] 40
5,6-Dichloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0134] 41
5-Chloro-6-methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole; [0135] 42
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-b-
enzoimidazole; [0136] 43
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0137] 44
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorome-
thyl-1H-benzoimidazole; [0138] 45
5-Chloro-6-fluoro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole; [0139] 46
5-Methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0140] 47
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole; [0141] 48
2-{3-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole; [0142] 49
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole; [0143] 50
5-Chloro-6-fluoro-2-{3-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole; [0144] 51
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methoxy-1H--
benzoimidazole; [0145] 52
5-tert-Butyl-2-{3,5-dibromo-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-pheny-
l}-1H-benzoimidazole; [0146] 53
2-{2-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorom-
ethyl-1H-benzoimidazole; [0147] 54
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluorome-
thyl-1H-benzoimidazole; [0148] 55
2-{3-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;
[0149] 56
(2-{3-[4-(4-Methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimid-
azol-5-yl)-phenyl-methanone; [0150] 57
6-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-me-
thyl-1H-benzoimidazole; [0151] 58
5-tert-Butyl-2-{3-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0152] 59
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5-dimethyl--
1H-benzoimidazole; [0153] 60
5-Chloro-6-methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0154] 61
5-Chloro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimida-
zole; [0155] 62
5-Chloro-6-fluoro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0156] 63
5-tert-Butyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoi-
midazole; [0157] 64
5-Methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimida-
zole; [0158] 65
2-{4-[3-(1-Methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;
[0159] 66
6-Chloro-2-{2-fluoro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-ph-
enyl}-4-methyl-1H-benzoimidazole; [0160] 67
5-Fluoro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0161] 68
4-Chloro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-b-
enzoimidazole; [0162] 69
6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phe-
nyl}-1H-benzoimidazole; [0163] 70
5-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-6-fl-
uoro-1H-benzoimidazole; [0164] 71
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-3H-naphtho[1,-
2-d]imidazole; [0165] 72
4,6-Dimethyl-2-{2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0166] 73
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-b-
enzoimidazole; [0167] 74
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-fluoro-4-me-
thyl-1H-benzoimidazole; [0168] 75
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-3H-naphtho[1,-
2-d]imidazole; [0169] 76
6-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5H-[1,3]dioxo-
lo[4',5':4,5]benzo[1,2-d]imidazole; [0170] 77
6-Chloro-2-{2-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}--
4-methyl-1H-benzoimidazole; [0171] 78
2-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl--
1H-benzoimidazole; [0172] 79
4,6-Dimethyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-ben-
zoimidazole; [0173] 80
5-Chloro-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimida-
zole; [0174] 81
2-{4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;
[0175] 82
{2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-pip-
eridin-4-yl)-propoxy]-benzyl}-dimethyl-amine; [0176] 83
{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-y-
l)-propoxy]-benzyl}-dimethyl-amine; [0177] 84
4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propy-
l}-[1,4]diazepan-5-one; [0178] 85
4-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-1--
methyl-[1,4]diazepan-5-one; [0179] 86
5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0180] 87
5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole; [0181] 88
6-Chloro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-ben-
zoimidazole; [0182] 89
5-Fluoro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-ben-
zoimidazole; [0183] 90
6-Chloro-2-{4-[3-(1-ethyl-piperidin-4-yl)-propoxy]-2-methyl-phenyl}-4-met-
hyl-1H-benzoimidazole; [0184] 91
{2-[3-Chloro-4-(4-methyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-methyl-(1-
-methyl-piperidin-4-yl)-amine; [0185] 92
6-Chloro-4-methyl-2-{2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-p-
henyl}-1H-benzoimidazole; [0186] 93
6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-
-yl)-propoxy]-phenyl}-1H-benzoimidazole; [0187] 94
5-Fluoro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-
-yl)-propoxy]-phenyl}-1H-benzoimidazole; [0188] 95
6-Fluoro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-be-
nzoimidazole; [0189] 96
7-Methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidaz-
ole; [0190] 97
6,7-Dimethyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoim-
idazole; [0191] 98
5-Chloro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-be-
nzoimidazole; [0192] 99
5,7-Dimethyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1-
H-benzoimidazole; [0193] 100
5-Chloro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phen-
yl}-1H-benzoimidazole; [0194] 101
6-Fluoro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phen-
yl}-1H-benzoimidazole; [0195] 102
6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1-
H-benzoimidazole; and [0196] 176
{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-y-
l)-propoxy]-phenyl}-methanol.
[0197] Compounds where W is N were made according to the synthetic
methods outlined in Schemes 1 through 6 and examples of such
compounds are provided in the group:
[0198] EX Compound [0199] 103
6-Chloro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl-
}-1H-benzoimidazole; [0200] 104
4-Methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benz-
oimidazole; [0201] 105
5-Fluoro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl-
}-1H-benzoimidazole; [0202] 106
4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benz-
oimidazole; [0203] 107
4,5-Dimethyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H--
benzoimidazole; [0204] 108
4-Chloro-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benz-
oimidazole; [0205] 109
6-Chloro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyr-
idin-3-yl}-1H-benzoimidazole; [0206] 110
4-Methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl-
}-1H-benzoimidazole; [0207] 111
5-Fluoro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyr-
idin-3-yl}-1H-benzoimidazole; [0208] 112
4,5-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin--
3-yl}-1H-benzoimidazole; [0209] 113
4,6-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin--
3-yl}-1H-benzoimidazole; [0210] 114
4-Chloro-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl-
}-1H-benzoimidazole; [0211] 115
2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-5-fluor-
o-4-methyl-1H-benzoimidazole; [0212] 116
2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methy-
l-1H-benzoimidazole; [0213] 117
6-Chloro-2-{4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl-
}-4-methyl-1H-benzoimidazole; [0214] 118
2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4,6-dim-
ethyl-1H-benzoimidazole; [0215] 119
2-{4-Methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-meth-
yl-1H-benzoimidazole; [0216] 120
5-Fluoro-2-{4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-y-
l}-4-methyl-1H-benzoimidazole; [0217] 121
5-Fluoro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-prop-
oxy]-pyridin-3-yl}-1H-benzoimidazole; [0218] 122
4-Methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyri-
din-3-yl}-1H-benzoimidazole; [0219] 123
6-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-prop-
oxy]-pyridin-3-yl}-1H-benzoimidazole; [0220] 124
4,5-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]--
pyridin-3-yl}-1H-benzoimidazole; [0221] 125
4,6-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]--
pyridin-3-yl}-1H-benzoimidazole; [0222] 126
5-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-prop-
oxy]-pyridin-3-yl}-1H-benzoimidazole; [0223] 127
5-Fluoro-4-methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-
-1-ylmethyl-pyridin-3-yl}-1H-benzoimidazole; [0224] 128
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl--
1H-benzoimidazole; [0225] 129
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro--
4-methyl-1H-benzoimidazole; [0226] 130
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-chloro--
4-methyl-1H-benzoimidazole; [0227] 131
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimet-
hyl-1H-benzoimidazole; [0228] 132
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimet-
hyl-1H-benzoimidazole; [0229] 133
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro--
4-methyl-1H-benzoimidazole; [0230] 134
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-tert-bu-
tyl-1H-benzoimidazole; [0231] 135
5-tert-Butyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-b-
enzoimidazole; [0232] 136
2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-
-4-methyl-1H-benzoimidazole; [0233] 137
2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dime-
thyl-1H-benzoimidazole; [0234] 138
4,6-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-b-
enzoimidazole; [0235] 139
4-Methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzo-
imidazole; [0236] 140
4,5-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-b-
enzoimidazole; [0237] 141
5-Fluoro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0238] 142
6-Chloro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0239] 143
5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-
-yl}-1H-benzoimidazole; [0240] 144
4,5-Dimethyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}--
1H-benzoimidazole; [0241] 145
4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-b-
enzoimidazole; [0242] 146
4-Methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzo-
imidazole; [0243] 147
5-Fluoro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0244] 148
4-Chloro-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzo-
imidazole; [0245] 149
4,5-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-b-
enzoimidazole; [0246] 150
6-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0247] 151
5-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0248] 152
5-tert-Butyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazo-
le; [0249] 153
4,6-Dimethyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazo-
le; [0250] 154
2-{2-[4-(1-Ethyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-be-
nzoimidazole; [0251] 155
4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-
-yl}-1H-benzoimidazole; [0252] 156
4-Methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0253] 157
6-Chloro-4-methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyri-
din-4-yl}-1H-benzoimidazole; [0254] 158
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-
-1H-benzoimidazole; [0255] 159
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dime-
thyl-1H-benzoimidazole; [0256] 160
4-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0257] 161
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-
-4-methyl-1H-benzoimidazole; [0258] 162
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dime-
thyl-1H-benzoimidazole; [0259] 163
6-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-4-methyl-1H-benzoimidazole; [0260] 164
5-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-4-methyl-1H-benzoimidazole; [0261] 165
5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyri-
din-4-yl}-1H-benzoimidazole; [0262] 166
5-Chloro-6-fluoro-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyri-
din-4-yl}-1H-benzoimidazole; [0263] 167
5-tert-Butyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-
-yl}-1H-benzoimidazole; [0264] 168
4,5-Dimethyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-
-yl}-1H-benzoimidazole; [0265] 169
2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dime-
thyl-1H-benzoimidazole; [0266] 170
5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-1H-benzoimidazole; [0267] 171
5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-6-fluoro-1H-benzoimidazole; [0268] 172
5-tert-Butyl-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-
-yl}-1H-benzoimidazole; [0269] 173
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-chloro--
1H-benzoimidazole; [0270] 174
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro--
6-fluoro-1H-benzoimidazole; [0271] 175
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro--
1H-benzoimidazole; and [0272] 177
{4-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-6-[4-(1-methyl-piperidin-4-yl)-bu-
toxy]-pyridin-3-yl}-methanol.
[0273] Embodiments of pharmaceutical compositions and methods of
use of compounds according to this invention are provided by
pharmaceutical compositions that comprise, and by methods of use
of, any of the compounds described herein and combinations
thereof.
[0274] Embodiments of pharmaceutical compositions for treating or
preventing an H.sub.4 receptor-mediated condition in a subject that
comprise a therapeutically effective amount of at least one H.sub.4
receptor modulator selected from compounds of formulae (I) and
(II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof,
further comprise a pharmaceutically acceptable carrier.
[0275] Embodiments of pharmaceutical compositions for inhibiting
leukocyte recruitment in a subject that comprise a therapeutically
effective amount of at least one leukocyte recruitment inhibitor
selected from compounds of formulae (I) and (II), enantiomers,
diastereomers, racemates thereof, pharmaceutically acceptable
salts, amides and esters thereof, further comprise a
pharmaceutically acceptable carrier.
[0276] Embodiments of anti-inflammatory compositions that comprise
a therapeutically effective amount of at least one
anti-inflammatory compound selected from compounds of formulae (I)
and (II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof,
further comprise a pharmaceutically acceptable carrier.
[0277] Embodiments of methods for treating or preventing
inflammation in a subject that comprise administering to the
subject in connection with an inflammatory response a
pharmaceutical composition comprising a therapeutically effective
amount of at least one anti-inflammatory compound selected from
compounds of formulae (I) and (II), enantiomers, diastereomers,
racemates thereof, pharmaceutically acceptable salts, amides and
esters thereof, include methods wherein said inflammatory response
is a response to at least one of the conditions: inflammatory
disorders, allergic disorders, dermatological disorders, autoimmune
disease, lymphatic disorders, itchy skin, and immunodeficiency
disorders.
[0278] Embodiments of methods for treating or preventing
inflammation in a subject that comprise administering to the
subject in connection with an inflammatory response a
pharmaceutical composition comprising a therapeutically effective
amount of at least one anti-inflammatory compound selected from
compounds of formulae (I) and (II), enantiomers, diastereomers,
racemates thereof, pharmaceutically acceptable salts, amides and
esters thereof, include methods wherein said inflammatory response
is a response to chemotherapy.
[0279] Embodiments of methods for treating or preventing
inflammation in a subject that comprise administering to the
subject in connection with an inflammatory response a
pharmaceutical composition comprising a therapeutically effective
amount of at least one anti-inflammatory compound selected from
compounds of formulae (I) and (II), enantiomers, diastereomers,
racemates thereof, pharmaceutically acceptable salts, amides and
esters thereof, include methods wherein at least one of the
following is satisfied: said inflammatory response is a response to
a physical stimulus; said inflammatory response is a response to a
chemical stimulus; said inflammatory response is a response to
infection; said inflammatory response is a response to an invasion
by a body that is foreign to said subject; said inflammatory
response is a response to an immunological stimulus; said
inflammatory response is a response to a non-immunological
stimulus; said inflammatory response is a response to at least one
of the conditions: allergy, asthma, chronic obstructed pulmonary
disease (COPD), atherosclerosis, rheumatoid arthritis, multiple
sclerosis, inflammatory bowel disease, and more specifically
wherein said inflammatory bowel disease is at least one of Crohn's
disease and ulcerative colitis, psoriasis, allergic rhinitis,
scleroderma, autoimmune thyroid disease, immune-mediated diabetes
mellitus, and lupus; said inflammatory response is a response to at
least one of the conditions: myasthenia gravis, autoimmune
neuropathy, and more specifically wherein said autoimmune
neuropathy is Guillain-Barre neuropathy, autoimmune uveitis,
autoimmune hemolytic anemia, pernicious anemia, autoimmune
thrombocytopenia, temporal arteritis, anti-phospholipid syndrome,
vasculitides, and more specifically wherein said vasculitides is
Wegener's granulomatosis, Behcet's disease, dermatitis
herpetiformis, pemphigus vulgaris, vitiligio, primary biliary
cirrhosis, autoimmune hepatitis, autoimmune oophoritis, autoimmune
orchitis, autoimmune disease of the adrenal gland, polymyositis,
dermatomyositis, spondyloarthropathy, and more specifically wherein
said spondyloarthropathy is ankylosing spondylitis, and Sjogren's
syndrome; said inflammatory response is acute inflammation; said
inflammatory response is allergic inflammation; and said
inflammatory response is chronic inflammation. Administration in
connection with an inflammatory response according to the present
invention includes administration at a time that is at least one of
prior to, at the onset of, and after inflammation is detected.
[0280] Embodiments of methods for modulating an H.sub.4 receptor
that comprise exposing an H.sub.4 receptor to at least one compound
selected from compounds of formulae (I) and (II), enantiomers,
diastereomers, racemates thereof, pharmaceutically acceptable
salts, amides and esters thereof, include methods wherein at least
one of the following is satisfied: said at least one compound
modulates the H.sub.4 receptor as a receptor antagonist, and said
at least one compound of modulates the H.sub.4 receptor as a
receptor partial agonist.
[0281] If more than one active agent is administered, such as a
compound of formula (I) or (II), the therapeutically effective
amount may be a jointly effective amount.
[0282] An illustration of the invention is a pharmaceutical
composition made by mixing at least one benzoimidazole compound
selected from compounds of formulae (I) and (II), enantiomers,
diastereomers, racemates thereof, pharmaceutically acceptable
salts, amides and esters thereof, and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing at least one
benzoimidazole compound selected from compounds of formulae (I) and
(II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof, and a
pharmaceutically acceptable carrier.
[0283] Another example of the invention is the use of a composition
that comprises at least one benzoimidazole compound selected from
compounds of formulae (I) and (II), enantiomers, diastereomers,
racemates thereof, pharmaceutically acceptable salts, amides and
esters thereof, in the preparation of a medication for treating any
one of the conditions referred to herein; one of such conditions is
inflammation. Another example of the invention is the use of a
composition that comprises at least one benzoimidazole compound
selected from compounds of formulae (I) and (II), enantiomers,
diastereomers, racemates thereof, pharmaceutically acceptable
salts, amides and esters thereof, in the treatment or prevention of
any one of the conditions referred to herein; one of such
conditions is inflammation.
[0284] Compounds according to the present invention may be made
according to processes within the skill of the art and/or according
to processes of this invention, such as those described in the
schemes and examples that follow and by matrix or combinatorial
methods. To obtain the various compounds herein, starting materials
may be employed that carry the ultimately desired substituents
though the reaction scheme with or without protection as
appropriate. Starting materials may be obtained from commercial
sources or synthesized by methods known to one skilled in the art.
Alternatively, it may be necessary to employ, in the place of the
ultimately desired substituent, a suitable group, which may be
carried through the reaction scheme and replaced as appropriate
with the desired substituent. Any product containing a chiral
center may be separated into its enantiomers by conventional
techniques. Those of ordinary skill in the art will be able to
modify and adapt the guidance provided herein to make compounds
according to the present invention.
[0285] Embodiments of processes illustrated herein include, when
chemically meaningful, one or more steps such as hydrolysis,
halogenation, protection, and deprotection. These steps can be
implemented in light of the teachings provided herein and the
ordinary skill in the art.
[0286] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. In addition, compounds of the invention may be modified
by using protecting groups; such compounds, precursors, or prodrugs
are also within the scope of the invention. This may be achieved by
means of conventional protecting groups, such as those described in
"Protective Groups in Organic Chemistry", ed. J. F. W. McOmie,
Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,
"Protective Groups in Organic Synthesis", 3.sup.rd ed., John Wiley
& Sons, 1999. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
##STR00003##
##STR00004##
[0287] Referring to Schemes 1 and 2, there are disclosed the
following notes and additions. The starting materials for the steps
described below regarding Schemes 1 and 2 are commercially
available or easily accessible to those skilled in the art.
[0288] Compounds of formula (I) or (II) are prepared by condensing
a suitably substituted diamino benzene (III) under oxidizing
conditions with a suitably substituted benzaldehyde (IV') or (IV'')
to form a compound of formula (I) when the benzaldehyde (IV') has a
para ether substitution with respect to the aldehyde group (Scheme
1), or a compound of formula (II) when the benzaldehyde (IV'') has
a meta ether substitution with respect to the aldehyde group
(Scheme 2). Suitable oxidants for this step include air,
Na.sub.2S.sub.2O.sub.5, Oxone, and chemically compatible oxidants
that have a similar oxidizing power, and mixtures thereof.
[0289] This condensation is preferably performed in a heated medium
in a chemically compatible solvent. Reaction medium temperatures
range preferably from about 40.degree. C. to about 150.degree. C.,
more preferably about 80.degree. C. to about 100.degree. C.
Solvents that can be used for this reaction include dioxane, THF,
benzotrifluoride, toluene, 1,2-dichloroethane, DMA, and DMSO,
preferably DMF, and mixtures thereof.
[0290] Suitably substituted benzaldehydes (IV') and (IV'') can be
prepared according to procedures known in the art. In one
preparation procedure, a suitably substituted hydroxy benzaldehyde
is reacted with a suitably substituted moiety to form the ether
link in compounds (IV') and (IV''). Reaction with suitably
substituted 4-hydroxy benzaldehyde leads to the formation of
compound (IV'), and reaction with a suitably substituted 3-hydroxy
benzaldehyde leads to the formation of compound (IV'').
[0291] Regarding the following Schemes 3 through 6, the starting
materials for the steps described below are commercially available
or easily accessible to those skilled in the art.
##STR00005##
[0292] Particular aldehydes (IV') may prepared as shown in Scheme
3. A suitable primary alcohol (V) is treated with a base such as
sodium hydride, potassium hydride, potassium t-butoxide, or lithium
diisopropylamide (LDA), in a polar solvent such as DMF or THF.
Preferred conditions include sodium hydride in DMF. The resulting
alkoxide is then treated with an optionally substituted
6-chloronicotinonitrile to form an aryl ether of formula (VII). The
reaction may be performed without heating or with heating up to
about 60.degree. C. Where R.sup.5 is H, compounds of formula (VII)
may be further reacted to install a non-hydrogen substituent at
that position. Compounds of formula (VII) are treated with a strong
base such as LDA, lithium 2,2,6,6-tetramethylpiperidine (LTMP), or
lithium bis(trimethylsilyl)amide (LHMDS), at low temperatures of
between about -78.degree. C. and about -50.degree. C., in a solvent
such as THF, diethyl ether, or toluene. Preferred conditions
include the use of LDA or LTMP in THF. The resulting lithiated
species is treated with a suitable electrophile, at temperatures
between about -78.degree. C. and room temperature. Preferred
electrophiles are methyl iodide and hexachloroethane. When R.sup.5
is then chloride, additional substituents may be introduced at that
position using nucleophilic substitution. Suitable nucleophiles
include C.sub.1-3alkoxides and primary and secondary amines. In a
particular embodiment, the preferred nucleophile is methoxide. Once
the desired substituents are in place, the nitrile functionality in
compounds of formula (VII) is then reduced with a suitable reducing
agent, such as diisobutylaluminum hydride, in a solvent such as
toluene or THF, to form aldehydes of formula (IV') where W is
N.
##STR00006##
[0293] Referring to Scheme 4, a suitable primary alcohol of formula
(VIII) is reacted with an appropriately substituted
2-chloropyridine of formula (IX) to generate pyridyl ethers of
formula (X), as shown in Scheme 3. Preferred reaction conditions
employ sodium hydride in DMF. Where R.sup.5 is hydrogen, additional
substituents may be introduced at that position by reaction of
ethers of formula (X) with a strong, hindered base followed by a
suitable electrophile as described in Scheme 3. Preferred
electrophiles include methyl iodide and hexachloroethane. Once the
desired substituents are in place, nitrites of formula (X) may be
reduced to aldehydes of formula (IV''), where W is N as shown,
through reduction of the nitrile group as described in Scheme 3.
Preferred reducing agents include diisobutylaluminum hydride.
##STR00007##
[0294] Referring to Scheme 5, dihalopyridines of formula (XI),
where Hal is either Cl or Br, are reacted with primary alcohols of
formulae (V) or (VIII), using conditions described above, to form
pyrido ethers of formula (XII). The resulting 3-halopyridines can
then be converted to the corresponding 3-formylpyridines of formula
(XIII) by halogen-metal exchange with a suitable alkyllithium
reagent, in a suitable solvent such as THF or diethyl ether,
followed by quenching with a formyl equivalent, such as DMF,
N-formylpiperidine, or ethyl chloroformate. Preferred conditions
employ n-BuLi or t-BuLi in THF, and a preferred electrophile is
DMF. Alternatively, 3-halopyridines of formula (XII) may be
converted into aldehydes of formula (XIV) according to the directed
lithiation and formyl trapping procedures described in Schemes 3
and 4. Aldehydes of formula (XIV), where Hal is Br, may be further
processed through a three-step sequence to provide aldehydes of
formula (XV). To that end, the aldehyde is first protected as a
suitable group, such as an acetal. The bromide may then reacted via
halogen-metal exchange using an alkyllithium reagent and
electrophilic trapping, as described above in the current scheme,
to introduce substituents E. Preferred electrophilic reagents
include methyl iodide and hexachloroethane, to produce compounds of
formula (XV) where E is methyl or chloro, respectively. Aldehydes
of formulae (XIII), (XIV), and (XV) may then be processed into
compound of the invention as shown in Schemes 1 and 2 above.
##STR00008##
[0295] Referring to Scheme 6, aldehydes of formula (XIV) may be
converted to aminomethyl analogs of formula (XVI) via reductive
amination, using a suitable reducing agent such as NaCNBH.sub.3 or
Na(OAc.sub.3)BH, in a suitable solvent such as 1,2-dichloroethane
or methanol. Optional additives may include acetic acid or a Lewis
acid such as ZnCl.sub.2. Amines of formula (XVI) may then be
transformed into aldehydes of formula (XVII) by performing
halogen-metal exchange and quenching procedures as described above.
Aldehydes of formula (XVII) may be processed into compounds of the
invention according to Scheme 1.
[0296] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
resolution, for example by formation of diastereomeric salts,
kinetic resolution including variants thereof, such as dynamic
resolution, preferential crystallization, biotransformation,
enzymatic transformation, and preparative chromatography. The
compounds may be prepared in racemic form, or individual
enantiomers may be prepared either by enantiospecific synthesis or
by resolution. The compounds may, for example, be resolved into
their component enantiomers by standard techniques, such as the
formation of diastereomeric pairs by salt formation with an
optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid
and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional
crystallization and regeneration of the free base. The compounds
may also be resolved by formation of diastereomeric esters or
amides, followed by chromatographic separation and removal of the
chiral auxiliary. Alternatively, the compounds may be separated
using a chiral HPLC column.
[0297] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value.
[0298] The expression of the H.sub.4 receptor in immune cells,
including some leukocytes and mast cells, establishes it as an
important target for therapeutic intervention in a range of
immunological and inflammatory disorders (such as allergic,
chronic, or acute inflammation). Specifically H.sub.4 receptor
ligands are expected to be useful for the treatment or prevention
of various mammalian disease states.
[0299] Thus, according to the invention, the disclosed compounds,
whether partial agonists or antagonists of the H.sub.4 receptor,
and compositions are useful for the amelioration of symptoms
associated with, the treatment of, and the prevention of, the
following conditions and diseases: inflammatory disorders, allergic
disorders, dermatological disorders, autoimmune disease, lymphatic
disorders, and immunodeficiency disorders, including the more
specific conditions and diseases given above. The disclosed
compounds may also be useful as adjuvants in chemotherapy or in the
treatment of itchy skin.
[0300] Aspects of the invention include (a) a pharmaceutical
composition comprising a benzoimidazole compound selected from
compounds of formulae (I) and (II), enantiomers, diastereomers,
racemates thereof, pharmaceutically acceptable salts, amides and
esters thereof, and a preferred compound as described herein, and a
pharmaceutically acceptable carrier; (b) a packaged drug comprising
(1) a pharmaceutical composition comprising at least one
benzoimidazole compound selected from compounds of formulae (I) and
(II), enantiomers, diastereomers, racemates thereof,
pharmaceutically acceptable salts, amides and esters thereof, or
one or more preferred compounds as described herein, and a
pharmaceutically acceptable carrier, and (2) instructions for the
administration of said composition for the treatment or prevention
of an H.sub.4-mediated disease or condition.
[0301] Embodiments of this invention provide methods for treating
an H.sub.4-mediated condition in a patient, said methods comprising
administering to the patient a pharmaceutically effective amount of
a composition comprising at least one benzoimidazole compound
selected from compounds of formulae (I) and (II), enantiomers,
diastereomers, racemates thereof, pharmaceutically acceptable
salts, amides and esters thereof, and other disclosed or preferred
compounds. In these conditions, the action of the H.sub.4 receptor
is involved. For example, the invention features a method for
treating an H.sub.4 mediated condition in a patient, said method
comprising administering to the patient a pharmaceutically
effective H.sub.4-antagonizing amount of a composition comprising
at least one benzoimidazole compound selected from compounds of
formulae (I) and (II), enantiomers, diastereomers, racemates
thereof, pharmaceutically acceptable salts, amides and esters
thereof. As used herein, "treating" a disorder, and grammatically
related terms, mean eliminating or otherwise ameliorating the cause
and/or effects thereof. Terms such as to "inhibit", and
grammatically related terms, the onset of a disorder or event, and
to "prevent" a disorder or condition, and grammatically related
terms, mean preventing, delaying or reducing the likelihood of such
onset.
[0302] The effect of an antagonist may also be produced by an
inverse agonist. Inverse agonism describes the property of a
compound to actively turn off a receptor that displays constitutive
activity. Constitutive activity can be identified in cells that
have been forced to over-express the human H.sub.4 receptor.
Constitutive activity can be measured by examining cAMP levels or
by measuring a reporter gene sensitive to cAMP levels after a
treatment with a cAMP-stimulating agent such as forskolin. Cells
that over-express H.sub.4 receptors will display lower cAMP levels
after forskolin treatment than non-expressing cells. Compounds that
behave as H.sub.4 agonists will dose-dependently lower
forskolin-stimulated cAMP levels in H.sub.4-expressing cells.
Compounds that behave as H.sub.4 inverse agonists will
dose-dependently stimulate cAMP levels in H.sub.4-expressing cells.
Compounds that behave as H.sub.4 antagonists will block either
H.sub.4 agonist-induced inhibition of cAMP or H.sub.4 inverse
agonist-induced increases in cAMP.
[0303] Further embodiments of the invention include disclosed
compounds that are inhibitors of a mammalian histamine H.sub.4
receptor function, inhibitors of inflammation or inflammatory
responses in vivo or in vitro, modulators of the expression of a
mammalian histamine H.sub.4 receptor protein, inhibitors of
polymorphonuclear leukocyte activation in vivo or in vitro, or
combinations of the above, and corresponding methods of treatment,
prophylaxis, and diagnosis comprising the use of a disclosed
compound.
[0304] The terms "unit dose" and their grammatical equivalent forms
are used herein to refer to physically discrete units suitable as
unitary dosages for human patients and other animals, each unit
containing a predetermined effective, pharmacologic amount of the
active ingredient calculated to produce the desired pharmacological
effect. The specifications for the novel unit dosage forms of this
invention are determined by, and are directly dependent on, the
characteristics of the active ingredient, and on the limitations
inherent in the art of compounding such an active ingredient for
therapeutic use in humans and other animals.
[0305] The pharmaceutical compositions can be prepared using
conventional pharmaceutical excipients and compounding techniques.
Examples of suitable unit dosage forms are tablets, capsules,
pills, powders, powder packets, granules, wafers, and the like,
segregated multiples of any unit dosage form, as well as liquid
solutions, and suspensions. Some liquid forms are aqueous, whereas
other embodiments of liquid forms are non-aqueous. Oral dosage
forms may be elixirs, syrups, capsules, tablets and the like.
Examples of solid carriers include those materials usually employed
in the manufacture of pills or tablets, such as lactose, starch,
glucose, methylcellulose, magnesium stearate, dicalcium phosphate,
mannitol and the like, thickeners such as tragacanth and
methylcellulose USP, finely divided SiO.sub.2,
polyvinylpyrrolidone, magnesium stearate, and the like. Typical
liquid oral excipients include ethanol, glycerol, water and the
like. All excipients may be mixed as needed with diluents (for
example, sodium and calcium carbonates, sodium and calcium
phosphates, and lactose), disintegrants (for example, cornstarch
and alginic acid), granulating agents, lubricants (for example,
magnesium stearate, stearic acid, and talc), binders (for example,
starch and gelatin), thickeners (for example, paraffin, waxes, and
petrolatum), flavoring agents, coloring agents, preservatives, and
the like by conventional techniques known to those of ordinary
skill in the art of preparing dosage forms. Coatings can be present
and include, for example, glyceryl monostearate and/or glyceryl
diestearate. Capsules for oral use include hard gelatin capsules in
which the active ingredient is mixed with a solid diluent, and soft
gelatin capsules, in which the active ingredient is mixed with
water or an oil, such as peanut oil, liquid paraffin, or olive
oil.
[0306] Parenteral dosage forms may be prepared using water or
another sterile carrier. Parenteral solutions can be packaged in
containers adapted for subdivision into individual doses. For
intramuscular, intraperitoneal, subcutaneous, and intravenous use,
the compounds of the invention will generally be provided in
sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity. Suitable aqueous vehicles include
Ringer's solution and isotonic sodium chloride. Aqueous suspensions
may include suspending agents such as cellulose derivatives, sodium
alginate, polyvinyl-pyrrolidone, and gum tragacanth, and a wetting
agent, such as lecithin. Suitable preservatives for aqueous
suspensions include ethyl and n-propyl p-hydroxybenzoate.
Parenteral formulations include pharmaceutically acceptable aqueous
or non-aqueous solutions, dispersion, suspensions, emulsions, and
sterile powders for the preparation thereof. Examples of carriers
include water, ethanol, polyols (propylene glycol, polyethylene
glycol), vegetable oils, and injectable organic esters such as
ethyl oleate. Fluidity can be maintained by the use of a coating
such as lecithin, a surfactant, or maintaining appropriate particle
size. Carriers for solid dosage forms include (a) fillers or
extenders, (b) binders, (c) humectants, (d) disintegrating agents,
(e) solution retarders, (f) absorption accelerators, (g)
adsorbants, (h) lubricants, (i) buffering agents, and (j)
propellants.
[0307] Compositions may also contain adjuvants such as preserving,
wetting, emulsifying, and dispensing agents; antimicrobial agents
such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic
agents such as a sugar or sodium chloride; absorption-prolonging
agents such as aluminum monostearate and gelatin; and
absorption-enhancing agents.
[0308] Physiologically acceptable carriers are well known in the
art. Examples of liquid carriers are solutions in which compounds
according to the present invention form solutions, emulsions, and
dispersions. Compatible antioxidants, such as methylparaben and
propylparaben, can be present in solid and/or liquid compositions,
as can sweeteners.
[0309] Pharmaceutical compositions according to the present
invention may include suitable emulsifiers typically used in
emulsion compositions. Such emulsifiers are described in standard
publications such as H. P. Fiedler, 1989, Lexikon der Hilfsstoffe
fur Pharmazie, Kosmetic und agrenzende Gebiete, Cantor ed.,
Aulendorf, Germany, and in Handbook of Pharmaceutical Excipients,
1986, American Pharmaceutical Association, Washington, D.C., and
the Pharmaceutical Society of Great Britain, London, UK, which are
incorporated herein by reference. Gelling agents may also be added
to compositions according to this invention. Polyacrylic acid
derivatives, such as carbomers, are examples of gelling agents, and
more particularly, various types of carbopol, which are typically
used in amounts from about 0.2% to about 2%. Suspensions may be
prepared as a cream, an ointment, including a water-free ointment,
a water-in-oil emulsion, an oil-in-water emulsion, an emulsion gel,
or a gel.
[0310] It is anticipated that the compounds of the invention can be
administered by oral or parenteral routes, including intravenous,
intramuscular, intraperitoneal, subcutaneous, rectal,
intracisternal, intravaginal, intravesical, topical or local
administration, and by inhalation (bucal or nasal, preferably in
the form of a spray). For oral administration, the compounds of the
invention will generally be provided in the form of tablets,
capsules, or as a solution or suspension. Other methods of
administration include controlled release formulations, such as
subcutaneous implants and dermal patches.
[0311] Effective doses of the compounds of the present invention
may be ascertained by conventional methods. The specific dosage
level required for any particular patient will depend on a number
of factors, including severity of the condition, type of symptoms
needing treatment, the route of administration, the weight, age,
and general condition of the patient, and the administration of
other medicaments.
[0312] In general, it is anticipated that the daily dose (whether
administered as a single dose or as divided doses) will be in the
range from about 0.01 mg to about 1000 mg per day, more usually
from about 1 mg to about 500 mg per day, and most usually form
about 10 mg to about 200 mg per day. Expressed as dosage per unit
body weight, a typical dose will be expected to be between about
0.0001 mg/kg and about 15 mg/kg, especially between about 0.01
mg/kg and about 7 mg/kg, and most especially between about 0.15
mg/kg and 2.5 mg/kg.
[0313] Anticipated oral dose ranges include from about 0.01 to 500
mg/kg, daily, more preferably from about 0.05 to about 100 mg/kg,
taken in 1-4 separate doses. Some compounds of the invention may be
orally dosed in the range of about 0.05 to about 50 mg/kg daily,
while others may be dosed at 0.05 to about 20 mg/kg daily. Infusion
doses can range from about 1.0 to about 1.0.times.10.sup.4
.mu.g/(kg.min) of inhibitor, admixed with a pharmaceutical carrier
over a period ranging from several minutes to several days. For
topical administration, compounds of the present invention may be
mixed with a pharmaceutical carrier at a concentration from about
0.1 to about 10% of drug to vehicle. Capsules, tablets or other
formulations (such as liquids and film-coated tablets) may be of
between 0.5 and 200 mg, such as 1, 3, 5, 10, 15, 25, 35, 50 mg, 60
mg, and 100 mg and can be administered according to the disclosed
methods. Daily dosages are envisaged to be, for example, between 10
mg and 5000 mg for an adult human being of normal weight.
EXAMPLES
General Experimental
[0314] NMR spectra were obtained on either a Bruker model DPX400
(400 MHz) or DPX500 (500 MHz) spectrometer. The format of the
.sup.1H NMR data below is: chemical shift in ppm down field of the
tetramethylsilane reference (multiplicity, coupling constant J in
Hz, integration).
[0315] Mass spectra were obtained on a Hewlett Packard (Agilent)
series 1100 MSD using electrospray ionization (ESI) in either
positive or negative mode as indicated. The "mass calculated" for a
molecular formula is the monoisotopic mass of the compound.
Purification Method 1: Reversed-Phase HPLC
[0316] HPLC retention times are reported in minutes, using the
methods and conditions reported below.
Instrument: Agilent HP-1100
Solvent: Acetonitrile (0.05% TFA)/H.sub.2O (0.05% TFA)
[0317] Flow rate: 0.75 mL/min Gradient: 1 min at 1% H.sub.2O; 7 min
linear ramp to 99% H.sub.2O; [0318] 4 min at 99% H.sub.2O.
Column: Zorbax Eclipse XDB-C8 (5 um, 4.6.times.150 mm)
Temperature: 35.degree. C.
[0319] Wavelength: Dual detection at 220 nM and 254 nM.
Purification Method 2: Normal-Phase Chromatography
[0320] 2-Arylbenzimidazoles were purified by chromatography on
silica gel eluting with dichloromethane, then 10% methanol in
dichloromethane, and subsequently 10% (2.0 M ammonia in methanol)
in dichloromethane. The reaction mixtures were loaded on the silica
gel without work-up.
Example 1
##STR00009##
[0321]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dim-
ethyl-1H-benzoimidazole
General Procedure 1
[0322] A. 2-Chloro-4-(3-chloro-propoxy)-benzaldehyde.
1-Bromo-3-chloropropane (2.55 g, 16.2 mmol, 1.0 equiv) was added to
a solution of the 2-chloro-4-hydroxybenzaldehyde (2.54 g, 16.2
mmol, 1.0 equiv) and K.sub.2CO.sub.3 (4.48 g, 32.4 mmol, 2.0 equiv)
in acetonitrile (41 mL). The mixture was heated at 65.degree. C.
for 18 h, then cooled to room temperature (rt) and filtered through
diatomaceous earth. The filtrate was concentrated under reduced
pressure yielding crude product, which was purified by column
chromatography (silica gel, 5% ethyl acetate in hexanes) to afford
3.19 g of a colorless oil (66%). .sup.1H NMR (400 MHz, CD.sub.3OD):
10.3 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.10 (d, J=4.0 Hz, 1H), 7.03
(dd, J=8.0, 4.0 Hz, 1H), 4.23 (t, J=8.0 Hz, 2H), 3.76 (t, J=8.0 Hz,
2H), 2.31-2.22 (m, 2H).
General Procedure 2.
[0323] B.
2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde.
N-Methylpiperazine (2.16 g, 21.5 mmol, 2.0 equiv),
2-chloro-4-(3-chloro-propoxy)-benzaldehyde (3.19 g, 10.8 mmol, 1.0
equiv), K.sub.2CO.sub.3 (4.46 g, 32.3 mmol, 3.0 equiv), and KI
(1.02 g, 5.38 mmol, 0.5 equiv) were stirred in n-butanol (22 mL) at
90.degree. C. for 18 h. The reaction mixture was diluted with water
and then extracted three times with ethyl acetate. The combined
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated,
yielding the crude product, which was purified by Method 2 to
afford 2.04 g (63%) of an orange oil. .sup.1H NMR (400 MHz,
CD.sub.3OD): 10.3 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.08 (d, J=2.0
Hz, 1H), 7.00 (dd, J=8.0, 2.0 Hz, 1H), 4.15 (t, J=8.0 Hz, 2H),
3.00-2.30 (br s, 10H), 2.29 (s, 3H), 2.05-1.90 (m, 2H).
General Procedure 3.
[0324] C.
2-{(2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-
-dimethyl-1H-benzoimidazole.
2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (91.5
mg, 0.31 mmol, 1.0 equiv) and 3,4-dimethyl-benzene-1,2-diamine (42
mg, 0.31 mmol, 1.0 equiv) were stirred with Na.sub.2S.sub.2O.sub.5
(76 mg, 0.40 mmol, 1.3 equiv) in DMF (0.25 M) at 90.degree. C. for
12 h. The reaction mixture was loaded directly on silica gel and
purified according to Method 2, which afforded 98 mg (76%) of the
title compound. MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.68 (br s, 1H), 7.33 (br s,
1H), 7.15 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.7, 2.5 Hz, 1H), 7.03 (dd,
J=8.7, 2.5 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 2.60-2.39 (m, 13H),
2.39 (s, 3H), 2.30 (s, 3H), 2.05-1.95 (m, 2H).
Example 2
##STR00010##
[0325]
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methy-
l-1H-benzoimidazole
[0326] A. 3-(1-Methyl-piperidin-4-yl)-propan-1-ol. To a refluxing
solution of 1 N lithium aluminum hydride in THF (40 mmol) was added
dropwise a solution of N--BOC-4-piperidinepropionic acid (3.0 g,
11.6 mmol) in THF (30 mL). The reaction mixture was heated for 3 h
and then cooled to rt. Upon further cooling to 0.degree. C., water
(1.5 mL) was added slowly, and the reaction mixture was allowed to
warm to rt over 15 min. The mixture was again cooled to 0.degree.
C., and 10% NaOH (1.5 mL) was added slowly. Upon warming up to rt
over 15 min, the mixture was again cooled to 0.degree. C. and more
water (4.5 mL) was added. The resultant mixture was allowed to warm
to rt over 18 h, and was then filtered through a diatomaceous earth
pad. The filtrate was concentrated under reduced pressure, and the
residue was purified by Method 2 to afford 1.9 g (100%) of
3-(1-methyl-piperidin-4-yl)-propan-1-ol as a yellow oil. MS
(electrospray): mass calculated for C.sub.9H.sub.19NO, 157.15; m/z
found, 158.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD):
3.45-3.41 (m, 2H), 2.77-2.74 (m, 2H), 1.89-1.85 (m, 2H), 1.64-1.61
(m, 2H), 1.47-1.43 (m, 2H), 1.21-1.12 (m, 5H).
[0327] B.
2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde. To
an ice-cooled solution of 2-chloro-4-hydroxybenzaldehyde (507 mg,
3.2 mmol, 1.0 equiv), triphenylphosphine (1.02 g, 3.9 mmol, 1.2
equiv), and 3-(1-methyl-piperidin-4-yl)-propan-1-ol (508 mg, 3.9
mmol, 1.2 equiv) in THF (15 mL) was added diethyl azodicarboxylate
(DEAD; 0.6 mL, 3.2 mmol, 1.0 equiv). The reaction mixture was
allowed to warm to rt and was stirred for 16 h. The mixture was
diluted with water and extracted three times with ethyl acetate.
The combined extracts were dried (Na.sub.2SO.sub.4) and
concentrated. Purification by Method 2 afforded 768 mg (80%) of the
desired aldehyde. MS (electrospray): mass calculated for
C.sub.16H.sub.23NO.sub.2, 261.17; m/z found, 262.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 9.85 (s, 1H), 7.80 (d, J=8.6 Hz,
2H), 6.97 (d, J=8.6 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 2.84-2.82 (m,
2H), 2.25 (s, 3H), 1.92-1.78 (m, 4H), 1.71-1.69 (m, 2H), 1.41-1.37
(m, 2H), 1.29-1.26 (m, 3H).
[0328] C.
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-me-
thyl-1H-benzoimidazole.
2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde and
3-methyl-benzene-1,2-diamine were stirred with
Na.sub.2S.sub.2O.sub.5 in DMF at 90.degree. C. for 12 h.
Purification of the reaction mixture by Method 2 afforded 129 mg
(73%) of the title compound. MS (electrospray): mass calculated for
C.sub.23H.sub.28ClN.sub.3O, 397.19; m/z found, 398.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.69 (d, J=8.5 Hz, 1H),
7.46-7.35 (m, 1H), 7.17-7.13 (m, 2H), 7.06-7.01 (m, 2H), 4.06 (t,
J=6.4 Hz, 2H), 2.95-2.85 (m, 2H), 2.59 (s, 3H), 2.27 (s, 3H),
2.10-1.95 (m, 2H), 1.86-1.76 (m, 4H), 1.50-1.49 (m, 2H), 1.32-1.25
(m, 3H).
Example 3
##STR00011##
[0329]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifl-
uoromethoxy-1H-benzoimidazole
[0330] This compound was prepared by the method described in
General Procedure 3 using
2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (200
mg, 0.68 mmol, 1.0 equiv), 4-trifluoromethoxy-benzene-1,2-diamine
(119 mg, 0.62 mmol, 0.92 equiv) and Na.sub.2S.sub.2O.sub.5 (167 mg,
0.88 mmol, 1.3 equiv). Purification by Method 2 afforded 72 mg
(23%) of the title compound. MS (electrospray): mass calculated for
C.sub.22H.sub.24ClF.sub.3N.sub.4O.sub.2, 468.15; m/z found, 469.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.82 (d, J=8.7 Hz,
1H), 7.69 (d, J=8.8 Hz, 1H), 7.55 (s, 1H), 7.23 (d, J=8.5 Hz, 1H),
7.21 (d, J=1.6 Hz, 1H), 7.1 (dd, J=8.6, 2.2 Hz, 1H), 4.17 (t, J=5.7
Hz, 2H), 2.88-2.38 (m, 10H), 2.32 (s, 3H), 2.10-1.95 (m, 2H).
Example 4
##STR00012##
[0331]
5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy-
]-phenyl}-1H-benzoimidazole
[0332] This compound was prepared by the method described in
Example 1, using
3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde
(62 mg, 0.20 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (33
mg, 0.20 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (50 mg, 0.26
mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2
afforded 31 mg (34%) of the title compound. MS (electrospray): mass
calculated for C.sub.26H.sub.35ClN.sub.4O, 454.25; m/z found, 455.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.12 (d, J=2.2 Hz,
1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.6 (s, 1H), 7.52 (d, J=8.5 Hz,
1H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 4.19 (t,
J=6.0 Hz, 2H), 2.84-2.74 (m, 10H), 2.40 (s, 3H), 2.08-1.97 (m, 2H),
1.90-1.83 (m, 2H), 1.41 (s, 9H).
Example 5
##STR00013##
[0333]
5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0334] This compound was prepared by the method described in
Example 2, using
3-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (98.6
mg, 0.36 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (59 mg,
0.36 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (89 mg, 0.47
mmol, 1.3 equiv) in Step C. Purification by Method 2 afforded 116
mg (77%) of the title compound. MS (electrospray): mass calculated
for C.sub.27H.sub.37N.sub.3O, 419.29; m/z found, 420.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.90-7.82 (m, 2H), 7.60-7.50 (m,
1H), 7.52-7.40 (m, 1H), 7.33 (dd, J=8.5, 1.8 Hz, 1H), 7.02 (d,
J=9.1 Hz, 1H), 4.07 (t, J=6.2 Hz, 2H), 2.92-2.85 (m, 2H), 2.30 (s,
3H), 2.28 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.80 (m, 2H), 1.80-1.70
(m, 2H), 1.55-1.45 (m, 2H), 1.49 (s, 9H), 1.49-1.26 (m, 3H).
Example 6
##STR00014##
[0335]
4,5-Dimethyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0336] This compound was prepared by the method described in
Example 1, using
3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (180
mg, 0.65 mmol, 1.0 equiv), 3,4-dimethyl-benzene-1,2-diamine (89 mg,
0.65 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (161 mg, 0.85
mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2
afforded 192 mg (75%) of the title compound. MS (electrospray):
mass calculated for C.sub.24H.sub.32N.sub.4O, 392.26; m/z found,
393.5 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.95-7.85 (m,
2H), 7.35-7.23 (m, 1H), 7.08-7.00 (m, 2H), 4.12 (t, J=6.0 Hz, 2H),
2.64-2.37 (m, 16H), 2.29 (s, 6H), 2.10-2.00 (m, 2H).
Example 7
##STR00015##
[0337]
5-tert-Butyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-b-
enzoimidazole
[0338] This compound was prepared by the method described in
Example 1, using
3-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzaldehyde (53 mg, 0.19
mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (32 mg, 0.19
mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (48 mg, 0.25 mmol, 1.3
equiv) in General Procedure 3. Purification by Method 2 afforded 75
mg (92%) of the title compound. MS (electrospray): mass calculated
for C.sub.26H.sub.36N.sub.4O, 420.29; m/z found, 421.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.68-7.56 (m, 3H), 7.54 (br d,
J=8.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.02 (dd, J=8.2, 2.2 Hz, 1H),
4.07 (t, J=6.1 Hz, 2H), 3.00-2.26 (m, 10H), 2.26 (s, 3H), 1.85-1.75
(m, 2H), 1.75-1.65 (m, 2H), 1.40 (s, 9H).
Example 8
##STR00016##
[0339]
5-tert-Butyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}--
1H-benzoimidazole
[0340] A. 3-(4-Chloro-butoxy)-benzaldehyde. This intermediate was
prepared by the method described in General Procedure 1 using
3-hydroxybenzaldehyde (2.0 g, 16.4 mmol, 1.0 equiv),
1-bromo-4-chlorobutane (1.62 mL, 16.4 mmol, 1.0 equiv), and
K.sub.2CO.sub.3 (4.53 g, 33 mmol, 1.0 equiv). Purification afforded
2.57 g (79%) of the desired product. .sup.1H NMR (400 MHz,
CDCl.sub.3): 9.98 (s, 1H), 7.47-7.43 (m, 2H), 7.40-7.37 (m, 1H),
7.27-7.25 (m, 1H), 4.09-4.03 (m, 2H), 3.66-3.58 (m, 2H), 2.03-1.93
(m, 4H).
[0341] B.
5-tert-Butyl-2-[3-(4-chloro-butoxy)-phenyl]-1H-benzoimidazole. This
intermediate was prepared by the method described in General
Procedure 3 using 3-(4-chloro-butoxy)-benzaldehyde (500 mg, 2.52
mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (414 mg, 2.52
mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (622 mg, 3.3 mmol, 1.3
equiv). The reaction mixture was loaded on a silica gel column and
purified by flash chromatography (25% ethyl acetate in hexanes) to
afford 348 mg (40%) of the desired product. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.72-7.48 (m, 4H), 7.47-7.35 (m, 2H), 7.08-7.03 (m,
1H), 4.17-4.10 (m, 2H), 3.70-3.64 (m, 2H), 2.03-1.96 (m, 4H), 1.41
(s, 9H).
[0342] C.
5-tert-Butyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pheny-
l}-1H-benzoimidazole. This compound was prepared by the method
described in General Procedure 2 using
5-tert-butyl-2-[3-(4-chloro-butoxy)-phenyl]-1H-benzoimidazole (51.2
mg, 0.15 mmol, 1.0 equiv), N-methyl-homo-piperazine (19 .mu.L, 0.15
mmol, 1.0 equiv), K.sub.2CO.sub.3 (40 mg, 0.30 mmol, 2.0 equiv),
and KI (12 mg, 0.08 mmol, 0.5 equiv). Purification by Method 2
afforded 19 mg (23%) of the title compound. MS (electrospray): mass
calculated for C.sub.27H.sub.38N.sub.4O, 434.30; m/z found, 435.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.66-7.62 (m, 3H),
7.52 (d, J=8.6 Hz, 1H), 7.45-7.35 (m, 1H), 7.37 (dd, J=8.6, 1.8 Hz,
1H), 7.06-7.02 (m, 1H), 4.11 (t, J=6.2 Hz, 2H), 2.78-2.75 (m, 4H),
2.69-2.65 (m, 4H), 2.60-2.55 (m, 2H), 2.32 (s, 3H), 1.85-1.79 (m,
4H), 1.75-1.68 (m, 2H), 1.40 (s, 9H).
Example 9
##STR00017##
[0343]
(1-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-2-chloro-phenoxy]-pro-
pyl}-pyrrolidin-3-yl)-dimethylamine
[0344] This compound was prepared by the method described in
Example 1, using
5-tert-butyl-2-[3-(4-chloro-butoxy)-phenyl]-1H-benzoimidazole (206
mg, 0.55 mmol, 1.0 equiv), dimethyl-pyrrolidin-3-yl-amine (125 mg,
1.09 mmol, 2.0 equiv), K.sub.2CO.sub.3 (227 mg, 1.64 mmol, 3.0
equiv), and KI (46 mg, 0.27 mmol, 0.5 equiv) in General Procedure
3. Purification by Method 2 afforded 137 mg (55%) of the title
compound. MS (electrospray): mass calculated for
C.sub.26H.sub.35ClN.sub.4O, 454.25; m/z found, 455.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.11 (d, J=2.2 Hz, 1H), 7.97
(dd, J=8.6, 2.2 Hz, 1H), 7.58 (br s, 1H), 7.65-7.45 (m, 1H), 7.36
(dd, J=8.6, 1.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 4.21 (t, J=6.0 Hz,
2H), 3.04-2.99 (m, 1H), 2.91-2.65 (m, 4H), 2.56-2.49 (m, 1H),
2.36-2.29 (m, 1H), 2.24 (s, 6H), 2.10-1.99 (m, 3H), 1.79-1.70 (m,
1H), 1.40 (s, 9H).
Example 10
##STR00018##
[0345]
5-Chloro-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-ph-
enyl}-6-methyl-1H-benzoimidazole
[0346] This compound was prepared by the method described in
Example 1, using
3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde
(61 mg, 0.20 mmol, 1.0 equiv),
4-chloro-5-methyl-benzene-1,2-diamine (31 mg, 0.20 mmol, 1.0
equiv), and Na.sub.2S.sub.2O.sub.5 (48 mg, 0.25 mmol, 1.3 equiv) in
General Procedure 3. Purification by Method 2 afforded 7.1 mg (8%)
of the title compound. MS (electrospray): mass calculated for
C.sub.23H.sub.28Cl.sub.2N.sub.4O, 446.16; m/z found, 447.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.96 (d, J=2.2 Hz,
1H), 7.83 (dd, J=8.6, 2.2 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.10
(d, J=8.7 Hz, 1H), 4.08 (t, J=6.0 Hz, 2H), 2.76-2.64 (m, 10H), 2.36
(s, 3H), 2.30 (s, 3H), 1.96-1.88 (m, 2H), 1.80-1.73 (m, 2H).
Example 11
##STR00019##
[0347]
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methy-
l-1H-benzoimidazole
[0348] This compound was prepared by the method described in
Example 1, using
3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (94
mg, 0.34 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (42 mg,
0.34 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (84 mg, 0.44
mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2
afforded 130 mg (100%) of the title compound. MS (electrospray):
mass calculated for C.sub.22H.sub.27FN.sub.4O, 382.22; m/z found,
383.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.86-7.78 (m,
2H), 7.40-7.37 (m, 1H), 7.12-6.97 (m, 3H), 3.99 (t, J=6.1 Hz, 2H),
3.00-2.30 (m, 13H), 2.25 (s, 3H), 1.94-1.90 (m, 2H).
Example 12
##STR00020##
[0349]
5-Methyl-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalen-1-yl-
}-1H-benzoimidazole
[0350] This compound was prepared by the method described in
Example 1, using
4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalene-1-carbaldehyde
(63 mg, 0.20 mmol, 1.0 equiv), 4-methyl-benzene-1,2-diamine (24 mg,
0.20 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (49 mg, 0.26
mmol, 1.3 equiv) in General Procedure 3. The desired product was
isolated from the reaction mixture using Method 1 and was
subsequently re-purified by Method 2 to afford 54.6 mg (66%) of the
title compound. MS (electrospray): mass calculated for
C.sub.26H.sub.30N.sub.4O, 414.24; m/z found, 415.62 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.48 (d, J=8.0 Hz, 1H), 8.10 (d,
J=8.4 Hz, 1H), 8.0 (d, J=8.2 Hz, 1H), 7.78-7.65 (m, 4H), 7.50 (d,
J=8.4 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 2H), 3.40
(br s, 4H), 3.30-3.00 (m, 6H), 2.88 (s, 3H), 2.59 (s, 3H),
2.36-2.30 (m, 2H).
Example 13
##STR00021##
[0351]
4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-pipe-
razin-1-yl)-butan-1-one
[0352] A.
3-[4-(4-Methyl-piperazin-1-yl)-4-oxo-butoxy]-benzaldehyde. To a
solution of 4-(3-formyl-phenoxy)-butyric acid (981 mg, 4.72 mmol,
1.0 equiv) and N-methylpiperazine (576 mg, 5.19 mmol, 1.1 equiv) in
dichloromethane at 0.degree. C. was added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI; 1.18 g, 6.14
mmol, 1.3 equiv) and 1-hydroxybenzotriazole hydrate (HOBT; 701 mg,
5.19 mmol, 1.1 equiv). The reaction mixture, which was allowed to
warm to rt, was stirred for 2.0 h and then poured into water. This
mixture was extracted three times with ethyl acetate. The combined
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated
under reduced pressure. The crude residue was purified by column
chromatography (silica gel, 5% MeOH in dichloromethane) to afford
847 mg (62%) of the desired product. .sup.1H NMR (400 MHz,
CD.sub.3OD): 9.72 (s, 1H), 7.29-7.23 (m, 2H), 7.22-7.19 (m, 1H),
7.05-6.98 (m, 1H), 3.87 (t, J=6.1 Hz, 2H), 3.43-3.31 (m, 4H), 2.39
(t, J=7.2 Hz, 2H), 2.27-2.17 (m, 4H), 2.08 (s, 3H), 1.92-1.80 (m,
2H).
[0353] B.
4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-p-
iperazin-1-yl)-butan-1-one. This compound was prepared by the
method described in General Procedure 3 using
3-[4-(4-methyl-piperazin-1-yl)-4-oxo-butoxy]-benzaldehyde (81.2 mg,
0.28 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (46 mg,
0.28 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (69 mg, 0.36
mmol, 1.3 equiv). Purification by Method 2 afforded 77 mg (64%) of
the title compound. MS (electrospray): mass calculated for
C.sub.26H.sub.34N.sub.4O.sub.2, 434.27; m/z found, 435.0
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.69-7.62 (m, 3H),
7.54 (d, J=8.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.06 (dd, J=8.2, 2.2 Hz,
1H), 4.13 (t, J=6.1 Hz, 2H), 3.70-3.50 (m, 4H), 2.62 (t, J=7.3 Hz,
2H), 2.49-2.40 (m, 4H), 2.32 (s, 3H), 2.16-2.09 (m, 2H), 1.41 (s,
9H).
Example 14
##STR00022##
[0354]
5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro--
1H-benzoimidazole
[0355] A.
4-{3-[2-Chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-pheno-
xy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester. This
compound was prepared by the method described in Example 1, using
4-[3-(2-chloro-4-formyl-phenoxy)-propyl]-piperazine-1-carboxylic
acid tert-butyl ester (1.0 g, 2.6 mmol, 1.0 equiv),
4-chloro-5-fluoro-benzene-1,2-diamine (421 mg, 2.6 mmol, 1.0
equiv), and Na.sub.2S.sub.2O.sub.5 (648 mg, 3.4 mmol, 1.3 equiv) in
General Procedure 3. Purification by Method 2 afforded 256 mg (15%)
of the title compound. MS (electrospray): mass calculated for
C.sub.25H.sub.29Cl.sub.2FN.sub.4O.sub.3, 522.16; m/z found, 545.3
[M+Na].sup.+.
[0356] B.
5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluo-
ro-1H-benzoimidazole. To a suspension of
4-{3-[2-chloro-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-phenoxy]-propy-
l}-piperazine-1-carboxylic acid tert-butyl ester (52.7 mg, 0.10
mmol) in dichloromethane (1.0 mL) at rt was added TFA (1.0 mL), and
the reaction mixture was stirred for 50 min. The mixture was
concentrated under reduced pressure, and the solid residue was
washed four times with dichloromethane. The title compound was
obtained in quantitative yield as the TFA salt. MS (electrospray):
mass calculated for C.sub.20H.sub.21Cl.sub.2FN.sub.4O, 422.11; m/z
found, 423.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.17
(d, J=2.3 Hz, 1H), 8.03 (dd, J=8.7, 2.3 Hz, 1H), 7.81 (d, J=6.4 Hz,
1H), 7.59 (d, J=8.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 4.33 (t, J=5.8
Hz, 2H), 3.50-3.47 (m, 4H), 3.36 (br s, 4H), 3.25 (t, J=7.4 Hz,
2H), 2.33-2.26 (m, 2H).
Example 15
##STR00023##
[0357]
5-tert-Butyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0358] This compound was prepared by the method described in
Example 1, using
3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (516
mg, 1.87 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (307
mg, 1.87 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (461 mg, 2.43
mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2
afforded 633 mg (81%) of the title compound. MS (electrospray):
mass calculated for C.sub.26H.sub.36N.sub.4O, 420.29; m/z found,
421.5 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.90-7.85 (m,
2H), 7.65-7.40 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.04 (d, J=8.1 Hz,
1H), 4.14-4.11 (m, 2H), 2.90-2.28 (m, 16H), 2.06-2.03 (m, 2H), 1.39
(s, 9H).
Example 16
##STR00024##
[0359]
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,6-dim-
ethyl-1H-benzoimidazole
[0360] This compound was prepared by the method described in
Example 2, using
2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (106
mg, 0.36 mmol, 1.0 equiv), 3,5-dimethyl-benzene-1,2-diamine (49 mg,
0.36 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (88 mg, 0.47
mmol, 1.3 equiv) in Step C. Purification by Method 2 afforded 128
mg (87%) of the title compound. MS (electrospray): mass calculated
for C.sub.24H.sub.30ClN.sub.3O, 411.21; m/z found, 412.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.68 (d, J=8.5 Hz,
1H), 7.21 (br s, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.7, 2.5
Hz, 1H), 6.90 (s, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.92-2.88 (m, 2H),
2.54 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.09-2.03 (m, 2H),
1.85-1.76 (m, 4H), 1.47-1.11 (m, 5H).
[0361] The following compounds in Examples 17-56 were prepared
using General Procedures 1, 2, and 3 as exemplified above.
Example 17
##STR00025##
[0362]
2-{2-Chloro-4-[2-methyl-3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-4-methyl-1H-benzoimidazole
[0363] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.75-7.65 (m, 1H), 7.50-7.35 (m,
1H), 7.20-7.13 (m, 2H), 7.15-7.02 (m, 2H), 4.06 (dd, J=9.2, 4.5 Hz,
1H), 3.94 (dd, J=9.2, 6.0 Hz, 1H), 2.80-2.35 (m, 13H), 2.35-2.20
(m, 4H), 2.28 (d, J=4.5 Hz, 3H).
Example 18
##STR00026##
[0364]
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-6-methyl-1H-benzoimidazole
[0365] MS (electrospray): mass calculated for
C.sub.22H.sub.26Cl.sub.2N.sub.4O, 432.15; m/z found, 432.8
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.19 (d, J=2.2 Hz,
1H), 8.05 (dd, J=8.6, 2.2 Hz, 1H), 7.66 (br s, 1H), 7.55 (br s,
1H), 7.32 (d, J=8.7 Hz, 1H), 4.30 (t, J=6.0 Hz, 2H), 3.00-2.43 (m,
13H), 2.42 (s, 3H), 2.18-2.14 (m, 2H).
Example 19
##STR00027##
[0366]
6-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-4-methyl-1H-benzoimidazole
[0367] MS (electrospray): mass calculated for
C.sub.22H.sub.26Cl.sub.2N.sub.4O, 432.15; m/z found, 433.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.70 (br s, 1H),
7.42 (br s, 1H), 7.17 (d, J=2.4 Hz, 1H), 7.08 (br s, 1H), 7.05 (dd,
J=8.7, 2.5 Hz, 1H), 4.13 (t, J=6.14 Hz, 2H), 3.00-2.40 (m, 13H),
2.30 (s, 3H), 2.03-1.98 (m, 2H).
Example 20
##STR00028##
[0368]
5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0369] MS (electrospray): mass calculated for
C.sub.25H.sub.33ClN.sub.4O, 440.23; m/z found, 441.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.31 (d, J=2.2 Hz, 1H), 8.17
(dd, J=8.6, 2.2 Hz, 1H), 7.78 (br s, 1H), 7.69 (br s, 1H), 7.55
(dd, J=8.6, 1.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 4.40 (t, J=6.0 Hz,
2H), 3.00-2.55 (m, 10H), 2.51 (s, 3H), 2.35-2.22 (m, 2H), 1.59 (s,
9H).
Example 21
##STR00029##
[0370]
5-Chloro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0371] MS (electrospray): mass calculated for
C.sub.21H.sub.24ClFN.sub.4O, 402.16; m/z found, 403.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.86-7.83 (m, 2H), 7.64 (d,
J=1.9 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.39 (dd, J=8.7, 1.9 Hz,
1H), 7.33-7.29 (m, 1H), 4.21 (t, J=5.9 Hz, 2H), 3.20-2.77 (m, 10H),
2.76 (s, 3H), 2.10-2.03 (m, 2H).
Example 22
##STR00030##
[0372]
2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,6-
-dimethyl-1H-benzoimidazole
[0373] MS (electrospray): mass calculated for
C.sub.24H.sub.31ClN.sub.4O, 426.22; m/z found, 427.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.58 (d, J=8.6 Hz, 1H), 7.11 (s,
1H), 7.03 (d, J=2.5 Hz, 1H), 6.91 (dd, J=8.7, 2.5 Hz, 1H), 6.80 (s,
1H), 3.99 (t, J=6.1 Hz, 2H), 2.75-2.58 (m, 10H), 2.45 (s, 3H), 2.32
(s, 3H), 2.30 (s, 3H), 1.89-1.85 (m, 2H), 1.78-1.74 (m, 2H).
Example 23
##STR00031##
[0374]
5-Chloro-6-methyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-
-1H-benzoimidazole
[0375] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.60-7.56 (m, 3H), 7.44-7.37 (m,
2H), 7.03-7.00 (m, 1H), 4.05 (t, J=6.1 Hz, 2H), 3.00-2.30 (m, 13H),
2.27 (s, 3H), 1.82-1.73 (m, 2H), 1.72-1.67 (m, 2H). .sup.13C NMR
(TFA salt, 100 MHz, CD.sub.3OD): 161.0, 154.0, 138.5, 131.9, 131.7,
131.3, 130.2, 120.0, 118.2, 116.7, 116.2, 113.4, 68.7, 58.0, 54.2,
51.7, 44.2, 27.8, 23.5, 20.8.
Example 24
##STR00032##
[0376]
5-Chloro-6-fluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propox-
y]-phenyl}-1H-benzoimidazole
[0377] MS (electrospray): mass calculated for
C.sub.21H.sub.23ClF.sub.2N.sub.4O, 420.15; m/z found, 421.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.80-7.75 (m, 2H),
7.66 (d, J=6.4 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.27 (t, J=9.3 Hz,
1H), 4.21 (t, J=8.0 Hz, 2H), 3.25 (br s, 4H), 3.02 (br s, 4H), 2.90
(t, J=7.8 Hz, 2H), 2.81 (s, 3H), 2.12-2.05 (m, 2H).
Example 25
##STR00033##
[0378]
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methy-
l-1H-benzoimidazole
[0379] MS (electrospray): mass calculated for
C.sub.22H.sub.27FN.sub.4O, 382.22; m/z found, 383.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.85-7.80 (m, 2H), 7.57 (d,
J=8.4 Hz, 1H), 7.49 (s, 1H), 7.38-7.34 (m, 2H), 4.22 (t, J=5.9 Hz,
2H), 3.24 (br s, 4H), 2.95 (br s, 4H), 2.84 (t, J=7.2 Hz, 2H), 2.77
(s, 3H), 2.46 (s, 3H), 2.12-2.05 (m, 2H).
Example 26
##STR00034##
[0380]
5,6-Difluoro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0381] MS (electrospray): mass calculated for
C.sub.21H.sub.23F.sub.3N.sub.4O, 404.18; m/z found, 405.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.79-7.73 (m, 2H),
7.50-7.45 (m, 2H), 7.28-7.22 (m, 1H), 4.18 (t, J=5.9 Hz, 2H),
3.04-2.83 (m, 10H), 2.76 (s, 3H), 2.10-2.03 (m, 2H).
Example 27
##STR00035##
[0382]
2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benz-
oimidazole
[0383] MS (electrospray): mass calculated for
C.sub.21H.sub.25FN.sub.4O, 368.20; m/z found, 369.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.88-7.81 (m, 2H), 7.71-7.66 (m,
2H), 7.52-7.48 (m, 2H), 7.37 (t, J=8.8 Hz, 1H), 4.22 (t, J=6.0 Hz,
2H), 3.04-2.76 (m, 13H), 2.10-2.03 (m, 2H).
Example 28
##STR00036##
[0384]
2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5-
-dimethyl-1H-benzoimidazole
[0385] MS (electrospray): mass calculated for
C.sub.24H.sub.31ClN.sub.4O, 426.22; m/z found, 427.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.75-7.65 (m, 1H), 7.40-7.25 (m,
1H), 7.15 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.04 (dd,
J=8.6, 2.5 Hz, 1H), 4.13 (t, J=6.1 Hz, 1H), 2.85-2.70 (m, 10H),
2.51 (br s, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 2.02-1.96 (m, 2H),
1.88-1.86 (m, 2H). .sup.13C NMR (100 MHz, CD.sub.3OD): 13.7, 19.4,
24.2, 26.9, 45.0, 50.9, 54.7, 55.4, 55.9, 56.6, 67.4, 112.2, 115.2,
117.7, 118.9, 123.7, 128.8, 133.6, 134.5, 134.7, 135.2, 135.5,
148.9, 163.5.
Example 29
##STR00037##
[0386]
5,6-Dimethyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-b-
enzoimidazole
[0387] HPLC: R.sub.t=5.96. MS (electrospray): mass calculated for
C.sub.24H.sub.32N.sub.4O, 392.26; m/z found, 393.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.57-7.50 (m, 3H), 7.48 (s, 2H),
7.23-7.20 (m, 1H), 4.08 (t, J=5.8 Hz, 2H), 3.16 (br s, 4H), 3.01
(br s, 4H), 2.82-2.79 (m, 2H), 2.71 (s, 3H), 2.38 (s, 6H),
1.85-1.74 (m, 4H).
Example 30
##STR00038##
[0388]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,6-dim-
ethyl-1H-benzoimidazole
[0389] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.68 (d, J=8.5 Hz, 1H), 7.21 (br
s, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H), 6.90
(s, 1H), 4.13 (t, J=6.2 Hz, 2H), 2.70-2.40 (m, 16H), 2.96 (s, 3H),
2.06-1.98 (m, 2H).
Example 31
##STR00039##
[0390]
2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-m-
ethyl-1H-benzoimidazole
[0391] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.72-7.69 (m, 1H), 7.50-7.35 (m,
1H), 7.18-7.13 (m, 2H), 7.06-7.03 (m, 2H), 4.14 (t, J=6.1 Hz, 2H),
2.85-2.70 (m, 10H), 2.59 (s, 3H), 2.40 (s, 3H), 2.02-1.96 (m, 2H),
1.89-1.85 (m, 2H).
Example 32
##STR00040##
[0392]
5-tert-Butyl-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0393] MS (electrospray): mass calculated for
C.sub.25H.sub.33ClN.sub.4O, 440.23; m/z found, 441.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.76 (d, J=8.7 Hz, 1H),
7.62-7.53 (m, 2H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 7.15 (d, J=2.5 Hz,
1H), 7.04 (dd, J=8.7, 2.5 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H),
2.80-2.20 (m, 13H), 2.06-1.96 (m, 2H), 1.40 (s, 9H)
Example 33
##STR00041##
[0394]
2-{3-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trif-
luoromethyl-1H-benzoimidazole
[0395] HPLC: R.sub.t=6.30. MS (electrospray): mass calculated for
C.sub.23H.sub.27F.sub.3N.sub.4O.sub.2, 448.21; m/z found, 449.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD): 7.93 (s, 1H), 7.79
(d, J=8.6 Hz, 1H), 7.69-7.66 (m, 3H), 7.11 (d, J=9.0 Hz, 1H), 4.16
(t, J=5.6 Hz, 2H), 3.90 (s, 3H), 3.45-3.39 (m, 7H), 3.21-3.18 (m,
3H), 3.18 (s, 3H), 2.21-2.17 (m, 2H).
Example 34
##STR00042##
[0396]
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-6-fluoro-1H-benzoimidazole
[0397] HPLC: R.sub.t=6.41. MS (electrospray): mass calculated for
C.sub.21H.sub.23Cl.sub.2FN.sub.4O, 436.12; m/z found, 437.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.98 (d, J=2.3 Hz,
1H), 7.87 (dd, J=8.7, 2.3 Hz, 1H), 7.63 (d, J=6.4 Hz, 1H), 7.41 (d,
J=8.8 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 4.19 (t, J=5.7 Hz, 2H), 3.39
(br s, 4H), 3.25-3.20 (m, 4H), 3.09 (t, J=7.3 Hz, 2H), 2.83 (s,
3H), 2.19-2.15 (m, 2H).
Example 35
##STR00043##
[0398]
5,6-Dichloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0399] HPLC: R.sub.t=6.64. MS (electrospray): mass calculated for
C.sub.21H.sub.23Cl.sub.3N.sub.4O, 452.09; m/z found, 453.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.74 (s, 2H), 7.60
(d, J=8.8 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 6.94 (dd, J=8.8, 2.4 Hz,
1H), 4.00 (t, J=5.8 Hz, 2H), 3.43 (br s, 7H), 3.19 (t, J=7.7 Hz,
2H), 3.05-3.04 (m, 1H), 2.74 (s, 3H), 2.10-2.02 (m, 2H).
Example 36
##STR00044##
[0400]
5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0401] HPLC: R.sub.t=6.09. MS (electrospray): mass calculated for
C.sub.21H.sub.24Cl.sub.2N.sub.4O, 418.13; m/z found, 419.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD): 7.76 (d, J=8.8 Hz,
1H), 7.73 (dd, J=1.9, 0.4 Hz, 1H), 7.69 (dd, J=8.8, 0.4 Hz, 1H),
7.47 (dd, J=8.8, 1.9 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H), 7.09 (dd,
J=8.8, 2.5 Hz, 1H), 4.15 (t, J=5.9 Hz, 2H), 3.45 (br s, 4H), 3.34
(br s, 4H), 3.16-3.12 (m, 2H), 2.85 (s, 3H), 2.18-2.12 (m, 2H).
Example 37
##STR00045##
[0402]
5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-6-fluoro-1H-benzoimidazole
[0403] HPLC: R.sub.t=6.36. MS (electrospray): mass calculated for
C.sub.21H.sub.23Cl.sub.2FN.sub.4O, 436.12; m/z found, 437.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.78 (d, J=6.4 Hz,
1H), 7.73 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.19 (d, J=2.5
Hz, 1H), 7.06 (dd, J=8.8, 2.5 Hz, 1H), 4.14 (t, J=5.8 Hz, 2H), 3.46
(br s, 4H), 3.37 (br s, 3H), 3.22-3.20 (m, 1H), 3.18-3.14 (m, 2H),
2.86 (s, 3H), 2.19-2.13 (m, 2H).
Example 38
##STR00046##
[0404]
5-Chloro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0405] HPLC: R.sub.t=6.20. MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O, 398.19; m/z found, 399.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.88 (dd, J=8.7, 2.3 Hz, 1H),
7.83-7.82 (m, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H),
7.46 (dd, J=8.7, 1.9 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 4.16 (t,
J=6.0 Hz, 2H), 3.24 (br s, 4H), 2.95 (br s, 4H), 2.88-2.85 (m, 2H),
2.77 (s, 3H), 2.26 (s, 3H), 2.11-2.05 (m, 2H).
Example 39
##STR00047##
[0406]
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methy-
l-1H-benzoimidazole
[0407] HPLC: R.sub.t=5.93. MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O, 398.19; m/z found, 399.3 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 8.10 (d, J=2.4 Hz, 1H), 7.97
(dd, J=8.7, 2.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.34
(d, J=8.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 4.24 (t, J=5.8 Hz, 2H),
3.34 (br s, 4H), 3.14 (br s, 4H), 3.02-2.99 (m, 2H), 2.80 (s, 3H),
2.45 (s, 3H), 2.18-2.12 (m, 2H).
Example 40
##STR00048##
[0408]
5,6-Dichloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0409] HPLC: R.sub.t=6.69. MS (electrospray): mass calculated for
C.sub.21H.sub.23Cl.sub.3N.sub.4O, 452.09; m/z found, 453.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.08 (d, J=2.3 Hz,
1H), 7.95 (dd, J=8.7, 2.3 Hz, 1H), 7.81 (s, 2H), 7.26 (d, J=8.8 Hz,
1H), 4.25 (t, J=5.7 Hz, 2H), 3.55 (br s, 8H), 3.36-3.32 (m, 2H),
2.90 (s, 3H), 2.31-2.25 (m, 2H).
Example 41
##STR00049##
[0410]
5-Chloro-6-methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propox-
y]-phenyl}-1H-benzoimidazole
[0411] HPLC: R.sub.t=6.40. MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.87 (dd, J=8.6, 2.5 Hz, 1H),
7.82-7.81 (m, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.14 (d, J=8.7 Hz,
1H), 4.15 (t, J=6.0 Hz, 2H), 3.20 (br s, 4H), 2.85 (br s, 4H),
2.83-2.79 (m, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H),
2.08-2.03 (m, 2H).
Example 42
##STR00050##
[0412]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methy-
l-1H-benzoimidazole
[0413] HPLC: R.sub.t=5.92. MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O, 398.19; m/z found, 399.3 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.87 (d, J=8.8 Hz, 1H), 7.72 (d,
J=8.5 Hz, 1H), 7.64 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.36 (d, J=2.4
Hz, 1H), 7.23 (dd, J=8.8, 2.4 Hz, 1H), 4.26 (t, J=5.8 Hz, 2H), 3.60
(br s, 4H), 3.51 (br s, 4H), 3.31-3.27 (m, 2H), 2.98 (s, 3H), 2.58
(s, 3H), 2.31-2.26 (m, 2H).
Example 43
##STR00051##
[0414]
5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0415] HPLC: R.sub.t=6.15. MS (electrospray): mass calculated for
C.sub.21H.sub.24Cl.sub.2N.sub.4O, 418.13; m/z found, 419.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD): 8.07 (d, J=2.3 Hz,
1H), 7.94 (dd, J=8.7, 2.3 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H), 7.59 (d,
J=8.7 Hz, 1H), 7.38 (dd, J=8.7, 1.9 Hz, 1H), 7.24 (d, J=8.8 Hz,
1H), 4.22 (t, J=5.8 Hz, 2H), 3.42 (br s, 4H), 3.29 (br s. 4H),
3.15-3.10 (m, 2H), 2.84 (s, 3H), 2.21-2.15 (m, 2H).
Example 44
##STR00052##
[0416]
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifl-
uoromethyl-1H-benzoimidazole
[0417] HPLC: R.sub.t=6.53. MS (electrospray): mass calculated for
C.sub.22H.sub.24ClF.sub.3N.sub.4O, 452.16; m/z found, 453.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD): 8.12 (d, J=2.3 Hz,
1H), 7.99 (dd, J=8.7, 2.3 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J=8.5 Hz,
1H), 7.61 (d, J=8.6 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 4.22 (t, J=5.8
Hz, 2H), 3.37 (br s, 4H), 3.21 (br s, 4H), 3.08-3.05 (m, 2H), 2.82
(s, 3H), 2.19-2.14 (m, 2H).
Example 45
##STR00053##
[0418]
5-Chloro-6-fluoro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propox-
y]-phenyl}-1H-benzoimidazole
[0419] HPLC: R.sub.t=6.34. MS (electrospray): mass calculated for
C.sub.22H.sub.26ClFN.sub.4O, 416.18; m/z found, 417.1 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.85 (dd, J=8.6, 2.3 Hz, 1H),
7.80-7.79 (m, 1H), 7.72 (d, J=6.3 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H),
7.10 (d, J=8.7 Hz, 1H), 4.14 (t, J=6.0 Hz, 2H), 3.20 (br s, 8H),
2.85-2.81 (m, 2H), 2.76 (s, 3H), 2.25 (s, 3H), 2.09-2.04 (m,
2H).
Example 46
##STR00054##
[0420]
5-Methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0421] HPLC: R.sub.t=6.13. MS (electrospray): mass calculated for
C.sub.23H.sub.30N.sub.4O, 378.24; m/z found, 379.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.87 (d, J=8.6 Hz, 1H),
7.82-7.81 (m, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.32 (d,
J=8.4 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.29
(br s, 4H), 3.06 (br s, 4H), 2.96-2.93 (m, 2H), 2.79 (s, 3H), 2.46
(s, 3H), 2.26 (s, 3H), 2.14-2.08 (m, 2H).
Example 47
##STR00055##
[0422]
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benz-
oimidazole
[0423] HPLC: R.sub.t=5.70. MS (electrospray): mass calculated for
C.sub.21H.sub.25ClN.sub.4O, 384.17; m/z found, 385.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 8.13 (d, J=2.3 Hz, 1H), 8.00
(dd, J=8.7, 2.3 Hz, 1H), 7.72-7.67 (m, 2H), 7.53-7.48 (m, 2H), 7.33
(d, J=8.8 Hz, 1H), 4.25 (t, J=5.9 Hz, 2H), 3.30 (br s, 4H), 3.06
(br s, 4H), 2.96-2.92 (m, 2H), 2.79 (s, 3H), 2.15-2.10 (m, 2H).
Example 48
##STR00056##
[0424]
2-{3-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benz-
oimidazole
[0425] HPLC: R.sub.t=5.89. MS (electrospray): mass calculated for
C.sub.22H.sub.28N.sub.4O, 364.23; m/z found, 365.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.90 (dd, J=8.5, 2.5 Hz, 1H),
7.85-7.84 (m, 1H), 7.70-7.66 (m, 2H), 7.52-7.47 (m, 2H), 7.15 (d,
J=8.6 Hz, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.23 (br s, 4H), 2.96 (br s,
4H), 2.87-2.84 (m, 2H), 2.77 (s, 3H), 2.27 (s, 3H), 2.11-2.05 (m,
2H).
Example 49
##STR00057##
[0426]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benz-
oimidazole
[0427] HPLC: R.sub.t=5.68. MS (electrospray): mass calculated for
C.sub.21H.sub.25ClN.sub.4O, 384.17; m/z found, 385.3 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.78 (d, J=8.8 Hz, 1H),
7.77-7.74 (m, 2H), 7.56-7.53 (m, 2H), 7.27 (d, J=2.4 Hz, 1H), 7.12
(dd, J=8.8, 2.4 Hz, 1H), 4.16 (t, J=5.9 Hz, 2H), 3.44 (br s, 4H),
3.32 (br s, 4H), 3.14-3.11 (m, 2H), 2.84 (s, 3H), 2.18-2.12 (m,
2H).
Example 50
##STR00058##
[0428]
5-Chloro-6-fluoro-2-{3-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propo-
xy]-phenyl}-1H-benzoimidazole
[0429] HPLC: R.sub.t=6.15. MS (electrospray): mass calculated for
C.sub.22H.sub.26ClFN.sub.4O.sub.2, 432.17; m/z found, 433.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.75-7.73 (m, 1H),
7.61-7.58 (m, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.09-7.07 (m, 1H), 4.16
(t, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.48 (br s, 8H), 3.25-3.22 (m,
2H), 2.86 (s, 3H), 2.22-2.19 (m, 2H).
Example 51
##STR00059##
[0430]
2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-metho-
xy-1H-benzoimidazole
[0431] HPLC: R.sub.t=5.85. MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O.sub.2, 414.18; m/z found, 415.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.08 (d, J=2.3 Hz,
1H), 7.94 (dd, J=8.7, 2.3 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.30 (d,
J=8.8 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.10 (dd, J=9.0, 2.3 Hz,
1H), 4.26 (t, J=5.7 Hz, 2H), 3.82 (s, 3H), 3.52 (br s, 8H),
3.30-3.26 (m, 2H), 2.88 (s, 3H), 2.29-2.22 (m, 2H).
Example 52
##STR00060##
[0432]
5-tert-Butyl-2-{3,5-dibromo-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-
-phenyl}-1H-benzoimidazole
[0433] HPLC: R.sub.t=6.81. MS (electrospray): mass calculated for
C.sub.25H.sub.32Br.sub.2N.sub.4O, 562.09; m/z found, 563.1
[M+H].sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD): 8.31 (s, 2H),
7.70-7.62 (m, 3H), 4.17 (t, J=5.8 Hz, 2H), 3.37 (br s, 4H), 3.20
(br s, 4H), 3.18-3.15 (m, 2H), 2.82 (s, 3H), 2.22-2.16 (m, 2H),
1.34 (s, 9H).
Example 53
##STR00061##
[0434]
2-{2-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trif-
luoromethyl-1H-benzoimidazole
[0435] HPLC: R.sub.t=6.34. MS (electrospray): mass calculated for
C.sub.23H.sub.27F.sub.3N.sub.4O.sub.2, 448.21; m/z found, 449.3
[M+H].sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD): 8.11-8.08 (m, 2H),
7.96 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 6.89-6.87 (m, 2H),
4.28 (t, J=5.8 Hz, 2H), 4.17 (s, 3H), 3.58 (br s, 4H), 3.49 (br s,
4H), 3.30-3.27 (m, 2H), 2.97 (s, 3H), 2.31-2.25 (m, 2H).
Example 54
##STR00062##
[0436]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifl-
uoromethyl-1H-benzoimidazole
[0437] HPLC: R.sub.t=6.47. MS (electrospray): mass calculated for
C.sub.22H.sub.24ClF.sub.3N.sub.4O, 452.16; m/z found, 453.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.09 (s, 1H), 7.93
(d, J=8.7 Hz, 1H), 7.85-7.80 (m, 2H), 7.29 (d, J=2.3 Hz, 1H), 7.15
(dd, J=8.8, 2.5 Hz, 1H), 4.20 (t, J=5.8 Hz, 2H), 3.62 (br s, 8H),
3.40-3.36 (m, 2H), 2.93 (s, 3H), 2.29-2.20 (m, 2H).
Example 55
##STR00063##
[0438]
2-{3-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazol-
e
[0439] HPLC: R.sub.t=5.51. MS (electrospray): mass calculated for
C.sub.21H.sub.26N.sub.4O, 350.21; m/z found, 351.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.75-7.72 (m, 2H), 7.70-7.60 (m,
2H), 7.54-7.51 (m, 3H), 7.26-7.24 (m, 1H), 4.16 (t, J=6.0 Hz, 2H),
3.35 (br s, 4H), 3.19 (br s, 4H), 3.05-3.01 (m, 2H), 2.81 (s, 3H),
2.14-2.10 (m, 2H).
Example 56
##STR00064##
[0440]
(2-{3-[4-(4-Methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazol-
-5-yl)-phenyl-methanone
[0441] HPLC: R.sub.t=6.36. MS (electrospray): mass calculated for
C.sub.29H.sub.32N.sub.4O.sub.2, 468.25; m/z found, 469.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.11 (s, 1H),
7.90-7.77 (m, 4H), 7.72-7.65 (m, 3H), 7.58-7.52 (m, 3H), 7.23-7.20
(m, 1H), 4.15 (t, J=5.7 Hz, 2H), 3.57 (br s, 8H), 3.26-3.21 (m,
2H), 2.95 (s, 3H), 1.96-1.93 (m, 4H).
[0442] The following compounds in Examples 57-71 were prepared
according to the procedures described in Example 2.
Example 57
##STR00065##
[0443]
6-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl-
}-4-methyl-1H-benzoimidazole
[0444] MS (electrospray): mass calculated for
C.sub.23H.sub.27Cl.sub.2N.sub.3O, 431.15; m/z found, 432.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.69 (d, J=8.0 Hz,
1H), 7.42 (br s, 1H), 7.14 (d, J=4.0 Hz, 1H), 7.07-7.05 (m, 1H),
7.02 (dd, J=8.0, 4.0 Hz, 1H), 4.04 (t, J=8.0 Hz, 2H), 2.95-2.85 (m,
2H), 2.58 (s, 3H), 2.28 (s, 3H), 2.10-2.00 (m, 2H), 1.84-1.75 (m,
4H), 1.46-1.41 (m, 2H), 1.22-1.35 (m, 3H).
Example 58
##STR00066##
[0445]
5-tert-Butyl-2-{3-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0446] MS (electrospray): mass calculated for
C.sub.26H.sub.34ClN.sub.3O, 439.24; m/z found, 440.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.10 (d, J=2.2 Hz, 1H), 7.97
(dd, J=8.6, 2.2 Hz, 1H), 7.58 (br s, 1H), 7.52-7.45 (m, 1H), 7.36
(dd, J=8.6, 1.7 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 4.14 (t, J=6.2 Hz,
2H), 2.93-2.85 (m, 2H), 2.28 (s, 3H), 2.11-2.00 (m, 2H), 1.92-1.83
(m, 2H), 1.82-1.74 (m, 2H), 1.52-1.45 (m, 2H), 1.42-1.20 (m,
12H).
Example 59
##STR00067##
[0447]
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5-dim-
ethyl-1H-benzoimidazole
[0448] MS (electrospray): mass calculated for
C.sub.24H.sub.30ClN.sub.3O, 411.21; m/z found, 412.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.73-7.63 (m, 1H), 7.31 (br s,
1H), 7.13 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.02 (dd,
J=8.7, 2.5 Hz, 1H), 4.06 (t, J=6.3 Hz, 2H), 2.93-2.89 (m, 2H), 2.51
(s, 3H), 2.40 (s, 3H), 2.29 (s, 3H), 2.00-2.15 (m, 2H), 1.86-1.77
(m, 4H), 1.48-1.42 (m, 2H), 1.35-1.24 (m, 3H).
Example 60
##STR00068##
[0449]
5-Chloro-6-methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0450] HPLC: R.sub.t=6.84. MS (electrospray): mass calculated for
C.sub.23H.sub.28ClN.sub.3O, 397.19; m/z found, 398.5 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.95 (d, J=9.0 Hz, 2H), 7.67 (s,
1H), 7.57 (s, 1H), 7.12 (d, J=9.0 Hz, 2H), 4.05 (t, J=6.3 Hz, 2H),
3.42 (d, J=10.4 Hz, 2H), 2.92-2.86 (m, 2H), 2.89 (s, 3H), 2.45 (s,
3H), 1.96-1.93 (m, 2H), 1.82-1.77 (m, 2H), 1.60-1.52 (m, 1H),
1.45-1.30 (m, 4H).
Example 61
##STR00069##
[0451]
5-Chloro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benz-
oimidazole
[0452] HPLC: R.sub.t=6.62. MS (electrospray): mass calculated for
C.sub.22H.sub.26ClN.sub.3O, 383.18; m/z found, 384.5 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.96 (d, J=9.0 Hz, 2H), 7.66 (d,
J=2.0 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.42 (dd, J=8.7, 1.9 Hz,
1H), 7.12 (d, J=9.0 Hz, 2H), 4.05 (t, J=6.3 Hz, 2H), 3.43-3.40 (m,
2H), 2.92-2.86 (m, 2H), 2.76 (s, 3H), 1.96-1.93 (m, 2H), 1.82-1.76
(m, 2H), 1.60-1.51 (m, 1H), 1.46-1.30 (m, 4H).
Example 62
##STR00070##
[0453]
5-Chloro-6-fluoro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0454] HPLC: R.sub.t=6.80. MS (electrospray): mass calculated for
C.sub.22H.sub.25ClFN.sub.3O, 401.17; m/z found, 402.5 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.93 (d, J=9.0 Hz, 2H), 7.71 (d,
J=6.3 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.08 (d, J=9.0 Hz, 2H), 4.03
(t, J=6.3 Hz, 2H), 3.44-3.40 (m, 2H), 2.92-2.86 (m, 2H), 2.76 (s,
3H), 1.96-1.93 (m, 2H), 1.82-1.76 (m, 2H), 1.60-1.51 (m, 1H),
1.43-1.29 (m, 4H).
Example 63
##STR00071##
[0455]
5-tert-Butyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H--
benzoimidazole
[0456] HPLC: R.sub.t=7.16. MS (electrospray): mass calculated for
C.sub.26H.sub.35N.sub.3O, 405.28; m/z found, 406.6 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 8.09 (d, J=9.0 Hz, 2H), 7.70 (s,
1H), 7.71 (s, 2H), 7.25 (d, J=9.0 Hz, 2H), 4.16 (t, J=6.3 Hz, 2H),
3.58-3.52 (m, 2H), 3.03-2.97 (m, 2H), 2.87 (s, 3H), 2.06-2.03 (m,
2H), 1.93-1.87 (m, 2H), 1.71-1.63 (m, 1H), 1.57-1.49 (m, 4H), 1.44
(s, 9H).
Example 64
##STR00072##
[0457]
5-Methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benz-
oimidazole
[0458] HPLC: R.sub.t=6.53. MS (electrospray): mass calculated for
C.sub.23H.sub.29N.sub.3O, 363.23; m/z found, 364.5 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 7.96 (d, J=9.0 Hz, 2H), 7.53 (d,
J=8.4 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.14 (d, J=9.0
Hz, 2H), 4.05 (t, J=6.2 Hz, 2H), 3.44-3.41 (m, 2H), 2.92-2.86 (m,
2H), 2.76 (s, 3H), 2.45 (s, 3H), 1.96-1.92 (m, 2H), 1.82-1.76 (m,
2H), 1.60-1.50 (m, 1H), 1.45-1.33 (m, 4H).
Example 65
##STR00073##
[0459]
2-{4-[3-(1-Methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazol-
e
[0460] HPLC: R.sub.t=6.28. MS (electrospray): mass calculated for
C.sub.22H.sub.27N.sub.3O, 349.22; m/z found, 350.5 [M+H].sup.+.
.sup.1H NMR (500 MHz, CD.sub.3OD): 8.00 (d, J=8.9 Hz, 2H),
7.70-7.66 (m, 2H), 7.51-7.47 (m, 2H), 7.15 (d, J=8.9 Hz, 2H), 4.06
(t, J=6.2 Hz, 2H), 3.43-3.40 (m, 2H), 2.92-2.85 (m, 2H), 2.76 (s,
3H), 1.96-1.93 (m, 2H), 1.82-1.77 (m, 2H), 1.60-1.50 (m, 1H),
1.45-1.33 (m, 4H).
Example 66
##STR00074##
[0461]
6-Chloro-2-{2-fluoro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl-
}-4-methyl-1H-benzoimidazole
[0462] MS (electrospray): mass calculated for
C.sub.23H.sub.27ClFN.sub.3O, 415.18; m/z found, 416.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.02 (s, 1H), 7.41 (s, 1H),
7.07-7.02 (m, 1H), 6.96-6.85 (m, 2H), 4.06 (t, J=6.3 Hz, 2H),
2.93-2.83 (m, 2H), 2.60 (s, 3H), 2.26 (s, 3H), 2.07-1.97 (m, 2H),
1.89-1.71 (m, 4H), 1.49-1.40 (m, 2H), 1.38-1.22 (m, 3H).
Example 67
##STR00075##
[0463]
5-Fluoro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0464] MS (electrospray): mass calculated for
C.sub.23H.sub.28FN.sub.3O, 381.22; m/z found, 382.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.61-7.52 (m, 2H), 7.29 (dd,
J=9.1, 2.3 Hz, 1H), 7.09-7.01 (m, 1H), 6.96-6.86 (m, 2H), 4.04 (t,
J=6.4 Hz, 2H), 2.95-2.82 (m, 2H), 2.52 (s, 3H), 2.28 (s, 3H),
2.08-1.96 (m, 2H), 1.88-1.72 (m, 4H), 1.51-1.40 (m, 2H), 1.38-1.19
(m, 3H).
Example 68
##STR00076##
[0465]
4-Chloro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl-
}-1H-benzoimidazole
[0466] MS (electrospray): mass calculated for
C.sub.23H.sub.28ClN.sub.3O, 397.19; m/z found, 398.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.56 (d, J=8.5 Hz, 1H), 7.54 (d,
J=7.7 Hz, 1H), 7.31-7.20 (m, 2H), 6.93 (d, J=2.3 Hz, 1H), 7.90 (dd,
J=8.5, 2.5 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H), 2.94-2.84 (m, 2H), 2.51
(s, 3H), 2.28 (s, 3H), 2.09-1.97 (m, 2H), 1.89-1.72 (m, 4H),
1.52-1.40 (m, 2H), 1.37-1.21 (m, 3H).
Example 69
##STR00077##
[0467]
6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propox-
y]-phenyl}-1H-benzoimidazole
[0468] MS (electrospray): mass calculated for
C.sub.24H.sub.30ClN.sub.3O, 411.21; m/z found, 412.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.54 (d, J=8.4 Hz, 1H), 7.42 (br
s, 1H), 7.09-7.05 (m, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.90 (dd, J=8.4,
2.4 Hz, 1H), 4.06 (t, J=6.3 Hz, 2H), 2.96-2.86 (m, 2H), 2.59 (s,
3H), 2.49 (s, 3H), 2.29 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.75 (m,
4H), 1.52-1.43 (m, 2H), 1.38-1.23 (m, 3H).
Example 70
##STR00078##
[0469]
5-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl-
}-6-fluoro-1H-benzoimidazole
[0470] MS (electrospray): mass calculated for
C.sub.22H.sub.24Cl.sub.2FN.sub.3O, 435.13; m/z found, 436.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.78 (d, J=8.7 Hz,
1H), 7.70 (d, J=6.6 Hz, 1H), 7.46 (d, J=9.3 Hz, 1H), 7.14 (d, J=2.4
Hz, 1H), 7.04 (dd, J=8.7, 2.5 Hz, 1H), 4.06 (t, J=6.4 Hz, 2H),
2.93-2.84 (m, 2H), 2.28 (s, 3H), 2.09-1.96 (m, 2H), 1.87-1.71 (m,
4H), 1.49-1.39 (m, 2H), 1.35-1.22 (m, 3H).
Example 71
##STR00079##
[0471]
2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-3H-naph-
tho[1,2-d]imidazole
[0472] MS (electrospray): mass calculated for
C.sub.26H.sub.28ClN.sub.3O, 433.19; m/z found, 434.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.52-8.44 (m, 1H), 7.97 (d,
J=8.2 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.74 (s, 2H), 7.64-7.57 (m,
1H), 7.53-7.47 (m, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.02 (dd, J=8.6,
2.5 Hz, 1H), 4.01 (t, J=6.3 Hz, 2H), 2.89-2.78 (m, 2H), 2.25 (s,
3H), 2.03-1.90 (m, 2H), 1.83-1.64 (m, 4H), 1.43-1.33 (m, 2H),
1.33-1.18 (m, 3H).
[0473] The following compounds in Examples 72-81 were prepared
according to the procedures described in Example 1.
Example 72
##STR00080##
[0474]
4,6-Dimethyl-2-{2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0475] MS (electrospray): mass calculated for
C.sub.24H.sub.32N.sub.4O, 392.26; m/z found, 393.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.51 (d, J=8.5 Hz, 1H), 7.20 (s,
1H), 6.92-6.70 (m, 3H), 4.07 (t, J=6.1 Hz, 2H), 2.72-2.40 (m, 19H),
2.30 (s, 3H), 2.02-1.98 (m, 2H).
Example 73
##STR00081##
[0476]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methy-
l-1H-benzoimidazole
[0477] MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O, 398.1.9; m/z found, 399.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.72-7.67 (m, 1H), 7.41 (s, 1H),
7.18-7.13 (m, 2H), 7.07-7.02 (m, 2H), 4.13 (t, J=6.1 Hz, 2H),
2.80-2.40 (m, 13H), 2.30 (s, 3H), 2.05-1.98 (m, 2H).
Example 74
##STR00082##
[0478]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-fluor-
o-4-methyl-1H-benzoimidazole
[0479] MS (electrospray): mass calculated for
C.sub.22H.sub.26ClFN.sub.4O, 416.18; m/z found, 417.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.76-7.65 (br s, 1H), 7.47-7.33
(br s, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.07-7.00 (m, 2H), 4.13 (t,
J=6.1 Hz, 2H), 2.68-2.40 (m, 13H), 2.32 (s, 3H), 2.08-1.97 (m,
2H).
Example 75
##STR00083##
[0480]
2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-3H-naph-
tho[1,2-d]imidazole
[0481] MS (electrospray): mass calculated for
C.sub.25H.sub.27ClN.sub.4O, 434.19; m/z found, 435.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.49 (s, 1H), 7.93 (d, J=8.1 Hz,
1H), 7.74-7.68 (m, 3H), 7.60-7.55 (m, 1H), 7.48-7.43 (m, 1H), 7.07
(d, J=2.5 Hz, 1H), 6.90 (dd, J=8.7, 2.5 Hz, 1H), 3.92 (t, J=6.1 Hz,
2H), 2.62-2.30 (m, 10H), 2.22 (s, 3H), 1.89-1.81 (m, 2H).
Example 76
##STR00084##
[0482]
6-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5H-[1,3-
]dioxolo[4',5':4,5]benzo[1,2-d]imidazole
[0483] MS (electrospray): mass calculated for
C.sub.22H.sub.25ClN.sub.4O.sub.3, 428.16; m/z found, 429.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.74 (d, J=8.7 Hz,
1H), 7.13 (d, J=2.5 Hz, 1H), 7.07-6.97 (m, 3H), 5.98 (s, 2H), 4.11
(t, J=6.2 Hz, 2H), 2.74-2.36 (m, 10H), 2.31 (s, 3H), 2.07-1.96 (m,
2H).
Example 77
##STR00085##
[0484]
6-Chloro-2-{2-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-ph-
enyl}-4-methyl-1H-benzoimidazole
[0485] MS (electrospray): mass calculated for
C.sub.23H.sub.28Cl.sub.2N.sub.4O, 446.16; m/z found, 447.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.72 (d, J=8.6 Hz,
1H), 7.44 (br s, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.10-7.08 (m, 1H),
7.05 (dd, J=8.7, 2.5 Hz, 1H), 4.14 (t, J=6.1 Hz, 2H), 2.83-2.78 (m,
4H), 2.75-2.69 (m, 6H), 2.60 (s, 3H), 2.39 (s, 3H), 2.04-1.96 (m,
2H), 1.90-1.84 (m, 2H).
Example 78
##STR00086##
[0486]
2-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-m-
ethyl-1H-benzoimidazole
[0487] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.19 (d, J=2.2 Hz, 1H), 8.04
(dd, J=8.6, 2.2 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.22 (d, J=8.7 Hz,
1H), 7.18-7.11 (m, 1H), 7.04 (d, J=7.2 Hz, 1H), 4.19 (t, J=6.0 Hz,
2H), 2.84-2.66 (m, 10H), 2.62 (s, 3H), 2.36 (s, 3H), 2.08-1.98 (m,
2H), 1.89-1.82 (m, 2H).
Example 79
##STR00087##
[0488]
4,6-Dimethyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}--
1H-benzoimidazole
[0489] MS (electrospray): mass calculated for
C.sub.25H.sub.34N.sub.4O, 406.27; m/z found, 407.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.75-7.70 (m, 1H), 7.69-7.64 (d,
J=7.7 Hz, 1H), 7.46-7.40 (m, 1H), 7.23 (br s, 1H), 7.04 (m, 1H),
6.90 (br s, 1H), 4.12 (t, J=6.2 Hz, 2H), 2.83-2.75 (m, 4H),
2.73-2.65 (m, 4H), 2.63-2.54 (m, 5H), 2.44 (s, 3H), 2.35 (s, 3H),
1.89-1.79 (m, 4H), 1.76-1.68 (m, 2H).
Example 80
##STR00088##
[0490]
5-Chloro-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benz-
oimidazole
Example 81
##STR00089##
[0491]
2-{4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazol-
e
Example 82
##STR00090##
[0492]
{2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperid-
in-4-yl)-propoxy]-benzyl}-dimethyl-amine
[0493] A. 4-Bromo-3-dimethylaminomethyl-phenol.
2-Bromo-5-hydroxy-benzaldehyde (5.0 g, 24.9 mmol, 1.0 equiv) and
2.0 M dimethylamine in THF (31 mL, 62 mmol, 2.5 equiv) were stirred
in dichloroethane (50 mL) at rt for 1.0 h. Sodium
triacetoxyborohydride (15.8 g, 75 mmol, 3.0 equiv) was added, and
the mixture was stirred for 3.0 h then poured into satd. aq.
NaHCO.sub.3. The aqueous mixture was extracted three times with
chloroform and the combined extracts were dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure. The residue was
purified by Method 2 to afford 2.12 g (38%) of the title compound.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.36 (dd, J=8.6, 1.8 Hz, 1H),
6.91-6.90 (m, 1H), 6.67-6.62 (m, 1H), 3.53 (d, J=1.3 Hz, 1H), 2.30
(m, 6H).
[0494] B.
{2-Bromo-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethy-
l-amine. To a solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol
(989 mg, 6.3 mmol, 1.0 equiv) and methanesulfonyl chloride (683
.mu.L, 8.8 mmol, 1.4 equiv) in dichloromethane (12 mL) at 0.degree.
C. was added triethylamine (1.57 mL, 11.3 mmol, 1.8 equiv). The
reaction mixture, which was allowed to warm to rt, was stirred for
12 h and then poured into satd. aq. NaHCO.sub.3. The aqueous
mixture was extracted three times with 10% 2-propanol in chloroform
and the extract was dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure. The residue was dissolved in
acetonitrile (21 mL) and 4-bromo-3-dimethylaminomethyl-phenol (1.44
g, 6.3 mmol, 1.0 equiv) and cesium carbonate (4.1 g, 12.6 mmol, 2.0
equiv) were added. The mixture was stirred at rt for 12 h, then
warmed to 40.degree. C. for 2.0 h, then 50.degree. C. for 1.0 h,
and finally 65.degree. C. for 1.5 h. The mixture was poured into
satd. aq. NaHCO.sub.3 and extracted two times with ethyl acetate
and one time with chloroform. The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. Purification by Method 2 afforded 814 mg (40%) of the
title compound. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.45 (d, J=8.8
Hz, 1H), 7.05 (d, J=3.1 Hz, 1H), 6.78 (dd, J=8.8, 3.1 Hz, 1H), 3.98
(t, J=6.4 Hz, 2H), 3.58 (s, 2H), 2.93-2.86 (m, 2H), 2.31 (s, 6H),
2.29 (s, 3H), 2.10-1.98 (m, 2H), 1.86-1.73 (m, 4H), 1.49-1.22 (m,
5H).
[0495] C.
{2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-pipe-
ridin-4-yl)-propoxy]-benzyl}-dimethyl-amine. To a solution of
{2-bromo-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine
(801 mg, 2.2 mmol, 1.0 equiv) in THF (10 mL) at -78.degree. C., 1.7
M tert-butyllithium in pentane (3.83 mL, 6.5 mmol, 3.0 equiv) was
added and the solution was stirred for 15 min. The solution was
then warmed to 0.degree. C., stirred for 5 min, and then re-cooled
to -78.degree. C. DMF (1.68 mL, 21.7 mmol, 10.0 equiv) was added
and the mixture was stirred for 30 min. Water (1.0 mL) was added
and the mixture was poured into satd. aq. NaHCO.sub.3. The aqueous
mixture was extracted three times with ethyl acetate and the
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure. The residue was partially
purified by Method 2 to afford 221 mg of a mixture of
2-dimethylaminomethyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyd-
e and several other unidentified products. The crude
dimethylaminomethyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde
(110 mg) was dissolved in DMF and
5-chloro-3-methyl-benzene-1,2-diamine (54 mg, 0.34 mmol) and
Na.sub.2S.sub.2O.sub.5 (85 mg, 0.45 mmol) were added. The mixture
was warmed to 90.degree. C. and stirred for 3 h. The reaction
mixture was purified by Method 2 to afford 15.2 mg of the title
compound. MS (electrospray): mass calculated for
C.sub.26H.sub.35ClN.sub.4O, 454.25; m/z found, 455.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.07 (d, J=8.6 Hz, 1H),
7.47-7.42 (m, 1H), 7.07-6.97 (m, 3H), 4.04 (t, J=6.4 Hz, 2H), 3.58
(s, 2H), 2.93-2.82 (m, 2H), 2.56 (s, 3H), 2.43 (s, 6H), 2.27 (s,
3H), 2.06-1.93 (m, 2H), 1.87-1.70 (m, 4H), 1.49-1.40 (m, 2H),
1.36-1.21 (m, 3H).
Example 83
##STR00091##
[0496]
{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperid-
in-4-yl)-propoxy]-benzyl}-dimethyl-amine
[0497] The title compound was prepared as described in Example 77.
MS (electrospray): mass calculated for C.sub.26H.sub.35FN.sub.4O,
438.28; m/z found, 439.5 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 8.06 (d, J=8.6 Hz, 1H), 7.43-7.40 (m, 1H), 7.06 (dd,
J=8.6, 2.6 Hz, 1H), 7.03-6.95 (m, 2H), 4.06 (t, J=6.4 Hz, 2H), 3.59
(s, 2H), 2.89-2.86 (m, 2H), 2.49 (s, 3H), 2.44 (s, 6H), 2.27 (s,
3H), 2.07-1.96 (m, 2H), 1.89-1.72 (m, 4H), 1.51-1.41 (m, 2H),
1.39-1.22 (m, 3H).
Example 84
##STR00092##
[0498]
4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-
-propyl}-[1,4]diazepan-5-one
[0499] A. 4-(3-Iodo-propoxy)-2-methyl-benzaldehyde.
1-Bromo-3-chloropropane (5.03 g, 32.0 mmol, 1.0 equiv) was added to
a solution of 2-methyl-4-hydroxybenzaldehyde (4.35 g, 32.0 mmol,
1.0 equiv) and K.sub.2CO.sub.3 (8.8 g, 64.0 mmol, 2.0 equiv) in
acetonitrile (75 mL). The mixture was heated at 65.degree. C. for
16 h, then cooled to rt and filtered through diatomaceous earth.
The filtrate was concentrated and the residue was purified by
column chromatography (silica gel, 10% ethyl acetate in hexanes) to
afford 5.58 g (82%) of 4-(3-chloro-propoxy)-2-methyl-benzaldehyde.
To a refluxing solution of
4-(3-chloro-propoxy)-2-methyl-benzaldehyde in acetone (100 mL), KI
(58 g) was added portion wise over 3 d. The mixture was cooled to
rt and water was added. The aqueous mixture was extracted three
times with ethyl acetate and the combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by column chromatography (silica gel, 5% ethyl acetate in
hexanes) to afford 6.13 g (77%) of the title compound. .sup.1H NMR
(400 MHz, CD.sub.3OD): 10.1 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.84
(dd, J=8.6, 2.5 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 4.11 (t, J=5.8 Hz,
2H), 3.36 (t, J=6.7 Hz, 2H), 2.65 (s, 3H), 2.29 (m, 2H).
[0500] B.
4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-pheno-
xy]-propyl}-[1,4]diazepan-5-one. To a stirred solution of
5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.0 g,
14.0 mmol, 1.0 equiv) in DMF (45 mL) at rt was added 60% sodium
hydride (560 mg, 14.0 mmol, 1.0 equiv). After stirring for 30 min,
4-(3-iodo-propoxy)-2-methyl-benzaldehyde (4.26 g, 14.0 mmol, 1.0
equiv) was added as a solution in DMF (5 mL). The mixture was
stirred for 16 h and then poured into water and extracted with
ethyl acetate. The combined extracts were dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was partially purified by
column chromatography (silica gel, 5-50% ethyl acetate in hexanes)
to afford
4-[3-(4-formyl-3-methyl-phenoxy)-propyl]-5-oxo-[1,4]diazepane-1-carboxyli-
c acid tert-butyl ester as a mixture with several unidentified
products. This impure mixture (200 mg),
5-chloro-3-methyl-benzene-1,2-diamine (80.1 mg), and
Na.sub.2S.sub.2O.sub.5 (97 mg) were stirred in DMF (1.0 mL) at
90.degree. C. for 3 h. After cooling to rt, the reaction mixture
was loaded on silica gel and was purified by Method 2 to afford
4-{3-[4-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propy-
l}-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a
mixture with several unidentified products. This mixture was
dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL) and stirred
at rt for 1 h. The reaction mixture was loaded on silica gel and
purified by Method 2 to afford 91.0 mg (42%) of the title compound.
MS (electrospray): mass calculated for
C.sub.23H.sub.27ClN.sub.4O.sub.2, 426.18; m/z found, 427.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.55 (d, J=8.5 Hz,
1H), 7.42 (br s, 1H), 7.09-7.06 (m, 1H), 6.97 (d, J=2.4 Hz, 1H),
6.93 (dd, J=8.5, 2.5 Hz, 1H), 4.10 (t, J=6.1 Hz, 2H), 3.67-3.56 (m,
4H), 2.98-2.89 (m, 4H), 2.72-2.66 (m, 2H), 2.59 (s, 3H), 2.50 (s,
3H), 2.12-2.01 (m, 2H).
Example 85
##STR00093##
[0501]
4-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-prop-
yl}-1-methyl-[1,4]diazepan-5-one
[0502]
4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-
-propyl}-[1,4]diazepan-5-one (95 mg, 0.22 mmol, 1.0 equiv) and 37%
aq. formaldehyde (35 .mu.L, 0.44 mmol, 2.0 equiv) were stirred in
dichloroethane at rt for 1.0 h. Sodium triacetoxyborohydride (139
mg, 0.66 mmol, 3.0 equiv) was added, and the mixture was stirred
for 1.0 h then poured into satd. aq. NaHCO.sub.3. The aqueous
mixture was extracted three times with ethyl acetate and the
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The residue was purified by Method 2 to afford 34 mg
(35%) of the title compound.
[0503] MS (electrospray): mass calculated for
C.sub.27H.sub.36N.sub.4O.sub.2, 448.28; m/z found, 449.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.62 (br s, 1H),
7.56 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.6,
1.7 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.5, 2.5 Hz, 1H),
4.09 (t, J=6.0 Hz, 2H), 3.65-3.59 (m, 4H), 2.73-2.59 (m, 6H), 2.52
(s, 3H), 2.38 (s, 3H), 2.11-2.02 (m, 2H). 1.43 (s, 9H).
Example 86
##STR00094##
[0504]
5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0505] The title compound was prepared as described in Example 84,
substituting 3-methyl-piperazine-1-carboxylic acid tert-butyl ester
for 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester. MS
(electrospray): mass calculated for C.sub.26H.sub.36N.sub.4O,
420.29; m/z found, 421.5 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.66-7.49 (m, 3H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 6.95
(d, J=2.2 Hz, 1H), 6.91 (dd, J=8.4, 2.5 Hz, 1H), 4.12 (t, J=6.2 Hz,
2H), 3.10-2.82 (m, 5H), 2.60-2.32 (m, 7H), 2.09-1.89 (m, 2H), 1.43
(s, 9H), 1.10 (d, J=6.0 Hz, 3H).
Example 87
##STR00095##
[0506]
5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-ph-
enyl}-1H-benzoimidazole
[0507] The title compound was prepared from
5-tert-butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}--
1H-benzoimidazole according to the method described in Example 85.
MS (electrospray): mass calculated for C.sub.27H.sub.38N.sub.4O,
434.30; m/z found, 435.5 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.69-7.47 (m, 3H), 7.38 (dd, J=8.6, 1.9 Hz, 1H), 6.95
(d, J=2.3 Hz, 1H), 6.91 (dd, J=8.5, 2.4 Hz, 1H), 4.11 (t, J=6.2 Hz,
2H), 3.10-2.94 (m, 2H), 2.84-2.70 (m, 2H), 2.56-2.39 (m, 6H),
2.31-2.19 (m, 4H), 2.09-1.88 (m, 3H), 1.43 (s, 9H), 1.12 (d, J=6.3
Hz, 3H).
Example 88
##STR00096##
[0508]
6-Chloro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]--
1H-benzoimidazole
[0509] To a solution of (3-hydroxy-propyl)-piperidine-1-carboxylic
acid tert-butyl ester (4.00 g, 16.4 mmol, 1.0 equiv) and
triethylamine (3.40 mL, 24.6 mmol, 1.5 equiv) in dichloromethane at
0.degree. C. was added methanesulfonyl chloride (1.53 mL, 19.7
mmol, 1.2 equiv). The solution was warmed to rt and stirred for 1.0
h then poured into satd. aq. NaHCO.sub.3. The aqueous mixture was
extracted three times with chloroform and the combined extracts
were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
residue was subjected to column chromatography (silica gel, 10%
methanol in dichloromethane). The partially purified
4-(3-methanesulfonyloxy-propyl)-piperidine-1-carboxylic acid
tert-butyl ester (500 mg, 1.56 mmol, 1.0 equiv) was stirred with
4-hydroxy-2-methyl-benzaldehyde (212 mg, 1.56 mmol, 1.0 equiv) and
cesium carbonate (1.01 g, 3.12 mmol, 2.0 equiv) in acetonitrile at
rt for 4 d. The mixture was filtered through diatomaceous earth and
the filtrate was concentrated. The crude material was partially
purified by column chromatography (silica gel, 25% ethyl acetate in
hexanes).
4-[3-(4-Formyl-3-methyl-phenoxy)-propyl]-piperidine-1-carboxylic
acid tert-butyl ester (146 mg, 0.41 mmol, 1.0 equiv),
5-chloro-3-methyl-benzene-1,2-diamine (63 mg, 0.41 mmol, 1.0
equiv), and Na.sub.2S.sub.2O.sub.5 (100 mg, 0.53 mmol, 1.3 equiv)
were stirred at 90.degree. C. in DMF for 2.5 h. The mixture was
cooled to rt and water (75 mL) was added causing a light brown
precipitate to form. The solid
4-{3-[4-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propy-
l}-piperidine-1-carboxylic acid tert-butyl ester was collected by
filtration, dissolved in a solution of dichloromethane (2.0 mL) and
trifluoroacetic acid (1.0 mL), and stirred at rt for 1.5 h. The
reaction mixture was loaded directly on silica gel and purified
according to Method 2, which afforded 52.1 mg of the title
compound. MS (electrospray): mass calculated for
C.sub.23H.sub.28ClN.sub.3O, 397.19; m/z found, 398.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.55 (d, J=8.4 Hz, 1H), 7.42 (br
s, 1H), 7.10-7.07 (m, 1H), 6.96-6.95 (m, 1H), 6.91 (dd, J=8.5, 2.4
Hz, 1H), 4.09 (t, J=6.2 Hz, 2H), 3.45-3.39 (m, 2H), 3.06-2.96 (m,
2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.07-1.99 (m, 2H), 1.93-1.84 (m,
2H), 1.76-1.64 (m, 1H), 1.59-1.50 (m, 2H), 1.48-1.36 (m, 2H).
Example 89
##STR00097##
[0510]
5-Fluoro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]--
1H-benzoimidazole
[0511] The title compound was prepared as described in Example 88.
MS (electrospray): mass calculated for C.sub.23H.sub.28FN.sub.3O,
381.22; m/z found, 382.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.56 (d, J=8.5 Hz, 1H), 7.44-7.38 (m, 1H), 7.09-7.02
(m, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.91 (dd, J=8.4, 2.5 Hz, 1H), 4.09
(t, J=6.2 Hz, 2H), 3.44-3.36 (m, 2H), 3.06-2.95 (m, 2H), 2.52 (d,
J=1.6 Hz, 3H), 2.50 (s, 3H), 2.08-1.98 (m, 2H), 1.94-1.83 (m, 2H),
1.77-1.65 (m, 1H), 1.59-1.50 (m, 2H), 1.48-1.35 (m, 2H).
Example 90
##STR00098##
[0512]
6-Chloro-2-{4-[3-(1-ethyl-piperidin-4-yl)-propoxy]-2-methyl-phenyl}-
-4-methyl-1H-benzoimidazole
[0513] The title compound was prepared as described in Example 85,
substituting acetaldehyde for aq. formaldehyde. MS (electrospray):
mass calculated for C.sub.25H.sub.32ClN.sub.3O, 425.22; m/z found,
426.4 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.53 (d,
J=8.5 Hz, 1H), 7.41 (br s, 1H), 7.09-7.04 (m, 1H), 6.93 (d, J=2.2
Hz, 1H), 6.89 (dd, J=8.4, 2.4 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H),
3.05-2.94 (m, 2H), 2.59 (s, 3H), 2.49 (s, 3H), 2.45 (q, J=7.2 Hz,
2H), 2.05-1.94 (m, 2H), 1.89-1.74 (m, 4H), 1.50-1.21 (m, 5H), 1.13
(t, J=7.2 Hz, 3H).
Example 91
##STR00099##
[0514]
{2-[3-Chloro-4-(4-methyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-met-
hyl-(1-methyl-piperidin-4-yl)-amine
[0515] A. 4-(2-Bromo-ethoxy)-2-chloro-benzaldehyde.
1,2-Dibromoethane (5.5 mL, 64.0 mmol, 5.0 equiv) was added to a
mixture of 2-chloro-4-hydroxy-benzaldehyde (2.0 g, 12.8 mmol, 1.0
equiv) and K.sub.2CO.sub.3 (4.0 g, 29.0 mmol, 2.25 equiv) in
acetonitrile (13 mL). The mixture was heated at reflux for 16 h,
cooled to rt, and filtered through diatomaceous earth. The filtrate
was concentrated to yield crude product, which was purified by
column chromatography (silica gel, 5% ethyl acetate in hexanes) to
afford 2.28 g (72%) of the title compound. .sup.1H NMR (400 MHz,
CD.sub.3OD): 10.3 (d, J=0.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.13
(d, J=2.4 Hz, 1H), 7.06 (ddd, J=8.8, 2.5, 0.7 Hz, 1H), 4.48-4.42
(m, 2H), 3.78-3.74 (m, 2H).
[0516] B.
2-Chloro-4-{(2-[methyl-(1-methyl-piperidin-4-yl)-amino]-ethoxy}--
benzaldehyde. To a solution of
4-(2-bromo-ethoxy)-2-chloro-benzaldehyde (1.24 g, 5.0 mmol, 1.0
equiv) and methyl-(1-methyl-piperidin-4-yl)-amine (1.28 g, 10.0
mmol, 2.0 equiv) in 1-butanol was added K.sub.2CO.sub.3 (2.10 g, 15
mmol, 3.0 equiv) and the solution was warmed to 90.degree. C. After
stirring for 16 h, the mixture was poured into water and extracted
two times with ethyl acetate. The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
purified by Method 2 to afford 467 mg (30%) of the title
compound.
[0517] .sup.1H NMR (400 MHz, CD.sub.3OD): 10.3 (s, 1H), 7.89 (d,
J=8.8 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz,
1H), 4.21 (t, J=5.5 Hz, 2H), 3.00-2.88 (m, 4H), 2.57-2.47 (m, 1H),
2.41 (s, 3H), 2.29 (s, 3H), 2.11-2.01 (m, 2H), 1.91-1.82 (m, 2H),
1.68-1.58 (m, 2H).
[0518] C.
{2-[3-Chloro-4-(4-methyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}--
methyl-(1-methyl-piperidin-4-yl)-amine. This compound was prepared
by the method described in General Procedure 3 using
2-chloro-4-{2-[methyl-(1-methyl-piperidin-4-yl)-amino]-ethoxy}-benzaldehy-
de (62.2 mg, 0.20 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine
(26 mg, 0.20 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (50 mg,
0.26 mmol, 1.3 equiv). Purification by Method 2 afforded 29 mg
(35%) of the title compound. MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.73 (d, J=8.6 Hz, 1H),
7.49-7.40 (m, 1H), 7.22-7.14 (m, 2H), 7.11-7.04 (m, 2H), 4.18 (t,
J=5.5 Hz, 2H), 3.00-2.92 (m, 4H), 2.62 (s, 3H), 2.56-2.48 (m, 1H),
2.41 (s, 3H), 2.28 (s, 3H), 2.11-1.99 (m, 2H), 1.92-1.81 (m, 2H),
1.70-1.55 (m, 2H).
Example 92
##STR00100##
[0519]
6-Chloro-4-methyl-2-{2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-eth-
oxy]-phenyl}-1H-benzoimidazole
[0520] A.
4-[2-(4-Formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidinium
toluene-4-sulfonate. To a solution of
1,4-dioxa-8-aza-spiro[4.5]decane (1.0 g, 7.0 mmol, 1.0 equiv) in
toluene (20 mL) at 0.degree. C. was added 1.0 M diisobutylaluminum
hydride in hexane (20 mL, 20 mmol, 2.9 equiv). The solution was
warmed to 80.degree. C. and stirred for 12 h. Methanol (20 mL),
satd. aq. sodium potassium tartrate (20 mL), and 10% 2-propanol in
chloroform (100 mL) were added and the mixture was stirred for 30
min. The chloroform layer was separated and the aqueous mixture was
extracted five times with 10% 2-propanol in chloroform (25 mL). The
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated to provide crude 2-(piperidin-4-yloxy)-ethanol as a
white solid. The solid was dissolved in dichloroethane (20 mL) and
37% aq. formaldehyde (0.60 mL, 6.9 mmol) was added. After stirring
for 30 min, sodium triacetoxyborohydride (2.04 g, 9.6 mmol) was
added and the mixture was stirred for 1.5 h. The reaction mixture
was diluted with satd. aq. NaHCO.sub.3 (20 mL) and extracted six
times with 10% 2-propanol in chloroform (80 mL). The combined
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated
to give 2-(1-methyl-piperidin-4-yloxy)-ethanol. The residue was
dissolved in dichloromethane, cooled to 0.degree. C., and pyridine
(463 .mu.L, 5.7 mmol) and p-toluenesulfonyl chloride (1.1 g, 5.7
mmol) were added. The solution was warmed to rt and stirred for 16
h. The reaction mixture was concentrated under reduced pressure and
the residue was partially purified by Method 2. The resulting
material, toluene-4-sulfonic acid
2-(1-methyl-piperidin-4-yloxy)-ethyl ester, was added to a mixture
of 4-hydroxy-2-methyl-benzaldehyde (275 mg, 2.0 mmol) and
K.sub.2CO.sub.3 (699 mg, 5.1 mmol) in DMF. The mixture was heated
to 100.degree. C. and stirred for 16 h. After cooling to rt, the
mixture was poured into water and extracted three times with ethyl
acetate. The combined extracts were dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The crude product was purified by
Method 2 to afford 409 mg of the title compound. .sup.1H NMR (400
MHz, CD.sub.3OD): 10.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.72 (d,
J=8.2 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.96 (dd, J=8.6, 2.4 Hz,
1H), 6.88 (d, J=2.1 Hz, 1H), 4.27-4.22 (m, 2H), 3.90-3.85 (m, 2H),
3.75-3.65 (m, 1H), 3.19-3.07 (m, 2H), 3.03-2.86 (m, 2H), 2.67 (s,
3H), 2.65 (s, 3H), 2.39 (s, 3H), 2.07-1.83 (m, 4H).
[0521] B.
6-Chloro-4-methyl-2-{2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)--
ethoxy]-phenyl}-1H-benzoimidazole. This compound was prepared by
the method described in General Procedure 3 using
4-[2-(4-formyl-3-methyl-phenoxy)-ethoxy]-1-methyl-piperidinium
toluene-4-sulfonate (47.5 mg, 0.11 mmol, 1.0 equiv),
5-chloro-3-methyl-benzene-1,2-diamine (27 mg, 0.17 mmol, 1.6
equiv), and Na.sub.2S.sub.2O.sub.5 (42 mg, 0.22 mmol, 2.1 equiv).
Purification by Method 2 afforded 20 mg (46%) of the title
compound. MS (electrospray): mass calculated for
C.sub.23H.sub.28ClN.sub.3O.sub.2, 413.19; m/z found, 414.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.55 (d, J=8.5 Hz,
1H), 7.42 (br s, 1H), 7.08-7.05 (m, 1H), 6.98 (d, J=2.3 Hz, 1H),
6.93 (dd, J=8.5, 2.5 Hz, 1H), 4.21-4.17 (m, 2H), 3.88-3.83 (m, 2H),
3.57-3.47 (m, 1H), 2.81-2.67 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H),
2.33-2.20 (m, 5H), 2.02-1.90 (m, 2H), 1.76-1.60 (m, 2H).
Example 93
##STR00101##
[0522]
6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyr-
idin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole
[0523] A. 3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propan-1-ol.
To a solution of 4-(3-hydroxy-propyl)-1-methyl-pyridinium iodide
(28 g, 100.4 mmol, 1.0 equiv) in ethanol (200 mL) at 0.degree. C.
was added sodium borohydride (5.7 g, 151 mmol, 1.5 equiv). The
reaction mixture, which was allowed to warm to rt, was stirred for
30 min and then poured into water. The aqueous solution was
extracted with ethyl acetate and the extract was dried
(Na.sub.2SO.sub.4), filtered, and concentrated to afford 15.2 g
(97%) of the title compound. .sup.1H NMR (400 MHz, CD.sub.3OD):
5.46-5.41 (m, 1H), 3.56 (t, J=6.6 Hz, 2H), 2.98-2.91 (m, 2H), 2.60
(t, J=5.9 Hz, 2H), 2.35 (s, 3H), 2.21-2.14 (m, 2H), 2.12-2.04 (m,
2H), 1.71-1.62 (m, 2H).
[0524] B.
2-Methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy-
]-benzaldehyde. To a solution of
3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propan-1-ol (2.24 g,
14.5 mmol, 1.0 equiv) and pyridine (1.64 mL, 20.2 mmol, 1.4 equiv)
in dichloromethane (50 mL) at 0.degree. C. was added
p-toluenesulfonyl chloride (3.85 g, 20.2 mmol, 1.4 equiv). The
reaction mixture, which was allowed to warm to rt, was stirred for
12 h and then poured into water. The aqueous mixture was extracted
with dichloromethane and the extract was dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was subjected to column
chromatography on silica gel (10% methanol in dichloromethane) and
the resulting oil was added to a mixture of
4-hydroxy-2-methyl-benzaldehyde (639 mg, 4.69 mmol) and
K.sub.2CO.sub.3 (1.62 g, 11.7 mmol) in DMF and warmed to
100.degree. C. After stirring for 16 h, the mixture was allowed to
cool to rt and filtered through a pad of diatomaceous earth. The
diatomaceous earth was rinsed with ethyl acetate, and the filtrate
was concentrated. The residue was purified by Method 2 to afford
356 mg (9%) of the title compound. .sup.1H NMR (400 MHz,
CD.sub.3OD): 10.1 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 6.92 (dd, J=8.6,
2.4 Hz, 1H), 6.84 (d, J=2.1 Hz, 1H), 5.49-5.43 (m, 1H), 4.09 (t,
J=6.3 Hz, 2H), 2.97-2.91 (m, 2H), 2.65-2.57 (m, 5H), 2.35 (s, 3H),
2.25-2.16 (m, 4H), 1.99-1.88 (m, 2H).
[0525] C.
6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro--
pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole. This compound was
prepared by the method described in General Procedure 3 using
2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-benzald-
ehyde (50 mg, 0.18 mmol, 1.0 equiv),
5-chloro-3-methyl-benzene-1,2-diamine (29 mg, 0.18 mmol, 1.0
equiv), and Na.sub.2S.sub.2O.sub.5 (45.2 mg, 0.24 mmol, 1.3 equiv).
Purification by Method 2 afforded 15.7 mg (21%) of the title
compound. MS (electrospray): mass calculated for
C.sub.24H.sub.28ClN.sub.3O, 409.19; m/z found, 410.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.53 (d, J=8.5 Hz, 1H), 7.41 (br
s, 1H), 7.08-7.04 (m, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.89 (dd, J=8.5,
2.5 Hz, 1H), 5.49-5.44 (m, 1H), 4.04 (t, J=6.3 Hz, 2H), 2.96-2.91
(m, 2H), 2.64-2.56 (m, 5H), 2.49 (s, 3H), 2.35 (s, 3H), 2.28-2.16
(m, 4H), 1.96-1.88 (m, 2H).
Example 94
##STR00102##
[0526]
5-Fluoro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyr-
idin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole
[0527] The title compound was prepared as described in Example 93.
MS (electrospray): mass calculated for C.sub.24H.sub.28FN.sub.3O,
393.22; m/z found, 394.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.54 (d, J=8.5 Hz, 1H), 7.39 (br s, 1H), 7.05-6.95 (m,
1H), 6.94 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.5, 2.5 Hz, 1H),
5.50-5.46 (m, 1H), 4.06 (t, J=6.3 Hz, 2H), 2.99-2.94 (m, 2H),
2.65-2.59 (m, 2H), 2.53-2.47 (m, 6H), 2.36 (s, 3H), 2.27-2.18 (m,
4H), 1.98-1.90 (m, 2H).
Example 95
##STR00103##
[0528]
6-Fluoro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-
-1H-benzoimidazole
[0529] A. 3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzonitrile.
4-(1-Methyl-piperidin-4-yl)-butan-1-ol (0.747 g, 4.37 mmol, 1.0
equiv), 3-hydroxy-benzonitrile (0.52 g, 4.37 mmol, 1.0 equiv), and
polymer-supported triphenylphosphine (2.3 g, 8.73 mmol, 2.0 equiv)
were suspended in THF (40 mL). The mixture was stirred under
N.sub.2 and cooled to 0.degree. C. Diisopropyl azodicarboxylate
(1.72 mL, 8.73 mmol, 2.0 equiv) was added dropwise via syringe.
After 6 h, the mixture was filtered and concentrated. The resulting
crude oil was purified by Method 2 to afford 0.84 g (71%) of the
title compound. MS (electrospray): mass calculated for
C.sub.17H.sub.24N.sub.2O, 272.19; m/z found, 273.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.38-7.33 (m, 1H), 7.24-7.20 (m,
1H), 7.14-7.09 (m, 2H), 3.96 (t, J=6.4 Hz, 2H), 2.88-2.80 (m, 2H),
2.26 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.73 (m, 2H), 1.72-1.64 (m,
2H), 1.52-1.42 (m, 2H), 1.34-1.17 (m, 5H).
[0530] B. 3-[4-(1-Methyl-piperidin-4-yl)-butoxy]-benzaldehyde. To a
stirred solution of
3-[4-(1-methyl-piperidin-4-yl)-butoxy]-benzonitrile (0.84 g, 3.09
mmol, 1.0 equiv) in toluene (5.0 mL) at 0.degree. C. was added 1.5
M diisobutylaluminum hydride in toluene (4.63 mL, 4.63 mmol, 1.5
equiv). After 3 h, methanol (9.0 mL) and 1.0 M H.sub.2SO.sub.4 (10
mL) were added dropwise. After stirring for 30 min, 1.0 M NaOH (10
mL) was added, followed by satd. aq. sodium potassium tartrate (40
mL) and dichloromethane (100 mL). The solution was extracted three
times with chloroform (50 mL) and the combined extracts were washed
with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The crude oil was purified by Method 2 to afford 0.56 g (66%) of
the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.97 (s,
1H), 7.46-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.19-7.15 (m, 1H), 4.02
(t, J=6.6 Hz, 2H), 2.86-2.80 (m, 2H), 2.25 (s, 3H), 1.92-1.83 (m,
2H), 1.83-1.75 (m, 2H), 1.73-1.63 (m, 2H), 1.54-1.44 (m, 2H),
1.34-1.18 (m, 5H).
[0531] C.
6-Fluoro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phen-
yl}-1H-benzoimidazole. This compound was prepared by the method
described in General Procedure 3 using
3-[4-(1-methyl-piperidin-4-yl)-butoxy]-benzaldehyde (20 mg, 0.07
mmol, 1.0 equiv), 4-fluoro-3-methyl-benzene-1,2-diamine (12 mg,
0.09 mmol, 1.0 equiv) and Na.sub.2S.sub.2O.sub.5 (18 mg, 0.10 mmol,
1.3 equiv). Purification by Method 2 afforded 28.7 mg (54%) of the
title compound. MS (electrospray): mass calculated for
C.sub.24H.sub.30FN.sub.3O, 395.24; m/z found, 396.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.72-7.62 (m, 2H), 7.47-7.32 (m,
2H), 7.08-6.94 (m, 2H), 4.07 (t, J=6.3 Hz, 2H), 2.90-2.80 (m, 2H),
2.53 (s, 3H), 2.24 (s, 3H), 2.04-1.92 (m, 2H), 1.85-1.66 (m, 4H),
1.59-1.47 (m, 2H), 1.39-1.17 (m, 5H).
[0532] The following compounds in Examples 96-101 were prepared
according to the procedures described in Example 95.
Example 96
##STR00104##
[0533]
7-Methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzo-
imidazole
[0534] MS (electrospray): mass calculated for
C.sub.24H.sub.31N.sub.3O, 377.25; m/z found, 378.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.86-7.71 (m, 2H), 7.44 (br s,
1H), 7.29-7.22 (m, 1H), 7.26-7.09 (m, 1H), 7.02 (d, J=7.3 Hz, 1H),
6.89 (dd, J=8.2, 1.8 Hz, 1H), 3.59 (t, J=6.4 Hz, 2H), 2.82 (m, 2H),
2.52 (br s, 3H), 2.25 (s, 3H), 1.89 (m, 2H), 1.63-1.47 (m, 4H),
1.28-1.07 (m, 7H).
Example 97
##STR00105##
[0535]
6,7-Dimethyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-b-
enzoimidazole
[0536] MS (electrospray): mass calculated for
C.sub.25H.sub.33N.sub.3O, 391.56; m/z found, 392.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.73-7.61 (m, 2H), 7.46-7.36 (m,
1H), 7.36-7.25 (m, 1H), 7.09-6.98 (m, 2H), 4.08 (t, J=6.3 Hz, 2H),
2.93-2.82 (m, 2H), 2.53 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H),
2.08-1.97 (m, 2H), 1.86-1.68 (m, 4H), 1.60-1.47 (m, 2H), 1.39-1.17
(m, 5H).
Example 98
##STR00106##
[0537]
5-Chloro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-
-1H-benzoimidazole
[0538] MS (electrospray): mass calculated for
C.sub.24H.sub.30ClN.sub.3O, 411.21; m/z found, 412.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.73-7.62 (m, 2H), 7.47-7.38 (m,
2H), 7.09-7.02 (m, 2H), 4.09 (t, J=6.3 Hz, 2H), 2.91-2.81 (m, 2H),
2.68 (s, 3H), 2.24 (s, 3H), 2.05-1.93 (m, 2H), 1.87-1.67 (m, 4H),
1.60-1.48 (m, 2H), 1.39-1.18 (m, 5H).
Example 99
##STR00107##
[0539]
5,7-Dimethyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phe-
nyl}-1H-benzoimidazole
[0540] MS (electrospray): mass calculated for
C.sub.26H.sub.35N.sub.3O, 405.28; m/z found, 406.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.30-7.23 (m, 1H), 7.19 (s, 1H),
7.16-7.11 (m, 1H), 7.07-7.01 (m, 1H), 6.89 (s, 1H), 4.04 (t, J=6.4
Hz, 2H), 2.89-2.80 (m, 2H), 2.54 (s, 3H), 2.43 (s, 3H), 2.29 (s,
3H), 2.23 (s, 3H), 2.04-1.91 (m, 2H), 1.88-1.77 (m, 2H), 1.77-1.68
(m, 2H), 1.61-1.49 (m, 2H), 1.40-1.17 (m, 5H).
Example 100
##STR00108##
[0541]
5-Chloro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy-
]-phenyl}-1H-benzoimidazole
[0542] MS (electrospray): mass calculated for
C.sub.25H.sub.32ClN.sub.3O, 425.22; m/z found, 426.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.40 (s, 1H), 7.33-7.24 (m, 1H),
7.17-7.10 (m, 1H), 7.10-7.02 (m, 2H), 4.04 (t, J=5.6 Hz, 2H),
2.91-2.80 (m, 2H), 2.56 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H),
2.04-1.92 (m, 2H), 1.89-1.65 (m, 4H), 1.63-1.48 (m, 2H), 1.41-1.16
(m, 5H).
Example 101
##STR00109##
[0543]
6-Fluoro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy-
]-phenyl}-1H-benzoimidazole
[0544] MS (electrospray): mass calculated for
C.sub.25H.sub.32FN.sub.3O, 409.25; m/z found, 410.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.43-7.33 (s, 1H), 7.30 (t,
J=7.8 Hz, 1H), 7.16-7.10 (s, 1H), 7.10-6.96 (m, 2H), 4.05 (t, J=5.4
Hz, 2H), 2.91-2.81 (m, 2H), 2.49 (s, 3H), 2.29 (s, 3H), 2.25 (s,
3H), 2.07-1.94 (m, 2H), 1.89-1.67 (m, 4H), 1.63-1.49 (m, 2H),
1.41-1.16 (m, 5H).
Example 102
##STR00110##
[0545]
6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phe-
nyl}-1H-benzoimidazole
[0546] A. 3-[3-(1-Methyl-piperidin-4-yloxy)-propoxy]-benzonitrile.
To a mixture of 3-(1-methyl-piperidin-4-yloxy)-propan-1-ol (295 mg,
1.7 mmol, 1.0 equiv) and polymer-supported triphenylphosphine (1.14
g, 3.41 mmol, 2.0 equiv) in THF (40 mL) at 0.degree. C. was added
diisopropyl azodicarboxylate (0.67 mL, 3.41 mmol, 2.0 equiv)
dropwise via syringe. After 6 h, the mixture was filtered through a
glass frit and the filtrate was concentrated. The crude oil was
purified by Method 2 to afford 187 mg (40%) of the title compound.
MS (electrospray): mass calculated for
C.sub.16H.sub.22N.sub.2O.sub.2, 274.17; m/z found, 275.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.40-7.33 (m, 1H),
7.25-7.21 (m, 1H), 7.17-7.10 (m, 2H), 4.09 (t, J=6.2 Hz, 2H), 3.61
(t, J=6.2 Hz, 2H), 3.34-3.25 (m, 1H), 2.73-2.61 (m, 2H), 2.26 (s,
3H), 2.17-2.00 (m, 4H), 1.94-1.84 (m, 2H), 1.68-1.55 (m, 2H).
[0547] B.
6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]--
phenyl}-1H-benzoimidazole. To a stirred solution of
3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzonitrile (0187 g,
0.68 mmol, 1.0 equiv) in toluene (5.0 mL) at 0.degree. C. was added
1.5 M diisobutylaluminum hydride in toluene (1.02 mL, 1.02 mmol,
1.5 equiv). After 3 h, methanol (9 mL) and 1 M H.sub.2SO.sub.4 (10
mL) were added. The mixture was stirred for 30 min, then 1.0 M NaOH
(10 mL) was added, followed by satd. aq. sodium potassium tartrate
(40 mL) and dichloromethane (100 mL). After stirring for 30 min,
the mixture was extracted three times with chloroform (50 mL) and
the combined extracts were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
partially purified by Method 2 to afford 106 mg of a mixture of
3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde and several
other unidentified products. A solution of the crude
3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde (53 mg),
4-fluoro-3-methyl-benzene-1,2-diamine (27 mg), and
Na.sub.2S.sub.2O.sub.5 in DMF was stirred at 90.degree. C. for 18
h. The reaction mixture was loaded directly on silica gel and
purified according to Method 2, which afforded 28.7 mg of the title
compound.
[0548] MS (electrospray): mass calculated for
C.sub.23H.sub.28FN.sub.3O.sub.2, 397.22; m/z found, 398.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.64-7.53 (m, 2H),
7.38-7.25 (m, 2H), 7.00-6.85 (m, 2H), 4.06 (t, J=6.1 Hz, 2H),
3.60-3.52 (m, 2H), 3.33-3.19 (br s, 1H), 2.58 (br s, 2H), 2.42 (s,
3H), 2.17-2.03 (m, 5H), 2.01-1.90 (m, 2H), 1.86-1.72 (m, 2H),
1.60-1.42 (m, 2H).
Example 103
##STR00111##
[0549]
6-Chloro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridi-
n-3-yl}-1H-benzoimidazole
[0550] A. 6-[3-(4-Methyl-piperazin-1-yl)-propoxy]-nicotinonitrile.
To a stirred solution of 3-(4-methyl-piperazin-1-yl)-propan-1-ol
(1.0 g, 6.32 mmol, 1.0 equiv) in DMF (60 mL) under an atmosphere of
nitrogen, was added 60% sodium hydride (379 mg, 9.48 mmol, 1.5
equiv) portion wise. Once the initial effervescence had subsided,
the mixture was heated at 60.degree. C. for 1 h then cooled to rt.
A solution of 6-chloronicotinonitrile (876 mg, 6.32 mmol, 1.0
equiv) in DMF (5 mL) was then added and the mixture stirred for 16
h. The reaction mixture was partitioned between satd. aq.
NaHCO.sub.3 (30 mL) and chloroform (60 mL). The organic layer was
dried (Na.sub.2SO.sub.4), filtered, and concentrated to give a
crude mixture, which was purified by column chromatography (silica
gel, 0-10% (2.0 M ammonia in methanol) in dichloromethane) to
afford 776 mg (47%) of a beige solid. MS (electrospray): mass
calculated for C.sub.14H.sub.20N.sub.4O, 260.16; m/z found, 261.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.47 (dd, J=2.3,
0.8 Hz, 1H), 7.77 (dd, J=8.6, 2.3 Hz, 1H), 6.80 (dd, J=8.6, 0.8 Hz,
1H), 4.41 (t, J=6.6 Hz, 2H), 2.76-2.35 (m, 10H), 2.29 (s, 3H),
2.01-1.95 (m, 2H).
[0551] B.
6-[3-(4-Methyl-piperazin-1-yl)-propoxy]-pyridine-3-carbaldehyde. To
a cooled (0.degree. C.) solution of
6-[3-(4-methyl-piperazin-1-yl)-propoxy]-nicotinonitrile (486 mg,
1.86 mmol, 1.0 equiv) in toluene (20 mL), under an atmosphere of
nitrogen, was added 1 M diisobutylaluminum hydride in hexanes (2.79
mL, 2.79 mmol, 1.5 equiv) dropwise. The mixture was warmed to rt
and stirred for 2 h. Methanol was added (5 mL), followed by 1 M
H.sub.2SO.sub.4 (10 mL). After stirring for 30 min, the solution
was neutralized with satd. aq. NaHCO.sub.3, diluted with satd. aq.
sodium potassium tartrate (10 mL), and stirred an additional 30 min
or until clear. The mixture was extracted with chloroform
(3.times.50 mL) and the combined extracts were dried
(Na.sub.2SO.sub.4), and concentrated, yielding the crude product,
which was purified by column chromatography (silica gel, 0-10% (2 M
ammonia in methanol) in dichloromethane) to afford 225 mg (46%) of
a colorless residue. MS (electrospray): mass calculated for
C.sub.14H.sub.21N.sub.3O.sub.2, 263.16; m/z found, 264.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .sup.1H NMR (400
MHz, CDCl.sub.3): 9.94 (1H, s), 8.61 (d, J=2.3 Hz, 1H), 8.06 (dd,
J=8.6, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 4.46 (t, J=6.6 Hz, 2H),
2.64-2.33 (m, 10H), 2.29 (s, 3H), 2.03-1.96 (m, 2H).
[0552] C.
6-Chloro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyr-
idin-3-yl}-1H-benzoimidazole. This compound was prepared by the
method described in General Procedure 3 using
6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridine-3-carbaldehyde (49
mg, 0.17 mmol, 1.0 equiv), 5-chloro-3-methyl-benzene-1,2-diamine
(27 mg, 0.17 mmol, 1.0 equiv), and Na.sub.2S.sub.2O.sub.5 (42 mg,
0.22 mmol, 1.3 equiv). Purification by Method 2 afforded 54 mg
(79%) of the title compound.
[0553] MS (electrospray): mass calculated for
C.sub.21H.sub.26ClN.sub.5O, 399.18; m/z found, 400.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.75 (s, 1H), 8.25 (dd, J=8.2,
2.4 Hz, 1H), 7.49-7.32 (m, 1H), 6.91 (s, 1H), 6.71 (d, J=8.7 Hz,
1H), 4.28 (t, J=6.7 Hz, 2H), 2.67-2.31 (m, 13H), 2.26 (s, 3H),
1.98-1.87 (m, 2H).
[0554] The following compounds in Examples 104-105 were prepared
according to the procedures described in Example 103.
Example 104
##STR00112##
[0555]
4-Methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1-
H-benzoimidazole
[0556] MS (electrospray): mass calculated for
C.sub.21H.sub.27N.sub.5O, 365.47; m/z found, 366.2 [M+H].sup.+.
Example 105
##STR00113##
[0557]
5-Fluoro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridi-
n-3-yl}-1H-benzoimidazole
[0558] MS (electrospray): mass calculated for
C.sub.21H.sub.26FN.sub.5O, 383.46; m/z found, 384.2
[M+H].sup.+.
Example 106
##STR00114##
[0559]
4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1-
H-benzoimidazole
[0560] A. 6-[3-(1-Methyl-Piperidin-4-yl)-propoxy]-nicotinonitrile.
To a stirred solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol
(5.0 g, 31.7 mmol, 1.1 equiv) in DMF (200 mL) under an atmosphere
of nitrogen, was added 60% sodium hydride (1.73 g, 43.3 mmol, 1.5
equiv) portion wise. Once the initial effervescence had subsided,
the mixture was heated at 60.degree. C. for 1 h then cooled to rt.
A solution of 6-chloronicotinonitrile (4.0 g, 28.9 mmol, 1.0 equiv)
in DMF (20 mL) was then added and the mixture stirred for 16 h. The
reaction was quenched with satd. aq. NaHCO.sub.3 (50 mL) and brine
(50 mL). A precipitate was formed and was collected by vacuum
filtration to afford 3.67 g of the desired product. The filtrate
was concentrated to half the volume and a second crop of
precipitate was collected and combined to give 5.64 g (76%) of an
orange solid, which was used without further purification. MS
(electrospray): mass calculated for C.sub.15H.sub.21N.sub.3O,
259.17; m/z found, 260.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.46 (dd, J=2.3, 0.8 Hz, 1H), 7.77 (dd, J=8.6, 2.3 Hz,
1H), 6.80 (dd, J=8.6, 0.8 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H),
2.96-2.82 (m, 2H), 2.25 (s, 3H), 1.92-1.68 (m, 7H), 1.37-1.34 (m,
2H), 0.89-0.81 (m, 2H).
[0561] B.
6-[3-(1-Methyl-Piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde. To
a cooled (0.degree. C.) solution of
6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (640 mg,
2.47 mmol, 1.0 equiv) in toluene (20 mL), under an atmosphere of
nitrogen, was added 1 M diisobutylaluminum hydride in hexanes (3.70
mL, 3.70 mmol, 1.5 equiv) dropwise. The mixture was warmed to rt
and stirred for 2 h. Methanol was added (5 mL), followed by 1 M
H.sub.2SO.sub.4 (10 mL). After stirring for 30 min the solution was
neutralized with satd. aq. NaHCO.sub.3, diluted with satd. aq.
sodium potassium tartrate (10 mL), and stirred an additional 30 min
or until clear. The mixture was extracted with chloroform
(3.times.50 mL) and the combined extracts were dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude product
was purified by column chromatography (silica gel, 0-10% (2 M
ammonia in methanol) in dichloromethane) to afford 598 mg (92%) of
a colorless oil. MS (electrospray): mass calculated for
C.sub.15H.sub.22N.sub.2O.sub.2, 262.17; m/z found, 263.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): .sup.1H NMR (400
MHz, CDCl.sub.3): 9.87 (br s, 1H), 8.53 (d, J=2.3 Hz, 1H), 7.98
(dd, J=8.6, 2.3 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 4.34 (t, J=6.6 Hz,
2H), 2.78-2.26 (m, 2H), 2.19 (s, 3H), 1.85-1.62 (m, 7H), 1.35-1.16
(m, 4H).
[0562] C.
4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl-
}-1H-benzoimidazole. This compound was prepared by the method
described in General Procedure 3 using
6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde
(100 mg, 0.38 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (46
mg, 0.38 mmol, 1.0 equiv) and Na.sub.2S.sub.2O.sub.5 (94 mg, 0.50
mmol, 1.3 equiv). Purification by Method 2 afforded 35 mg (25%) of
the title compound. MS (electrospray): mass calculated for
C.sub.22H.sub.28N.sub.4O, 364.23; m/z found, 365.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.77 (s, 1H), 8.23 (dd, J=8.7,
2.3 Hz, 1H), 7.25 (m, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.04-6.98 (m,
1H), 6.74 (d, J=8.7 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.84-2.76 (m,
2H), 2.73-2.34 (br s, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H),
1.81-1.62 (m, 4H), 1.39-1.17 (m, 5H).
[0563] The following compounds in Examples 107-108 were prepared
according to the procedures described in Example 106.
Example 107
##STR00115##
[0564]
4,5-Dimethyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-y-
l}-1H-benzoimidazole
[0565] MS (electrospray): mass calculated for
C.sub.23H.sub.30N.sub.4O, 378.24; m/z found, 379.4 [M+H].sup.+.
Example 108
##STR00116##
[0566]
4-Chloro-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1-
H-benzoimidazole
[0567] MS (electrospray): mass calculated for
C.sub.21H.sub.25ClN.sub.4O, 384.17; m/z found, 385.3
[M+H].sup.+.
Example 109
##STR00117##
[0568]
6-Chloro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propox-
y]-pyridin-3-yl}-1H-benzoimidazole
[0569] A.
4-Methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile- .
To a stirred solution of 2,2,6,6-tetramethyl-piperidine (0.20 mL,
1.16 mmol, 1.5 equiv) in THF (3 mL) at -78.degree. C. was added 2.5
M n-butyllithium in hexanes (0.46 mL, 1.16 mmol, 1.5 equiv). After
10 min, the reaction mixture was warmed to 0.degree. C. for 45 min
before re-cooling to -78.degree. C. A solution of
6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (200 mg,
0.77 mmol, 1.0 equiv) in THF (3 mL) was then added. After stirring
for 1 h at -78.degree. C., the mixture was treated with methyl
iodide (0.05 mL, 0.84 mmol, 1.1 equiv) and stirring was continued
for 1.5 h before quenching at -78.degree. C. with satd. aq.
NaHCO.sub.3 (5 mL). The mixture was warmed to rt and extracted with
chloroform (2.times.10 mL). The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a crude
residue, which was purified by Method 2 to give 120 mg (57%) of the
title compound. MS (electrospray): mass calculated for
C.sub.16H.sub.23N.sub.3O, 273.18; m/z found, 274.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.39 (s, 1H), 6.67 (s, 1H), 4.31
(t, J=6.7 Hz, 2H), 2.90-2.79 (m, 2H), 2.48 (s, 3H), 2.28 (s, 3H),
1.95-1.63 (m, 6H), 1.40-1.20 (m, 5H).
[0570] B.
4-Methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-Carb-
aldehyde. To a solution of
4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile
(260 mg, 0.95 mmol, 1.0 equiv) in toluene (10 mL) at 0.degree. C.
was added 1.5 M diisobutylaluminum hydride in toluene (1.26 mL,
1.90 mmol, 2.0 equiv). The mixture was warmed to rt and stirred for
2 h. Methanol (2 mL) was added, followed by 1.0 M H.sub.2SO.sub.4
(3 mL). After stirring for 30 min, the solution was neutralized
with satd. aq. NaHCO.sub.3, diluted with satd. aq. sodium potassium
tartrate (10 mL), and stirred an additional 30 min or until clear.
The mixture was extracted with chloroform (3.times.15 mL) and the
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated to afford 200 mg of the crude product, which was used
without purification. .sup.1H NMR (400 MHz, CDCl.sub.3): 10.0 (s,
1H), 8.47 (s, 1H), 6.57 (s, 1H), 4.35 (t, J=6.7 Hz, 2H), 2.86-2.80
(m, 2H), 2.59 (s, 3H), 2.25 (s, 3H), 1.92-1.66 (m, 6H), 1.43-1.22
(m, 5H).
[0571] C.
4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl-
}-1H-benzoimidazole. This compound was prepared by the method
described in General Procedure 3 using
4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-3-carbaldehyde
(60 mg, 0.22 mmol, 1.0 equiv),
5-chloro-3-methyl-benzene-1,2-diamine (34 mg, 0.22 mmol, 1.0 equiv)
and Na.sub.2S.sub.2O.sub.5 (54 mg, 0.29 mmol, 1.3 equiv).
Purification by Method 2 afforded 27 mg (30%) of the title
compound. MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.77 (s, 1H), 8.23 (dd, J=8.7,
2.3 Hz, 1H), 7.25 (m, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.04-6.98 (m,
1H), 6.74 (d, J=8.7 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 2.84-2.76 (m,
2H), 2.73-2.34 (br s, 3H), 2.23 (s, 3H), 1.92-1.83 (m, 2H),
1.81-1.62 (m, 4H), 1.39-1.17 (m, 4H).
[0572] The following compounds in Examples 110-114 were prepared
according to the procedures described in Example 109.
Example 110
##STR00118##
[0573]
4-Methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridi-
n-3-yl}-1H-benzoimidazole
[0574] MS (electrospray): mass calculated for
C.sub.23H.sub.30N.sub.4O, 378.24; m/z found, 379.5 [M+H].sup.+.
Example 111
##STR00119##
[0575]
5-Fluoro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propox-
y]-pyridin-3-yl}-1H-benzoimidazole
[0576] MS (electrospray): mass calculated for
C.sub.23H.sub.29FN.sub.4O, 396.23; m/z found, 397.4
[M+H].sup.+.
Example 112
##STR00120##
[0577]
4,5-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-py-
ridin-3-yl}-1H-benzoimidazole
[0578] MS (electrospray): mass calculated for
C.sub.24H.sub.32N.sub.4O, 392.26; m/z found, 393.5 [M+H].sup.+.
Example 113
##STR00121##
[0579]
4,6-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-py-
ridin-3-yl}-1H-benzoimidazole
[0580] MS (electrospray): mass calculated for
C.sub.24H.sub.32N.sub.4O, 392.26; m/z found, 393.5 [M+H].sup.+.
Example 114
##STR00122##
[0581]
4-Chloro-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridi-
n-3-yl}-1H-benzoimidazole
[0582] MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O, 398.19; m/z found, 399.3
[M+H].sup.+.
Example 115
##STR00123##
[0583]
2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-5-
-fluoro-4-methyl-1H-benzoimidazole
[0584] A.
4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile- .
To a stirred solution of 2,2,6,6-tetramethyl-piperidine (0.31 mL,
2.32 mmol, 1.2 equiv) in THF (10 mL) at -78.degree. C. was added
1.6 M n-butyllithium in hexanes (1.45 mL, 2.32 mmol, 1.2 equiv).
After 10 min the reaction mixture was warmed to 0.degree. C. for 45
min before re-cooling to -78.degree. C. A solution of
6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (500 mg,
1.93 mmol, 1.0 equiv) in THF (10 mL) was then added. After stirring
for 1 h at -78.degree. C., the mixture was treated with
hexachloroethane (0.05 mL, 0.84 mmol, 1.1 equiv) in THF (2 mL) and
allowed to warm to 0.degree. C. Stirring was continued for 1.5 h
before quenching at 0.degree. C. with sodium hydrogen carbonate (10
mL). The mixture was warmed to rt and extracted with chloroform
(2.times.20 mL). The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a crude
residue, which was purified by Method 2 to give 380 mg (67%) of the
title compound. MS (electrospray): mass calculated for
C.sub.15H.sub.20ClN.sub.3O, 293.13; m/z found, 294.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.43 (s, 1H), 6.87 (s, 1H), 4.35
(t, J=6.7 Hz, 2H), 2.97-2.88 (m, 2H), 2.33 (s, 3H), 2.05-1.94 (m,
2H), 1.83-1.67 (m, 5H), 1.43-1.23 (m, 4H).
[0585] B.
2-[4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl-
]-5-fluoro-4-methyl-1H-benzoimidazole. To a solution of
4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile
(380 mg, 1.30 mmol, 1.0 equiv) in toluene (10 mL) at 0.degree. C.
was added 1.5 M diisobutylaluminum hydride in toluene (1.72 mL,
2.60 mmol, 2.0 equiv). The mixture was warmed to rt and stirred for
2 h. Methanol was added (5 mL), followed by 1.0 M H.sub.2SO.sub.4
(5 mL). After stirring for 30 min, the solution was neutralized
with satd. aq. NaHCO.sub.3, diluted with satd. aq. sodium potassium
tartrate (10 mL), and stirred an additional 30 min or until clear.
The mixture was extracted with chloroform (3.times.15 mL) and the
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated to afford 132 mg of the crude product which was used
without purification. This crude mixture (33 mg, 0.11 mmol, 1.0
equiv) was used as described in General Procedure 3 with
4-fluoro-3-methyl-benzene-1,2-diamine (16 mg, 0.11 mmol, 1.0 equiv)
and Na.sub.2S.sub.2O.sub.5 (27 mg, 0.14 mmol, 1.3 equiv).
Purification by Method 2 afforded 12 mg (26%) of an oily residue.
MS (electrospray): mass calculated for C.sub.22H.sub.26ClFN.sub.4O,
416.18; m/z found, 417.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 8.48 (s, 1H), 7.41 (dd, J=8.7, 4.3 Hz, 1H), 7.46-6.99
(m, 2H), 4.36 (t, J=6.6 Hz, 2H), 2.91-2.82 (m, 2H), 2.50 (s, 3H),
2.25 (s, 3H), 2.06-1.95 (m, 2H), 1.88-1.69 (m, 4H), 1.47-1.18 (m,
5H).
[0586] The following compounds in Examples 116-118 were prepared
according to the procedures described in Example 115.
Example 116
##STR00124##
[0587]
2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-
-methyl-1H-benzoimidazole
[0588] MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O, 398.19; m/z found, 399.3.
[M+H].sup.+.
Example 117
##STR00125##
[0589]
6-Chloro-2-{4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridi-
n-3-yl}-4-methyl-1H-benzoimidazole
[0590] MS (electrospray): mass calculated for
C.sub.22H.sub.26Cl.sub.2N.sub.4O, 432.15; m/z found, 433.3
[M+H].sup.+.
Example 118
##STR00126##
[0591]
2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-
,6-dimethyl-1H-benzoimidazole
[0592] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found, 413.4
[M+H].sup.+.
Example 119
##STR00127##
[0593]
2-{4-Methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}--
4-methyl-1H-benzoimidazole
[0594] A solution of
4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile
(Example 115) in methanol (0.2 M) was treated with sodium methoxide
(4 equiv) at reflux temperature for 4 h. The mixture was cooled to
rt, diluted with satd. aq. NaHCO.sub.3, and extracted with
chloroform. The organic extract was dried (Na.sub.2SO.sub.4),
filtered, and concentrated to yield
4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile
(100%). This intermediate was converted to the title compound
according to Example 115. MS (electrospray): mass calculated for
C.sub.23H.sub.30ClN.sub.4O.sub.2, 394.24; m/z found, 395.4
[M+H].sup.+.
Example 120
##STR00128##
[0595]
5-Fluoro-2-{4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyrid-
in-3-yl}-4-methyl-1H-benzoimidazole
[0596] The title compound was prepared according to the procedures
described in Example 119. MS (electrospray): mass calculated for
C.sub.23H.sub.29FN.sub.4O.sub.2, 412.23; m/z found, 413.4
[M+H].sup.+.
Example 121
##STR00129##
[0597]
5-Fluoro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl-
)-propoxy]-pyridin-3-yl}-1H-benzoimidazole
[0598] A.
6-[3-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-nicotin-
onitrile. To a stirred solution of
3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propan-1-ol (1.23 g,
7.94 mmol, 1.1 equiv) in DMF (50 mL), under an atmosphere of
nitrogen, was added 60% sodium hydride (433 mg, 10.8 mmol, 1.5
equiv) portion wise. Once the initial effervescence had subsided,
the mixture was heated at 60.degree. C. for 1 h then cooled to rt.
A solution of 6-chloronicotinonitrile (1.0 g, 7.21 mmol, 1.0 equiv)
in DMF (5 mL) was then added and the mixture was stirred for 16 h.
The reaction was quenched with satd. aq. NaHCO.sub.3 (10 mL) and
brine (10 mL). The mixture was extracted with chloroform
(2.times.50 mL). The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a crude
residue, which was purified by Method 2 affording 1.43 g (77%) of
the title compound. MS (electrospray): mass calculated for
C.sub.15H.sub.19N.sub.3O, 257.15; m/z found, 258.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.46 (dd, J=2.4, 0.6 Hz, 1H),
7.76 (dd, J=8.7, 2.4 Hz, 1H), 6.80 (dd, J=8.7, 0.6 Hz, 1H),
5.44-5.39 (m, 1H), 4.35 (t, J=6.6 Hz, 2H), 2.92-2.87 (m, 2H), 2.51
(t, J=5.8 Hz, 2H), 2.34 (s, 3H), 2.18-2.08 (m, 4H), 1.96-1.83 (m,
2H).
[0599] B.
6-[3-(1-Methyl-1,2,3,6-tetrahydro-Pyridin-4-yl)-propoxy]-pyridin-
e-3-carbaldehyde. To a cooled (0.degree. C.) solution of
6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-nicotinonitrile
(1.42 mg, 5.56 mmol, 1.0 equiv) in toluene (40 mL), under an
atmosphere of nitrogen, was added 1.0 M diisobutylaluminum hydride
in hexanes (8.34 mL, 8.34 mmol, 1.5 equiv). dropwise. The mixture
was warmed to rt and stirred for 2 h. Methanol was added (5 mL),
followed by 1.0 M H.sub.2SO.sub.4 (10 mL). After stirring for 30
min, the solution was neutralized with satd. aq. NaHCO.sub.3,
diluted with satd. aq. sodium potassium tartrate (25 mL), and
stirred an additional 30 min or until clear. The mixture was
extracted with chloroform (3.times.50 mL) and the combined extracts
were dried (Na.sub.2SO.sub.4), filtered, and concentrated to afford
1.29 g of the product which was used without purification. .sup.1H
NMR (400 MHz, CDCl.sub.3): 9.93 (s, 1H), 8.60 (d, J=2.3 Hz, 1H),
8.05 (dd, J=8.7, 2.3 Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 5.45-5.39 (m,
1H), 4.40 (t, J=6.6 Hz, 2H), 2.92-2.86 (m, 2H), 2.54-2.48 (m, 2H),
2.30 (s, 3H), 2.18-2.09 (m, 4H), 2.98-1.84 (m, 2H).
[0600] C.
5-Fluoro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-
-yl)-Propoxy]-pyridin-3-yl}-1H-benzoimidazole. This compound was
prepared by the method described in General Procedure 3 using
6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridine-3-carba-
ldehyde (100 mg, 0.39 mmol, 1.0 equiv),
4-fluoro-3-methyl-benzene-1,2-diamine (66 mg, 0.39 mmol, 1.0 equiv)
and Na.sub.2S.sub.2O.sub.5 (96 mg, 0.51 mmol, 1.3 equiv).
Purification by Method 2 afforded 24 mg (16%) of the title
compound. MS (electrospray): mass calculated for
C.sub.22H.sub.25FN.sub.4O, 380.20; m/z found, 381.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 11.8-10.8 (br s, 1H), 8.86-8.58
(m, 1H), 8.24 (dd, J=8.7, 2.5 Hz, 1H), 7.58-7.36 (m, 0.5H),
7.21-7.03 (m, 0.5H), 6.93 (t, J=9.9 Hz, 1H), 6.73 (d, J=8.7 Hz,
1H), 5.42-5.33 (m, 1H), 4.29 (t, J=6.7 Hz, 2H), 2.92-2.81 (m, 2H),
2.58-2.44 (m, 4H), 2.36-2.26 (m, 4H), 2.18-2.02 (m, 4H), 1.93-1.82
(m, 2H).
[0601] The following compounds in Examples 122-126 were prepared
according to the procedures described in Example 121.
Example 122
##STR00130##
[0602]
4-Methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy-
]-pyridin-3-yl}-1H-benzoimidazole
[0603] MS (electrospray): mass calculated for
C.sub.22H.sub.26N.sub.4O, 362.21; m/z found, 363.4 [M+H].sup.+.
Example 123
##STR00131##
[0604]
6-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl-
)-propoxy]-pyridin-3-yl}-1H-benzoimidazole
[0605] MS (electrospray): mass calculated for
C.sub.22H.sub.25ClN.sub.4O, 396.17; m/z found, 397.4
[M+H].sup.+.
Example 124
##STR00132##
[0606]
4,5-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pro-
poxy]-pyridin-3-yl}-1H-benzoimidazole
[0607] MS (electrospray): mass calculated for
C.sub.23H.sub.28N.sub.4O, 376.23; m/z found, 377.4 [M+H].sup.+.
Example 125
##STR00133##
[0608]
4,6-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pro-
poxy]-pyridin-3-yl}-1H-benzoimidazole
[0609] MS (electrospray): mass calculated for
C.sub.23H.sub.28N.sub.4O, 376.23; m/z found, 377.4 [M+H].sup.+.
Example 126
##STR00134##
[0610]
5-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl-
)-propoxy]-pyridin-3-yl}-1H-benzoimidazole
[0611] MS (electrospray): mass calculated for
C.sub.22H.sub.25ClN.sub.4O, 396.17; m/z found, 397.4
[M+H].sup.+.
Example 127
##STR00135##
[0612]
5-Fluoro-4-methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrr-
olidin-1-ylmethyl-pyridin-3-yl}-1H-benzoimidazole
[0613] A. 5-Bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine.
To a stirred solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol
(2.0 g, 12.7 mmol, 1.0 equiv), in DMF (100 mL) under an atmosphere
of nitrogen, was added 60% sodium hydride (764 mg, 19.1 mmol, 1.5
equiv) portion wise. Once the initial effervescence had subsided,
the mixture was heated at 60.degree. C. for 1 h, then was cooled to
rt. A solution of 2,5-dibromopyridine (3.0 g, 12.7 mmol, 1.0 equiv)
in DMF (7 mL) was then added and the mixture was stirred for 16 h.
The reaction was quenched with satd. aq. NaHCO.sub.3 (25 mL) and
brine (25 mL). The mixture was extracted with chloroform
(2.times.30 mL). The organic extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a crude
residue, which was purified by Method 2 affording 3.31 g (88%) of
the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.18-8.13
(m, 1H), 7.65-7.58 (m, 1H), 6.65-6.60 (m, 1H), 4.21 (t, J=6.7 Hz,
2H), 2.87-2.80 (m, 2H), 2.26 (s, 3H), 1.94-1.62 (m, 6H), 1.43-1.17
(m, 5H).
[0614] B.
5-Bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-4-carba-
ldehyde. To a cooled solution (-78.degree. C.) of 2.0 M LDA in
heptane/THF (4.05 mL, 8.07 mmol, 2.0 equiv) in THF (20 mL), was
added a solution of
5-bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine (1.2 g,
3.85 mmol, 1.0 equiv) in THF (15 mL) dropwise. After 30 min, DMF
(1.49 mL, 19.2 mmol, 5.0 equiv) was added dropwise and the mixture
stirred for an additional 20 min at -78.degree. C. then warmed to
0.degree. C. and quenched with satd. aq. NaHCO.sub.3 (5 mL). The
mixture was warmed to rt and extracted with chloroform (2.times.30
mL). The combined extracts were dried (Na.sub.2SO.sub.4), filtered,
and concentrated to afford 1.10 g of a crude oil, which was used
without purification. .sup.1H NMR (400 MHz, CDCl.sub.3): 10.3 (s,
1H), 8.39 (s, 1H), 7.15 (s, 1H), 4.31 (t, J=6.7 Hz, 2H), 2.87-2.75
(m, 2H), 2.28 (s, 3H), 1.97-1.60 (m, 6H), 1.43-1.15 (m, 5H).
[0615] C.
5-Bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-y-
lmethyl-pyridine. To a mixture of
5-bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine-4-carbaldehyde
(85 mg, 0.25 mmol, 1.0 equiv) and pyrrolidine (0.05 mL, 0.62 mmol,
2.5 equiv) in dichloroethane (5 mL), was added sodium
triacetoxyborohydride (156 mg, 0.74 mmol, 3.0 equiv). After 24 h,
the mixture was neutralized with satd. aq. NaHCO.sub.3 and
extracted with chloroform (2.times.15 mL). The combined extracts
were dried (Na.sub.2SO.sub.4), filtered, and concentrated to give a
crude oil product, which was purified by Method 2 to give 38 mg of
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.15 (s, 1H),
6.90 (s, 1H), 4.24 (t, J=6.7 Hz, 2H), 3.65 (s, 2H), 2.87-2.77 (m,
2H), 2.64-2.53 (m, 4H), 2.25 (s, 3H), 1.95-1.62 (m, 10H), 1.42-1.20
(m, 5H).
[0616] D.
5-Fluoro-4-methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-p-
yrrolidin-1-ylmethyl-pyridin-3-yl}-1H-benzoimidazole. To a cooled
solution (-78.degree. C.) of
5-bromo-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-ylmethyl-p-
yridine (38 mg, 0.10 mmol, 1.0 equiv) in dry THF (2 mL), under an
atmosphere of nitrogen, was added n-butyllithium (2.75 M in
hexanes, 0.04 mL, 0.11 mmol, 1.1 equiv) dropwise. After 10 min, DMF
(0.07 mL, 1.00 mmol, 10.0 equiv) was added. The solution was warmed
to 0.degree. C., quenched with satd. aq. NaHCO.sub.3 (2 mL), and
extracted with chloroform (2.times.10 mL). The combined extracts
were dried (Na.sub.2SO.sub.4), filtered, and concentrated to obtain
a crude residue. This residue was immediately dissolved in DMF (2
mL) and treated with 4-fluoro-4-fluoro-3-methyl-benzene-1,2-diamine
(15 mg, 0.11 mmol, 1.1 equiv) and Na.sub.2S.sub.2O.sub.5 (25 mg,
0.13 mmol, 1.3 equiv) according to General Procedure 3.
Purification by Method 2 afforded 10 mg (22%) of the title
compound. MS (electrospray): mass calculated for
C.sub.27H.sub.36FN.sub.5O, 465.26; m/z found, 466.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.81 (s, 1H), 7.42 (dd, J=8.7,
4.3 Hz, 1H), 7.01 (dd, J=10.3, 8.8 Hz, 1H), 6.95 (s, 1H), 4.40 (t,
J=6.6 Hz, 2H), 3.79 (s, 3H), 2.94-2.81 (m, 2H), 2.77-2.66 (m, 4H),
2.51 (s, 3H), 2.25 (s, 3H), 2.00-1.92 (m, 6H), 1.89-1.70 (m, 4H),
1.46-1.19 (m, 5H).
Example 128
##STR00136##
[0617]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-m-
ethyl-1H-benzoimidazole
[0618] A. 5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-Pyridine.
To a stirred solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol
(3.98 g, 623 mmol, 1.1 equiv) in DMF (100 mL), under an atmosphere
of nitrogen, was added 60% sodium hydride (1.26 mg, 6.81 mmol, 1.5
equiv) portion wise. Once the initial effervescence had subsided,
the mixture was heated at 60.degree. C. for 1 h, then was cooled to
rt. A solution of 2,5-dibromopyridine (5 mg, 21.1 mmol, 1.0 equiv)
in DMF (50 mL) was then added and the mixture was stirred for 16 h.
The mixture was partitioned between satd. aq. NaHCO.sub.3 (100 mL)
and chloroform (200 mL). The chloroform layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a crude
mixture, which was purified by column chromatography (silica gel,
0-10% (2 M ammonia in methanol) in dichloromethane) to afford 2.73
g (40%) of a white solid. MS (electrospray): mass calculated for
C.sub.15H.sub.23BrN.sub.2O, 326.1; m/z found, 327.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.17 (d, J=2.5 Hz, 1H), 7.63
(dd, J=7.6, 2.5 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 4.24 (t, J=6.6 Hz,
2H), 2.91-2.80 (m, 2H), 2.27 (s, 3H), 1.98-1.88 (m, 2H), 1.79-1.63
(m, 4H), 1.49-1.38 (m, 2H), 1.34-1.20 (m, 5H).
[0619] B.
5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-Pyridine-4-carbal-
dehyde. To a cooled solution (-78.degree. C.) of 2.0 M LDA in
heptane/THF (3.47 mL, 6.94 mmol, 2.0 equiv) in THF (10 ML), was
added a solution of
5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (1.13 g,
3.47 mmol, 1.0 equiv) in THF (15 mL) dropwise. After 30 min, DMF
(1.07 mL, 13.9 mmol, 4.0 equiv) was added dropwise and the mixture
stirred for an additional 20 min at -78.degree. C. The mixture was
warmed to 0.degree. C. and satd. aq. NaHCO.sub.3 (5 mL) was added.
After warming to rt, the mixture was extracted with chloroform
(2.times.20 mL). The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give 1.34 g of a
crude orange oil which was used without purification. .sup.1H NMR
(400 MHz, CDCl.sub.3): 10.3 (s, 1H), 8.39 (s, 1H), 7.14 (s, 1H),
4.31 (t, J=6.7 Hz, 2H), 2.89-2.79 (m, 2H), 2.28 (s, 3H), 1.96-1.63
(m, 9H), 1.43-1.20 (m, 4H).
[0620] C.
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}--
4-methyl-1H-benzoimidazole. This compound was prepared by the
method described in General Procedure 3 using
5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde
(100 mg, 0.28 mmol, 1.0 equiv), 3-methyl-benzene-1,2-diamine (38
mg, 0.31 mmol, 1.1 equiv) and Na.sub.2S.sub.2O.sub.5 (70 mg, 0.37
mmol, 1.3 equiv). Purification by Method 2 afforded 25 mg (20%) of
the title compound.
[0621] MS (electrospray): mass calculated for
C.sub.23H.sub.29BrN.sub.4O, 456.15; m/z found, 466.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 10.6-10.3 (br s, 1H), 8.45-8.28
(m, 1H), 7.76-7.62 (m, 2H), 7.25-7.21 (m, 1H), 7.19-7.07 (m, 1H),
4.29 (t, J=6.7 Hz, 2H), 2.87-2.77 (m, 2H), 2.76-2.63 (m, 3H), 2.25
(s, 3H), 1.95-1.61 (m, 7H), 1.53-1.39 (m, 2H), 1.35-1.15 (m,
4H).
[0622] The following compounds in Examples 129-135 were prepared
according to the procedures described in Example 128.
Example 129
##STR00137##
[0623]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-f-
luoro-4-methyl-1H-benzoimidazole
[0624] MS (electrospray): mass calculated for
C.sub.23H.sub.28BrFN.sub.5O, 474.14; m/z found, 477.4
[M+H].sup.+.
Example 130
##STR00138##
[0625]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-c-
hloro-4-methyl-1H-benzoimidazole
[0626] MS (electrospray): mass calculated for
C.sub.23H.sub.28BrClN.sub.5O, 490.1; m/z found, 493.4
[M+H].sup.+.
Example 131
##STR00139##
[0627]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-
-dimethyl-1H-benzoimidazole
[0628] MS (electrospray): mass calculated for
C.sub.24H.sub.31BrN.sub.4O, 470.17; m/z found, 471.4
[M+H].sup.+.
Example 132
##STR00140##
[0629]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-
-dimethyl-1H-benzoimidazole
[0630] MS (electrospray): mass calculated for
C.sub.24H.sub.31BrN.sub.4O, 470.17; m/z found, 471.4
[M+H].sup.+.
Example 133
##STR00141##
[0631]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-c-
hloro-4-methyl-1H-benzoimidazole
[0632] MS (electrospray): mass calculated for
C.sub.24H.sub.31BrN.sub.4O, 470.17 m/z found, 471.4 [M+H].sup.+. MS
(electrospray): mass calculated for C.sub.23H.sub.28BrClN.sub.4O,
490.11; m/z found, 493.4 [M+H].sup.+.
Example 134
##STR00142##
[0633]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-t-
ert-butyl-1H-benzoimidazole
[0634] MS (electrospray): mass calculated for
C.sub.26H.sub.35BrN.sub.4O, 498.20; m/z found, 501.4
[M+H].sup.+.
Example 135
##STR00143##
[0635]
5-tert-Butyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl-
}-1H-benzoimidazole
[0636] MS (electrospray): mass calculated for
C.sub.26H.sub.36N.sub.4O, 420.29; m/z found, 421.5 [M+H].sup.+.
Example 136
##STR00144##
[0637]
2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5--
fluoro-4-methyl-1H-benzoimidazole
[0638] A. 5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine.
To a stirred solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol
(1.5 g, 8.77 mmol, 1.0 equiv) in DMF (10 mL) under an atmosphere of
nitrogen, was added 60% sodium hydride (573 mg, 14.3 mmol, 1.5
equiv) portion wise. Once the initial effervescence had subsided,
the mixture was heated at 60.degree. C. for 1 h, then was cooled to
rt.
[0639] A solution of 2,5-dichloropyridine (1.42 mg, 9.55 mmol, 1.1
equiv) in DMF (10 mL) was then added and the mixture was stirred
for 4 h. The mixture was partitioned between satd. aq. NaHCO.sub.3
(20 mL) and chloroform (40 mL). The chloroform layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a crude
mixture, which was purified by column chromatography (silica gel,
0-10% (2 M ammonia in methanol) in dichloromethane) to afford 1.62
g (65%) of a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.07
(dd, J=2.5, 0.4 Hz, 1H), 7.51 (dd, J=8.8, 2.7 Hz, 1H), 6.67 (dd,
J=8.8, 0.4 Hz, 1H), 4.27 (t, J=6.6 Hz, 2H), 2.86-2.78 (m, 2H), 2.26
(s, 3H), 1.94-1.60 (m, 7H), 1.52-1.37 (m, 2H), 1.35-1.14 (m,
4H).
[0640] B.
5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carba-
ldehyde. To a cooled solution (-78.degree. C.) of 2.0 M LDA in
heptane/THF (5.74 mL, 11.5 mmol, 2.0 equiv) in THF (10 ML), was
added a solution of
5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (1.62 g,
5.74 mmol, 1.0 equiv) in THF (15 mL) dropwise. After 30 min, DMF
(2.22 mL, 28.7 mmol, 5.0 equiv) was added dropwise and the mixture
was stirred for an additional 20 min at -78.degree. C. The mixture
was warmed to 0.degree. C. and quenched with satd. aq. NaHCO.sub.3
(5 mL). The mixture was warmed to rt and extracted with chloroform
(2.times.20 mL). The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give 968 mg of a
crude residue, which was used without purification. .sup.1H NMR
(400 MHz, CDCl.sub.3): 10.4 (s, 1H), 8.26 (s, 1H), 7.13 (s, 1H),
4.31 (t, J=6.6 Hz, 2H), 2.87-2.80 (m, 2H), 2.25 (s, 3H), 1.99-1.60
(m, 7H), 1.51-1.38 (m, 2H), 1.43-1.20 (m, 4H).
[0641] C.
2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-
-5-fluoro-4-methyl-1H-benzoimidazole. This compound was prepared by
the method described in General Procedure 3 using
5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde
(45 mg, 0.15 mmol, 1.0 equiv),
4-fluoro-3-methyl-benzene-1,2-diamine (23 mg, 0.17 mmol, 1.1 equiv)
and Na.sub.2S.sub.2O.sub.5 (37 mg, 0.20 mmol, 1.3 equiv).
Purification by Method 2 afforded 12 mg (18%) of the title
compound. MS (electrospray): mass calculated for
C.sub.23H.sub.28ClFN.sub.4O, 430.19; m/z found, 431.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.30 (s, 1H), 7.45 (dd, J=8.9,
4.5 Hz, 1H), 7.22-7.19 (m, 1H), 7.07 (dd, J=10.2, 8.9 Hz 1H), 4.31
(t, J=6.6 Hz, 2H), 2.88-2.81 (m, 2H), 2.53 (s, 3H), 2.24 (s, 3H),
2.05-1.90 (m, 2H), 1.84-1.66 (m, 4H), 1.55-1.42 (m, 2H), 1.37-1.15
(m, 5H).
Example 137
##STR00145##
[0642]
2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,-
5-dimethyl-1H-benzoimidazole
[0643] The title compound was prepared according to the methods
described in Example 136. MS (electrospray): mass calculated for
C.sub.24H.sub.31ClN.sub.4O, 426.22; m/z found, 427.4
[M+H].sup.+.
Example 138
##STR00146##
[0644]
4,6-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl-
}-1H-benzoimidazole
[0645] A.
2-[4-(4-Methyl-piperazin-1-yl)-butoxy]-isonicotinonitrile. To a
solution of 4-(4-methyl-piperazin-1-yl)-butan-1-ol (2.5 g, 14.5
mmol, 1.0 equiv) in DMF (25 mL) at 0.degree. C. was added sodium
hydride (60% dispersion in oil, 0.70 g, 17.4 mmol, 1.2 equiv). The
mixture was warmed to rt and stirred for 1 h before re-cooling to
0.degree. C. A solution of 2-chloro-isonicotinonitrile (2.01 g,
14.5 mmol, 1.0 equiv) in DMF (12 mL) was added dropwise. The
mixture was stirred at rt for 18 h. The reaction was diluted with
water (5 mL) and satd. aq. NaHCO.sub.3 (25 mL) was added. The
mixture was extracted with chloroform (3.times.25 mL), and the
combined extracts were concentrated. Purification by Method 2
afforded 1.07 g of impure compound. Mass calculated for
C.sub.15H.sub.22N.sub.4O, 274.18; m/z found, 275.4 [M+H].sup.+.
[0646] B.
4,6-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-Pyridin-4-
-yl}-1H-benzoimidazole. To a stirred solution of
2-[4-(4-methyl-piperazin-1-yl)-butoxy]-isonicotinonitrile) in
toluene (5.0 mL) at 0.degree. C. was added 1.5 M diisobutylaluminum
hydride in toluene (3.9 mL, 5.86 mmol, 1.5 equiv). After 3 h,
methanol (9 mL) and 1.0 M H.sub.2SO.sub.4 (10 mL) were added. The
mixture was stirred for 30 min, and then 1.0 M NaOH (10 mL) was
added, followed by satd. aq. sodium potassium tartrate (40 mL) and
dichloromethane (100 mL). After stirring for 30 min, the mixture
was extracted with chloroform (3.times.50 mL) and the combined
extracts were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was partially purified by
Method 2 to afford 240 mg of a mixture of
3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde and several
other unidentified products. A portion of the crude
3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-benzaldehyde (40 mg),
3,5-dimethyl-benzene-1,2-diamine (17.6 mg), and
Na.sub.2S.sub.2O.sub.5 (32 mg) were stirred in DMF (4 mL) at
90.degree. C. for 18 h. The reaction mixture was loaded directly on
silica gel and purified by Method 2, which afforded 19 mg of the
title compound. MS (electrospray): mass calculated for
C.sub.23H.sub.31N.sub.5O, 393.25; m/z found, 394.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.26 (d, J=5.4 Hz, 1H), 7.63 (d,
J=5.5 Hz, 1H), 7.49 (s, 1H), 7.25 (br s, 1H), 6.95 (s, 1H), 4.38
(t, J=6.3 Hz, 2H), 2.76-2.33 (m, 16H), 2.32-2.24 (s, 3H), 1.92-1.79
(m, 2H), 1.79-1.66 (m, 2H).
[0647] The following compounds in Examples 139-142 were prepared
according to the procedures described in Example 138.
Example 139
##STR00147##
[0648]
4-Methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-
-benzoimidazole
[0649] MS (electrospray): mass calculated for
C.sub.22H.sub.29N.sub.5O, 379.24; m/z found, 380.4 [M+H].sup.+.
Example 140
##STR00148##
[0650]
4,5-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl-
}-1H-benzoimidazole
[0651] MS (electrospray): mass calculated for
C.sub.23H.sub.31N.sub.5O, 393.25; m/z found, 394.5 [M+H].sup.+.
Example 141
##STR00149##
[0652]
5-Fluoro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0653] MS (electrospray): mass calculated for
C.sub.22H.sub.28FN.sub.5O, 397.23; m/z found, 398.4
[M+H].sup.+.
Example 142
##STR00150##
[0654]
6-Chloro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0655] MS (electrospray): mass calculated for
C.sub.22H.sub.28ClN.sub.5O, 413.20; m/z found, 414.4
[M+H].sup.+.
Example 143
##STR00151##
[0656]
5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyr-
idin-4-yl}-1H-benzoimidazole
[0657] A.
2-[4-(4-Methyl-[1,4]diazepan-1-yl)-butoxy]-isonicotinonitrile. To a
solution of 1-methyl-[1,4]diazepane (21.3 g, 185 mmol, 2.0 equiv)
and 4-chloro-butan-1-ol (10.0 g, 92.6 mmol, 1.0 equiv) in 1-butanol
(200 mL) were added K.sub.2CO.sub.3 (38.0 g, 278 mmol, 3.0 equiv)
and NaI (13.9 g, 92.6 mmol, 1.0 equiv). The mixture was warmed to
95.degree. C. and stirred for 36 h. The mixture was then cooled to
rt, diluted with water, and extracted with chloroform (3.times.100
mL). The combined extracts were washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. Purification by Method 2
afforded 9.3 g of 4-(4-methyl-[1,4]diazepan-1-yl)-butan-1-ol with a
small unidentified impurity. A portion of the impure alcohol (5.0
g) was dissolved in DMF (50 mL) and cooled to 0.degree. C. Sodium
hydride (60% dispersion in oil, 1.29 g, 32.2 mmol, 1.2 equiv) was
added. The mixture was warmed to rt, stirred for 1 h, and then
re-cooled to 0.degree. C. A solution of 2-chloro-isonicotinonitrile
(3.72 g, 26.8 mmol, 1.0 equiv) in DMF (25 mL) was added dropwise.
The mixture was stirred at rt for 18 h, then was diluted with water
(25 mL) and satd. aq. NaHCO.sub.3 (100 mL), and was extracted with
chloroform (3.times.100 mL). The combined extracts were washed with
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated.
Purification by Method 2 afforded the title compound (1.0 g). MS
(electrospray): mass calculated for C.sub.16H.sub.24N.sub.4O,
288.20; m/z found, 289.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.28 (dd, J=4.4 Hz, 0.8 Hz, 1H), 7.05 (dd, J=3.9, 1.1
Hz, 1H) 6.96 (s, 1H), 4.33 (t, J=6.6 Hz, 2H), 2.75-2.68 (m, 4H),
2.65-2.57 (m, 4H), 2.56-2.49 (m, 2H), 2.35 (s, 3H), 1.84-1.74 (m,
4H), 1.66-1.55 (m, 2H).
[0658] B.
5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]--
pyridin-4-yl}-1H-benzoimidazole. To a stirred solution of
2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-isonicotinonitrile (1.0
g, 3.47 mmol, 1.0 equiv) in toluene (5.0 mL) at 0.degree. C. was
added 1.0 M diisobutylaluminum hydride in toluene (5.2 mL, 5.2
mmol, 1.5 equiv). After 3 h, methanol (9 mL) and 1.0 M
H.sub.2SO.sub.4 (10 mL) were added. The mixture was stirred for 30
min, and then 1.0 M NaOH (10 mL) was added, followed by satd. aq.
sodium potassium tartrate (40 mL) and dichloromethane (100 mL).
After stirring for 30 min, the mixture was extracted with
chloroform (3.times.50 mL) and the combined extracts were washed
with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The residue was partially purified by Method 2 to afford 268 mg of
a mixture of
2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridine-4-carbaldehyde
and several other unidentified products. A portion of the impure
2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridine-4-carbaldehyde
(63 mg), 4-fluoro-3-methyl-benzene-1,2-diamine (30.3 mg), and
Na.sub.2S.sub.2O.sub.5 (53.4 mg) were stirred in DMF (3 mL) at
90.degree. C. for 18 h. The reaction mixture was loaded directly on
silica gel and purified by Method 2, which afforded 5.0 mg of the
title compound. MS (electrospray): mass calculated for
C.sub.23H.sub.30FN.sub.5O, 411.24; m/z found, 412.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.27 (dd, J=4.8, 0.5 Hz, 1H),
7.63 (dd, J=4.0, 1.4 Hz, 1H), 7.52-7.40 (m, 2H), 7.10-7.01 (m, 1H),
4.27 (t, J=6.3 Hz, 2H), 2.86-2.77 (m, 4H), 2.77-2.68 (m, 4H),
2.65-2.57 (m, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.90-1.66 (m,
6H).
Example 144
##STR00152##
[0659]
4,5-Dimethyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin--
4-yl}-1H-benzoimidazole
[0660] This compound was prepared according to the methods
described in Example 143. MS (electrospray): mass calculated for
C.sub.24H.sub.33N.sub.5O, 407.27; m/z found, 408.5 [M+H].sup.+.
Example 145
##STR00153##
[0661]
4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl-
}-1H-benzoimidazole
[0662] A.
2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile. To a
solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (1.0 g, 5.85
mmol, 1.0 equiv) in DMF (25 mL) at 0.degree. C. was added sodium
hydride (60% dispersion in oil, 0.28 g, 7.02 mmol, 1.2 equiv). The
mixture was warmed to rt and stirred for 1 h. The mixture was then
re-cooled to 0.degree. C. and a solution of
2-chloro-isonicotinonitrile (0.81 g, 5.85 mmol, 1.0 equiv) in DMF
(10 mL) was added dropwise. The mixture was stirred at rt for 18 h,
then was diluted with water (25 mL) and satd. aq. NaHCO.sub.3 (100
mL). The mixture was extracted with chloroform (3.times.100 mL),
and the combined extracts were concentrated. Purification by Method
2 afforded 0.44 g (28%) of title compound. MS (electrospray): mass
calculated for C.sub.16H.sub.23N.sub.3O, 273.18; m/z found, 274.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.28 (dd, J=5.2,
0.7 Hz, 1H), 7.05 (dd, J=5.2, 1.3 Hz, 1H), 6.99-6.95 (m, 1H), 4.21
(t, J=6.6 Hz, 2H), 2.88-2.79 (m, 2H), 2.26 (s, 3H), 1.95-1.83 (m,
2H), 1.81-1.59 (m, 4H), 1.51-1.38 (m, 2H), 1.34-1.16 (m, 5H).
[0663] B.
4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-
-yl}-1H-benzoimidazole. To a stirred solution of
2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (440 mg,
1.61 mmol, 1.0 equiv) in toluene (5.0 mL) at 0.degree. C. was added
1.0 M diisobutylaluminum hydride in toluene (2.41 mL, 2.41 mmol,
1.5 equiv). After 3 h, methanol (8 mL) and 1.0 M H.sub.2SO.sub.4 (5
mL) were added. The mixture was stirred for 30 min, and then 1.0 M
NaOH (10 mL) was added, followed by satd. aq. sodium potassium
tartrate (40 mL) and dichloromethane (100 mL). After stirring for
30 min, the mixture was extracted with chloroform (3.times.50 mL)
and the combined extracts were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
partially purified by Method 2 to afford 318 mg of a mixture of
2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde and several
other unidentified products. A portion of the crude of
2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde (100 mg),
3,5-dimethyl-benzene-1,2-diamine (70 mg), and
Na.sub.2S.sub.2O.sub.5 (93 mg) were stirred in DMF (3 mL) at
90.degree. C. for 18 h. The reaction mixture was loaded directly on
silica gel and purified according to Method 2, which afforded 38 mg
of the title compound. MS (electrospray): mass calculated for
C.sub.24H.sub.32N.sub.4O, 392.26; m/z found 393.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.25 (d, J=5.3 Hz, 1H), 7.62
(dd, J=4.5, 1.0 Hz, 1H), 7.48 (s, 1H), 7.24 (s, 1H), 6.95 (s, 1H),
4.34 (t, J=6.6 Hz, 2H), 2.91-2.83 (m, 2H), 2.58 (s, 3H), 2.43 (s,
3H), 2.25 (s, 3H), 2.07-1.95 (m, 2H), 1.86-1.69 (m, 5H), 1.57-1.18
(m, 6H).
[0664] The following compounds in Examples 146-151 were prepared
according to the methods described for Example 145.
Example 146
##STR00154##
[0665]
4-Methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-
-benzoimidazole
[0666] MS (electrospray): mass calculated for
C.sub.23H.sub.30N.sub.4O, 378.24; m/z found, 379.4 [M+H].sup.+.
Example 147
##STR00155##
[0667]
5-Fluoro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0668] MS (electrospray): mass calculated for
C.sub.23H.sub.29FN.sub.4O, 396.23; m/z found, 387.4
[M+H].sup.+.
Example 148
##STR00156##
[0669]
4-Chloro-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-
-benzoimidazole
[0670] MS (electrospray): mass calculated for
C.sub.22H.sub.27ClN.sub.4O, 398.19; m/z found, 398.4
[M+H].sup.+.
Example 149
##STR00157##
[0671]
4,5-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl-
}-1H-benzoimidazole
[0672] MS (electrospray): mass calculated for
C.sub.24H.sub.32N.sub.4O, 392.26; m/z found, 393.5 [M+H].sup.+.
Example 150
##STR00158##
[0673]
6-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0674] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.20 m/z found; 413.4
[M+H].sup.+.
Example 151
##STR00159##
[0675]
5-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0676] MS (electrospray): mass calculated for
C.sub.23H.sub.29ClN.sub.4O, 412.24; m/z found, 413.4
[M+H].sup.+.
Example 152
##STR00160##
[0677]
5-tert-Butyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoi-
midazole
[0678] The title compound was prepared according to the methods
described in Example 145, substituting
4-(4-hydroxy-butyl)-piperidine-1-carboxylic acid tert-butyl ester
for 4-(1-methyl-piperidin-4-yl)-butan-1-ol to give
4-{4-[4-(5-tert-butyl-1H-benzoimidazol-2-yl)-pyridin-2-yloxy]-butyl}-pipe-
ridine-1-carboxylic acid tert-butyl ester. This intermediate was
then converted to the title compound as described in Example 14. MS
(electrospray): mass calculated for C.sub.25H.sub.34N.sub.4O,
406.27; m/z found, 407.5 [M+H].sup.+.
Example 153
##STR00161##
[0679]
4,6-Dimethyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoi-
midazole
[0680] The title compound was prepared according to the procedures
as described in Example 152. MS (electrospray): mass calculated for
C.sub.23H.sub.30N.sub.4O, 378.24; m/z found, 379.5 [M+H].sup.+.
Example 154
##STR00162##
[0681]
2-{2-[4-(1-Ethyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-
-1H-benzoimidazole
[0682] The title compound was prepared according to the methods
described in Example 90. MS (electrospray): mass calculated for
C.sub.25H.sub.34N.sub.4O, 406.27; m/z found, 407.4 [M+H].sup.+.
Example 155
##STR00163##
[0683]
4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyr-
idin-4-yl}-1H-benzoimidazole
[0684] A.
3-Methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitri-
le. To an oven dried flask under N.sub.2 was added
2,2,6,6-tetramethylpiperidine (2.13 mL, 12.6 mmol 1.5 equiv) and
THF (50 mL). The flask was cooled to -78.degree. C. and
n-butyllithium (2.5 M in hexanes, 5.03 mL, 12.6 mmol, 1.5 equiv)
was added. The mixture was warmed to 0.degree. C. for 1 h, and then
was re-cooled to -78.degree. C. A solution of
2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile (2.3 g,
8.38 mmol, 1.0 equiv) in THF (15 mL) was added dropwise and the
resulting mixture was stirred at -78.degree. C. for 1 h. Methyl
iodide (1.30 g, 9.22 mmol, 1.1 equiv) in THF (10 mL) was added
dropwise. After 1 h, the reaction was quenched with satd. aq.
NaHCO.sub.3, warmed to rt, diluted with chloroform and washed with
satd. aq. NaHCO.sub.3. The organic layer was dried
(Na.sub.2SO.sub.4), filtered, and concentrated. Purification by
Method 2 afforded 405 mg of a mixture of
3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile
and other unidentified products. MS (electrospray): mass calculated
for C.sub.17H.sub.25N.sub.3O, 287.20; m/z found, 288.4
[M+H].sup.+.
[0685] B.
4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]--
pyridin-4-yl}-1H-benzoimidazole. To a stirred solution of impure
3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-isonicotinonitrile
(283 mg) at 0.degree. C. was added 1.5 M diisobutylaluminum hydride
in toluene (1.32 mL). After 3 h, methanol (8 mL) and 1.0 M
H.sub.2SO.sub.4 (5 mL) were added. The mixture was stirred for 30
min, then 1.0 M NaOH (10 mL) was added, followed by satd. aq.
sodium potassium tartrate (40 mL) and dichloromethane (100 mL).
After stirring for 30 min, the mixture was extracted with
chloroform (3.times.50 mL) and the combined extracts were washed
with brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The residue was partially purified by Method 2 to afford 180 mg of
a mixture of 2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde
and several other unidentified products. A portion of the impure
2-(4-piperidin-4-yl-butoxy)-pyridine-4-carbaldehyde (19.5 mg),
3,5-dimethyl-benzene-1,2-diamine (9.2 mg), and
Na.sub.2S.sub.2O.sub.5 (16.6 mg) were stirred in DMF (3 mL) at
90.degree. C. for 18 h. The reaction mixture was loaded directly on
silica gel and purified by Method 2, which afforded 9.4 mg of the
title compound. MS (electrospray): mass calculated for
C.sub.25H.sub.34N.sub.4O, 406.27; m/z found, 407.5 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.06 (dd, J=5.3, 0.4 Hz, 1H),
7.23 (s, 1H), 7.13 (d, J=5.3 Hz, 1H), 6.94 (s, 1H), 4.36 (t, J=6.4
Hz, 2H), 2.92-2.81 (m, 2H), 2.56 (s, 3H), 2.43 (s, 3H), 2.33 (s,
3H), 2.24 (s, 3H), 2.07-1.94 (m, 2H), 1.87-1.67 (m, 4H), 1.60-1.46
(m, 2H), 1.40-1.15 (m, 5H).
[0686] The following compounds in Examples 156-157 were prepared
according to the procedures described for Example 155.
Example 156
##STR00164##
[0687]
4-Methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0688] MS (electrospray): mass calculated for
C.sub.24H.sub.32N.sub.4O, 392.26; m/z found, 393.4 [M+H].sup.+.
Example 157
##STR00165##
[0689]
6-Chloro-4-methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy-
]-pyridin-4-yl}-1H-benzoimidazole
[0690] MS (electrospray): mass calculated for
C.sub.24H.sub.31ClN.sub.4O, 426.22; m/z found, 427.4
[M+H].sup.+.
Example 158
##STR00166##
[0691]
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4--
methyl-1H-benzoimidazole
[0692] The title compound was prepared as described in Example 155,
substituting hexachloroethane for methyl iodide. MS (electrospray):
mass calculated for C.sub.23H.sub.29ClN.sub.4O, 412.20; m/z found,
413.4 [M+H].sup.+.
[0693] The following compounds in Examples 159-164 were prepared
according to the procedures described in Example 158.
Example 159
##STR00167##
[0694]
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,-
5-dimethyl-1H-benzoimidazole
[0695] MS (electrospray): mass calculated for
C.sub.24H.sub.31ClN.sub.4O, 426.22; m/z found, 427.4
[M+H].sup.+.
Example 160
##STR00168##
[0696]
4-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0697] MS (electrospray): mass calculated for
C.sub.22H.sub.26Cl.sub.2N.sub.4O, 432.15; m/z found, 433.3
[M+H].sup.+.
Example 161
##STR00169##
[0698]
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5--
fluoro-4-methyl-1H-benzoimidazole
[0699] MS (electrospray): mass calculated for
C.sub.23H.sub.28ClFN.sub.4O, 430.19; m/z found, 431.4
[M+H].sup.+.
Example 162
##STR00170##
[0700]
2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,-
6-dimethyl-1H-benzoimidazole
[0701] MS (electrospray): mass calculated for
C.sub.24H.sub.31ClN.sub.4O, 426.22; m/z found 427.4
[M+H].sup.+.
Example 163
##STR00171##
[0702]
6-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-4-methyl-1H-benzoimidazole
[0703] MS (electrospray): mass calculated for
C.sub.23H.sub.28Cl.sub.2N.sub.4O, 446.16; m/z found, 446.4
[M+H].sup.+.
Example 164
##STR00172##
[0704]
5-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-4-methyl-1H-benzoimidazole
[0705] MS (electrospray): mass calculated for
C.sub.23H.sub.28Cl.sub.2N.sub.4O, 446.16; m/z found, 446.4
[M+H].sup.+.
Example 165
##STR00173##
[0706]
5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy-
]-pyridin-4-yl}-1H-benzoimidazole
[0707] A. 5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine.
To a solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (14.9 g,
86.9 mmol, 1.0 equiv) in DMF (180 mL) at 0.degree. C. was added
sodium hydride (60% dispersion in oil 4.86 g, 122 mmol, 1.4 equiv).
The mixture was warmed to rt for 1 h, and then was re-cooled to
0.degree. C. A solution of 5-bromo-2-chloro-pyridine (20.6 g, 86.9
mmol, 1.0 equiv) in DMF (20 mL) was added dropwise. The mixture was
stirred at rt for 18 h, then was diluted with water (100 mL) and
satd. aq. NaHCO.sub.3 (250 mL). The mixture was extracted with
chloroform (3.times.100 mL) and the combined extracts were
concentrated. Purification by Method 2 afforded 8.82 g of
5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine as a
mixture with several unidentified impurities. MS (electrospray):
mass calculated for C.sub.15H.sub.23BrN.sub.2O, 326.10; m/z found,
327.3 [M+H].sup.+.
[0708] B.
5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-but-
oxy]-pyridin-4-yl}-1H-benzoimidazole. To a solution of LDA (2.0 M
in THF, 18.2 mL, 36.4 mmol, 2.2 equiv) at -78.degree. C. in a oven
dried 100 mL round bottom flask was added a solution of
5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine (5.40 g,
16.6 mmol, 1.0 equiv) in THF (20 mL) dropwise. The solution was
stirred at -78.degree. C. for 45 min, and then DMF (6.05 mL, 82.8
mmol, 5.0 equiv) was added dropwise. The solution was quenched with
satd. aq. NaHCO.sub.3 (25 mL) and extracted with chloroform
(3.times.50 mL). The combined extracts were washed with brine and
concentrated. The crude residue was diluted with ethanol (5 mL) and
treated with sodium bisulfite (2.1 g). The precipitate that formed
was collected by vacuum filtration and washed with diethyl ether.
The solid was diluted with chloroform (50 mL) and washed with satd.
aq. NaHCO.sub.3 (50 mL). The organic layer was dried
(Na.sub.2SO.sub.4), filtered and concentrated to afford
5-bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbaldehyde
as a mixture with several other unidentified products. A solution
of this crude mixture in methanol (15 mL) was treated with conc.
H.sub.2SO.sub.4 (1 mL) and the resulting solution was stirred for
14 h. The mixture was diluted with satd. aq. NaHCO.sub.3 (25 mL)
and extracted with chloroform (3.times.25 mL). The combined
extracts were concentrated to provide
5-bromo-4-dimethoxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-
. A -78.degree. C. solution of the pyridine (2.0 g, 5.0 mmol, 1.0
equiv) in THF (50 mL) was treated with n-butyllithium (2.5 M in
hexanes, 2.2 mL, 5.5 mmol, 1.1 equiv). The solution was stirred for
30 min, and then methyl iodide (0.312 g, 5.0 mmol, 1.0 equiv) was
added. After 30 min, the reaction was quenched with satd. aq.
NaHCO.sub.3 (10 mL) and extracted with chloroform (3.times.25 mL).
The combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated to afford
4-dimethoxymethyl-5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
e as a crude mixture. A solution of
4-dimethoxymethyl-5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
e (0.64 mg) in THF (100 mL) was treated with 1.0 M HCl (20 mL) and
the mixture was stirred for 4 h. The mixture was diluted with satd.
aq. NaHCO.sub.3 and extracted with chloroform (3.times.100 mL). The
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated to provide
5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbal-
dehyde. A portion of this aldehyde (110 mg),
4-fluoro-3-methyl-benzene-1,2-diamine (60 mg), and
Na.sub.2S.sub.2O.sub.5 (100 mg) were stirred in DMF (2 mL) at
90.degree. C. for 36 h. The reaction mixture was concentrated and
purified by reverse phase HPLC to provide the title compound. MS
(electrospray): mass calculated for C.sub.24H.sub.31FN.sub.4O,
410.25; m/z found, 411.5 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 8.17 (s, 1H), 7.54-7.43 (m, 1H), 7.19-7.05 (m, 2H),
4.34 (t, J=6.4 Hz, 2H), 3.53-3.43 (m, 2H), 3.04-2.89 (m, 2H), 2.84
(s, 3H), 2.53 (s, 3H), 2.43 (s, 3H), 2.06-1.95 (m, 2H), 1.85-1.76
(m, 2H), 1.64-1.29 (m, 7H).
[0709] The following compounds in Examples 166-168 were prepared
according to the procedures described for Example 165.
Example 166
##STR00174##
[0710]
5-Chloro-6-fluoro-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy-
]-pyridin-4-yl}-1H-benzoimidazole
[0711] MS (electrospray): mass calculated for
C.sub.23H.sub.28ClFN.sub.4O, 430.19; m/z found, 431.4
[M+H].sup.+.
Example 167
##STR00175##
[0712]
5-tert-Butyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyr-
idin-4-yl}-1H-benzoimidazole
[0713] MS (electrospray): mass calculated for
C.sub.27H.sub.38N.sub.4O, 434.30; m/z found, 435.5 [M+H].sup.+.
Example 168
##STR00176##
[0714]
4,5-Dimethyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyr-
idin-4-yl}-1H-benzoimidazole
[0715] MS (electrospray): mass calculated for
C.sub.25H.sub.34N.sub.4O, 406.27; m/z found, 407.5 [M+H].sup.+.
Example 169
##STR00177##
[0716]
2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,-
6-dimethyl-1H-benzoimidazole
[0717] The title compound was prepared as described in Example 165,
substituting hexachloroethane for methyl iodide. MS (electrospray):
mass calculated for C.sub.24H.sub.31ClN.sub.4O, 426.22; m/z found,
427.4 [M+H].sup.+.
[0718] The following compounds in Examples 170-172 were prepared
according to the procedures described in Example 169.
Example 170
##STR00178##
[0719]
5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-1H-benzoimidazole
[0720] MS (electrospray): mass calculated for
C.sub.22H.sub.26Cl.sub.2N.sub.4O, 432.15; m/z found 433.3
[M+H].sup.+.
Example 171
##STR00179##
[0721]
5-Chloro-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-
-4-yl}-6-fluoro-1H-benzoimidazole
[0722] MS (electrospray): mass calculated for
C.sub.22H.sub.25Cl.sub.2FN.sub.4O, 450.14; m/z found 451.3
[M+H].sup.+.
Example 172
##STR00180##
[0723]
5-tert-Butyl-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyr-
idin-4-yl}-1H-benzoimidazole
[0724] MS (electrospray): mass calculated for
C.sub.26H.sub.35ClN.sub.4O, 454.25; m/z found 455.5
[M+H].sup.+.
[0725] The following compounds in Examples 173-175 were prepared
according to the procedures described for Example 128.
Example 173
##STR00181##
[0726]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-c-
hloro-1H-benzoimidazole
[0727] MS (electrospray): mass calculated for
C.sub.22H.sub.26BrClN.sub.4O, 476.10; m/z found 477.3
[M+H].sup.+.
Example 174
##STR00182##
[0728]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-c-
hloro-6-fluoro-1H-benzoimidazole
[0729] MS (electrospray): mass calculated for
C.sub.22H.sub.25BrClFN.sub.4O, 494.09; m/z found 495.3
[M+H].sup.+.
Example 175
##STR00183##
[0730]
2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-c-
hloro-1H-benzoimidazole
[0731] MS (electrospray): mass calculated for
C.sub.22H.sub.26BrClN.sub.4O, 476.10; m/z found 477.3
[M+H].sup.+.
Example 176
##STR00184##
[0732]
{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperid-
in-4-yl)-propoxy]-phenyl}-methanol
[0733] A.
4-[3-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-propyl]-1-methyl-piper-
idine. To a solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol
(7.07 g, 45 mmol, 1.0 equiv) and methanesulfonyl chloride (4.18 mL,
54 mmol, 1.2 equiv) in dichloromethane (100 mL) at 0.degree. C. was
added triethylamine (9.41 mL, 68 mmol, 1.5 equiv). The reaction
mixture, which was allowed to warm to rt, was stirred for 30 min
and then poured into satd. aq. NaHCO.sub.3. The aqueous mixture was
extracted with chloroform and then ethyl acetate. The combined
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The residue was dissolved in acetonitrile (100 mL) and
4-bromo-3-[1,3]dioxan-2-yl-phenol (11.7 g, 45 mmol, 1.0 equiv) and
cesium carbonate (29.2 mg, 90 mmol, 2.0 equiv) were added. The
mixture was stirred at rt for 12 h, then warmed to 50.degree. C.
for 1.0 h. The mixture was poured into satd. aq. NaHCO.sub.3 and
extracted with ethyl acetate (2.times.) and chloroform. The
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated. Purification by Method 2 afforded 4.82 g (27%) of the
title compound. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.43 (d, J=8.8
Hz, 1H), 7.19 (d, J=3.1 Hz, 1H), 6.83 (dd, J=8.8, 3.1 Hz, 1H), 5.72
(s, 1H), 4.27-4.19 (m, 2H), 4.10-4.00 (m, 2H), 3.97 (t, J=6.4 Hz,
2H), 2.93-2.85 (m, 2H), 2.28 (s, 3H), 2.25-2.11 (m, 1H), 2.07-1.97
(m, 2H), 1.85-1.72 (m, 4H), 1.52-1.21 (m, 6H).
[0734] B.
2-{2-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-ph-
enyl}-5-fluoro-4-methyl-1H-benzoimidazole. To a stirred solution of
4-[3-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-propyl]-1-methyl-piperidine
(4.82 g, 12.4 mmol, 1.0 equiv) in THF (62 mL) at -78.degree. C. was
added 2.5 M n-butyllithium in hexanes (22 mL, 55 mmol, 4.4 equiv).
The resulting orange solution was stirred for 30 min then DMF (9.6
mL, 124 mmol, 10.0 equiv) was added. The solution was warmed to rt
and stirred for 1.0 h then re-cooled to -78.degree. C. and satd.
aq. NaHCO.sub.3 was added. The mixture was warmed to rt, poured
into water, and extracted with ethyl acetate. The combined extracts
were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
crude residue was partially purified by Method 2. The resultant
2-[1,3]dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde
(491 mg, 1.41 mmol, 1.0 equiv) was stirred with
4-fluoro-3-methyl-benzene-1,2-diamine (198 mg, 1.41 mmol, 1.0
equiv) and Na.sub.2S.sub.2O.sub.5 (350 mg, 1.84 mmol, 1.3 equiv) in
DMF (7.0 mL) at 90.degree. C. for 2 h. The mixture was loaded onto
silica gel and purified by Method 2 to afford 509 mg (77%) of the
title compound. MS (electrospray): mass calculated for
C.sub.27H.sub.34FN.sub.3O.sub.3, 467.26; m/z found, 468.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.62 (d, J=8.5 Hz,
1H), 7.44-7.37 (m, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.09-6.99 (m, 2H),
5.97 (s, 1H), 4.19-4.13 (m, 2H), 4.09 (t, J=6.4 Hz, 2H), 3.95-3.86
(m, 2H), 2.95-2.87 (m, 2H), 2.53 (s, 3H), 2.30 (s, 3H), 2.22-1.99
(m, 3H), 1.93-1.76 (m, 4H), 1.51-1.22 (m, 6H).
[0735] C.
{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-pipe-
ridin-4-yl)-propoxy]-phenyl}-methanol.
2-{2-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-5-f-
luoro-4-methyl-1H-benzoimidazole (401 mg) and p-toluenesulfonic
acid (1.0 g) were stirred in a solution of acetone (10 mL) and
water (1.0 mL) at reflux for 16 h. The solution was poured into
satd. aq. NaHCO.sub.3 and extracted with ethyl acetate. The
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated. A portion of the crude residue (43.3 mg) was
dissolved in ethanol (2.0 mL) and sodium borohydride (300 mg) was
added. The mixture was stirred for 1.0 h and then poured into satd.
aq. NaHCO.sub.3. The aqueous mixture was extracted with ethyl
acetate and the combined extracts were dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The residue was purified by Method 2 to
afford 6.0 mg of the title compound. MS (electrospray): mass
calculated for C.sub.24H.sub.30FN.sub.3O.sub.2, 411.23; m/z found,
412.4 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.82 (d,
J=8.6 Hz, 1H), 7.43-7.33 (m, 1H), 7.14-7.10 (m, 1H), 7.06-6.97 (m,
2H), 4.72 (s, 2H), 4.09 (t, J=6.3 Hz, 2H), 2.94-2.86 (m, 2H), 2.52
(s, 3H), 2.29 (s, 3H), 2.11-1.99 (m, 2H), 1.91-1.74 (m, 4H),
1.52-1.42 (m, 2H), 1.41-1.21 (m, 4H).
Example 177
##STR00185##
[0736]
{4-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-6-[4-(1-methyl-piperidin-4--
yl)-butoxy]-pyridin-3-yl}-methanol
[0737]
5-Bromo-4-dimethoxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-py-
ridine (0.5 g, 1.25 mmol, 1.0 equiv) was dissolved in THF (6 mL)
and cooled to -78.degree. C. A 2.5 M solution of n-butyllithium in
hexanes (0.6 mL, 1.5 mmol, 1.2 equiv) was added dropwise. The
solution was stirred for 45 min, and then DMF (0.55 mL, 1.25 mmol,
1.0 equiv) was added. After 1 h, sodium borohydride (38 mg, 1.36
mmol, 1.1 equiv) was added. The mixture was allowed to warm to
-40.degree. C. for 30 min, then was quenched with satd. aq.
NaHCO.sub.3 (10 mL). The mixture was extracted with chloroform
(3.times.30 mL), and the combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated to afford
{4-dimethoxymethyl-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-3-yl}-m-
ethanol as a crude mixture. This crude material (88 mg) was
dissolved in THF (3 mL) and 1.0 M HCl (3 mL) was added portionwise
over 3 h at 60.degree. C. The mixture was cooled, satd. aq.
NaHCO.sub.3 was added, and the mixture was extracted with
chloroform (3.times.30 mL). The combined extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. A portion of the
resulting crude
5-hydroxymethyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine-4-carbald-
ehyde (33 mg), 3,5-dimethyl-benzene-1,2-diamine (22 mg), and
Na.sub.2S.sub.2O.sub.5 (36 mg) were stirred in DMF (2 mL) at
90.degree. C. for 36 h. The reaction mixture was purified by Method
2 to afford 5.3 mg of the title compound. MS (electrospray): mass
calculated for C.sub.25H.sub.34N.sub.4O.sub.2, 422.27; m/z found,
423.5 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.21 (s, 1H),
7.30 (s, 1H), 7.23 (br s, 1H), 6.95 (br s, 1H), 4.68 (s, 2H), 4.34
(t, J=6.4 Hz, 2H), 2.95-2.82 (m, 2H), 2.57 (s, 3H), 2.44 (s, 3H),
2.27 (s, 3H), 2.11-1.98 (m, 2H), 1.86-1.68 (m, 4H), 1.57-1.44 (m,
2H), 1.39-1.15 (m, 5H).
Biological Examples
Binding Assay on Recombinant Human Histamine H.sub.4 Receptor
[0738] SK-N-MC cells or COS7 cells were transiently transfected
with pH4R and grown in 150 cm.sup.2 tissue culture dishes. Cells
were washed with saline solution, scraped with a cell scraper and
collected by centrifugation (1000 rpm, 5 min). Cell membranes were
prepared by homogenization of the cell pellet in 20 mM Tris-HCl
with a polytron tissue homogenizer for 10 s at high speed.
Homogenate was centrifuged at 1000 rpm for 5 min at 4.degree. C.
The supernatant was then collected and centrifuged at
20,000.times.g for 25 min at 4.degree. C. The final pellet was
resuspended in 50 mM Tris-HCl. Cell membranes were incubated with
.sup.3H-histamine (5-70 nM) in the presence or absence of excess
histamine (10,000 nM). Incubation occurred at room temperature for
45 min. Membranes were harvested by rapid filtration over Whatman
GF/C filters and washed 4 times with ice-cold 50 mM Tris HCl.
Filters were then dried, mixed with scintillant and counted for
radioactivity. SK-N-MC or COS7 cells expressing human histamine
H.sub.4 receptor were used to measure the affinity of binding of
other compounds and their ability to displace H-ligand binding by
incubating the above-described reaction in the presence of various
concentrations of inhibitor or compound to be tested. For
competition binding studies using H-histamine, K.sub.i values were
calculated, based on an experimentally determined K.sub.D value of
5 nM and a ligand concentration of 5 nM, according to Y.-C. Cheng
and W. H. Prusoff (Biochem. Pharmacol. 1973, 22(23):3099-3108):
K.sub.i=(IC.sub.50)/(1+([L]/(K.sub.D)).
Binding Assay Results
TABLE-US-00002 [0739] TABLE K.sub.i EX (nM) 1 46 2 9 3 21 4 26 5 43
6 61 7 66 8 138 9 250 10 89 11 59 12 224 13 257 14 497 15 22 16 16
17 136 18 64 19 18 20 65 21 84 22 1 23 103 24 109 25 119 26 142 27
74 28 9 29 326 30 22 31 9 32 93 33 81 34 112 35 28 36 35 37 36 38
65 39 66 40 74 41 78 42 79 43 82 44 87 45 110 46 113 47 129 48 154
49 173 50 187 51 278 52 641 53 872 54 30 55 203 56 324 57 17 58 101
59 86 60 39 61 49 62 51 63 57 64 121 65 157 66 32 67 1 68 5 69 6 70
20 71 26 72 5 73 69 74 22 75 28 76 121 77 4 78 21 79 14 80 128 81
150 82 23 83 161 84 267 85 39 86 103 87 61 88 52 89 120 90 73 91
633 92 113 93 7 94 13 95 4 96 1 97 25 98 28 99 38 100 41 101 55 102
321 103 41 104 266 105 85 106 12 107 26 108 31 109 6 110 6 111 21
112 6 113 4 114 11 115 4 116 12 117 5 118 4 119 51 120 94 121 60
122 71 123 67 124 86 125 77 126 427 127 773 128 3 129 5 130 5 131 3
132 5 133 12 134 117 135 47 136 1 137 3 138 46 139 69 140 144 141
60 142 73 143 6 144 8 145 3 146 5 147 8 148 17 149 4 150 19 151 21
152 117 153 179 154 111 155 13 156 20 157 28 158 21 159 19 160 53
161 20 162 15 163 12 164 7 165 3 166 6 167 4 168 6 169 1 170 5 171
12 172 1 173 21 174 31 175 6 176 4 177 4
Mast Cell Chemotaxis Assay
[0740] Mast cell accumulation in mucosal epithelia is a well-known
characteristic of allergic rhinitis and asthma. In addition, it is
known that mast cell numbers increase in a number of inflammatory
conditions. Some of this is due to chemotaxis of mast cells to the
sites of inflammation. This chemotaxis to specific agents can be
mimicked in vitro. Transwells (Costar, Cambridge, Mass.) of a pore
size 8 .mu.m are coated with 100 .mu.L of 100 ng/mL human
fibronectin (Sigma) for 2 h at room temperature. After removal of
the fibronectin, 600 .mu.L of RPMI with 5% BSA, in the presence of
10 .mu.M histamine, is added to the bottom chamber. To test the
various histamine receptor (HR) antagonists, 10 .mu.M and/or 1
.mu.M solutions of the test compounds are added to the top and
bottom chambers. Mast cells (2.times.10.sup.5/well) are added to
the top chamber. The plates are incubated for 3 h at 37.degree. C.
Transwells are removed and the cells in the bottom chamber are
counted for sixty seconds using a flow cytometer. HR inhibition
data are thus obtained.
Cell-Type Distribution of H.sub.4 Expression
[0741] RNA was prepared from the different cells using an RNeasy
kit (Qiagen, Valencia, Calif.) according to the manufacturer's
instructions. Total RNA was extracted from purified human cells
using the RNeasy kit (Qiagen, Valencia, Calif.) and reverse
transcribed to cDNA using the RT reaction kit (Invitrogen)
according to the manufacturer's instructions. H.sub.4 receptor RNA
was detected by RT-PCR using human H.sub.4 receptor-specific
primers 5'-ATGCCAGATACTAATAGCACA and 5'-CAGTCGGTCAGTATCTTCT. The
amplified PCR band for H.sub.4 receptor is 1170 bp.
Results
[0742] The RT-PCR results indicate that the H.sub.4 receptor is
expressed on mast cells, dendritic cells, basophils, and
eosinophils. These positive results are consistent with the
published literature (e.g. Oda et al., Nguyen et al., and Morse et
al. in the Background section). Accumulation of mast cells and
eosinophils in affected tissues is one of the principal
characteristics of allergic rhinitis and asthma. Since H.sub.4
receptor expression is found in these cell types, H.sub.4 receptor
signalling is likely to mediate the infiltration of mast cells and
eosinophils in response to histamine. The following table reports
the Cell-type Distribution of H.sub.4 Expression by RT-PCR.
TABLE-US-00003 Species Cell Type H.sub.4 Human Eosinophils +
Immature Dendritic Cells + Mature Dendritic Cells + Mast Cells +
Basophils + CD14.sup.+ Monocytes - CD4.sup.+ T Cells + CD8.sup.+ T
Cells - B Cells - Neutrophils - Mouse/(Rat) Eosinophils +
Peritoneal Mast Cells (Rat) + Bone Marrow-Derived + Mast Cells
Immature Dendritic Cells + Mature Dendritic Cells + Bone
Marrow-Derived - Macrophages Peritoneal Macrophages - CD4.sup.+ T
Cells - CD8.sup.+ T Cells - B Cells -
The Inhibition of Eosinophil Shape Change by Histamine H.sub.4
Receptor Antagonists
[0743] Eosinophil accumulation in sites of allergic reaction is a
well-known characteristic of allergic rhinitis and asthma. This
example demonstrates that histamine H.sub.4 receptor antagonists
can block the shape change response in human eosinophils in
response to histamine. Shape change is a cellular characteristic
that precedes eosinophil chemotaxis.
Methods
[0744] Human granulocytes were isolated from human blood by a
Ficoll gradient. The red blood cells were lysed with 5-10.times.
Qiagen lysis buffer at room temperature for 5-7 min. Granulocytes
were harvested and washed once with FACS buffer. The cells were
resuspended at a density of 2.times.10.sup.6 cells/mL in reaction
buffer. To test inhibition by specific histamine receptor
antagonists, 90 .mu.L of the cell suspension
(.about.2.times.10.sup.5 cells) was incubated with 10 .mu.M of one
of the various test compound solutions. After 30 min, 11 .mu.L of
one of the various concentrations of histamine was added. Ten
minutes later the cells were transferred to ice and fixed with 250
.mu.L of ice-cold fixative buffer (2% formaldehyde) for 1 min. The
shape change was quantitated using a gated autofluoescence forward
scatter assay (GAFS) (S. A. Bryan et al., Am. J. Respir. Crit. Care
Med. 2002, 165(12):1602-1609).
Results--Histamine Mediates Eosinophil Shape Change Through H.sub.4
Receptor
[0745] The change in shape of eosinophils is due to cytoskeletal
changes that preceed chemotaxis and thus is a measure of
chemotaxis. The data in the following table show that histamine
induces a dose-dependent shape change in eosinophils. Histamine
receptor (HR) antagonists were used to sort out which histamine
receptor is responsible for the shape change. Antagonists specific
for the histamine H, receptor (diphenhydramine) or the H.sub.2
receptor (ranatidine) did not alter the histamine-induced shape
change. However, a dual H.sub.3/H.sub.4 antagonist (thioperamide)
and a specific histamine H.sub.4 receptor antagonist
((5-chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone,
K.sub.i=5 nM) inhibited histamine-induced eosinophil shape change
with an IC.sub.50 of 1.5 and 0.27 .mu.M, respectively.
TABLE-US-00004 Fold Change Histamine (.mu.M): 10 1 0.1 0.01 0 No HR
1.34 1.31 1.21 1.01 1.00 Antagonist 10 .mu.M H.sub.4 1.09 1.05 1.05
1.01 1.00 Antagonist 10 .mu.M 1.08 1.05 1.01 1.04 1.00 Thiop 10
.mu.M 1.63 1.50 1.18 1.03 1.00 Diphen 10 .mu.M 1.64 1.49 1.21 1.04
1.00 Ranat
The Inhibition of Eosinophil Chemotaxis by Histamine H.sub.4
Receptor Antagonists
[0746] Eosinophil accumulation in sites of allergic reaction is a
well-known characteristic of allergic rhinitis and asthma.
Eosinophils are purified from human blood with standard methods.
Chemotaxis assays are carried out using transwells (Costar,
Cambridge, Mass.) of a pore size 5 .mu.m coated with 100 .mu.L of
100 ng/mL human fibronectin (Sigma) for 2 h at room temperature.
After removal of the fibronectin, 600 .mu.L of RPMI with 5% BSA in
the presence of histamine (ranging from 1.25-20 .mu.M) is added to
the bottom chamber. To test the various histamine receptor
antagonists 10 .mu.M of the test compounds can be added to the top
and bottom chambers. Eosinophils will be added to the top chamber
whereas histamine or chemotactic factors will be placed in the
lower chamber. The plates are incubated for 3 h at 37.degree. C.
Transwells are removed and the number of cells in the bottom
chamber can be counted for 60 s using a flow cytometer, or can be
quantitated by using Giemsa staining.
The Inhibition of Zymosan-Induced Peritonitis in Mice by Histamine
H.sub.4 Receptor Antagonists
[0747] It has been demonstrated that histamine H.sub.4 receptor
antagonists can block the peritonitis induced by zymosan, which is
the insoluble polysaccharide component on the cell wall of
Saccharomyces cerevisiae. This is commonly used to induce
peritonitis in mice and appears to act in a mast cell-dependent
manner. Compounds of the present invention can be tested in such a
model to demonstrate their use as anti-inflammatory agents. At time
0 mice are given compound or PBS, either s.c. or p.o. Fifteen
minutes later each mouse receives 1 mg zymosan A (Sigma) i.p. The
mice are sacrificed 4 h later, and the peritoneal cavities are
washed with 3 mL of PBS containing 3 mM EDTA. The number of
migrated leukocytes is determined by taking an aliquot (100 .mu.L)
of the lavage fluid and diluting 1:10 in Turk's solution (0.01%
crystal violet in 3% acetic acid). The samples are then vortexed,
and 10 .mu.L of the stained cell solution is placed in a Neubauer
haemocytometer. Differential cell counts are performed using a
light microscope (Olympus B061). In view of their chromatic
characteristics and their nucleus and cytoplasm appearance,
polymorphonuclear leukocytes (PMN; >95% neutrophils) can be
easily identified. Treatment with zymosan increases the number of
neutrophils, which is representative of an inflammatory response.
Treatment with H.sub.4 receptor antagonist blocks this
increase.
Inhibition of Mast Cell Chemotaxis by H.sub.4 Receptor Antagonist
in an Animal Model of Asthma and Allergic Rhinitis
[0748] An animal model is used to test the observation that mast
cells accumulate in response to allergic inflammation and that this
can be blocked by H.sub.4 receptor antagonists. Compounds of the
present invention can be tested in this model to demonstrate their
use as treatments for allergic rhinitis or asthma. Mice are
sensitized by intraperitoneal injection of ovalbumin/Alum (10 .mu.g
in 0.2 ml Al(OH).sub.3, 2%) on Day Q and Day 14. On Day 21 through
23 mice are challenged by PBS or ovalbumin, and sacrificed 24 h
after the last challenge on Day 24. A section of the trachea is
removed and fixed in formalin. Paraffin embedding and longitudinal
sectioning of tracheas are performed followed by staining of mast
cells with toluidine blue. Alternatively, trachea are frozen in OCT
for frozen sectioning, and mast cells are identified by IgE
staining. Mast cells are quantified as sub-mucosal or
sub-epithelial depending on their location within each tracheal
section. Exposure to allergen should increase the number of
sub-epithelial mast cells, and this effect is blocked by H.sub.4
receptor antagonists.
[0749] The features and advantages of the invention are apparent to
one of ordinary skill in the art. Based on this disclosure,
including the summary, detailed description, background, examples,
and claims, one of ordinary skill in the art will be able to make
modifications and adaptations to various conditions and usages.
Publications described herein are incorporated by reference in
their entirety. These other embodiments are also within the scope
of the invention.
Sequence CWU 1
1
3121DNAArtificialHuman H4 Receptor forward primer 1atgccagata
ctaatagcac a 21219DNAArtificialHuman H4 Receptor reverse primer
2cagtcggtca gtatcttct 1931173DNAHomo Sapiens 3atgccagata ctaatagcac
aatcaattta tcactaagca ctcgtgttac tttagcattt 60tttatgtcct tagtagcttt
tgctataatg ctaggaaatg ctttggtcat tttagctttt 120gtggtggaca
aaaaccttag acatcgaagt agttattttt ttcttaactt ggccatctct
180gacttctttg tgggtgtgat ctccattcct ttgtacatcc ctcacacgct
gttcgaatgg 240gattttggaa aggaaatctg tgtattttgg ctcactactg
actatctgtt atgtacagca 300tctgtatata acattgtcct catcagctat
gatcgatacc tgtcagtctc aaatgctgtg 360tcttatagaa ctcaacatac
tggggtcttg aagattgtta ctctgatggt ggccgtttgg 420gtgctggcct
tcttagtgaa tgggccaatg attctagttt cagagtcttg gaaggatgaa
480ggtagtgaat gtgaacctgg atttttttcg gaatggtaca tccttgccat
cacatcattc 540ttggaattcg tgatcccagt catcttagtc gcttatttca
acatgaatat ttattggagc 600ctgtggaagc gtgatcatct cagtaggtgc
caaagccatc ctggactgac tgctgtctct 660tccaacatct gtggacactc
attcagaggt agactatctt caaggagatc tctttctgca 720tcgacagaag
ttcctgcatc ctttcattca gagagacaga ggagaaagag tagtctcatg
780ttttcctcaa gaaccaagat gaatagcaat acaattgctt ccaaaatggg
ttccttctcc 840caatcagatt ctgtagctct tcaccaaagg gaacatgttg
aactgcttag agccaggaga 900ttagccaagt cactggccat tctcttaggg
gtttttgctg tttgctgggc tccatattct 960ctgttcacaa ttgtcctttc
attttattcc tcagcaacag gtcctaaatc agtttggtat 1020agaattgcat
tttggcttca gtggttcaat tcctttgtca atcctctttt gtatccattg
1080tgtcacaagc gctttcaaaa ggctttcttg aaaatatttt gtataaaaaa
gcaacctcta 1140ccatcacaac acagtcggtc agtatcttct taa 1173
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