U.S. patent application number 15/068131 was filed with the patent office on 2016-07-07 for nampt inhibitors.
This patent application is currently assigned to AbbVie Inc.. The applicant listed for this patent is AbbVie Inc.. Invention is credited to Michael L. Curtin, Todd M. Hansen, Kenton Longenecker, Marina A. Pliushchev, Ramzi F. Sweis.
Application Number | 20160193209 15/068131 |
Document ID | / |
Family ID | 48483233 |
Filed Date | 2016-07-07 |
United States Patent
Application |
20160193209 |
Kind Code |
A1 |
Sweis; Ramzi F. ; et
al. |
July 7, 2016 |
NAMPT INHIBITORS
Abstract
Disclosed are compounds which inhibit the activity of NAMPT,
compositions containing the compounds and methods of treating
diseases during which NAMPT is expressed.
Inventors: |
Sweis; Ramzi F.; (Lake
Bluff, IL) ; Curtin; Michael L.; (Pleasant Prairie,
WI) ; Pliushchev; Marina A.; (Vernon Hills, IL)
; Hansen; Todd M.; (Grayslake, IL) ; Longenecker;
Kenton; (Grayslake, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Assignee: |
AbbVie Inc.
North Chicago
IL
|
Family ID: |
48483233 |
Appl. No.: |
15/068131 |
Filed: |
March 11, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13891338 |
May 10, 2013 |
9334264 |
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15068131 |
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Current U.S.
Class: |
514/254.02 ;
514/255.05; 514/256; 514/341; 514/370; 514/371 |
Current CPC
Class: |
A61P 31/12 20180101;
A61P 1/00 20180101; A61P 13/12 20180101; A61K 31/506 20130101; A61P
35/02 20180101; A61P 43/00 20180101; A61P 17/06 20180101; A61K
31/496 20130101; A61P 9/14 20180101; A61P 17/00 20180101; A61P 1/04
20180101; A61P 37/00 20180101; A61P 29/00 20180101; A61P 25/00
20180101; A61P 11/00 20180101; A61P 19/02 20180101; A61K 31/497
20130101; C07D 417/12 20130101; A61K 31/427 20130101; C07D 417/14
20130101; A61P 37/02 20180101; A61P 9/10 20180101; A61P 3/10
20180101; A61P 35/00 20180101; A61P 25/28 20180101; A61P 31/18
20180101; A61P 11/06 20180101; A61P 37/06 20180101; A61K 31/4439
20130101; A61P 9/08 20180101; A61P 17/04 20180101; A61P 13/00
20180101; A61P 9/00 20180101; A61P 19/00 20180101 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 31/496 20060101 A61K031/496; A61K 31/497 20060101
A61K031/497; A61K 31/4439 20060101 A61K031/4439; A61K 31/427
20060101 A61K031/427 |
Claims
1-9. (canceled)
10. A method of treating inflammatory and tissue repair disorders;
particularly rheumatoid arthritis, inflammatory bowel disease,
asthma and COPD (chronic obstructive pulmonary disease),
osteoarthritis, osteoporosis and fibrotic diseases; dermatosis,
including psoriasis, atopic dermatitis and ultra-violet induced
skin damage; autoimmune diseases including systemic lupus
erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing
spondylitis, tissue and organ rejection, Alzheimer's disease,
stroke, athersclerosis, restenosis, diabetes, glomerulonephritis,
cancer, particularly wherein the cancer is selected from breast,
prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas,
leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation
associated with infection and certain viral infections, including
Acquired Immune Deficiency Syndrome (AIDS), adult respiratory
distress syndrome, and ataxia telengiectasia in a patient, said
method comprising administering to the patient a therapeutically
effective amount of a compound of formula (I), or a therapeutically
acceptable salt thereof, ##STR00015## wherein R.sup.1 and R.sup.2
are each independently selected from the group consisting of
R.sup.6, C(O)R.sup.6, C(O)NHR.sup.6, and C(O)N(R.sup.6).sub.2:
wherein at least one of R.sup.1 and R.sup.2 is R.sup.6; or R.sup.1
and R.sup.2, together with the nitrogen to which they are attached
form a heterocycloalkyl or heterocycloalkenyl ring: wherein the
ring formed with R.sup.1 and R.sup.2 together with the nitrogen to
which they are attached is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7,
C(O)R.sup.7, CO(O)R.sup.7, OC(O)R.sup.7, OC(O)OR.sup.7, NH.sub.2,
NHR.sup.7, N(R.sup.7).sub.2, NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7,
NHS(O).sub.2R.sup.7, NR.sup.7S(O).sub.2R.sup.7, NHC(O)OR.sup.7,
NR.sup.7C(O)OR.sup.7, NHC(O)NH.sub.2, NHC(O)NHR.sup.7,
NHC(O)N(R.sup.7).sub.2, NR.sup.7C(O)NHR.sup.7,
NR.sup.7C(O)N(R.sup.7).sub.2, C(O)NH.sub.2, C(O)NHR.sup.7,
C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
R.sup.3, R.sup.4, and R.sup.5 are each independently selected from
the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, C.sub.1-6
hydroxyalkyl, F, Cl, Br and I; R.sup.6, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.6 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8SO.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N, NO.sub.2, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9), C(O)H,
C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2, CNOH,
CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F Cl, Br and I; R.sup.7, at
each occurrence, is independently selected from the group
consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by R.sup.7 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.7 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I; R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl: wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.10, OR.sup.10,
SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10, C(O)R.sup.10,
CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10, NH.sub.2, NHR.sup.10,
N(R.sup.10).sub.2, NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10,
NHS(O).sub.2R.sup.10, NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
R.sup.9, at each occurrence, is independently selected from the
group consisting of C.sub.1-6 alkyl C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6 alkyl,
C.sub.1-6 alkenyl, and C.sub.2-6 alkynyl represented by R.sup.9 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12,
C(O)R.sup.12, CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
NH.sub.2, NHR.sup.12, N(R.sup.12).sub.2, NHC(O)R.sup.12,
NR.sup.12C(O)R.sup.12, NHS(O).sub.2R.sup.12,
NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3s OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
R.sup.10, at each occurrence, is independently selected from the
group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, and C.sub.1-6 hydroxyalkyl; R.sup.11,
at each occurrence, is independently selected from the group
consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by R.sup.11
are each independently optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I; and R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl: wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.13 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of alkoxy, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
11-13. (canceled)
Description
[0001] This application claims priority to Patent Cooperation
Treaty Patent Application Serial No. PCT/CN2012/075327, filed May
11, 2012, which is incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention pertains to compounds which inhibit the
activity of NAMPT, compositions containing the compounds, and
methods of treating diseases during which NAMPT is expressed.
BACKGROUND OF THE INVENTION
[0003] NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that
plays a critical role in many physiologically essential processes
(Ziegkel, M. Eur. J. Biochem. 267, 1550-1564, 2000). NAD is
necessary for several signaling pathways including among others
poly ADP-ribosylation in DNA repair, mono-ADP-ribosylation in both
the immune system and G-protein-coupled signaling, and NAD is also
required by sirtuins for their deacetylase activity (Garten, A. et
al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).
[0004] NAMPT (also known as pre-B-cell-colony-enhancing factor
(PBEF) and visfatin) is an enzyme that catalyzes the
phosphoribosylation of nicotinamide and is the rate-limiting enzyme
in one of two pathways that salvage NAD.
##STR00001##
[0005] Increasing evidence suggests that NAMPT inhibitors have
potential as anticancer agents. Cancer cells have a higher basal
turnover of NAD and also display higher energy requirements
compared with normal cells. Additionally, increased NAMPT
expression has been reported in colorectal cancer (Van Beijnum, J.
R. et allnt. J. Cancer 101, 118-127, 2002) and NAMPT is involved in
angiogenesis (Kim, S. R. et al. Biochem. Biophys. Res. Commun. 357,
150-156, 2007). Small-molecule inhibitors of NAMPT have been shown
to cause depletion of intracellular NAD+ levels and ultimately
induce tumor cell death (Hansen, C M et al. Anticancer Res. 20,
42111-4220, 2000) as well as inhibit tumor growth in xenograft
models (Olese, U. H. et al. Mol Cancer Ther. 9, 1609-1617,
2010).
[0006] NAMPT inhibitors also have potential as therapeutic agents
in inflammatory and metabolic disorders (Galli, M. et al Cancer
Res. 70, 8-11, 2010). For example, NAMPT is the predominant enzyme
in T and B lymphocytes. Selective inhibition of NAMPT leads to NAD+
depletion in lymphocytes blocking the expansion that accompanies
autoimmune disease progression whereas cell types expressing the
other NAD+ generating pathways might be spared. A small molecule
NAMPT inhibitor (FK866) has been shown to selectively block
proliferation and induce apoptosis of activated T cells and was
efficacious in animal models of arthritis (collagen-induced
arthritis) (Busso, N. et al. Plos One 3, e2267, 2008). FK866
ameliorated the manifestations of experimental autoimmune
encephalomyelitis (EAE), a model of T-cell mediated autoimmune
disorders. (Bruzzone, S et al. Plos One 4, e7897, 2009). NaMPT
activity increases NF-kB transcriptional activity in human vascular
endothelial cell, resulting in MMP-2 and MMP-9 activation,
suggesting a role for NAMPT inhibitors in the prevention of
inflammatory mediated complications of obesity and type 2 diabetes
(Adya, R. et. Al. Diabetes Care, 31, 758-760, 2008).
SUMMARY OF THE INVENTION
[0007] One embodiment of this invention, therefore, pertains to
compounds or pharmaceutically acceptable salts thereof, which are
useful as inhibitors of NAMPT, the compounds having Formula (I)
##STR00002##
wherein
[0008] R.sup.1 and R.sup.2 are each independently selected from the
group consisting of R.sup.6, C(O)R.sup.6, C(O)NHR.sup.6, and
C(O)N(R.sup.6).sub.2; wherein at least one of R.sup.1 and R.sup.2
is R.sup.6; or R.sup.1 and R.sup.2, together with the nitrogen to
which they are attached form a heterocycloalkyl or
heterocycloalkenyl ring; wherein the ring formed with R.sup.1 and
R.sup.2 together with the nitrogen to which they are attached is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7,
OC(O)R.sup.7, OC(O)OR.sup.7, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7, NHS(O).sub.2R.sup.7,
NR.sup.7S(O).sub.2R.sup.7, NHC(O)OR.sup.7, NR.sup.7C(O)OR.sup.7,
NHC(O)NH.sub.2, NHC(O)NHR.sup.7, NHC(O)N(R.sup.7).sub.2,
NR.sup.7C(O)NHR.sup.7, NR.sup.7C(O)N(R.sup.7).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0009] R.sup.3, R.sup.4, and R.sup.5 are each independently
selected from the group consisting of hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 hydroxyalkyl, F, Cl, Br and I;
[0010] R.sup.6, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.6 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.8, OR.sup.8, SR.sup.8, S(O)R.sup.8, SO.sub.2R.sup.8,
C(O)R.sup.8, CO(O)R.sup.8, OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2,
NHR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8,
NHS(O).sub.2R.sup.8, NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8,
NR.sup.8C(O)OR.sup.8, NHC(O)NH.sub.2, NHC(O)NHR.sup.8,
NHC(O)N(R.sup.8).sub.2, NR.sup.8C(O)NHR.sup.8,
NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8SO.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0011] R.sup.7, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.7 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3,
NO.sub.2, F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.7 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I;
[0012] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.8 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
C(O)R.sup.10, CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10,
NH.sub.2, NHR.sup.10, N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHS(O).sub.2R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0013] R.sup.9, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.9 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12,
C(O)R.sup.12, CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
NH.sub.2, NHR.sup.12, N(R.sup.12).sub.2, NHC(O)R.sup.12,
NR.sup.12C(O)R.sup.12, NHS(O).sub.2R.sup.12,
NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0014] R.sup.10, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6haloalkyl, and C.sub.1-6
hydroxyalkyl;
[0015] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.11 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0016] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.12 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; and
[0017] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl represented by R.sup.13 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of alkoxy,
NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and
I.
[0018] In one embodiment of Formula (I), R.sup.1 is C(O)R.sup.6;
and R.sup.2 is R.sup.6. In another embodiment of Formula (I),
R.sup.1 and R.sup.2 are each R.sup.6. In another embodiment of
Formula (I), R.sup.1 is C(O)NHR.sup.6; and R.sup.2 is R.sup.6. In
another embodiment of Formula (I), R.sup.1 is C(O)N(R.sup.6).sub.2;
and R.sup.2 is R.sup.6. In another embodiment of Formula (I),
R.sup.3, R.sup.4 and R.sup.5 are hydrogen. In another embodiment of
Formula (I), R.sup.6, at each occurrence, is independently selected
from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
aryl, heterocycloalkyl, heteroaryl, and cycloalkyl; wherein the
C.sub.1-6 alkyl, and C.sub.2-6 alkenyl represented by R.sup.6 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, CO(O)R.sup.8, OC(O)R.sup.8,
N(R.sup.8).sub.2, NHC(O)R.sup.8, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the aryl,
heterocycloalkyl, heteroaryl, and cycloalkyl represented by R.sup.6
are each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)NH.sub.2, C(O)OH, OH, CN, F, Cl, Br and
I.
[0019] Still another embodiment pertains to compounds, which are
[0020]
2-{(4-fluorobenzyl)[4-(pyridin-3-yl)benzyl]amino}-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0021]
N-[3-(1H-imidazol-1-yl)propyl]-2-{methyl[4-(pyridin-3-yl)benzyl]amino}-1,-
3-thiazole-5-carboxamide; [0022]
2-[(4-fluorobenzyl)(methyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0023]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0024]
2-[(cyclohexylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0025]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0026]
2-{(4-fluorobenzyl)[3-(morpholin-4-yl)propyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0027] 2-{(4-fluorobenzyl)
[3-(piperidin-1-yl)propyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide; [0028] 2-{(4-fluorobenzyl)
[2-(pyrrolidin-1-yl)ethyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide; [0029] 2-[(4-fluorobenzyl)
{2-[4-(propan-2-yl)piperazin-1-yl]ethyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0030]
2-[(4-cyanobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0031]
2-[(3-chlorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0032]
2-[(4-fluorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0033]
2-{[(5-chloro-1,3-benzodioxol-4-yl)methyl](4-fluorobenzyl)amino}-N-[3-(1H-
-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0034]
2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0035]
2-[(2-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0036]
2-[(2,5-dichlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0037]
2-{(4-fluorobenzyl)[2-(methylamino)-2-oxoethyl]amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0038]
2-{(4-fluorobenzyl)[2-oxo-2-(propan-2-ylamino)ethyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0039]
2-{[2-(dimethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0040]
2-{[2-(diethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0041]
2-{(4-fluorobenzyl)[2-(morpholin-4-yl)-2-oxoethyl]amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0042]
2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0043]
2-[(4-fluorobenzyl)(methoxyacetyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0044]
2-[(4-fluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0045]
2-[(N,N-dimethylglycyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0046]
2-[(3,6-dihydropyridin-1(2H)-ylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0047]
2-{(4-fluorobenzyl)
[(4-methylpiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-
-thiazole-5-carboxamide; [0048] 2-{(4-fluorobenzyl)
[(4-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0049]
2-{(4-fluorobenzyl)[(4-methylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0050]
2-[(4-fluorobenzyl)
{[4-(propan-2-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0051]
2-{(4-fluorobenzyl)[(4-formylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0052]
2-[(4-fluorobenzyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylacetyl)amino]--
N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0053]
2-[{[4-(cyclopropylmethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0054]
2-[{[4-(2-ethoxyethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3-(-
1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0055]
2-[(cyclopropylcarbonyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0056] 2-[(4-fluorobenzyl)
{[4-(prop-2-en-1-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0057] 2-[(4-fluorobenzyl)
{[4-(3-methoxypropyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0058]
2-[{[3-(dimethylamino)pyrrolidin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0059]
2-[(4-fluorobenzyl)(morpholin-4-ylacetyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0060] 2-{(4-fluorobenzyl)
[(3-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0061] 2-[(4-fluorobenzyl)
{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0062]
2-[(1,4-dioxa-7-azaspiro[4.4]non-7-ylacetyl)
(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carb-
oxamide; [0063]
1-{2-[(4-fluorobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thia-
zol-2-yl)amino]-2-oxoethyl}pyridinium; [0064]
2-{[2-(4-fluorophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0065]
2-[(4-fluorobenzyl)(propan-2-ylcarbamoyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0066]
2-[(4-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0067]
2-{[2-(4-cyanophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0068]
2-{[2-(4-cyanophenyl)ethyl](tetrahydro-2H-pyran-4-ylacetyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0069]
2-[(4-cyanobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0070]
2-[(4-cyanobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0071]
2-{[2-(4-cyanophenyl)ethyl](tetrahydrofuran-3-ylacetyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0072]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(2-methyl-1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0073]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(4-methyl-1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0074]
2-[(2-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0075]
2-[(3-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0076]
2-[(2-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0077]
2-[(3-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0078]
2-[(4-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0079]
2-[(4-cyanobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0080]
2-[(4-cyanobenzyl)(tetrahydrofuran-3-ylacetyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0081]
2-[(4-cyanobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)propy-
l]-1,3-thiazole-5-carboxamide; [0082]
2-{(4-fluorobenzyl)[(3-methylbutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0083] 2-{(4-fluorobenzyl)
[(2-methylpropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0084]
N.sup.1-(4-fluorobenzyl)-N.sup.1-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoy-
l}-1,3-thiazol-2-yl)piperidine-1,3-dicarboxamide; [0085]
2-{(4-fluorobenzyl)
[(3-hydroxyazetidin-1-yl)carbonyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0086]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxamide; [0087]
2-{(4-fluorobenzyl)[(3-methoxypyrrolidin-1-yl)carbonyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0088]
2-{(4-fluorobenzyl)[(2-methoxyethyl)(methyl)carbamoyl]amino}-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0089]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,6-dimethylmorpholine-4-carboxamide; [0090]
2-{[ethyl(2-methoxyethyl)carbamoyl](4-fluorobenzyl(4-fluorobenzyl)amino}--
N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0091]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,2-dimethylmorpholine-4-carboxamide; [0092]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-oxazepane-4-carboxamide; [0093]
2-[(4-fluorobenzoyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0094]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(4-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0095]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-N-(3-methy-
lbutyl)-1,2-oxazole-5-carboxamide; [0096]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenoxypropanoyl)amin-
o]-1,3-thiazole-5-carboxamide; [0097]
2-{(4-fluorobenzyl)[(2-propoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0098] 2-{(4-fluorobenzyl)
[(tetrahydrofuran-2-ylmethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0099]
2-{(4-fluorobenzyl)[(1-methoxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0100]
2-{(4-fluorobenzyl)[(tetrahydro-2H-pyran-2-ylmethyl)carbamoyl]amino}-N-[3-
-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0101]
2-{(4-fluorobenzyl)[(2-methoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0102]
2-{[(2-ethoxyethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0103]
2-{(4-fluorobenzyl)[(1-methoxybutan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0104]
2-{[2-(4-cyanophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0105]
2-{[(1,3-dioxolan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0106]
2-[(4-fluorobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0107]
2-{[(1,4-dioxan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0108]
2-{[(1,3-dimethoxypropan-2-yl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0109]
2-{(4-fluorobenzyl)[(2-methoxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0110]
2-[(4-fluorobenzyl)(tetrahydrofuran-3-ylcarbamoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0111]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-3-ylcarbamoyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0112]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyrimidin-2-ylmeth-
yl)amino]-1,3-thiazole-5-carboxamide; [0113]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(2-methoxypyridin-4-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0114]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(1,3-oxazol-4-ylmet-
hyl)amino]-1,3-thiazole-5-carboxamide; [0115]
2-{[(5-chloropyridin-2-yl)methyl](3-methoxypropanoyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0116]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(4-methylpyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0117] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methoxypyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0118] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0119]
2-{[2-(3-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0120]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyridin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide acetate
(1:1); [0121]
2-{[2-(1,3-benzodioxol-5-yl)ethyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0122]
2-{[2-(4-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0123]
2-{[2-(3-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0124]
2-{[2-(4-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0125]
2-{[2-(3-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0126]
N-[3-(1H-imidazol-1-yl)propyl]-2-{[2-(3-methoxyphenyl)ethyl](3-methoxypro-
panoyl)amino}-1,3-thiazole-5-carboxamide acetate (1:1); [0127]
2-{[2-(2-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0128]
2-{[2-hydroxy-2-(4-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0129]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[1-(pyridin-2-yl)et-
hyl]amino}-1,3-thiazole-5-carboxamide; [0130]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[(1-methyl-1H-pyraz-
ol-4-yl)methyl]amino}-1,3-thiazole-5-carboxamide; [0131]
2-[(2,6-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0132]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methylpyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0133]
2-[(4-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0134]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyrazin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0135]
2-[(3-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0136]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyridin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0137]
2-[(2,5-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0138]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(2-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0139]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0140]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-2-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0141]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-3-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0142] 2-[(4-cyanobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide;
[0143]
2-{(4-cyanobenzyl)[(2-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0144]
2-[(4-cyanobenzyl)
{[2-(2-hydroxyethoxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0145] 2-[(4-cyanobenzyl)
{[3-(propan-2-yloxy)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0146]
2-{(4-cyanobenzyl)[(3-hydroxy-2,2-dimethylpropyl)carbamoyl]amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0147]
2-{(4-cyanobenzyl)[(2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0148]
2-{(4-cyanobenzyl)[(1-hydroxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0149]
2-{(4-cyanobenzyl)[(3-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0150] 2-[(4-cyanobenzyl)
{[(2S)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0151]
2-{(4-cyanobenzyl)[(4-hydroxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0152]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2R)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0153]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2S)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0154]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-5-methyl-N-
-(3-methylbutyl)-1,2-oxazole-3-carboxamide; [0155]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(phenoxyacetyl)amino]-1,-
3-thiazole-5-carboxamide; [0156]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(3-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0157]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0158]
2-{[(4-fluorophenyl)acetyl](3-methylbutyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0159]
2-{[(3-amino-3-oxopropyl)carbamoyl](4-cyanobenzyl)amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0160]
2-[{[3-(acetylamino)-2-methylpropyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0161]
2-[(4-cyanobenzyl){[3-(dimethylamino)-3-oxopropyl]carbamoyl}amino]-N-[3-(-
1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0162]
2-{(4-cyanobenzyl)[(3-ethoxy-2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0163]
2-[(4-cyanobenzyl)
{[3-(diethylamino)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0164]
2-[{[2-(acetylamino)ethyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0165]
2-[(4-cyanobenzyl)
{[2-(diethylamino)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0166]
2-[(4-cyanobenzyl)({2-[(2-methylpropanoyl)amino]ethyl}carbamoyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0167]
2-[(4-cyanobenzyl)
{[(2R)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0168] 2-[(4-cyanobenzyl)
{[3-(3-hydroxyazetidin-1-yl)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0169]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbutyl)amin-
o]-1,3-thiazole-5-carboxamide; [0170]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(methoxyacetyl)(3-methylbutyl)amino]-1,-
3-thiazole-5-carboxamide; [0171]
2-[(cyclopropylcarbonyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0172]
(2S)-1-[(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)(3-me-
thylbutyl)amino]-1-oxopropan-2-yl acetate; [0173]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydro-2H-pyran-4-y-
lacetyl)amino]-1,3-thiazole-5-carboxamide; [0174]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylcar-
bonyl)amino]-1,3-thiazole-5-carboxamide; [0175]
2-{[2-hydroxy-2-(3-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0176]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyrazin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0177]
2-{[1-(3-hydroxyphenyl)propan-2-yl](3-methoxypropanoyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0178] ethyl
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alaninate; [0179] ethyl
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [0180] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [0181] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoate; [0182] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoate; [0183]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}cyclobutanecarboxylic acid; [0184] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoate; [0185]
2-{(4-cyanobenzyl)[(3-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0186]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [0187]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoic acid; [0188]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoic acid; [0189]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoic acid; [0190]
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alanine; [0191]
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [0192]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-2-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0193]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0194]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(3-methoxypropanoyl)ami-
no]-1,3-thiazole-5-carboxamide; [0195]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methoxypropyl)am-
ino]-1,3-thiazole-5-carboxamide; [0196]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydro-2H-pyra-
n-2-ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0197]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydrofuran-2--
ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0198]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(propan-2-yloxy)ethyl]amino}-1,3-thiazole-5-carboxamide; [0199]
2-{[2-(1,3-dioxolan-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0200]
2-[(1,4-dioxan-2-ylmethyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0201]
2-{[3-(4-fluorophenyl)propanoyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0202]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)
[3-(pyridin-3-yl)propanoyl]amino}-1,3-thiazole-5-carboxamide;
[0203]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-3-ylacetyl)ami-
no]-1,3-thiazole-5-carboxamide; [0204]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(naphthalen-2-ylacetyl)-
amino]-1,3-thiazole-5-carboxamide; [0205]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)[(4-phenoxyphenyl)acety-
l]amino}-1,3-thiazole-5-carboxamide; [0206]
2-{[(4-cyanophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0207]
2-{[(4-aminophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0208]
2-[{2-[di(prop-2-en-1-yl)amino]ethyl}(3-methoxypropanoyl)amino]-N-[3-(1H--
imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0209]
2-{[3-(diethylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0210]
2-{[2-(diethylamino)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0211]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(pyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0212]
2-{[(1-ethyl-5-oxopyrrolidin-3-yl)methyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0213]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-oxopyrrolidin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0214]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[3-oxo-3-(pyrrolidi-
n-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide; [0215]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[2-oxo-2-(piperidin-
-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0216]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0217] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0218] N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)
{2-[(2-methylpropanoyl)amino]ethyl}amino]-1,3-thiazole-5-carboxamide;
[0219] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(methylamino)-3-oxopropyl]amino}-1,3-thiazole-5-carboxamide;
[0220]
2-{[3-(acetylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0221]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0222]
2-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0223]
2-[3-(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0224]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydro-2H-pyran-4-ylcarbonyl)amino}-
-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0225]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydrofuran-3-ylcarbonyl)amino}-N-[-
3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0226]
2-{[2-(5-chloropyridin-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0227]
2-{[2-(5-chloropyridin-2-yl)ethyl](tetrahydrofuran-3-ylcarbonyl)amino}-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0228]
2-{[2-(5-chloropyridin-2-yl)ethyl][(2-methoxy
ethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carb-
oxamide; [0229]
2-([2-(5-chloropyridin-2-yl)ethyl]{[2-(propan-2-yloxy)ethyl]carbamoyl}ami-
no)-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide;
[0230]
2-[(1,3-benzodioxol-5-ylacetyl)(2-methoxyethyl)amino]-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0231]
2-{(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxaz-
olidin-3-yl}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide;
[0232]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-2-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; and pharmaceutically
acceptable salts thereof.
[0233] Another embodiment pertains to a composition for treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic upus erythematosis, multiple sclerosis,
psoriatic arthritis, ankylosing spondylitis, tissue and organ
rejection, Alzheimer's disease, stroke, athersclerosis, restenosis,
diabetes, glomerulonephritis, cancer, particularly wherein the
cancer is selected from breast, prostate, lung, colon, cervix,
ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia, said composition comprising an excipient and a
therapeutically effective amount of a compound of Formula (I), or
pharmaceutically acceptable salts thereof.
[0234] Another embodiment pertains to a method of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia in a patient, said method comprising administering
to the patient a therapeutically effective amount of a compound of
Formula (I), or pharmaceutically acceptable salts thereof.
[0235] Another embodiment pertains to a method of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia or spleen cancer in a patient, said method
comprising administering to the patient therapeutically effective
amount of the compound of Formula (I), or pharmaceutically
acceptable salts thereof; and a therapeutically effective amount of
one additional therapeutic agent or more than one additional
therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
[0236] This detailed description is intended only to acquaint
others skilled in the art with Applicants' invention, its
principles, and its practical application so that others skilled in
the art may adapt and apply the invention in its numerous forms, as
they may be best suited to the requirements of a particular use.
This description and its specific examples are intended for
purposes of illustration only. This invention, therefore, is not
limited to the embodiments described in this patent application,
and may be variously modified.
ABBREVIATIONS AND DEFINITIONS
[0237] Unless otherwise defined herein, scientific and technical
terms used in connection with the present invention shall have the
meanings that are commonly understood by those of ordinary skill in
the art. The meaning and scope of the terms should be clear,
however, in the event of any latent ambiguity, definitions provided
herein take precedent over any dictionary or extrinsic definition.
In this application, the use of "or" means "and/or" unless stated
otherwise. Furthermore, the use of the term "including", as well as
other forms, such as "includes" and "included", is not limiting.
With reference to the use of the words "comprise" or "comprises" or
"comprising" in this patent application (including the claims),
Applicants note that unless the context requires otherwise, those
words are used on the basis and clear understanding that they are
to be interpreted inclusively, rather than exclusively, and that
Applicants intend each of those words to be so interpreted in
construing this patent application, including the claims below. For
a variable that occurs more than one time in any substituent or in
the compound of the invention or any other formulae herein, its
definition on each occurrence is independent of its definition at
every other occurrence. Combinations of substituents are
permissible only if such combinations result in stable compounds.
Stable compounds are compounds which can be isolated in a useful
degree of purity from a reaction mixture.
[0238] It is meant to be understood that proper valences are
maintained for all combinations herein, that monovalent moieties
having more than one atom are attached through their left ends, and
that divalent moieties are drawn from left to right.
[0239] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0240] The term "alkyl" (alone or in combination with another
term(s)) means a straight- or branched-chain saturated hydrocarbyl
substituent typically containing from 1 to about 10 carbon atoms;
or in another embodiment, from 1 to about 8 carbon atoms; in
another embodiment, from 1 to about 6 carbon atoms; and in another
embodiment, from 1 to about 4 carbon atoms. Examples of such
substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl and
the like.
[0241] The term "alkenyl" (alone or in combination with another
term(s)) means a straight- or branched-chain hydrocarbyl
substituent containing one or more double bonds and typically from
2 to about 10 carbon atoms; or in another embodiment, from 2 to
about 8 carbon atoms; in another embodiment, from 2 to about 6
carbon atoms; and in another embodiment, from 2 to about 4 carbon
atoms. Examples of such substituents include ethenyl (vinyl),
2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl,
2-butenyl, and 3-butenyl and the like.
[0242] The term "alkynyl" (alone or in combination with another
term(s)) means a straight- or branched-chain hydrocarbyl
substituent containing one or more triple bonds and typically from
2 to about 10 carbon atoms; or in another embodiment, from 2 to
about 8 carbon atoms; in another embodiment, from 2 to about 6
carbon atoms; and in another embodiment, from 2 to about 4 carbon
atoms. Examples of such substituents include ethynyl, 2-propynyl,
3-propynyl, 2-butynyl, and 3-butynyl and the like.
[0243] The term "carbocyclyl" (alone or in combination with another
term(s)) means a saturated cyclic (i.e., "cycloalkyl"), partially
saturated cyclic (i.e., "cycloalkenyl"), or completely unsaturated
(i.e., "aryl") hydrocarbyl substituent containing from 3 to 14
carbon ring atoms ("ring atoms" are the atoms bound together to
form the ring or rings of a cyclic substituent). A carbocyclyl may
be a single-ring (monocyclic) or polycyclic ring structure.
[0244] A carbocyclyl may be a single ring structure, which
typically contains from 3 to 8 ring atoms, more typically from 3 to
6 ring atoms, and even more typically 5 to 6 ring atoms. Examples
of such single-ring carbocyclyls include cyclopropyl
(cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl
(cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl
(cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A
carbocyclyl may alternatively be polycyclic (i.e., may contain more
than one ring). Examples of polycyclic carbocyclyls include
bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic
carbocyclyl, one atom is common to two different rings. An example
of a spirocyclic carbocyclyl is spiropentanyl. In a bridged
carbocyclyl, the rings share at least two common non-adjacent
atoms. Examples of bridged carbocyclyls include
bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl.
In a fused-ring carbocyclyl system, two or more rings may be fused
together, such that two rings share one common bond. Examples of
two- or three-fused ring carbocyclyls include naphthalenyl,
tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl
(dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
[0245] The term "cycloalkyl" (alone or in combination with another
term(s)) means a saturated cyclic hydrocarbyl substituent
containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a
single carbon ring, which typically contains from 3 to 8 carbon
ring atoms and more typically from 3 to 6 ring atoms. Examples of
single-ring cycloalkyls include cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl. A cycloalkyl may alternatively be
polycyclic or contain more than one ring. Examples of polycyclic
cycloalkyls include bridged, fused, and spirocyclic
carbocyclyls.
[0246] The term "aryl" (alone or in combination with another
term(s)) means an aromatic carbocyclyl containing from 6 to 14
carbon ring atoms. An aryl may be monocyclic or polycyclic (i.e.,
may contain more than one ring). In the case of polycyclic aromatic
rings, only one ring the polycyclic system is required to be
unsaturated while the remaining ring(s) may be saturated, partially
saturated or unsaturated. Examples of aryls include phenyl,
naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.
[0247] In some instances, the number of carbon atoms in a
hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or
cycloalkyl) is indicated by the prefix "C.sub.x-C.sub.y-", wherein
x is the minimum and y is the maximum number of carbon atoms in the
substituent. Thus, for example, "C.sub.1-C.sub.6-alkyl" refers to
an alkyl substituent containing from 1 to 6 carbon atoms.
[0248] Illustrating further, C.sub.3-C.sub.5-cycloalkyl means a
saturated hydrocarbyl ring containing from 3 to 8 carbon ring
atoms.
[0249] The term "hydrogen" (alone or in combination with another
term(s)) means a hydrogen radical, and may be depicted as --H.
[0250] The term "hydroxy" (alone or in combination with another
term(s)) means --OH.
[0251] The term "carboxy" (alone or in combination with another
term(s)) means --C(O)--OH.
[0252] The term "amino" (alone or in combination with another
term(s)) means --NH.sub.2.
[0253] The term "halogen" or "halo" (alone or in combination with
another term(s)) means a fluorine radical (which may be depicted as
--F), chlorine radical (which may be depicted as --Cl), bromine
radical (which may be depicted as --Br), or iodine radical (which
may be depicted as --I).
[0254] If a substituent is described as being "substituted", a
non-hydrogen radical is in the place of hydrogen radical on a
carbon or nitrogen of the substituent. Thus, for example, a
substituted alkyl substituent is an alkyl substituent in which at
least one non-hydrogen radical is in the place of a hydrogen
radical on the alkyl substituent. To illustrate, monofluoroalkyl is
alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl
substituted with two fluoro radicals. It should be recognized that
if there are more than one substitution on a substituent, each
non-hydrogen radical may be identical or different (unless
otherwise stated).
[0255] If a substituent is described as being "optionally
substituted", the substituent may be either (1) not substituted or
(2) substituted. If a substituent is described as being optionally
substituted with up to a particular number of non-hydrogen
radicals, that substituent may be either (1) not substituted; or
(2) substituted by up to that particular number of non-hydrogen
radicals or by up to the maximum number of substitutable positions
on the substituent, whichever is less. Thus, for example, if a
substituent is described as a heteroaryl optionally substituted
with up to 3 non-hydrogen radicals, then any heteroaryl with less
than 3 substitutable positions would be optionally substituted by
up to only as many non-hydrogen radicals as the heteroaryl has
substitutable positions. To illustrate, tetrazolyl (which has only
one substitutable position) would be optionally substituted with up
to one non-hydrogen radical. To illustrate further, if an amino
nitrogen is described as being optionally substituted with up to 2
non-hydrogen radicals, then a primary amino nitrogen will be
optionally substituted with up to 2 non-hydrogen radicals, whereas
a secondary amino nitrogen will be optionally substituted with up
to only 1 non-hydrogen radical.
[0256] This patent application uses the terms "substituent" and
"radical" interchangeably.
[0257] The prefix "halo" indicates that the substituent to which
the prefix is attached is substituted with one or more
independently selected halogen radicals. For example, haloalkyl
means an alkyl substituent in which at least one hydrogen radical
is replaced with a halogen radical. Examples of haloalkyls include
chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized
that if a substituent is substituted by more than one halogen
radical, those halogen radicals may be identical or different
(unless otherwise stated).
[0258] The prefix "perhalo" indicates that every hydrogen radical
on the substituent to which the prefix is attached is replaced with
independently selected halogen radicals, i.e., each hydrogen
radical on the substituent is replaced with a halogen radical. If
all the halogen radicals are identical, the prefix typically will
identify the halogen radical. Thus, for example, the term
"perfluoro" means that every hydrogen radical on the substituent to
which the prefix is attached is substituted with a fluorine
radical. To illustrate, the term "perfluoroalkyl" means an alkyl
substituent wherein a fluorine radical is in the place of each
hydrogen radical.
[0259] The term "carbonyl" (alone or in combination with another
term(s)) means --C(O)--.
[0260] The term "aminocarbonyl" (alone or in combination with
another term(s)) means --C(O)--NH.sub.2.
[0261] The term "oxo" (alone or in combination with another
term(s)) means (.dbd.O).
[0262] The term "oxy" (alone or in combination with another
term(s)) means an ether substituent, and may be depicted as
--O--.
[0263] The term "alkylhydroxy" (alone or in combination with
another term(s)) means -alkyl-OH.
[0264] The term "alkylamino" (alone or in combination with another
term(s)) means -alkyl-NH.sub.2.
[0265] The term "alkyloxy" (alone or in combination with another
term(s)) means an alkylether substituent, i.e., --O-alkyl. Examples
of such a substituent include methoxy (--O--CH.sub.3), ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and
tert-butoxy.
[0266] The term "alkylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-alkyl.
[0267] The term "aminoalkylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-alkyl-NH.sub.2.
[0268] The term "alkyloxycarbonyl" (alone or in combination with
another term(s)) means --C(O)--O-alkyl.
[0269] The term "carbocyclylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-carbocyclyl.
[0270] Similarly, the term "heterocyclylcarbonyl" (alone or in
combination with another term(s)) means --C(O)-heterocyclyl.
[0271] The term "carbocyclylalkylcarbonyl" (alone or in combination
with another term(s)) means --C(O)-alkyl-carbocyclyl.
[0272] Similarly, the term "heterocyclylalkylcarbonyl" (alone or in
combination with another term(s)) means
--C(O)-alkyl-heterocyclyl.
[0273] The term "carbocyclyloxycarbonyl" (alone or in combination
with another term(s)) means --C(O)--O-carbocyclyl.
[0274] The term "carbocyclylalkyloxycarbonyl" (alone or in
combination with another term(s)) means
--C(O)--O-alkyl-carbocyclyl.
[0275] The term "thio" or "thia" (alone or in combination with
another term(s)) means a thiaether substituent, i.e., an ether
substituent wherein a divalent sulfur atom is in the place of the
ether oxygen atom. Such a substituent may be depicted as --S--.
This, for example, "alkyl-thio-alkyl" means alkyl-S-alkyl
(alkyl-sulfanyl-alkyl).
[0276] The term "thiol" or "sulfhydryl" (alone or in combination
with another term(s)) means a sulfhydryl substituent, and may be
depicted as --SH.
[0277] The term "(thiocarbonyl)" (alone or in combination with
another term(s)) means a carbonyl wherein the oxygen atom has been
replaced with a sulfur. Such a substituent may be depicted as
--C(S)--.
[0278] The term "sulfonyl" (alone or in combination with another
term(s)) means --S(O).sub.2--.
[0279] The term "aminosulfonyl" (alone or in combination with
another term(s)) means --S(O).sub.2--NH.sub.2.
[0280] The term "sulfinyl" or "sulfoxido" (alone or in combination
with another term(s)) means --S(O)--.
[0281] The term "heterocyclyl" (alone or in combination with
another term(s)) means a saturated (i.e., "heterocycloalkyl"),
partially saturated (i.e., "heterocycloalkenyl"), or completely
unsaturated (i.e., "heteroaryl") ring structure containing a total
of 3 to 14 ring atoms. At least one of the ring atoms is a
heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining
ring atoms being independently selected from the group consisting
of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a
single-ring (monocyclic) or polycyclic ring structure.
[0282] A heterocyclyl may be a single ring, which typically
contains from 3 to 7 ring atoms, more typically from 3 to 6 ring
atoms, and even more typically 5 to 6 ring atoms. Examples of
single-ring heterocyclyls include 1,2,3,6-tetrahydropyridine,
thiomorpholinyl, tetrahydropyranyl, furanyl, dihydrofuranyl,
tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl,
tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,
imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,
pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl,
isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,
isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl,
oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl
(including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),
dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,
1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,
oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl,
tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl
(including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl),
or pyrazinyl (1,4-diazinyl)), piperazinyl, pyrrolidin-2-only,
triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl, and
1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl,
or 1,4-oxazinyl)), oxathiazinyl (including 1,2,3-oxathiazinyl,
1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)),
oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl,
1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)), morpholinyl, azepinyl,
oxepinyl, thiepinyl, and diazepinyl.
[0283] A heterocyclyl may alternatively be polycyclic (i.e., may
contain more than one ring). Examples of polycyclic heterocyclyls
include bridged, fused, and spirocyclic heterocyclyls. In a
spirocyclic heterocyclyl, one atom is common to two different
rings. In a bridged heterocyclyl, the rings share at least two
common non-adjacent atoms. In a fused-ring heterocyclyl, two or
more rings may be fused together, such that two rings share one
common bond. Examples of fused-ring heterocyclyls include
hexahydro-furo[3,4-c]pyrrole, hexahydro-furo[3,4-b]pyrrole,
octahydro-pyrrolo[3,4-b]pyridine, octahydro-pyrrolo[3,4-c]pyridine,
(3aR,6aR)-5-methyl-octahydro-pyrrolo[3,4-b]pyrrole,
(3aR,6aR)-octahydro-pyrrolo[3,4-b]pyrrole,
6-methyl-2,6-diaza-bicyclo[3.2.0]heptane,
(3aS,6aR)-2-methyl-octahydro-pyrrolo[3,4-c]pyrrole,
decahydro-[1,5]naphthyridine, 2,3-dihydrobenzofuranyl,
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, thieno[3,2-c]pyridinyl,
furo[3,2-c]pyridinyl, phthalazin-1(2H)-onyl, isoquinolinyl,
isoquinolin-1(2H)-onyl, 5,6,7,8-tetrahydrophthalazin-1(2H)-onyl,
fluorophthalazin-1(2H)-onyl,
(Z)-3H-benzo[d][1,2]diazepin-4(5H)-onyl,
(trifluoromethyl)phthalazin-1(2H)-onyl,
pyrrolo[1,2-d][1,2,4]triazin-1 (2H)-onyl,
1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,
5,6,7,8-tetrahydrophthalazin-1(2H)-onyl,
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl, thieno[3,2-c]pyridinyl,
furo[3,2-c]pyridinyl, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl,
purinyl, naphthyridinyl, pyridopyridinyl (including
pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or
pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of
fused-ring heterocyclyls include benzo-fused heterocyclyls, such as
benzimidazolyl, benzo[d][1,3]dioxolyl, indolyl, isoindolyl
(isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl),
isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl
(1-benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl,
quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl
(1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)),
benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl
(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl,
2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), and benzisoxazinyl
(including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl). Examples of
spirocyclic heterocyclyls include
1,4-dioxa-8-azaspiro[4.5]decanyl.
[0284] The term "heterocycloalkyl" (alone or in combination with
another term(s)) means a saturated heterocyclyl.
[0285] The term "heteroaryl" (alone or in combination with another
term(s)) means an aromatic heterocyclyl containing from 5 to 14
ring atoms. A heteroaryl may be a single ring or 2 or 3 fused
rings. Examples of heteroaryl substituents include 6-membered ring
substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl,
and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents
such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl
and isothiazolyl; 6/5-membered fused ring substituents such as
benzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl; and
6/6-membered fused rings such as benzopyranyl, quinolinyl,
isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
[0286] A prefix attached to a multi-component substituent only
applies to the first component. To illustrate, the term
"alkylcycloalkyl" contains two components: alkyl and cycloalkyl.
Thus, the C.sub.1-C.sub.6-prefix on C.sub.1-C.sub.6-alkylcycloalkyl
means that the alkyl component of the alkylcycloalkyl contains from
1 to 6 carbon atoms; the C.sub.1-C.sub.6-prefix does not describe
the cycloalkyl component. To illustrate further, the prefix "halo"
on haloalkyloxyalkyl indicates that only the alkyloxy component of
the alkyloxyalkyl substituent is substituted with one or more
halogen radicals. If halogen substitution may alternatively or
additionally occur on the alkyl component, the substituent would
instead be described as "halogen-substituted alkyloxyalkyl" rather
than "haloalkyloxyalkyl." And finally, if the halogen substitution
may only occur on the alkyl component, the substituent would
instead be described as "alkyloxyhaloalkyl."
[0287] The terms "treat", "treating" and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms.
[0288] The terms "prevent", "preventing" and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring a disease.
[0289] The term "therapeutically effective amount" refers to that
amount of the compound being administered sufficient to prevent
development of or alleviate to some extent one or more of the
symptoms of the condition or disorder being treated.
[0290] The term "modulate" refers to the ability of a compound to
increase or decrease the function, or activity, of a kinase.
"Modulation", as used herein in its various forms, is intended to
encompass antagonism, agonism, partial antagonism and/or partial
agonism of the activity associated with kinase. Kinase inhibitors
are compounds that, e.g., bind to, partially or totally block
stimulation, decrease, prevent, delay activation, inactivate,
desensitize, or down regulate signal transduction. Kinase
activators are compounds that, e.g., bind to, stimulate, increase,
open, activate, facilitate, enhance activation, sensitize or up
regulate signal transduction.
[0291] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0292] The "subject" is defined herein to include animals such as
mammals, including, but not limited to, primates (e.g., humans),
cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like. In preferred embodiments, the subject is a human.
Isotope Enriched or Labeled Compounds
[0293] Compounds of the invention can exist in isotope-labeled or
-enriched form containing one or more atoms having an atomic mass
or mass number different from the atomic mass or mass number most
abundantly found in nature. Isotopes can be radioactive or
non-radioactive isotopes. Isotopes of atoms such as hydrogen,
carbon, phosphorous, sulfur, fluorine, chlorine, and iodine
include, but are not limited to, .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl, and .sup.125I. Compounds that contain other isotopes of
these and/or other atoms are within the scope of this
invention.
[0294] In another embodiment, the isotope-labeled compounds contain
deuterium (.sup.2H), tritium (.sup.3H) or .sup.14C isotopes.
Isotope-labeled compounds of this invention can be prepared by the
general methods well known to persons having ordinary skill in the
art. Such isotope-labeled compounds can be conveniently prepared by
carrying out the procedures disclosed in the Examples disclosed
herein and Schemes by substituting a readily available
isotope-labeled reagent for a non-labeled reagent. In some
instances, compounds may be treated with isotope-labeled reagents
to exchange a normal atom with its isotope, for example, hydrogen
for deuterium can be exchanged by the action of a deuteric acid
such as D.sub.2SO.sub.4/D.sub.2O. In addition to the above,
relevant procedures and intermediates are disclosed, for instance,
in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J
et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org
Lett, 5(7), 963 (2003); PCT publications WO1997010223,
WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;
7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013;
and US Patent Application Publication Nos. 20090137457;
20090131485; 20090131363; 20090118238; 20090111840; 20090105338;
20090105307; 20090105147; 20090093422; 20090088416; and
20090082471, the methods are hereby incorporated by reference.
[0295] The isotope-labeled compounds of the invention may be used
as standards to determine the effectiveness in binding assays.
Isotope containing compounds have been used in pharmaceutical
research to investigate the in vivo metabolic fate of the compounds
by evaluation of the mechanism of action and metabolic pathway of
the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci.
64, 3, 367-391 (1975)). Such metabolic studies are important in the
design of safe, effective therapeutic drugs, either because the in
vivo active compound administered to the patient or because the
metabolites produced from the parent compound prove to be toxic or
carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.
2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp.
Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J.
Physiol. Pharmacol., 77, 79-88 (1999).
[0296] In addition, non-radio active isotope containing drugs, such
as deuterated drugs called "heavy drugs," can be used for the
treatment of diseases and conditions related to NAMPT activity.
Increasing the amount of an isotope present in a compound above its
natural abundance is called enrichment. Examples of the amount of
enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79,
84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15%
of normal atom with a heavy isotope has been effected and
maintained for a period of days to weeks in mammals, including
rodents and dogs, with minimal observed adverse effects (Czajka D M
and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F,
Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.
Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% in
human fluids with deuterium was found not to cause toxicity
(Blagojevic N et al. in "Dosimetry & Treatment Planning for
Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds.
1994. Advanced Medical Publishing, Madison Wis. pp. 125-134;
Diabetes Metab. 23: 251 (1997)).
[0297] Stable isotope labeling of a drug can alter its
physico-chemical properties such as pKa and lipid solubility. These
effects and alterations can affect the pharmacodynamic response of
the drug molecule if the isotopic substitution affects a region
involved in a ligand-receptor interaction. While some of the
physical properties of a stable isotope-labeled molecule are
different from those of the unlabeled one, the chemical and
biological properties are the same, with one important exception:
because of the increased mass of the heavy isotope, any bond
involving the heavy isotope and another atom will be stronger than
the same bond between the light isotope and that atom. Accordingly,
the incorporation of an isotope at a site of metabolism or
enzymatic transformation will slow said reactions potentially
altering the pharmacokinetic profile or efficacy relative to the
non-isotopic compound.
Compounds
[0298] Suitable groups for R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 in compounds of Formula (I) are independently selected. The
described embodiments of the present invention may be combined.
Such combination is contemplated and within the scope of the
present invention. For example, it is contemplated that embodiments
for any of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 can be
combined with embodiments defined for any other of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, and R.sup.5.
Embodiments of Formula (I)
[0299] One embodiment of this invention, therefore, pertains to
compounds or pharmaceutically acceptable salts thereof, which are
useful as inhibitors of NAMPT, the compounds having Formula (I)
##STR00003##
wherein
[0300] R.sup.1 and R.sup.2 are each independently selected from the
group consisting of R.sup.6, C(O)R.sup.6, C(O)NHR.sup.6, and
C(O)N(R.sup.6).sub.2; wherein at least one of R.sup.1 and R.sup.2
is R.sup.6; or
[0301] R.sup.1 and R.sup.2, together with the nitrogen to which
they are attached form a heterocycloalkyl or heterocycloalkenyl
ring; wherein the ring formed with R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.7, OR.sup.7, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7,
OC(O)R.sup.7, OC(O)OR.sup.7, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7, NHS(O).sub.2R.sup.7,
NR.sup.7S(O).sub.2R.sup.7, NHC(O)OR.sup.7, NR.sup.7C(O)OR.sup.7,
NHC(O)NH.sub.2, NHC(O)NHR.sup.7, NHC(O)N(R.sup.7).sub.2,
NR.sup.7C(O)NHR.sup.7, NR.sup.7C(O)N(R.sup.7).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0302] R.sup.3, R.sup.4, and R.sup.5 are each independently
selected from the group consisting of hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
C.sub.1-6 hydroxyalkyl, F, Cl, Br and I;
[0303] R.sup.6, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.6 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.8, OR.sup.8, SR.sup.8, S(O)R.sup.8, SO.sub.2R.sup.8,
C(O)R.sup.8, CO(O)R.sup.8, OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2,
NHR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8,
NHS(O).sub.2R.sup.8, NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8,
NR.sup.8C(O)OR.sup.8, NHC(O)NH.sub.2, NHC(O)NHR.sup.8,
NHC(O)N(R.sup.8).sub.2, NR.sup.8C(O)NHR.sup.8,
NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8SO.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0304] R.sup.7, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.7 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3,
NO.sub.2, F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.7 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I;
[0305] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.8 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
C(O)R.sup.10, CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10,
NH.sub.2, NHR.sup.10, N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHS(O).sub.2R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0306] R.sup.9, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.9 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12,
C(O)R.sup.12, CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
NH.sub.2, NHR.sup.12, N(R.sup.12).sub.2, NHC(O)R.sup.12,
NR.sup.12C(O)R.sup.12, NHS(O).sub.2R.sup.12,
NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0307] R.sup.10, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6haloalkyl, and C.sub.1-6
hydroxyalkyl;
[0308] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.11 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0309] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.12 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; and
[0310] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl represented by R.sup.13 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of alkoxy,
NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and
I.
[0311] In one embodiment of Formula (I), R.sup.3, R.sup.4, and
R.sup.5 are each independently selected from the group consisting
of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6haloalkyl, C.sub.1-6 hydroxyalkyl, F, Cl, Br and I. In
another embodiment of Formula (I), R.sup.3, R.sup.4, and R.sup.5
are are each independently selected from the group consisting of
hydrogen and C.sub.1-6 alkyl. In another embodiment of Formula (I),
one of R.sup.3, R.sup.4, and R.sup.5 is C.sub.1-6 alkyl, and the
remainder are hydrogen. In another embodiment of Formula (I),
R.sup.3 is C.sub.1-6 alkyl, and R.sup.4 and R.sup.5 are hydrogen.
In another embodiment of Formula (I), R.sup.4 is C.sub.1-6 alkyl,
and R.sup.3 and R.sup.5 are hydrogen. In another embodiment of
Formula (I), R.sup.5 is C.sub.1-6 alkyl, and R.sup.3 and R.sup.4
are hydrogen. In another embodiment of Formula (I), R.sup.3,
R.sup.4 and R.sup.5 are hydrogen.
[0312] In another embodiment of Formula (I), R.sup.3, R.sup.4, and
R.sup.5 are each independently selected from the group consisting
of hydrogen and methyl. In another embodiment of Formula (I), one
of R.sup.3, R.sup.4, and R.sup.5 is methyl, and the remainder are
hydrogen. In another embodiment of Formula (I), R.sup.3 is methyl,
and R.sup.4 and R.sup.5 are hydrogen. In another embodiment of
Formula (I), R.sup.4 is methyl, and R.sup.3 and R.sup.5 are
hydrogen. In another embodiment of Formula (I), R.sup.5 is methyl,
and R.sup.3 and R.sup.4 are hydrogen.
[0313] In one embodiment of Formula (I), R.sup.1 and R.sup.2 are
each independently selected from the group consisting of R.sup.6,
C(O)R.sup.6, C(O)NHR.sup.6, and C(O)N(R.sup.6).sub.2; wherein at
least one of R.sup.1 and R.sup.2 is R.sup.6. In another embodiment
of Formula (I), R.sup.6, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl;
wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8SO.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (I), R.sup.6, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl, heteroaryl, and
cycloalkyl; wherein the C.sub.1-6 alkyl, and C.sub.2-6 alkenyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
CO(O)R.sup.8, OC(O)R.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, and OH;
wherein the aryl, heterocycloalkyl, heteroaryl, and cycloalkyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)NH.sub.2,
C(O)OH, OH, CN, F, Cl, Br and I.
[0314] In one embodiment of Formula (I), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.10, OR.sup.10,
SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10, C(O)R.sup.10,
CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10, NH.sub.2, NHR.sup.10,
N(R.sup.7).sub.2, NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10,
NHS(O).sub.2R.sup.10, NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (I), R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6 alkenyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, and cycloalkyl; wherein the C.sub.1-6 alkyl and
C.sub.2-6 alkenyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of OH, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, and heteroaryl represented by R.sup.8
are each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.11, OR.sup.11, NH.sub.2, N(R.sup.11).sub.2, C(O)H, OH, CN, F,
Cl, Br and I.
[0315] In one embodiment of Formula (I), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.9 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
SR.sup.2, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (I), R.sup.9, at each occurrence, is
C.sub.1-6 alkyl.
[0316] In one embodiment of Formula (I), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6
haloalkyl, and C.sub.1-6 hydroxyalkyl.
[0317] In one embodiment of Formula (I), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6alkynyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.11 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (I), R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, aryl, and heteroaryl; wherein the C.sub.1-6alkyl
and C.sub.2-6alkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6alkoxy, cycloalkyl,
OH, F, Cl, Br and I.
[0318] In one embodiment of Formula (I), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6alkynyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I.
[0319] In one embodiment of Formula (I), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; wherein
the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.13 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of alkoxy, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[0320] In another embodiment of Formula (I), R.sup.1 is
C(O)R.sup.6; and R.sup.2 is R.sup.6. In another embodiment of
Formula (I), R.sup.6, at each occurrence, is independently selected
from the group consisting of C.sub.1-6 alkyl, aryl,
heterocycloalkyl, heteroaryl, and cycloalkyl; wherein the C.sub.1-6
alkyl represented by R.sup.6 is independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, C(O)NHR.sup.8, and
OH; wherein the aryl, heterocycloalkyl, and heteroaryl represented
by R.sup.6 are each independently optionally substituted with one
or more substituents independently selected from the group
consisting of R.sup.9, OR.sup.9, C(O)NH.sub.2, OH, CN, F, Cl, Br
and I. In another embodiment of Formula (I), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, and cycloalkyl; wherein the aryl,
heterocycloalkyl, and heteroaryl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, NH.sub.2, N(R.sup.11).sub.2, C(O)H, OH, CN, F, Cl, Br
and I. In another embodiment of Formula (I), R.sup.9, at each
occurrence, is C.sub.1-6 alkyl. In another embodiment of Formula
(I), R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
aryl; wherein the C.sub.1-6 alkyl and C.sub.2-6 alkenyl represented
by R.sup.11 are each independently optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-6alkoxy, cycloalkyl, OH, F, Cl, Br and I.
[0321] In another embodiment of Formula (I), R.sup.1 and R.sup.2
are each R.sup.6. In another embodiment of Formula (I), R.sup.6, at
each occurrence, is C.sub.1-6alkyl; wherein the C.sub.1-6alkyl
represented by R.sup.6 is independently optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.8, C(O)R.sup.8, C(O)NHR.sup.8, and
C(O)N(R.sup.8).sub.2.
[0322] In another embodiment of Formula (I), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, aryl, and heterocycloalkyl; wherein the aryl, and
heterocycloalkyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.11, CN, F, Cl, Br and
I. In another embodiment of Formula (I), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl and heteroaryl.
[0323] In another embodiment of Formula (I), R.sup.1 is
C(O)NHR.sup.6; and R.sup.2 is R.sup.6. In another embodiment of
Formula (I), R.sup.6, at each occurrence, is independently selected
from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
heterocycloalkyl, and cycloalkyl; wherein the C.sub.1-6alkyl and
C.sub.2-6 alkenyl represented by R.sup.6 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.8, OR.sup.8,
C(O)OR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, C(O)NH.sub.2,
C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the heterocycloalkyl,
and cycloalkyl represented by R.sup.6 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C(O)NH.sub.2, C(O)OH, F, Cl,
Br and I. In another embodiment of Formula (I), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, aryl, heterocycloalkyl, and heteroaryl; wherein
the C.sub.1-6alkyl represented by R.sup.8 is independently
optionally substituted with one or more OH; wherein the aryl,
heterocycloalkyl, and heteroaryl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of OH, CN, F, Cl,
Br and I.
[0324] In another embodiment of Formula (I), R.sup.1 is
C(O)N(R.sup.6).sub.2; and R.sup.2 is R.sup.6. In another embodiment
of Formula (I), R.sup.6, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, heterocycloalkyl, and cycloalkyl; wherein the
C.sub.1-6alkyl and C.sub.2-6 alkenyl represented by R.sup.6 are
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.8,
OR.sup.8, C(O)OR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the
heterocycloalkyl, and cycloalkyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of OH, F, Cl, Br
and I. In another embodiment of Formula (I), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, aryl, and heterocycloalkyl; wherein the
C.sub.1-6alkyl represented by R.sup.8 is independently optionally
substituted with one or more OH; wherein the aryl and
heterocycloalkyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of OH, CN, F, Cl, Br and I.
[0325] In another embodiment of Formula (I), R.sup.6, at each
occurrence, is C.sub.1. alkyl; wherein the C.sub.1-6 alkyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, and OR.sup.8. In another
embodiment of Formula (I), R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, and aryl; wherein the aryl represented by R.sup.8 is
independently optionally substituted with one or more substituents
independently selected from the group consisting of F, Cl, Br and
I.
[0326] In another embodiment of Formula (I), R.sup.1 and R.sup.2,
together with the nitrogen to which they are attached form a
heterocycloalkyl or heterocycloalkenyl ring. In another embodiment
of Formula (I), R.sup.1 and R.sup.2, together with the nitrogen to
which they are attached form a heterocycloalkyl ring. In another
embodiment of Formula (I), R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1. alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl;
wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl represented by R.sup.7 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.7 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (I), R.sup.1 and R.sup.2, together
with the nitrogen to which they are attached form a
heterocycloalkyl ring wherein the ring formed with R.sup.1 and
R.sup.2 together with the nitrogen to which they are attached is
optionally substituted with one or more R. In another embodiment of
Formula (I), R.sup.7, at each occurrence, is independently selected
from the group consisting of C.sub.1-6alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.7 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3,
NO.sub.2, F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.7 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (I), R.sup.7, at each occurrence, is independently selected
from the group consisting of C.sub.1-6 alkyl, and aryl; wherein the
C.sub.1-6alkyl represented by R.sup.7 is independently optionally
substituted with one or more substituents independently selected
from the group consisting of aryl and OH; wherein the aryl
represented by R.sup.7 is independently optionally substituted with
one or more substituents independently selected from the group
consisting of F, Cl, Br and I.
[0327] Still another embodiment pertains to compounds having
Formula (I), which include [0328]
2-{(4-fluorobenzyl)[4-(pyridin-3-yl)benzyl]amino}-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0329]
N-[3-(1H-imidazol-1-yl)propyl]-2-{methyl[4-(pyridin-3-yl)benzyl]amino}-1,-
3-thiazole-5-carboxamide; [0330]
2-[(4-fluorobenzyl)(methyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0331]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0332]
2-[(cyclohexylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0333]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0334]
2-{(4-fluorobenzyl)[3-(morpholin-4-yl)propyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0335]
2-{(4-fluorobenzyl)[3-(piperidin-1-yl)propyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0336]
2-{(4-fluorobenzyl)[2-(pyrrolidin-1-yl)ethyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0337] 2-[(4-fluorobenzyl)
{2-[4-(propan-2-yl)piperazin-1-yl]ethyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0338]
2-[(4-cyanobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0339]
2-[(3-chlorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0340]
2-[(4-fluorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0341]
2-{[(5-chloro-1,3-benzodioxol-4-yl)methyl](4-fluorobenzyl)amino}-N-[3-(1H-
-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0342]
2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0343]
2-[(2-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0344]
2-[(2,5-dichlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0345]
2-{(4-fluorobenzyl)[2-(methylamino)-2-oxoethyl]amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0346]
2-{(4-fluorobenzyl)[2-oxo-2-(propan-2-ylamino)ethyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0347]
2-{[2-(dimethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0348]
2-{[2-(diethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0349]
2-{(4-fluorobenzyl)[2-(morpholin-4-yl)-2-oxoethyl]amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0350]
2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0351]
2-[(4-fluorobenzyl)(methoxyacetyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0352]
2-[(4-fluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0353]
2-[(N,N-dimethylglycyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0354]
2-[(3,6-dihydropyridin-1(2H)-ylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0355]
2-{(4-fluorobenzyl)
[(4-methylpiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-
-thiazole-5-carboxamide; [0356] 2-{(4-fluorobenzyl)
[(4-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0357]
2-{(4-fluorobenzyl)[(4-methylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0358]
2-[(4-fluorobenzyl)
{[4-(propan-2-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0359]
2-{(4-fluorobenzyl)[(4-formylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0360]
2-[(4-fluorobenzyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylacetyl)amino]--
N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0361]
2-[{[4-(cyclopropylmethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0362]
2-[{[4-(2-ethoxyethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3-(-
1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0363]
2-[(cyclopropylcarbonyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0364] 2-[(4-fluorobenzyl)
{[4-(prop-2-en-1-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0365] 2-[(4-fluorobenzyl)
{[4-(3-methoxypropyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0366]
2-[{[3-(dimethylamino)pyrrolidin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0367]
2-[(4-fluorobenzyl)(morpholin-4-ylacetyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0368]
2-{(4-fluorobenzyl)[(3-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0369]
2-[(4-fluorobenzyl)
{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0370]
2-[(1,4-dioxa-7-azaspiro[4.4]non-7-ylacetyl)
(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carb-
oxamide; [0371]
1-{2-[(4-fluorobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thia-
zol-2-yl)amino]-2-oxoethyl}pyridinium; [0372]
2-{[2-(4-fluorophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0373]
2-[(4-fluorobenzyl)(propan-2-ylcarbamoyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0374]
2-[(4-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0375]
2-{[2-(4-cyanophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0376]
2-{[2-(4-cyanophenyl)ethyl](tetrahydro-2H-pyran-4-ylacetyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0377]
2-[(4-cyanobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0378]
2-[(4-cyanobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0379]
2-{[2-(4-cyanophenyl)ethyl](tetrahydrofuran-3-ylacetyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0380]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(2-methyl-1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0381]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(4-methyl-1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0382]
2-[(2-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0383]
2-[(3-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0384]
2-[(2-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0385]
2-[(3-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0386]
2-[(4-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0387]
2-[(4-cyanobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0388]
2-[(4-cyanobenzyl)(tetrahydrofuran-3-ylacetyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0389]
2-[(4-cyanobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)propy-
l]-1,3-thiazole-5-carboxamide; [0390]
2-{(4-fluorobenzyl)[(3-methylbutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0391] 2-{(4-fluorobenzyl)
[(2-methylpropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0392]
N.sup.1-(4-fluorobenzyl)-N.sup.1-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoy-
l}-1,3-thiazol-2-yl)piperidine-1,3-dicarboxamide; [0393]
2-{(4-fluorobenzyl)
[(3-hydroxyazetidin-1-yl)carbonyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0394]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxamide; [0395]
2-{(4-fluorobenzyl)[(3-methoxypyrrolidin-1-yl)carbonyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0396]
2-{(4-fluorobenzyl)[(2-methoxyethyl)(methyl)carbamoyl]amino}-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0397]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,6-dimethylmorpholine-4-carboxamide; [0398]
2-{[ethyl(2-methoxyethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0399]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,2-dimethylmorpholine-4-carboxamide; [0400]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-oxazepane-4-carboxamide; [0401]
2-[(4-fluorobenzoyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0402]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(4-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0403]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-N-(3-methy-
lbutyl)-1,2-oxazole-5-carboxamide; [0404]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenoxypropanoyl)amin-
o]-1,3-thiazole-5-carboxamide; [0405]
2-{(4-fluorobenzyl)[(2-propoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0406] 2-{(4-fluorobenzyl)
[(tetrahydrofuran-2-ylmethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0407] 2-{(4-fluorobenzyl)
[(1-methoxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0408]
2-{(4-fluorobenzyl)[(tetrahydro-2H-pyran-2-ylmethyl)carbamoyl]amino}-N-[3-
-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0409]
2-{(4-fluorobenzyl)[(2-methoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0410]
2-{[(2-ethoxyethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0411]
2-{(4-fluorobenzyl)[(1-methoxybutan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0412]
2-{[2-(4-cyanophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0413]
2-{[(1,3-dioxolan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0414]
2-[(4-fluorobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0415]
2-{[(1,4-dioxan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0416]
2-{[(1,3-dimethoxypropan-2-yl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0417]
2-{(4-fluorobenzyl)[(2-methoxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0418]
2-[(4-fluorobenzyl)(tetrahydrofuran-3-ylcarbamoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0419]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-3-ylcarbamoyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0420]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyrimidin-2-ylmeth-
yl)amino]-1,3-thiazole-5-carboxamide; [0421]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[(2-methoxypyridin--
4-yl)methyl]amino}-1,3-thiazole-5-carboxamide; [0422]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(1,3-oxazol-4-ylmet-
hyl)amino]-1,3-thiazole-5-carboxamide; [0423]
2-{[(5-chloropyridin-2-yl)methyl](3-methoxypropanoyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0424]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(4-methylpyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0425] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methoxypyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0426] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0427]
2-{[2-(3-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0428]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyridin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide acetate
(1:1); [0429]
2-{[2-(1,3-benzodioxol-5-yl)ethyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0430]
2-{[2-(4-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0431]
2-{[2-(3-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0432]
2-{[2-(4-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0433]
2-{[2-(3-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0434]
N-[3-(1H-imidazol-1-yl)propyl]-2-{[2-(3-methoxyphenyl)ethyl](3-methoxypro-
panoyl)amino}-1,3-thiazole-5-carboxamide acetate (1:1); [0435]
2-{[2-(2-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0436]
2-{[2-hydroxy-2-(4-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0437]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[1-(pyridin-2-yl)et-
hyl]amino}-1,3-thiazole-5-carboxamide; [0438]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(1-methyl-1H-pyrazol-4-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0439]
2-[(2,6-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0440]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methylpyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0441]
2-[(4-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0442]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyrazin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0443]
2-[(3-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0444]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyridin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0445]
2-[(2,5-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0446]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(2-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0447]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0448]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-2-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0449]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-3-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0450] 2-[(4-cyanobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide;
[0451]
2-{(4-cyanobenzyl)[(2-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0452]
2-[(4-cyanobenzyl)
{[2-(2-hydroxyethoxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0453] 2-[(4-cyanobenzyl)
{[3-(propan-2-yloxy)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0454]
2-{(4-cyanobenzyl)[(3-hydroxy-2,2-dimethylpropyl)carbamoyl]amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0455]
2-{(4-cyanobenzyl)[(2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0456]
2-{(4-cyanobenzyl)[(1-hydroxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0457]
2-{(4-cyanobenzyl)[(3-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0458] 2-[(4-cyanobenzyl)
{[(2S)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0459]
2-{(4-cyanobenzyl)[(4-hydroxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0460]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2R)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0461]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2S)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0462]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-5-methyl-N-
-(3-methylbutyl)-1,2-oxazole-3-carboxamide; [0463]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(phenoxyacetyl)amino]-1,-
3-thiazole-5-carboxamide; [0464]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(3-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0465]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0466]
2-{[(4-fluorophenyl)acetyl](3-methylbutyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0467]
2-{[(3-amino-3-oxopropyl)carbamoyl](4-cyanobenzyl)amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0468]
2-[{[3-(acetylamino)-2-methylpropyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0469]
2-[(4-cyanobenzyl)
{[3-(dimethylamino)-3-oxopropyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0470]
2-{(4-cyanobenzyl)[(3-ethoxy-2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0471]
2-[(4-cyanobenzyl)
{[3-(diethylamino)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0472]
2-[{[2-(acetylamino)ethyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0473]
2-[(4-cyanobenzyl)
{[2-(diethylamino)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0474]
2-[(4-cyanobenzyl)({2-[(2-methylpropanoyl)amino]ethyl}carbamoyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0475]
2-[(4-cyanobenzyl){[(2R)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-
-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0476]
2-[(4-cyanobenzyl)
{[3-(3-hydroxyazetidin-1-yl)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0477]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbutyl)amin-
o]-1,3-thiazole-5-carboxamide; [0478]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(methoxyacetyl)(3-methylbutyl)amino]-1,-
3-thiazole-5-carboxamide; [0479]
2-[(cyclopropylcarbonyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0480]
(2S)-1-[(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)(3-me-
thylbutyl)amino]-1-oxopropan-2-yl acetate; [0481]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydro-2H-pyran-4-y-
lacetyl)amino]-1,3-thiazole-5-carboxamide; [0482]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylcar-
bonyl)amino]-1,3-thiazole-5-carboxamide; [0483]
2-{[2-hydroxy-2-(3-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0484]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyrazin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0485]
2-{[1-(3-hydroxyphenyl)propan-2-yl](3-methoxypropanoyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0486] ethyl
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alaninate; [0487] ethyl
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [0488] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [0489] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoate; [0490] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoate; [0491]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}cyclobutanecarboxylic acid; [0492] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoate; [0493]
2-{(4-cyanobenzyl)[(3-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0494]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [0495]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoic acid; [0496]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoic acid; [0497]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoic acid; [0498]
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alanine; [0499]
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [0500]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-2-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0501]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0502]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(3-methoxypropanoyl)ami-
no]-1,3-thiazole-5-carboxamide; [0503]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methoxypropyl)am-
ino]-1,3-thiazole-5-carboxamide; [0504]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydro-2H-pyra-
n-2-ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0505]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydrofuran-2--
ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0506]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(propan-2-yloxy)ethyl]amino}-1,3-thiazole-5-carboxamide; [0507]
2-{[2-(1,3-dioxolan-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0508]
2-[(1,4-dioxan-2-ylmethyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0509]
2-{[3-(4-fluorophenyl)propanoyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0510]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)
[3-(pyridin-3-yl)propanoyl]amino}-1,3-thiazole-5-carboxamide;
[0511]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-3-ylacetyl)ami-
no]-1,3-thiazole-5-carboxamide; [0512]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(naphthalen-2-ylacetyl)-
amino]-1,3-thiazole-5-carboxamide; [0513]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)[(4-phenoxyphenyl)acety-
l]amino}-1,3-thiazole-5-carboxamide; [0514]
2-{[(4-cyanophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0515]
2-{[(4-aminophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0516]
2-[{2-[di(prop-2-en-1-yl)amino]ethyl}(3-methoxypropanoyl)amino]-N-[3-(1H--
imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0517]
2-{[3-(diethylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0518]
2-{[2-(diethylamino)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0519]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(pyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0520]
2-{[(1-ethyl-5-oxopyrrolidin-3-yl)methyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0521]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-oxopyrrolidin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0522]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[3-oxo-3-(pyrrolidi-
n-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide; [0523]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[2-oxo-2-(piperidin-
-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0524]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0525] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0526] N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)
{2-[(2-methylpropanoyl)amino]ethyl}amino]-1,3-thiazole-5-carboxamide;
[0527] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(methylamino)-3-oxopropyl]amino}-1,3-thiazole-5-carboxamide;
[0528]
2-{[3-(acetylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0529]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[2-oxo-2-(pyrrolidi-
n-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0530]
2-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0531]
2-[3-(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0532]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydro-2H-pyran-4-ylcarbonyl)amino}-
-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0533]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydrofuran-3-ylcarbonyl)amino}-N-[-
3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0534]
2-{[2-(5-chloropyridin-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0535]
2-{[2-(5-chloropyridin-2-yl)ethyl](tetrahydrofuran-3-ylcarbonyl)amino}-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0536]
2-{[2-(5-chloropyridin-2-yl)ethyl][(2-methoxyethyl)carbamoyl]amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0537]
2-([2-(5-chloropyridin-2-yl)ethyl]{[2-(propan-2-yloxy)ethyl]carbamoyl}ami-
no)-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide;
[0538]
2-[(1,3-benzodioxol-5-ylacetyl)(2-methoxyethyl)amino]-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0539]
2-{(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxaz-
olidin-3-yl}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide;
[0540]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-2-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; and pharmaceutically
acceptable salts thereof.
Embodiments of Formula (II)
[0541] In another aspect, the present invention provides compounds
of Formula (II)
##STR00004##
and pharmaceutically acceptable salts thereof; wherein R.sup.1 and
R.sup.2 are as described herein for Formula (I).
[0542] One embodiment of this invention pertains to compounds of
Formula (II) or pharmaceutically acceptable salts thereof;
wherein
[0543] R.sup.1 and R.sup.2 are each independently selected from the
group consisting of R.sup.6, C(O)R.sup.6, C(O)NHR.sup.6, and
C(O)N(R.sup.6).sub.2; wherein at least one of R.sup.1 and R.sup.2
is R.sup.6; or
[0544] R.sup.1 and R.sup.2, together with the nitrogen to which
they are attached form a heterocycloalkyl or heterocycloalkenyl
ring; wherein the ring formed with R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.7, OR.sup.7, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7,
OC(O)R.sup.7, OC(O)OR.sup.7, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7, NHS(O).sub.2R.sup.7,
NR.sup.7S(O).sub.2R.sup.7, NHC(O)OR.sup.7, NR.sup.7C(O)OR.sup.7,
NHC(O)NH.sub.2, NHC(O)NHR.sup.7, NHC(O)N(R.sup.7).sub.2,
NR.sup.7C(O)NHR.sup.7, NR.sup.7C(O)N(R.sup.7).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.7, C(N)N(R.sup.7).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0545] R.sup.6, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.6 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.8, OR.sup.8, SR.sup.8, S(O)R.sup.8, SO.sub.2R.sup.8,
C(O)R.sup.8, CO(O)R.sup.8, OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2,
NHR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8,
NHS(O).sub.2R.sup.8, NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8,
NR.sup.8C(O)OR.sup.8, NHC(O)NH.sub.2, NHC(O)NHR.sup.8,
NHC(O)N(R.sup.8).sub.2, NR.sup.8C(O)NHR.sup.8,
NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0546] R.sup.7, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.7 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3,
NO.sub.2, F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.7 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I;
[0547] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.8 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
C(O)R.sup.10, CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10,
NH.sub.2, NHR.sup.10, N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHS(O).sub.2R.sup.10,
NR.sup.10S(O).sub.2R.sup.7, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0548] R.sup.9, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.9 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12, CO(O)R.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0549] R.sup.10, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, and C.sub.1-6
hydroxyalkyl;
[0550] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl represented by
R.sup.11 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0551] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl represented
by R.sup.12 are each independently optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-6 alkoxy, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.12 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I; and
[0552] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; wherein the C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl represented by R.sup.13 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of alkoxy, NH.sub.2, C(O)H,
C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[0553] In one embodiment of Formula (II), R.sup.1 and R.sup.2 are
each independently selected from the group consisting of R.sup.6,
C(O)R.sup.6, C(O)NHR.sup.6, and C(O)N(R.sup.6).sub.2; wherein at
least one of R and R.sup.2 is R.sup.6. In another embodiment of
Formula (II), R.sup.6, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl;
wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (II), R.sup.6, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl, heteroaryl, and
cycloalkyl; wherein the C.sub.1-6 alkyl, and C.sub.2-6 alkenyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
CO(O)R.sup.8, OC(O)R.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, and OH;
wherein the aryl, heterocycloalkyl, heteroaryl, and cycloalkyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)NH.sub.2,
C(O)OH, OH, CN, F, Cl, Br and I.
[0554] In one embodiment of Formula (II), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.10, OR.sup.10,
SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10, C(O)R.sup.10,
CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10, NH.sub.2, NHR.sup.10,
N(R.sup.10).sub.2, NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10,
NHS(O).sub.2R.sup.10, NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (II), R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6 alkenyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, and cycloalkyl; wherein the C.sub.1-6 alkyl and
C.sub.2-6 alkenyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of OH, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, and heteroaryl represented by R.sup.8
are each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.11, OR.sup.11, NH.sub.2, N(R.sup.11).sub.2, C(O)H, OH, CN, F,
Cl, Br and I.
[0555] In one embodiment of Formula (II), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.9 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (II), R.sup.9, at each occurrence, is
C.sub.1-6 alkyl.
[0556] In one embodiment of Formula (II), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6haloalkyl, and C.sub.1-6 hydroxyalkyl.
[0557] In one embodiment of Formula (II), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.11 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (II), R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, aryl, and heteroaryl; wherein the C.sub.1-6alkyl and
C.sub.2-6 alkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6alkoxy, cycloalkyl,
OH, F, Cl, Br and I.
[0558] In one embodiment of Formula (II), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I.
[0559] In one embodiment of Formula (II), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.13 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of alkoxy, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[0560] In another embodiment of Formula (II), R.sup.1 is
C(O)R.sup.6; and R.sup.2 is R.sup.6. In another embodiment of
Formula (II), R.sup.6, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, aryl,
heterocycloalkyl, heteroaryl, and cycloalkyl; wherein the C.sub.1-6
alkyl represented by R.sup.6 is independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, C(O)NHR.sup.8, and
OH; wherein the aryl, heterocycloalkyl, and heteroaryl represented
by R.sup.6 are each independently optionally substituted with one
or more substituents independently selected from the group
consisting of R.sup.9, OR.sup.9, C(O)NH.sub.2, OH, CN, F, Cl, Br
and I. In another embodiment of Formula (II), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, and cycloalkyl; wherein the aryl,
heterocycloalkyl, and heteroaryl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, NH.sub.2, N(R.sup.11).sub.2, C(O)H, OH, CN, F, Cl, Br
and I. In another embodiment of Formula (II), R.sup.9, at each
occurrence, is C.sub.1-6 alkyl. In another embodiment of Formula
(II), R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
aryl; wherein the C.sub.1-6 alkyl and C.sub.2-6 alkenyl represented
by R.sup.11 are each independently optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-6alkoxy, cycloalkyl, OH, F, Cl, Br and I.
[0561] In another embodiment of Formula (II), R.sup.1 and R.sup.2
are each R.sup.6. In another embodiment of Formula (II), R.sup.6,
at each occurrence, is C.sub.1-6alkyl; wherein the C.sub.1-6alkyl
represented by R.sup.6 is independently optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.8, C(O)R.sup.8, C(O)NHR.sup.8, and
C(O)N(R.sup.8).sub.2. In another embodiment of Formula (II),
R.sup.8, at each occurrence, is independently selected from the
group consisting of C.sub.1-6alkyl, aryl, and heterocycloalkyl;
wherein the aryl, and heterocycloalkyl represented by R.sup.8 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.11, CN, F, Cl, Br and I. In another embodiment of Formula
(II), R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6alkyl and heteroaryl.
[0562] In another embodiment of Formula (II), R.sup.1 is
C(O)NHR.sup.6; and R.sup.2 is R.sup.6. In another embodiment of
Formula (II), R.sup.6, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, heterocycloalkyl, and cycloalkyl; wherein the
C.sub.1-6alkyl and C.sub.2-6 alkenyl represented by R.sup.6 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)OR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the
heterocycloalkyl, and cycloalkyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of C(O)NH.sub.2,
C(O)OH, F, Cl, Br and I. In another embodiment of Formula (II),
R.sup.8, at each occurrence, is independently selected from the
group consisting of C.sub.1-6 alkyl, aryl, heterocycloalkyl, and
heteroaryl; wherein the C.sub.1-6 alkyl is independently optionally
substituted with one or more OH; wherein the aryl,
heterocycloalkyl, and heteroaryl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of OH, CN, F, Cl,
Br and I.
[0563] In another embodiment of Formula (II), R.sup.1 is
C(O)N(R.sup.6).sub.2; and R.sup.2 is R.sup.6. In another embodiment
of Formula (II), R.sup.6, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, heterocycloalkyl, and cycloalkyl; wherein the
C.sub.1-6alkyl and C.sub.2-6 alkenyl represented by R.sup.6 are
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.8,
OR.sup.8, C(O)OR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the
heterocycloalkyl, and cycloalkyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of OH, F, Cl, Br
and I. In another embodiment of Formula (II), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, aryl, and heterocycloalkyl; wherein the C.sub.1-6
alkyl is independently optionally substituted with one or more OH;
wherein the aryl and heterocycloalkyl represented by R.sup.8 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
OH, CN, F, Cl, Br and I.
[0564] In another embodiment of Formula (II), R.sup.1 and R.sup.2,
together with the nitrogen to which they are attached form a
heterocycloalkyl or heterocycloalkenyl ring. In another embodiment
of Formula (II), R.sup.1 and R.sup.2, together with the nitrogen to
which they are attached form a heterocycloalkyl ring. In another
embodiment of Formula (II), R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.7 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (II), R.sup.1 and R.sup.2, together
with the nitrogen to which they are attached form a
heterocycloalkyl ring wherein the ring formed with R.sup.1 and
R.sup.2 together with the nitrogen to which they are attached is
optionally substituted with one or more R. In another embodiment of
Formula (II), R.sup.7, at each occurrence, is independently
selected from the group consisting of C.sub.1-6alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl;
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl represented by R.sup.7 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.7 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (II), R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, and aryl; wherein the C.sub.1-6alkyl is independently
optionally substituted with one or more substituents independently
selected from the group consisting of aryl and OH; wherein the aryl
represented by R.sup.7 is independently optionally substituted with
one or more substituents independently selected from the group
consisting of F, Cl, Br and I.
[0565] Still another embodiment pertains to compounds having
Formula (II), which include [0566]
2-{(4-fluorobenzyl)[4-(pyridin-3-yl)benzyl]amino}-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0567]
N-[3-(1H-imidazol-1-yl)propyl]-2-{methyl[4-(pyridin-3-yl)benzyl]amino}-1,-
3-thiazole-5-carboxamide; [0568]
2-[(4-fluorobenzyl)(methyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0569]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0570]
2-[(cyclohexylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0571]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0572]
2-{(4-fluorobenzyl)[3-(morpholin-4-yl)propyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0573] 2-{(4-fluorobenzyl)
[3-(piperidin-1-yl)propyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide; [0574] 2-{(4-fluorobenzyl)
[2-(pyrrolidin-1-yl)ethyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide; [0575] 2-[(4-fluorobenzyl)
{2-[4-(propan-2-yl)piperazin-1-yl]ethyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0576]
2-[(4-cyanobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0577]
2-[(3-chlorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0578]
2-[(4-fluorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0579]
2-{[(5-chloro-1,3-benzodioxol-4-yl)methyl](4-fluorobenzyl)amino}-N-[3-(1H-
-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0580]
2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0581]
2-[(2-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0582]
2-[(2,5-dichlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0583]
2-{(4-fluorobenzyl)[2-(methylamino)-2-oxoethyl]amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0584]
2-{(4-fluorobenzyl)[2-oxo-2-(propan-2-ylamino)ethyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0585]
2-{[2-(dimethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0586]
2-{[2-(diethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0587]
2-{(4-fluorobenzyl)[2-(morpholin-4-yl)-2-oxoethyl]amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0588]
2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0589]
2-[(4-fluorobenzyl)(methoxyacetyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0590]
2-[(4-fluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0591]
2-[(N,N-dimethylglycyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0592]
2-[(3,6-dihydropyridin-1(2H)-ylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0593]
2-{(4-fluorobenzyl)[(4-methylpiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0594]
2-{(4-fluorobenzyl)
[(4-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0595]
2-{(4-fluorobenzyl)[(4-methylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0596]
2-[(4-fluorobenzyl)
{[4-(propan-2-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0597]
2-{(4-fluorobenzyl)[(4-formylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0598]
2-[(4-fluorobenzyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylacetyl)amino]--
N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0599]
2-[{[4-(cyclopropylmethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0600]
2-[{[4-(2-ethoxyethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3-(-
1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0601]
2-[(cyclopropylcarbonyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0602] 2-[(4-fluorobenzyl)
{[4-(prop-2-en-1-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0603] 2-[(4-fluorobenzyl)
{[4-(3-methoxypropyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0604]
2-[{[3-(dimethylamino)pyrrolidin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0605]
2-[(4-fluorobenzyl)(morpholin-4-ylacetyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0606]
2-{(4-fluorobenzyl)[(3-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0607]
2-[(4-fluorobenzyl)
{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0608]
2-[(1,4-dioxa-7-azaspiro[4.4]non-7-ylacetyl)
(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carb-
oxamide; [0609]
1-{2-[(4-fluorobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thia-
zol-2-yl)amino]-2-oxoethyl}pyridinium; [0610]
2-{[2-(4-fluorophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0611]
2-[(4-fluorobenzyl)(propan-2-ylcarbamoyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0612]
2-[(4-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0613]
2-{[2-(4-cyanophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0614]
2-{[2-(4-cyanophenyl)ethyl](tetrahydro-2H-pyran-4-ylacetyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0615]
2-[(4-cyanobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0616]
2-[(4-cyanobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0617]
2-{[2-(4-cyanophenyl)ethyl](tetrahydrofuran-3-ylacetyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0618]
2-[(2-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0619]
2-[(3-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0620]
2-[(2-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0621]
2-[(3-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0622]
2-[(4-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0623]
2-[(4-cyanobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0624]
2-[(4-cyanobenzyl)(tetrahydrofuran-3-ylacetyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0625]
2-[(4-cyanobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)propy-
l]-1,3-thiazole-5-carboxamide; [0626]
2-{(4-fluorobenzyl)[(3-methylbutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0627] 2-{(4-fluorobenzyl)
[(2-methylpropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0628]
N.sup.1-(4-fluorobenzyl)-N.sup.1-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoy-
l}-1,3-thiazol-2-yl)piperidine-1,3-dicarboxamide; [0629]
2-{(4-fluorobenzyl)[(3-hydroxyazetidin-1-yl)carbonyl]amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0630]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxamide; [0631]
2-{(4-fluorobenzyl)[(3-methoxypyrrolidin-1-yl)carbonyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0632]
2-{(4-fluorobenzyl)[(2-methoxyethyl)(methyl)carbamoyl]amino}-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0633]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,6-dimethylmorpholine-4-carboxamide; [0634]
2-{[ethyl(2-methoxyethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0635]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,2-dimethylmorpholine-4-carboxamide; [0636]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-oxazepane-4-carboxamide; [0637]
2-[(4-fluorobenzoyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0638]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(4-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0639]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-N-(3-methy-
lbutyl)-1,2-oxazole-5-carboxamide; [0640]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenoxypropanoyl)amin-
o]-1,3-thiazole-5-carboxamide; [0641]
2-{(4-fluorobenzyl)[(2-propoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0642]
2-{(4-fluorobenzyl)[(tetrahydrofuran-2-ylmethyl)carbamoyl]amino}-N-[3-(1H-
-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0643]
2-{(4-fluorobenzyl)
[(1-methoxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0644]
2-{(4-fluorobenzyl)[(tetrahydro-2H-pyran-2-ylmethyl)carbamoyl]amino}-N-[3-
-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0645]
2-{(4-fluorobenzyl)[(2-methoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0646]
2-{[(2-ethoxyethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0647]
2-{(4-fluorobenzyl)[(1-methoxybutan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0648]
2-{[2-(4-cyanophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0649]
2-{[(1,3-dioxolan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0650]
2-[(4-fluorobenzyl){[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0651]
2-{[(1,4-dioxan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0652]
2-{[(1,3-dimethoxypropan-2-yl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0653]
2-{(4-fluorobenzyl)[(2-methoxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0654]
2-[(4-fluorobenzyl)(tetrahydrofuran-3-ylcarbamoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0655]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-3-ylcarbamoyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0656]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyrimidin-2-ylmeth-
yl)amino]-1,3-thiazole-5-carboxamide; [0657]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(2-methoxypyridin-4-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0658]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(1,3-oxazol-4-ylmet-
hyl)amino]-1,3-thiazole-5-carboxamide; [0659]
2-{[(5-chloropyridin-2-yl)methyl](3-methoxypropanoyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0660]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[(4-methylpyridin-3-
-yl)methyl]amino}-1,3-thiazole-5-carboxamide; [0661]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methoxypyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0662] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0663]
2-{[2-(3-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0664]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyridin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide acetate
(1:1); [0665]
2-{[2-(1,3-benzodioxol-5-yl)ethyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0666]
2-{[2-(4-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0667]
2-{[2-(3-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0668]
2-{[2-(4-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0669]
2-{[2-(3-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0670]
N-[3-(1H-imidazol-1-yl)propyl]-2-{[2-(3-methoxyphenyl)ethyl](3-methoxypro-
panoyl)amino}-1,3-thiazole-5-carboxamide acetate (1:1); [0671]
2-{[2-(2-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0672]
2-{[2-hydroxy-2-(4-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0673]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[1-(pyridin-2-yl)et-
hyl]amino}-1,3-thiazole-5-carboxamide; [0674]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(1-methyl-1H-pyrazol-4-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0675]
2-[(2,6-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0676]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methylpyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0677]
2-[(4-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0678]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyrazin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0679]
2-[(3-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0680]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyridin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0681]
2-[(2,5-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0682]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(2-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0683]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0684]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-2-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0685]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-3-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0686]
2-[(4-cyanobenzyl){[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0687]
2-{(4-cyanobenzyl)[(2-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0688] 2-[(4-cyanobenzyl)
{[2-(2-hydroxyethoxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide;
[0689] 2-[(4-cyanobenzyl)
{[3-(propan-2-yloxy)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0690]
2-{(4-cyanobenzyl)[(3-hydroxy-2,2-dimethylpropyl)carbamoyl]amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0691]
2-{(4-cyanobenzyl)[(2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0692]
2-{(4-cyanobenzyl)[(1-hydroxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0693]
2-{(4-cyanobenzyl)[(3-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0694] 2-[(4-cyanobenzyl)
{[(2S)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0695]
2-{(4-cyanobenzyl)[(4-hydroxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0696]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2R)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0697]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2S)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0698]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-5-methyl-N-
-(3-methylbutyl)-1,2-oxazole-3-carboxamide; [0699]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(phenoxy
acetyl)amino]-1,3-thiazole-5-carboxamide; [0700]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(3-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0701]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0702]
2-{[(4-fluorophenyl)acetyl](3-methylbutyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0703]
2-{[(3-amino-3-oxopropyl)carbamoyl](4-cyanobenzyl)amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0704]
2-[{[3-(acetylamino)-2-methylpropyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0705]
2-[(4-cyanobenzyl)
{[3-(dimethylamino)-3-oxopropyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0706]
2-{(4-cyanobenzyl)[(3-ethoxy-2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0707]
2-[(4-cyanobenzyl)
{[3-(diethylamino)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0708]
2-[{[2-(acetylamino)ethyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0709]
2-[(4-cyanobenzyl){[2-(diethylamino)ethyl]carbamoyl}amino]-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0710]
2-[(4-cyanobenzyl)({2-[(2-methylpropanoyl)amino]ethyl}carbamoyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0711]
2-[(4-cyanobenzyl)
{[(2R)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0712] 2-[(4-cyanobenzyl)
{[3-(3-hydroxyazetidin-1-yl)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0713]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbutyl)amin-
o]-1,3-thiazole-5-carboxamide; [0714]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(methoxyacetyl)(3-methylbutyl)amino]-1,-
3-thiazole-5-carboxamide; [0715]
2-[(cyclopropylcarbonyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0716]
(2S)-1-[(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)(3-me-
thylbutyl)amino]-1-oxopropan-2-yl acetate; [0717]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydro-2H-pyran-4-y-
lacetyl)amino]-1,3-thiazole-5-carboxamide; [0718]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylcar-
bonyl)amino]-1,3-thiazole-5-carboxamide; [0719]
2-{[2-hydroxy-2-(3-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0720]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyrazin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0721]
2-{[1-(3-hydroxyphenyl)propan-2-yl](3-methoxypropanoyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0722] ethyl
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alaninate; [0723] ethyl
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [0724] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [0725] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoate; [0726] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoate; [0727]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}cyclobutanecarboxylic acid; [0728] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoate; [0729]
2-{(4-cyanobenzyl)[(3-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0730]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [0731]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoic acid; [0732]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoic acid; [0733]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoic acid; [0734]
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alanine; [0735]
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [0736]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-2-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0737]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0738]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(3-methoxypropanoyl)ami-
no]-1,3-thiazole-5-carboxamide; [0739]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methoxypropyl)am-
ino]-1,3-thiazole-5-carboxamide; [0740]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydro-2H-pyra-
n-2-ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0741]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydrofuran-2--
ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0742]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(propan-2-yloxy)ethyl]amino}-1,3-thiazole-5-carboxamide; [0743]
2-{[2-(1,3-dioxolan-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0744]
2-[(1,4-dioxan-2-ylmethyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0745]
2-{[3-(4-fluorophenyl)propanoyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0746]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)
[3-(pyridin-3-yl)propanoyl]amino}-1,3-thiazole-5-carboxamide;
[0747]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-3-ylacetyl)ami-
no]-1,3-thiazole-5-carboxamide; [0748]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(naphthalen-2-ylacetyl)-
amino]-1,3-thiazole-5-carboxamide; [0749]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)[(4-phenoxyphenyl)acety-
l]amino}-1,3-thiazole-5-carboxamide; [0750]
2-{[(4-cyanophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0751]
2-{[(4-aminophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0752]
2-[{2-[di(prop-2-en-1-yl)amino]ethyl}(3-methoxypropanoyl)amino]-N-[3-(1H--
imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0753]
2-{[3-(diethylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0754]
2-{[2-(diethylamino)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0755]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(pyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0756]
2-{[(1-ethyl-5-oxopyrrolidin-3-yl)methyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0757]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-oxopyrrolidin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0758]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[3-oxo-3-(pyrrolidi-
n-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide; [0759]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-oxo-2-(piperidin-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0760] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0761] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0762] N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)
{2-[(2-methylpropanoyl)amino]ethyl}amino]-1,3-thiazole-5-carboxamide;
[0763] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(methylamino)-3-oxopropyl]amino}-1,3-thiazole-5-carboxamide;
[0764]
2-{[3-(acetylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0765]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0766]
2-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0767]
2-[3-(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0768]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydro-2H-pyran-4-ylcarbonyl)amino}-
-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0769]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydrofuran-3-ylcarbonyl)amino}-N-[-
3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0770]
2-{[2-(5-chloropyridin-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0771]
2-{[2-(5-chloropyridin-2-yl)ethyl](tetrahydrofuran-3-ylcarbonyl)amino}-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0772]
2-{[2-(5-chloropyridin-2-yl)ethyl][(2-methoxy
ethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carb-
oxamide; [0773]
2-([2-(5-chloropyridin-2-yl)ethyl]{[2-(propan-2-yloxy)ethyl]carbamoyl}ami-
no)-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide;
[0774]
2-[(1,3-benzodioxol-5-ylacetyl)(2-methoxyethyl)amino]-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0775]
2-{(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxaz-
olidin-3-yl}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide;
[0776]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-2-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; and pharmaceutically
acceptable salts thereof.
Embodiments of Formula (III)
[0777] In another aspect, the present invention provides compounds
of Formula (III)
##STR00005##
and pharmaceutically acceptable salts thereof; wherein each R.sup.6
is as described herein for Formula (I).
[0778] One embodiment of this invention pertains to compounds of
Formula (III) or pharmaceutically acceptable salts thereof;
wherein
[0779] R.sup.6, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.6 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.8, OR.sup.8, SR.sup.8, S(O)R.sup.8, SO.sub.2R.sup.8,
C(O)R.sup.8, CO(O)R.sup.8, OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2,
NHR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8,
NHS(O).sub.2R.sup.8, NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8,
NR.sup.8C(O)OR.sup.8, NHC(O)NH.sub.2, NHC(O)NHR.sup.8,
NHC(O)N(R.sup.8).sub.2, NR.sup.8C(O)NHR.sup.8,
NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0780] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.8 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
C(O)R.sup.10, CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10,
NH.sub.2, NHR.sup.10, N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHS(O).sub.2R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.7).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0781] R.sup.9, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.9 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12,
C(O)R.sup.12, CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
NH.sub.2, NHR.sup.12, N(R.sup.12).sub.2, NHC(O)R.sup.12,
NR.sup.12C(O)R.sup.12, NHS(O).sub.2R.sup.12,
NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0782] R.sup.10, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6haloalkyl, and C.sub.1-6
hydroxyalkyl;
[0783] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.11 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0784] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.12 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; and
[0785] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl represented by R.sup.13 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of alkoxy,
NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and
I.
[0786] In another embodiment of Formula (III), R.sup.6, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.6 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (III), R.sup.6, at each occurrence,
is independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl, heteroaryl, and
cycloalkyl; wherein the C.sub.1-6 alkyl, and C.sub.2-6 alkenyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
CO(O)R.sup.8, OC(O)R.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, and OH;
wherein the aryl, heterocycloalkyl, heteroaryl, and cycloalkyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)NH.sub.2,
C(O)OH, OH, CN, F, Cl, Br and I.
[0787] In one embodiment of Formula (III), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.10, OR.sup.10,
SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10, C(O)R.sup.10,
CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10, NH.sub.2, NHR.sup.10,
N(R.sup.7).sub.2, NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10,
NHS(O).sub.2R.sup.10, NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.7).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (III), R.sup.8, at each occurrence,
is independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, and cycloalkyl; wherein the
C.sub.1-6 alkyl and C.sub.2-6 alkenyl represented by R.sup.8 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
OH, F, Cl, Br and I; wherein the aryl, heterocycloalkyl, and
heteroaryl represented by R.sup.8 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, NH.sub.2,
N(R.sup.11).sub.2, C(O)H, OH, CN, F, Cl, Br and I.
[0788] In one embodiment of Formula (III), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.9 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (III), R.sup.9, at each occurrence,
is C.sub.1-6 alkyl.
[0789] In one embodiment of Formula (III), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, and C.sub.1-6 hydroxyalkyl.
[0790] In one embodiment of Formula (III), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.11 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (III), R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, aryl, and heteroaryl; wherein the C.sub.1-6 alkyl and
C.sub.2-6 alkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, cycloalkyl,
OH, F, Cl, Br and I.
[0791] In one embodiment of Formula (III), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I.
[0792] In one embodiment of Formula (III), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.13 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of alkoxy, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[0793] In another embodiment of Formula (III), R.sup.6, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, aryl, heterocycloalkyl, heteroaryl, and
cycloalkyl; wherein the C.sub.1-6 alkyl represented by R.sup.6 is
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.8,
OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, C(O)NHR.sup.8, and OH; wherein the aryl,
heterocycloalkyl, and heteroaryl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, C(O)NH.sub.2, OH, CN, F, Cl, Br and I. In another
embodiment of Formula (III), R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, and cycloalkyl; wherein the aryl,
heterocycloalkyl, and heteroaryl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, NH.sub.2, N(R.sup.11).sub.2, C(O)H, OH, CN, F, Cl, Br
and I. In another embodiment of Formula (III), R.sup.9, at each
occurrence, is C.sub.1-6 alkyl. In another embodiment of Formula
(III), R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
aryl; wherein the C.sub.1-6 alkyl and C.sub.2-6 alkenyl represented
by R.sup.11 are each independently optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-6alkoxy, cycloalkyl, OH, F, Cl, Br and I.
[0794] Still another embodiment pertains to compounds having
Formula (III), which include [0795]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0796]
2-[(cyclohexylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0797]
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [0798]
2-[(4-cyanobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0799]
2-[(3-chlorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0800]
2-[(4-fluorobenzoyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0801]
2-[(4-fluorobenzyl)(methoxyacetyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0802]
2-[(4-fluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0803]
2-[(N,N-dimethylglycyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0804]
2-[(3,6-dihydropyridin-1(2H)-ylacetyl)(4-fluorobenzyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0805]
2-{(4-fluorobenzyl)[(4-methylpiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0806]
2-{(4-fluorobenzyl)[(4-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0807]
2-{(4-fluorobenzyl)[(4-methylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0808]
2-[(4-fluorobenzyl){[4-(propan-2-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-
-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0809]
2-{(4-fluorobenzyl)[(4-formylpiperazin-1-yl)acetyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0810]
2-[(4-fluorobenzyl)(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylacetyl)amino]--
N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0811]
2-[{[4-(cyclopropylmethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0812]
2-[{[4-(2-ethoxyethyl)piperazin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3-(-
1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0813]
2-[(cyclopropylcarbonyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [0814] 2-[(4-fluorobenzyl)
{[4-(prop-2-en-1-yl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0815] 2-[(4-fluorobenzyl)
{[4-(3-methoxypropyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0816]
2-[{[3-(dimethylamino)pyrrolidin-1-yl]acetyl}(4-fluorobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0817]
2-[(4-fluorobenzyl)(morpholin-4-ylacetyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0818] 2-{(4-fluorobenzyl)
[(3-hydroxypiperidin-1-yl)acetyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0819] 2-[(4-fluorobenzyl)
{[4-(2-hydroxyethyl)piperazin-1-yl]acetyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0820]
2-[(1,4-dioxa-7-azaspiro[4.4]non-7-ylacetyl)(4-fluorobenzyl)amino]-N-[3-(-
1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0821]
1-{2-[(4-fluorobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thia-
zol-2-yl)amino]-2-oxoethyl}pyridinium; [0822]
2-{[2-(4-fluorophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0823]
2-{[2-(4-cyanophenyl)ethyl](3-methylbutanoyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0824]
2-{[2-(4-cyanophenyl)ethyl](tetrahydro-2H-pyran-4-ylacetyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0825]
2-[(4-cyanobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0826]
2-[(4-cyanobenzyl)(tetrahydro-2H-pyran-4-ylacetyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0827]
2-{[2-(4-cyanophenyl)ethyl](tetrahydrofuran-3-ylacetyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0828]
2-[(4-cyanobenzyl)(tetrahydrofuran-3-ylacetyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0829]
2-[(4-cyanobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)propy-
l]-1,3-thiazole-5-carboxamide; [0830]
N.sup.1-(4-fluorobenzyl)-N.sup.1-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoy-
l}-1,3-thiazol-2-yl)piperidine-1,3-dicarboxamide; [0831]
2-{(4-fluorobenzyl)
[(3-hydroxyazetidin-1-yl)carbonyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0832]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxamide; [0833]
2-{(4-fluorobenzyl)[(3-methoxypyrrolidin-1-yl)carbonyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0834]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,6-dimethylmorpholine-4-carboxamide; [0835]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-2,2-dimethylmorpholine-4-carboxamide; [0836]
N-(4-fluorobenzyl)-N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiaz-
ol-2-yl)-1,4-oxazepane-4-carboxamide; [0837]
2-[(4-fluorobenzoyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0838]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(4-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0839]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-N-(3-methy-
lbutyl)-1,2-oxazole-5-carboxamide; [0840]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenoxypropanoyl)amin-
o]-1,3-thiazole-5-carboxamide; [0841]
2-{[2-(4-cyanophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0842]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyrimidin-2-ylmeth-
yl)amino]-1,3-thiazole-5-carboxamide; [0843]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[(2-methoxypyridin--
4-yl)methyl]amino}-1,3-thiazole-5-carboxamide; [0844]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(1,3-oxazol-4-ylmet-
hyl)amino]-1,3-thiazole-5-carboxamide; [0845]
2-{[(5-chloropyridin-2-yl)methyl](3-methoxypropanoyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0846]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(4-methylpyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0847] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methoxypyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0848] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(4-methyl-1,3-thiazol-5-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0849]
2-{[2-(3-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0850]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyridin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide acetate
(1:1); [0851]
2-{[2-(1,3-benzodioxol-5-yl)ethyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0852]
2-{[2-(4-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0853]
2-{[2-(3-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0854]
2-{[2-(4-hydroxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0855]
2-{[2-(3-chlorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0856]
N-[3-(1H-imidazol-1-yl)propyl]-2-{[2-(3-methoxyphenyl)ethyl](3-methoxypro-
panoyl)amino}-1,3-thiazole-5-carboxamide acetate (1:1); [0857]
2-{[2-(2-fluorophenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1); [0858]
2-{[2-hydroxy-2-(4-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide acetate (1:1);
[0859]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[1-(pyridin-2-yl)et-
hyl]amino}-1,3-thiazole-5-carboxamide; [0860]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(1-methyl-1H-pyrazol-4-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0861]
2-[(2,6-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0862]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(6-methylpyridin-3-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0863]
2-[(4-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0864]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyrazin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0865]
2-[(3-chlorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0866]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-methylpyridin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0867]
2-[(2,5-difluorobenzyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0868]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(2-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0869]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbenzyl)ami-
no]-1,3-thiazole-5-carboxamide; [0870]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-2-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0871]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(pyridin-3-ylmethyl-
)amino]-1,3-thiazole-5-carboxamide; [0872]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2R)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0873]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methylbutyl)[(2S)-2-phenoxypropanoyl-
]amino}-1,3-thiazole-5-carboxamide; [0874]
N-(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)-5-methyl-N-
-(3-methylbutyl)-1,2-oxazole-3-carboxamide; [0875]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(phenoxyacetyl)amino]-1,-
3-thiazole-5-carboxamide; [0876]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(3-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0877]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(2-phenylpropanoyl)amino-
]-1,3-thiazole-5-carboxamide; [0878]
2-{[(4-fluorophenyl)acetyl](3-methylbutyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0879]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methylbutyl)amin-
o]-1,3-thiazole-5-carboxamide; [0880]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(methoxyacetyl)(3-methylbutyl)amino]-1,-
3-thiazole-5-carboxamide; [0881]
2-[(cyclopropylcarbonyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0882]
(2S)-1-[(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-2-yl)(3-me-
thylbutyl)amino]-1-oxopropan-2-yl acetate; [0883]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydro-2H-pyran-4-y-
lacetyl)amino]-1,3-thiazole-5-carboxamide; [0884]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylcar-
bonyl)amino]-1,3-thiazole-5-carboxamide; [0885]
2-{[2-hydroxy-2-(3-methoxyphenyl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0886]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(pyrazin-2-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0887]
2-{[1-(3-hydroxyphenyl)propan-2-yl](3-methoxypropanoyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0888]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-2-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0889]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methylbutyl)(tetrahydrofuran-3-ylace-
tyl)amino]-1,3-thiazole-5-carboxamide; [0890]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(3-methoxypropanoyl)ami-
no]-1,3-thiazole-5-carboxamide; [0891]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(3-methoxypropyl)am-
ino]-1,3-thiazole-5-carboxamide; [0892]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydro-2H-pyra-
n-2-ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0893]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)(tetrahydrofuran-2--
ylmethyl)amino]-1,3-thiazole-5-carboxamide; [0894]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(propan-2-yloxy)ethyl]amino}-1,3-thiazole-5-carboxamide; [0895]
2-{[2-(1,3-dioxolan-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0896]
2-[(1,4-dioxan-2-ylmethyl)(3-methoxypropanoyl)amino]-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0897]
2-{[3-(4-fluorophenyl)propanoyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0898]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)
[3-(pyridin-3-yl)propanoyl]amino}-1,3-thiazole-5-carboxamide;
[0899]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-3-ylacetyl)ami-
no]-1,3-thiazole-5-carboxamide; [0900]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(naphthalen-2-ylacetyl)-
amino]-1,3-thiazole-5-carboxamide; [0901]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(2-methoxyethyl)
[(4-phenoxyphenyl)acetyl]amino}-1,3-thiazole-5-carboxamide; [0902]
2-{[(4-cyanophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0903]
2-{[(4-aminophenyl)acetyl](2-methoxyethyl)amino}-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [0904]
2-[{2-[di(prop-2-en-1-yl)amino]ethyl}(3-methoxypropanoyl)amino]-N-[3-(1H--
imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0905]
2-{[3-(diethylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0906]
2-{[2-(diethylamino)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0907]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(pyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0908]
2-{[(1-ethyl-5-oxopyrrolidin-3-yl)methyl](3-methoxypropanoyl)amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0909]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[(5-oxopyrrolidin-2-yl)methyl]amino}-1,3-thiazole-5-carboxamide;
[0910]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[3-oxo-3-(pyrrolidi-
n-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide; [0911]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-oxo-2-(piperidin-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0912] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3-thiazole-5-carboxamide;
[0913] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]amino}-1,3-thiazole-5-carboxamide;
[0914] N-[3-(1H-imidazol-1-yl)propyl]-2-[(3-methoxypropanoyl)
{2-[(2-methylpropanoyl)amino]ethyl}amino]-1,3-thiazole-5-carboxamide;
[0915] N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)
[3-(methylamino)-3-oxopropyl]amino}-1,3-thiazole-5-carboxamide;
[0916]
2-{[3-(acetylamino)propyl](3-methoxypropanoyl)amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide;
[0917]
N-[3-(1H-imidazol-1-yl)propyl]-2-{(3-methoxypropanoyl)[2-oxo-2-(py-
rrolidin-1-yl)ethyl]amino}-1,3-thiazole-5-carboxamide; [0918]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydro-2H-pyran-4-ylcarbonyl)amino}-
-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0919]
2-{[(5-chloropyridin-2-yl)methyl](tetrahydrofuran-3-ylcarbonyl)amino}-N-[-
3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0920]
2-{[2-(5-chloropyridin-2-yl)ethyl](3-methoxypropanoyl)amino}-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0921]
2-{[2-(5-chloropyridin-2-yl)ethyl](tetrahydrofuran-3-ylcarbonyl)amino}-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0922]
2-[(1,3-benzodioxol-5-ylacetyl)(2-methoxyethyl)amino]-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0923]
N-[3-(1H-imidazol-1-yl)propyl]-2-[(2-methoxyethyl)(pyridin-2-ylacetyl)ami-
no]-1,3-thiazole-5-carboxamide; and pharmaceutically acceptable
salts thereof.
Embodiments of Formula (IV)
[0924] In another aspect, the present invention provides compounds
of Formula (IV)
##STR00006##
and pharmaceutically acceptable salts thereof; wherein each R.sup.6
is as described herein for Formula (I).
[0925] One embodiment of this invention pertains to compounds of
Formula (IV) or pharmaceutically acceptable salts thereof;
wherein
[0926] R.sup.6, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0927] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.8 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
C(O)R.sup.10, CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10,
NH.sub.2, NHR.sup.10, N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHS(O).sub.2R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0928] R.sup.9, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.9 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12,
C(O)R.sup.12, CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
NH.sub.2, NHR.sup.12, N(R.sup.12).sub.2, NHC(O)R.sup.12,
NR.sup.12C(O)R.sup.12, NHS(O).sub.2R.sup.12,
NR.sup.12S(O).sub.2R.sup.2, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0929] R.sup.10, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6haloalkyl, and C.sub.1-6
hydroxyalkyl;
[0930] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.11 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0931] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl represented
by R.sup.12 are each independently optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-6 alkoxy, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein
the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.12 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of NH.sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I; and
[0932] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl; wherein the C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl represented by R.sup.13 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of alkoxy, NH.sub.2, C(O)H,
C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[0933] In one embodiment of Formula (IV), R.sup.6, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.6 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.6, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl, heteroaryl, and
cycloalkyl; wherein the C.sub.1-6 alkyl, and C.sub.2-6 alkenyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
CO(O)R.sup.8, OC(O)R.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, and OH;
wherein the aryl, heterocycloalkyl, heteroaryl, and cycloalkyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)NH.sub.2,
C(O)OH, OH, CN, F, Cl, Br and I.
[0934] In one embodiment of Formula (IV), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.10, OR.sup.10,
SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10, C(O)R.sup.10,
CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10, NH.sub.2, NHR.sup.10,
N(R.sup.10).sub.2, NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10,
NHS(O).sub.2R.sup.10, NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, and cycloalkyl; wherein the
C.sub.1-6 alkyl and C.sub.2-6 alkenyl represented by R.sup.8 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
OH, F, Cl, Br and I; wherein the aryl, heterocycloalkyl, and
heteroaryl represented by R.sup.8 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, NH.sub.2,
N(R.sup.11).sub.2, C(O)H, OH, CN, F, Cl, Br and I.
[0935] In one embodiment of Formula (IV), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.9 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
SR.sup.2, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.11, NH.sub.2, NHR.sup.7,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.9, at each occurrence, is
C.sub.1-6 alkyl.
[0936] In one embodiment of Formula (IV), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, and C.sub.1-6 hydroxyalkyl.
[0937] In one embodiment of Formula (IV), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.11 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (IV), R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, aryl, and heteroaryl; wherein the C.sub.1-6 alkyl and
C.sub.2-6 alkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, cycloalkyl,
OH, F, Cl, Br and I.
[0938] In one embodiment of Formula (IV), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I.
[0939] In one embodiment of Formula (IV), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.13 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of alkoxy, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[0940] In another embodiment of Formula (IV), R.sup.6, at each
occurrence, is C.sub.1-6 alkyl; wherein the C.sub.1-6 alkyl
represented by R.sup.6 is independently optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.8, C(O)R.sup.8, C(O)NHR.sup.8, and
C(O)N(R.sup.8).sub.2. In another embodiment of Formula (IV),
R.sup.8, at each occurrence, is independently selected from the
group consisting of C.sub.1-6 alkyl, aryl, and heterocycloalkyl;
wherein the aryl, and heterocycloalkyl represented by R.sup.8 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.11, CN, F, Cl, Br and I. In another embodiment of Formula
(IV), R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl and heteroaryl.
[0941] Still another embodiment pertains to compounds having
Formula (IV), which include [0942]
2-{(4-fluorobenzyl)[4-(pyridin-3-yl)benzyl]amino}-N-[3-(1H-imidazol-1-yl)-
propyl]-1,3-thiazole-5-carboxamide; [0943]
N-[3-(1H-imidazol-1-yl)propyl]-2-{methyl[4-(pyridin-3-yl)benzyl]amino}-1,-
3-thiazole-5-carboxamide; [0944]
2-[(4-fluorobenzyl)(methyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0945] 2-{(4-fluorobenzyl)
[3-(morpholin-4-yl)propyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide; [0946] 2-{(4-fluorobenzyl)
[3-(piperidin-1-yl)propyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide; [0947] 2-{(4-fluorobenzyl)
[2-(pyrrolidin-1-yl)ethyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide; [0948]
2-[(4-fluorobenzyl){2-[4-(propan-2-yl)piperazin-1-yl]ethyl}amino]-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0949]
2-{[(5-chloro-1,3-benzodioxol-4-yl)methyl](4-fluorobenzyl)amino}-N-[3-(1H-
-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0950]
2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0951]
2-[(2-chlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0952]
2-[(2,5-dichlorobenzyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0953]
2-{(4-fluorobenzyl)[2-(methylamino)-2-oxoethyl]amino}-N-[3-(1H-imidazol-1-
-yl)propyl]-1,3-thiazole-5-carboxamide; [0954]
2-{(4-fluorobenzyl)[2-oxo-2-(propan-2-ylamino)ethyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0955]
2-{[2-(dimethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-
-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0956]
2-{[2-(diethylamino)-2-oxoethyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol--
1-yl)propyl]-1,3-thiazole-5-carboxamide; [0957]
2-{(4-fluorobenzyl)[2-(morpholin-4-yl)-2-oxoethyl]amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0958]
2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [0959]
2-[(4-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0960]
2-[(2-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0961]
2-[(3-fluorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0962]
2-[(2-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0963]
2-[(3-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0964]
2-[(4-chlorobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [0965]
2-[(4-cyanobenzyl)(3-methylbutyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; and pharmaceutically acceptable salts
thereof.
Embodiments of Formula (V)
[0966] In another aspect, the present invention provides compounds
of Formula (V)
##STR00007##
and pharmaceutically acceptable salts thereof; wherein each R.sup.6
is as described herein for Formula (I).
[0967] One embodiment of this invention pertains to compounds of
Formula (V) or pharmaceutically acceptable salts thereof;
wherein
[0968] R.sup.6, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.6 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.8, OR.sup.8, SR.sup.8, S(O)R.sup.8, SO.sub.2R.sup.8,
C(O)R.sup.8, CO(O)R.sup.8, OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2,
NHR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8,
NHS(O).sub.2R.sup.8, NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8,
NR.sup.8C(O)OR.sup.8, NHC(O)NH.sub.2, NHC(O)NHR.sup.8,
NHC(O)N(R.sup.8).sub.2, NR.sup.8C(O)NHR.sup.8,
NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0969] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.8 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
C(O)R.sup.10, CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10,
NH.sub.2, NHR.sup.10, N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHS(O).sub.2R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.7).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0970] R.sup.9, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.9 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12, CO(O)R.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0971] R.sup.10, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, and C.sub.1-6
hydroxyalkyl;
[0972] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.11 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[0973] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.12 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; and
[0974] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl represented by R.sup.13 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of alkoxy,
NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and
I.
[0975] In one embodiment of Formula (V), R.sup.6, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.6 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (V), R.sup.6, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl, heteroaryl, and
cycloalkyl; wherein the C.sub.1-6 alkyl, and C.sub.2-6 alkenyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
CO(O)R.sup.8, OC(O)R.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, and OH;
wherein the aryl, heterocycloalkyl, heteroaryl, and cycloalkyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)NH.sub.2,
C(O)OH, OH, CN, F, Cl, Br and I.
[0976] In one embodiment of Formula (V), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.10, OR.sup.10,
SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10, C(O)R.sup.10,
CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10, NH.sub.2, NHR.sup.10,
N(R.sup.1).sub.2, NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10,
NHS(O).sub.2R.sup.10, NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (V), R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, and cycloalkyl; wherein the
C.sub.1-6 alkyl and C.sub.2-6 alkenyl represented by R.sup.8 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
OH, F, Cl, Br and I; wherein the aryl, heterocycloalkyl, and
heteroaryl represented by R.sup.8 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, NH.sub.2,
N(R.sup.11).sub.2, C(O)H, OH, CN, F, Cl, Br and I.
[0977] In one embodiment of Formula (V), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.9 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (V), R.sup.9, at each occurrence, is
C.sub.1-6 alkyl.
[0978] In one embodiment of Formula (V), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, and C.sub.1-6 hydroxyalkyl.
[0979] In one embodiment of Formula (V), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.11 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (V), R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, aryl, and heteroaryl; wherein the C.sub.1-6 alkyl and
C.sub.2-6 alkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6alkoxy, cycloalkyl,
OH, F, Cl, Br and I.
[0980] In one embodiment of Formula (V), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I.
[0981] In one embodiment of Formula (V), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; wherein
the C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.13 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of alkoxy, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[0982] In another embodiment of Formula (V), R.sup.6, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, heterocycloalkyl, and
cycloalkyl; wherein the C.sub.1-6 alkyl and C.sub.2-6 alkenyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)OR.sup.8,
N(R.sup.8).sub.2, NHC(O)R.sup.8, C(O)NH.sub.2,
C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the heterocycloalkyl,
and cycloalkyl represented by R.sup.6 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C(O)NH.sub.2, C(O)OH, F, Cl,
Br and I. In another embodiment of Formula (V), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, aryl, heterocycloalkyl, and heteroaryl; wherein
the C.sub.1-6 alkyl is independently optionally substituted with
one or more OH; wherein the aryl, heterocycloalkyl, and heteroaryl
represented by R.sup.8 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of OH, CN, F, Cl, Br and I.
[0983] Still another embodiment pertains to compounds having
Formula (V), which include [0984]
2-[(4-fluorobenzyl)(propan-2-ylcarbamoyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [0985]
2-{(4-fluorobenzyl)[(3-methylbutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0986] 2-{(4-fluorobenzyl)
[(2-methylpropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thia-
zole-5-carboxamide; [0987]
2-{(4-fluorobenzyl)[(2-propoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0988] 2-{(4-fluorobenzyl)
[(tetrahydrofuran-2-ylmethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [0989] 2-{(4-fluorobenzyl)
[(1-methoxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,-
3-thiazole-5-carboxamide; [0990]
2-{(4-fluorobenzyl)[(tetrahydro-2H-pyran-2-ylmethyl)carbamoyl]amino}-N-[3-
-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0991]
2-{(4-fluorobenzyl)[(2-methoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0992]
2-{[(2-ethoxyethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [0993]
2-{(4-fluorobenzyl)[(1-methoxybutan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0994]
2-{[(1,3-dioxolan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0995]
2-[(4-fluorobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [0996]
2-{[(1,4-dioxan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0997]
2-{[(1,3-dimethoxypropan-2-yl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [0998]
2-{(4-fluorobenzyl)[(2-methoxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [0999]
2-[(4-fluorobenzyl)(tetrahydrofuran-3-ylcarbamoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1000]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-3-ylcarbamoyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1001]
2-[(4-cyanobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [1002]
2-{(4-cyanobenzyl)[(2-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1003] 2-[(4-cyanobenzyl)
{[2-(2-hydroxyethoxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [1004] 2-[(4-cyanobenzyl)
{[3-(propan-2-yloxy)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [1005]
2-{(4-cyanobenzyl)[(3-hydroxy-2,2-dimethylpropyl)carbamoyl]amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1006]
2-{(4-cyanobenzyl)[(2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1007]
2-{(4-cyanobenzyl)[(1-hydroxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1008]
2-{(4-cyanobenzyl)[(3-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1009] 2-[(4-cyanobenzyl)
{[(2S)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [1010]
2-{(4-cyanobenzyl)[(4-hydroxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [1011]
2-{[(3-amino-3-oxopropyl)carbamoyl](4-cyanobenzyl)amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1012]
2-[{[3-(acetylamino)-2-methylpropyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1013]
2-[(4-cyanobenzyl)
{[3-(dimethylamino)-3-oxopropyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [1014]
2-{(4-cyanobenzyl)[(3-ethoxy-2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1015]
2-[(4-cyanobenzyl)
{[3-(diethylamino)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [1016]
2-[{[2-(acetylamino)ethyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1017]
2-[(4-cyanobenzyl)
{[2-(diethylamino)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [1018]
2-[(4-cyanobenzyl)({2-[(2-methylpropanoyl)amino]ethyl}carbamoyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1019]
2-[(4-cyanobenzyl)
{[(2R)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [1020] 2-[(4-cyanobenzyl)
{[3-(3-hydroxyazetidin-1-yl)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [1021] ethyl
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alaninate; [1022] ethyl
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [1023] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [1024] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoate; [1025] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoate; [1026]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}cyclobutanecarboxylic acid; [1027] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoate; [1028]
2-{(4-cyanobenzyl)[(3-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1029]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [1030]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoic acid; [1031]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoic acid; [1032]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoic acid; [1033]
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alanine; [1034]
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [1035]
2-{[2-(5-chloropyridin-2-yl)ethyl][(2-methoxyethyl)carbamoyl]amino}-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1036]
2-([2-(5-chloropyridin-2-yl)ethyl]{[2-(propan-2-yloxy)ethyl]carbamoyl}ami-
no)-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; and
pharmaceutically acceptable salts thereof.
Embodiments of Formula (VI)
[1037] In another aspect, the present invention provides compounds
of Formula (VI)
##STR00008##
and pharmaceutically acceptable salts thereof; wherein each R.sup.6
is as described herein for Formula (I), and RX is as described
herein for substituents on R.sup.8 when R.sup.8 is aryl.
[1038] One embodiment of this invention pertains to compounds of
Formula (VI) or pharmaceutically acceptable salts thereof;
wherein
[1039] R.sup.6, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[1040] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.8 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
C(O)R.sup.10, CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10,
NH.sub.2, NHR.sup.10, N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHS(O).sub.2R.sup.10,
NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.10).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.7).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[1041] Rx is independently selected from the group consisting of
R.sup.11, OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11,
C(O)R.sup.11, CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11,
NH.sub.2, NHR.sup.11, N(R.sup.11).sub.2, NHC(O)R.sup.11,
NR.sup.11C(O)R.sup.11, NHS(O).sub.2R.sup.11,
NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[1042] R.sup.9, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.9 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12,
C(O)R.sup.12, CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12,
NH.sub.2, NHR.sup.12, N(R.sup.12).sub.2, NHC(O)R.sup.12,
NR.sup.12C(O)R.sup.12, NHS(O).sub.2R.sup.12,
NR.sup.12S(O).sub.2R.sup.2, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[1043] R.sup.10, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, and C.sub.1-6
hydroxyalkyl;
[1044] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the C.sub.1-6
alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl represented by
R.sup.11 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-6alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I; wherein the aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
[1045] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heterocycloalkyl, heterocycloalkenyl,
heteroaryl, cycloalkyl, and cycloalkenyl; wherein the
C.sub.1-6alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I; and
[1046] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl; wherein the C.sub.1-6alkyl, C.sub.2-6 alkenyl,
and C.sub.2-6 alkynyl represented by R.sup.13 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of alkoxy,
NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and
I.
[1047] In one embodiment of Formula (IV), R.sup.6 is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl;
wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6
alkynyl represented by R.sup.6 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8O.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.8, C(N)N(R.sup.8).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.9,
OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9,
CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2, NHR.sup.9,
N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.9, C(N)N(R.sup.9).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.6 is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, aryl, heterocycloalkyl, heteroaryl, and cycloalkyl;
wherein the C.sub.1-6 alkyl, and C.sub.2-6 alkenyl represented by
R.sup.6 are each independently optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.8, OR.sup.8, C(O)R.sup.8, CO(O)R.sup.8, OC(O)R.sup.8,
N(R.sup.8).sub.2, NHC(O)R.sup.8, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the aryl,
heterocycloalkyl, heteroaryl, and cycloalkyl represented by R.sup.6
are each independently optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)NH.sub.2, C(O)OH, OH, CN, F, Cl, Br and
I.
[1048] In one embodiment of Formula (IV), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.8 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.10, OR.sup.10,
SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10, C(O)R.sup.10,
CO(O)R.sup.10, OC(O)R.sup.10, OC(O)OR.sup.10, NH.sub.2, NHR.sup.10,
N(R.sup.7).sub.2, NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10,
NHS(O).sub.2R.sup.10, NR.sup.10S(O).sub.2R.sup.10, NHC(O)OR.sup.10,
NR.sup.10C(O)OR.sup.10, NHC(O)NH.sub.2, NHC(O)NHR.sup.10,
NHC(O)N(R.sup.7).sub.2, NR.sup.10C(O)NHR.sup.10,
NR.sup.10C(O)N(R.sup.10).sub.2, C(O)NH.sub.2, C(O)NHR.sup.10,
C(O)N(R.sup.10).sub.2, C(O)NHOH, C(O)NHOR.sup.10,
C(O)NHSO.sub.2R.sup.10, C(O)NR.sup.10SO.sub.2R.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.10, C(N)N(R.sup.10).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11, C(O)R.sup.11,
CO(O)R.sup.11, OC(O)R.sup.11, OC(O)OR.sup.11, NH.sub.2, NHR.sup.11,
N(R.sup.11).sub.2, NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11,
NHS(O).sub.2R.sup.11, NR.sup.11S(O).sub.2R.sup.11, NHC(O)OR.sup.11,
NR.sup.11C(O)OR.sup.11, NHC(O)NH.sub.2, NHC(O)NHR.sup.11,
NHC(O)N(R.sup.11).sub.2, NR.sup.11C(O)NHR.sup.11,
NR.sup.11C(O)N(R.sup.11).sub.2, C(O)NH.sub.2, C(O)NHR.sup.11,
C(O)N(R.sup.11).sub.2, C(O)NHOH, C(O)NHOR.sup.11,
C(O)NHSO.sub.2R.sup.11, C(O)NR.sup.11SO.sub.2R.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.11, C(N)N(R.sup.11).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, and cycloalkyl; wherein the
C.sub.1-6 alkyl and C.sub.2-6 alkenyl represented by R.sup.8 are
each independently optionally substituted with one or more
substituents independently selected from the group consisting of
OH, F, Cl, Br and I; wherein the aryl, heterocycloalkyl, and
heteroaryl represented by R.sup.8 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, NH.sub.2,
N(R.sup.11).sub.2, C(O)H, OH, CN, F, Cl, Br and I.
[1049] In one embodiment of Formula (IV), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.9 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
SR.sup.2, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I;
wherein the aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,
cycloalkyl, and cycloalkenyl represented by R.sup.9 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.13, C(N)N(R.sup.13).sub.2,
CNOH, CNOCH.sub.3, OH, CN, N.sub.3, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.9, at each occurrence, is
C.sub.1-6 alkyl.
[1050] In one embodiment of Formula (IV), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, and C.sub.1-6 hydroxyalkyl.
[1051] In one embodiment of Formula (IV), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.11 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (IV), R.sup.13, at each occurrence, is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, aryl, and heteroaryl; wherein the C.sub.1-6 alkyl and
C.sub.2-6 alkenyl represented by R.sup.11 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, cycloalkyl,
OH, F, Cl, Br and I.
[1052] In one embodiment of Formula (IV), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and
cycloalkenyl; wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and
C.sub.2-6 alkynyl represented by R.sup.12 are each independently
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-6 alkoxy, aryl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl,
cycloalkenyl, NH.sub.2, C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2,
F, Cl, Br and I; wherein the aryl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl
represented by R.sup.12 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of NH.sub.2, C(O)H, C(O)OH, OH, CN,
N.sub.3, NO.sub.2, F, Cl, Br and I.
[1053] In one embodiment of Formula (IV), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl; wherein
the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl
represented by R.sup.13 are each independently optionally
substituted with one or more substituents independently selected
from the group consisting of alkoxy, NH.sub.2, C(O)H, C(O)OH, OH,
CN, N.sub.3, NO.sub.2, F, Cl, Br and I.
[1054] In one embodiment of Formula (IV), R.sup.6 is independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6
alkenyl, heterocycloalkyl, and cycloalkyl; wherein the C.sub.1-6
alkyl and C.sub.2-6 alkenyl represented by R.sup.6 are
independently optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.8,
OR.sup.8, C(O)OR.sup.8, N(R.sup.8).sub.2, NHC(O)R.sup.8,
C(O)NH.sub.2, C(O)N(R.sup.8).sub.2, C(O)OH, and OH; wherein the
heterocycloalkyl, and cycloalkyl represented by R.sup.6 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of C(O)OH, F, Cl,
Br and I. In another embodiment of Formula (IV), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-6 alkyl and heterocycloalkyl; wherein the C.sub.1-6 alkyl
is independently optionally substituted with one or more OH;
wherein the heterocycloalkyl represented by R.sup.8 are each
independently optionally substituted with one or more substituents
independently selected from the group consisting of OH, F, Cl, Br
and I.
[1055] In one embodiment of Formula (IV), Rx is selected from the
group consisting of CN, F, Cl, Br and I. In another embodiment of
Formula (IV), Rx is selected from the group consisting of F, Cl, Br
and I. In another embodiment of Formula (IV), Rx is CN. In another
embodiment of Formula (IV), Rx is F.
[1056] Still another embodiment pertains to compounds having
Formula (VI), which include [1057]
2-[(4-fluorobenzyl)(propan-2-ylcarbamoyl)amino]-N-[3-(1H-imidazol-1-yl)pr-
opyl]-1,3-thiazole-5-carboxamide; [1058]
2-{(4-fluorobenzyl)[(3-methylbutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [1059]
2-{(4-fluorobenzyl)[(2-methylpropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1060]
2-{(4-fluorobenzyl)[(2-propoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1061] 2-{(4-fluorobenzyl)
[(tetrahydrofuran-2-ylmethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-yl)prop-
yl]-1,3-thiazole-5-carboxamide; [1062]
2-{(4-fluorobenzyl)[(1-methoxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imida-
zol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1063]
2-{(4-fluorobenzyl)[(tetrahydro-2H-pyran-2-ylmethyl)carbamoyl]amino}-N-[3-
-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1064]
2-{(4-fluorobenzyl)[(2-methoxyethyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1065]
2-{[(2-ethoxyethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [1066]
2-{(4-fluorobenzyl)[(1-methoxybutan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1067]
2-{[(1,3-dioxolan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1068]
2-[(4-fluorobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [1069]
2-{[(1,4-dioxan-2-ylmethyl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-imid-
azol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1070]
2-{[(1,3-dimethoxypropan-2-yl)carbamoyl](4-fluorobenzyl)amino}-N-[3-(1H-i-
midazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1071]
2-{(4-fluorobenzyl)[(2-methoxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1072]
2-[(4-fluorobenzyl)(tetrahydrofuran-3-ylcarbamoyl)amino]-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1073]
2-[(4-fluorobenzyl)(tetrahydro-2H-pyran-3-ylcarbamoyl)amino]-N-[3-(1H-imi-
dazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1074]
2-[(4-cyanobenzyl)
{[2-(propan-2-yloxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide; [1075]
2-{(4-cyanobenzyl)[(2-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1076] 2-[(4-cyanobenzyl)
{[2-(2-hydroxyethoxy)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [1077] 2-[(4-cyanobenzyl)
{[3-(propan-2-yloxy)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl-
]-1,3-thiazole-5-carboxamide; [1078]
2-{(4-cyanobenzyl)[(3-hydroxy-2,2-dimethylpropyl)carbamoyl]amino}-N-[3-(1-
H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1079]
2-{(4-cyanobenzyl)[(2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1080]
2-{(4-cyanobenzyl)[(1-hydroxypropan-2-yl)carbamoyl]amino}-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1081]
2-{(4-cyanobenzyl)[(3-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1082] 2-[(4-cyanobenzyl)
{[(2S)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [1083]
2-{(4-cyanobenzyl)[(4-hydroxybutyl)carbamoyl]amino}-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [1084]
2-{[(3-amino-3-oxopropyl)carbamoyl](4-cyanobenzyl)amino}-N-[3-(1H-imidazo-
l-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1085]
2-[{[3-(acetylamino)-2-methylpropyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3--
(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1086]
2-[(4-cyanobenzyl)
{[3-(dimethylamino)-3-oxopropyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)p-
ropyl]-1,3-thiazole-5-carboxamide; [1087]
2-{(4-cyanobenzyl)[(3-ethoxy-2-hydroxypropyl)carbamoyl]amino}-N-[3-(1H-im-
idazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1088]
2-[(4-cyanobenzyl)
{[3-(diethylamino)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]--
1,3-thiazole-5-carboxamide; [1089]
2-[{[2-(acetylamino)ethyl]carbamoyl}(4-cyanobenzyl)amino]-N-[3-(1H-imidaz-
ol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1090]
2-[(4-cyanobenzyl)
{[2-(diethylamino)ethyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)propyl]-1-
,3-thiazole-5-carboxamide; [1091]
2-[(4-cyanobenzyl)({2-[(2-methylpropanoyl)amino]ethyl}carbamoyl)amino]-N--
[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide; [1092]
2-[(4-cyanobenzyl)
{[(2R)-1-hydroxybut-3-en-2-yl]carbamoyl}amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide; [1093] 2-[(4-cyanobenzyl)
{[3-(3-hydroxyazetidin-1-yl)propyl]carbamoyl}amino]-N-[3-(1H-imidazol-1-y-
l)propyl]-1,3-thiazole-5-carboxamide; [1094] ethyl
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alaninate; [1095] ethyl
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [1096] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoate; [1097] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoate; [1098] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoate; [1099]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}cyclobutanecarboxylic acid; [1100] ethyl
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoate; [1101]
2-{(4-cyanobenzyl)[(3-methoxypropyl)carbamoyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide; [1102]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; [1103]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-4-methylpentanoic acid; [1104]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2,2-dimethylpropanoic acid; [1105]
3-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}-2-methylpropanoic acid; [1106]
N-[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol--
2-yl)carbamoyl]-beta-alanine; [1107]
4-{[(4-cyanobenzyl)(5-{[3-(1H-imidazol-1-yl)propyl]carbamoyl}-1,3-thiazol-
-2-yl)carbamoyl]amino}butanoic acid; and pharmaceutically
acceptable salts thereof.
Pharmaceutical Compositions, Combination Therapies, Methods of
Treatment, and Administration
[1108] Another embodiment comprises pharmaceutical compositions
comprising a compound having Formula (I) and an excipient.
[1109] Still another embodiment comprises methods of treating
cancer in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound having Formula
(I).
[1110] Still another embodiment pertains to compositions for
treating diseases during which NAMPT is expressed, said
compositions comprising an excipient and a therapeutically
effective amount of the compound having Formula (I).
[1111] Still another embodiment pertains to methods of treating
disease in a patient during which NAMPT is expressed, said methods
comprising administering to the patient a therapeutically effective
amount of a compound having Formula (I).
[1112] Still another embodiment pertains to compositions for
treating inflammatory and tissue repair disorders; particularly
rheumatoid arthritis, inflammatory bowel disease, asthma and COPD
(chronic obstructive pulmonary disease), osteoarthritis,
osteoporosis and fibrotic diseases; dermatosis, including
psoriasis, atopic dermatitis and ultra-violet induced skin damage;
autoimmune diseases including systemic lupus erythematosis,
multiple sclerosis, psoriatic arthritis, ankylosing spondylitis,
tissue and organ rejection, Alzheimer's disease, stroke,
athersclerosis, restenosis, diabetes, glomerulonephritis, cancer,
particularly wherein the cancer is selected from breast, prostate,
lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia,
lymphoma or Hodgkin's disease, cachexia, inflammation associated
with infection and certain viral infections, including Acquired
Immune Deficiency Syndrome (AIDS), adult respiratory distress
syndrome, and ataxia telengiectasia, said compositions comprising
an excipient and a therapeutically effective amount of the compound
having Formula (I).
[1113] Still another embodiment pertains to methods of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia in a patient, said methods comprising administering
to the patient a therapeutically effective amount of a compound
having Formula (I).
[1114] Still another embodiment pertains to compositions for
treating diseases during which NAMPT is expressed, said
compositions comprising an excipient and a therapeutically
effective amount of the compound having Formula (I) and a
therapeutically effective amount of one additional therapeutic
agent or more than one additional therapeutic agent.
[1115] Still another embodiment pertains to methods of treating
disease in a patient during which NAMPT is expressed, said methods
comprising administering to the patient a therapeutically effective
amount of a compound having Formula (I) and a therapeutically
effective amount of one additional therapeutic agent or more than
one additional therapeutic agent.
[1116] Still another embodiment pertains to compositions for
treating inflammatory and tissue repair disorders; particularly
rheumatoid arthritis, inflammatory bowel disease, asthma and COPD
(chronic obstructive pulmonary disease), osteoarthritis,
osteoporosis and fibrotic diseases; dermatosis, including
psoriasis, atopic dermatitis and ultra-violet induced skin damage;
autoimmune diseases including systemic lupus erythematosis,
multiple sclerosis, psoriatic arthritis, ankylosing spondylitis,
tissue and organ rejection, Alzheimer's disease, stroke,
athersclerosis, restenosis, diabetes, glomerulonephritis, cancer,
particularly wherein the cancer is selected from breast, prostate,
lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia,
lymphoma or Hodgkin's disease, cachexia, inflammation associated
with infection and certain viral infections, including Acquired
Immune Deficiency Syndrome (AIDS), adult respiratory distress
syndrome, and ataxia telengiectasia, said compositions comprising
an excipient and a therapeutically effective amount of the compound
having Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[1117] Still another embodiment pertains to methods of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia in a patient, said methods comprising administering
to the patient a therapeutically effective amount of the compound
having Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[1118] Metabolites of compounds having Formula (I), produced by in
vitro or in vivo metabolic processes, may also have utility for
treating diseases associated with NAMPT.
[1119] Certain precursor compounds which may be metabolized in
vitro or in vivo to form compounds having Formula (I) may also have
utility for treating diseases associated with NAMPT.
[1120] Compounds having Formula (I) may exist as acid addition
salts, basic addition salts or zwitterions. Salts of the compounds
are prepared during isolation or following purification of the
compounds. Acid addition salts of the compounds are those derived
from the reaction of the compounds with an acid. For example, the
acetate, adipate, alginate, bicarbonate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsufonate, digluconate, formate, fumarate, glycerophosphate,
glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, lactobionate, lactate, maleate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate,
picrate, propionate, succinate, tartrate, thiocyanate,
trichloroacetic, trifluoroacetic, para-toluenesulfonate, and
undecanoate salts of the compounds are contemplated as being
embraced by this invention. Basic addition salts of the compounds
are those derived from the reaction of the compounds with the
hydroxide, carbonate or bicarbonate of cations such as lithium,
sodium, potassium, calcium, and magnesium.
[1121] The compounds having Formula (I) may be administered, for
example, bucally, ophthalmically, orally, osmotically, parenterally
(intramuscularly, intraperitoneally intrasternally, intravenously,
subcutaneously), rectally, topically, transdermally or
vaginally.
[1122] Therapeutically effective amounts of compounds having
Formula (I) depend on the recipient of the treatment, the disorder
being treated and the severity thereof, the composition containing
the compound, the time of administration, the route of
administration, the duration of treatment, the compound potency,
its rate of clearance and whether or not another drug is
co-administered. The amount of a compound of this invention having
Formula (I) used to make a composition to be administered daily to
a patient in a single dose or in divided doses is from about 0.03
to about 200 mg/kg body weight. Single dose compositions contain
these amounts or a combination of submultiples thereof.
[1123] Compounds having Formula (I) may be administered with or
without an excipient. Excipients include, for example,
encapsulating materials or additives such as absorption
accelerators, antioxidants, binders, buffers, coating agents,
coloring agents, diluents, disintegrating agents, emulsifiers,
extenders, fillers, flavoring agents, humectants, lubricants,
perfumes, preservatives, propellants, releasing agents, sterilizing
agents, sweeteners, solubilizers, wetting agents and mixtures
thereof.
[1124] Excipients for preparation of compositions comprising a
compound having Formula (I) to be administered orally in solid
dosage form include, for example, agar, alginic acid, aluminum
hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol,
carbomers, castor oil, cellulose, cellulose acetate, cocoa butter,
corn starch, corn oil, cottonseed oil, cross-povidone,
diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl
oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,
groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic
saline, lactose, magnesium hydroxide, magnesium stearate, malt,
mannitol, monoglycerides, olive oil, peanut oil, potassium
phosphate salts, potato starch, povidone, propylene glycol,
Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl
cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium
sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose,
surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol,
triglycerides, water, and mixtures thereof. Excipients for
preparation of compositions comprising a compound of this invention
having Formula (I) to be administered ophthalmically or orally in
liquid dosage forms include, for example, 1,3-butylene glycol,
castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of
sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive
oil, polyethylene glycols, propylene glycol, sesame oil, water and
mixtures thereof. Excipients for preparation of compositions
comprising a compound of this invention having Formula (I) to be
administered osmotically include, for example,
chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of
this invention having Formula (I) to be administered parenterally
include, for example, 1,3-butanediol, castor oil, corn oil,
cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic
acid, olive oil, peanut oil, Ringer's solution, safflower oil,
sesame oil, soybean oil, U.S.P. or isotonic sodium chloride
solution, water and mixtures thereof. Excipients for preparation of
compositions comprising a compound of this invention having Formula
(I) to be administered rectally or vaginally include, for example,
cocoa butter, polyethylene glycol, wax and mixtures thereof.
[1125] Compounds having Formula (I) are expected to be useful when
used with alkylating agents, angiogenesis inhibitors, antibodies,
antimetabolites, antimitotics, antiproliferatives, antivirals,
aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL,
Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway,
Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager)
antibodies, antibody drug conjugates, biologic response modifiers,
cyclin-dependent kinase inhibitors, cell cycle inhibitors,
cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog
(ErbB2) receptor inhibitors, growth factor inhibitors, heat shock
protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors,
hormonal therapies, immunologicals, inhibitors of inhibitors of
apoptosis proteins (IAPs), intercalating antibiotics, kinase
inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target
of rapamycin inhibitors, microRNA's, mitogen-activated
extracellular signal-regulated kinase inhibitors, multivalent
binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs),
poly ADP (adenosine diphosphate)-ribose polymerase (PARP)
inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)
inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteosome
inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine
kinase inhibitors, retinoids/deltoids plant alkaloids, small
inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,
ubiquitin ligase inhibitors, and the like, and in combination with
one or more of these agents.
[1126] BiTE antibodies are bi-specific antibodies that direct
T-cells to attack cancer cells by simultaneously binding the two
cells. The T-cell then attacks the target cancer cell. Examples of
BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one
of the mechanisms by which T-cells elicit apoptosis of the target
cancer cell is by exocytosis of cytolytic granule components, which
include perforin and granzyme B.
[1127] SiRNAs are molecules having endogenous RNA bases or
chemically modified nucleotides. The modifications do not abolish
cellular activity, but rather impart increased stability and/or
increased cellular potency. Examples of chemical modifications
include phosphorothioate groups, 2'-deoxynucleotide,
2'-OCH.sub.3-containing ribonucleotides, 2'-F-ribonucleotides,
2'-methoxyethyl ribonucleotides, combinations thereof and the like.
The siRNA can have varying lengths (e.g., 10-200 bps) and
structures (e.g., hairpins, single/double strands, bulges,
nicks/gaps, mismatches) and are processed in cells to provide
active gene silencing. A double-stranded siRNA (dsRNA) can have the
same number of nucleotides on each strand (blunt ends) or
asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be
present on the sense and/or the antisense strand, as well as
present on the 5'- and/or the 3'-ends of a given strand.
[1128] Multivalent binding proteins are binding proteins comprising
two or more antigen binding sites. Multivalent binding proteins are
engineered to have the three or more antigen binding sites and are
generally not naturally occurring antibodies. The term
"multispecific binding protein" means a binding protein capable of
binding two or more related or unrelated targets. Dual variable
domain (DVD) binding proteins are tetravalent or multivalent
binding proteins binding proteins comprising two or more antigen
binding sites. Such DVDs may be monospecific (i.e., capable of
binding one antigen) or multispecific (i.e., capable of binding two
or more antigens). DVD binding proteins comprising two heavy chain
DVD polypeptides and two light chain DVD polypeptides are referred
to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD
polypeptide, a light chain DVD polypeptide, and two antigen binding
sites. Each binding site comprises a heavy chain variable domain
and a light chain variable domain with a total of 6 CDRs involved
in antigen binding per antigen binding site.
[1129] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, CLORETAZINE.RTM. (laromustine, VNP
40101M), cyclophosphamide, decarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, TREANDA.RTM.
(bendamustine), treosulfan, trofosfamide and the like.
[1130] Angiogenesis inhibitors include endothelial-specific
receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth
factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[1131] Antimetabolites include ALIMTA.RTM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, XELODA.RTM. (capecitabine),
carmofur, LEUSTAT.RTM. (cladribine), clofarabine, cytarabine,
cytarabine ocfosfate, cytosine arabinoside, decitabine,
deferoxamine, doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or
in combination with leucovorin, GEMZAR.RTM. (gemcitabine),
hydroxyurea, ALKERAN.RTM.(melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,
tegafur, TS-1, vidarabine, UFT and the like.
[1132] Antivirals include ritonavir, hydroxychloroquine and the
like.
[1133] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora
B-specific kinase inhibitors and pan-Aurora kinase inhibitors and
the like.
[1134] Bcl-2 protein inhibitors include AT-101 ((-)gossypol),
GENASENSE.RTM. (G3139 or oblimersen (Bcl-2-targeting antisense
oligonucleotide)), IPI-194, IPI-565,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4--
(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobe-
nzenesulfonamide) (ABT-737),
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide
(ABT-263), GX-070 (obatoclax) and the like.
[1135] Bcr-Abl kinase inhibitors include DASATINIB.RTM.
(BMS-354825), GLEEVEC.RTM. (imatinib) and the like.
[1136] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
[1137] COX-2 inhibitors include ABT-963, ARCOXIA.RTM. (etoricoxib),
BEXTRA.RTM. (valdecoxib), BMS347070, CELEBREX.RTM. (celecoxib),
COX-189 (lumiracoxib), CT-3, DERAMAXX.RTM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole),
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, S-2474, T-614, VIOXX.RTM. (rofecoxib) and the
like.
[1138] EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes,
EGF-vaccine, EMD-7200, ERBITUX.RTM. (cetuximab), HR3, IgA
antibodies, IRESSA.RTM. (gefitinib), TARCEVA.RTM. (erlotinib or
OSI-774), TP-38, EGFR fusion protein, TYKERB.RTM. (lapatinib) and
the like.
[1139] ErbB2 receptor inhibitors include CP-724-714, CI-1033
(canertinib), HERCEPTIN.RTM. (trastuzumab), TYKERB.RTM.
(lapatinib), OMNITARG.RTM. (2C4, petuzumab), TAK-165, GW-572016
(ionafarnib), GW-282974, EKB-569, PI-166, dHER.sup.2 (HER.sup.2
vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific
antibody, B7.her2IgG3, AS HER.sup.2 trifunctional bispecfic
antibodies, mAB AR-209, mAB 2B-1 and the like.
[1140] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[1141] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101,
CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
MYCOGRAB.RTM. (human recombinant antibody to HSP-90), NCS-683664,
PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the
like.
[1142] Inhibitors of inhibitors of apoptosis proteins include HGS
1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
[1143] Antibody drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19Am SGN-35, SGN-75 and the like
[1144] Activators of death receptor pathway include TRAIL,
antibodies or other agents that target TRAIL or death receptors
(e.g., DR.sup.4 and DR.sup.5) such as Apomab, conatumumab,
ETR.sup.2-ST01, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762
and trastuzumab.
[1145] Kinesin inhibitors include Eg5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
[1146] JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
[1147] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901,
PD-98059 and the like. mTOR inhibitors include AP-23573, CCI-779,
everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive
TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and
the like.
[1148] Non-steroidal anti-inflammatory drugs include AMIGESIC.RTM.
(salsalate), DOLOBID.RTM. (diflunisal), MOTRIN.RTM. (ibuprofen),
ORUDIS.RTM. (ketoprofen), RELAFEN.RTM. (nabumetone), FELDENE.RTM.
(piroxicam), ibuprofen cream, ALEVE.RTM. (naproxen) and
NAPROSYN.RTM. (naproxen), VOLTAREN.RTM. (diclofenac), INDOCIN.RTM.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.RTM. (tolmetin),
LODINE.RTM. (etodolac), TORADOL.RTM. (ketorolac), DAYPRO.RTM.
(oxaprozin) and the like.
[1149] PDGFR inhibitors include C-451, CP-673, CP-868596 and the
like.
[1150] Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin, picoplatin and the like.
[1151] Polo-like kinase inhibitors include BI-2536 and the
like.
[1152] Phosphoinositide-3 kinase (PI3K) inhibitors include
wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658,
PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
[1153] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[1154] VEGFR inhibitors include AVASTIN.RTM. (bevacizumab),
ABT-869, AEE-788, ANGIOZYME.TM. (a ribozyme that inhibits
angiogenesis (Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron,
(Emeryville, Calif.)), axitinib (AG-13736), AZD-2171, CP-547,632,
IM-862, MACUGEN (pegaptamib), NEXAVAR.RTM. (sorafenib, BAY43-9006),
pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT.RTM.
(sunitinib, SU-11248), VEGF trap, ZACTIMA.TM. (vandetanib, ZD-6474)
and the like.
[1155] Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.RTM.
(bleomycin), daunorubicin, CAELYX.RTM. or MYOCET.RTM. (liposomal
doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS.RTM.
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
VALSTAR.RTM. (valrubicin), zinostatin and the like.
[1156] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, CAMPTOSAR.RTM. (irinotecan hydrochloride), camptothecin,
CARDIOXANE.RTM. (dexrazoxine), diflomotecan, edotecarin,
ELLENCE.RTM. or PHARMORUBICIN.RTM. (epirubicin), etoposide,
exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,
mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan,
sobuzoxane, SN-38, tafluposide, topotecan and the like.
[1157] Antibodies include AVASTIN.RTM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, ERBITUX.RTM. (cetuximab),
HUMAX-CD4.RTM. (zanolimumab), IGF1R-specific antibodies,
lintuzumab, PANOREX.RTM. (edrecolomab), RENCAREX.RTM. (WX G250),
RITUXAN.RTM. (rituximab), ticilimumab, trastuzimab, CD20 antibodies
types I and II and the like.
[1158] Hormonal therapies include ARIMIDEX.RTM. (anastrozole),
AROMASIN.RTM. (exemestane), arzoxifene, CASODEX.RTM.
(bicalutamide), CETROTIDE.RTM. (cetrorelix), degarelix, deslorelin,
DESOPAN.RTM. (trilostane), dexamethasone, DROGENIL.RTM.
(flutamide), EVISTA.RTM. (raloxifene), AFEMA.TM. (fadrozole),
FARESTON.RTM. (toremifene), FASLODEX.RTM. (fulvestrant),
FEMARA.RTM. (letrozole), formestane, glucocorticoids, HECTOROL.RTM.
(doxercalciferol), RENAGEL.RTM. (sevelamer carbonate),
lasofoxifene, leuprolide acetate, MEGACE.RTM. (megesterol),
MIFEPREX.RTM. (mifepristone), NILANDRON.TM. (nilutamide),
NOLVADEX.RTM. (tamoxifen citrate), PLENAXIS.TM. (abarelix),
prednisone, PROPECIA.RTM. (finasteride), rilostane, SUPREFACT.RTM.
(buserelin), TRELSTAR.RTM. (luteinizing hormone releasing hormone
(LHRH)), VANTAS.RTM. (Histrelin implant), VETORYL.RTM. (trilostane
or modrastane), ZOLADEX.RTM. (fosrelin, goserelin) and the
like.
[1159] Deltoids and retinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.RTM. (aliretinoin),
ATRAGEN.RTM. (liposomal tretinoin), TARGRETIN.RTM. (bexarotene),
LGD-1550 and the like.
[1160] PARP inhibitors include ABT-888 (veliparib), olaparib,
KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231
and the like.
[1161] Plant alkaloids include, but are not limited to,
vincristine, vinblastine, vindesine, vinorelbine and the like.
[1162] Proteasome inhibitors include VELCADE.RTM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[1163] Examples of immunologicals include interferons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamma-1a, ACTIMMUNE.RTM. (interferon gamma-1b) or
interferon gamma-n1, combinations thereof and the like. Other
agents include ALFAFERONE.RTM., (IFN-.alpha.), BAM-002 (oxidized
glutathione), BEROMUN.RTM. (tasonermin), BEXXAR.RTM. (tositumomab),
CAMPATH.RTM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
decarbazine, denileukin, epratuzumab, GRANOCYTE.RTM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
MYLOTARG.TM. (gemtuzumab ozogamicin), NEUPOGEN.RTM. (filgrastim),
OncoVAC-CL, OVAREX.RTM. (oregovomab), pemtumomab (Y-muHMFG1),
PROVENGE.RTM. (sipuleucel-T), sargaramostim, sizofilan, teceleukin,
THERACYS.RTM. (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN.RTM.
(immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific
Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)),
PROLEUKIN.RTM. (aldesleukin), ZADAXIN.RTM. (thymalfasin),
ZENAPAX.RTM. (daclizumab), ZEVALIN.RTM. (90Y-Ibritumomab tiuxetan)
and the like.
[1164] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity and include krestin, lentinan,
sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
[1165] Pyrimidine analogs include cytarabine (ara C or Arabinoside
C), cytosine arabinoside, doxifluridine, FLUDARA.RTM.
(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR.RTM.
(gemcitabine), TOMUDEX.RTM. (ratitrexed), TROXATYL.TM.
(triacetyluridine troxacitabine) and the like.
[1166] Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM. (mercaptopurine).
[1167] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS 247550), paclitaxel, TAXOTERE.RTM. (docetaxel),
PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine,
ZK-EPO (synthetic epothilone) and the like.
[1168] Ubiquitin ligase inhibitors include MDM2 inhibitors, such as
nutlins, NEDD8 inhibitors such as MLN4924 and the like.
[1169] Compounds of this invention can also be used as
radiosensitizers that enhance the efficacy of radiotherapy.
Examples of radiotherapy include external beam radiotherapy,
teletherapy, brachytherapy and sealed, unsealed source radiotherapy
and the like.
[1170] Additionally, compounds having Formula (I) may be combined
with other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (farnesyl transferase inhibitor), ADVEXIN.RTM. (Ad5CMV-p53
vaccine), ALTOCOR.RTM. or MEVACOR.RTM. (lovastatin), AMPLIGEN.RTM.
(poly I:poly C12U, a synthetic RNA), APTOSYN.RTM. (exisulind),
AREDIA.RTM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.RTM. (tazarotene),
AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or
cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC.RTM.
(cancer vaccine), CELEUK.RTM. (celmoleukin), CEPLENE.RTM.
(histamine dihydrochloride), CERVARIX.RTM. (human papillomavirus
vaccine), CHOP.RTM. (C: CYTOXAN.RTM. (cyclophosphamide); H:
ADRIAMYCIN.RTM. (hydroxydoxorubicin); O: Vincristine
(ONCOVIN.RTM.); P: prednisone), CYPAT.TM. (cyproterone acetate),
combrestatin A4P, DAB(389)EGF (catalytic and translocation domains
of diphtheria toxin fused via a His-Ala linker to human epidermal
growth factor) or TransMID-107R.TM. (diphtheria toxins),
dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid
(DMXAA), eniluracil, EVIZON.TM. (squalamine lactate),
DIMERICINE.RTM. (T4N5 liposome lotion), discodermolide, DX-8951f
(exatecan mesylate), enzastaurin, EP0906 (epithilone B),
GARDASIL.RTM. (quadrivalent human papillomavirus (Types 6, 11, 16,
18) recombinant vaccine), GASTRIMMUNE.RTM., GENASENSE.RTM., GMK
(ganglioside conjugate vaccine), GVAX.RTM. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox),
IL-13-pseudomonas exotoxin, interferon-.alpha., interferon-.gamma.,
JUNOVAN.TM. or MEPACT.TM. (mifamurtide), lonafarnib,
5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT.RTM.(AE-941), NEUTREXIN.RTM.
(trimetrexate glucuronate), NIPENT.RTM. (pentostatin),
ONCONASE.RTM. (a ribonuclease enzyme), ONCOPHAGE.RTM. (melanoma
vaccine treatment), ONCOVAX.RTM. (IL-2 Vaccine), ORATHECIN.TM.
(rubitecan), OSIDEM.RTM. (antibody-based cell drug), OVAREX.RTM.
MAb (murine monoclonal antibody), paclitaxel, PANDIMEX.TM.
(aglycone saponins from ginseng comprising 20(S)protopanaxadiol
(aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
PANVAC.RTM.-VF (investigational cancer vaccine), pegaspargase, PEG
Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB.RTM.
(catumaxomab), REVLIMID.RTM. (lenalidomide), RSR.sup.13
(efaproxiral), SOMATULINE.RTM. LA (lanreotide),
SORIATANE.RTM.(acitretin), staurosporine (Streptomyces
staurospores), talabostat (PT100), TARGRETIN.RTM. (bexarotene),
TAXOPREXIN.RTM. (DHA-paclitaxel), TELCYTA.RTM. (canfosfamide,
TLK286), temilifene, TEMODAR.RTM. (temozolomide), tesmilifene,
thalidomide, THERATOPE.RTM. (STn-KLH), thymitaq
(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline
dihydrochloride), TNFERADE.TM. (adenovector: DNA carrier containing
the gene for tumor necrosis factor-.alpha.), TRACLEER.RTM. or
ZAVESCA.RTM. (bosentan), tretinoin (Retin-A), tetrandrine,
TRISENOX.RTM. (arsenic trioxide), VIRULIZIN.RTM., ukrain
(derivative of alkaloids from the greater celandine plant), vitaxin
(anti-alphavbeta3 antibody), XCYTRIN.RTM. (motexafin gadolinium),
XINLAY.TM. (atrasentan), XYOTAX.TM. (paclitaxel poliglumex),
YONDELIS.RTM. (trabectedin), ZD-6126, ZINECARD.RTM. (dexrazoxane),
ZOMETA.RTM. (zolendronic acid), zorubicin and the like.
Data
[1171] Determination of the utility of compounds having Formula (I)
as binders to and inhibitors of NAMPT was performed using
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)
binding assays.
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)
Binding Assay of NAMPT
[1172] Test compounds were serially diluted (typically 11 half log
dilutions) in neat DMSO to 50.times. final concentrations prior to
dilution with assay buffer (50 mM HEPES (NaOH), pH 7.5, 100 mM
NaCl, 10 mM MgCl.sub.2, 1 mM DTT, 1% Glycerol) to 3.times. and 6%
DMSO. Six L were transferred to 384-well low-volume plates (Owens
Corning #3673). To this, 12 L of a 1.5.times. solution containing
enzyme, probe and antibody were added. Final concentrations in the
18 L reactions were 1.times. assay buffer, 2% DMSO, 6.8 nM NAMPT
(human, recombinant, C-terminally His-tagged), 200 nM probe (a
potent nicotinamide-competitive inhibitor conjugated to Oregon
Green 488) and 1 nM Tb-anti-His antibody (Invitrogen #PV5895).
Reactions were equilibrated at room temperature for 3 hours prior
to reading on an Envision multi-label plate reader (Perkin Elmer;
Ex=337 nm, Em=520 and 495 nm). Time-resolved FRET ratios
(Em.sub.520/Em.sub.495) were normalized to controls, plotted as a
function of compound concentration and fit with the four-parameter
logistic equation to determine IC50s.
[1173] Time-Resolved Fluorescence Resonance Energy Transfer
(TR-FRET) Binding Assay of NAMPT with PRPP
[1174] Compound handling and data processing were identical to the
assay in the absence of substrates (above). Final concentrations
were 1.times. assay buffer, 2% DMSO, 2 nM NAMPT, 2 nM probe, 1 nM
Tb-anti-His antibody (Invitrogen #PV5895), 200 M PRPP and 2.5 mM
ATP. Reactions were equilibrated for 16 hours prior to measurement
to allow for potential enzymatic modification of test
compounds.
[1175] Table 1 shows the utility of compounds having Formula I to
functionally inhibit NAMPT.
TABLE-US-00001 TABLE 1 TR-FRET Binding - TR-FRET IC50 (with Binding
- PRPP) Example IC50 (.mu.M) (.mu.M) 1 0.0638 nd 2 7.56 0.00429 3
12.5 0.0715 4 1.22 0.000548 5 0.72 0.000461 6 nd nd 7 1.61 0.486 8
3.16 0.29 9 12.5 0.641 10 0.281 0.0196 11 0.476 0.00047 12 0.303
0.000241 13 1.75 0.000403 14 12.5 0.338 15 3.82 0.0921 16 4.72
0.217 17 12.5 1.22 18 4.82 0.814 19 12.5 12.5 20 12.5 12.5 21 0.996
0.505 22 0.384 0.0602 23 nd nd 24 4.14 0.000682 25 1.63 0.0014 26
12.5 0.00121 27 >10 0.000632 28 7.02 0.000833 29 >10 0.00216
30 >10 0.00229 31 3.6 0.000893 32 >10 0.00133 33 8.95 0.00122
34 7.57 0.000502 35 >10 0.00318 36 2.42 0.000725 37 4.81
0.000531 38 2.69 0.00135 39 2.39 0.000938 40 2.2 0.00199 41 8.5
0.0297 42 >10 0.0246 43 8.11 0.000709 44 >10 0.00777 45 0.611
0.000206 46 9.52 0.0022 47 nd nd 48 0.807 0.000701 49 1.69 0.00107
50 1.18 0.00252 51 >10 0.00494 52 1.01 0.000881 53 2.53 0.32 54
2.11 0.0056 55 >10 3.18 56 6.07 0.000719 57 >10 1.16 58 1.72
0.807 59 >10 0.266 60 >10 0.00497 61 1.9 0.00178 62 0.81
0.00108 63 2.25 0.000693 64 1.85 0.00297 65 >10 0.00537 66
>10 0.00242 67 >10 0.00353 68 >10 0.00468 69 >10
0.00398 70 >10 0.00508 71 0.533 0.0007 72 >10 0.00399 73
>10 0.00704 74 nd nd 75 nd nd 76 nd nd 77 0.0956 0.000774 78 2.9
0.000969 79 6.58 0.00277 80 8.02 0.00137 81 5.28 0.00178 82 7.54
0.00172 83 2.89 0.000998 84 3.2 0.00172 85 nd nd 86 >10 0.00266
87 2.26 0.00126 88 >10 0.000602 89 5.83 0.00198 90 >10
0.00225 91 8.69 0.000543 92 >10 0.000868 93 >10 0.0166 94
2.87 0.00122 95 3.89 0.0151 96 4.19 0.00335 97 >10 0.00589 98
1.5 0.00147 99 3.56 0.0015 100 nd nd 101 5.62 0.00284 102 0.306
0.00216 103 0.709 0.00306 104 0.445 0.00131 105 nd nd 106 1.93
0.0018 107 0.814 0.00224 108 1.45 0.00161 109 >10 0.00374 110
>10 0.0232 111 >10 0.00587 112 3.68 0.00208 113 4.99 0.00676
114 1.99 0.00231 115 1.42 0.0036 116 nd nd 117 1.25 0.00302 118 nd
nd 119 4.57 0.00189 120 3.78 0.00229 121 >10 0.00925 122 >10
0.00431 123 3.82 0.000631 124 3.52 0.000624 125 >10 0.000712 126
4.18 0.0013 127 3.18 0.000533 128 >10 0.000727 129 >10
0.00116 130 >10 0.00111 131 4.78 0.000743 132 4.85 0.00102 133
0.0589 0.000527 134 0.2 0.000617 135 0.0937 0.000169 136 0.0244
0.000174 137 0.0402 0.000236 138 0.0555 0.000541 139 0.0561
0.000251 140 >10 0.0223 141 >10 0.0231 142 6.04 0.0169 143
>10 0.0137 144 >10 0.0332 145 >10 0.107 146 >10 0.098
147 >10 0.0719 148 >10 0.0606 149 >10 0.0942 150 0.252
0.00021 151 0.219 0.000412 152 0.768 0.000232 153 1.43 0.000286 154
0.23 0.000518 155 0.669 0.000254 156 nd nd 157 nd nd 158 nd nd 159
8.23 0.291 160 >10 0.195 161 >10 0.215 162 3.33 0.187 163 6.8
0.171 164 >10 0.583 165 0.34 0.0991 166 >10 0.63 167 nd nd
168 >10 1.39 169 8.45 0.266 170 nd nd 171 8.79 0.0321 172 >10
0.153 173 0.707 0.00233 174 0.334 0.000714 175 1.15 0.0006 176 7.36
0.000365 177 4.62 0.000653 178 6.97 0.000813 179 9.8 0.000492 180
7.71 0.000333 181 >10 0.000556 182 2.59 0.000264 183 2.94
0.000281 184 0.763 0.000285 185 0.633 0.000476 186 1.1 0.00123 187
3.21 0.000216 188 0.356 0.000195 189 4.7 0.000586 190 2.61 0.000606
191 >10 0.000265 192 >10 0.000262 193 6.06 0.000755 194 7.25
0.00112 195 >10 0.000338 196 7.01 0.000538 197 9.21 0.000251 198
2.61 0.000633 199 >10 0.000493 200 >10 0.000747 201 >10
0.000457 202 4.99 0.000405 203 >10 0.0136 204 3.73 0.00146 205
0.739 0.000177 206 5.63 0.000633 207 3.86 0.000331 208 2.89 0.00025
209 6.7 0.000245 210 2.74 0.000192 211 nd nd 212 5.71 0.00103 213
9.86 0.000411 nd = no data
[1176] Compounds which inhibit NAMPT are useful for treating
diseases in which activation of NF-KB is implicated. Such methods
are useful in the treatment of a variety of diseases including
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukaemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia.
[1177] Involvement of NAMPT in the treatment of cancer is described
in WO 97/48696. Involvement of NAMPT in immuno-supression is
described in WO 97/48397. Involvement of NAMPT for the treatment of
diseases involving angiogenesis is described in WO 2003/80054.
Involvement of NAMPT for the treatment of rheumatoid arthritis and
septic shock is described in WO 2008/025857. Involvement of NAMPT
for the prophlaxis and treatment of ischaemia is described in WO
2009/109610.
[1178] Cancers include, but are not limited to, hematologic and
solid tumor types such as acoustic neuroma, acute leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia (monocytic,
myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,
myelomonocytic and promyelocytic), acute t-cell leukemia, basal
cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,
breast cancer (including estrogen-receptor positive breast cancer),
bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,
chronic lymphocytic leukemia, chronic myelocytic (granulocytic)
leukemia, chronic myelogenous leukemia, colon cancer, colorectal
cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative
changes (dysplasias and metaplasias), embryonal carcinoma,
endometrial cancer, endotheliosarcoma, ependymoma, epithelial
carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor
positive breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, gastric carcinoma, germ cell testicular cancer,
gestational trophobalstic disease, glioblastoma, head and neck
cancer, heavy chain disease, hemangioblastoma, hepatoma,
hepatocellular cancer, hormone insensitive prostate cancer,
leiomyosarcoma, liposarcoma, lung cancer (including small cell lung
cancer and non-small cell lung cancer),
lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic
leukemia, lymphoma (lymphoma, including diffuse large B-cell
lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's
lymphoma), malignancies and hyperproliferative disorders of the
bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and
uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia,
medullary carcinoma, medulloblastoma, melanoma, meningioma,
mesothelioma, multiple myeloma, myelogenous leukemia, myeloma,
myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma,
pinealoma, polycythemia vera, prostate cancer (including
hormone-insensitive (refractory) prostate cancer), rectal cancer,
renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma,
sebaceous gland carcinoma, seminoma, skin cancer, small cell lung
carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,
squamous cell carcinoma, synovioma, sweat gland carcinoma,
testicular cancer (including germ cell testicular cancer), thyroid
cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine
cancer, Wilms' tumor and the like.
Schemes and Experimentals
[1179] The following abbreviations have the meanings indicated.
ADDP means 1,1'-(azodicarbonyl)dipiperidine; AD-mix-.beta. means a
mixture of (DHQD).sub.2PHAL, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3,
and K.sub.2SO.sub.4; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc
means tert-butoxycarbonyl; (DHQD).sub.2PHAL means hydroquinidine
1,4-phthalazinediyl diethyl ether; DBU means
1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum
hydride; DIEA means diisopropylethylamine; DMAP means
N,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe
means 1,2-bis(dimethylphosphino)ethane; DMSO means
dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)-butane;
dppe means 1,2-bis(diphenylphosphino)ethane; dppf means
1,1'-bis(diphenylphosphino)ferrocene; dppm means
1,1-bis(diphenylphosphino)methane; EDAC HCl means
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc
means fluorenylmethoxycarbonyl; HATU means
O-(7-azabenzotriazol-1-yl)-N,N'N'N'-tetramethyluronium
hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means
isopropyl alcohol; MP-BH.sub.3 means macroporous triethylammonium
methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA
means trifluoroacetic acid; THF means tetrahydrofuran; NCS means
N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means
N-methylpyrrolidine; PPh.sub.3 means triphenylphosphine.
[1180] The following schemes are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention. Compounds
of this invention may be made by synthetic chemical processes,
examples of which are shown herein. It is meant to be understood
that the order of the steps in the processes may be varied, that
reagents, solvents and reaction conditions may be substituted for
those specifically mentioned, and that vulnerable moieties may be
protected and deprotected, as necessary.
Schemes
##STR00009##
[1182] As shown in Scheme 1, 2-bromothiazole-5-carboxylic acid can
be coupled with a suitable amine of formula (1), wherein R.sup.3,
R.sup.4, and R.sup.5 are as described herein, under reaction
conditions known to those skilled in the art and readily available
in the literature, to provide compounds of formula (2). Compounds
of formula (2) can be reacted with suitable amines of formula (3),
wherein R.sup.6 is as described herein, to provide compounds of
formula (4). The reaction is typically performed at an elevated
temperature in a solvent such as but not limited to acetonitrile.
Compounds of formula (6), which are representative of compounds of
Formula (I), can be prepared by reacting compounds of formula (4)
with a suitable compound of formula (5), wherein R.sup.6 as
described herein. The reaction is typically performed in a suitable
solvent such as but not limited to dichloromethane at ambient
temperature in the presence of a base such as but not limited to
pyridine.
##STR00010##
[1183] Compounds of formula (4), which can be prepared as described
in Scheme 1, can be reacted with
bis(2,5-dioxopyrrolidin-1-yl)carbonate at an elevated temperature
in the presence of a base such as but not limited to pyridine,
followed by the addition of a base such as but not limited to
N,N-diisopropylethylamine, and an amine of formula (3) to provide
compounds of formula (6) which are representative of the compounds
of Formula (I).
##STR00011##
[1184] As shown in Scheme 3, compounds of formula (4), which can be
prepared as described in Scheme 1, can be reacted with a suitable
alkyl halide of formula (7), wherein X is an appropriate halide and
R.sup.6 is as described herein, to provide compounds of formula
(8), which are representative of the compounds of Formula (I). The
reaction is typically performed at an elevated temperature in a
suitable solvent such as but not limited to acetonitrile, and may
involve the use of microwave heating.
##STR00012##
[1185] Compounds of formula (4), which can be prepared as described
in Scheme 1, can be reacted with compounds of formula (9), wherein
R.sup.6 is as described herein, in the presence of a base such as
but not limited to N, N-diisopropylethylamine, to provide compounds
of formula (10), which are representative of the compounds of
Formula (I). The reaction is typically performed at an elevated
temperature in a suitable solvent such as but not limited to
dimethylsulfoxide, methanol, or mixtures thereof.
##STR00013##
[1186] As shown in Scheme 5, chloroacetyl bromide can be reacted
with compounds of formula (4), which can be prepared as described
in Scheme 5, in the presence of a base such as but not limited to
pyridine, at a reduced temperature followed by reaction with a
suitable amine of formula (11), wherein each R.sup.8 is as
described herein, at an elevated temperature, to provide compounds
of formula (12). The reaction is typically performed in a solvent
such as but not limited to dichloromethane.
##STR00014##
[1187] As shown in Scheme 6, compounds of formula (2), which can be
prepared as described in Scheme 1, can be coupled with a suitable
amine of formula (13), wherein R.sup.1 and R.sup.2 taken together
with the N to which they are attached form a heterocycloalkyl or
heterocycloalkenyl ring, to provide compounds of formula (14). The
reaction is typically performed at an elevated temperature in the
presence of potassium phosphate, a catalyst such as but not limited
to tris(dibenzylideneacetone)dipalladium(0), and a ligand such as
but not limited to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(XantPhos). The reaction is typically performed in a suitable
solvent such as but not limited to dioxane.
EXAMPLES
[1188] The following examples are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention. Each
exemplified compound and intermediate was named using
ACD/ChemSketch Version 12.5 (13 May 2009), Advanced Chemistry
Development Inc., Toronto, Ontario), or ChemDraw R Ver. 9.0.5
(CambridgeSoft, Cambridge, Mass.).
Experimentals
Example 1
2-{(4-fluorobenzyl)[4-(pyridin-3-yl)benzyl]amino}-N-[3-(1H-imidazazol-1-yl-
)propyl]-1,3-thiazole-5-carboxamide
[1189] The title compound was prepared as described in Example 9,
substituting 3-(4-(chloromethyl)phenyl)pyridine for
1-(2-chloroethyl)pyrrolidine.
Example 2
N-[3-(1H-imidazol-1-yl)propyl]-2-{methyl[4-(pyridin-3-yl)benzyl]amino}-1,3-
-thiazole-5-carboxamide
Example 2A
methyl 2-(4-(pyridin-3-yl)benzylamino)thiazole-5-carboxylate
[1190] To a 250 mL round-bottomed flask was added
4-(pyridin-3-yl)benzaldehyde (4 g, 21.8 mmol), methyl
2-aminothiazole-5-carboxylate (3.45 g, 21.83 mmol) and acetic acid
(0.375 ml, 6.55 mmol) in toluene (109 ml). The reaction mixture was
heated at reflux under Dean-Stark conditions for 3 hours, cooled to
room temperature, and the volatiles were removed by rotary
evaporation. Methanol was added, the solution was cooled to
0.degree. C., and sodium borohydride (1.322 g, 34.9 mmol) was
carefully added. The reaction was stirred at 0.degree. C. for 15
minutes and allowed to warm to room temperature while stirring for
an additional 2 hour. The solids were filtered off, washed with
water and dried under high vaccuum to give the title compound which
was used in the next step without further purification.
Example 2B
2-(methyl(4-(pyridin-3-yl)benzyl)amino)thiazole-5-carboxylic
acid
[1191] Example 2A (500 mg, 1.537 mmol) was dissolved in
tetrahydrofuran (7683 .mu.l) and sodium hydride (92 mg, 2.305 mmol)
was added carefully. The suspension was allowed to stir for about
20 minutes at room temperature. Iodomethane (106 .mu.l, 1.690 mmol)
was then added and the reaction was stirred for an additional 30
minutes. To the mixture was added excess 1N aqueous NaOH followed
by additional methanol and stirred at 55.degree. C. for 1.5 hours.
The reaction mixture was concentrated by rotary evaporation and the
residue was taken up in water. The pH was adjusted to around 5-6 by
addition of 2 N aqueous HCl, upon which time white solids
precipitated out and were collected by vacuum filtration. The
solids were washed with water, diethyl ether, and dried under high
vacuum overnight to provide the title compound.
Example 2C
N-[3-(1H-imidazol-1-yl)propyl]-2-{methyl[4-(pyridin-3-yl)benzyl]amino}-1,3-
-thiazole-5-carboxamide
[1192] To a 20 mL vial was added Example 2B (100 mg, 0.307 mmol)
and 3-(1H-imidazol-1-yl)propan-1-amine (40.3 .mu.l, 0.338 mmol) in
DMF (1229 .mu.l). 1-Ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
hydrochloride (103 mg, 0.538 mmol) and 1-hydroxybenzotriazole
hydrate (82 mg, 0.538 mmol) were added and the reaction mixture was
stirred over the weekend at room temperature. The reaction mixture
was purified directly by HPLC (0-70% water acetonitrile) to give
the title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
8.88 (d, J=1.8 Hz, 1H), 8.56 (dd, J=4.8, 1.5 Hz, 1H), 8.22 (t,
J=5.6 Hz, 1H), 8.10-8.00 (m, 1H), 7.80 (s, 1H), 7.72 (d, J=8.2 Hz,
2H), 7.64 (s, 1H), 7.52-7.44 (m, 1H), 7.40 (d, J 8.2 Hz, 2H), 7.19
(s, 1H), 6.88 (s, 1H), 4.79 (s, 2H), 3.99 (t, J=6.9 Hz, 2H),
3.20-3.11 (m, 2H), 3.11 (s, 3H), 1.90 (p, J=6.9 Hz, 2H); MS
(ESI(+)) m/e 433.13 (M+H).sup.+.
Example 3
2-[(4-fluorobenzyl)(methyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide
Example 3A
methyl 2-(4-fluorobenzylamino)thiazole-5-carboxylate
[1193] The title compound was prepared as described in Example 2A,
substituting 4-fluorobenzaldehyde for
4-(pyridin-3-yl)benzaldehyde.
Example 3B
2-((4-fluorobenzyl)(methyl)amino)thiazole-5-carboxylic acid
[1194] The title compound was prepared as described in Example 2B,
substituting Example 3A for Example 2A.
Example 3C
2-[(4-fluorobenzyl)(methyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide
[1195] The title compound was prepared as described in Example 2C,
substituting Example 3B for Example 2B. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.20 (t, J=5.6 Hz, 1H), 7.78 (s, 1H), 7.63
(s, 1H), 7.37-7.28 (m, 2H), 7.22-7.13 (m, 3H), 6.88 (t, J=1.1 Hz,
1H), 4.71 (bs, 2H), 3.99 (t, J=6.9 Hz, 2H), 3.20-3.09 (m, 2H), 3.05
(s, 3H), 1.90 (p, J=6.9 Hz, 2H); MS (ESI(+)) m/e 374.1
(M+H).sup.+.
Example 6
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide
Example 6A
N-(3-(1H-imidazol-1-yl)propyl)-2-bromothiazole-5-carboxamide
[1196] 2-Bromothiazole-5-carboxylic acid (0.4 g, 1.923 mmol),
3-(1H-imidazole-1-yl)propan-1-amine (0.265 g, 2.115 mmol), and
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) (0.935 g, 2.115 mmol) were mixed in
dichloromethane (7 ml), treated with Hunig's base (0.705 ml, 4.04
mmol) and stirred at 25.degree. C. for 2 hours. The reaction
mixture was diluted with dichloromethane and washed with water and
brine. The organic layer was dried (MgSO.sub.4), filtered and
concentrated. Purification by flash chromatography (silica gel,
2-20% methanol/dichloromethane) afforded the title compound.
Example 6B
N-(3-(1H-imidazol-1-yl)propyl)-2-((4-fluorobenzyl)amino)thiazole-5-carboxa-
mide
[1197] Example 6A (2 g, 6.35 mmol) and (4-fluorophenyl)methanamine
(0.794 g, 6.35 mmol) in acetonitrile (10 ml) were stirred at
120.degree. C. overnight. The reaction mixture was cooled,
concentrated, taken into ethyl acetate and washed with saturated
aqueous NaHCO.sub.3 and brine. The combined aqueous layers were
extracted twice with ethyl acetate. The combined organic extracts
were dried (MgSO.sub.4) and filtered. The filtrate was concentrated
until solid material precipitated. The mixture was filtered to
provide the title compound.
Example 6C
2-[(4-fluorobenzyl)(3-methylbutanoyl)amino]-N-[3-(1H-imidazol-1-yl)propyl]-
-1,3-thiazole-5-carboxamide
[1198] Example 6B (0.2 g, 0.556 mmol) was dissolved in
dichloromethane (2.7 ml) and pyridine (0.3 ml) and was treated
dropwise with a solution of 3-methylbutanoyl chloride (0.102 ml,
0.835 mmol) in dichloromethane (0.5 ml). The reaction mixture was
stirred at 25.degree. C. for 2 hours, concentrated, and purified
using reverse phase HPLC (Phenomenex Luna C8(2) 5 um 100A AXIA
column (30 mm.times.75 mm) run with a gradient of acetonitrile (A)
and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50
mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A,
7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A) to
afford the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.87 (s, 1H), 7.60 (s, 1H), 7.19-7.07 (m, 3H), 7.07-6.97
(m, 3H), 5.89 (s, 1H), 5.47 (s, 2H), 4.07 (t, J=6.9 Hz, 2H), 3.46
(q, J=6.6 Hz, 2H), 2.43 (d, J=6.8 Hz, 2H), 2.36-2.19 (m, 1H),
2.19-2.04 (m, 2H), 0.93 (d, J 6.6 Hz, 6H); MS (ESI(+)) m/e 443.5
(M+H).sup.+.
[1199] The following examples were prepared as described in Example
6, substituting the appropriate amine in Example 6B and the
appropriate acyl chloride in Example 6C. Title compounds were
purified by either flash chromatography (silica gel column eluting
with a gradient of 0-10% methanol in dichloromethane) or
reverse-phase HPLC (as described in Example 6C). Accordingly, some
examples were isolated as trifluoroacetic acid salts.
TABLE-US-00002 MS EX NAME .sup.1H NMR DATA DATA 4 2-[(4- .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
fluorobenzyl)(tetrahydro- 9.08 (s, 1H), 7.93 (s, 1H), 7.36 (d, J =
14.1 Hz, m/e 486 2H-pyran-4- 2H), 7.17-7.08 (m, 2H), (M + H).sup.+
ylacetyl)amino]-N-[3-(1H- 7.03 (t, J = 8.5 Hz, 2H), 6.76 (ddd,
imidazol-1-yl)propyl]-1,3- J = 47.8, 25.3, 16.1 Hz, 1H),
thiazole-5-carboxamide 5.47 (s, 2H), 4.31 (d, J = 2.8 Hz, 2H), 3.93
(d, J = 11.0 Hz, 2H), 3.50 (dd, J = 11.4, 5.8 Hz, 2H), 3.42 (t, J =
11.8 Hz, 2H), 2.48 (d, J = 6.7 Hz, 2H), 2.27-2.20 (m, 2H), 1.65 (d,
J = 11.2 Hz, 2H), 1.30-1.14 (m, 2H). 5 2-[(cyclohexylacetyl)(4-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
fluorobenzyl)amino]-N-[3- 9.00 (s, 1H), 7.95 (s, 1H), 7.32 (d, J =
17.1 Hz, m/e 484 (1H-imidazol-1-yl)propyl]- 2H), 7.19-7.08 (m, 2H),
(M + H).sup.+ 1,3-thiazole-5-carboxamide 7.02 (t, J = 8.6 Hz, 2H),
6.77 (s, 1H), 5.46 (s, 2H), 4.29 (t, J = 6.5 Hz, 2H), 3.55-3.40 (m,
2H), 2.42 (d, J = 6.7 Hz, 2H), 2.23 (d, J = 6.8 Hz, 2H), 2.19 (d, J
= 6.4 Hz, 1H), 1.71 (dd, J = 35.7, 15.8 Hz, 2H), 1.35-1.19 (m, 2H),
1.15 (d, J = 12.4 Hz, 2H), 1.00 (t, J = 12.6 Hz, 2H), 0.87 (dd, J =
22.6, 10.6 Hz, 2H). 11 2-[(4-cyanobenzoyl)(4- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) fluorobenzyl)amino]-N-[3- 9.33 (s,
1H), 8.05 (d, J = 6.3 Hz, 1H), m/e 489 (1H-imidazol-1-yl)propyl]-
7.69 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.3 Hz, (M + H)+
1,3-thiazole-5-carboxamide 2H), 7.31 (s, 2H), 6.97-6.89 (m, 4H),
6.82-6.71 (m, 1H), 5.31 (s, 2H), 4.35 (d, J = 4.9 Hz, 2H), 3.49 (d,
J = 5.9 Hz, 2H), 2.23 (dd, J = 7.9, 2.8 Hz, 2H). 12
2-[(3-chlorobenzoyl)(4- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) fluorobenzyl)amino]-N-[3- 9.16 (s, 1H), 8.00 (s, 1H), m/e
498 (1H-imidazol-1-yl)propyl]- 7.51-7.44 (m, 1H), 7.38-7.32 (m,
4H), (M + H)+ 1,3-thiazole-5-carboxamide 7.01-6.88 (m, 5H), 5.37
(s, 2H), 4.34 (t, J = 6.4 Hz, 2H), 3.53-3.47 (m, 2H), 2.30-2.19 (m,
2H). 13 2-[(4-fluorobenzoyl)(4- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) fluorobenzyl)amino]-N-[3- 9.20 (s, 1H), 7.99 (s,
1H), m/e 482 (1H-imidazol-1-yl)propyl]- 7.48-7.39 (m, 2H), 7.35 (d,
J = 15.2 Hz, 2H), (M + H)+ 1,3-thiazole-5-carboxamide 7.12 (dt, J =
19.0, 8.6 Hz, 2H), 6.96 (qd, J = 8.7, 6.0 Hz, 4H), 5.39 (s, 2H),
4.34 (t, J = 6.5 Hz, 2H), 3.51 (dd, J = 11.6, 6.0 Hz, 2H),
2.31-2.19 (m, 2H). 24 2-[(4- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) fluorobenzyl)(methoxyacetyl)amino]- 7.88 (s, 1H),
7.61 (s, 1H), 7.15 (dd, J = 8.6, m/e 432 N-[3-(1H- 5.2 Hz, 2H),
7.10 (s, 1H), (M + H)+ imidazol-1-yl)propyl]-1,3- 7.03 (d, J = 8.6
Hz, 2H), 6.99 (d, J = 8.1 Hz, thiazole-5-carboxamide 2H), 5.45 (s,
2H), 4.30-4.24 (m, 2H), 4.07 (t, J = 6.9 Hz, 2H), 3.48-3.43 (m,
5H), 2.18-2.10 (m, 2H). 25 2-[(4-fluorobenzyl)(3- .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ESI(+)) methoxypropanoyl)amino]- 7.88 (s,
1H), 7.60 (s, 1H), 7.16 (dd, J = 8.6, m/e 446 N-[3-(1H-imidazol-1-
5.2 Hz, 2H), 7.10 (s, 1H), (M + H)+ yl)propyl]-1,3-thiazole-5-
7.04-6.99 (m, 2H), 6.98 (s, 1H), carboxamide 5.92 (s, 1H), 5.51 (s,
2H), 4.06 (t, J = 6.9 Hz, 2H), 3.75 (t, J = 6.2 Hz, 2H), 3.48-3.41
(m, 2H), 3.33 (s, 3H), 2.81 (t, J = 6.2 Hz, 2H), 2.12 (dd, J = 6.9,
3.9 Hz, 2H). 44 1-{2-[(4-fluorobenzyl)(5- (ESI(+))
{[3-(1H-imidazol-1- m/e 480 yl)propyl]carbamoyl}-1,3- (M + H)+
thiazol-2-yl)amino]-2- oxoethyl}pyridinium 45 2-{[2-(4- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ESI(+)) fluorophenyl)ethyl](3- 7.98
(s, 1H), 7.58 (s, 1H), m/e 458 methylbutanoyl)amino}-N- 7.20-7.07
(m, 3H), 7.07-6.95 (m, 3H), (M + H)+ [3-(1H-imidazol-1- 5.87 (dd, J
= 8.9, 3.5 Hz, 1H), 4.35 (t, J = 7.3 Hz, yl)propyl]-1,3-thiazole-5-
2H), 4.07 (t, J = 6.9 Hz, carboxamide 2H), 3.46 (dd, J = 8.0, 4.8
Hz, 2H), 3.04 (t, J = 7.3 Hz, 2H), 2.21 (d, J = 6.7 Hz, 2H),
2.19-2.16 (m, 1H), 2.16-2.08 (m, 2H), 0.92 (d, J = 6.2 Hz, 6H). 48
2-{[2-(4- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
cyanophenyl)ethyl](3- 9.09 (s, 1H), 8.01 (s, 1H), 7.63 (d, J = 8.1
Hz, m/e 465 methylbutanoyl)amino}-N- 2H), 7.37 (s, 1H), 7.33 (d, J
= 7.9 Hz, (M + H)+ [3-(1H-imidazol-1- 3H), 6.74 (s, 1H), 4.39 (t,
yl)propyl]-1,3-thiazole-5- J = 7.4 Hz, 2H), 4.33 (t, J = 6.3 Hz,
carboxamide 2H), 3.51 (d, J = 5.4 Hz, 2H), 3.20-3.07 (m, 2H),
2.31-2.21 (m, 5H), 0.95 (d, J = 6.4 Hz, 6H). 49 2-{[2-(4- .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
cyanophenyl)ethyl](tetrahydro- 9.12 (s, 1H), 8.00 (s, 1H), 7.63 (d,
J = 8.0 Hz, m/e 507 2H-pyran-4- 2H), 7.39 (s, 1H), 7.33 (d, J = 8.2
Hz, (M + H)+ ylacetyl)amino}-N-[3-(1H- 3H), 6.72 (s, 1H),
imidazol-1-yl)propyl]-1,3- 4.45-4.25 (m, 4H), 3.97 (d, J = 8.2 Hz,
thiazole-5-carboxamide 2H), 3.60-3.33 (m, 4H), 3.14 (t, J = 7.3 Hz,
2H), 2.33 (d, J = 6.5 Hz, 4H), 1.65 (d, J = 12.9 Hz, 2H), 1.36-1.19
(m, 2H). 50 2-[(4-cyanobenzyl)(3- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) methylbutanoyl)amino]-N- 9.21 (dd, J = 17.5, 1.7
Hz, 1H), 7.91 (d, m/e 451 [3-(1H-imidazol-1- J = 4.2 Hz, 1H), 7.64
(d, J = 8.3 Hz, (M + H)+ yl)propyl]-1,3-thiazole-5- 2H), 7.35 (d, J
= 18.5 Hz, 2H), carboxamide 7.24 (s, 1H), 7.04-6.89 (m, 1H), 5.53
(s, 2H), 4.34 (dd, J = 9.6, 3.6 Hz, 2H), 3.57-3.43 (m, 2H), 2.38
(d, J = 6.7 Hz, 2H), 2.29-2.19 (m, 3H), 0.93 (d, J = 6.6 Hz, 6H).
51 2-[(4- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
cyanobenzyl)(tetrahydro- 9.12 (s, 1H), 8.00 (s, 1H), 7.63 (d, J =
8.0 Hz, m/e 493 2H-pyran-4- 2H), 7.39 (s, 1H), 7.33 (d, J = 8.2 Hz,
(M + H)+ ylacetyl)amino]-N-[3-(1H- 3H), 6.72 (s, 1H),
imidazol-1-yl)propyl]-1,3- 5.53 (s, 2H), 4.45-4.25 (m, 2H),
thiazole-5-carboxamide 3.97 (d, J = 8.2 Hz, 2H), 3.60-3.33 (m, 2H),
3.14 (t, J = 7.3 Hz, 2H), 2.33 (d, J = 6.5 Hz, 4H), 1.65 (d, J =
12.9 Hz, 2H), 1.36-1.19 (m, 3H). 52 2-{[2-(4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) cyanophenyl)ethyl](tetrahydrofuran-
.delta. 9.00 (s, 1H), 8.06 (s, 1H), 7.73 (s, m/e 493
3-ylacetyl)amino}- 1H), 7.68 (d, J = 8.1 Hz, 2H), (M + H)+
N-[3-(1H-imidazol-1- 7.59 (s, 1H), 7.41 (d, J = 8.1 Hz, 2H),
yl)propyl]-1,3-thiazole-5- 4.47 (t, J = 7.2 Hz, 2H), 4.34 (t, J =
6.9 Hz, carboxamide 2H), 4.02-3.88 (m, 1H), 3.79 (dt, J = 8.1, 4.0
Hz, 1H), 3.73 (dd, J = 15.5, 7.6 Hz, 1H), 3.41 (t, J = 6.4 Hz, 2H),
3.27-3.23 (m, 1H), 3.19 (t, J = 7.2 Hz, 2H), 2.64 (d, J = 9.4 Hz,
2H), 2.62-2.57 (m, 1H), 2.24-2.16 (m, 2H), 2.16-2.08 (m, 1H), 1.47
(dd, J = 12.6, 6.3 Hz, 1H). 53 2-[(4-fluorobenzyl)(3- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ESI(+)) methylbutanoyl)amino]-N-
7.94 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), m/e 458
[3-(2-methyl-1H-imidazol- 7.18-7.08 (m, 2H), 7.02 (t, J = 8.5 Hz,
(M + H)+ 1-yl)propyl]-1,3-thiazole-5- 2H), 6.66 (s, 1H), 5.47 (s,
carboxamide 2H), 4.13 (t, J = 6.9 Hz, 2H), 3.52 (d, J = 5.9 Hz,
2H), 2.68 (s, 3H), 2.44 (d, J = 6.8 Hz, 2H), 2.31-2.22 (m, 1H),
2.14 (d, J = 6.4 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H). 54
2-[(4-fluorobenzyl)(3- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) methylbutanoyl)amino]-N- 8.85 (s, 1H), 7.95 (d, J = 7.1
Hz, 1H), m/e 458 [3-(4-methyl-1H-imidazol- 7.11 (dd, J = 8.5, 5.3
Hz, 2H), (M + H)+ 1-yl)propyl]-1,3-thiazole-5- 7.00 (dd, J = 20.2,
11.7 Hz, 4H), carboxamide 5.45 (s, 2H), 4.21 (t, J = 6.6 Hz, 2H),
3.55-3.40 (m, 2H), 2.45-2.38 (m, 2H), 2.32 (d, J = 5.6 Hz, 3H),
2.29-2.23 (m, 1H), 2.21-2.15 (m, 2H), 0.92 (d, J = 6.6 Hz, 6H). 61
2-[(4- .sup.1H NMR (400 MHz, methanol-d.sub.4) (ESI(+))
cyanobenzyl)(tetrahydrofuran- .delta. 8.99 (s, 1H), 7.94 (s, 1H),
m/e 479 3-ylacetyl)amino]-N-[3- 7.74-7.70 (m, 3H), 7.58 (s, 1H),
7.36 (d, (M + H)+ (1H-imidazol-1-yl)propyl]- J = 8.1 Hz, 2H), 5.63
(d, J = 4.1 Hz, 1,3-thiazole-5-carboxamide 2H), 4.32 (t, J = 6.9
Hz, 2H), 4.03-3.91 (m, 1H), 3.81-3.67 (m, 2H), 3.42-3.32 (m, 3H),
2.84-2.77 (m, 1H), 2.76-2.69 (m, 2H), 2.26-2.09 (m, 3H), 1.61-1.46
(m, 1H). 62 2-[(4-cyanobenzyl)(3- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) methoxypropanoyl)amino]- 9.18 (s, 1H), 7.91 (s,
1H), 7.63 (d, J = 8.3 Hz, m/e 453 N-[3-(1H-imidazol-1- 2H), 7.36
(d, J = 18.0 Hz, (M + H)+ yl)propyl]-1,3-thiazole-5- 2H), 7.28 (d,
J = 8.3 Hz, 2H), carboxamide 6.92 (s, 1H), 5.58 (s, 2H), 4.34 (t, J
= 6.5 Hz, 2H), 3.76 (t, J = 6.0 Hz, 2H), 3.50 (d, J = 5.8 Hz, 2H),
3.33 (s, 3H), 2.77 (t, J = 6.0 Hz, 2H), 2.32-2.18 (m, 2H). 74
2-[(4-fluorobenzoyl)(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ESI(+)) methylbutyl)amino]-N-[3- 8.56 (t, J = 5.5 Hz, 1H), 8.15
(s, m/e 444 (1H-imidazol-1-yl)propyl]- 1H), 7.72 (dd, J = 8.7, 5.3
Hz, 3H), (M + H)+ 1,3-thiazole-5-carboxamide 7.39 (t, J = 8.9 Hz,
2H), 7.23 (s, 1H), 6.92 (s, 1H), 4.04 (dd, J = 15.5, 8.6 Hz, 4H),
3.21 (dd, J = 12.8, 6.7 Hz, 2H), 1.97 (dd, J = 13.9, 6.9 Hz, 2H),
1.49 (dd, J = 15.2, 7.1 Hz, 2H), 1.38 (dt, J = 13.2, 6.4 Hz, 1H),
0.67 (d, J = 6.5 Hz, 6H). 75 N-[3-(1H-imidazol-1- .sup.1H NMR (400
MHz, DMSO- (ESI(+)) yl)propyl]-2-[(3- d.sub.6/D.sub.2O) .delta. ppm
8.80 (s, 1 H) m/e 442 methoxypropanoyl)(4- 7.98 (s, 1 H) 7.62 (s, 1
H) 7.49 (s, 1 H) (M + H)+ methylbenzyl)amino]-1,3- 7.11-7.17 (m, 3
H) 7.04-7.07 (m, thiazole-5-carboxamide 2 H) 5.46 (s, 2 H) 4.24 (t,
J = 7.02 Hz, 3 H) 3.65 (t, J = 5.95 Hz, 2 H) 3.28-3.31 (m, 3 H)
2.86 (t, J = 5.95 Hz, 2 H) 2.27 (s, 4 H) 2.06-2.13 (m, 2 H). 76
N-(5-{[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]carbamoyl}-1,3- 9.16 (s, 1H), 8.42 (s, 1H), 8.08
(s, 1H), m/e 417 thiazol-2-yl)-N-(3- 7.35 (d, J = 13.4 Hz, 2H), (M
+ H)+ methylbutyl)-1,2-oxazole-5- 7.24-7.08 (m, 1H), 7.05 (s, 1H),
4.45 (d, carboxamide J = 6.7 Hz, 2H), 4.36 (t, J = 6.4 Hz, 2H),
3.55-3.49 (m, 2H), 2.28-2.23 (m, 3H), 1.75-1.69 (m, 2H), 1.52 (dd,
J = 14.7, 7.1 Hz, 1H), 0.95 (d, J = 3.8 Hz, 6H). 77
N-[3-(1H-imidazol-1- .sup.1H NMR (500 MHz, DMSO- (ESI(+))
yl)propyl]-2-[(3- d.sub.6/D.sub.2O) .delta. 8.12 (s, 1H), 7.68 (s,
m/e 470 methylbutyl)(2- 1H), 7.33 (t, J = 8.0 Hz, 2H), (M + H)+
phenoxypropanoyl)amino]- 7.21 (s, 1H), 7.01 (t, J = 7.4 Hz, 1H),
1,3-thiazole-5-carboxamide 6.97 (d, J = 8.3 Hz, 2H), 6.91 (s, 1H),
5.58 (q, J = 6.3 Hz, 1H), 4.24 (t, J = 9.8 Hz, 1H), 4.07 (d, J =
10.8 Hz, 1H), 4.02 (t, J = 6.9 Hz, 2H), 3.20 (t, J = 6.9 Hz, 2H),
1.95 (p, J = 6.9 Hz, 2H), 1.60 (dd, J = 11.9, 7.6 Hz, 1H), 1.56 (d,
J = 6.3 Hz, 3H), 1.51 (dd, J = 12.9, 6.5 Hz, 1H), 0.81 (dd, J =
28.5, 6.3 Hz, 6H). 85 2-{[2-(4- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) cyanophenyl)ethyl](3- 9.06 (s, 1H), 7.99 (s, 1H),
7.62 (d, J = 8.2 Hz, m/e 467
methoxypropanoyl)amino}- 2H), 7.39-7.33 (m, 4H), (M + H)+
N-[3-(1H-imidazol-1- 4.42 (s, 2H), 4.32 (s, 2H), 3.75 (t, J = 6.1
Hz, yl)propyl]-1,3-thiazole-5- 2H), 3.51 (d, J = 5.6 Hz,
carboxamide 2H), 3.36 (s, 3H), 3.12-3.16 (m, 2H), 2.74 (t, J = 6.1
Hz, 2H), 2.20-2.25 (m, 2H). 93 N-[3-(1H-imidazol-1- .sup.1H NMR
(400 MHz, DMSO- (ESI(+)) yl)propyl]-2-[(3- d.sub.6/D.sub.2O)
.delta. ppm 8.72 (d, J = 4.88 Hz, m/e 430
methoxypropanoyl)(pyrimidin- 2 H) 7.87 (s, 1 H) 7.59 (s, 1 H) (M +
H)+ 2-ylmethyl)amino]-1,3- 7.38 (t, J = 4.88 Hz, 1 H) 7.13 (s, 1
thiazole-5-carboxamide H) 6.88 (s, 1 H) 5.65 (s, 2 H) 4.01 (t, J =
7.02 Hz, 2 H) 3.69 (t, J = 6.26 Hz, 2 H) 3.21-3.25 (m, 5 H) 2.89
(t, J = 6.26 Hz, 2 H) 1.93-2.02 (m, 2 H). 94 N-[3-(1H-imidazol-1-
.sup.1H NMR (400 MHz, DMSO- (ESI(+)) yl)propyl]-2-{(3-
d.sub.6/D.sub.2O) .delta. ppm 8.09 (d, J = 5.19 Hz, m/e 459
methoxypropanoyl)[(2- 1 H) 7.96 (s, 1 H) 7.60 (s, 1 H) (M + H)+
methoxypyridin-4- 7.13 (s, 1 H) 6.89 (s, 1 H) 6.79 (s, 1
yl)methyl]amino}-1,3- H) 6.51 (s, 1 H) 5.47 (s, 2 H)
thiazole-5-carboxamide 4.02 (t, J = 6.87 Hz, 2 H) 3.82-3.86 (m, 3
H) 3.66 (t, J = 5.95 Hz, 2 H) 3.22-3.25 (m, 2 H) 3.21 (s, 3 H) 2.84
(t, J = 6.10 Hz, 2 H) 1.98 (t, J = 7.02 Hz, 2 H). 95
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-[(3- d.sub.6/D.sub.2O) .delta. ppm 8.00 (s, 1 H), m/e
419 methoxypropanoyl)(1,3- 7.60 (s, 1 H), 7.13 (s, 1 H), 6.89 (s, 1
H), (M + H)+ oxazol-4-ylmethyl)amino]- 5.36 (s, 1 H), 4.02 (t, 2
H), 1,3-thiazole-5-carboxamide 3.50-3.75 (m, 3 H), 3.22-3.25 (m, 4
H), 3.13 (t, J = 6.26 Hz, 2 H), 2.29-2.40 (m, 1 H), 1.94-2.03 (m, 2
H). 96 2-{[(5-chloropyridin-2- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) yl)methyl](3- .delta. 8.97 (s, 1H), 8.46
(d, J = 2.4 Hz, m/e 463 methoxypropanoyl)amino}- 1H), 7.90 (s, 1H),
7.80 (dd, J = 8.4, (M + H)+ N-[3-(1H-imidazol-1- 2.5 Hz, 1H), 7.70
(d, J = 1.6 Hz, yl)propyl]-1,3-thiazole-5- 1H), 7.57 (s, 1H), 7.39
(d, J = 8.4 Hz, carboxamide 1H), 5.60 (s, 2H), 4.31 (t, J = 6.9 Hz,
2H), 3.77 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 3.33 (s,
3H), 3.03 (t, J = 6.0 Hz, 2H), 2.25-2.08 (m, 2H). 97
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.31 (d, J = 4.88
Hz, m/e 443 methoxypropanoyl)[(4- 1 H), 7.93-7.95 (m, 1 H), (M +
H)+ methylpyridin-3- 7.89 (s, 1 H), 7.60 (s, 1 H), 7.24 (d, J =
4.88 Hz, yl)methyl]amino}-1,3- 1 H), 7.13 (s, 1 H),
thiazole-5-carboxamide 6.88 (s, 1 H), 5.48 (s, 1 H), 4.02 (t, J =
6.87 Hz, 2 H), 3.67 (q, J = 6.31 Hz, 2 H), 3.22-3.24 (m, 2 H), 3.20
(s, 3 H), 2.85 (t, J = 5.95 Hz, 2 H), 2.39 (s, 3 H), 1.94-2.02 (m,
2 H). 98 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.04 (d, J = 2.44
Hz, m/e 459 methoxypropanoyl)[(6- 1 H), 8.00 (s, 1 H), 7.60 (s, 1
(M + H)+ methoxypyridin-3- H), 7.55 (dd, J = 8.54, 2.44 Hz, 1
yl)methyl]amino}-1,3- H), 7.13 (s, 1 H), 6.89 (s, 1 H),
thiazole-5-carboxamide 6.76 (d, J = 8.54 Hz, 1 H), 5.43 (s, 2 H),
4.02 (t, J = 6.87 Hz, 2 H), 3.82-3.86 (m, 3 H), 3.68 (t, J = 6.10
Hz, 3 H), 3.24 (d, J = 2.44 Hz, 2 H), 3.22 (s, 3 H), 2.90-2.95 (m,
2 H), 1.95-2.03 (m, 2 H), 1.22 (s, 1 H). 99 N-[3-(1H-imidazol-1-
.sup.1H NMR (400 MHz, DMSO- (ESI(+)) yl)propyl]-2-{(3-
d.sub.6/D.sub.2O) .delta. ppm 8.80 (s, 1 H), m/e 449
methoxypropanoyl)[(4- 8.05 (s, 1 H), 7.60 (s, 1 H), 7.14 (s, 1 H),
(M + H)+ methyl-1,3-thiazol-5- 6.89 (s, 1 H), 5.58 (s, 2 H), 4.02
(t, yl)methyl]amino}-1,3- J = 7.02 Hz, 2 H), 3.69 (t, J = 6.10 Hz,
thiazole-5-carboxamide 2 H), 3.22-3.25 (m, 5 H), 2.95 (t, J = 6.10
Hz, 2 H), 2.46 (s, 3 H), 1.95-2.03 (m, 2 H). 100 2-{[2-(3- .sup.1H
NMR (400 MHz, DMSO- (ESI(+)) hydroxyphenyl)ethyl](3-
d.sub.6/D.sub.2O) .delta. ppm 7.63 (s, 1 H), m/e 458
methoxypropanoyl)amino}- 7.58-7.61 (m, 1 H), 7.33 (s, 1 H) 7.13 (s,
(M + H)+ N-[3-(1H-imidazol-1- 2 H), 6.94-6.99 (m, 1 H), 6.89 (s,
yl)propyl]-1,3-thiazole-5- 1 H), 3.98-4.02 (m, 2 H), 3.69 (t,
carboxamide J = 6.26 Hz, 2 H), 3.50 (s, 2 H), 3.30 (s, 3 H), 3.19
(t, J = 6.87 Hz, 2 H), 2.88-2.93 (m, 2 H), 2.76-2.80 (m, 3 H),
1.93-1.97 (m, J = 6.41 Hz, 3 H). 101 N-[3-(1H-imidazol-1- .sup.1H
NMR (400 MHz, DMSO- (ESI(+)) yl)propyl]-2-{(3- d.sub.6/D.sub.2O)
.delta. ppm 8.49 (d, J = 4.88 Hz, m/e 443 methoxypropanoyl)[2- 1
H), 8.03 (s, 1 H), 7.62-7.71 (m, (M + H)+
(pyridin-2-yl)ethyl]amino}- 2 H), 7.21-7.25 (m, 2 H), 7.16 (s,
1,3-thiazole-5-carboxamide 1 H), 6.91 (s, 1 H), 4.52-4.57 (m,
acetate (1:1) 2 H), 4.04 (t, J = 6.87 Hz, 2 H), 3.64 (t, J = 6.26
Hz, 2 H), 3.58-3.62 (m, 1 H), 3.24 (s, 3 H), 3.17-3.21 (m, 3 H),
2.84 (t, J = 6.26 Hz, 2 H), 1.96-2.04 (m, 2 H), 1.92 (s, 1 H). 102
2-{[2-(1,3-benzodioxol-5- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 8.06 (s, 1 H), m/e 486
methoxypropanoyl)amino}- 7.61 (s, 1 H), 7.14 (s, 1 H), 6.89 (s, 1
H), (M + H)+ N-[3-(1H-imidazol-1- 6.79 (d, J = 7.93 Hz, 1 H), 6.76
(d, yl)propyl]-1,3-thiazole-5- J = 1.53 Hz, 1 H), 6.65 (dd, J =
7.93, carboxamide acetate (1:1) 1.53 Hz, 1 H), 5.93 (s, 2 H),
4.34-4.38 (m, 2 H), 4.03 (t, J = 7.02 Hz, 2 H), 3.62 (t, J = 6.26
Hz, 2 H), 3.26-3.27 (m, 2 H), 3.24 (s, 3 H), 2.94 (t, J = 7.32 Hz,
2 H), 2.77 (t, J = 6.26 Hz, 2 H), 1.96-2.06 (m, 1 H), 1.88 (s, 1
H). 103 2-{[2-(4- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
chlorophenyl)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 8.05 (s, 1 H),
m/e 476 methoxypropanoyl)amino}- 7.61 (s, 1 H), 7.31-7.34 (m, 2 H),
(M + H)+ N-[3-(1H-imidazol-1- 7.23 (d, 2 H), 7.14 (s, 1 H), 6.89
(s, 1 yl)propyl]-1,3-thiazole-5- H), 4.37-4.42 (m, 2 H), 4.03 (t, J
= 7.02 Hz, carboxamide acetate (1:1) 2 H), 3.63 (t, J = 6.26 Hz, 2
H), 3.25 (s, 2 H), 3.24 (s, 3 H), 3.02 (t, J = 7.32 Hz, 2 H), 2.79
(t, J = 6.26 Hz, 2 H), 1.96-2.04 (m, 2 H), 1.88 (s, 1 H). 104
2-{[2-(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
fluorophenyl)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 8.06 (s, 1 H),
m/e 460 methoxypropanoyl)amino}- 7.61 (s, 1 H), 7.30-7.37 (m, 1 H),
(M + H)+ N-[3-(1H-imidazol-1- 7.14 (s, 1 H), 6.99-7.08 (m, 3 H),
yl)propyl]-1,3-thiazole-5- 6.90 (s, 1 H), 4.40-4.44 (m, 2 H),
carboxamide acetate (1:1) 4.03 (t, J = 7.02 Hz, 2 H), 3.63 (t, J =
6.26 Hz, 2 H), 3.25 (s, 2 H), 3.24 (s, 3 H), 3.05 (t, J = 7.48 Hz,
2 H), 2.80 (t, J = 6.10 Hz, 2 H), 1.96-2.04 (m, 2 H), 1.90 (s, 1
H). 105 2-{[2-(4- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
hydroxyphenyl)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 7.59-7.63 (m,
2 m/e 458 methoxypropanoyl)amino}- H), 7.27 (d, J = 8.24 Hz, 2 H),
(M + H)+ N-[3-(1H-imidazol-1- 7.13 (s, 1 H), 7.00-7.04 (m, 2 H),
yl)propyl]-1,3-thiazole-5- 6.89 (s, 1 H), 4.00 (t, J = 7.02 Hz, 2
H), carboxamide acetate (1:1) 3.69 (t, J = 6.10 Hz, 2 H), 3.50 (t,
J = 7.17 Hz, 2 H), 3.30 (s, 2 H), 3.17-3.24 (m, 3 H), 2.89 (t, J =
7.17 Hz, 2 H), 2.77 (t, J = 6.26 Hz, 2 H), 1.96 (q, J = 7.12 Hz, 2
H), 1.85 (s, 2 H). 106 2-{[2-(3- .sup.1H NMR (400 MHz, DMSO-
(ESI(+)) chlorophenyl)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 8.06
(s, 1 H), m/e 476 methoxypropanoyl)amino}- 7.62 (s, 1 H), 7.23-7.34
(m, 3 H), (M + H)+ N-[3-(1H-imidazol-1- 7.14-7.19 (m, 2 H), 6.90
(s, 1 H), yl)propyl]-1,3-thiazole-5- 4.39-4.44 (m, 2 H), 4.03 (t, J
= 6.87 Hz, carboxamide acetate (1:1) 2 H), 3.63 (t, J = 6.26 Hz, 2
H), 3.22-3.26 (m, 5 H), 3.04 (t, J = 7.32 Hz, 2 H), 2.81 (t, J =
6.26 Hz, 2 H), 1.96-2.04 (m, 2 H), 1.92 (s, 1 H). 107
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{[2-(3- d.sub.6/D.sub.2O) .delta. ppm 8.07 (s, 1 H),
m/e 472 methoxyphenyl)ethyl](3- 7.61 (s, 1 H), 7.21 (t, J = 7.78
Hz, 1 H), (M + H)+ methoxypropanoyl)amino}- 7.14 (s, 1 H), 6.90 (s,
1 H), 1,3-thiazole-5-carboxamide 6.75-6.82 (m, 3 H), 4.40 (t, J =
7.32 Hz, acetate (1:1) 2 H), 4.03 (t, J = 7.02 Hz, 2 H), 3.73 (s, 3
H), 3.60 (t, J = 6.10 Hz, 2 H), 3.24 (s, 2 H), 3.23 (s, 3 H), 2.99
(t, J = 7.32 Hz, 2 H), 2.74 (t, J = 6.26 Hz, 2 H), 1.96-2.05 (m, 2
H), 1.91 (s, 1 H). 108 2-{[2-(2- .sup.1H NMR (400 MHz, DMSO-
(ESI(+)) fluorophenyl)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 8.03
(s, 1 H), m/e 460 methoxypropanoyl)amino}- 7.61 (s, 1 H), 7.25-7.31
(m, 2 H), (M + H)+ N-[3-(1H-imidazol-1- 7.08-7.15 (m, 3 H), 6.90
(s, 1 H), yl)propyl]-1,3-thiazole-5- 4.43 (t, J = 7.32 Hz, 2 H),
4.03 (t, J = 6.87 Hz, carboxamide acetate (1:1) 2 H), 3.62 (t, J =
6.26 Hz, 2 H), 3.25 (s, 2 H), 3.23 (s, 3 H), 3.08 (t, J = 7.17 Hz,
2 H), 2.78 (t, J = 6.26 Hz, 2 H), 1.96-2.03 (m, 2 H), 1.90 (s, 1
H). 109 2-{[2-hydroxy-2-(4- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methoxyphenyl)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 7.63 (s, 1
H), m/e 488 methoxypropanoyl)amino}- 7.59 (s, 1 H), 7.29 (d, J =
8.85 Hz, 2 H), (M + H)+ N-[3-(1H-imidazol-1- 7.13 (s, 1 H),
6.88-6.94 (m, 3 H), yl)propyl]-1,3-thiazole-5- 5.89 (t, J = 6.41
Hz, 1 H), 4.00 (t, J = 7.02 Hz, carboxamide acetate (1:1) 2 H),
3.76 (s, 3 H), 3.63 (d, J = 6.41 Hz, 2 H), 3.56 (t, J = 6.41 Hz, 2
H), 3.22 (s, 1 H), 3.20 (s, 3 H), 3.17-3.19 (m, 1 H), 2.54-2.57 (m,
2 H), 1.91-1.99 (m, 2 H), 1.86 (s, 1 H). 110 N-[3-(1H-imidazol-1-
.sup.1H NMR (400 MHz, DMSO- (ESI(+)) yl)propyl]-2-{(3-
d.sub.6/D.sub.2O) .delta. ppm 8.95 (s, 1 H), m/e 443
methoxypropanoyl)[1- 8.47 (s, 1 H), 7.94 (d, J = 14.04 Hz, 1 (M +
H)+ (pyridin-2-yl)ethyl]amino}- H), 7.73-7.81 (m, 1 H), 7.68 (d, J
= 4.88 Hz, 1,3-thiazole-5-carboxamide 1 H), 7.56 (d, J = 1.83 Hz, 1
H), 7.40 (d, J = 7.93 Hz, 1 H), 7.28 (d, J = 5.19 Hz, 1 H),
6.07-6.14 (m, 1 H), 4.26 (q, J = 7.02 Hz, 3 H), 3.60-3.69 (m, 3 H),
3.20 (s, 3 H), 2.71 (t, J = 6.26 Hz, 2 H), 2.05-2.15 (m, 3 H), 1.82
(d, J = 7.32 Hz, 3 H). 111 N-[3-(1H-imidazol-1- .sup.1H NMR (400
MHz, DMSO- (ESI(+)) yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm
8.96 (d, J = 6.10 Hz, m/e 432 methoxypropanoyl)[(1- 1 H), 8.08 (d,
J = 27.77 Hz, 1 H), (M + H)+ methyl-1H-pyrazol-4- 7.69 (d, J = 4.88
Hz, 1 H), yl)methyl]amino}-1,3- 7.56-7.59 (m, 1 H), 7.49 (s, 1 H),
thiazole-5-carboxamide 7.27 (s, 1 H), 5.28 (s, 1 H), 4.24-4.32 (m,
4 H), 4.24-4.31 (m, 4 H), 3.75-3.79 (m, 4 H), 3.70 (t, J = 6.10 Hz,
1 H), 3.61 (t, J = 6.41 Hz, 1 H), 3.25 (s, 2 H), 3.23 (s, 2 H),
3.00 (t, J = 6.10 Hz, 1 H), 2.61 (t, 1 H), 2.11 (m, 1 H). 112
2-[(2,6-difluorobenzyl)(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methoxypropanoyl)amino]- d.sub.6/D.sub.2O) .delta. ppm 8.70 (s, 1
H), m/e 461 N-[3-(1H-imidazol-1- 7.93 (s, 1 H), 7.58 (s, 1 H), 7.43
(s, 1 H), (M + H)+ yl)propyl]-1,3-thiazole-5- 7.36 (s, 1 H), 7.01
(t, J = 8.54 Hz, 2 carboxamide H), 5.53 (s, 2 H), 4.21 (t, J = 7.02
Hz, 2 H), 3.70 (t, J = 6.10 Hz, 2 H), 3.24 (s, 3 H), 2.99 (t, J =
6.26 Hz, 2 H), 2.03-2.10 (m, 2 H), 1.10 (td, 3 H). 113
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.95 (s, 1 H), m/e
443 methoxypropanoyl)[(6- 8.35 (s, 1 H), 7.98 (s, 1 H), 7.68 (d, J
= 1.83 Hz, (M + H)+ methylpyridin-3- 1 H), 7.62 (dd, J = 8.24,
yl)methyl]amino}-1,3- 2.14 Hz, 1 H), 7.56 (s, 1 H),
thiazole-5-carboxamide 7.32 (d, J = 8.24 Hz, 1 H), 5.50 (s, 2 H),
4.26 (t, J = 7.17 Hz, 2 H), 3.65-3.70 (m, 3 H), 3.22 (s, 3 H), 2.92
(t, J = 5.95 Hz, 2 H), 2.48 (s, 3 H), 2.10 (q, J = 6.92 Hz, 3
H).
114 2-[(4-chlorobenzyl)(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methoxypropanoyl)amino]- d.sub.6/D.sub.2O) .delta. ppm 8.85 (s, 1
H), m/e 462 N-[3-(1H-imidazol-1- 7.97 (s, 1 H), 7.64 (s, 1 H), 7.51
(s, 1 H), (M + H)+ yl)propyl]-1,3-thiazole-5- 7.37 (d, J = 8.24 Hz,
2 H), 7.20 (d, carboxamide J = 8.54 Hz, 2 H), 5.49 (s, 2 H), 4.24
(t, J = 7.17 Hz, 2 H), 3.66 (t, J = 5.95 Hz, 2 H), 3.28-3.30 (m, 2
H), 3.20 (s, 3 H), 2.86 (t, J = 6.10 Hz, 2 H), 2.06-2.14 (m, 2 H).
115 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.96 (s, 1 H), m/e
444 methoxypropanoyl)[(5- 8.52 (s, 1 H), 8.40 (s, 1 H), 7.92 (s, 1
H), (M + H)+ methylpyrazin-2- 7.68 (s, 1 H), 7.56 (s, 1 H), 5.56
(s, yl)methyl]amino}-1,3- 2 H), 4.25 (t, J = 7.02 Hz, 2 H),
thiazole-5-carboxamide 3.70 (t, J = 6.26 Hz, 2 H), 3.18-3.25 (m, 5
H), 3.02 (t, J = 6.10 Hz, 2 H), 2.46 (s, 3 H), 2.06-2.13 (m, 2 H).
116 2-[(3-chlorobenzyl)(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methoxypropanoyl)amino]- d.sub.6/D.sub.2O) .delta. ppm 8.72 (s, 1
H), m/e 462 N-[3-(1H-imidazol-1- 7.98 (s, 1 H), 7.59 (s, 1 H), 7.45
(s, 1 H), (M + H)+ yl)propyl]-1,3-thiazole-5- 7.37 (t, J = 7.78 Hz,
2 H), 7.22 (s, 1 carboxamide H), 7.12-7.16 (m, 1 H), 5.50 (s, 2 H),
4.22 (t, J = 7.02 Hz, 2 H), 3.66 (t, J = 6.10 Hz, 2 H), 3.28-3.30
(m, 2 H), 3.20 (s, 3 H), 2.87 (t, J = 5.95 Hz, 2 H), 2.08 (q, J =
6.92 Hz, 2 H). 117 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO-
(ESI(+)) yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1
H), m/e 443 methoxypropanoyl)[(5- 8.30 (s, 1 H), 7.92 (s, 1 H),
7.69 (s, 1 H), (M + H)+ methylpyridin-2- 7.56-7.61 (m, 2 H), 7.22
(d, J = 7.93 Hz, yl)methyl]amino}-1,3- 1 H), 5.52 (s, 1 H),
thiazole-5-carboxamide 4.26 (t, J = 6.87 Hz, 2 H), 3.68 (t, J =
6.26 Hz, 2 H), 3.26 (s, 2 H), 3.23 (s, 3 H), 2.95 (t, J = 6.26 Hz,
2 H), 2.27 (s, 3 H), 2.05-2.15 (m, 2 H). 118
2-[(2,5-difluorobenzyl)(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methoxypropanoyl)amino]- d.sub.6/D.sub.2O) .delta. ppm 8.73 (s, 1
H), m/e 464 N-[3-(1H-imidazol-1- 7.59 (s, 1 H), 7.45 (s, 1 H) (M +
H)+ yl)propyl]-1,3-thiazole-5- 7.21-7.28 (m, J = 4.88 Hz, 1 H),
carboxamide 7.05-7.17 (m, 2 H), 6.83 (s, 1 H), 5.50 (s, 2 H), 4.22
(t, J = 6.87 Hz, 2 H), 3.69 (t, J = 5.95 Hz, 2 H), 3.29 (t, 1 H),
3.24 (s, 1 H), 3.22 (s, 3 H), 2.91 (t, J = 6.10 Hz, 2 H), 2.05-2.12
(m, 2 H). 119 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO-
(ESI(+)) yl)propyl]-2-[(3- d.sub.6/D.sub.2O) .delta. ppm 8.92 (s, 1
H), m/e 442 methoxypropanoyl)(2- 7.67 (s, 1 H), 7.54 (s, 1 H), (M +
H)+ methylbenzyl)amino]-1,3- 7.21-7.25 (m, 1 H), 7.14-7.19 (m, 2
H), thiazole-5-carboxamide 7.05-7.11 (m, 1 H), 6.68 (d, J = 7.63
Hz, 1 H), 5.45 (s, 2 H), 4.26 (t, J = 6.87 Hz, 2 H), 3.65 (t, J =
6.10 Hz, 2 H), 3.19 (s, 3 H), 2.80 (t, J = 6.10 Hz, 2 H), 2.37 (s,
3 H), 2.28 (d, J = 5.49 Hz, 2 H), 2.03-2.14 (m, 2 H). 120
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-[(3- d.sub.6/D.sub.2O) .delta. ppm 8.94 (s, 1 H), m/e
442 methoxypropanoyl)(3- 7.68 (s, 1 H), 7.56 (s, 1 H), 7.21 (t, J =
7.63 Hz, (M + H)+ methylbenzyl)amino]-1,3- 1 H), 7.02-7.10 (m, 2
thiazole-5-carboxamide H), 7.00 (s, 1 H), 6.93 (d, J = 7.63 Hz, 1
H), 5.48 (s, 2 H), 4.21-4.29 (m, 2 H), 3.65 (t, J = 6.10 Hz, 2 H),
3.29-3.31 (m, 2 H), 3.20 (s, 3 H), 2.86 (t, J = 6.10 Hz, 2 H), 2.26
(s, 3 H), 2.06-2.15 (m, 2 H). 121 N-[3-(1H-imidazol-1- .sup.1H NMR
(400 MHz, DMSO- (ESI(+)) yl)propyl]-2-[(3- d.sub.6/D.sub.2O)
.delta. ppm 8.96 (s, 1 H), m/e 429 methoxypropanoyl)(pyridin- 8.47
(d, 1 H), 7.92 (s, 1 H), (M + H)+ 2-ylmethyl)amino]-1,3- 7.72-7.79
(m, 1 H), 7.69 (d, J = 1.53 Hz, 1 H), thiazole-5-carboxamide 7.57
(d, J = 1.83 Hz, 1 H), 7.26-7.34 (m, 2 H), 5.57 (s, 2 H), 4.26 (t,
J = 6.87 Hz, 2 H), 3.68 (t, J = 5.95 Hz, 2 H), 3.26 (s, 2 H), 3.22
(s, 3 H), 2.95 (t, J = 6.26 Hz, 2 H), 2.06-2.14 (m, J = 13.35,
6.60, 6.60 Hz, 2 H). 122 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
DMSO- (ESI(+)) yl)propyl]-2-[(3- d.sub.6/D.sub.2O) .delta. ppm 8.95
(s, 1 H), m/e 429 methoxypropanoyl)(pyridin- 8.45-8.51 (m, 2 H),
7.98 (s, 1 H), (M + H)+ 3-ylmethyl)amino]-1,3- 7.68 (s, 1 H), 7.64
(d, 1 H), 7.56 (s, 1 thiazole-5-carboxamide H), 7.40 (d, J = 4.88
Hz, 1 H), 5.53 (s, 2 H), 4.26 (t, J = 7.17 Hz, 2 H), 3.68 (t, J =
6.10 Hz, 2 H), 3.29-3.31 (m, 2 H), 3.21 (s, 3 H), 2.91 (t, J = 5.95
Hz, 2 H), 2.07-2.14 (m, 2 H). 133 N-[3-(1H-imidazol-1- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ESI(+)) yl)propyl]-2-{(3- 9.07 (s,
1H), 8.00 (s, 1H), 7.35 (d, J = 8.9 Hz, m/e 470
methylbutyl)[(2R)-2- 2H), 7.30 (t, J = 8.0 Hz, (M + H)+
phenoxypropanoyl]amino}- 2H), 7.01 (t, J = 7.4 Hz, 1H),
1,3-thiazole-5-carboxamide 6.89 (d, J = 8.0 Hz, 3H), 5.23 (d, J =
6.4 Hz, 1H), 4.31 (t, J = 6.5 Hz, 3H), 4.14 (t, J = 11.2 Hz, 1H),
3.48 (dd, J = 10.8, 5.2 Hz, 2H), 2.25-2.16 (m, 3H), 1.70 (d, J =
6.5 Hz, 3H), 1.63 (m, 2H), 0.90 (dd, J = 5.8, 3.4 Hz, 6H). 134
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]-2-{(3- 9.06 (s, 1H), 8.00 (s, 1H), 7.35 (d, J =
9.8 Hz, m/e 470 methylbutyl)[(2S)-2- 2H), 7.30 (t, J = 8.0 Hz, (M +
H)+ phenoxypropanoyl]amino}- 2H), 7.01 (t, J = 7.3 Hz, 1H),
1,3-thiazole-5-carboxamide 6.90 (d, J = 8.1 Hz, 2H), 6.77 (s, 1H),
5.23 (d, J = 6.3 Hz, 1H), 4.30 (t, J = 6.5 Hz, 3H), 4.16 (s, 1H),
3.49 (dd, J = 10.8, 5.2 Hz, 2H), 2.24-2.17 (m, 3H), 1.70 (d, J =
6.5 Hz, 3H), 1.63 (m, 2H), 0.90 (dd, J = 5.9, 3.2 Hz, 6H). 135
N-(5-{[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]carbamoyl}-1,3- 9.13 (s, 1H), 8.08 (s, 1H), 7.35
(d, J = 9.6 Hz, m/e 431 thiazol-2-yl)-5-methyl-N-(3- 2H), 7.12 (s,
1H), 6.44 (s, (M + H)+ methylbutyl)-1,2-oxazole-3- 1H), 4.61-4.49
(m, 2H), 4.35 (t, J = 6.5 Hz, carboxamide 2H), 3.51 (d, J = 5.6 Hz,
2H), 2.54 (s, 3H), 2.29-2.20 (m, 2H), 1.70-1.61 (m, 3H), 0.90 (d, J
= 6.0 Hz, 6H). 136 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) yl)propyl]-2-[(3- 9.06 (s, 1H), 7.99
(s, 1H), m/e 456 methylbutyl)(phenoxyacetyl)amino]- 7.36-7.28 (m,
4H), 7.03 (t, J = 7.3 Hz, 2H), (M + H)+ 1,3-thiazole-5- 6.94 (d, J
= 8.3 Hz, 2H), 4.99 (s, carboxamide 2H), 4.30 (t, J = 6.5 Hz, 2H),
4.24-4.08 (m, 2H), 3.47 (d, J = 5.6 Hz, 2H), 2.23-2.18 (m, 2H),
1.76-1.63 (m, 3H), 0.99 (d, J = 6.2 Hz, 6H). 137
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]-2-[(3- 9.07 (s, 1H), 7.98 (s, 1H), 7.36 (d, J =
3.5 Hz, m/e 454 methylbutyl)(3- 2H), 7.34-7.29 (m, 2H), (M + H)+
phenylpropanoyl)amino]- 7.26-7.17 (m, 3H), 6.90 (s, 1H),
1,3-thiazole-5-carboxamide 4.32 (t, J = 6.5 Hz, 2H), 4.18-4.05 (m,
2H), 3.50 (d, J = 5.8 Hz, 2H), 3.10 (t, J = 7.5 Hz, 2H), 2.97-2.92
(m, 2H), 2.27-2.19 (m, 2H), 1.66 (dt, J = 12.9, 6.4 Hz, 1H), 1.53
(dd, J = 16.0, 7.1 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H). 138
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]-2-[(3- 9.06 (s, 1H), 7.96 (s, 1H), 7.36 (dd, J
= 11.5, m/e 454 methylbutyl)(2- 7.2 Hz, 4H), 7.29 (d, J = 7.2 Hz,
(M + H)+ phenylpropanoyl)amino]- 1H), 7.24 (s, 2H), 6.62 (s, 1H),
1,3-thiazole-5-carboxamide 4.31 (t, J = 6.5 Hz, 2H), 4.20 (dt, J =
15.7, 8.4 Hz, 1H), 4.10 (q, J = 6.9 Hz, 1H), 3.94 (dt, J = 10.3,
7.4 Hz, 1H), 3.50 (d, J = 5.9 Hz, 2H), 2.25-2.18 (m, 2H), 1.63-1.58
(m, 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.45 (dd, J = 15.8, 7.3 Hz, 2H),
0.93 (dd, J = 19.8, 6.6 Hz, 6H). 139 2-{[(4- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) fluorophenyl)acetyl](3- 9.04 (s, 1H),
7.97 (s, 1H), 7.33 (d, J = 9.4 Hz, m/e 458 methylbutyl)amino}-N-[3-
2H), 7.24 (dd, J = 8.4, 5.3 Hz, (M + H)+ (1H-imidazol-1-yl)propyl]-
2H), 7.06 (t, J = 8.6 Hz, 2H), 1,3-thiazole-5-carboxamide 6.78 (s,
1H), 4.29 (t, J = 6.2 Hz, 2H), 4.24-4.12 (m, 2H), 3.97 (s, 2H),
3.48 (d, J = 5.4 Hz, 2H), 2.23-2.18 (m, 2H), 1.71 (dt, J = 13.1,
6.6 Hz, 1H), 1.65-1.58 (m, 2H), 0.99 (d, J = 6.5 Hz, 6H). 150
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) yl)propyl]-2-[(3- .delta. 8.98 (s, 1H), 8.01 (s, 1H), 7.71
(s, m/e 408 methoxypropanoyl)(3- 1H), 7.57 (s, 1H), 4.33 (t, J =
6.9 Hz, (M + H)+ methylbutyl)amino]-1,3- 2H), 4.30-4.23 (m, 2H),
thiazole-5-carboxamide 3.79 (t, J = 5.9 Hz, 2H), 3.39 (t, J = 6.4
Hz, 2H), 3.36 (s, 3H), 2.97 (t, J = 5.9 Hz, 2H), 2.18 (p, J = 6.7
Hz, 2H), 1.72 (dt, J = 13.1, 6.7 Hz, 1H), 1.68-1.59 (m, 2H), 1.00
(d, J = 6.5 Hz, 6H). 151 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) yl)propyl]-2- .delta. 8.98 (s, 1H), 8.03
(s, 1H), 7.71 (s, m/e 394 [(methoxyacetyl)(3- 1H), 7.57 (s, 1H),
4.49 (s, 2H), (M + H)+ methylbutyl)amino]-1,3- 4.33 (t, J = 6.8 Hz,
2H), thiazole-5-carboxamide 4.19-4.07 (m, 2H), 3.49 (s, 3H), 3.40
(t, J = 6.4 Hz, 2H), 2.19 (p, J = 6.6 Hz, 2H), 1.71 (dt, J = 12.8,
6.5 Hz, 1H), 1.67-1.56 (m, 2H), 1.00 (d, J = 6.4 Hz, 6H). 152
2-[(cyclopropylcarbonyl)(3- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) methylbutyl)amino]-N-[3- .delta. 8.97 (s, 1H), 8.00 (s,
1H), 7.70 (t, m/e 390 (1H-imidazol-1-yl)propyl]- J = 1.6 Hz, 1H),
7.56 (t, J = 1.6 Hz, (M + H)+ 1,3-thiazole-5-carboxamide 1H),
4.53-4.41 (m, 2H), 4.32 (t, J = 6.8 Hz, 2H), 3.39 (t, J = 6.4 Hz,
2H), 2.28-2.10 (m, 3H), 1.81-1.63 (m, 3H), 1.16-1.04 (m, 4H), 1.01
(d, J = 6.2 Hz, 6H). 153 (2S)-1-[(5-{[3-(1H- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) imidazol-1- .delta. 8.97 (s, 1H), 8.03
(s, 1H), 7.71 (s, m/e 436 yl)propyl]carbamoyl}-1,3- 1H), 7.57 (s,
1H), 5.50 (q, J = 6.8 Hz, (M + H)+ thiazol-2-yl)(3- 1H), 4.53 (s,
1H), 4.33 (t, J = 6.8 Hz, methylbutyl)amino]-1- 2H), 4.04-3.91 (m,
1H), oxopropan-2-yl acetate 3.39 (dd, J = 6.9, 5.6 Hz, 2H), 2.19
(p, J = 6.6 Hz, 2H), 2.12 (s, 3H), 1.80 (d, J = 5.4 Hz, 1H), 1.72
(dt, J = 11.2, 6.2 Hz, 2H), 1.54 (d, J = 6.8 Hz, 3H), 1.00 (dd, J =
6.1, 2.0 Hz, 6H). 154 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) yl)propyl]-2-[(3- .delta. 10.13 (d, J =
1.5 Hz, 1H), m/e 448 methylbutyl)(tetrahydro-2H- 8.98 (s, 1H), 8.01
(s, 1H), 7.71 (s, 1H), (M + H)+ pyran-4-ylacetyl)amino]- 7.57 (s,
1H), 4.32 (t, J = 6.9 Hz, 1,3-thiazole-5-carboxamide 2H), 4.28-4.19
(m, 2H), 3.94 (dd, J = 11.4, 3.5 Hz, 2H), 3.47 (t, J = 11.0 Hz,
2H), 3.39 (t, J = 6.5 Hz, 2H), 2.67 (d, J = 6.7 Hz, 2H), 2.19 (dd,
J = 13.3, 6.7 Hz, 3H), 1.73 (dd, J = 13.3, 6.4 Hz, 3H), 1.61 (dd, J
= 15.7, 7.1 Hz, 2H), 1.39 (dd, J = 12.9, 4.3 Hz, 2H), 1.01 (d, J =
6.5 Hz, 6H). 155 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) yl)propyl]-2-[(3- .delta. 8.98 (s, 1H),
8.02 (s, 1H), 7.71 (s, m/e 420 methylbutyl)(tetrahydrofuran- 1H),
7.57 (s, 1H), 4.31 (dt, J = 15.2, (M + H)+ 3-ylcarbonyl)amino]-1,3-
7.8 Hz, 4H), 4.07 (t, J = 8.2 Hz, thiazole-5-carboxamide 1H),
4.02-3.91 (m, 2H), 3.87 (dd, J = 14.7, 7.5 Hz, 1H), 3.74-3.59 (m,
1H), 3.39 (t, J = 6.5 Hz, 2H), 2.31 (dt, J = 15.2, 7.1 Hz, 1H),
2.19 (dq, J = 13.2, 6.6 Hz, 3H), 1.73 (td, J = 13.0, 6.4 Hz, 1H),
1.64 (dd, J = 14.5, 7.3 Hz,
2H), 1.01 (d, J = 6.5 Hz, 6H). 156 2-{[2-hydroxy-2-(3- .sup.1H NMR
(400 MHz, DMSO- (ESI(+)) methoxyphenyl)ethyl](3- d.sub.6/D.sub.2O)
.delta. ppm 9.03 (s, 1 H), m/e 488 methoxypropanoyl)amino}- 7.74
(s, 1 H), 7.66 (s, 1 H), 7.63 (s, 1 H), (M + H)+
N-[3-(1H-imidazol-1- 7.29-7.34 (m, 1 H), yl)propyl]-1,3-thiazole-5-
6.89-6.96 (m, 3 H), 5.86-5.90 (m, 1 H), carboxamide 4.23 (t, J =
6.71 Hz, 2 H), 3.53-3.66 (m, 4 H), 3.22 (d, J = 2.44 Hz, 2 H), 3.20
(s, 3 H), 2.57-2.62 (m, 2 H), 2.02-2.06 (m, 2 H), 1.01-1.14 (m, 3
H). 157 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 9.04 (s, 1 H), m/e
444 methoxypropanoyl)[2- 8.55-8.57 (m, 2 H), 8.50 (d, J = 2.14 Hz,
(M + H)+ (pyrazin-2-yl)ethyl]amino}- 1 H), 8.03 (s, 1 H), 7.75 (t,
J = 1.68 Hz, 1,3-thiazole-5-carboxamide 1 H), 7.62-7.65 (m, 1 H),
4.55-4.59 (m, 2 H), 4.25 (t, J = 6.87 Hz, 3 H), 3.65 (t, J = 5.95
Hz, 2 H), 3.24-3.28 (m, 7 H), 2.92 (t, J = 6.10 Hz, 2 H), 2.06-2.11
(m, 2 H). 158 2-{[1-(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
hydroxyphenyl)propan-2- d.sub.6/D.sub.2O) .delta. ppm 9.02 (s, 1
H), m/e 472 yl](3- 7.74 (t, J = 1.83 Hz, 1 H), 7.63 (s, 2 H), (M +
H)+ methoxypropanoyl)amino}- 7.34 (t, J = 7.63 Hz, 1 H), 7.14 (s, 1
N-[3-(1H-imidazol-1- H), 6.94-6.98 (m, 1 H),
yl)propyl]-1,3-thiazole-5- 6.59-6.63 (m, 1 H), 4.22 (t, J = 6.87
Hz, carboxamide 2 H), 3.66 (t, J = 6.10 Hz, 3 H), 3.29 (s, 3 H),
3.17-3.24 (m, 4 H), 2.80 (t, J = 5.95 Hz, 3 H), 2.00-2.08 (m, 2 H),
1.15 (d, J = 6.41 Hz, 3 H). 173 N-[3-(1H-imidazol-1- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ESI(+)) yl)propyl]-2-[(3- 9.10 (s,
1H), 7.98 (s, 1H), 7.38 (d, J = 4.8 Hz, m/e 434
methylbutyl)(tetrahydrofuran- 2H), 6.83 (dd, J = 5.1, 2.6 Hz, (M +
H)+ 2-ylacetyl)amino]-1,3- 1H), 4.42 (dd, J = 12.9, 6.7 Hz,
thiazole-5-carboxamide 1H), 4.34 (t, J = 6.5 Hz, 2H), 4.20 (t, J =
8.3 Hz, 2H), 3.92 (dd, J = 15.0, 6.9 Hz, 1H), 3.80 (dd, J = 15.1,
6.9 Hz, 1H), 3.51 (ddd, J = 5.9, 4.6, 2.9 Hz, 2H), 3.04-2.96 (m,
2H), 2.78 (dd, J = 15.9, 5.4 Hz, 2H), 2.25 (dt, J = 15.8, 6.1 Hz,
3H), 1.97 (dt, J = 13.9, 6.9 Hz, 2H), 1.79-1.69 (m, 1H), 1.67-1.52
(m, 3H), 0.99 (d, J = 6.5 Hz, 6H). 174 N-[3-(1H-imidazol-1- .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+)) yl)propyl]-2-[(3- 9.15
(s, 1H), 8.00 (s, 1H), 7.37 (d, J = 9.6 Hz, m/e 434
methylbutyl)(tetrahydrofuran- 2H), 6.81 (dd, J = 7.5, 3.3 Hz, (M +
H)+ 3-ylacetyl)amino]-1,3- 1H), 4.34 (t, J = 6.5 Hz, 2H),
thiazole-5-carboxamide 4.15 (dd, J = 9.7, 6.7 Hz, 2H), 4.04 (dd, J
= 8.7, 6.9 Hz, 1H), 3.94 (td, J = 8.3, 5.1 Hz, 1H), 3.81 (dd, J =
15.9, 7.6 Hz, 1H), 3.51 (dt, J = 10.0, 5.1 Hz, 3H), 2.84 (dt, J =
10.4, 4.2 Hz, 1H), 2.79-2.66 (m, 2H), 2.36-2.18 (m, 3H), 1.72 (dt,
J = 13.2, 6.6 Hz, 1H), 1.66-1.55 (m, 3H), 1.05-0.89 (m, 6H). 175
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]-2-[(2- 9.21-9.10 (m, 1H), 7.99 (s, 1H), m/e 396
methoxyethyl)(3- 7.42-7.33 (m, 2H), 7.04-6.85 (m, 1H), (M + H)+
methoxypropanoyl)amino]- 4.40 (t, J = 4.9 Hz, 2H), 4.34 (dd, J =
9.2, 1,3-thiazole-5-carboxamide 3.5 Hz, 2H), 3.79 (t, J = 6.2 Hz,
2H), 3.68 (t, J = 4.9 Hz, 2H), 3.53-3.46 (m, 2H), 3.39 (s, 3H),
3.30 (s, 3H), 3.09 (t, J = 6.2 Hz, 2H), 2.26-2.21 (m, 2H). 176
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]-2-[(3- 9.26-9.13 (m, 1H), 8.05-7.97 (m, m/e 410
methoxypropanoyl)(3- 1H), 7.36 (d, J = 8.6 Hz, 2H), (M + H)+
methoxypropypamino]-1,3- 7.04-6.87 (m, 1H), 4.40-4.32 (m,
thiazole-5-carboxamide 2H), 4.32-4.23 (m, 2H), 3.81 (t, J = 6.1 Hz,
2H), 3.50 (d, J = 5.5 Hz, 2H), 3.44 (t, J = 5.6 Hz, 2H), 3.39 (s,
3H), 3.34 (s, 3H), 2.98 (t, J = 6.1 Hz, 2H), 2.26-2.20 (m, 2H),
2.08-1.99 (m, 2H). 177 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) yl)propyl]-2-[(3- 9.17 (s, 1H), 8.00
(s, 1H), 7.37 (dd, J = 8.1, m/e 436 methoxypropanoyl)(tetrahydro-
3.9 Hz, 2H), 6.88-6.77 (m, (M + H)+ 2H-pyran-2- 1H), 4.46-4.36 (m,
1H), ylmethyl)amino]-1,3- 4.37-4.30 (m, 2H), 4.03-3.84 (m, 2H),
thiazole-5-carboxamide 3.84-3.73 (m, 2H), 3.74-3.61 (m, 2H),
3.55-3.46 (m, 2H), 3.39 (s, 3H), 3.33-3.19 (m, 3H), 2.99 (dt, J =
16.8, 6.8 Hz, 1H), 2.28-2.21 (m, 2H), 1.89-1.85 (m, 1H), 1.73 (ddd,
J = 3.0, 1.3, 0.6 Hz, 1H), 1.52-1.48 (m, 2H), 1.23-1.13 (m, 2H).
178 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) yl)propyl]-2-[(3- 9.16 (d, J = 4.8 Hz, 1H), 8.00 (d, J =
4.2 Hz, m/e 422 methoxypropanoyl)(tetrahydrofuran- 1H), 7.36 (d, J
= 7.9 Hz, (M + H)+ 2-ylmethyl)amino]- 2H), 6.89-6.78 (m, 1H), 4.54
(dd, 1,3-thiazole-5-carboxamide J = 14.5, 1.6 Hz, 1H), 4.37-4.30
(m, 2H), 4.30-4.23 (m, 1H), 4.10-3.95 (m, 1H), 3.87 (dd, J = 14.7,
6.5 Hz, 1H), 3.82-3.76 (m, 2H), 3.71 (dd, J = 8.2, 6.6 Hz, 1H),
3.55-3.45 (m, 2H), 3.39 (s, 3H), 3.26-3.12 (m, 1H), 3.03 (dt, J =
16.7, 6.8 Hz, 1H), 2.24-2.20 (m, 2H), 1.93 (d, J = 7.2 Hz, 2H),
1.66-1.50 (m, 2H). 179 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) yl)propyl]-2-{(3- 9.25-9.09 (m, 1H),
8.07-7.96 (m, m/e 424 methoxypropanoyl)[2- 1H), 7.35 (d, J = 11.4
Hz, 2H), (M + H)+ (propan-2- 6.98-6.78 (m, 1H), 4.38 (t, J = 4.9
Hz, yloxy)ethyl]amino}-1,3- 2H), 4.36-4.30 (m, 2H),
thiazole-5-carboxamide 3.79 (dd, J = 8.1, 4.5 Hz, 2H), 3.75-3.68
(m, 3H), 3.49 (dd, J = 10.9, 4.8 Hz, 2H), 3.38 (s, 3H), 3.27 (dd, J
= 7.0, 3.4 Hz, 1H), 3.13 (dd, J = 8.1, 4.4 Hz, 2H), 2.24-2.20 (m,
2H), 1.06 (d, J = 6.1 Hz, 6H). 180 2-{[2-(1,3-dioxolan-2- .sup.1H
NMR (400 MHz, methanol-d.sub.4) (ESI(+)) yl)ethyl](3- .delta. 8.98
(s, 1H), 8.59-8.49 (m, 1H), m/e 438 methoxypropanoyl)amino}- 8.02
(s, 1H), 7.71 (d, J = 1.5 Hz, (M + H)+ N-[3-(1H-imidazol-1- 1H),
7.57 (s, 1H), 4.95 (t, J = 4.3 Hz, yl)propyl]-1,3-thiazole-5- 1H),
4.37 (dd, J = 12.7, 5.0 Hz, carboxamide 2H), 4.34-4.29 (m, 2H),
3.99-3.91 (m, 2H), 3.85 (dd, J = 8.8, 5.1 Hz, 2H), 3.79 (t, J = 6.0
Hz, 2H), 3.43-3.37 (m, 2H), 3.36 (s, 3H), 3.03 (t, J = 6.0 Hz, 2H),
2.26-2.17 (m, 2H), 2.17-2.11 (m, 2H). 181 2-[(1,4-dioxan-2-
(ESI(+)) ylmethyl)(3- m/e 438 methoxypropanoyl)amino]- (M + H)+
N-[3-(1H-imidazol-1- yl)propyl]-1,3-thiazole-5- carboxamide 182
2-{[3-(4- .sup.1H NMR (400 MHz, methanol-d.sub.4) (ESI(+))
fluorophenyl)propanoyl](2- .delta. 8.96 (s, 1H), 7.99 (s, 1H), 7.70
(t, m/e methoxyethyl)amino}-N-[3- J = 1.7 Hz, 1H), 7.57 (t, J = 1.6
Hz, 55460 (1H-imidazol-1-yl)propyl]- 1H), 7.27 (dd, J = 8.6, 5.5
Hz, (M + H)+ 1,3-thiazole-5-carboxamide 2H), 6.99 (t, J = 8.8 Hz,
2H), 4.41 (t, J = 5.1 Hz, 2H), 4.33 (t, J = 6.9 Hz, 2H), 3.66 (t, J
= 5.0 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 3.26 (s, 3H), 3.17 (t, J =
7.3 Hz, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.24-2.09 (m, 2H). 183
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) yl)propyl]-2-{(2- .delta. 8.98 (s, 1H), 8.84 (s, 1H), m/e
443 methoxyethyl)[3-(pyridin-3- 8.70 (d, J = 5.5 Hz, 1H), 8.59 (d,
J = 8.2 Hz, (M + H)+ yl)propanoyl]amino}-1,3- 1H), 8.01 (dd, J =
8.1, 5.7 Hz, thiazole-5-carboxamide 1H), 7.99 (s, 1H), 7.70 (t, J =
1.7 Hz, 1H), 7.57 (t,, J = 1.7 Hz, 1H), 4.45 (t, J = 5.0 Hz, 2H),
4.32 (t, J = 6.9 Hz, 2H), 3.69 (t, J = 4.9 Hz, 2H), 3.40 (dt, J =
9.9, 6.9 Hz, 4H), 3.27 (s, 3H), 2.18 (m, 2H). 184
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) yl)propyl]-2-[(2- .delta. 8.97 (s, 1H), 8.81 (d, J = 9.1
Hz, m/e 429 methoxyethyl)(pyridin-3- 2H), 8.52 (d, J = 8.1 Hz, 1H),
(M + H)+ ylacetyl)amino]-1,3- 8.06 (dd, J = 7.9, 5.9 Hz, 1H), 8.04
(s, thiazole-5-carboxamide 1H), 7.70 (t, J = 1.7 Hz, 1H), 7.56 (t,
J = 1.7 Hz, 1H), 4.61 (t, J = 5.0 Hz, 2H), 4.58 (s, 2H), 4.32 (t, J
= 6.9 Hz, 2H), 3.80 (t, J = 4.9 Hz, 2H), 3.39 (t, J = 6.4 Hz, 2H),
3.38 (s, 3H), 2.18 (m, 2H). 185 N-[3-(1H-imidazol-1- .sup.1H NMR
(400 MHz, methanol-d.sub.4) (ESI(+)) yl)propyl]-2-[(2- .delta. 8.98
(s, 1H), 8.04 (s, 1H), m/e 478 methoxyethyl)(naphthalen- 7.92-7.79
(m, 0033H), 7.74 (d, J = 15.9 Hz, (M + H)+ 2-ylacetyl)amino]-1,3-
2H), 7.59 (s, 1H), 7.51 (dd, J = 6.8, thiazole-5-carboxamide 2.8
Hz, 2H), 7.42 (dd, J = 8.5, 1.7 Hz, 1H), 4.57 (t, J = 5.1 Hz, 2H),
4.44 (s, 2H), 4.35 (t, J = 6.8 Hz, 2H), 3.78 (t, J = 5.0 Hz, 2H),
3.42 (t, J = 6.2 Hz, 2H), 3.40 (s, 3H), 2.29-2.11 (m, 2H). 186
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) yl)propyl]-2-{(2- .delta. 8.95 (s, 1H), 8.03 (t, J = 1.3
Hz, m/e 520 methoxyethyl)[(4- 1H), 7.70 (s, 1H), 7.58 (s, 1H), (M +
H)+ phenoxyphenyl)acetyl]amino}- 7.40-7.33 (m, 2H), 7.27 (d, J =
8.5 Hz, 1,3-thiazole-5- 2H), 7.12 (dd, J = 11.3, 3.9 Hz,
carboxamide 2H), 7.03-6.95 (m, 4H), 4.52 (t, J = 5.1 Hz, 2H), 4.35
(t, J = 6.9 Hz, 2H), 4.24 (s, 2 H), 3.76 (t, J = 5.1 Hz, 2H), 3.43
(t, J = 6.5 Hz, 2H), 3.38 (s, 3H), 2.34-2.12 (m, 2H). 187 2-{[(4-
.sup.1H NMR (400 MHz, methanol-d.sub.4) (ESI(+))
cyanophenyl)acetyl](2- .delta. ppm 8.94 (s, 1 H), 8.01 (s, 1H), m/e
453 methoxyethyl)amino}-N-[3- 7.70 (m, 3 H), 7.55 (s, 1 H), (M +
H)+ (1H-imidazol-1-yl)propyl]- 7.44 (d, J = 8.1 Hz, 2H), 4.53 (t, J
= 4.9 Hz, 1,3-thiazole-5-carboxamide 2H), 4.35 (s, 2H), 4.32 (t, J
= 6.9 Hz, 2H), 3.75 (t, J = 4.9 Hz, 2H), 3.39 (t, J = 6.5 Hz, 2H),
3.36 (s, 3H), 2.19 (m, 2H). 188 2-{[(4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) aminophenyl)acetyl](2- .delta. 9.02 (s,
1H), 8.07 (s, 1H), 7.74 (s, m/e 443 methoxyethyl)amino}-N-[3- 1H),
7.59 (s, 1H), 7.47 (d, J = 8.4 Hz, (M + H)+
(1H-imidazol-1-yl)propyl]- 2H), 7.40 (d, J = 8.4 Hz, 2H),
1,3-thiazole-5-carboxamide 4.57 (t, J = 4.9 Hz, 2H), 4.40-4.28 (m,
4H), 3.79 (t, J = 5.0 Hz, 2H), 3.42 (t, J = 6.5 Hz, 2H), 3.39 (s,
3H), 2.21 (m, 2H). 189 2-[{2-[di(prop-2-en-1- .sup.1H NMR (400 MHz,
DMSO- (ESI(+)) yl)amino]ethyl}(3- d.sub.6/D.sub.2O) .delta. ppm
8.98 (s, 1 H), m/e 461 methoxypropanoyl)amino]- 8.05 (s, 1 H), 7.70
(s, 1 H), 7.59 (s, 1 H), (M + H)+ N-[3-(1H-imidazol-1- 5.89-6.01
(m, 2 H), yl)propyl]-1,3-thiazole-5- 5.49-5.59 (m, 4 H), 4.51 (t, 2
H), 4.27 (t, J = 7.02 Hz, carboxamide 2 H), 3.77 (d, J = 7.02 Hz, 4
H), 3.72 (t, J = 6.26 Hz, 2 H), 3.31-3.37 (m, 3 H), 3.29 (s, 4 H),
2.98 (t, J = 6.26 Hz, 2 H). 190 2-{[3- .sup.1H NMR (400 MHz, DMSO-
(ESI(+)) (diethylamino)propyl](3- d.sub.6/D.sub.2O) .delta. ppm
8.96 (s, 1 H), m/e 451 methoxypropanoyl)amino}- 8.04 (s, 1 H), 7.69
(s, 1 H), 7.57 (s, 1 H), (M + H)+ N-[3-(1H-imidazol-1- 4.21-4.30
(m, 4 H), 3.74 (t, J = 6.10 Hz, yl)propyl]-1,3-thiazole-5- 2 H),
3.31 (s, 2 H), carboxamide 3.29 (s, 3 H), 3.12-3.20 (m, 6 H), 2.98
(t, J = 6.10 Hz, 2 H), 2.07-2.15 (m, 4 H), 1.23 (t, J = 7.17 Hz, 6
H). 191 2-{[2- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
(diethylamino)ethyl](3- d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1
H), m/e 437 methoxypropanoyl)amino}- 8.07 (s, 1 H), 7.69 (s, 1 H),
7.58 (s, 1 H), (M + H)+ N-[3-(1H-imidazol-1- 4.52 (t, 2 H), 4.27
(t, J = 7.02 Hz, 2 yl)propyl]-1,3-thiazole-5- H), 3.74 (t, J = 6.10
Hz, 2 H), carboxamide 3.44 (t, 2 H), 3.30 (s, 4 H), 3.29-3.29 (m, 3
H), 3.27 (s, 2 H), 3.01 (t, J = 6.10 Hz,
2 H), 2.07-2.16 (m, 2 H), 1.29 (t, J = 7.32 Hz, 6 H). 192
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1 H), m/e
449 methoxypropanoyl)[3- 8.04 (s, 1 H), 7.69 (s, 1 H), 7.57 (s, 1
H), (M + H)+ (pyrrolidin-1- 4.21-4.31 (m, 4 H), 3.74 (t, J = 5.95
Hz, yl)propyl]amino}-1,3- 2 H), 3.29-3.31 (m, 6
thiazole-5-carboxamide H), 3.22-3.27 (m, 5 H), 2.98 (t, J = 6.10
Hz, 2 H), 2.07-2.16 (m, 4 H), 1.94-2.03 (m, 4 H). 193
2-{[(1-ethyl-5- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
oxopyrrolidin-3- d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1 H), m/e
463 yl)methyl](3- 8.02 (s, 1 H), 7.69 (s, 1 H), 7.57 (s, 1 H), (M +
H)+ methoxypropanoyl)amino}- 4.24-4.33 (m, 4 H), 3.72 (t, J = 6.10
Hz, N-[3-(1H-imidazol-1- 2 H), 3.41 (dd, J = 9.77,
yl)propyl]-1,3-thiazole-5- 7.63 Hz, 1 H), 3.29-3.31 (m, 2 H),
carboxamide 3.27 (s, 4 H), 3.14-3.21 (m, 3 H), 2.96 (t, J = 5.95
Hz, 2 H), 2.35 (dd, J = 16.63, 8.70 Hz, 1 H), 2.08-2.15 (m, 3 H),
1.00-1.04 (m, 3 H). 194 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
DMSO- (ESI(+)) yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.94
(s, 1 H), m/e 435 methoxypropanoyl)[(5- 8.01 (s, 1 H), 7.68 (s, 1
H), 7.56 (s, 1 H), (M + H)+ oxopyrrolidin-2- 4.21-4.31 (m, 4 H),
3.72 (t, J = 6.26 Hz, yl)methyl]amino}-1,3- 2 H), 3.29-3.31 (m, 2
thiazole-5-carboxamide H), 3.28 (s, 3 H), 2.89-3.04 (m, 3 H),
2.24-2.31 (m, 1 H), 2.07-2.19 (m, 4 H), 1.77-1.84 (m, 1 H). 195
N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1 H), m/e
463 methoxypropanoyl)[3-oxo- 8.02 (s, 1 H), 7.69 (s, 1 H), 7.57 (s,
1 H), (M + H)+ 3-(pyrrolidin-1- 4.39-4.43 (m, 2 H), 4.27 (t, J =
7.02 Hz, yl)propyl]amino}-1,3- 2 H), 3.71 (t, J = 6.10 Hz,
thiazole-5-carboxamide 2 H), 3.29-3.43 (m, 8 H), 3.03 (t, J = 6.26
Hz, 2 H), 2.71-2.76 (m, 2 H), 2.08-2.15 (m, 2 H), 1.73-1.89 (m, 4
H). 196 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1 H), m/e
463 methoxypropanoyl)[2-oxo- 7.95 (s, 1 H), 7.69 (s, 1 H), 7.57 (s,
1 H), (M + H)+ 2-(piperidin-1- 5.13 (s, 2 H), 4.27 (t, J = 7.02 Hz,
2 yl)ethyl]amino}-1,3- H), 3.68 (t, J = 6.26 Hz, 2 H),
thiazole-5-carboxamide 3.42-3.54 (m, 4 H), 3.29-3.31 (m, 2 H),
3.27-3.27 (m, 3 H), 2.80 (t, J = 6.26 Hz, 2 H), 2.07-2.15 (m, 2 H),
1.47-1.68 (m, 6 H). 197 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
DMSO- (ESI(+)) yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.98
(s, 1 H), m/e 463 methoxypropanoyl)[3-(2- 8.03 (s, 1 H), 7.67-7.72
(m, 1 H), (M + H)+ oxopyrrolidin-1- 7.57 (s, 1 H), 4.27 (t, J =
7.02 Hz, 2 H), yl)propyl]amino}-1,3- 4.15-4.19 (m, 2 H), 3.72 (t, J
= 6.10 Hz, thiazole-5-carboxamide 2 H), 3.38 (t, J = 7.02 Hz, 2 H),
3.31 (s, 1 H), 3.28 (s, 5 H), 3.26 (s, 1 H), 2.95 (t, J = 6.10 Hz,
2 H), 2.24 (t, J = 8.09 Hz, 2 H), 2.07-2.15 (m, 2 H), 1.88-2.00 (m,
4 H). 198 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
yl)propyl]-2-{(3- d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1 H), m/e
451 methoxypropanoyl)[2-(2- 8.03 (s, 1 H), 7.69 (s, 1 H), 7.57 (s,
1 H), (M + H)+ oxo-1,3-oxazolidin-3- 4.39 (t, J = 6.26 Hz, 2 H),
4.27 (t, J = 7.02 Hz, yl)ethyl]amino}-1,3- 2 H), 4.16-4.20 (m, 2
thiazole-5-carboxamide H), 3.73 (t, J = 6.10 Hz, 2 H), 3.57-3.62
(m, 2 H), 3.53 (t, J = 6.26 Hz, 2 H), 3.28-3.32 (m, 5 H), 2.98 (t,
J = 6.26 Hz, 2 H), 2.08-2.15 (m, 2 H). 199 N-[3-(1H-imidazol-1-
.sup.1H NMR (400 MHz, DMSO- (ESI(+)) yl)propyl]-2-[(3-
d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1 H), m/e 451
methoxypropanoyl){2-[(2- 8.02 (s, 1 H), 7.66-7.71 (m, 1 H), (M +
H)+ methylpropanoyl)amino]ethyl}amino]- 7.57-7.58 (m, 1 H), 4.26
(q, J = 6.92 Hz, 1,3-thiazole-5- 4 H), 3.71 (t, J = 6.10 Hz, 2 H),
carboxamide 3.43 (t, J = 6.41 Hz, 2 H), 3.29-3.32 (m, 2 H), 3.28
(s, 3 H), 3.00 (t, J = 6.26 Hz, 2 H), 2.27-2.35 (m, 1 H), 2.08-2.15
(m, 2 H), 0.98 (d, J = 7.02 Hz, 6 H). 200 N-[3-(1H-imidazol-1-
.sup.1H NMR (400 MHz, DMSO- (ESI(+)) yl)propyl]-2-{(3-
d.sub.6/D.sub.2O) .delta. ppm 8.97 (s, 1 H), m/e 423
methoxypropanoyl)[3- 8.02 (s, 1 H), 7.69 (s, 1 H), 7.57 (s, 1 H),
(M + H)+ (methylamino)-3- 4.37-4.41 (m, 2 H), 4.27 (t, J = 7.02 Hz,
oxopropyl]amino}-1,3- 2 H), 3.71 (t, J = 6.10 Hz,
thiazole-5-carboxamide 2 H), 3.31 (s, 2 H), 3.28 (s, 3 H), 3.01 (t,
J = 6.26 Hz, 2 H), 2.58 (s, 3 H), 2.07-2.15 (m, 2 H). 201 2-{[3-
.sup.1H NMR (400 MHz, DMSO- (ESI(+)) (acetylamino)propyl](3-
d.sub.6/D.sub.2O) .delta. ppm 8.98 (s, 1 H), m/e 437
methoxypropanoyl)amino}- 8.02 (s, 1 H), 7.68-7.70 (m, 1 H), (M +
H)+ N-[3-(1H-imidazol-1- 7.57 (s, 1 H), 4.27 (t, J = 7.02 Hz, 2 H),
yl)propyl]-1,3-thiazole-5- 4.17-4.22 (m, 2 H), 3.72 (t, J = 6.10
Hz, carboxamide 2 H), 3.31 (s, 2 H), 3.28 (s, 3 H), 3.13 (t, J =
6.87 Hz, 2 H), 2.94 (t, J = 6.10 Hz, 2 H), 2.08-2.15 (m, 2 H),
1.85-1.90 (m, 2 H), 1.84 (s, 3 H). 202 N-[3-(1H-imidazol-1- .sup.1H
NMR (400 MHz, DMSO- (ESI(+)) yl)propyl]-2-{(3- d.sub.6/D.sub.2O)
.delta. ppm 8.96-8.98 (m, 1 m/e 449 methoxypropanoyl)[2-oxo- H),
8.02 (s, 1 H), 7.68-7.70 (m, 1 (M + H)+ 2-(pyrrolidin-1- H), 7.58
(s, 1 H), 4.25-4.32 (m, 4 yl)ethyl]amino}-1,3- H), 3.72 (t, J =
5.95 Hz, 2 H), thiazole-5-carboxamide 3.40 (dd, J = 10.07, 7.63 Hz,
1 H), 3.29-3.31 (m, 2 H), 3.28-3.29 (m, 3 H), 3.15 (dd, J = 10.07,
5.49 Hz, 1 H), 2.95 (t, J = 6.10 Hz, 2 H), 2.85-2.92 (m, 1 H), 2.71
(s, 3 H), 2.34 (dd, J = 16.63, 8.70 Hz, 1 H), 2.08-2.15 (m, 3 H).
205 2-{[(5-chloropyridin-2- .sup.1H NMR (500 MHz, methanol-d.sub.4)
(ESI(+)) yl)methyl](tetrahydro-2H- .delta. 8.97 (s, 1H), 8.45 (d, J
= 2.3 Hz, m/e 489 pyran-4-ylcarbonyl)amino}- 1H), 7.91 (s, 1H),
7.81 (dd, J = 8.4, (M + H)+ N-[3-(1H-imidazol-1- 2.4 Hz, 1H), 7.70
(s, 1H), 7.56 (s, yl)propyl]-1,3-thiazole-5- 1H), 7.42 (d, J = 8.4
Hz, 1H), carboxamide 5.66 (s, 2H), 4.32 (t, J = 6.9 Hz, 2H), 3.96
(dd, J = 11.6, 2.0 Hz, 2H), 3.44 (t, J = 11.2 Hz, 2H), 3.38 (t, J =
6.4 Hz, 2H), 3.26 (dt, J = 7.0, 5.2 Hz, 1H), 2.18 (p, J = 6.7 Hz,
2H), 1.90 (qd, J = 12.3, 4.4 Hz, 2H), 1.73 (d, J = 13.1 Hz, 2H).
206 2-{[(5-chloropyridin-2- .sup.1H NMR (500 MHz, methanol-d.sub.4)
(ESI(+)) yl)methyl](tetrahydrofuran- .delta. 8.97 (s, 1H), 8.45 (d,
J = 2.4 Hz, m/e 475 3-ylcarbonyl)amino}-N-[3- 1H), 7.95-7.76 (m,
2H), 7.70 (t, J = 1.6 Hz, (M + H)+ (1H-imidazol-1-yl)propyl]- 1H),
7.56 (t, J = 1.6 Hz, 1,3-thiazole-5-carboxamide 1H), 7.42 (d, J =
8.5 Hz, 1H), 5.66 (s, 2H), 4.32 (t, J = 6.9 Hz, 2H), 3.97 (dq, J =
14.5, 6.0 Hz, 3H), 3.80 (dt, J = 14.3, 7.3 Hz, 2H), 3.38 (t, J =
6.4 Hz, 2H), 2.19 (tt, J = 13.2, 6.8 Hz, 4H). 207
2-{[2-(5-chloropyridin-2- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) yl)ethyl](3- .delta. 9.00 (s, 1H), 8.52 (d, J = 2.5 Hz,
m/e 477 methoxypropanoyl)amino}- 1H), 8.01 (s, 1H), 7.81 (dd, J =
8.4, (M + H)+ N-[3-(1H-imidazol-1- 2.5 Hz, 1H), 7.72 (t, J = 1.6
Hz, yl)propyl]-1,3-thiazole-5- 1H), 7.58 (t, J = 1.6 Hz, 1H),
carboxamide 7.32 (d, J = 8.4 Hz, 1H), 4.69-4.54 (m, 2H), 4.34 (t, J
= 6.8 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H),
3.34 (s, 3H), 3.27 (d, J = 7.3 Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H),
2.27-2.08 (m, 2H). 208 2-{[2-(5-chloropyridin-2- .sup.1H NMR (400
MHz, methanol-d.sub.4) (ESI(+)) yl)ethyl](tetrahydrofuran-3-
.delta. 9.00 (s, 1H), 8.51 (d, J = 2.5 Hz, m/e 489
ylcarbonyl)amino}-N-[3- 1H), 8.03 (s, 1H), 7.79 (dd, J = 8.3, (M +
H)+ (1H-imidazol-1-yl)propyl]- 2.5 Hz, 1H), 7.72 (t, J = 1.6 Hz,
1,3-thiazole-5-carboxamide 1H), 7.58 (t, J = 1.5 Hz, 1H), 7.32 (d,
J = 8.4 Hz, 1H), 4.64 (dd, J = 8.2, 6.1 Hz, 2H), 4.34 (t, J = 6.8
Hz, 2H), 4.01-3.94 (m, 1H), 3.91 (dd, J = 8.5, 5.9 Hz, 2H),
3.86-3.79 (m, 1H), 3.71-3.56 (m, 1H), 3.40 (t, J = 6.5 Hz, 2H),
3.28 (d, J = 7.1 Hz, 2H), 2.27-2.18 (m, 2H), 2.17-1.98 (m, 2H). 209
2-{[2-(5-chloropyridin-2- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) yl)ethyl][(2- .delta. 8.99 (s, 1H), 8.54 (d, J = 2.4 Hz,
m/e 493 methoxyethyl)carbamoyl]amino}- 1H), 8.01-7.77 (m, 2H), 7.71
(t, J = 1.6 Hz, (M + H)+ N-[3-(1H-imidazol- 1H), 7.58 (t, J = 1.5
Hz, 1-yl)propyl]-1,3-thiazole-5- 1H), 7.35 (d, J = 8.4 Hz, 1H),
carboxamide 4.46 (t, J = 7.1 Hz, 2H), 4.33 (t, J = 6.9 Hz, 2H),
3.51 (dd, J = 8.2, 3.0 Hz, 2H), 3.45 (t, J = 5.1 Hz, 2H), 3.40 (t,
J = 6.7 Hz, 2H), 3.38 (s, 3H), 3.24 (t, J = 7.1 Hz, 2H), 2.18 (p, J
= 6.7 Hz, 2H). 210 2-([2-(5-chloropyridin-2- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) yl)ethyl]{[2-(propan-2- .delta. 8.99 (s,
1H), 8.54 (d, J = 2.5 Hz, m/e 521 yloxy)ethyl]carbamoyl}amino)-
1H), 7.89 (s, 1H), 7.80 (dd, J = 8.4, (M + H)+ N-[3-(1H-imidazol-1-
2.5 Hz, 1H), 7.71 (s, 1H), 7.58 (d, J = 1.5 Hz,
yl)propyl]-1,3-thiazole-5- 1H), 7.34 (d, J = 8.4 Hz, carboxamide
1H), 4.46 (t, J = 7.1 Hz, 2H), 4.33 (t, J = 6.8 Hz, 2H), 3.65 (dt,
J = 12.2, 6.1 Hz, 1H), 3.56 (t, J = 5.7 Hz, 2H), 3.43 (t, J = 5.6
Hz, 2H), 3.38 (t, J = 6.4 Hz, 2H), 3.22 (dt, J = 7.8, 4.0 Hz, 2H),
2.18 (p, J = 6.7 Hz, 2H), 1.16 (d, J = 6.1 Hz, 6H). 211
2-[(1,3-benzodioxol-5- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) ylacetyl)(2- .delta. 8.01 (s, 1H), 7.71 (s, 1H), 7.19 (s,
m/e 472 methoxyethyl)amino]-N-[3- 1H), 6.98 (s, 1H), 6.87-6.69 (m,
(M + H)+ (1H-imidazol-1-yl)propyl]- 3H), 5.95 (s, 2H), 4.49 (t, J =
5.0 Hz, 1,3-thiazole-5-carboxamide 2H), 4.15 (s, 3H), 4.12 (t, J =
7.0 Hz, 2H), 3.73 (t, J = 5.1 Hz, 2H), 3.40-3.35 (m, 5H), 2.17-1.88
(m, 2H). 213 N-[3-(1H-imidazol-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ESI(+)) yl)propyl]-2-[(2- 8.55-8.31 (m, 1H),
8.09 (s, 1H), m/e 429 methoxyethyl)(pyridin-2- 7.79 (td, J = 7.7,
1.8 Hz, 1H), (M + H)+ ylacetyl)amino]-1,3- 7.64 (s, 1H), 7.64 (s,
1H), 7.37 (d, J = 7.8 Hz, thiazole-5-carboxamide 1H), 7.31 (dd, J =
7.5, 4.9 Hz, 1H), 7.19 (s, 1H), 6.88 (s, 1H), 4.45 (t, J = 5.2 Hz,
2H), 4.00 (t, J = 6.9 Hz, 2H), 3.66 (t, J = 5.3 Hz, 2H), 3.26 (s,
3H), 3.23-3.11 (m, 2H), 2.16-1.83 (m, 2H).
Example 46
2-[(4-fluorobenzyl)(propan-2-ylcarbamoyl)amino]-N-[3-(1H-imidazol-1-yl)pro-
pyl]-1,3-thiazole-5-carboxamide
[1200] Example 6B (0.072 g, 0.2 mmol) was dissolved in acetonitrile
(1 ml) and pyridine (0.1 ml) and treated with
bis(2,5-dioxopyrrolidin-1-yl)carbonate (0.064 g, 0.25 mmol). The
reaction mixture was stirred at 50.degree. C. for 3 hours, cooled,
and treated with Hunig's base (0.105 ml, 0.6 mmol) and
propan-2-amine (0.02 ml, 0.23 mmol). The reaction mixture was
stirred further at 25.degree. C. for 3 hours, concentrated purified
by reverse-phase HPLC (as described in Example 6C) to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.12
(s, 1H), 8.45 (t, J=5.6 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J=1.5 Hz,
1H), 7.70 (d, J=1.5 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.22 (dd,
J=8.7, 5.7 Hz, 2H), 7.16 (t, J=8.9 Hz, 2H), 5.37 (s, 2H), 4.22 (t,
J=7.0 Hz, 2H), 3.93-3.87 (m, 1H), 3.21 (q, J=6.3 Hz, 2H), 2.04 (t,
J=6.8 Hz, 2H), 1.10 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 444.5
(M+H)+.
[1201] The following examples were prepared as described in Example
6B followed by Example 46, substituting the appropriate amines in
Example 6B and Example 46. Title compounds were purified by either
flash chromatography (silica gel column eluting with a gradient of
0-10% methanol in dichloromethane) or reverse-phase HPLC (as
described in Example 6C). Accordingly, some examples were isolated
as trifluoroacetic acid salts.
TABLE-US-00003 MS EX NAME .sup.1H NMR DATA DATA 63
2-{(4-fluorobenzyl)[(3- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) methylbutyl)carbamoyl]amino}- 9.15 (s, 1H), 8.70 (s, 1H),
7.83 (s, m/e 473 N-[3-(1H-imidazol-1- 1H), 7.32 (d, J = 20.0 Hz,
2H), (M + H)+ yl)propyl]-1,3-thiazole-5- 7.27 (dd, J = 9.4, 4.5 Hz,
2H), carboxamide 7.11 (s, 1H), 7.02 (t, J = 8.6 Hz, 2H), 5.15 (s,
2H), 4.30 (t, J = 6.5 Hz, 2H), 3.44-3.38 (m, 4H), 2.26-2.16 (m,
2H), 1.62 (dt, J = 13.4, 6.8 Hz, 1H), 1.48 (dd, J = 14.6, 7.1 Hz,
2H), 0.92 (t, J = 6.8 Hz, 6H). 64 2-{(4-fluorobenzyl)[(2- .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
methylpropyl)carbamoyl]amino}- 9.15 (s, 1H), 8.80 (s, 1H), 7.84 (s,
m/e 459 N-[3-(1H-imidazol-1- 1H), 7.35 (s, 1H), 7.30 (s, 1H), (M +
H)+ yl)propyl]-1,3-thiazole-5- 7.27 (d, J = 4.4 Hz, 2H), 7.04 (s,
carboxamide 1H), 7.02 (t, J = 8.5 Hz, 2H), 5.16 (s, 2H), 4.30 (t, J
= 6.5 Hz, 2H), 3.44 (dd, J = 11.6, 6.0 Hz, 2H), 3.22 (t, J = 6.0
Hz, 2H), 2.28-2.17 (m, 2H), 1.85 (dd, J = 13.5, 6.7 Hz, 1H), 0.93
(d, J = 6.6 Hz, 6H). 65 N.sup.1-(4-fluorobenzyl)-N.sup.1-(5-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
{[3-(1H-imidazol-1- 9.16 (dd, J = 1.6, 1.0 Hz, 1H), m/e 514
yl)propyl]carbamoyl}-1,3- 7.79 (s, 1H), 7.34 (d, J = 0.5 Hz, (M +
H)+ thiazol-2-yl)piperidine-1,3- 1H), 7.33-7.31 (m, 1H), 7.30 (d,
dicarboxamide J = 5.4 Hz, 1H), 7.28 (s, 1H), 7.03-6.97 (m, 3H),
6.82-6.75 (m, 1H), 6.48-6.39 (m, 1H), 5.04 (d, J = 9.7 Hz, 2H),
4.36-4.30 (m, 2H), 3.69-3.62 (m, 1H), 3.56 (s, 1H), 3.50-3.42 (m,
3H), 3.04 (ddd, J = 11.6, 6.9, 2.5 Hz, 1H), 2.49 (d, J = 3.9 Hz,
1H), 2.26-2.21 (m, 2H), 1.42-1.33 (m, 2H), 0.97 (t, J = 7.4 Hz,
2H). 66 2-{(4-fluorobenzyl)[(3- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) hydroxyazetidin-1- .delta. 8.98 (s, 1H),
7.85 (s, 1H), m/e 459 yl)carbonyl]amino}-N-[3- 7.70 (d, J = 1.6 Hz,
1H), 7.57 (s, 1H), (M + H)+ (1H-imidazol-1-yl)propyl]- 7.21 (dd, J
= 8.6, 5.3 Hz, 2H), 1,3-thiazole-5-carboxamide 7.05 (t, J = 8.7 Hz,
2H), 5.28 (s, 2H), 4.49 (ddd, J = 11.2, 5.6, 3.4 Hz, 1H), 4.31 (dd,
J = 14.6, 7.2 Hz, 4H), 3.88 (dd, J = 9.6, 4.4 Hz, 2H), 3.37 (dd, J
= 12.9, 6.5 Hz, 2H), 2.17 (p, J = 6.7 Hz, 2H). 67
N-(4-fluorobenzyl)-N-(5- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) {[3-(1H-imidazol-1- 9.07 (s, 1H), 7.84 (s, 1H), 7.34 (d,
m/e 515 yl)propyl]carbamoyl}-1,3- J = 13.9 Hz, 2H), 7.30-7.24 (m,
(M + H)+ thiazol-2-yl)-1,4-dioxa-7- 2H), 6.99 (t, J = 8.5 Hz, 2H),
azaspiro[4.4]nonane-7- 6.86 (s, 1H), 5.09 (s, 2H), 4.29 (t, J = 6.3
Hz, carboxamide 2H), 3.96 (dd, J = 11.8, 3.4 Hz, 4H), 3.91 (dd, J =
12.4, 5.1 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 3.48-3.52 (m, 2H),
2.24-2.19 (m, 2H), 2.04 (t, J = 7.3 Hz, 2H). 68
2-{(4-fluorobenzyl)[(3- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) methoxypyrrolidin-1- 9.06 (s, 1H), 7.85 (s, 1H), 7.34 (s,
m/e 487 yl)carbonyl]amino}-N-[3- 1H), 7.31 (s, 1H), 7.29-7.24 (m,
(M + H)+ (1H-imidazol-1-yl)propyl]- 2H), 7.16 (s, 1H), 6.98 (t, J =
8.6 Hz, 1,3-thiazole-5-carboxamide 2H), 5.19-5.01 (m, 2H), 4.29 (t,
J = 6.5 Hz, 2H), 3.94 (s, 1H), 3.56 (dt, J = 12.6, 7.3 Hz, 2H),
3.46 (dd, J = 13.5, 7.7 Hz, 4H), 3.27 (s, 3H), 2.23-2.16 (m, 2H),
2.09-2.03 (m, 1H), 1.98-1.81 (m, 1H). 69 2-{(4-fluorobenzyl)[(2-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
methoxyethyl)(methyl)carbamoyl]amino}- 9.10 (s, 1H), 7.82 (s, 1H),
7.34 (d, m/e 475 N-[3-(1H- J = 8.9 Hz, 3H), 7.28 (s, 1H), (M + H)+
imidazol-1-yl)propyl]-1,3- 7.11 (s, 1H), 6.98 (t, J = 8.6 Hz, 2H),
thiazole-5-carboxamide 5.03 (s, 2H), 4.29 (t, J = 6.3 Hz, 2H), 3.49
(s, 4H), 3.43 (d, J = 5.4 Hz, 2H), 3.30 (s, 3H), 2.98 (s, 3H),
2.21-2.16 (m, 2H). 70 N-(4-fluorobenzyl)-N-(5- .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ESI(+)) {[3-(1H-imidazol-1- 9.16-9.05 (m,
1H), 7.81 (s, 1H), m/e 501 yl)propyl]carbamoyl}-1,3- 7.38-7.28 (m,
4H), (M + H)+ thiazol-2-yl)-2,6- 7.03-6.95 (m, 2H), 6.96-6.88 (m,
1H), dimethylmorpholine-4- 5.06 (s, 2H), 4.30 (dd, J = 8.4, 4.0 Hz,
carboxamide 2H), 3.65 (d, J = 12.8 Hz, 2H), 3.45 (dd, J = 6.9, 3.2
Hz, 4H), 2.66 (dd, J = 12.9, 10.8 Hz, 2H), 2.21-2.17 (m, 2H), 1.12
(d, J = 6.2 Hz, 6H). 71 2-{[ethyl(2- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) methoxyethyl)carbamoyl](4- 9.07 (s,
1H), 7.80 (s, 1H), m/e 489 fluorobenzyl)amino}-N-[3- 7.41-7.28 (m,
4H), 6.98 (t, J = 8.6 Hz, (M + H)+ (1H-imidazol-1-yl)propyl]- 3H),
5.04 (s, 2H), 4.29 (d, J = 6.1 Hz, 1,3-thiazole-5-carboxamide 2H),
3.50-3.39 (m, 6H), 3.37 (d, J = 7.0 Hz, 2H), 3.29 (s, 3H),
2.20-2.16 (m, 2H), 1.07 (t, J = 7.0 Hz, 3H). 72
N-(4-fluorobenzyl)-N-(5- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) {[3-(1H-imidazol-1- 9.12-9.04 (m, 1H), 7.80 (s, 1H), m/e
501 yl)propyl]carbamoyl}-1,3- 7.34 (dt, J = 4.2, 3.7 Hz, 3H), (M +
H)+ thiazol-2-yl)-2,2- 7.29 (d, J = 0.4 Hz, 1H),
dimethylmorpholine-4- 7.03-6.95 (m, 2H), 6.86-6.79 (m, 1H),
carboxamide 5.06 (s, 2H), 4.29 (td, J = 6.4, 3.2 Hz, 2H), 3.64 (dd,
J = 5.9, 3.7 Hz, 2H), 3.48-3.41 (m, 2H), 3.39-3.34 (m, 2H), 3.21
(d, J = 3.6 Hz, 2H), 2.23-2.17 (m, 2H), 1.10 (d, J = 4.9 Hz, 6H).
73 N-(4-fluorobenzyl)-N-(5- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) {[3-(1H-imidazol-1- 9.14-9.06 (m, 1H), 7.80 (s,
1H), m/e 487 yl)propyl]carbamoyl}-1,3- 7.38-7.33 (m, 3H), 7.28 (s,
1H), (M + H)+ thiazol-2-yl)-1,4-oxazepane- 7.00 (t, J = 8.6 Hz,
2H), 6.94 (s, 4-carboxamide 1H), 5.02 (s, 2H), 4.30 (dd, J = 7.9,
4.8 Hz, 2H), 3.66-3.62 (m, 2H), 3.62-3.58 (m, 2H), 3.53 (dd, J =
11.0, 5.9 Hz, 4H), 3.48-3.39 (m, 2H), 2.21-2.17 (m, 2H), 1.85 (dd,
J = 10.1, 4.6 Hz, 2H). 78 2-{(4-fluorobenzyl)[(2- .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ESI(+)) propoxyethyl)carbamoyl]amino}-
9.11 (s, 1H), 8.46 (t, J = 5.7 Hz, m/e 489 N-[3-(1H-imidazol-1-
1H), 7.90 (s, 1H), 7.85 (t, J = 5.3 Hz, (M + H)+
yl)propyl]-1,3-thiazole-5- 1H), 7.81 (t, J = 1.4 Hz, 1H),
carboxamide 7.69 (t, J = 1.4 Hz, 1H), 7.23 (dd, J = 8.6, 5.6 Hz,
2H), 7.13 (dd, J = 12.3, 5.4 Hz, 2H), 5.33 (s, 2H), 4.22 (t, J =
6.9 Hz, 2H), 3.40 (t, J = 5.6 Hz, 2H), 3.32 (dd, J = 10.9, 5.4 Hz,
2H), 3.26 (d, J = 6.6 Hz, 2H), 3.21 (dd, J = 12.3, 6.3 Hz, 2H),
2.03 (t, J = 6.8 Hz, 2H), 1.43 (dd, J = 14.1, 7.0 Hz, 2H),
1.33-1.09 (m, 1H), 0.80 (t, J = 7.4 Hz, 3H). 79 2-{(4- .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ESI(+))
fluorobenzyl)[(tetrahydrofuran- 9.12 (s, 1H), 8.46 (t, J = 5.7 Hz,
m/e 487 2- 1H), 7.91 (s, 1H), 7.85 (t, J = 5.5 Hz, (M + H)+
ylmethyl)carbamoyl]amino}- 1H), 7.81 (t, J = 1.5 Hz, 1H),
N-[3-(1H-imidazol-1- 7.70 (t, J = 1.5 Hz, 1H),
yl)propyl]-1,3-thiazole-5- 7.28-7.20 (m, 2H), 7.20-7.10 (m, 2H),
carboxamide 5.37 (q, J = 17.1 Hz, 2H), 4.23 (t, J = 7.0 Hz, 2H),
3.87 (dd, J = 12.2, 5.9 Hz, 1H), 3.28-3.17 (m, 4H), 2.08-2.00 (m,
2H), 1.82-1.65 (m, 3H), 1.42 (ddd, J = 9.1, 8.3, 6.0 Hz, 1H). 80
2-{(4-fluorobenzyl)[(1- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ESI(+)) methoxypropan-2- 9.10 (s, 1H), 8.44 (t, J = 5.7 Hz, m/e
475 yl)carbamoyl]amino}-N-[3- 1H), 7.90 (s, 1H), 7.81 (t, J = 1.5
Hz, (M + H)+ (1H-imidazol-1-yl)propyl]- 1H), 7.69 (t, J = 1.4 Hz,
1H), 1,3-thiazole-5-carboxamide 7.54 (d, J = 7.9 Hz, 1H), 7.31-7.21
(m, 2H), 7.21-7.09 (m, 2H), 5.36 (d, J = 2.5 Hz, 2H), 4.22 (t, J =
7.0 Hz, 2H), 4.00 (dt, J = 18.2, 5.6 Hz, 1H), 3.32 (dd, J = 9.6,
6.6 Hz, 2H), 3.26-3.21 (m, 5H), 2.03 (t, J = 6.8 Hz, 2H), 1.08 (d,
J = 6.8 Hz, 3H). 81 2-{(4- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ESI(+)) fluorobenzyl)[(tetrahydro- 9.11 (s, 1H), 8.45 (t,
J = 5.7 Hz, m/e 501 2H-pyran-2- 1H), 7.91 (s, 1H), 7.87-7.75 (m, (M
+ H)+ ylmethyl)carbamoyl]amino}- 2H), 7.69 (t, J = 1.4 Hz, 1H),
N-[3-(1H-imidazol-1- 7.24 (dd, J = 8.6, 5.6 Hz, 2H),
yl)propyl]-1,3-thiazole-5- 7.20-7.09 (m, 2H), 5.36 (s, 2H),
carboxamide 4.22 (dd, J = 9.0, 5.0 Hz, 2H), 3.82 (dd, J = 11.0, 2.7
Hz, 1H), 3.32-3.24 (m, 2H), 3.23-3.15 (m, 4H), 2.09-1.98 (m, 2H),
1.76-1.66 (m, 1H), 1.46-1.33 (m, 4H), 1.09-0.98 (m, 1H). 82
2-{(4-fluorobenzyl)[(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ESI(+)) methoxyethyl)carbamoyl]amino}- 9.12 (s, 1H), 8.46 (t, J =
5.7 Hz, m/e 461 N-[3-(1H-imidazol- 1H), 7.91 (s, 1H), 7.87 (t, J =
5.1 Hz, (M + H)+ 1-yl)propyl]-1,3-thiazole-5- 1H), 7.82 (t, J = 1.5
Hz, 1H), carboxamide 7.70 (t, J = 1.5 Hz, 1H), 7.30-7.20 (m, 2H),
7.20-7.12 (m, 2H), 5.35 (s, 2H), 4.23 (t, J = 7.0 Hz, 2H), 3.39
(dd, J = 8.4, 3.2 Hz, 2H), 3.34 (dd, J = 9.9, 4.6 Hz, 2H),
3.24-3.18 (m, 5H), 2.04 (t, J = 6.8 Hz, 2H). 83 2-{[(2- .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ESI(+)) ethoxyethyl)carbamoyl](4-
9.11 (s, 1H), 8.46 (t, J = 5.6 Hz, m/e 475
fluorobenzyl)amino}-N-[3- 1H), 7.90 (s, 1H), 7.85 (t, J = 5.3 Hz,
(M + H).sup.+ (1H-imidazol-1-yl)propyl]- 1H), 7.80 (d, J = 1.4 Hz,
1H), 1,3-thiazole-5-carboxamide 7.69 (d, J = 1.4 Hz, 1H), 7.29-7.18
(m, 2H), 7.18-7.09 (m, 2H), 5.34 (s, 2H), 4.22 (t, J = 7.0 Hz, 2H),
3.41-3.38 (m, 2H), 3.37 (d, J = 7.0 Hz, 2H), 3.33 (dd, J = 9.9, 4.7
Hz, 2H), 3.24-3.17 (m, 2H), 2.11-1.94 (m, 2H), 1.05 (t, J = 7.0 Hz,
3H). 84 2-{(4-fluorobenzyl)[(1- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ESI(+)) methoxybutan-2- 9.11 (s, 1H), 8.44 (t, J = 5.8 Hz,
m/e 489 yl)carbamoyl]amino}-N-[3- 1H), 7.90 (s, 1H), 7.81 (d, J =
1.4 Hz, (M + H).sup.+ (1H-imidazol-1-yl)propyl]- 1H), 7.69 (d, J =
1.3 Hz, 1H), 1,3-thiazole-5-carboxamide 7.41 (d, J = 8.2 Hz, 1H),
7.24 (dd, J = 8.6, 5.6 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 5.39 (dd,
J = 39.3, 17.0 Hz, 2H), 4.22 (t, J = 7.0 Hz, 2H), 3.85-3.78 (m,
1H), 3.30 (dt, J = 9.7, 3.7 Hz, 2H), 3.24-3.19 (m, 5H), 2.09-1.98
(m, 2H), 1.52 (ddd, J = 12.5, 7.2, 5.0 Hz, 1H), 1.42-1.32 (m, 1H),
0.73 (t, J = 7.4 Hz, 3H). 86 2-{[(1,3-dioxolan-2- .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ESI(+)) ylmethyl)carbamoyl](4- 9.35-9.24
(m, 1H), m/e 489 fluorobenzyl)amino}-N-[3- 8.88-8.68 (m, 1H),
7.94-7.85 (m, 1H), (M + H)+ (1H-imidazol-1-yl)propyl]- 7.39-7.34
(m, 1H), 7.32-7.27 (m, 1,3-thiazole-5-carboxamide 3H), 7.21-7.08
(m, 1H), 7.01 (t, J = 8.6 Hz, 2H), 5.21-5.09 (m, 2H), 5.06 (t, J =
3.4 Hz, 1H), 4.35-4.25 (m, 2H), 3.99-3.82 (m, 4H), 3.64 (dd, J =
5.1, 3.5 Hz, 2H), 3.44 (dt, J = 10.2, 2.9 Hz, 2H), 2.24-2.19 (m,
2H). 87 2-[(4-fluorobenzyl){[2- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) (propan-2- 9.30 (ddd, J = 3.5, 2.1, 0.8 Hz, m/e
489 yloxy)ethyl]carbamoyl]amino}- 1H), 8.55-8.35 (m, 1H), (M + H)+
N-[3-(1H-imidazol-1- 7.94-7.86 (m, 1H), 7.35 (s, 1H),
yl)propyl]-1,3-thiazole-5- 7.32-7.27 (m, 3H), 7.10-7.04 (m, 1H),
carboxamide 7.03-6.95 (m, 2H), 5.18 (s, 2H), 4.32 (dd, J = 9.5, 3.5
Hz, 2H), 3.62-3.49 (m, 6H), 3.48-3.41 (m, 2H), 2.23-2.20 (m, 2H),
1.13 (t, J = 4.9 Hz, 6H). 88 2-{[(1,4-dioxan-2- .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ESI(+)) ylmethyl)carbamoyl](4- 9.43-9.29
(m, 1H), m/e 503 fluorobenzyl)amino}-N-[3- 8.77-8.63 (m, 1H),
7.98-7.88 (m, 1H), (M + H)+ (1H-imidazol-1-yl)propyl]- 7.35 (s,
1H), 7.31-7.27 (m, 3H), 1,3-thiazole-5-carboxamide 7.22-7.11 (m,
1H), 7.06-6.95 (m, 2H), 5.27-5.06 (m, 2H), 4.33 (ddd, J = 5.9, 4.1,
3.0 Hz, 2H), 3.82-3.73 (m, 3H), 3.73-3.67 (m, 2H), 3.63-3.49 (m,
2H), 3.49-3.39 (m, 2H), 3.39-3.25 (m, 2H), 2.23-2.20 (m, 2H). 89
2-{[(1,3-dimethoxypropan- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) 2-yl)carbamoyl](4- 9.26-9.18 (m, 1H), 8.30 (s, 1H), m/e
505 fluorobenzyl)amino}-N-[3- 7.89 (s, 1H), 7.35 (s, 1H), 7.30 (d,
(M + H)+ (1H-imidazol-1-yl)propyl]- J = 1.8 Hz, 1H), 7.28 (d, J =
3.0 Hz, 1,3-thiazole-5-carboxamide 2H), 7.13-7.04 (m, 1H), 7.02 (t,
J = 8.6 Hz, 2H), 5.19 (s, 2H), 4.31 (t, J = 6.4 Hz, 2H), 4.24-4.13
(m, 1H), 3.55 (dd, J = 9.5, 4.5 Hz, 2H), 3.44 (dd, J = 9.6, 5.6 Hz,
4H), 3.34 (s, 6H), 2.27-2.15 (m, 2H). 90 2-{(4-fluorobenzyl)[(2-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
methoxybutyl)carbamoyl]amino}- 9.22 (s, 1H), 8.47-8.29 (m, 1H), m/e
489 N-[3-(1H-imidazol- 7.88 (s, 1H), 7.35 (s, 1H), 7.30 (s, (M +
H)+ 1-yl)propyl]-1,3-thiazole-5- 1H), 7.29-7.26 (m, 2H),
carboxamide 7.14-7.05 (m, 1H), 7.02 (t, J = 8.6 Hz, 2H), 5.19 (q, J
= 16.6 Hz, 2H), 4.31 (t, J = 6.5 Hz, 2H), 3.68-3.59 (m, 1H),
3.48-3.40 (m, 2H), 3.32 (s, 3H), 3.30-3.23 (m, 2H), 2.27-2.15 (m,
2H), 1.66-1.53 (m, 1H), 1.47 (dt, J = 13.6, 6.9 Hz, 1H), 0.93 (dd,
J = 9.4, 5.6 Hz, 3H). 91 2-[(4- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) fluorobenzyl)(tetrahydrofuran- 9.47-9.31 (m, 2H),
m/e 473 3-ylcarbamoyl)amino]-N- 7.94-7.85 (m, 1H), 7.35 (s, 1H),
7.29 (d, J = 8.7 Hz, (M + H)+ [3-(1H-imidazol-1- 3H), 7.25-7.18 (m,
1H), yl)propyl]-1,3-thiazole-5- 7.08-6.95 (m, 2H), 5.12 (s, 2H),
carboxamide 4.59-4.50 (m, 1H), 4.33 (td, J = 5.4, 1.1 Hz, 2H),
4.00-3.90 (m, 2H), 3.86 (td, J = 8.6, 5.5 Hz, 1H), 3.78 (dd, J =
9.4, 2.8 Hz, 1H), 3.44 (dt, J = 8.9, 3.6 Hz, 2H), 2.35-2.28 (m,
1H), 2.26-2.20 (m, 2H), 1.96-1.87 (m, 1H). 92 2-[(4- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ESI(+)) fluorobenzyl)(tetrahydro-
9.22 (s, 1H), 9.01-8.81 (m, 1H), m/e 487 2H-pyran-3- 7.88 (s, 1H),
7.35 (s, 1H), 7.29 (t, (M + H)+ ylcarbamoyl)amino]-N-[3- J = 6.9
Hz, 3H), 7.07 (dd, J = 8.5, (1H-imidazol-1-yl)propyl]- 3.5 Hz, 1H),
7.02 (t, J = 8.6 Hz, 1,3-thiazole-5-carboxamide 2H), 5.26 (d, J =
16.7 Hz, 1H), 5.08 (d, J = 16.6 Hz, 1H), 4.31 (t, J = 6.4 Hz, 2H),
3.99 (ddd, J = 8.8, 3.5, 1.6 Hz, 1H), 3.83-3.78 (m, 1H), 3.64
(dddd, J = 22.5, 16.6, 7.9, 3.3 Hz, 3H), 3.44 (dd, J = 11.4, 5.9
Hz, 2H), 2.29-2.14 (m, 2H), 1.91 (ddd, J = 8.1, 6.4, 2.7 Hz, 1H),
1.79-1.68 (m, 1H), 1.68-1.53 (m, 2H). 123 2-[(4-cyanobenzyl){[2-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+)) (propan-2-
9.22-9.13 (m, 1H), m/e 496 yloxy)ethyl]carbamoyl]amino}- 8.93-8.79
(m, 1H), 7.82 (s, 1H), 7.63 (d, J = 8.1 Hz, (M + H)+
N-[3-(1H-imidazol-1- 2H), 7.45-7.32 (m, 3H),
yl)propyl]-1,3-thiazole-5- 7.29 (s, 1H), 7.07-6.96 (m, 1H),
carboxamide 5.25 (s, 2H), 4.30 (t, J = 6.4 Hz, 2H), 3.65-3.54 (m,
5H), 3.46-3.40 (m, 2H), 2.23 (dd, J = 7.3, 3.9 Hz, 2H), 1.15 (d, J
= 6.1 Hz, 6H). 124 2-{(4-cyanobenzyl)[(2- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) methoxypropyl)carbamoyl]amino}-
9.33-9.20 (m, 1H), m/e 482 N-[3-(1H-imidazol- 8.83-8.73 (m, 1H),
7.90-7.81 (m, 1H), (M + H)+ 1-yl)propyl]-1,3-thiazole-5- 7.63 (d, J
= 8.2 Hz, 2H), 7.39 (dd, J = 15.0, carboxamide 7.1 Hz, 3H), 7.28
(s, 1H), 7.12-6.99 (m, 1H), 5.33-5.14 (m, 2H), 4.37-4.25 (m, 2H),
4.21-4.11 (m, 1H), 3.48-3.39 (m, 4H), 3.36 (s, 3H), 2.26-2.20 (m,
2H), 1.29-1.23 (m, 3H). 125 2-[(4-cyanobenzyl){[2-(2- .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. (ESI(+))
hydroxyethoxy)ethyl]carbamoyl]amino}- 9.39-9.27 (m, 1H), m/e 498
N-[3-(1H- 9.26-9.16 (m, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.2 Hz, (M
+ H)+ imidazol-1-yl)propyl]-1,3- 2H), 7.41-7.34 (m, 3H),
thiazole-5-carboxamide 7.28 (s, 1H), 7.15-7.05 (m, 1H), 5.22 (s,
2H), 4.55-4.5 (m, 2H), 4.36-4.29 (m, 2H), 3.85-3.75 (m, 2H), 3.67
(d, J = 4.7 Hz, 3H), 3.65-3.60 (m, 2H), 3.46-3.40 (m, 2H),
2.25-2.19 (m, 2H). 126 2-[(4-cyanobenzyl){[3- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) (propan-2- 9.26-9.14 (m, 1H), 8.61 (s,
1H), m/e 510 yloxy)propyl]carbamoyl]amino}- 7.81 (s, 1H), 7.62 (d,
J = 8.2 Hz, (M + H)+ N-[3-(1H-imidazol-1- 2H), 7.38 (d, J = 8.2 Hz,
3H), yl)propyl]-1,3-thiazole-5- 7.29 (s, 1H), 6.96 (s, 1H), 5.24
(s, carboxamide 2H), 4.35-4.30 (m, 2H), 3.53 (dt, J = 16.3, 5.8 Hz,
5H), 3.45-3.40 (m, 2H), 2.26-2.20 (m, 2H), 1.88-1.82 (m, 2H), 1.12
(d, J = 6.1 Hz, 6H). 127 2-{(4-cyanobenzyl)[(3- .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ESI(+)) hydroxy-2,2- 9.67 (s, 1H), 9.34
(s, 1H), 7.87 (s, m/e 496 dimethylpropyl)carbamoyl]amino}- 1H),
7.63 (d, J = 8.2 Hz, 2H), (M + H)+ N-[3-(1H-imidazol- 7.45-7.34 (m,
3H), 1-yl)propyl]-1,3-thiazole-5- 7.25-7.18 (m, 1H), 5.20 (s, 2H),
4.32 (t, J = 6.1 Hz, carboxamide 2H), 4.18-4.12 (m, 2H), 3.42 (d, J
= 4.4 Hz, 2H), 3.38 (d, J = 6.1 Hz, 2H), 2.25-2.20 (m, 2H), 1.06
(s, 6H). 128 2-{(4-cyanobenzyl)[(2- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) hydroxypropyl)carbamoyl]amino}- 9.85
(s, 1H), 9.32 (s, 1H), m/e 468 N-[3-(1H-imidazol- 7.85-7.74 (m,
1H), 7.63 (d, J = 8.2 Hz, (M + H)+ 1-yl)propyl]-1,3-thiazole-5-
2H), 7.42-7.35 (m, 3H), 7.24 (s, carboxamide 1H), 5.39-5.29 (m,
1H), 5.28-5.10 (m, 2H), 4.40-4.25 (m, 2H), 3.93-3.81 (m, 1H),
3.53-3.46 (m, 1H), 3.46-3.36 (m, 2H), 2.27-2.21 (m, 2H), 1.43 (d, J
= 6.4 Hz, 3H). 129 2-{(4-cyanobenzyl)[(1- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) hydroxypropan-2- 9.74-9.65 (m, 1H),
m/e 468 yl)carbamoyl]amino}-N-[3- 9.38-9.18 (m, 1H), 7.80 (d, J =
4.4 Hz, 1H), (M + H)+ (1H-imidazol-1-yl)propyl]- 7.63 (d, J = 8.3
Hz, 2H), 1,3-thiazole-5-carboxamide 7.42-7.35 (m, 3H), 7.23-7.08
(m, 1H), 5.20 (dt, J = 21.5, 9.8 Hz, 2H), 4.63-4.52 (m, 1H),
4.47-4.40 (m, 1H), 4.40-4.34 (m, 1H), 4.34-4.27 (m, 2H), 3.48-3.38
(m, 2H), 2.26-2.21 (m, 4H), 1.37 (d, J = 6.7 Hz, 3H). 130
2-{(4-cyanobenzyl)[(3- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) hydroxypropyl)carbamoyl]amino}- 9.58 (d, J = 4.9 Hz, 1H),
9.41 (d, J = 6.0 Hz, m/e 468 N-[3-(1H-imidazol- 1H), 7.90 (s, 1H),
(M + H)+ 1-yl)propyl]-1,3-thiazole-5- 7.63 (d, J = 8.2 Hz, 2H),
7.39 (d, J = 8.3 Hz, carboxamide 2H), 7.35 (s, 1H), 7.24 (s, 1H),
5.19 (s, 2H), 4.47 (t, J = 6.1 Hz, 2H), 4.33 (dd, J = 7.1, 5.8 Hz,
2H), 3.54 (d, J = 5.9 Hz, 2H), 3.42 (d, J = 2.0 Hz, 2H), 2.27-2.21
(m, 2H), 2.13-2.08 (m, 2H). 131 2-[(4-cyanobenzyl){[(2S)-1- .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+)) hydroxybut-3-en-2- 10.02
(s, 1H), 9.31 (s, 1H), m/e 480 yl]carbamoyl}amino]-N-[3- 7.84 (s,
1H), 7.63 (d, J = 8.2 Hz, 2H), (M + H)+ (1H-imidazol-1-yl)propyl]-
7.45-7.34 (m, 3H), 7.23 (s, 1H), 1,3-thiazole-5-carboxamide
6.01-5.84 (m, 1H), 5.38 (t, J = 14.8 Hz, 2H), 5.20 (dd, J = 39.0,
17.5 Hz, 2H), 4.98-4.90 (m, 1H), 4.61 (dd, J = 11.2, 4.3 Hz, 1H),
4.50 (dd, J = 11.1, 5.0 Hz, 1H), 4.31 (t, J = 6.4 Hz, 2H), 3.42 (d,
J = 5.8 Hz, 2H), 2.26-2.21 (m, 2H). 132 2-{(4-cyanobenzyl)[(4-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
hydroxybutyl)carbamoyl]amino}- 9.53 (s, 1H), 9.30 (s, 1H), 7.85 (s,
m/e 482 N-[3-(1H-imidazol-1- 1H), 7.62 (d, J = 8.2 Hz, 2H), (M +
H)+ yl)propyl]-1,3-thiazole-5- 7.39 (d, J = 8.2 Hz, 2H), 7.35 (s,
carboxamide 1H), 5.20 (s, 2H), 4.41 (t, J = 6.4 Hz, 2H), 4.32 (t, J
= 6.3 Hz, 2H), 3.54-3.45 (m, 2H), 3.45-3.36 (m, 2H), 2.26-2.21 (m,
3H), 1.85 (dd, J = 15.1, 6.7 Hz, 2H), 1.75 (dd, J = 14.9, 6.5 Hz,
2H). 140 2-{[(3-amino-3- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) oxopropyl)carbamoyl](4- .delta. 8.97 (s, 1H), 7.79 (s,
1H), m/e 481 cyanobenzyl)amino}-N-[3- 7.73 (d, J = 8.2 Hz, 2H),
7.69 (s, 1H), (M + H)+ (1H-imidazol-1-yl)propyl]- 7.57 (s, 1H),
7.51 (d, J = 8.2 Hz, 1,3-thiazole-5-carboxamide 2H), 5.35 (s, 2H),
4.30 (t, J = 6.8 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.35 (t, J =
6.4 Hz, 2H), 2.41 (dd, J = 16.2, 9.2 Hz, 2H), 2.15 (p, J = 6.6 Hz,
2H). 141 2-[{[3-(acetylamino)-2- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) methylpropyl]carbamoyl}(4- .delta. 8.96
(s, 1H), 7.76 (d, J = 9.6 Hz, m/e 523 cyanobenzyl)amino]-N-[3- 2H),
7.73 (s, 1H), 7.69 (s, 1H), (M + H)+ (1H-imidazol-1-yl)propyl]-
7.57 (s, 1H), 7.52 (d, J = 8.1 Hz, 1,3-thiazole-5-carboxamide 2H),
5.36 (s, 2H), 4.30 (t, J = 6.8 Hz, 2H), 3.35 (t, J = 6.4 Hz, 2H),
3.10 (d, J = 6.4 Hz, 4H), 2.14 (p, J = 6.5 Hz, 2H), 1.95 (s, 3H),
1.85 (dd, J = 12.9, 6.4 Hz, 1H), 0.92 (d, J = 6.8 Hz, 3H). 142
2-[(4-cyanobenzyl){[3- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) (dimethylamino)-3- .delta. 8.97 (s, 1H), 7.78 (s, 1H), m/e
509 oxopropyl]carbamoyl}amino]- 7.73 (d, J = 8.3 Hz, 2H), 7.70 (s,
1H), (M + H)+ N-[3-(1H-imidazol-1- 7.57 (s, 1H), 7.49 (d, J = 8.0
Hz, yl)propyl]-1,3-thiazole-5- 2H), 5.34 (s, 2H), 4.30 (t, J = 6.8
Hz, carboxamide 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.35 (t, J = 6.4 Hz,
2H), 3.03 (s, 3H), 2.92 (s, 3H), 2.64 (d, J = 14.3 Hz, 2H),
2.22-2.07 (m, 2H) 143 2-{(4-cyanobenzyl)[(3- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) ethoxy-2- .delta. 8.96 (s, 1H), 7.78 (s,
1H), m/e 512 hydroxypropyl)carbamoyl]amino}- 7.73 (t, J = 7.2 Hz,
2H), 7.69 (s, 1H), (M + H)+ N-[3-(1H-imidazol- 7.57 (s, 1H), 7.51
(d, J = 8.1 Hz, 1-yl)propyl]-1,3-thiazole-5- 2H), 5.36 (s, 2H),
4.30 (t, J = 6.8 Hz, carboxamide 2H), 3.82 (t, J = 4.8 Hz, 1H),
3.52 (q, J = 7.1 Hz, 2H), 3.48-3.38 (m, 2H), 3.35 (d, J = 6.6 Hz,
2H), 3.22 (dd, J = 13.7, 7.0 Hz, 2H), 2.15 (t, J = 6.6 Hz, 2H),
1.18 (t, J = 7.1 Hz, 3H). 144 2-[(4-cyanobenzyl){[3- .sup.1H NMR
(400 MHz, methanol-d.sub.4) (ESI(+))
(diethylamino)propyl]carbamoyl}amino]- .delta. 8.97 (s, 1H), 7.85
(s, 1H), m/e 523 N-[3-(1H- 7.73 (d, J = 8.2 Hz, 2H), 7.70 (s, 1H),
(M + H)+ imidazol-1-yl)propyl]-1,3- 7.57 (s, 1H), 7.50 (d, J = 8.2
Hz, thiazole-5-carboxamide 2H), 5.36 (s, 2H), 4.31 (t, J = 6.9 Hz,
2H), 3.35 (dd, J = 11.6, 5.0 Hz, 4H), 3.23 (q, J = 7.3 Hz, 4H),
3.18-3.11 (m, 2H), 2.15 (p, J = 6.8 Hz, 2H), 2.03-1.85 (m, 2H),
1.31 (t, J = 7.3 Hz, 6H). 145 2-[{[2- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+))
(acetylamino)ethyl]carbamoyl}(4- .delta. 8.97 (s, 1H), 7.79 (s,
1H), m/e 495 cyanobenzyl)amino]- 7.74 (d, J = 8.2 Hz, 2H), 7.69 (s,
1H), (M + H)+ N-[3-(1H-imidazol-1- 7.57 (s, 1H), 7.51 (d, J = 8.1
Hz, yl)propyl]-1,3-thiazole-5- 2H), 5.35 (s, 2H), 4.30 (t, J = 6.8
Hz, carboxamide 2H), 3.35 (t, J = 6.5 Hz, 2H), 2.22-2.07 (m, 2H),
1.93 (s, 3H). 146 2-[(4-cyanobenzyl){[2- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (diethylamino)ethyl]carbamoyl}amino]-
.delta. 8.97 (s, 1H), 7.87 (s, 1H), m/e 509 N-[3-(1H- 7.74 (d, J =
8.2 Hz, 2H), 7.70 (s, 1H), (M + H)+ imidazol-1-yl)propyl]-1,3- 7.58
(s, 1H), 7.49 (d, J = 8.2 Hz, thiazole-5-carboxamide 2H), 5.37 (s,
2H), 4.31 (t, J = 6.9 Hz, 2H), 3.56 (t, J = 5.9 Hz, 2H), 3.35 (t, J
= 6.5 Hz, 2H), 3.27 (dd, J = 7.3, 2.8 Hz, 4H), 2.15 (t, J = 6.7 Hz,
2H), 1.33 (t, J = 7.3 Hz, 6H). 147 2-[(4-cyanobenzyl)({2-[(2-
.sup.1H NMR (400 MHz, methanol-d.sub.4) (ESI(+))
methylpropanoyl)amino]ethyl}carbamoyl)amino]- .delta. 8.96 (s, 1H),
7.78 (s, 1H), m/e 523 N-[3- 7.73 (d, J = 8.2 Hz, 2H), 7.69 (s, 1H),
(M + H)+ (1H-imidazol-1-yl)propyl]- 7.57 (s, 1H), 7.50 (d, J = 8.2
Hz, 1,3-thiazole-5-carboxamide 2H), 5.34 (s, 2H), 4.29 (t, J = 6.8
Hz, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.39 (dt, J = 13.9, 7.0 Hz, 1H),
2.14 (p, J = 6.6 Hz, 2H), 1.07 (d, J = 6.9 Hz, 6H). 148
2-[(4-cyanobenzyl){[(2R)-1- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) hydroxybut-3-en-2- .delta. 8.96 (s, 1H), 7.78 (s, 1H), m/e
480 yl]carbamoyl}amino]-N-[3- 7.74 (d, J = 8.2 Hz, 2H), 7.69 (s,
1H), (M + H)+ (1H-imidazol-1-yl)propyl]- 7.57 (s, 1H), 7.52 (d, J =
8.1 Hz, 1,3-thiazole-5-carboxamide 2H), 5.97-5.81 (m, 1H),
5.47-5.31 (m, 2H), 5.24 (d, J = 17.0 Hz, 1H), 5.16 (d, J = 10.6 Hz,
1H), 4.39-4.33 (m, 1H), 4.30 (t, J = 6.8 Hz, 2H), 3.64-3.50 (m,
2H), 3.35 (t, J = 6.4 Hz, 2H), 2.14 (p, J = 6.8 Hz, 2H). 149
2-[(4-cyanobenzyl){[3-(3- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) hydroxyazetidin-1- .delta. 8.97 (s, 1H), 7.84 (s, 1H), m/e
523 yl)propyl]carbamoyl}amino]- 7.74 (d, J = 8.2 Hz, 2H), 7.69 (d,
J = 1.5 Hz, (M + H)+ N-[3-(1H-imidazol-1- 1H), 7.58 (t, J = 1.6 Hz,
yl)propyl]-1,3-thiazole-5- 1H), 7.50 (d, J = 8.0 Hz, 2H),
carboxamide 5.36 (s, 2H), 4.68-4.58 (m, 1H), 4.47 (dd, J = 10.2,
8.2 Hz, 1H), 4.30 (t, J = 6.9 Hz, 2H), 4.26-4.14 (m, 1H), 4.06 (d,
J = 8.9 Hz, 1H), 3.87-3.79 (m, 1H), 3.35 (t, J = 6.5 Hz, 2H), 3.27
(t, J = 6.7 Hz, 3H), 3.23-3.16 (m, 1H), 2.15 (p, J = 6.7 Hz, 2H),
1.80 (dt, J = 13.9, 7.1 Hz, 2H). 159 ethyl N-[(4-cyanobenzyl)(5-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
{[3-(1H-imidazol-1- 9.15 (s, 1H), 8.04-7.96 (m, 1H), m/e 510
yl)propyl]carbamoyl}-1,3- 7.96-7.84 (m, 1H), 7.64 (d, J = 8.2 Hz,
(M + H)+ thiazol-2-yl)carbamoyl]- 2H), 7.37 (d, J = 8.1 Hz,
beta-alaninate 2H), 7.31 (s, 1H), 5.50-5.36 (m, 2H), 4.33 (t, J =
6.2 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.57 (t, J = 6.2 Hz, 2H),
3.41 (td, J = 5.6, 1.0 Hz, 2H), 2.61-2.51 (m, 2H), 2.21 (qd, J =
6.8, 3.4 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H). 160 ethyl 4-{[(4-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
cyanobenzyl)(5-{[3-(1H- 9.39 (s, 1H), 8.00 (d, J = 46.6 Hz, m/e 524
imidazol-1- 1H), 7.71-7.60 (m, 2H), (M + H)+
yl)propyl]carbamoyl}-1,3- 7.44-7.34 (m, 3H), 7.28 (d, J = 1.5 Hz,
thiazol-2- 1H), 5.50-5.42 (m, 1H), yl)carbamoyl]amino}butanoate
4.41-4.31 (m, 2H), 4.18-4.05 (m, 2H), 3.46-3.37 (m, 2H), 3.38-3.26
(m, 2H), 2.39-2.34 (m, 3H), 2.24-2.20 (m, 3H), 1.96-1.82 (m, 2H),
1.33-1.18 (m, 3H). 161 ethyl 3-{[(4- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) cyanobenzyl)(5-{[3-(1H- 9.15 (s, 1H),
8.09-8.00 (m, 1H), m/e 524 imidazol-1- 7.65 (d, J = 8.2 Hz, 2H),
7.39 (dd, (M + H)+ yl)propyl]carbamoyl}-1,3- J = 11.3, 4.8 Hz, 3H),
7.33 (s, thiazol-2- 1H), 5.54-5.47 (m, 2H),
yl)carbamoyl]amino}butanoate 4.40-4.23 (m, 3H), 4.12 (q, J = 7.1
Hz, 2H), 3.42 (dd, J = 10.1, 5.1 Hz, 2H), 2.65-2.43 (m, 2H),
2.28-2.18 (m, 2H), 1.29-1.18 (m, 6H). 162 ethyl 3-{[(4- .sup.1H NMR
NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+)) cyanobenzyl)(5-{[3-(1H-
9.13 (s, 1H), 8.10 (dd, J = 6.0, 1.4 Hz, m/e 552 imidazol-1- 1H),
8.05 (s, 1H), 7.65 (d, J = 8.2 Hz, (M + H)+
yl)propyl]carbamoyl}-1,3- 2H), 7.39 (d, J = 8.6 Hz, thiazol-2- 3H),
7.33 (d, J = 7.9 Hz, 1H), yl)carbamoyl]amino}-4- 7.04-6.94 (m, 1H),
5.48 (d, J = 24.0 Hz, methylpentanoate 2H), 5.35-5.26 (m, 1H), 4.33
(t, J = 6.3 Hz, 2H), 4.16-3.94 (m, 3H), 3.46-3.34 (m, 2H),
2.64-2.41 (m, 2H), 2.26-2.15 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H),
0.93 (d, J = 6.5 Hz, 6H). 163 ethyl 3-{[(4- .sup.1H NMR NMR (400
MHz, CDCl.sub.3) .delta. (ESI(+)) cyanobenzyl)(5-{[3-(1H- 9.21-9.08
(m, 1H), m/e 538 imidazol-1- 8.06-7.96 (m, 1H), 7.91 (dd, J = 5.9,
1.8 Hz, (M + H)+ yl)propyl]carbamoyl}-1,3- 1H), 7.65 (d, J = 8.1
Hz, 2H), thiazol-2- 7.38 (d, J = 8.2 Hz, 3H), 7.31 (s,
yl)carbamoyl]amino}-2,2- 1H), 6.90-6.64 (m, 1H), 5.44 (d,
dimethylpropanoate J = 20.7 Hz, 2H), 4.33 (t, J = 6.1 Hz, 2H),
4.18-4.08 (m, 2H), 3.49-3.37 (m, 4H), 2.24-2.13 (m, 2H), 1.31-1.17
(m, 9H). 164 3-{[(4-cyanobenzyl)(5-{[3- .sup.1H NMR NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (1H-imidazol-1- .delta. 8.97 (s, 1H),
7.80 (s, 1H), m/e 508 yl)propyl]carbamoyl}-1,3- 7.74 (d, J = 8.0
Hz, 2H), 7.69 (s, 1H), (M + H)+ thiazol-2- 7.57 (s, 1H), 7.52 (d, J
= 7.9 Hz, yl)carbamoyl]amino}cyclobutanecarboxylic 2H), 5.37 (d, J
= 9.8 Hz, 2H), acid 4.30 (t, J = 6.8 Hz, 2H), 4.26-4.11 (m, 1H),
3.34 (d, J = 3.4 Hz, 2H), 2.80 (d, J = 8.4 Hz, 1H), 2.55 (d, J =
8.1 Hz, 2H), 2.25-2.04 (m, 4H). 165 ethyl 3-{[(4- .sup.1H NMR NMR
(400 MHz, CDCl.sub.3) .delta. (ESI(+)) cyanobenzyl)(5-{[3-(1H- 9.26
(s, 1H), 7.94 (s, 1H), m/e 524 imidazol-1- 7.78 (ddd, J = 3.7, 2.7,
2.0 Hz, 1H), (M + H)+ yl)propyl]carbamoyl}-1,3- 7.64 (d, J = 8.1
Hz, 2H), 7.38 (d, J = 7.2 Hz, thiazol-2- 3H), 7.29 (s, 1H),
yl)carbamoyl]amino}-2- 6.52 (d, J = 1.6 Hz, 1H), 5.37 (s, 2H),
methylpropanoate 4.34 (t, J = 6.2 Hz, 2H), 4.21-4.07 (m, 2H),
3.46-3.33 (m, 4H), 2.75-2.68 (m, 1H), 2.24-2.15 (m, 2H), 1.33-1.12
(m, 6H). 166 2-{(4-cyanobenzyl)[(3- .sup.1H NMR NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) methoxypropyl)carbamoyl]amino}- 8.96
(s, 1H), 7.75 (d, J = 5.6 Hz, m/e 482 N-[3-(1H-imidazol- 2H), 7.73
(s, 1H), 7.69 (s, 1H), (M + H)+ 1-yl)propyl]-1,3-thiazole-5- 7.57
(s, 1H), 7.51 (d, J = 8.2 Hz, carboxamide 2H), 5.35 (s, 2H),
4.33-4.24 (m, 2H), 3.44 (t, J = 6.3 Hz, 2H), 3.39-3.34 (m, 3H),
3.28-3.23 (m, 2H), 2.20-2.08 (m, 2H), 1.84-1.72 (m, 2H). 167
3-{[(4-cyanobenzyl)(5-{[3- .sup.1H NMR NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (1H-imidazol-1- .delta. 8.97 (s, 1H),
7.75 (d, J = 6.1 Hz, m/e 496 yl)propyl]carbamoyl}-1,3- 2H), 7.72
(s, 1H), 7.69 (s, 1H), (M + H)+ thiazol-2- 7.57 (s, 1H), 7.51 (d, J
= 8.2 Hz, yl)carbamoyl]amino}butanoic 2H), 5.35 (s, 2H), 4.30 (t, J
= 6.8 Hz, acid 3H), 4.25-4.12 (m, 1H), 3.39-3.33 (m, 2H), 2.59 (dd,
J = 15.3, 6.2 Hz, 1H), 2.42 (dd, J = 15.3, 7.0 Hz, 1H), 2.20-2.09
(m, 2H), 1.23 (d, J = 6.7 Hz, 3H). 168 3-{[(4-cyanobenzyl)(5-{[3-
.sup.1H NMR NMR (400 MHz, methanol-d.sub.4) (ESI(+))
(1H-imidazol-1- .delta. 8.96 (s, 1H), 7.73 (d, J = 8.3 Hz, m/e 524
yl)propyl]carbamoyl}-1,3- 3H), 7.69 (s, 1H), 7.57 (s, 1H), (M + H)+
thiazol-2- 7.52 (d, J = 8.2 Hz, 2H), 5.37 (dt,
yl)carbamoyl]amino}-4- J = 26.9, 11.8 Hz, 2H), methylpentanoic acid
4.36-4.24 (m, 2H), 4.08-3.93 (m, 1H), 3.35 (d, J = 6.6 Hz, 2H),
2.54 (dd, J = 15.4, 5.1 Hz, 1H), 2.49-2.38 (m, 1H), 2.22-2.07 (m,
2H), 1.91-1.79 (m, 1H), 0.94 (dd, J = 6.7, 2.6 Hz, 6H). 169
3-{[(4-cyanobenzyl)(5-{[3- .sup.1H NMR NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (1H-imidazol-1- .delta. 8.96 (s, 1H),
7.80-7.71 (m, m/e 510 yl)propyl]carbamoyl}-1,3- 3H), 7.69 (s, 1H),
7.57 (s, 1H), (M + H)+ thiazol-2- 7.51 (d, J = 8.2 Hz, 2H), 5.37
(s, yl)carbamoyl]amino}-2,2- 2H), 4.29 (t, J = 6.8 Hz, 2H),
dimethylpropanoic acid 3.43-3.32 (m, 4H), 2.22-2.07 (m, 2H), 1.18
(s, 6H). 170 3-{[(4-cyanobenzyl)(5-{[3- .sup.1H NMR NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (1H-imidazol-1- .delta. 8.96 (s, 1H),
7.81-7.71 (m, m/e 496 yl)propyl]carbamoyl}-1,3- 3H), 7.69 (s, 1H),
7.57 (s, 1H), (M + H)+ thiazol-2- 7.51 (d, J = 8.1 Hz, 2H), 5.35
(s, yl)carbamoyl]amino}-2- 2H), 4.30 (t, J = 6.8 Hz, 2H),
methylpropanoic acid 3.50-3.33 (m, 4H), 2.75-2.61 (m, 1H), 2.15
(dd, J = 12.9, 6.4 Hz, 2H), 1.17 (d, J = 7.2 Hz, 3H) 171
N-[(4-cyanobenzyl)(5-{[3- .sup.1H NMR NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (1H-imidazol-1- .delta. 8.97 (s, 1H),
7.77 (s, 1H), m/e 482 yl)propyl]carbamoyl}-1,3- 7.73 (d, J = 8.2
Hz, 2H), 7.70 (s, 1H), (M + H)+ thiazol-2-yl)carbamoyl]- 7.57 (s,
1H), 7.51 (d, J = 8.2 Hz, beta-alanine 2H), 5.35 (s, 2H), 4.30 (t,
J = 6.8 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H), 3.39-3.33 (m, 2H), 2.54
(t, J = 6.8 Hz, 2H), 2.22-2.08 (m, 2H). 172
4-{[(4-cyanobenzyl)(5-{[3- .sup.1H NMR NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (1H-imidazol-1- .delta. 8.97 (s, 1H),
7.77 (s, 1H), m/e 496 yl)propyl]carbamoyl}-1,3- 7.74 (d, J = 8.2
Hz, 2H), 7.70 (s, 1H), (M + H)+ thiazol-2- 7.57 (s, 1H), 7.52 (d, J
= 8.1 Hz, yl)carbamoyl]amino}butanoic 2H), 5.35 (s, 2H), 4.30 (t, J
= 6.8 Hz, acid 2H), 3.39-3.33 (m, 2H), 3.24 (t, J = 6.9 Hz, 2H),
2.34 (t, J = 7.5 Hz, 2H), 2.14 (dd, J = 8.4, 4.9 Hz, 2H), 1.81 (dd,
J = 8.4, 5.9 Hz, 2H).
Example 9
2-{(4-fluorobenzyl)
[2-(pyrrolidin-1-yl)ethyl]amino}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiaz-
ole-5-carboxamide
[1202] Example 6B (0.018 g, 0.05 mmol) was dissolved in
acetonitrile (0.5 ml), and treated with potassium carbonate (0.021
g, 0.15 mmol) and 1-(2-chloroethyl)pyrrolidine (0.017 g, 0.1 mmol).
The reaction mixture was heated via microwave at 180.degree. C. for
30 minutes, concentrated in vacuo, and submitted to reverse-phase
HPLC (as described in Example 6C) to provide the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.78 (s, 1H), 9.07 (s,
1H), 7.94 (s, 1H), 7.33 (dd, J=8.7, 5.1 Hz, 3H), 7.11 (s, 1H), 7.04
(t, J=8.6 Hz, 2H), 4.48-4.38 (m, 4H), 4.30 (t, J=5.8 Hz, 2H), 3.41
(dd, J=11.1, 5.5 Hz, 2H), 2.88 (d, J=5.4 Hz, 2H), 2.65-2.55 (m,
4H), 2.20-2.19 (m, 3H), 1.78 (t, J=3.2 Hz, 5H); MS (ESI(+)) m/e
456.6 (M+H)+.
[1203] The following examples were prepared as described in Example
6B followed by Example 9, substituting the appropriate amine in
Example 6B and the appropriate alkyl halide in Example 9. Title
compounds were purified by either flash chromatography (silica gel
column eluting with a gradient of 0-10% methanol in
dichloromethane) or reverse-phase HPLC (as in Example 6C).
Accordingly, some examples were isolated as trifluoroacetic acid
salts.
TABLE-US-00004 MS EX NAME .sup.1H NMR DATA DATA 7
2-{(4-fluorobenzyl)[3- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) (morpholin-4- 10.52 (s, 1H), 8.75 (d, J = 5.5 Hz, m/e 487
yl)propyl]amino}-N-[3-(1H- 1H), 7.85 (s, 1H), 7.33 (dd, J = 8.5, (M
+ H).sup.+ imidazol-1-yl)propyl]-1,3- 5.3 Hz, 2H), 7.20 (s, 1H),
thiazole-5-carboxamide 7.10 (s, 1H), 7.04 (t, J = 8.6 Hz, 2H),
4.47-4.37 (m, 4H), 4.25 (t, J = 7.0 Hz, 2H), 3.74-3.66 (m, 5H),
3.42 (dd, J = 11.2, 5.6 Hz, 2H), 2.44-2.36 (m, 4H), 2.34 (t, J =
6.6 Hz, 2H), 2.22 (dd, J = 11.3, 5.7 Hz, 2H), 2.02-1.91 (m, 2H). 8
2-{(4-fluorobenzyl)[3- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) (piperidin-1- 10.69 (s, 1H), 8.90 (s, 1H), m/e 485
yl)propyl]amino}-N-[3-(1H- 7.90 (s, 1H), 7.33 (dd, J = 8.5, 5.3 Hz,
(M + H).sup.+ imidazol-1-yl)propyl]-1,3- 2H), 7.21 (s, 1H), 7.15
(s, 1H), thiazole-5-carboxamide 7.04 (t, J = 8.6 Hz, 2H), 4.42 (d,
J = 10.4 Hz, 4H), 4.26 (t, J = 7.0 Hz, 2H), 3.42 (dd, J = 11.1, 5.6
Hz, 2H), 2.44 (d, J = 27.4 Hz, 4H), 2.26-2.18 (m, 2H), 2.02-1.93
(m, 4H), 1.64-1.61 (m, 4H), 1.46-1.5 (m, 2H). 10
2-[(4-fluorobenzyl){2-[4- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) (propan-2-yl)piperazin-1- 7.56 (s, 1H), 7.48 (s, 1H), m/e
514 yl]ethyl}amino]-N-[3-(1H- 7.32 (dd, J = 8.5, 5.5 Hz, 2H), 7.07
(s, (M + H)+ imidazol-1-yl)propyl]-1,3- 1H), 7.01 (t, J = 8.7 Hz,
2H), thiazole-5-carboxamide 6.97 (s, 1H), 4.24 (s, 2H), 4.04 (t, J
= 6.9 Hz, 2H), 3.93 (t, J = 6.1 Hz, 2H), 3.39 (d, J = 6.3 Hz, 2H),
2.85-2.78 (m, 2H), 2.75-2.65 (m, 5H), 2.10-2.05 (m, 4H), 1.11 (d, J
= 6.4 Hz, 6H). 14 2-{[(5-chloro-1,3- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) benzodioxol-4-yl)methyl](4- 11.17 (s,
1H), 9.15 (t, J = 5.6 Hz, m/e 529 fluorobenzyl)amino}-N-[3- 1H),
7.99 (s, 1H), 7.38-7.29 (m, (M + H)+ (1H-imidazol-1-yl)propyl]-
2H), 7.14 (s, 1H), 7.09 (dt, J = 11.7, 1,3-thiazole-5-carboxamide
1.7 Hz, 2H), 7.06-6.98 (m, 2H), 6.86 (s, 1H), 6.02 (s, 2H), 5.38
(s, 2H), 4.45 (s, 2H), 4.43-4.38 (m, 2H), 3.41 (dd, J = 11.0, 5.6
Hz, 2H), 2.28-2.14 (m, 2H), 2.06 (s, 6H). 15 2-[(4-chlorobenzyl)(4-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ESI(+))
fluorobenzyl)amino]-N-[3- 11.45 (s, 1H), 9.23 (dd, J = 7.2, m/e 484
(1H-imidazol-1-yl)propyl]- 3.6 Hz, 1H), 8.02 (s, 1H), (M + H)+
1,3-thiazole-5-carboxamide 7.43-7.36 (m, 2H), 7.36-7.31 (m, 2H),
7.29 (t, J = 5.4 Hz, 2H), 7.13 (t, J = 1.7 Hz, 1H), 7.09-6.95 (m,
2H), 6.89 (t, J = 1.7 Hz, 1H), 5.34 (s, 2H), 4.45 (s, 2H),
4.45-4.37 (m, 2H), 3.48-3.35 (m, 2H), 2.29-2.17 (m, 2H). 16
2-[(2-chlorobenzyl)(4- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) fluorobenzyl)amino]-N-[3- 11.25 (s, 1H), 9.21-9.12 (m,
1H), m/e 484 (1H-imidazol-1-yl)propyl]- 8.03 (s, 1H), 7.62 (dd, J =
6.8, 2.4 Hz, (M + H)+ 1,3-thiazole-5-carboxamide 1H), 7.46-7.41 (m,
1H), 7.40-7.30 (m, 4H), 7.10 (dt, J = 12.9, 1.6 Hz, 2H), 7.06-6.98
(m, 2H), 5.50 (s, 2H), 4.45 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 3.41
(dd, J = 11.1, 5.6 Hz, 2H), 2.22 (ddd, J = 7.4, 5.9, 2.1 Hz, 2H).
17 2-[(2,5-dichlorobenzyl)(4- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ESI(+)) fluorobenzyl)amino]-N-[3- 9.23 (s, 1H), 8.61 (t, J
= 6.0 Hz, m/e 519 (1H-imidazol-1-yl)propyl]- 1H), 8.25 (t, J = 5.8
Hz, 1H), (M + H)+ 1,3-thiazole-5-carboxamide 7.81 (t, J = 1.7 Hz,
1H), 7.75 (t, J = 1.7 Hz, 1H), 7.63 (s, 1H), 7.59-7.55 (m, 2H),
7.53 (dd, J = 8.6, 2.4 Hz, 1H), 7.34 (dd, J = 8.6, 5.6 Hz, 2H),
7.15 (dd, J = 12.3, 5.5 Hz, 2H), 5.47 (s, 2H), 4.41 (d, J = 5.1 Hz,
2H), 4.18 (t, J = 7.0 Hz, 2H), 3.15 (s, 2H), 1.98 (t, J = 6.8 Hz,
2H). 23 2-[(4-fluorobenzyl)(4- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ESI(+)) methylbenzyl)amino]-N-[3- 9.10 (d, J = 1.2 Hz,
1H), 8.28 (t, J = 5.7 Hz, m/e 464 (1H-imidazol-1-yl)propyl]- 1H),
7.79 (dd, J = 5.8, (M + H)+ 1,3-thiazole-5-carboxamide 4.1 Hz, 2H),
7.68 (t, J = 1.6 Hz, 1H), 7.38-7.27 (m, 2H), 7.21-7.11 (m, 6H),
4.72 (s, 2H), 4.68 (s, 2H), 4.20 (d, J = 7.0 Hz, 2H), 3.18 (q, J =
6.6 Hz, 3H), 2.01 (p, J = 6.8 Hz, 2H). 47 2-[(4-fluorobenzyl)(3-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ESI(+))
methylbutyl)amino]-N-[3- 9.11 (s, 1H), 8.27 (t, J = 5.7 Hz, m/e 430
(1H-imidazol-1-yl)propyl]- 1H), 7.81 (d, J = 1.4 Hz, 1H), (M + H)+
1,3-thiazole-5-carboxamide 7.75 (s, 1H), 7.69 (t, J = 1.5 Hz, 1H),
7.33 (dd, J = 8.6, 5.6 Hz, 2H), 7.23-7.08 (m, 2H), 4.69 (s, 2H),
4.22 (t, J = 7.0 Hz, 2H), 3.46-3.42 (m, 2H), 3.19 (dd, J = 11.6,
5.5 Hz, 2H), 2.02 (p, J = 6.8 Hz, 2H), 1.54 (dt, J = 12.9, 6.5 Hz,
1H), 1.46 (dd, J = 15.0, 7.1 Hz, 2H), 0.88 (d, J = 6.4 Hz, 6H). 55
2-[(2-fluorobenzyl)(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methylbutyl)amino]-N-[3- d.sub.6/D.sub.2O) .delta. 9.22 (s, 1H),
7.78 (t, J = 1.7 Hz, m/e 430 (1H-imidazol-1-yl)propyl]- 1H), 7.73
(t, J = 1.7 Hz, (M + H)+ 1,3-thiazole-5-carboxamide 1H), 7.67 (s,
1H), 7.53-7.46 (m, 2H), 7.33-7.26 (m, 2H), 5.48 (s, 2H), 4.21 (t, J
= 7.0 Hz, 2H), 3.31-3.22 (m, 2H), 3.20 (t, J = 6.6 Hz, 2H),
2.10-1.95 (m, 2H), 1.63 (dt, J = 13.3, 6.7 Hz, 1H), 1.45 (dd, J =
14.4, 7.0 Hz, 2H), 0.89 (d, J = 6.6 Hz, 6H). 56
2-[(3-fluorobenzyl)(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methylbutyl)amino]-N-[3- d.sub.6/D.sub.2O) .delta. 9.03 (s, 1H),
7.74 (d, J = 2.1 Hz, m/e 430 (1H-imidazol-1-yl)propyl]- 2H), 7.64
(s, 1H), (M + H)+ 1,3-thiazole-5-carboxamide 7.41 (dd, J = 14.1,
7.9 Hz, 1H), 7.10 (dd, J = 17.6, 9.2 Hz, 3H), 4.73 (s, 2H), 4.22
(t, J = 7.0 Hz, 2H), 3.54-3.42 (m, 2H), 3.20 (t, J = 6.5 Hz, 2H),
2.03 (t, J = 6.8 Hz, 2H), 1.59-1.51 (m, 1H), 1.50-1.43 (m, 2H),
0.88 (d, J = 6.4 Hz, 6H). 57 2-[(2-chlorobenzyl)(3- .sup.1H NMR
(400 MHz, DMSO- (ESI(+)) methylbutyl)amino]-N-[3- d.sub.6/D.sub.2O)
.delta. 9.22 (s, 1H), 7.80 (t, J = 1.7 Hz, m/e 447
(1H-imidazol-1-yl)propyl]- 1H), 7.71 (t, J = 1.7 Hz, (M + H)+
1,3-thiazole-5-carboxamide 1H), 7.67 (s, 1H), 7.57 (d, J = 7.5 Hz,
1H), 7.51-7.42 (m, 3H), 5.51 (s, 2H), 4.22 (t, J = 7.0 Hz, 2H),
3.28-3.23 (m, 2H), 3.20 (t, J = 6.7 Hz, 2H), 2.03 (p, J = 6.7 Hz,
2H), 1.63 (dt, J = 13.3, 6.7 Hz, 1H), 1.45 (dd, J = 14.4, 7.0 Hz,
2H), 0.89 (d, J = 6.6 Hz, 6H). 58 2-[(3-chlorobenzyl)(3- .sup.1H
NMR (400 MHz, DMSO- (ESI(+)) methylbutyl)amino]-N-[3-
d.sub.6/D.sub.2O) .delta. 9.02 (s, 1H), 7.74 (s, m/e 447
(1H-imidazol-1-yl)propyl]- 2H), 7.63 (s, 1H), 7.39 (dd, J = 13.9,
(M + H)+ 1,3-thiazole-5-carboxamide 6.6 Hz, 3H), 7.32 (s, 1H), 7.25
(d, J = 7.4 Hz, 1H), 4.72 (s, 2H), 4.22 (t, J = 7.0 Hz, 2H), 3.47
(d, J = 7.1 Hz, 2H), 3.20 (t, J = 6.5 Hz, 2H), 2.09-1.97 (m, 2H),
1.54 (d, J = 6.2 Hz, 1H), 1.50-1.44 (m, 2H), 0.88 (d, J = 6.4 Hz,
6H). 59 2-[(4-chlorobenzyl)(3- .sup.1H NMR (400 MHz, DMSO- (ESI(+))
methylbutyl)amino]-N-[3- d.sub.6/D.sub.2O) .delta. 7.73 (s, 2H),
7.62 (s, m/e 447 (1H-imidazol-1-yl)propyl]- 1H), 7.41 (d, J = 8.5
Hz, 3H), (M + H)+ 1,3-thiazole-5-carboxamide 7.38 (s, 1H), 7.30 (d,
J = 8.5 Hz, 2H), 4.69 (s, 2H), 4.21 (t, J = 7.1 Hz, 2H), 3.47 (dd,
J = 11.5, 4.4 Hz, 2H), 3.19 (t, J = 6.6 Hz, 2H), 2.03 (t, J = 6.8
Hz, 2H), 1.53 (d, J = 6.7 Hz, 1H), 1.51-1.44 (m, 2H), 0.88 (d, J =
6.4 Hz, 6H). 60 2-[(4-cyanobenzyl)(3- .sup.1H NMR (400 MHz, DMSO-
(ESI(+)) methylbutyl)amino]-N-[3- d.sub.6/D.sub.2O) .delta.
7.85-7.78 (m, 3H), m/e 437 (1H-imidazol-1-yl)propyl]- 7.74 (s, 1H),
7.72 (s, 1H), 7.64 (s, (M + H)+ 1,3-thiazole-5-carboxamide 1H),
7.46 (d, J = 8.2 Hz, 2H), 4.80 (s, 2H), 4.22 (t, J = 6.9 Hz, 2H),
3.49 (m, 2H), 3.19 (t, J = 6.7 Hz, 2H), 2.09-1.97 (m, 2H), 1.55 (s,
1H), 1.48 (d, J = 8.4 Hz, 2H), 0.89 (d, J = 6.4 Hz, 6H).
Example 18
2-{(4-fluorobenzyl)[2-(methylamino)-2-oxoethyl]amino}-N-[3-(1H-imidazol-1--
yl)propyl]-1,3-thiazole-5-carboxamide
[1204] Example 6B (0.018 g, 0.05 mmol) was dissolved in
DMSO:CH.sub.3OH 1:1 (0.5 ml), Hunig's base (0.02 mL, 0.15 mmol) and
2-chloro-N-methylacetamide (0.006 g, 0.6 mmol). The reaction
mixture was heated at 80.degree. C. overnight and submitted to
reverse-phase HPLC (as described in Example 6C) to afford the title
compound. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 7.70 (d,
J=1.9 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.36 (dd,
J=8.4, 5.5 Hz, 2H), 7.06 (t, J=8.7 Hz, 2H), 4.97 (s, 2H), 4.48 (s,
2H), 4.29 (t, J=6.9 Hz, 2H), 3.35 (t, J=6.4 Hz, 2H), 2.79 (s, 3H),
2.14 (p, J=6.7 Hz, 2H); MS (ESI(+)) m/e 431 (M+H)+.
[1205] The following examples were prepared as described in Example
18, substituting the appropriate chloro-acetamide. Title compounds
were purified by either flash chromatography (silica gel column
eluting with a gradient of 0-10% methanol in dichloromethane) or
reverse-phase HPLC (as described in Example 6C). Accordingly, some
examples were isolated as trifluoroacetic acid salts.
TABLE-US-00005 MS EX NAME .sup.1H NMR DATA DATA 19
2-{(4-fluorobenzyl)[2-oxo- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. (ESI(+)) 2-(propan-2- 10.95-10.86 (m, 1H), m/e 459
ylamino)ethyl]amino}-N-[3- 8.81-8.68 (m, 1H), 8.67-8.53 (m, 1H), (M
+ H).sup.+ (1H-imidazol-1-yl)propyl]- 8.02-7.93 (m, 1H), 7.51 (ddd,
J = 5.5, 1,3-thiazole-5-carboxamide 4.8, 1.7 Hz, 1H), 7.34 (dd, J =
8.4, 5.5 Hz, 2H), 7.14 (s, 1H), 7.07-6.99 (m, 2H), 5.04 (s, 2H),
4.46 (s, 2H), 4.38-4.27 (m, 2H), 3.96 (dd, J = 13.5, 6.8 Hz, 1H),
3.40-3.27 (m, 2H), 2.19-2.17 (m, 2H), 1.18 (d, J = 6.6 Hz, 6H). 20
2-{[2-(dimethylamino)-2- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) oxoethyl](4- 10.99-10.90 (m, 1H), m/e 445
fluorobenzyl)amino}-N-[3- 8.97-8.89 (m, 1H), 8.01 (s, 1H), (M +
H).sup.+ (1H-imidazol-1-yl)propyl]- 7.36-7.29 (m, 2H), 7.22 (t, J =
1.6 Hz, 1H), 1,3-thiazole-5-carboxamide 7.13 (t, J = 1.7 Hz, 1H),
7.07-6.99 (m, 2H), 5.36 (s, 2H), 4.45 (s, 2H), 4.41-4.32 (m, 2H),
3.38 (dd, J = 11.1, 5.7 Hz, 2H), 3.12 (s, 3H), 3.00 (s, 3H),
2.23-2.19 (m, 2H). 21 2-{[2-(diethylamino)-2- .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. (ESI(+)) oxoethyl](4- 11.08-11.00 (m, 1H), m/e
473 fluorobenzyl)amino}-N-[3- 9.04-8.96 (m, 1H), 8.11-8.02 (m, 1H),
(M + H).sup.+ (1H-imidazol-1-yl)propyl]- 7.33 (dd, J = 8.5, 5.4 Hz,
2H), 7.25 (t, 1,3-thiazole-5-carboxamide J = 1.6 Hz, 1H), 7.13 (s,
1H), 7.04 (dd, J = 9.8, 7.5 Hz, 2H), 5.34 (s, 2H), 4.45 (s, 2H),
4.36 (dd, J = 7.8, 4.0 Hz, 2H), 3.44-3.37 (m, 6H), 2.24-2.19 (m,
2H), 1.29 (t, J = 5.4 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). 22
2-{(4-fluorobenzyl)[2- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
(ESI(+)) (morpholin-4-yl)-2- 11.09-11.00 (m, 1H), m/e 487
oxoethyl]amino}-N-[3-(1H- 8.92-8.79 (m, 1H), 8.11-8.02 (m, 1H), (M
+ H).sup.+ imidazol-1-yl)propyl]-1,3- 7.36-7.29 (m, 2H), 7.24 (d, J
= 1.5 Hz, thiazole-5-carboxamide 1H), 7.19-7.11 (m, 1H), 7.06-6.99
(m, 2H), 5.46 (dd, J = 4.8, 2.0 Hz, 2H), 4.45 (d, J = 3.3 Hz, 2H),
4.41-4.30 (m, 2H), 3.78 (ddd, J = 6.4, 5.3, 2.4 Hz, 2H), 3.75-3.70
(m, 2H), 3.63-3.57 (m, 4H), 3.37 (tdd, J = 7.3, 2.3, 1.4 Hz, 2H),
2.27-2.18 (m, 2H).
Example 26
2-[(N,N-dimethylglycyl)(4-fluorobenzyl)amino]-N-[3-(1H-imidazol-1-yl)propy-
l]-1,3-thiazole-5-carboxamide
[1206] Example 6B (0.036 g, 0.1 mmol) was dissolved in
dichloromethane:pyridine 10:1 (1 ml), cooled to -10.degree. C., and
treated with chloroacetyl bromide (0.011 mL, 0.125 mmol). The
resultant solution was stirred at room temperature for 30 minutes.
The reaction mixture was then treated with an excess of
dimethylamine in tetrahydrofuran (0.5 mL, 1M solution). The
reaction mixture was heated at 80.degree. C. overnight and purified
by reverse-phase HPLC (as described in Example 6C) to afford the
title compound. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
8.98 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.35-7.23
(m, 2H), 7.10 (t, J=8.7 Hz, 2H), 5.48 (s, 2H), 4.60-4.45 (m, 2H),
4.32 (t, J=6.9 Hz, 2H), 3.40 (t, J=6.5 Hz, 2H), 2.98 (s, 6H), 2.18
(t, J=6.7 Hz, 2H); MS (ESI(+)) m/e 445 (M+H)+.
[1207] The following examples were prepared as described in Example
26, substituting the appropriate alkyl halide in Example 26. Title
compounds were purified by either flash chromatography (silica gel
column eluting with a gradient of 0-10% methanol in
dichloromethane) or reverse-phase HPLC (as in described Example
6C). Accordingly, some examples were isolated as trifluoroacetic
acid salts.
TABLE-US-00006 MS EX NAME .sup.1H NMR DATA DATA 27
2-[(3,6-dihydropyridin- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) 1(2H)-ylacetyl)(4- .delta. 8.95 (s, 1H), 8.03 (s, 1H), m/e
483 fluorobenzyl)amino]-N-[3- 7.69 (s, 1H), 7.56 (s, 1H), 7.28 (s,
2H), (M + H).sup.+ (1H-imidazol-1-yl)propyl]- 7.10 (t, J = 8.7 Hz,
2H), 5.98 (s, 1,3-thiazole-5-carboxamide 1H), 5.73 (s, 1H), 5.51
(s, 2H), 4.53-2.44 (m, 2H), 4.32 (t, J = 6.9 Hz, 2H), 3.88-3.78 (m,
1H), 3.57-3.42 (m, 1H), 3.40 (t, J = 6.6 Hz, 1H), 2.52-2.46 (m,
2H), 2.17 (dd, J = 13.5, 6.8 Hz, 2H). 28 2-{(4-fluorobenzyl)[(4-
.sup.1H NMR (400 MHz, methanol-d.sub.4) (ESI(+)) methylpiperidin-1-
.delta. 8.98 (s, 1H), 8.03 (s, 1H), m/e 499
yl)acetyl]amino}-N-[3-(1H- 7.71 (s, 1H), 7.58 (s, 1H), 7.27 (s,
2H), (M + H).sup.+ imidazol-1-yl)propyl]-1,3- 7.10 (t, J = 8.7 Hz,
2H), 5.49 (s, thiazole-5-carboxamide 2H), 4.45 (s, 2H), 4.32 (dd, J
= 8.9, 4.9 Hz, 2H), 3.63 (d, J = 10.7 Hz, 2H), 3.40 (t, J = 6.5 Hz,
2H), 3.04 (t, J = 12.6 Hz, 2H), 2.21-2.14 (m, 2H), 1.92 (d, J =
15.0 Hz, 2H), 1.71 (s, 1H), 1.56 (d, J = 12.4 Hz, 2H), 1.03 (d, J =
6.4 Hz, 3H). 29 2-{(4-fluorobenzyl)[(4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) hydroxypiperidin-1- .delta. 8.98 (s,
1H), 8.03 (s, 1H), m/e 501 yl)acetyl]amino}-N-[3-(1H- 7.71 (s, 1H),
7.58 (s, 1H), 7.28 (s, 2H), (M + H).sup.+
imidazol-1-yl)propyl]-1,3- 7.10 (t, J = 8.7 Hz, 2H), 5.49 (s,
thiazole-5-carboxamide 2H), 4.49 (s, 2H), 4.32 (t, J = 7.0 Hz, 2H),
3.46 (d, J = 5.3 Hz, 1H), 3.40 (t, J = 6.6 Hz, 2H), 2.19 (dd, J =
13.7, 6.8 Hz, 2H), 2.12 (d, J = 22.1 Hz, 2H), 1.91-1.85 (m, 2H). 30
2-{(4-fluorobenzyl)[(4- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) methylpiperazin-1- .delta. 8.99 (s, 1H), 7.99 (s, 1H), m/e
500 yl)acetyl]amino}-N-[3-(1H- 7.71 (d, J = 1.4 Hz, 1H), 7.59 (s,
1H), (M + H).sup.+ imidazol-1-yl)propyl]-1,3- 7.27-7.15 (m, 2H),
7.08 (t, J = 8.7 Hz, thiazole-5-carboxamide 2H), 5.54 (s, 2H), 4.33
(t, J = 7.0 Hz, 2H), 3.71 (s, 2H), 3.40 (t, J = 6.5 Hz, 2H),
3.13-2.91 (m, 4H), 2.88 (s, 3H), 2.82-2.66 (m, 2H), 2.19 (p, J =
7.0 Hz, 2H). 31 2-[(4-fluorobenzyl){[4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (propan-2-yl)piperazin-1- .delta. 8.99
(s, 1H), 7.99 (s, 1H), m/e 528 yl]acetyl}amino]-N-[3-(1H- 7.72 (t,
J = 1.6 Hz, 1H), 7.59 (t, J = 1.6 Hz, (M + H).sup.+
imidazol-1-yl)propyl]-1,3- 1H), 7.21 (dd, J = 8.6, 5.3 Hz,
thiazole-5-carboxamide 2H), 7.08 (dd, J = 12.2, 5.3 Hz, 2H), 5.55
(s, 2H), 4.33 (t, J = 6.9 Hz, 2H), 3.71 (s, 2H), 3.51-3.37 (m, 4H),
3.15-2.91 (m, 4H), 2.75-2.67 (m, 1H), 2.19 (t, J = 6.7 Hz, 2H),
1.33 (d, J = 6.7 Hz, 6H). 32 2-{(4-fluorobenzyl)[(4- .sup.1H NMR
(400 MHz, methanol-d.sub.4) (ESI(+)) formylpiperazin-1- .delta.
8.99 (s, 1H), 8.05 (s, 1H), m/e 514 yl)acetyl]amino}-N-[3-(1H- 8.00
(d, J = 9.0 Hz, 1H), 7.72 (s, 1H), (M + H).sup.+
imidazol-1-yl)propyl]-1,3- 7.59 (s, 1H), 7.31-7.19 (m, 2H),
thiazole-5-carboxamide 7.15-7.03 (m, 2H), 5.66-5.41 (m, 2H), 4.33
(t, J = 7.0 Hz, 2H), 4.21-4.03 (m, 2H), 3.68 (tdd, J = 5.0, 4.5,
1.3 Hz, 2H), 3.66-3.60 (m, 2H), 3.46-3.38 (m, 2H), 3.16-2.93 (m,
4H), 2.25-2.13 (m, 2H). 33 2-[(4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) fluorobenzyl)(hexahydropyrrolo[1,
.delta. 8.99 (s, 1H), 7.99 (s, 1H), m/e 526 2-a]pyrazin-2(1H)- 7.72
(t, J = 1.6 Hz, 1H), 7.59 (t, J = 1.5 Hz, (M + H).sup.+
ylacetyl)amino]-N-[3-(1H- 1H), 7.21 (dd, J = 8.5, 5.3 Hz,
imidazol-1-yl)propyl]-1,3- 2H), 7.08 (t, J = 8.7 Hz, 2H),
thiazole-5-carboxamide 5.54 (s, 2H), 4.33 (t, J = 6.9 Hz, 2H),
3.81-3.68 (m, 2H), 3.39 (d, J = 6.5 Hz, 2H), 3.26-2.68 (m, 6H),
2.28-2.01 (m, 5H). 34 2-[{[4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (cyclopropylmethyl)piperazin- .delta.
8.99 (s, 1H), 8.00 (s, 1H), m/e 540 1-yl]acetyl}(4- 7.72 (t, J =
1.7 Hz, 1H), 7.59 (s, 1H), (M + H).sup.+ fluorobenzyl)amino]-N-[3-
7.27-7.15 (m, 2H), (1H-imidazol-1-yl)propyl]- 7.15-7.02 (m, 2H),
5.55 (s, 2H), 4.33 (t, J = 6.9 Hz, 1,3-thiazole-5-carboxamide 2H),
3.72 (s, 2H), 3.65-3.50 (m, 2H), 3.40 (dd, J = 8.0, 5.1 Hz, 2H),
3.17-2.97 (m, 6H), 2.88-2.68 (m, 2H), 2.26-2.11 (m, 2H), 1.06 (d, J
= 7.2 Hz, 1H), 0.83-0.70 (m, 2H), 0.43 (dd, J = 5.6, 4.9 Hz, 2H).
35 2-[{[4-(2- .sup.1H NMR (400 MHz, methanol-d.sub.4) (ESI(+))
ethoxyethyl)piperazin-1- .delta. 8.99 (s, 1H), 7.99 (s, 1H), m/e
558 yl]acetyl}(4- 7.72 (s, 1H), 7.59 (s, 1H), 7.21 (dd, J = 8.6, (M
+ H).sup.+ fluorobenzyl)amino]-N-[3- 5.2 Hz, 2H), 7.09-7.06 (m,
(1H-imidazol-1-yl)propyl]- 2H), 5.55 (s, 2H), 4.39-4.24 (m,
1,3-thiazole-5-carboxamide 2H), 3.74 (dd, J = 6.4, 3.6 Hz, 2H),
3.71 (s, 2H), 3.57 (q, J = 7.1 Hz, 2H), 3.40 (t, J = 6.5 Hz, 2H),
2.95 (d, J = 58.3 Hz, 6H), 2.26-2.09 (m, 2H), 1.22 (t, J = 7.0 Hz,
3H). 37 2-[(4-fluorobenzyl){[4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) (prop-2-en-1-yl)piperazin-1- .delta.
8.99 (s, 1H), 8.00 (s, 1H), m/e 526 yl]acetyl}amino]-N-[3-(1H- 7.71
(d, J = 7.5 Hz, 1H), 7.58 (s, 1H), (M + H)+
imidazol-1-yl)propyl]-1,3- 7.21 (dd, J = 8.5, 5.3 Hz, 2H),
thiazole-5-carboxamide 7.08 (t, J = 8.7 Hz, 2H), 6.01-5.82 (m, 1H),
5.62 (s, 1H), 5.59 (d, J = 6.2 Hz, 1H), 5.54 (s, 2H), 4.33 (t, J =
6.9 Hz, 2H), 3.74 (d, J = 7.3 Hz, 2H), 3.75-3.70 (m, 2H), 3.40 (t,
J = 6.5 Hz, 2H), 2.95-2.9 (m, 4H), 2.19 (p, J = 6.9 Hz, 2H). 38
2-[(4-fluorobenzyl){[4-(3- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) methoxypropyl)piperazin-1- .delta. 8.99 (s, 1H), 8.00 (s,
1H), m/e 558 yl]acetyl}amino]-N-[3-(1H- 7.71 (s, 1H), 7.58 (s, 1H),
7.21 (dd, J = 8.5, (M + H)+ imidazol-1-yl)propyl]-1,3- 5.3 Hz, 2H),
7.08 (t, J = 8.7 Hz, thiazole-5-carboxamide 2H), 5.55 (s, 2H), 4.33
(t, J = 6.9 Hz, 2H), 3.71 (s, 2H), 3.48 (t, J = 5.6 Hz, 2H), 3.40
(t, J = 6.5 Hz, 2H), 3.34 (s, 3H), 3.23 (t, J = 8.0 Hz, 2H),
2.26-2.09 (m, 2H), 1.97 (dd, J = 9.7, 5.8 Hz, 2H). 39 2-[{[3-
.sup.1H NMR (400 MHz, methanol-d.sub.4) (ESI(+))
(dimethylamino)pyrrolidin- .delta. 8.99 (s, 1H), 8.01 (s, 1H), m/e
514 1-yl]acetyl}(4- 7.71 (s, 1H), 7.58 (s, 1H), 7.24 (dd, J = 8.5,
(M + H)+ fluorobenzyl)amino]-N-[3- 5.3 Hz, 2H), 7.08 (t, J = 8.7
Hz, (1H-imidazol-1-yl)propyl]- 2H), 5.51 (s, 2H), 4.33 (t, J = 6.9
Hz, 1,3-thiazole-5-carboxamide 2H), 4.06 (d, J = 32.5 Hz, 2H),
3.97-3.90 (m, 1H), 3.52-3.43 (m, 1H), 3.40 (t, J = 6.5 Hz, 2H),
3.13 (s, 1H), 2.91 (s, 6H), 2.40 (dd, J = 13.1, 4.6 Hz, 1H),
2.26-2.06 (m, 3H). 40 2-[(4- .sup.1H NMR (400 MHz,
methanol-d.sub.4) (ESI(+)) fluorobenzyl)(morpholin-4- .delta. 8.99
(s, 1H), 8.04 (s, 1H), m/e 487 ylacetyl)amino]-N-[3-(1H- 7.71 (s,
1H), 7.58 (s, 1H), (M + H)+ imidazol-1-yl)propyl]-1,3- 7.35-7.23
(m, 2H), 7.10 (t, J = 8.7 Hz, 2H), thiazole-5-carboxamide 5.50 (s,
2H), 4.54 (s, 2H), 4.33 (t, J = 6.9 Hz, 2H), 3.99-3.90 (m, 4H),
3.53-3.33 (m, 6H), 2.19 (p, J = 6.8 Hz, 2H). 41
2-{(4-fluorobenzyl)[(3- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) hydroxypiperidin-1- .delta. 8.99 (s, 1H), 8.04 (s, 1H),
m/e 501 yl)acetyl]amino}-N-[3-(1H- 7.71 (s, 1H), 7.59 (s, 1H), (M +
H)+ imidazol-1-yl)propyl]-1,3- 7.34-7.23 (m, 2H), 7.10 (t, J = 8.7
Hz, 2H), thiazole-5-carboxamide 5.50 (s, 2H), 4.50 (m, 1H), 4.33
(t, J = 7.0 Hz, 2H), 4.15-4.1 (m, 1H), 3.76-3.49 (m, 1H), 3.40 (t,
J = 6.6 Hz, 2H), 3.27-2.95 (m, 2H), 2.19 (p, J = 6.8 Hz, 2H), 1.79
(d, J = 15.5 Hz, 2H). 42 2-[(4-fluorobenzyl){[4-(2- .sup.1H NMR
(400 MHz, methanol-d.sub.4) (ESI(+)) hydroxyethyl)piperazin-1-
.delta. 8.99 (s, 1H), 8.00 (s, 1H), m/e 530
yl]acetyl}amino]-N-[3-(1H- 7.72 (s, 1H), 7.58 (s, 1H), 7.22 (dd, J
= 8.6, (M + H)+ imidazol-1-yl)propyl]-1,3- 5.3 Hz, 2H), 7.08 (t, J
= 8.7 Hz, thiazole-5-carboxamide 2H), 5.55 (s, 2H), 4.33 (t, J =
6.9 Hz, 2H), 3.91-3.80 (m, 2H), 3.75-3.65 (m, 2H), 3.40 (t, J = 6.5
Hz, 2H), 3.26-3.21 (m, 2H), 2.98-2.88 (m, 4H), 2.19 (p, J = 6.7 Hz,
2H). 43 2-[(1,4-dioxa-7- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) azaspiro[4.4]non-7- .delta. 8.99 (s, 1H), 8.03 (s, 1H),
m/e 529 ylacetyl)(4- 7.71 (s, 1H), 7.58 (s, 1H), (M + H)+
fluorobenzyl)amino]-N-[3- 7.35-7.23 (m, 2H), 7.10 (t, J = 8.7 Hz,
2H), (1H-imidazol-1-yl)propyl]- 5.48 (s, 2H), 4.64 (s, 2H), 4.33
(t, 1,3-thiazole-5-carboxamide J = 6.9 Hz, 2H), 3.99 (d, J = 3.7
Hz, 4H), 3.72-3.63 (m, 2H), 3.6-3.5 (m, 2H), 3.40 (t, J = 6.5 Hz,
2H), 2.29 (t, J = 7.7 Hz, 2H), 2.19 (p, J = 6.7 Hz, 2H).
Example 212
2-{(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazo-
lidin-3-yl}-N-[3-(1H-imidazol-1-yl)propyl]-1,3-thiazole-5-carboxamide
[1208] Example 6A (0.095 g, 0.3 mmol),
(R)-2-((2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (0.049 g,
0.2 mmol), and potassium phosphate (0.127 g, 0.6 mmol) were
suspended in dry dioxane, and nitrogen was bubbled through for 5
minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.018 g. 0.02
mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(XantPhos, 0.035 g, 0.06 mmol) were added to the reaction, and the
vial capped. The reaction was stirred at 90.degree. C. for 5 hours,
concentrated and submitted to reverse phase HPLC (as described in
Example 6C) to afford the title compound. .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 8.98 (s, 1H), 7.95 (s, 1H), 7.90 (dt,
J=7.3, 3.7 Hz, 2H), 7.87-7.80 (m, 2H), 7.71 (d, J=1.6 Hz, 1H), 7.58
(t, J=1.6 Hz, 1H), 5.16 (dt, J=12.7, 5.8 Hz, 1H), 4.40 (dd, J=10.2,
8.8 Hz, 1H), 4.33 (t, J=6.8 Hz, 2H), 4.20 (dd, J 10.4, 5.8 Hz, 1H),
4.10 (ddd, J=19.6, 14.6, 5.9 Hz, 2H), 3.39 (dd, J=11.2, 6.1 Hz,
2H), 2.18 (p, J=6.7 Hz, 2H); MS (ESI(+)) m/e 480.5 (M+H)+.
[1209] The following examples were prepared as described in Example
212, substituting the appropriate imidazolidinone for the
oxazolidinone. Title compounds were purified by either flash
chromatography (silica gel column eluting with a gradient of 0-10%
methanol in dichloromethane) or reverse-phase HPLC (as described in
Example 6C). Accordingly, some examples were isolated as
trifluoroacetic acid salts.
TABLE-US-00007 MS EX NAME .sup.1H NMR DATA DATA 203
2-[3-(2-hydroxyethyl)-2- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) oxoimidazolidin-1-yl]-N-[3- .delta. 7.89 (s, 1H), 7.70 (s,
1H), m/e 365 (1H-imidazol-1-yl)propyl]- 7.18 (s, 1H), 6.97 (s, 1H),
4.10 (dd, J = 11.6, (M + H).sup.+ 1,3-thiazole-5-carboxamide 4.7
Hz, 4H), 3.74 (dd, J = 12.9, 7.2 Hz, 4H), 3.43 (t, J = 5.4 Hz, 2H),
3.34 (t, J = 6.8 Hz, 2H), 2.07 (p, J = 6.8 Hz, 2H). 204
2-[3-(4-fluorophenyl)-2- .sup.1H NMR (400 MHz, methanol-d.sub.4)
(ESI(+)) oxoimidazolidin-1-yl]-N-[3- .delta. 8.99 (s, 1H), 7.95 (s,
1H), m/e 415 (1H-imidazol-1-yl)propyl]- 7.76-7.54 (m, 4H), 7.15 (t,
J = 8.8 Hz, (M + H).sup.+ 1,3-thiazole-5-carboxamide 2H), 4.34 (t,
J = 6.8 Hz, 2H), 4.24 (dd, J = 10.0, 6.5 Hz, 2H), 4.13 (dd, J =
9.9, 6.7 Hz, 2H), 3.40 (dd, J = 11.5, 6.0 Hz, 2H), 2.19 (p, J = 6.6
Hz, 2H).
* * * * *