U.S. patent application number 16/157672 was filed with the patent office on 2019-09-05 for heterocyclic modulators of lipid synthesis.
The applicant listed for this patent is 3-V Biosciences, Inc.. Invention is credited to Douglas I. BUCKLEY, Gregory DUKE, Marc EVANCHIK, Robert S. MCDOWELL, Allan S. WAGMAN.
Application Number | 20190269694 16/157672 |
Document ID | / |
Family ID | 58637097 |
Filed Date | 2019-09-05 |
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United States Patent
Application |
20190269694 |
Kind Code |
A1 |
BUCKLEY; Douglas I. ; et
al. |
September 5, 2019 |
HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS
Abstract
Compounds that are fatty acid synthesis modulators are provided.
The compounds may be used to treat disorders characterized by
disregulation of the fatty acid synthase function by modulating the
function and/or the fatty acid synthase pathway. Methods are
provided for treating such disorders including viral infections,
such as hepatitis C infection, cancer and metabolic disorders, such
as non-alcoholic steatohepatitis (NASH).
Inventors: |
BUCKLEY; Douglas I.; (Menlo
Park, CA) ; DUKE; Gregory; (Menlo Park, CA) ;
WAGMAN; Allan S.; (Belmont, CA) ; EVANCHIK; Marc;
(San Jose, CA) ; MCDOWELL; Robert S.; (San
Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
3-V Biosciences, Inc. |
Menlo Park |
CA |
US |
|
|
Family ID: |
58637097 |
Appl. No.: |
16/157672 |
Filed: |
October 11, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15349960 |
Nov 11, 2016 |
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16157672 |
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14874961 |
Oct 5, 2015 |
9809591 |
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15349960 |
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14315133 |
Jun 25, 2014 |
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14874961 |
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13415660 |
Mar 8, 2012 |
8871790 |
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14315133 |
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15201824 |
Jul 5, 2016 |
10053450 |
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15349960 |
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14587908 |
Dec 31, 2014 |
9428502 |
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15201824 |
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PCT/US2013/048950 |
Jul 1, 2013 |
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14587908 |
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15110154 |
Jul 7, 2016 |
9994550 |
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PCT/US2015/010459 |
Jan 7, 2015 |
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15349960 |
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61450561 |
Mar 8, 2011 |
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61508611 |
Jul 16, 2011 |
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61585642 |
Jan 11, 2012 |
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61667894 |
Jul 3, 2012 |
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61698511 |
Sep 7, 2012 |
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61699819 |
Sep 11, 2012 |
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61785933 |
Mar 14, 2013 |
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61924520 |
Jan 7, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 513/04 20130101;
C07D 491/107 20130101; C07D 401/14 20130101; C07D 491/052 20130101;
A61K 31/501 20130101; C07D 471/04 20130101; A61K 31/453 20130101;
C07D 487/04 20130101; C07D 405/12 20130101; C07D 491/10 20130101;
A61K 31/4545 20130101; C07D 401/06 20130101; A61K 31/451 20130101;
C07D 491/048 20130101; A61K 31/496 20130101; C07D 401/12 20130101;
A61K 31/454 20130101; C07D 405/14 20130101; C07D 413/10 20130101;
A61K 31/506 20130101; C07D 401/04 20130101; C07D 405/04 20130101;
C07D 413/14 20130101; A61K 31/437 20130101; A61K 31/55 20130101;
C07D 405/10 20130101; A61K 31/4525 20130101; C07D 401/10 20130101;
A61K 31/5377 20130101 |
International
Class: |
A61K 31/55 20060101
A61K031/55; A61K 31/437 20060101 A61K031/437; C07D 401/14 20060101
C07D401/14; A61K 31/501 20060101 A61K031/501; A61K 31/496 20060101
A61K031/496; A61K 31/5377 20060101 A61K031/5377; A61K 31/4545
20060101 A61K031/4545; A61K 31/454 20060101 A61K031/454; A61K
31/4525 20060101 A61K031/4525; A61K 31/453 20060101 A61K031/453;
A61K 31/451 20060101 A61K031/451; C07D 513/04 20060101 C07D513/04;
C07D 491/107 20060101 C07D491/107; C07D 491/052 20060101
C07D491/052; C07D 491/048 20060101 C07D491/048; C07D 491/10
20060101 C07D491/10; C07D 487/04 20060101 C07D487/04; C07D 471/04
20060101 C07D471/04; C07D 413/10 20060101 C07D413/10; C07D 405/12
20060101 C07D405/12; C07D 405/10 20060101 C07D405/10; C07D 405/04
20060101 C07D405/04; C07D 401/12 20060101 C07D401/12; C07D 401/10
20060101 C07D401/10; C07D 401/06 20060101 C07D401/06; C07D 401/04
20060101 C07D401/04; C07D 413/14 20060101 C07D413/14; C07D 405/14
20060101 C07D405/14; A61K 31/506 20060101 A61K031/506 |
Claims
1-35. (canceled)
36. A pharmaceutical composition comprising a compound of the
formula: ##STR01855## and a pharmaceutically acceptable
carrier.
37. A pharmaceutical composition comprising a compound of the
formula: ##STR01856## and a pharmaceutically acceptable
carrier.
38. A pharmaceutical composition comprising a compound of the
formula: ##STR01857## and a pharmaceutically acceptable carrier.
Description
RELATED APPLICATIONS
[0001] This application is continuation in part of U.S. application
Ser. No. 14/874,961, filed on Oct. 5, 2015, which is a continuation
of U.S. application Ser. No. 14/315,133, filed on Jun. 25, 2014,
now abandoned, which is a continuation of U.S. application Ser. No.
13/415,660, filed Mar. 8, 2012, now U.S. Pat. No. 8,871,790, which
claims the benefit of the earlier filed U.S. Provisional
Application No. 61/450,561 filed on Mar. 8, 2011, U.S. Provisional
Application No. 61/508,611, filed on Jul. 16, 2011, and U.S.
Provisional Application 61/585,642, filed on Jan. 11, 2012; is a
continuation in part of U.S. application Ser. No. 15/201,824, filed
on Jul. 5, 2016, which is a divisional of U.S. application Ser. No.
14/587,908, filed on Dec. 31, 2014, now U.S. Pat. No. 9,428,502,
which is a U.S. National Phase application, filed under 35 U.S.C.
.sctn. 371, of PCT/US2013/048950, filed on Jul. 1, 2013, which
claims the benefit of the earlier filed U.S. Provisional
Application No. 61/667,294, filed on Jul. 3, 2012, U.S. Provisional
Application No. 61/698,511, filed on Sep. 7, 2012, U.S. Provisional
Application 61/699,819, filed on Sep. 11, 2012, and U.S.
Provisional Application 61/785,933, filed on Mar. 14, 2013; and is
a continuation in part of U.S. application Ser. No. 15/110,154,
filed on Jul. 7, 2016, which is a U.S. National Phase application,
filed under 35 U.S.C. .sctn. 371, of PCT/US2015/010459, filed on
Jan. 7, 2015, which claims the benefit of the earlier filed U.S.
Provisional Application No. 61/924,520, filed on Jan. 7, 2014. The
entire contents of each of these applications are incorporated by
reference in their entireties for all purposes.
FIELD
[0002] The present disclosure relates generally to heterocyclic
modulators of lipid synthesis and methods of use thereof. The
present heterocyclic modulators of lipid synthesis can be used for
the treatment of disorders characterized by dysregulation in the
fatty acid synthase function in a subject by modulating the fatty
acid synthase pathway and/or the fatty acid synthase function.
BACKGROUND
[0003] Viral disease is a significant health concern that threatens
large segments of human populations. Some of the features related
to viral infection which are of concern to health care
professionals include its highly contagious nature (e.g., HIV,
SARS, etc.) and high mutability. Some viruses are also oncogenic
(such as HPV, EBV and HBV). While viruses are structurally amongst
the simplest of organisms, they are regarded to be among the most
difficult to control and present a formidable challenge for
antiviral drug R&D. Thus far, there have been a few antiviral
drugs widely used in patients, such as Amantadine and Oseltamivir
for influenza, Acyclovir for HSV-related infections, Ganciclovir
for CMV infection, and multiple agents including co-formulated
drugs (Efavirenz, emtricitabine, and tonfovir disoproxil fumarate)
for AIDS treatments. These drugs possess a variety of undesirable
neurological, metabolic and immunological side-effects. Therefore,
development of new antiviral therapy has become a major focus of
medical and pharmaceutical research and development.
[0004] Infection by hepatitis C virus (HCV) is a serious health
issue. It is estimated that 170 million people worldwide are
chronically infected with HCV. HCV infection can lead to chronic
hepatitis, cirrhosis, liver failure and hepatocellular carcinoma.
Chronic HCV infection is thus a major worldwide cause of
liver-related premature mortality.
[0005] The present standard of care treatment regimen for HCV
infection involves combination therapy with interferon-alpha and
ribavirin, often with the addition of a direct-acting protease
inhibitor (Telaprevir or Boceprevir). The treatment is cumbersome
and sometimes has debilitating and severe side effects. For this
reason, many patients are not treated in early stages of the
disease. Additionally, some patient populations do not durably
respond to treatment. New and effective methods of treating HCV
infection are urgently needed.
[0006] The dominant therapeutic approaches that are currently
employed to treat cancer include surgical removal of primary
tumors, tumor irradiation, and parenteral application of
anti-mitotic cytotoxic agents. Unfortunately, only a relatively
small cross-section of cancer patients have tumors that are
"addicted" to a specific pathway, and can therefore be treated with
newer targeted agents. The continued dominance of these long
established therapies is mirrored by the lack of improvement in
survival rates for most cancers. In addition to limited clinical
success, devastating side effects accompany classic therapies. Both
radiation- and cytotoxic-based therapies result in the destruction
of rapidly dividing hematopoietic and intestinal epithelial cells
leading to compromised immune function, anemia, and impaired
nutrient absorption. Surgical intervention often results in a
release of tumor cells into the circulation or lymph systems from
which metastatic tumors can subsequently be established. Improved
methods for the treatment of cancer are needed.
[0007] Non-alcoholic liver disease (NAFLD), a condition in which
the liver contains more than 5% fat by weight and is not caused by
alcohol consumption, is a disease which currently affects
.about.20-30% of the US and general western world population, and
is associated with a significant increased risk of morbidity
extending beyond the liver to cardiovascular disease (i.e., carotid
atherosclerotic plaques and endothelial dysfunction), chronic
kidney disease and malignancy. Obesity and metabolic syndrome are
two key risk factors for NAFLD which are characterized as an
imbalance in energy utilization and storage. This imbalance leads
to dysregulated metabolic pathways and inflammatory responses that
drive further changes leading to liver damage and comorbid
conditions. Along with the progression of metabolic syndrome, NAFLD
leads to more advanced liver disease starting with non-alcoholic
steatohepatitis (NASH) which can then progress to significant liver
diseases including cirrhosis and hepatocellular carcinoma.
[0008] The synthesis of fatty acids in the liver, a pathway termed
hepatic de novo lipogenesis (DNL), is increased in subjects with
metabolic syndrome and NAFLD (Donnelly, K. L, et. al., "Sources of
Fatty Acids Stored in Liver and Secreted via Lipoproteins in
Patients with Nonalcoholic Fatty Liver Disease," J. Clin. Invest.
115 (5). 2005, 1343-51; Lambert, J. E, et. al., "Increased De Novo
Lipogenesis Is a Distinct Characteristic of Individuals with
Nonalcoholic Fatty Liver Disease," Ygast 146 (3). 2014, 726-35).
The DNL pathway not only produces fatty acids that contribute to
elevated liver stores of triglycerides, but the fatty acids that
are produced are saturated fatty acid species, primarily palmitate,
which contribute to signaling events that increase liver
inflammation (Wei, Y., "Saturated Fatty Acids Induce Endoplasmic
Reticulum Stress and Apoptosis Independently of Ceramide in Liver
Cells," Am. J. Physio. Endocrinol. Metab. 291 (2): 2006, E275-81;
Kakazu, E., et al., "Hepatocytes Release Ceramide-rich
Proinflammatory Extracellular Vesicles in an IRE1alpha dependent
manner," Abstract 58. AASLD--The Liver Meeting, San Francisco,
Calif., USA, 13-17, November, 2015). One of the key enzymes in the
DNL pathway is fatty acid synthase (FASN) which is solely
responsible for synthesizing palmitate. Thus, DNL is an important
pathway for therapeutic intervention to reduce the consequences
associated with metabolic syndrome and NAFLD.
[0009] Inhibition of FASN has the potential to be a treatment for a
wide range of diseases including cancer, viral disease, metabolic
disease, NAFLD, NASH, and inflammatory diseases, (i.e., rheumatoid
arthritis, gout, pulmonary fibrosis, COPD, IBD and transplant
rejection). Additionally, FASN inhibition may provide therapeutic
benefits in cardiovascular disease, type II diabetes, and metabolic
syndrome. Successful treatment of these diseases is still a highly
unmet need. While there are treatments available for diabetes and
cardiovascular disease, there are currently no drugs approved to
treat metabolic syndrome, NAFLD, or NASH. Thus, there is a need for
novel and potent small molecule inhibitors of FASN for the
treatment of these diseases.
SUMMARY
[0010] The present disclosure addresses the deficiencies for
antiviral and anticancer treatments by providing novel heterocyclic
modulators of lipid synthesis having improved antiviral and
anticancer activities.
[0011] In various aspects, the present disclosure provides for
compounds of Structure (I):
##STR00001##
[0012] or a pharmaceutically acceptable salt thereof, wherein:
[0013] X, Y, and Z are each independently CR or NR', wherein R is
hydrogen or C.sub.1-6 alkyl and R' is hydrogen, C.sub.1-6 alkyl, or
absent; [0014] A is CH or N; [0015] R.sub.1 is hydrogen, cyano,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [0016] q is 0, 1, 2, 3,
or 4; [0017] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [0018] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [0019] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [0020] R.sub.4 is hydrogen, heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6),
--N(R.sub.7)C(.dbd.O)R.sub.8, --N(R.sub.9R.sub.10), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, or R.sub.4 and
R.sub.11 taken together with the atoms to which they are attached
join together to form a heteroaryl; [0021] R.sub.11 is hydrogen,
halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[0022] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [0023] R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9R.sub.10, R.sub.13, and R.sub.14 are each independently
hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, alkylamino, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [0024] R.sub.15 and R.sub.16 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, or alkylamino; [0025] R.sub.17 and
R.sub.18 are each independently hydrogen or alkyl or can optionally
join together to form a bond; [0026] n is 1 or 2; and [0027] m is 0
or 1.
[0028] In various aspects, the present disclosure provides for
compounds of Structure (II):
##STR00002##
[0029] or a pharmaceutically acceptable salt thereof, wherein:
[0030] X, Y, and Z are each independently CR or NR', wherein R is
hydrogen or C.sub.1-6 alkyl and R' is hydrogen, C.sub.1-6 alkyl, or
absent; [0031] L and D are each independently C or N; [0032]
R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [0033] q is 0, 1, 2, 3,
or 4; [0034] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [0035] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [0036] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [0037] R.sub.4 is hydrogen, heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6),
--N(R.sub.7)C(.dbd.O)R.sub.8, --N(R.sub.9R.sub.10), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, or R.sub.4 and
R.sub.11 taken together with the atoms to which they are attached
join together to form a heteroaryl; [0038] R.sub.11 is hydrogen,
halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[0039] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [0040] R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9R.sub.10, R.sub.13, and R.sub.14 are each independently
hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, alkylamino, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [0041] R.sub.15 and R.sub.16 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, or alkylamino; [0042] R.sub.17 and
R.sub.18 are each independently hydrogen or alkyl or can optionally
join together to form a bond; [0043] n is 1 or 2; and [0044] m is 0
or 1.
[0045] In various aspects, the present disclosure provides for
compounds of Structure (III):
##STR00003##
[0046] or a pharmaceutically acceptable salt thereof, wherein:
[0047] X, Y, and Z are each independently CR or NR', wherein R is
hydrogen or C.sub.1-6 alkyl and R' is hydrogen, C.sub.1-6 alkyl, or
absent; [0048] Q is C or N; [0049] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or if Q is N then R.sub.3
is absent; [0050] R.sub.4 is hydrogen, heteroaryl, heterocyclyl,
--C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [0051] R.sub.11 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken
together with the atoms to which they are attached join together to
form a heteroaryl, or R.sub.11 and R.sub.12 taken together with the
atoms to which they are attached join together to form a
heteroaryl; [0052] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12
taken together with the atoms to which they are attached join
together to form a heteroaryl; [0053] R.sub.20 is hydrogen or
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14);
[0054] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9R.sub.10,
R.sub.13, and R.sub.14 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
alkylamino, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
[0055] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or
alkylamino; [0056] R.sub.17 and R.sub.18 are each independently
hydrogen or alkyl or can optionally join together to form a bond;
[0057] R.sub.19 is aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0058] n is 0, 1, or 2; and [0059] m is 0 or 1.
[0060] In various aspects, the present disclosure provides for
compounds of Structures (IV-A), (IV-B), or (IV-C):
##STR00004##
[0061] or a pharmaceutically acceptable salt thereof, wherein:
[0062] L.sub.1, L.sub.2, L.sub.3, L.sub.4, and A are each
independently CH or N; [0063] R.sub.1 is hydrogen, cyano, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [0064] q is 0, 1, 2, 3,
or 4; [0065] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [0066] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [0067] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[0068] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [0069] R.sub.23 is hydrogen,
--N(R.sub.13)(R.sub.14), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, is
absent if L.sub.1 is N, or R.sub.23 and R.sub.24 taken together
with the atoms to which they are attached join together to form a
heterocyclyl, heteroaryl, or cycloalkyl; [0070] R.sub.24 is
hydrogen, --N(R.sub.13)(R.sub.14), C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --(C.sub.1-6 alkoxy)(heterocyclyl), heterocyclyl, or
R.sub.23 and R.sub.24 taken together with the atoms to which they
are attached join together to form a heterocyclyl, heteroaryl, or
cycloalkyl; [0071] R.sub.26 is hydrogen, heteroaryl, heterocyclyl,
--N(R.sub.13)(R.sub.14), or --S(.dbd.O).sub.2R.sub.20; [0072]
R.sub.13 and R.sub.14 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
alkylamino, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
[0073] R.sub.25 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
and [0074] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, or alkylamino.
[0075] In various aspects, the present disclosure provides for
compounds of Structure (V):
##STR00005##
[0076] or a pharmaceutically acceptable salt thereof, wherein:
[0077] L.sub.7 is N or O, wherein R.sub.30 is absent if L.sub.7 is
O; [0078] A is CH or N; [0079] R.sub.1 is hydrogen, cyano, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; q is 0, 1, 2, 3, or 4;
[0080] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
or --N(R.sub.13)(R.sub.14); [0081] R.sub.2 is hydrogen, halo,
C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [0082] R.sub.3 is halo,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [0083] R.sub.21 and R.sub.22
are each independently hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [0084] R.sub.29 and R.sub.30 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
hydroxyalkyl, heteroaryl, heterocyclyl, --N(R.sub.15R.sub.16),
--C(.dbd.O)R.sub.46, --R.sub.48C(.dbd.O)R.sub.47, or R.sub.29 and
R.sub.30 taken together with the atoms to which they are attached
join together to form a heteroaryl or heterocyclyl, wherein
R.sub.30 is absent if L.sub.7 is O; [0085] R.sub.46 and R.sub.47
are each independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [0086] R.sub.48 is alkyl or is absent;
[0087] R.sub.31 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[0088] R.sub.13 and R.sub.14 are each independently hydrogen,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
hydroxyalkyl, alkylamino, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [0089] R.sub.15 and R.sub.16 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino; and [0090] v
is 0 or 1.
[0091] In various aspects, the present disclosure provides for
compounds of Structures (VI-A) or (VI-B):
##STR00006##
[0092] or a pharmaceutically acceptable salt thereof, wherein:
[0093] L.sub.13, L.sub.14, L.sub.15, and A are each independently
CH or N; [0094] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; q is 0, 1, 2, 3, or 4;
[0095] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
or --N(R.sub.13)(R.sub.14); [0096] R.sub.2 is hydrogen, halo,
C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [0097] R.sub.3 is halo,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [0098] R.sub.21 and R.sub.22
are each independently hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [0099] R.sub.34 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl,
heterocyclyl, heteroaryl, alkylamino, CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or --N(R.sub.15R.sub.16); [0100]
R.sub.35 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [0101]
R.sub.36 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.15R.sub.16), heterocyclyl, or heteroaryl; [0102] R.sub.13
and R.sub.14 are each independently hydrogen, C.sub.1-6 alkyl,
cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
alkylamino, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
and [0103] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, or alkylamino.
[0104] In various aspects, the present disclosure provides for
compounds of Structure (VI-J):
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein: [0105]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or branched
alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [0106] the C.sub.3-C.sub.5
cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
and [0107] when R.sup.1 is not H, --CN or halogen, it is optionally
substituted with one or more halogens; [0108] each R.sup.2 is
independently H, halogen or C.sub.1-C.sub.4 straight or branched
alkyl; [0109] R.sup.3 is H, --OH, or halogen; [0110] R.sup.21 is
cyclobutyl, azetidin-1-yl, or cyclopropyl; [0111] R.sup.22 is H,
halogen, or C.sub.1-C.sub.2 alkyl; [0112] R.sup.35 is
--C(O)--R.sup.351, --C(O)--NHR.sup.351, --C(O)--O--R.sup.351 or
S(O).sub.2R.sup.351; and [0113] R.sup.351 is C.sub.1-C.sub.6
straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or
heteroaryl.
[0114] In some aspects of Structure (VI-J), R.sup.3 is H or
halogen.
[0115] In some aspects of Structure (VI-J), R.sup.1 is halogen,
--CN or C.sub.1-C.sub.2 haloalkyl.
[0116] In some aspects of Structure (VI-J), R.sup.22 is
C.sub.1-C.sub.2 alkyl.
[0117] In some aspects of Structure (VI-J), R.sup.21 is cyclobutyl
and R.sup.22 is C.sub.1-C.sub.2 alkyl.
[0118] In some aspects of Structure (VI-J), R.sup.21 is
cyclobutyl.
[0119] In some aspects of Structure (VI-J), R.sup.3 is H or F.
[0120] In some aspects of Structure (VI-J), R.sup.1 is --CN.
[0121] In some aspects of Structure (VI-J), R.sup.1 is
--CF.sub.3.
[0122] In some aspects of Structure (VI-J), R.sup.22 is H, methyl
or ethyl.
[0123] In some aspects of Structure (VI-J), R.sup.22 is H.
[0124] In some aspects of Structure (VI-J), R.sup.22 is methyl.
[0125] In some aspects of Structure (VI-J), R.sup.35 is
--C(O)--NHR.sup.351.
[0126] In some aspects of Structure (VI-J), R.sup.351 is isopropyl,
isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,
(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,
(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.
[0127] In some aspects of Structure (VI-J), R.sup.351 is
(R)-(tetrahydrofuran-2-yl)methyl or
(S)-(tetrahydrofuran-2-yl)methyl.
[0128] In some aspects of Structure (VI-J), R.sup.1 is --CN, each
R.sup.2 is hydrogen, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is H, R.sup.35 is --C(O)--NHR.sup.351 where
R.sup.351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,
(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,
(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or
(S)-tetrahydro-2H-pyran-3-yl.
[0129] In some aspects of Structure (VI-J), R.sup.35 is
--C(O)--O--R.sup.351.
[0130] In some aspects of Structure (VI-J), R.sup.351 is isopropyl,
isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,
(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,
(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
[0131] In some aspects of Structure (VI-J), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is H, R.sup.35 is --C(O)--O--R.sup.351 where
R.sup.351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,
(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,
(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or
(S)-tetrahydro-2H-pyran-3-yl.
[0132] In some aspects of Structure (VI-J), R.sup.351 is
(R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.
[0133] In some aspects of Structure (VI-J), compounds have a
structure selected from the group consisting of:
##STR00008## ##STR00009##
[0134] In various aspects, the present disclosure provides for
compounds of Structures (VII-A) or (VII-B):
##STR00010##
[0135] or a pharmaceutically acceptable salt thereof, wherein:
[0136] L.sub.16 is C or N, wherein R.sub.41 is absent if L.sub.16
is N; [0137] L.sub.17, L.sub.8, and A are each independently CH or
N; [0138] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; q is 0, 1, 2, 3, or 4;
[0139] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
or --N(R.sub.13)(R.sub.14); [0140] R.sub.2 is hydrogen, halo,
C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [0141] R.sub.3 is hydrogen,
hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [0142]
R.sub.21 and R.sub.22 are each independently hydrogen, halo, cyano,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [0143] R.sub.40, R.sub.42, and R.sub.43
are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, --C(.dbd.O)R, hydroxyalkyl, hydroxyl,
--N(R.sub.13R.sub.14), or R.sub.41 and R.sub.42 taken together with
the atoms to which they are attached join together to form a
heteroaryl or heterocyclyl; [0144] R.sub.41 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, --C(.dbd.O)R,
hydroxyalkyl, hydroxyl, --N(R.sub.13R.sub.14), R.sub.41 is absent
if L.sub.16 is N, or R.sub.41 and R.sub.42 taken together with the
atoms to which they are attached join together to form a heteroaryl
or heterocyclyl; [0145] R is hydrogen, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [0146]
R.sub.39 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [0147]
R.sub.13 and R.sub.14 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
alkylamino, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
and [0148] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
hydroxyalkyl, or alkylamino.
[0149] In various aspects, the present disclosure provides for
compounds of Structures (VIII-A), (VIII-B), or (VIII-C):
##STR00011##
[0150] or a pharmaceutically acceptable salt thereof, wherein:
[0151] L.sub.19 and A are each independently CH or N; [0152]
R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [0153] q is 0, 1, 2, 3,
or 4; [0154] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [0155] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [0156] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[0157] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [0158] R.sub.39 is hydrogen, C.sub.1-6
alkyl, or C.sub.1-6 alkoxy; [0159] R.sub.44 and R.sub.45 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
cycloalkyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, --S(.dbd.O).sub.2R.sub.20, --C(.dbd.O)R, or
--N(R.sub.13R.sub.14); and [0160] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; and [0161]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino.
[0162] In various aspects, compounds of Structure (IX) are
provided:
##STR00012##
[0163] or a pharmaceutically acceptable salt thereof, wherein:
[0164] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0165]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0166] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0167] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0168] R.sup.3 is H,
--OH, or halogen; [0169] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0170] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0171] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [0172] t is 0 or 1; [0173] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0174] L.sup.1 is CR.sup.23 or N; [0175]
L.sup.2 is CH or N; [0176] at least one of L.sup.1 or L.sup.2 is N;
and [0177] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl.
[0178] In some aspects of Structure (IX), R.sup.24 is
C.sub.1-C.sub.4 straight or branched alkyl or --(C.sub.1-C.sub.4
alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or branched alkyl)
wherein t is 0 or 1.
[0179] In some aspects of Structure (IX), R.sup.21 is halogen,
C.sub.1-C.sub.4 straight or branched alkyl, C.sub.3-C.sub.5
cycloalkyl wherein the C.sub.3-C.sub.5 cycloalkyl optionally
includes an oxygen or nitrogen heteroatom,
--S(O).sub.u--(C.sub.1-C.sub.4 straight or branched alkyl) wherein
u is 0 or 2, or --S(O).sub.u--(C.sub.3-C.sub.5 cycloalkyl) wherein
u is 0 or 2;
[0180] In some aspects of Structure (IX), R.sup.3 is H or
halogen.
[0181] In some aspects of Structure (IX), R.sup.1 is halogen, --CN
or C.sub.1-C.sub.2 haloalkyl.
[0182] In some aspects of Structure (IX), both L.sup.1 and L.sup.2
are N.
[0183] In some aspects of Structure (IX), R.sup.21 is
C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is
C.sub.1-C.sub.2 alkyl.
[0184] In some aspects of Structure (IX), R.sup.21 is
C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[0185] In some aspects of Structure (IX), R.sup.24 is
--(C.sub.1-C.sub.2 alkyl).sub.t-O--(C.sub.1-C.sub.2 alkyl) wherein
t is 0 or 1.
[0186] In some aspects of Structure (IX), R.sup.21 is
C.sub.3-C.sub.5 cycloalkyl, R.sup.22 is C.sub.1-C.sub.2 alkyl and
R.sup.24 is C.sub.1-C.sub.2 alkyl.
[0187] In some aspects of Structure (IX), R.sup.21 is cyclobutyl,
R.sup.22 is C.sub.1-C.sub.2 alkyl and R.sup.24 is C.sub.1-C.sub.2
alkyl.
[0188] In some aspects of Structure (IX), R.sup.21 is
cyclobutyl.
[0189] In some aspects of Structure (IX), R.sup.3 is H or F.
[0190] In some aspects of Structure (IX), R.sup.1 is --CN.
[0191] In some aspects of Structure (IX), R.sup.1 is
--CF.sub.3.
[0192] In some aspects of Structure (IX), R.sup.22 is H, methyl or
ethyl.
[0193] In some aspects of Structure (IX), R.sup.22 is H.
[0194] In some aspects of Structure (IX), R.sup.22 is methyl.
[0195] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 and L.sup.2 are N, and
R.sup.24 is methyl, ethyl, hydroxymethyl, methoxymethyl,
2-methoxyethyl.
[0196] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 and L.sup.2 are N, and
R.sup.24 is methoxy or ethoxy.
[0197] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 is CH, L.sup.2 is N, and
R.sup.24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or
2-methoxyethyl.
[0198] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 is N, L.sup.2 is CH, and
R.sup.24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or
2-methoxyethyl.
[0199] In some aspects of Structure (IX), compounds have a
structure selected from the group consisting of:
##STR00013##
[0200] In various aspects, compounds of Structure (X) are
provided:
##STR00014##
[0201] or a pharmaceutically acceptable salt thereof, wherein:
[0202] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0203]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0204] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0205] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0206] R.sup.3 is H,
--OH or halogen; [0207] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [0208] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[0209] t is 0 or 1, and [0210] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [0211] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.501).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [0212] t is 0
or 1, and [0213] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [0214] n is 1, 2 or 3; [0215] m
is 1 or 2; [0216] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [0217] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [0218] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [0219] t is 0 or 1, and [0220]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0221] s is 0, 1 or 2; [0222] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [0223] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.5, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601.
[0224] In some aspects of Structure (X), R.sup.21 is halogen,
C.sub.1-C.sub.4 straight or branched alkyl or C.sub.3-C.sub.5
cycloalkyl.
[0225] In some aspects of Structure (X), R.sup.3 is H or
halogen.
[0226] In some aspects of Structure (X), R.sup.1 is --CN or
C.sub.1-C.sub.2 haloalkyl.
[0227] In some aspects of Structure (X), R.sup.3 is H or F.
[0228] In some aspects of Structure (X), R.sup.1 is --CN.
[0229] In some aspects of Structure (X), R.sup.1 is --CF.sub.3.
[0230] In some aspects of Structure (X), n is 1.
[0231] In some aspects of Structure (X), n is 2.
[0232] In some aspects of Structure (X), m is 1
[0233] In some aspects of Structure (X), m is 2.
[0234] In some aspects of Structure (X), R.sup.21 is
C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is
C.sub.1-C.sub.2 alkyl.
[0235] In some aspects of Structure (X), R.sup.21 is
C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[0236] In some aspects of Structure (X), n is 2, m is 1, L.sup.3 is
--N--C(O)--O--(C.sub.1-C.sub.2 alkyl).
[0237] In some aspects of Structure (X), L.sup.3 is NR.sup.50;
R.sup.50 is C.sub.1-C.sub.2 alkyl; R.sup.21 is cyclobutyl; R.sup.22
is H or methyl; R.sup.3 is H; R.sup.1 is --CN; m is 2 and n is 1 or
2.
[0238] In some aspects of Structure (X), n is 2, m is 1, L.sup.3 is
O and s is 0.
[0239] In some aspects of Structure (X), R.sup.22 is H, methyl or
ethyl.
[0240] In some aspects of Structure (X), R.sup.22 is methyl.
[0241] In some aspects of Structure (X), R.sup.22 is H.
[0242] In some aspects of Structure (X), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, n is 2 and L.sup.3 is NR.sup.50
where R.sup.50 is methyl or ethyl.
[0243] In some aspects of Structure (X), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, n is 2 and L.sup.3 is O.
[0244] In some aspects of Structure (X), the compound has a
structure selected from the group consisting of:
##STR00015##
[0245] In various aspects, compounds of Structure (XI) are
provided:
##STR00016##
or a pharmaceutically acceptable salt thereof, wherein: [0246]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or branched
alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [0247] the C.sub.3-C.sub.5
cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
and [0248] when R.sup.1 is not H, --CN or halogen, it is optionally
substituted with one or more halogens; [0249] each R.sup.2 is
independently H, halogen or C.sub.1-C.sub.4 straight or branched
alkyl; [0250] R.sup.3 is H, --OH, or halogen; [0251] R.sup.21 is
cyclobutyl, azetidin-1-yl, or cyclopropyl; [0252] R.sup.22 is H,
halogen, C.sub.1-C.sub.2 alkyl; and [0253] R.sup.351 is
C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or C.sub.2
alkyl).
[0254] In some aspects of Structure (XI), R.sup.3 is H or
halogen.
[0255] In some aspects of Structure (XI), R.sup.1 is halogen, --CN
or C.sub.1-C.sub.2 haloalkyl.
[0256] In some aspects of Structure (XI), R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[0257] In some aspects of Structure (XI), R.sup.21 is cyclobutyl
and R.sup.22 is C.sub.1-C.sub.2 alkyl.
[0258] In some aspects of Structure (XI), R.sup.21 is
cyclobutyl.
[0259] In some aspects of Structure (XI), R.sup.3 is H or F.
[0260] In some aspects of Structure (XI), R.sup.1 is --CN.
[0261] In some aspects of Structure (XI), R.sup.1 is
--CF.sub.3.
[0262] In some aspects of Structure (XI), R.sup.22 is H, methyl or
ethyl.
[0263] In some aspects of Structure (XI), R.sup.22 is H.
[0264] In some aspects of Structure (XI), R.sup.22 is methyl.
[0265] In some aspects of Structure (XI), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is cyclobutyl, R.sup.22
is methyl and R.sup.351 is methyl or ethyl.
[0266] In some aspects of Structure (XI), the compound has a
structure selected from the group consisting of:
##STR00017##
[0267] In various aspects, the present disclosure provides
pharmaceutical compositions comprising any one of the compounds of
Structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
(X) or (XI) and a pharmaceutically acceptable carrier, excipient,
or diluent.
[0268] In various aspects, the present disclosure provides methods
of treating a condition characterized by disregulation of a fatty
acid synthase function in subject, the method comprising
administering to the subject in need of such treatment an effective
amount of a compound of any one of the Structures (I), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI). In various
aspects the condition characterized by disregulation of the fatty
acid synthase function is a viral infection or cancer. In various
aspects the viral infection is treated using a compound of any one
of the Structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII),
(IX), (X) or (XI) in combination with one or more additional
antiviral treatments. In various aspects the cancer is treated
using a compound of any one of the Structures (I), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combination
with one or more additional cancer treatments. In various aspects,
the viral infection is hepatitis C.
[0269] In various aspects, the present disclosure relates to a
method of treating fatty liver disease in a subject in need
thereof, the method comprising administering to the subject a fatty
acid synthase inhibitor having a formula of:
[0270] (a) Formula (IX)
##STR00018##
[0271] or a pharmaceutically acceptable salt thereof, wherein:
[0272] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0273]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0274] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0275] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0276] R.sup.3 is H,
--OH, or halogen; [0277] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0278] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0279] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [0280] t is 0 or 1; [0281] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0282] L.sup.1 is CR.sup.23 or N; [0283]
L.sup.2 is CH or N; [0284] at least one of L.sup.1 or L.sup.2 is N;
and [0285] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[0286] (b) Formula (X):
##STR00019##
[0287] or a pharmaceutically acceptable salt thereof, wherein:
[0288] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0289]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0290] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0291] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0292] R.sup.3 is H,
--OH or halogen; [0293] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [0294] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[0295] t is 0 or 1, and [0296] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [0297] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.501).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [0298] t is 0
or 1, and [0299] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [0300] n is 1, 2 or 3; [0301] m
is 1 or 2; [0302] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [0303] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [0304] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [0305] t is 0 or 1, and [0306]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0307] s is 0, 1 or 2; [0308] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [0309] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.5, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[0310] (c) Formula (VI-J)
##STR00020##
[0311] or a pharmaceutically acceptable salt thereof, wherein:
[0312] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0313]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0314] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0315] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0316] R.sup.3 is H, --OH, or halogen;
[0317] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[0318] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [0319]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [0320] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or (d) Formula (XII):
##STR00021##
[0321] or pharmaceutically acceptable salts thereof, wherein:
[0322] L-Ar is
[0322] ##STR00022## [0323] Ar is
[0323] ##STR00023## [0324] Het is a 5- to 6-membered heteroaryl;
[0325] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0326] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0327] R.sup.3 is H or
F; [0328] R.sup.11 is H or --CH.sub.3; [0329] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0330] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0331] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0332] t is 0 or 1; [0333] u is 0 or 1; [0334] with the proviso
that when u is 1, t is 1; and [0335] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [0336] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[0337] (e) Formula (XIII):
##STR00024## [0338] or pharmaceutically acceptable salts thereof,
wherein: [0339] L-Ar is
[0339] ##STR00025## [0340] Ar is
[0340] ##STR00026## [0341] Het is a 5- to 6-membered heteroaryl;
[0342] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0343] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0344] R.sup.3 is H or
F; [0345] R.sup.11 is H or --CH.sub.3; [0346] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0347] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0348] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0349] each t is independently 0 or 1; [0350] each
u is independently 0 or 1; and [0351] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[0352] (f) Formula (XIV):
##STR00027##
[0353] or pharmaceutically acceptable salts thereof, wherein:
[0354] L-Ar is
[0354] ##STR00028## [0355] Ar is
[0355] ##STR00029## with the proviso that when L-Ar is
##STR00030## Ar is not
##STR00031## [0356] Het is a 5- to 6-membered heteroaryl; [0357]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0358] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0359] R.sup.3 is H or
F; [0360] R.sup.11 is H or --CH.sub.3; [0361] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0362] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [0363] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0364] each t is independently 0 or 1; and [0365]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[0366] (g) Formula (XV):
##STR00032##
[0367] or pharmaceutically acceptable salts thereof, wherein:
[0368] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [0369] n is 1, 2, or 3; [0370] m is 1
or 2 with the proviso that n+m.gtoreq.3; [0371] L-Ar is
[0371] ##STR00033## [0372] Ar is
[0372] ##STR00034## with the proviso that when L-Ar is
##STR00035## Ar is not
##STR00036## [0373] Het is a 5- to 6-membered heteroaryl; [0374]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0375] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0376] R.sup.3 is H or
F; [0377] R.sup.11 is H or --CH.sub.3; [0378] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [0379] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[0380] (h) Formula (XVI):
##STR00037##
[0381] or pharmaceutically acceptable salts thereof, wherein:
[0382] L-Ar is
[0382] ##STR00038## [0383] Ar is
[0383] ##STR00039## [0384] Het is a 5- to 6-membered heteroaryl;
[0385] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0386] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0387] R.sup.3 is H or
F; [0388] R.sup.11 is H or --CH.sub.3; [0389] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0390] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0391] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[0392] (i) Formula (XVII):
##STR00040##
[0393] or pharmaceutically acceptable salts thereof, wherein:
[0394] L-Ar is
[0394] ##STR00041## [0395] Ar is
[0395] ##STR00042## with the proviso that when L-Ar is
##STR00043## Ar is not
##STR00044## [0396] Het is a 5- to 6-membered heteroaryl; [0397]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0398] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0399] R.sup.3 is H or
F; [0400] R.sup.11 is H or --CH.sub.3; [0401] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0402] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0403] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0404] t is 0 or 1; [0405] u is 0 or 1; [0406] with the proviso
that when u is 1, t is 1; and [0407] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[0408] (j) Formula (XVIII):
##STR00045##
[0409] or pharmaceutically acceptable salts thereof, wherein:
[0410] L-Ar is
[0410] ##STR00046## [0411] Ar is
[0411] ##STR00047## with the proviso that when L-Ar is
##STR00048## Ar is not
##STR00049## [0412] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[0413] Het is a 5- to 6-membered heteroaryl; [0414] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [0415] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [0416] R.sup.3 is H or F; [0417] R.sup.11 is
H or --CH.sub.3; [0418] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[0419] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [0420]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[0421] (k) Formula (XIX):
##STR00050##
[0422] or pharmaceutically acceptable salts thereof, wherein:
[0423] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[0424] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [0425] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [0426] Ar is
[0426] ##STR00051## [0427] Het is a 5- to 6-membered heteroaryl;
[0428] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [0429] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [0430] R.sup.3 is H or F; [0431]
R.sup.11 is H or --CH.sub.3; [0432] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [0433] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[0434] (l) Formula (XX):
##STR00052##
[0435] or a pharmaceutically acceptable salt thereof, wherein:
[0436] L-Ar is
[0436] ##STR00053## [0437] Ar is
[0437] ##STR00054## [0438] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [0439] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0440]
R.sup.3 is H or F; [0441] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[0442] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [0443]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [0444] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[0445] (m) Formula (XI):
##STR00055##
[0446] or a pharmaceutically acceptable salt thereof, wherein:
[0447] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0448]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0449] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0450] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0451] R.sup.3 is H, --OH, or halogen;
[0452] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[0453] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [0454]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[0455] In various aspects, the present disclosure relates to a
method of treating non-alcoholic steatohepatitis (NASH) in a
subject in need thereof, the method comprising administering to the
subject a fatty acid synthase inhibitor having a formula of:
[0456] (a) Formula (IX)
##STR00056##
[0457] or a pharmaceutically acceptable salt thereof, wherein:
[0458] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0459]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0460] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0461] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0462] R.sup.3 is H,
--OH, or halogen; [0463] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0464] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0465] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [0466] t is 0 or 1; [0467] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0468] L.sup.1 is CR.sup.23 or N; [0469]
L.sup.2 is CH or N; [0470] at least one of L.sup.1 or L.sup.2 is N;
and [0471] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[0472] (b) Formula (X):
##STR00057##
[0473] or a pharmaceutically acceptable salt thereof, wherein:
[0474] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0475]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0476] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
each R.sup.2 is independently hydrogen, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0477] R.sup.3 is H, --OH or halogen;
[0478] L.sup.3 is C(R.sup.60).sub.2, O or NR.sup.50; [0479] each
R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[0480] t is 0 or 1, and [0481] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [0482] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [0483] t is 0
or 1, and [0484] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [0485] n is 1, 2 or 3; [0486] m
is 1 or 2; [0487] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [0488] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [0489] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [0490] t is 0 or 1, and [0491]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0492] s is 0, 1 or 2; [0493] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [0494] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[0495] (c) Formula (VI-J)
##STR00058##
[0496] or a pharmaceutically acceptable salt thereof, wherein:
[0497] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0498]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0499] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0500] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0501] R.sup.3 is H, --OH, or halogen;
[0502] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[0503] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [0504]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [0505] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[0506] (d) Formula (XII):
##STR00059##
[0507] or pharmaceutically acceptable salts thereof, wherein:
[0508] L-Ar is
[0508] ##STR00060## [0509] Ar is
[0509] ##STR00061## [0510] Het is a 5- to 6-membered heteroaryl;
[0511] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0512] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0513] R.sup.3 is H or
F; [0514] R.sup.11 is H or --CH.sub.3; [0515] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0516] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0517] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0518] t is 0 or 1; [0519] u is 0 or 1; [0520] with the proviso
that when u is 1, t is 1; and [0521] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [0522] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[0523] (e) Formula (XIII):
##STR00062##
[0524] or pharmaceutically acceptable salts thereof, wherein:
[0525] L-Ar is
[0525] ##STR00063## [0526] Ar is
[0526] ##STR00064## [0527] Het is a 5- to 6-membered heteroaryl;
[0528] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0529] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0530] R.sup.3 is H or
F; [0531] R.sup.11 is H or --CH.sub.3; [0532] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0533] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0534] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0535] each t is independently 0 or 1; [0536] each
u is independently 0 or 1; and [0537] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[0538] (f) Formula (XIV):
##STR00065##
[0539] or pharmaceutically acceptable salts thereof, wherein:
[0540] L-Ar is
[0540] ##STR00066## [0541] Ar is
[0541] ##STR00067## with the proviso that when L-Ar is
##STR00068## Ar is not
##STR00069## [0542] Het is a 5- to 6-membered heteroaryl; [0543]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0544] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0545] R.sup.3 is H or
F; [0546] R.sup.11 is H or --CH.sub.3; [0547] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0548] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [0549] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0550] each t is independently 0 or 1; and [0551]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[0552] (g) Formula (XV):
##STR00070##
[0553] or pharmaceutically acceptable salts thereof, wherein:
[0554] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [0555] n is 1, 2, or 3; [0556] m is 1
or 2 with the proviso that n+m.gtoreq.3; [0557] L-Ar is
[0557] ##STR00071## [0558] Ar is
##STR00072##
[0558] ##STR00073## with the proviso that when L-Ar is
##STR00074## Ar is not
##STR00075## [0559] Het is a 5- to 6-membered heteroaryl; [0560]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0561] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0562] R.sup.3 is H or
F; [0563] R.sup.11 is H or --CH.sub.3; [0564] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [0565] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[0566] (h) Formula (XVI):
##STR00076##
[0567] or pharmaceutically acceptable salts thereof, wherein:
[0568] L-Ar is
[0568] ##STR00077## [0569] Ar is
[0569] ##STR00078## [0570] Het is a 5- to 6-membered heteroaryl;
[0571] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0572] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0573] R.sup.3 is H or
F; [0574] R.sup.11 is H or --CH.sub.3; [0575] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0576] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0577] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[0578] (i) Formula (XVII):
##STR00079##
[0579] or pharmaceutically acceptable salts thereof, wherein:
[0580] L-Ar is
##STR00080## [0581] Ar is
[0581] ##STR00081## with the proviso that when L-Ar is
##STR00082## Ar is not
##STR00083## [0582] Het is a 5- to 6-membered heteroaryl; [0583]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0584] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0585] R.sup.3 is H or
F; [0586] R.sup.11 is H or --CH.sub.3; [0587] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0588] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0589] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0590] t is 0 or 1; [0591] u is 0 or 1; [0592] with the proviso
that when u is 1, t is 1; and [0593] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[0594] (j) Formula (XVIII):
##STR00084##
[0595] or pharmaceutically acceptable salts thereof, wherein:
[0596] L-Ar is
[0596] ##STR00085## [0597] Ar is
[0597] ##STR00086## [0598] with the proviso that when L-Ar is
[0598] ##STR00087## Ar is not
##STR00088## [0599] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[0600] Het is a 5- to 6-membered heteroaryl; [0601] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [0602] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [0603] R.sup.3 is H or F; [0604] R.sup.11 is
H or --CH.sub.3; [0605] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[0606] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [0607]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[0608] (k) Formula (XIX):
##STR00089##
[0609] or pharmaceutically acceptable salts thereof, wherein:
[0610] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[0611] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [0612] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [0613] Ar is
[0613] ##STR00090## [0614] Het is a 5- to 6-membered heteroaryl;
[0615] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [0616] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [0617] R.sup.3 is H or F; [0618]
R.sup.11 is H or --CH.sub.3; [0619] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [0620] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[0621] (l) Formula (XX):
##STR00091##
[0622] or a pharmaceutically acceptable salt thereof, wherein:
[0623] L-Ar is
[0623] ##STR00092## [0624] Ar is
[0624] ##STR00093## [0625] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [0626] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0627]
R.sup.3 is H or F; [0628] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[0629] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [0630]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [0631] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[0632] (m) Formula (XI):
##STR00094##
[0633] or a pharmaceutically acceptable salt thereof, wherein:
[0634] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0635]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0636] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0637] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0638] R.sup.3 is H, --OH, or halogen;
[0639] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[0640] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [0641]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[0642] In various aspects, the present disclosure relates to a
method of treating non-alcoholic fatty liver disease (NAFLD) in a
subject in need thereof, the method comprising administering to the
subject a fatty acid synthase inhibitor having a formula of:
[0643] (a) Formula (IX)
##STR00095##
[0644] or a pharmaceutically acceptable salt thereof, wherein:
[0645] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0646]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0647] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0648] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0649] R.sup.3 is H,
--OH, or halogen; [0650] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0651] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0652] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [0653] t is 0 or 1; [0654] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0655] L.sup.1 is CR.sup.23 or N; [0656]
L.sup.2 is CH or N; [0657] at least one of L.sup.1 or L.sup.2 is N;
and [0658] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[0659] (b) Formula (X):
##STR00096##
[0660] or a pharmaceutically acceptable salt thereof, wherein:
[0661] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0662]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0663] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0664] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0665] R.sup.3 is H,
--OH or halogen; [0666] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [0667] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[0668] t is 0 or 1, and [0669] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [0670] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.501).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [0671] t is 0
or 1, and [0672] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [0673] n is 1, 2 or 3; [0674] m
is 1 or 2; [0675] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [0676] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [0677] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [0678] t is 0 or 1, and [0679]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0680] s is 0, 1 or 2; [0681] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [0682] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[0683] (c) Formula (VI-J)
##STR00097##
[0684] or a pharmaceutically acceptable salt thereof, wherein:
[0685] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0686]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0687] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0688] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0689] R.sup.3 is H, --OH, or halogen;
[0690] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[0691] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [0692]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [0693] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[0694] (d) Formula (XII):
##STR00098##
[0695] or pharmaceutically acceptable salts thereof, wherein:
[0696] L-Ar is
[0696] ##STR00099## [0697] Ar is
[0697] ##STR00100## [0698] Het is a 5- to 6-membered heteroaryl;
[0699] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0700] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0701] R.sup.3 is H or
F; [0702] R.sup.11 is H or --CH.sub.3; [0703] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0704] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0705] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0706] t is 0 or 1; [0707] u is 0 or 1; [0708] with the proviso
that when u is 1, t is 1; and [0709] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [0710] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[0711] (e) Formula (XIII):
##STR00101##
[0712] or pharmaceutically acceptable salts thereof, wherein:
[0713] L-Ar is
[0713] ##STR00102## [0714] Ar is
[0714] ##STR00103## [0715] Het is a 5- to 6-membered heteroaryl;
[0716] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0717] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0718] R.sup.3 is H or
F; [0719] R.sup.11 is H or --CH.sub.3; [0720] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0721] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0722] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0723] each t is independently 0 or 1; [0724] each
u is independently 0 or 1; and [0725] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[0726] (f) Formula (XIV):
##STR00104##
[0727] or pharmaceutically acceptable salts thereof, wherein:
[0728] L-Ar is
[0728] ##STR00105## [0729] Ar is
[0729] ##STR00106## with the proviso that when L-Ar is
##STR00107## Ar is not
##STR00108## [0730] Het is a 5- to 6-membered heteroaryl; [0731]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0732] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0733] R.sup.3 is H or
F; [0734] R.sup.11 is H or --CH.sub.3; [0735] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0736] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [0737] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0738] each t is independently 0 or 1; and [0739]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[0740] (g) Formula (XV):
##STR00109##
[0741] or pharmaceutically acceptable salts thereof, wherein:
[0742] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [0743] n is 1, 2, or 3; [0744] m is 1
or 2 with the proviso that n+m.gtoreq.3; [0745] L-Ar is
[0745] ##STR00110## [0746] Ar is
[0746] ##STR00111## with the proviso that when L-Ar is
##STR00112## Ar is not
##STR00113## [0747] Het is a 5- to 6-membered heteroaryl; [0748]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0749] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0750] R.sup.3 is H or
F; [0751] R.sup.11 is H or --CH.sub.3; [0752] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [0753] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[0754] (h) Formula (XVI):
##STR00114##
[0755] or pharmaceutically acceptable salts thereof, wherein:
[0756] L-Ar is
[0756] ##STR00115## [0757] Ar is
[0757] ##STR00116## [0758] Het is a 5- to 6-membered heteroaryl;
[0759] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0760] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0761] R.sup.3 is H or
F; [0762] R.sup.11 is H or --CH.sub.3; [0763] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0764] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0765] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[0766] (i) Formula (XVII):
##STR00117##
[0767] or pharmaceutically acceptable salts thereof, wherein:
[0768] L-Ar is
[0768] ##STR00118## [0769] Ar is
[0769] ##STR00119## with the proviso that when L-Ar is
##STR00120## Ar is not
##STR00121## [0770] Het is a 5- to 6-membered heteroaryl; [0771]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0772] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0773] R.sup.3 is H or
F; [0774] R.sup.11 is H or --CH.sub.3; [0775] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0776] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0777] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0778] t is 0 or 1; [0779] u is 0 or 1; [0780] with the proviso
that when u is 1, t is 1; and [0781] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[0782] (j) Formula (XVIII):
##STR00122##
[0783] or pharmaceutically acceptable salts thereof, wherein:
[0784] L-Ar is
[0784] ##STR00123## [0785] Ar is
[0785] ##STR00124## [0786] with the proviso that when L-Ar is
[0786] ##STR00125## Ar is not
##STR00126## [0787] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[0788] Het is a 5- to 6-membered heteroaryl; [0789] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [0790] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [0791] R.sup.3 is H or F; [0792] R.sup.11 is
H or --CH.sub.3; [0793] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[0794] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [0795]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[0796] (k) Formula (XIX):
##STR00127##
[0797] or pharmaceutically acceptable salts thereof, wherein:
[0798] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[0799] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [0800] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [0801] Ar is
[0801] ##STR00128## [0802] Het is a 5- to 6-membered heteroaryl;
[0803] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [0804] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [0805] R.sup.3 is H or F; [0806]
R.sup.11 is H or --CH.sub.3; [0807] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [0808] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[0809] (l) Formula (XX):
##STR00129##
[0810] or a pharmaceutically acceptable salt thereof, wherein:
[0811] L-Ar is
[0811] ##STR00130## [0812] Ar is
[0812] ##STR00131## [0813] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [0814] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0815]
R.sup.3 is H or F; [0816] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[0817] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [0818]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [0819] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[0820] (m) Formula (XI):
##STR00132##
[0821] or a pharmaceutically acceptable salt thereof, wherein:
[0822] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0823]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0824] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0825] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0826] R.sup.3 is H, --OH, or halogen;
[0827] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[0828] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [0829]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[0830] In various aspects, the present disclosure relates to a
method of treating metabolic syndrome in a subject in need thereof,
the method comprising administering to the subject a fatty acid
synthase inhibitor having a formula of:
[0831] (a) Formula (IX)
##STR00133##
[0832] or a pharmaceutically acceptable salt thereof, wherein:
[0833] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0834]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0835] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0836] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0837] R.sup.3 is H,
--OH, or halogen; [0838] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0839] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0840] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [0841] t is 0 or 1; [0842] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0843] L.sup.1 is CR.sup.23 or N; [0844]
L.sup.2 is CH or N; [0845] at least one of L.sup.1 or L.sup.2 is N;
and [0846] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[0847] (b) Formula (X):
##STR00134##
[0848] or a pharmaceutically acceptable salt thereof, wherein:
[0849] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0850]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0851] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0852] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [0853] R.sup.3 is H,
--OH or halogen; [0854] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [0855] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[0856] t is 0 or 1, and [0857] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [0858] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [0859] t is 0
or 1, and [0860] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [0861] n is 1, 2 or 3; [0862] m
is 1 or 2; [0863] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [0864] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [0865] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [0866] t is 0 or 1, and [0867]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [0868] s is 0, 1 or 2; [0869] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [0870] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[0871] (c) Formula (VI-J)
##STR00135##
[0872] or a pharmaceutically acceptable salt thereof, wherein:
[0873] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [0874]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [0875] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[0876] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [0877] R.sup.3 is H, --OH, or halogen;
[0878] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[0879] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [0880]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [0881] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[0882] (d) Formula (XII):
##STR00136##
[0883] or pharmaceutically acceptable salts thereof, wherein:
[0884] L-Ar is
[0884] ##STR00137## [0885] Ar is
[0885] ##STR00138## [0886] Het is a 5- to 6-membered heteroaryl;
[0887] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0888] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0889] R.sup.3 is H or
F; [0890] R.sup.11 is H or --CH.sub.3; [0891] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0892] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [0893] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0894] t is 0 or 1; [0895] u is 0 or 1; [0896] with the proviso
that when u is 1, t is 1; and [0897] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [0898] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[0899] (e) Formula (XIII):
##STR00139##
[0900] or pharmaceutically acceptable salts thereof, wherein:
[0901] L-Ar is
[0901] ##STR00140## [0902] Ar is
[0902] ##STR00141## [0903] Het is a 5- to 6-membered heteroaryl;
[0904] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0905] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0906] R.sup.3 is H or
F; [0907] R.sup.11 is H or --CH.sub.3; [0908] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0909] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0910] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0911] each t is independently 0 or 1; [0912] each
u is independently 0 or 1; and [0913] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[0914] (f) Formula (XIV):
##STR00142##
[0915] or pharmaceutically acceptable salts thereof, wherein:
[0916] L-Ar is
[0916] ##STR00143## [0917] Ar is
[0917] ##STR00144## with the proviso that when L-Ar is
##STR00145## Ar is not
##STR00146## [0918] Het is a 5- to 6-membered heteroaryl; [0919]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0920] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0921] R.sup.3 is H or
F; [0922] R.sup.11 is H or --CH.sub.3; [0923] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0924] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [0925] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [0926] each t is independently 0 or 1; and [0927]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[0928] (g) Formula (XV):
##STR00147##
[0929] or pharmaceutically acceptable salts thereof, wherein:
[0930] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [0931] n is 1, 2, or 3; [0932] m is 1
or 2 with the proviso that n+m.gtoreq.3; [0933] L-Ar is
[0933] ##STR00148## [0934] Ar is
[0934] ##STR00149## with the proviso that when L-Ar is
##STR00150## Ar is not
##STR00151## [0935] Het is a 5- to 6-membered heteroaryl; [0936]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0937] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0938] R.sup.3 is H or
F; [0939] R.sup.11 is H or --CH.sub.3; [0940] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [0941] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[0942] (h) Formula (XVI):
##STR00152##
[0943] or pharmaceutically acceptable salts thereof, wherein:
[0944] L-Ar is
[0944] ##STR00153## [0945] Ar is
[0945] ##STR00154## [0946] Het is a 5- to 6-membered heteroaryl;
[0947] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0948] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0949] R.sup.3 is H or
F; [0950] R.sup.11 is H or --CH.sub.3; [0951] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0952] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0953] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[0954] (i) Formula (XVII):
##STR00155##
[0955] or pharmaceutically acceptable salts thereof, wherein:
[0956] L-Ar is
[0956] ##STR00156## [0957] Ar is
[0957] ##STR00157## with the proviso that when L-Ar is
##STR00158## Ar is not
##STR00159## [0958] Het is a 5- to 6-membered heteroaryl; [0959]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [0960] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [0961] R.sup.3 is H or
F; [0962] R.sup.11 is H or --CH.sub.3; [0963] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [0964] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [0965] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[0966] t is 0 or 1; [0967] u is 0 or 1; [0968] with the proviso
that when u is 1, t is 1; and [0969] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[0970] (j) Formula (XVIII):
##STR00160##
[0971] or pharmaceutically acceptable salts thereof, wherein:
[0972] L-Ar is
[0972] ##STR00161## [0973] Ar is
[0973] ##STR00162## [0974] with the proviso that when L-Ar is
[0974] ##STR00163## Ar is not
##STR00164## [0975] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[0976] Het is a 5- to 6-membered heteroaryl; [0977] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [0978] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [0979] R.sup.3 is H or F; [0980] R.sup.11 is
H or --CH.sub.3; [0981] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[0982] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [0983]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[0984] (k) Formula (XIX):
##STR00165##
[0985] or pharmaceutically acceptable salts thereof, wherein:
[0986] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[0987] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [0988] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [0989] Ar is
[0989] ##STR00166## [0990] Het is a 5- to 6-membered heteroaryl;
[0991] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [0992] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [0993] R.sup.3 is H or F; [0994]
R.sup.11 is H or --CH.sub.3; [0995] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [0996] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[0997] (l) Formula (XX):
##STR00167##
[0998] or a pharmaceutically acceptable salt thereof, wherein:
[0999] L-Ar is
[0999] ##STR00168## [1000] Ar is
[1000] ##STR00169## [1001] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [1002] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1003]
R.sup.3 is H or F; [1004] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1005] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [1006]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [1007] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[1008] (m) Formula (XI):
##STR00170##
[1009] or a pharmaceutically acceptable salt thereof, wherein:
[1010] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1011]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1012] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1013] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1014] R.sup.3 is H, --OH, or halogen;
[1015] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1016] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [1017]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[1018] In various aspects, the present disclosure relates to a
method of treating liver cirrhosis in a subject in need thereof,
the method comprising administering to the subject a fatty acid
synthase inhibitor having a formula of:
[1019] (a) Formula (IX)
##STR00171##
[1020] or a pharmaceutically acceptable salt thereof, wherein:
[1021] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1022]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1023] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1024] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1025] R.sup.3 is H,
--OH, or halogen; [1026] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1027] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1028] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [1029] t is 0 or 1; [1030] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1031] L.sup.1 is CR.sup.23 or N; [1032]
L.sup.2 is CH or N; [1033] at least one of L.sup.1 or L.sup.2 is N;
and [1034] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[1035] (b) Formula (X):
##STR00172##
[1036] or a pharmaceutically acceptable salt thereof, wherein:
[1037] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1038]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1039] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1040] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1041] R.sup.3 is H,
--OH or halogen; [1042] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [1043] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[1044] t is 0 or 1, and [1045] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [1046] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [1047] t is 0
or 1, and [1048] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [1049] n is 1, 2 or 3; [1050] m
is 1 or 2; [1051] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [1052] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [1053] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [1054] t is 0 or 1, and [1055]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1056] s is 0, 1 or 2; [1057] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [1058] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[1059] (c) Formula (VI-J)
##STR00173##
[1060] or a pharmaceutically acceptable salt thereof, wherein:
[1061] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1062]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1063] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1064] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1065] R.sup.3 is H, --OH, or halogen;
[1066] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1067] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [1068]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [1069] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[1070] (d) Formula (XII):
##STR00174##
[1071] or pharmaceutically acceptable salts thereof, wherein:
[1072] L-Ar is
[1072] ##STR00175## [1073] Ar is
[1073] ##STR00176## [1074] Het is a 5- to 6-membered heteroaryl;
[1075] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1076] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1077] R.sup.3 is H or
F; [1078] R.sup.11 is H or --CH.sub.3; [1079] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1080] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1081] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1082] t is 0 or 1; [1083] u is 0 or 1; [1084] with the proviso
that when u is 1, t is 1; and [1085] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [1086] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[1087] (e) Formula (XIII):
##STR00177##
[1088] or pharmaceutically acceptable salts thereof, wherein:
[1089] L-Ar is
[1089] ##STR00178## [1090] Ar is
[1090] ##STR00179## [1091] Het is a 5- to 6-membered heteroaryl;
[1092] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1093] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1094] R.sup.3 is H or
F: [1095] R.sup.11 is H or --CH.sub.3; [1096] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1097] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1098] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1099] each t is independently 0 or 1; [1100] each
u is independently 0 or 1; and [1101] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[1102] (f) Formula (XIV):
##STR00180##
[1103] or pharmaceutically acceptable salts thereof, wherein:
[1104] L-Ar is
[1104] ##STR00181## [1105] Ar is
[1105] ##STR00182## with the proviso that when L-Ar is
##STR00183## Ar is not
##STR00184## [1106] Het is a 5- to 6-membered heteroaryl; [1107]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1108] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1109] R.sup.3 is H or
F; [1110] R.sup.11 is H or --CH.sub.3; [1111] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1112] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [1113] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1114] each t is independently 0 or 1; and [1115]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[1116] (g) Formula (XV):
##STR00185##
[1117] or pharmaceutically acceptable salts thereof, wherein:
[1118] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [1119] n is 1, 2, or 3; [1120] m is 1
or 2 with the proviso that n+m.gtoreq.3; [1121] L-Ar is
[1121] ##STR00186## [1122] Ar is
[1122] ##STR00187## with the proviso that when L-Ar is
##STR00188## Ar is not
##STR00189## [1123] Het is a 5- to 6-membered heteroaryl; [1124]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1125] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1126] R.sup.3 is H or
F; [1127] R.sup.11 is H or --CH.sub.3; [1128] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [1129] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[1130] (h) Formula (XVI):
##STR00190##
[1131] or pharmaceutically acceptable salts thereof, wherein:
[1132] L-Ar is
[1132] ##STR00191## [1133] Ar is
[1133] ##STR00192## [1134] Het is a 5- to 6-membered heteroaryl;
[1135] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1136] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1137] R.sup.3 is H or
F; [1138] R.sup.11 is H or --CH.sub.3; [1139] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1140] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1141] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[1142] (i) Formula (XVII):
##STR00193##
[1143] or pharmaceutically acceptable salts thereof, wherein:
[1144] L-Ar is
[1144] ##STR00194## [1145] Ar is
[1145] ##STR00195## with the proviso that when L-Ar is
##STR00196## Ar is not
##STR00197## [1146] Het is a 5- to 6-membered heteroaryl; [1147]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1148] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1149] R.sup.3 is H or
F; [1150] R.sup.11 is H or --CH.sub.3; [1151] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1152] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1153] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1154] t is 0 or 1; [1155] u is 0 or 1; [1156] with the proviso
that when u is 1, t is 1; and [1157] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[1158] (j) Formula (XVIII):
##STR00198##
[1159] or pharmaceutically acceptable salts thereof, wherein:
[1160] L-Ar is
[1160] ##STR00199## [1161] Ar is
[1161] ##STR00200## [1162] with the proviso that when L-Ar is
[1162] ##STR00201## Ar is not
##STR00202## [1163] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[1164] Het is a 5- to 6-membered heteroaryl; [1165] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [1166] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [1167] R.sup.3 is H or F; [1168] R.sup.11 is
H or --CH.sub.3; [1169] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1170] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [1171]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[1172] (k) Formula (XIX):
##STR00203##
[1173] or pharmaceutically acceptable salts thereof, wherein:
[1174] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[1175] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [1176] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [1177] Ar is
[1177] ##STR00204## [1178] Het is a 5- to 6-membered heteroaryl;
[1179] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [1180] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [1181] R.sup.3 is H or F; [1182]
R.sup.11 is H or --CH.sub.3; [1183] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [1184] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[1185] (l) Formula (XX):
##STR00205##
[1186] or a pharmaceutically acceptable salt thereof, wherein:
[1187] L-Ar is
[1187] ##STR00206## [1188] Ar is
[1188] ##STR00207## [1189] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [1190] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1191]
R.sup.3 is H or F; [1192] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1193] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [1194]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [1195] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[1196] (m) Formula (XI):
##STR00208##
[1197] or a pharmaceutically acceptable salt thereof, wherein:
[1198] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1199]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1200] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1201] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1202] R.sup.3 is H, --OH, or halogen;
[1203] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1204] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [1205]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[1206] In various aspects, the present disclosure relates to a
method of treating liver fibrosis in a subject in need thereof, the
method comprising administering to the subject a fatty acid
synthase inhibitor having a formula of:
[1207] (a) Formula (IX)
##STR00209##
[1208] or a pharmaceutically acceptable salt thereof, wherein:
[1209] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1210]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1211] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1212] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1213] R.sup.3 is H,
--OH, or halogen; [1214] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1215] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1216] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [1217] t is 0 or 1; [1218] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1219] L.sup.1 is CR.sup.23 or N; [1220]
L.sup.2 is CH or N; [1221] at least one of L.sup.1 or L.sup.2 is N;
and [1222] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[1223] (b) Formula (X):
##STR00210##
[1224] or a pharmaceutically acceptable salt thereof, wherein:
[1225] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1226]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1227] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1228] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1229] R.sup.3 is H,
--OH or halogen; [1230] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [1231] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[1232] t is 0 or 1, and [1233] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [1234] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [1235] t is 0
or 1, and [1236] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [1237] n is 1, 2 or 3; [1238] m
is 1 or 2; [1239] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [1240] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [1241] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [1242] t is 0 or 1, and [1243]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1244] s is 0, 1 or 2; [1245] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [1246] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[1247] (c) Formula (VI-J)
##STR00211##
[1248] or a pharmaceutically acceptable salt thereof, wherein:
[1249] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1250]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1251] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1252] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1253] R.sup.3 is H, --OH, or halogen;
[1254] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1255] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [1256]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [1257] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[1258] (d) Formula (XII):
##STR00212##
[1259] or pharmaceutically acceptable salts thereof, wherein:
[1260] L-Ar is
[1260] ##STR00213## [1261] Ar is
[1261] ##STR00214## [1262] Het is a 5- to 6-membered heteroaryl;
[1263] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1264] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1265] R.sup.3 is H or
F; [1266] R.sup.11 is H or --CH.sub.3; [1267] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1268] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1269] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1270] t is 0 or 1; [1271] u is 0 or 1; [1272] with the proviso
that when u is 1, t is 1; and [1273] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [1274] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[1275] (e) Formula (XIII):
##STR00215##
[1276] or pharmaceutically acceptable salts thereof, wherein:
[1277] L-Ar is
[1277] ##STR00216## [1278] Ar is
[1278] ##STR00217## [1279] Het is a 5- to 6-membered heteroaryl;
[1280] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1281] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1282] R.sup.3 is H or
F; [1283] R.sup.11 is H or --CH.sub.3; [1284] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1285] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1286] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1287] each t is independently 0 or 1; [1288] each
u is independently 0 or 1; and [1289] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[1290] (f) Formula (XIV):
##STR00218##
[1291] or pharmaceutically acceptable salts thereof, wherein:
[1292] L-Ar is
[1292] ##STR00219## [1293] Ar is
[1293] ##STR00220## with the proviso that when L-Ar is
##STR00221## Ar is not
##STR00222## [1294] Het is a 5- to 6-membered heteroaryl; [1295]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1296] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1297] R.sup.3 is H or
F; [1298] R.sup.11 is H or --CH.sub.3; [1299] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1300] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [1301] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1302] each t is independently 0 or 1; and [1303]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[1304] (g) Formula (XV):
##STR00223##
[1305] or pharmaceutically acceptable salts thereof, wherein:
[1306] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [1307] n is 1, 2, or 3; [1308] m is 1
or 2 with the proviso that n+m.gtoreq.3; [1309] L-Ar is
[1309] ##STR00224## [1310] Ar is
[1310] ##STR00225## with the proviso that when L-Ar is
##STR00226## Ar is not
##STR00227## [1311] Het is a 5- to 6-membered heteroaryl; [1312]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1313] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1314] R.sup.3 is H or
F; [1315] R.sup.11 is H or --CH.sub.3; [1316] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [1317] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[1318] (h) Formula (XVI):
##STR00228##
[1319] or pharmaceutically acceptable salts thereof, wherein:
[1320] L-Ar is
[1320] ##STR00229## [1321] Ar is
[1321] ##STR00230## [1322] Het is a 5- to 6-membered heteroaryl;
[1323] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1324] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1325] R.sup.3 is H or
F; [1326] R.sup.11 is H or --CH.sub.3; [1327] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1328] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1329] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[1330] (i) Formula (XVII):
##STR00231##
[1331] or pharmaceutically acceptable salts thereof, wherein:
[1332] L-Ar is
[1332] ##STR00232## [1333] Ar is
[1333] ##STR00233## with the proviso that when L-Ar is
##STR00234## Ar is not
##STR00235## [1334] Het is a 5- to 6-membered heteroaryl; [1335]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1336] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1337] R.sup.3 is H or
F; [1338] R.sup.11 is H or --CH.sub.3; [1339] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1340] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1341] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1342] t is 0 or 1; [1343] u is 0 or 1; [1344] with the proviso
that when u is 1, t is 1; and [1345] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[1346] (j) Formula (XVIII):
##STR00236##
[1347] or pharmaceutically acceptable salts thereof, wherein:
[1348] L-Ar is
[1348] ##STR00237## [1349] Ar is
[1349] ##STR00238## [1350] with the proviso that when L-Ar is
[1350] ##STR00239## Ar is not
##STR00240## [1351] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[1352] Het is a 5- to 6-membered heteroaryl; [1353] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [1354] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [1355] R.sup.3 is H or F; [1356] R.sup.11 is
H or --CH.sub.3; [1357] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1358] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [1359]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[1360] (k) Formula (XIX):
##STR00241##
[1361] or pharmaceutically acceptable salts thereof, wherein:
[1362] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[1363] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [1364] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [1365] Ar is
[1365] ##STR00242## [1366] Het is a 5- to 6-membered heteroaryl;
[1367] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [1368] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [1369] R.sup.3 is H or F; [1370]
R.sup.11 is H or --CH.sub.3; [1371] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [1372] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[1373] (l) Formula (XX):
##STR00243##
[1374] or a pharmaceutically acceptable salt thereof, wherein:
[1375] L-Ar is
[1375] ##STR00244## [1376] Ar is
[1376] ##STR00245## [1377] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [1378] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1379]
R.sup.3 is H or F; [1380] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1381] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [1382]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [1383] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[1384] (m) Formula (XI):
##STR00246##
[1385] or a pharmaceutically acceptable salt thereof, wherein:
[1386] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1387]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1388] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1389] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1390] R.sup.3 is H, --OH, or halogen;
[1391] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1392] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [1393]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[1394] In various aspects, the present disclosure relates to a
method of treating liver cancer in a subject in need thereof, the
method comprising administering to the subject a fatty acid
synthase inhibitor having a formula of:
[1395] (a) Formula (IX)
##STR00247##
[1396] or a pharmaceutically acceptable salt thereof, wherein:
[1397] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1398]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1399] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1400] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1401] R.sup.3 is H,
--OH, or halogen; [1402] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1403] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1404] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [1405] t is 0 or 1; [1406] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1407] L.sup.1 is CR.sup.23 or N; [1408]
L.sup.2 is CH or N; [1409] at least one of L.sup.1 or L.sup.2 is N;
and [1410] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[1411] (b) Formula (X):
##STR00248##
[1412] or a pharmaceutically acceptable salt thereof, wherein:
[1413] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1414]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1415] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1416] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1417] R.sup.3 is H,
--OH or halogen; [1418] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [1419] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[1420] t is 0 or 1, and [1421] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [1422] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [1423] t is 0
or 1, and [1424] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [1425] n is 1, 2 or 3; [1426] m
is 1 or 2; [1427] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [1428] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [1429] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [1430] t is 0 or 1, and [1431]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1432] s is 0, 1 or 2; [1433] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [1434] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[1435] (c) Formula (VI-J)
##STR00249##
[1436] or a pharmaceutically acceptable salt thereof, wherein:
[1437] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1438]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1439] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1440] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1441] R.sup.3 is H, --OH, or halogen;
[1442] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1443] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [1444]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [1445] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[1446] (d) Formula (XII):
##STR00250##
[1447] or pharmaceutically acceptable salts thereof, wherein:
[1448] L-Ar is
[1448] ##STR00251## [1449] Ar is
[1449] ##STR00252## [1450] Het is a 5- to 6-membered heteroaryl;
[1451] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1452] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1453] R.sup.3 is H or
F; [1454] R.sup.11 is H or --CH.sub.3; [1455] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1456] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1457] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1458] t is 0 or 1; [1459] u is 0 or 1; [1460] with the proviso
that when u is 1, t is 1; and [1461] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [1462] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[1463] (e) Formula (XIII):
##STR00253##
[1464] or pharmaceutically acceptable salts thereof, wherein:
[1465] L-Ar is
[1465] ##STR00254## [1466] Ar is
[1466] ##STR00255## [1467] Het is a 5- to 6-membered heteroaryl;
[1468] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1469] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1470] R.sup.3 is H or
F; [1471] R.sup.11 is H or --CH.sub.3; [1472] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1473] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1474] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1475] each t is independently 0 or 1; [1476] each
u is independently 0 or 1; and [1477] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[1478] (f) Formula (XIV):
##STR00256##
[1479] or pharmaceutically acceptable salts thereof, wherein:
[1480] L-Ar is
[1480] ##STR00257## [1481] Ar is
[1481] ##STR00258## with the proviso that when L-Ar is
##STR00259## Ar is not
##STR00260## [1482] Het is a 5- to 6-membered heteroaryl; [1483]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1484] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1485] R.sup.3 is H or
F; [1486] R.sup.11 is H or --CH.sub.3; [1487] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1488] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [1489] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1490] each t is independently 0 or 1; and [1491]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[1492] (g) Formula (XV):
##STR00261##
[1493] or pharmaceutically acceptable salts thereof, wherein:
[1494] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [1495] n is 1, 2, or 3; [1496] m is 1
or 2 with the proviso that n+m.gtoreq.3; [1497] L-Ar is
[1497] ##STR00262## [1498] Ar is
[1498] ##STR00263## with the proviso that when L-Ar is
##STR00264## Ar is not
##STR00265## [1499] Het is a 5- to 6-membered heteroaryl; [1500]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1501] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1502] R.sup.3 is H or
F; [1503] R.sup.11 is H or --CH.sub.3; [1504] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [1505] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[1506] (h) Formula (XVI):
##STR00266##
[1507] or pharmaceutically acceptable salts thereof, wherein:
[1508] L-Ar is
[1508] ##STR00267## [1509] Ar is
[1509] ##STR00268## [1510] Het is a 5- to 6-membered heteroaryl;
[1511] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1512] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1513] R.sup.3 is H or
F; [1514] R.sup.11 is H or --CH.sub.3; [1515] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1516] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1517] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[1518] (i) Formula (XVII):
##STR00269##
[1519] or pharmaceutically acceptable salts thereof, wherein:
[1520] L-Ar is
[1520] ##STR00270## [1521] Ar is
[1521] ##STR00271## with the proviso that when L-Ar is
##STR00272## Ar is not
##STR00273## [1522] Het is a 5- to 6-membered heteroaryl; [1523]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1524] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1525] R.sup.3 is H or
F; [1526] R.sup.11 is H or --CH.sub.3; [1527] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1528] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1529] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1530] t is 0 or 1; [1531] u is 0 or 1; [1532] with the proviso
that when u is 1, t is 1; and [1533] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[1534] (j) Formula (XVIII):
##STR00274##
[1535] or pharmaceutically acceptable salts thereof, wherein:
[1536] L-Ar is
[1536] ##STR00275## [1537] Ar is
[1537] ##STR00276## [1538] with the proviso that when L-Ar is
[1538] ##STR00277## Ar is not
##STR00278## [1539] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[1540] Het is a 5- to 6-membered heteroaryl; [1541] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [1542] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [1543] R.sup.3 is H or F; [1544] R.sup.11 is
H or --CH.sub.3; [1545] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1546] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [1547]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[1548] (k) Formula (XIX):
##STR00279##
[1549] or pharmaceutically acceptable salts thereof, wherein:
[1550] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[1551] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [1552] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [1553] Ar is
[1553] ##STR00280## [1554] Het is a 5- to 6-membered heteroaryl;
[1555] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [1556] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [1557] R.sup.3 is H or F; [1558]
R.sup.11 is H or --CH.sub.3; [1559] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [1560] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[1561] (l) Formula (XX):
##STR00281##
[1562] or a pharmaceutically acceptable salt thereof, wherein:
[1563] L-Ar is
[1563] ##STR00282## [1564] Ar is
[1564] ##STR00283## [1565] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [1566] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1567]
R.sup.3 is H or F; [1568] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1569] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [1570]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [1571] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[1572] (m) Formula (XI):
##STR00284##
[1573] or a pharmaceutically acceptable salt thereof, wherein:
[1574] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1575]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1576] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1577] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1578] R.sup.3 is H, --OH, or halogen;
[1579] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1580] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [1581]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[1582] In various aspects, the present disclosure relates to a
method of treating a disease or condition in which interleukin 1
beta (IL1.beta.) levels are elevated in a subject in need thereof,
the method comprising administering to the subject a fatty acid
synthase inhibitor having a formula of:
[1583] (a) Formula (IX)
##STR00285##
[1584] or a pharmaceutically acceptable salt thereof, wherein:
[1585] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1586]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1587] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1588] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1589] R.sup.3 is H,
--OH, or halogen; [1590] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1591] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1592] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [1593] t is 0 or 1; [1594] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1595] L.sup.1 is CR.sup.23 or N; [1596]
L.sup.2 is CH or N; [1597] at least one of L.sup.1 or L.sup.2 is N;
and [1598] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[1599] (b) Formula (X):
##STR00286##
[1600] or a pharmaceutically acceptable salt thereof, wherein:
[1601] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1602]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1603] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1604] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1605] R.sup.3 is H,
--OH or halogen; [1606] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [1607] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[1608] t is 0 or 1, and [1609] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [1610] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [1611] t is 0
or 1, and [1612] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [1613] n is 1, 2 or 3; [1614] m
is 1 or 2; [1615] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [1616] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [1617] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [1618] t is 0 or 1, and [1619]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1620] s is 0, 1 or 2; [1621] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [1622] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[1623] (c) Formula (VI-J)
##STR00287##
[1624] or a pharmaceutically acceptable salt thereof, wherein:
[1625] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1626]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1627] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1628] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1629] R.sup.3 is H, --OH, or halogen;
[1630] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1631] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [1632]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [1633] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[1634] (d) Formula (XII):
##STR00288##
[1635] or pharmaceutically acceptable salts thereof, wherein:
[1636] L-Ar is
[1636] ##STR00289## [1637] Ar is
[1637] ##STR00290## [1638] Het is a 5- to 6-membered heteroaryl;
[1639] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1640] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1641] R.sup.3 is H or
F; [1642] R.sup.11 is H or --CH.sub.3; [1643] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1644] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1645] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1646] t is 0 or 1; [1647] u is 0 or 1; [1648] with the proviso
that when u is 1, t is 1; and [1649] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [1650] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[1651] (e) Formula (XIII):
##STR00291##
[1652] or pharmaceutically acceptable salts thereof, wherein:
[1653] L-Ar is
[1653] ##STR00292## [1654] Ar is
[1654] ##STR00293## [1655] Het is a 5- to 6-membered heteroaryl;
[1656] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1657] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1658] R.sup.3 is H or
F; [1659] R.sup.11 is H or --CH.sub.3; [1660] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1661] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1662] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1663] each t is independently 0 or 1; [1664] each
u is independently 0 or 1; and [1665] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[1666] (f) Formula (XIV):
##STR00294##
[1667] or pharmaceutically acceptable salts thereof, wherein:
[1668] L-Ar is
[1668] ##STR00295## [1669] Ar is
[1669] ##STR00296## with the proviso that when L-Ar is
##STR00297## Ar is not
##STR00298## [1670] Het is a 5- to 6-membered heteroaryl; [1671]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1672] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1673] R.sup.3 is H or
F; [1674] R.sup.11 is H or --CH.sub.3; [1675] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1676] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [1677] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1678] each t is independently 0 or 1; and [1679]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[1680] (g) Formula (XV):
##STR00299##
[1681] or pharmaceutically acceptable salts thereof, wherein:
[1682] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [1683] n is 1, 2, or 3; [1684] m is 1
or 2 with the proviso that n+m.gtoreq.3; [1685] L-Ar is
[1685] ##STR00300## [1686] Ar is
[1686] ##STR00301## with the proviso that when L-Ar is
##STR00302## Ar is not
##STR00303## [1687] Het is a 5- to 6-membered heteroaryl; [1688]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1689] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1690] R.sup.3 is H or
F; [1691] R.sup.11 is H or --CH.sub.3; [1692] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [1693] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[1694] (h) Formula (XVI):
##STR00304##
[1695] or pharmaceutically acceptable salts thereof, wherein:
[1696] L-Ar is
[1696] ##STR00305## [1697] Ar is
[1697] ##STR00306## [1698] Het is a 5- to 6-membered heteroaryl;
[1699] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1700] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1701] R.sup.3 is H or
F; [1702] R.sup.11 is H or --CH.sub.3; [1703] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1704] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1705] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[1706] (i) Formula (XVII):
##STR00307##
[1707] or pharmaceutically acceptable salts thereof, wherein:
[1708] L-Ar is
[1708] ##STR00308## [1709] Ar is
[1709] ##STR00309## with the proviso that when L-Ar is
##STR00310## Ar is not
##STR00311## [1710] Het is a 5- to 6-membered heteroaryl; [1711]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1712] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1713] R.sup.3 is H or
F; [1714] R.sup.11 is H or --CH.sub.3; [1715] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1716] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1717] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1718] t is 0 or 1; [1719] u is 0 or 1; [1720] with the proviso
that when u is 1, t is 1; and [1721] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[1722] (j) Formula (XVIII):
##STR00312##
[1723] or pharmaceutically acceptable salts thereof, wherein:
[1724] L-Ar is
[1724] ##STR00313## [1725] Ar is
[1725] ##STR00314## [1726] with the proviso that when L-Ar is
[1726] ##STR00315## Ar is not
##STR00316## [1727] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[1728] Het is a 5- to 6-membered heteroaryl; [1729] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [1730] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [1731] R.sup.3 is H or F; [1732] R.sup.11 is
H or --CH.sub.3; [1733] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1734] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [1735]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[1736] (k) Formula (XIX):
##STR00317##
[1737] or pharmaceutically acceptable salts thereof, wherein:
[1738] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[1739] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [1740] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [1741] Ar is
[1741] ##STR00318## [1742] Het is a 5- to 6-membered heteroaryl;
[1743] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [1744] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [1745] R.sup.3 is H or F; [1746]
R.sup.11 is H or --CH.sub.3; [1747] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [1748] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[1749] (l) Formula (XX):
##STR00319##
[1750] or a pharmaceutically acceptable salt thereof, wherein:
[1751] L-Ar is
[1751] ##STR00320## [1752] Ar is
[1752] ##STR00321## [1753] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [1754] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1755]
R.sup.3 is H or F; [1756] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1757] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [1758]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [1759] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[1760] (m) Formula (XI):
##STR00322##
[1761] or a pharmaceutically acceptable salt thereof, wherein:
[1762] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1763]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1764] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1765] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1766] R.sup.3 is H, --OH, or halogen;
[1767] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1768] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [1769]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[1770] In various aspects, the present disclosure relates to a
method of treating a disease or condition in which t-helper
(T.sub.h) cell levels are elevated in a subject in need thereof,
the method comprising administering to the subject a fatty acid
synthase inhibitor having a formula of:
[1771] (a) Formula (IX)
##STR00323##
[1772] or a pharmaceutically acceptable salt thereof, wherein:
[1773] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1774]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1775] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1776] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1777] R.sup.3 is H,
--OH, or halogen; [1778] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1779] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1780] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [1781] t is 0 or 1; [1782] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1783] L.sup.1 is CR.sup.23 or N; [1784]
L.sup.2 is CH or N; [1785] at least one of L.sup.1 or L.sup.2 is N;
and [1786] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[1787] (b) Formula (X):
##STR00324##
[1788] or a pharmaceutically acceptable salt thereof, wherein:
[1789] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1790]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1791] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1792] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1793] R.sup.3 is H,
--OH or halogen; [1794] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [1795] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[1796] t is 0 or 1, and [1797] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [1798] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [1799] t is 0
or 1, and [1800] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [1801] n is 1, 2 or 3; [1802] m
is 1 or 2; [1803] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [1804] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [1805] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [1806] t is 0 or 1, and [1807]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1808] s is 0, 1 or 2; [1809] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [1810] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[1811] (c) Formula (VI-J)
##STR00325##
[1812] or a pharmaceutically acceptable salt thereof, wherein:
[1813] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1814]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1815] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1816] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1817] R.sup.3 is H, --OH, or halogen;
[1818] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1819] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [1820]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [1821] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[1822] (d) Formula (XII):
##STR00326##
[1823] or pharmaceutically acceptable salts thereof, wherein:
[1824] L-Ar is
[1824] ##STR00327## [1825] Ar is
[1825] ##STR00328## [1826] Het is a 5- to 6-membered heteroaryl;
[1827] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1828] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1829] R.sup.3 is H or
F; [1830] R.sup.11 is H or --CH.sub.3; [1831] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1832] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1833] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1834] t is 0 or 1; [1835] u is 0 or 1; [1836] with the proviso
that when u is 1, t is 1; and [1837] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [1838] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[1839] (e) Formula (XIII):
##STR00329##
[1840] or pharmaceutically acceptable salts thereof, wherein:
[1841] L-Ar is
[1841] ##STR00330## [1842] Ar is
[1842] ##STR00331## [1843] Het is a 5- to 6-membered heteroaryl;
[1844] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1845] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1846] R.sup.3 is H or
F; [1847] R.sup.11 is H or --CH.sub.3; [1848] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1849] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1850] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1851] each t is independently 0 or 1; [1852] each
u is independently 0 or 1; and [1853] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[1854] (f) Formula (XIV):
##STR00332##
[1855] or pharmaceutically acceptable salts thereof, wherein:
[1856] L-Ar is
[1856] ##STR00333## [1857] Ar is
[1857] ##STR00334## with the proviso that when L-Ar is
##STR00335## Ar is not
##STR00336## [1858] Het is a 5- to 6-membered heteroaryl; [1859]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1860] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1861] R.sup.3 is H or
F; [1862] R.sup.11 is H or --CH.sub.3; [1863] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1864] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [1865] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [1866] each t is independently 0 or 1; and [1867]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[1868] (g) Formula (XV):
##STR00337##
[1869] or pharmaceutically acceptable salts thereof, wherein:
[1870] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [1871] n is 1, 2, or 3; [1872] m is 1
or 2 with the proviso that n+m.gtoreq.3; [1873] L-Ar is
[1873] ##STR00338## [1874] Ar is
[1874] ##STR00339## with the proviso that when L-Ar is
##STR00340## Ar is not
##STR00341## [1875] Het is a 5- to 6-membered heteroaryl; [1876]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1877] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1878] R.sup.3 is H or
F; [1879] R.sup.11 is H or --CH.sub.3; [1880] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [1881] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[1882] (h) Formula (XVI):
##STR00342##
[1883] or pharmaceutically acceptable salts thereof, wherein:
[1884] L-Ar is
[1884] ##STR00343## [1885] Ar is
[1885] ##STR00344## [1886] Het is a 5- to 6-membered heteroaryl;
[1887] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1888] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1889] R.sup.3 is H or
F; [1890] R.sup.11 is H or --CH.sub.3; [1891] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1892] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1893] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[1894] (i) Formula (XVII):
##STR00345##
[1895] or pharmaceutically acceptable salts thereof, wherein:
[1896] L-Ar is
[1896] ##STR00346## [1897] Ar is
[1897] ##STR00347## with the proviso that when L-Ar is
##STR00348## Ar is not
##STR00349## [1898] Het is a 5- to 6-membered heteroaryl; [1899]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [1900] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1901] R.sup.3 is H or
F; [1902] R.sup.11 is H or --CH.sub.3; [1903] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [1904] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [1905] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[1906] t is 0 or 1; [1907] u is 0 or 1; [1908] with the proviso
that when u is 1, t is 1; and [1909] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[1910] (j) Formula (XVIII):
##STR00350##
[1911] or pharmaceutically acceptable salts thereof, wherein:
[1912] L-Ar is
[1912] ##STR00351## [1913] Ar is
[1913] ##STR00352## [1914] with the proviso that when L-Ar is
[1914] ##STR00353## Ar is not
##STR00354## [1915] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[1916] Het is a 5- to 6-membered heteroaryl; [1917] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [1918] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [1919] R.sup.3 is H or F; [1920] R.sup.11 is
H or --CH.sub.3; [1921] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1922] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [1923]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[1924] (k) Formula (XIX):
##STR00355##
[1925] or pharmaceutically acceptable salts thereof, wherein:
[1926] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[1927] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [1928] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [1929] Ar is
[1929] ##STR00356## [1930] Het is a 5- to 6-membered heteroaryl;
[1931] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [1932] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [1933] R.sup.3 is H or F; [1934]
R.sup.11 is H or --CH.sub.3; [1935] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [1936] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[1937] (l) Formula (XX):
##STR00357##
[1938] or a pharmaceutically acceptable salt thereof, wherein:
[1939] L-Ar is
[1939] ##STR00358## [1940] Ar is
[1940] ##STR00359## [1941] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [1942] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [1943]
R.sup.3 is H or F; [1944] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[1945] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [1946]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [1947] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[1948] (m) Formula (XI):
##STR00360##
[1949] or a pharmaceutically acceptable salt thereof, wherein:
[1950] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1951]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1952] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1953] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [1954] R.sup.3 is H, --OH, or halogen;
[1955] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[1956] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [1957]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
[1958] In various aspects, the present disclosure relates to a
method of treating a disease or condition in which regulatory t
cells (T.sub.reg) are reduced or suppressed in a subject in need
thereof, the method comprising administering to the subject a fatty
acid synthase inhibitor having a formula of:
[1959] (a) Formula (IX)
##STR00361##
[1960] or a pharmaceutically acceptable salt thereof, wherein:
[1961] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1962]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1963] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1964] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1965] R.sup.3 is H,
--OH, or halogen; [1966] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1967] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [1968] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [1969] t is 0 or 1; [1970] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1971] L.sup.1 is CR.sup.23 or N; [1972]
L.sup.2 is CH or N; [1973] at least one of L.sup.1 or L.sup.2 is N;
and [1974] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl; or
[1975] (b) Formula (X):
##STR00362##
[1976] or a pharmaceutically acceptable salt thereof, wherein:
[1977] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [1978]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [1979] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[1980] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [1981] R.sup.3 is H,
--OH or halogen; [1982] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [1983] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[1984] t is 0 or 1, and [1985] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [1986] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.50).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [1987] t is 0
or 1, and [1988] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [1989] n is 1, 2 or 3; [1990] m
is 1 or 2; [1991] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [1992] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [1993] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [1994] t is 0 or 1, and [1995]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [1996] s is 0, 1 or 2; [1997] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [1998] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.50, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601; or
[1999] (c) Formula (VI-J)
##STR00363##
[2000] or a pharmaceutically acceptable salt thereof, wherein:
[2001] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [2002]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [2003] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[2004] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [2005] R.sup.3 is H, --OH, or halogen;
[2006] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[2007] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; [2008]
R.sup.35 is --C(O)--R.sup.351, --C(O)--NHR.sup.351,
--C(O)--O--R.sup.351 or S(O).sub.2R.sup.351; and [2009] R.sup.351
is C.sub.1-C.sub.6 straight or branched alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl; or
[2010] (d) Formula (XII):
##STR00364##
[2011] or pharmaceutically acceptable salts thereof, wherein:
[2012] L-Ar is
[2012] ##STR00365## [2013] Ar is
[2013] ##STR00366## [2014] Het is a 5- to 6-membered heteroaryl;
[2015] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [2016] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [2017] R.sup.3 is H or
F; [2018] R.sup.11 is H or --CH.sub.3; [2019] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [2020] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [2021] R.sup.24 is H, --CN,
--(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[2022] t is 0 or 1; [2023] u is 0 or 1; [2024] with the proviso
that when u is 1, t is 1; and [2025] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; and [2026] R.sup.25 is
halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.2 alkyl
or cyclopropyl; or
[2027] (e) Formula (XIII):
##STR00367##
[2028] or pharmaceutically acceptable salts thereof, wherein:
[2029] L-Ar is
[2029] ##STR00368## [2030] Ar is
[2030] ##STR00369## [2031] Het is a 5- to 6-membered heteroaryl;
[2032] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [2033] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [2034] R.sup.3 is H or
F; [2035] R.sup.11 is H or --CH.sub.3; [2036] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [2037] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [2038] each R.sup.24 and R.sup.25 is
independently H, halogen, --CN, --(C.sub.1-C.sub.4 alkyl)-CN,
C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [2039] each t is independently 0 or 1; [2040] each
u is independently 0 or 1; and [2041] each R.sup.241 is
independently H or C.sub.1-C.sub.2 alkyl; or
[2042] (f) Formula (XIV):
##STR00370##
[2043] or pharmaceutically acceptable salts thereof, wherein:
[2044] L-Ar is
[2044] ##STR00371## [2045] Ar is
[2045] ##STR00372## with the proviso that when L-Ar is
##STR00373## Ar is not
##STR00374## [2046] Het is a 5- to 6-membered heteroaryl; [2047]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [2048] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [2049] R.sup.3 is H or
F; [2050] R.sup.11 is H or --CH.sub.3; [2051] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [2052] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; and [2053] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
alkyl), wherein: [2054] each t is independently 0 or 1; and [2055]
each R.sup.241 is independently H or C.sub.1-C.sub.2 alkyl; or
[2056] (g) Formula (XV):
##STR00375##
[2057] or pharmaceutically acceptable salts thereof, wherein:
[2058] L.sup.3 is --CH.sub.2--, --CHR.sup.50--, --O--,
--NR.sup.50--, --NC(O)R.sup.50-- or --NC(O)OR.sup.50--, wherein
R.sup.50 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5 cycloalkyl, or
4- to 6-membered heterocycle; [2059] n is 1, 2, or 3; [2060] m is 1
or 2 with the proviso that n+m.gtoreq.3; [2061] L-Ar is
[2061] ##STR00376## [2062] Ar is
[2062] ##STR00377## with the proviso that when L-Ar is
##STR00378## Ar is not
##STR00379## [2063] Het is a 5- to 6-membered heteroaryl; [2064]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [2065] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [2066] R.sup.3 is H or
F; [2067] R.sup.11 is H or --CH.sub.3; [2068] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4-
to 6-membered heterocycle; and [2069] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; or
[2070] (h) Formula (XVI):
##STR00380##
[2071] or pharmaceutically acceptable salts thereof, wherein:
[2072] L-Ar is
[2072] ##STR00381## [2073] Ar is
[2073] ##STR00382## [2074] Het is a 5- to 6-membered heteroaryl;
[2075] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [2076] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [2077] R.sup.3 is H or
F; [2078] R.sup.11 is H or --CH.sub.3; [2079] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [2080] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [2081] each of R.sup.24 and R.sup.25 is
independently H, --C.sub.1-C.sub.4 alkyl, or halogen; or
[2082] (i) Formula (XVII):
##STR00383##
[2083] or pharmaceutically acceptable salts thereof, wherein:
[2084] L-Ar is
[2084] ##STR00384## [2085] Ar is
[2085] ##STR00385## with the proviso that when L-Ar is
##STR00386## Ar is not
##STR00387## [2086] Het is a 5- to 6-membered heteroaryl; [2087]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1
is not H, --CN or halogen, R.sup.1 is optionally substituted with
one or more halogens; [2088] each R.sup.2 is independently
hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [2089] R.sup.3 is H or
F; [2090] R.sup.11 is H or --CH.sub.3; [2091] R.sup.21 is H,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle; [2092] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; and [2093] R.sup.24 is H, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl), wherein:
[2094] t is 0 or 1; [2095] u is 0 or 1; [2096] with the proviso
that when u is 1, t is 1; and [2097] R.sup.241 is H or
C.sub.1-C.sub.2 alkyl; or
[2098] (j) Formula (XVIII):
##STR00388##
[2099] or pharmaceutically acceptable salts thereof, wherein:
[2100] L-Ar is
[2100] ##STR00389## [2101] Ar is
[2101] ##STR00390## [2102] with the proviso that when L-Ar is
[2102] ##STR00391## Ar is not
##STR00392## [2103] L.sup.2 is --NHR.sup.35 or --C(O)NHR.sup.351,
wherein R.sup.351 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.5
cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;
[2104] Het is a 5- to 6-membered heteroaryl; [2105] R.sup.1 is H,
--CN, halogen, C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle),
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H, --CN or
halogen, R.sup.1 is optionally substituted with one or more
halogens; [2106] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 alkyl; [2107] R.sup.3 is H or F; [2108] R.sup.11 is
H or --CH.sub.3; [2109] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[2110] R.sup.22 is H, halogen, or C.sub.1-C.sub.2 alkyl; and [2111]
R.sup.35 is --C(O)R.sup.351, --C(O)NHR.sup.351, C(O)OR.sup.351 or
S(O).sub.2R.sup.351 wherein R.sup.351 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.5 cycloalkyl, 4- to 6-membered heterocycle, aryl or
heteroaryl; or
[2112] (k) Formula (XIX):
##STR00393##
[2113] or pharmaceutically acceptable salts thereof, wherein:
[2114] each W, X, Y and Z is independently --N-- or --CR.sup.26--
with the proviso that not more than 2 of W, X, Y and Z are --N--;
[2115] each R.sup.26 is independently H, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.1-C.sub.4 alkyl), --N(R.sup.27).sub.2,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkyl); [2116] each R.sup.27 is independently H or C.sub.1-C.sub.4
alkyl or both R.sup.27 are C.sub.1-C.sub.4 alkyl and join to form a
3- to 6-membered ring together with the N to which they are
attached and wherein the ring optionally includes one oxygen atom
as one of the members of the ring; [2117] Ar is
[2117] ##STR00394## [2118] Het is a 5- to 6-membered heteroaryl;
[2119] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 alkyl,
--O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4- to 6-membered
heterocycle), --O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is
not H, --CN or halogen, R.sup.1 is optionally substituted with one
or more halogens; [2120] each R.sup.2 is independently hydrogen,
halogen or C.sub.1-C.sub.4 alkyl; [2121] R.sup.3 is H or F; [2122]
R.sup.11 is H or --CH.sub.3; [2123] R.sup.21 is H, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or a 4- to
6-membered heterocycle; and [2124] R.sup.22 is H, halogen or
C.sub.1-C.sub.2 alkyl; or
[2125] (l) Formula (XX):
##STR00395##
[2126] or a pharmaceutically acceptable salt thereof, wherein:
[2127] L-Ar is
[2127] ##STR00396## [2128] Ar is
[2128] ##STR00397## [2129] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O-(4-
to 6-membered heterocycle) or --O--(C.sub.1-C.sub.4 alkyl), wherein
when R.sup.1 is not H, --CN or halogen, R.sup.1 is optionally
substituted with one or more halogen; [2130] each R.sup.2 is
independently hydrogen, halogen or C.sub.1-C.sub.4 alkyl; [2131]
R.sup.3 is H or F; [2132] R.sup.21 is H, halogen, C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to 6-membered heterocycle;
[2133] R.sup.22 is H, halogen or C.sub.1-C.sub.2 alkyl; [2134]
R.sup.24 is --O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --O--(C.sub.3-C.sub.5
cycloalkyl), or --O-(4- to 6-membered heterocycle), wherein
R.sup.24 is optionally substituted with one or more hydroxyl or
halogen; and [2135] R.sup.25 is H, halogen, C.sub.1-C.sub.4 alkyl
or C.sub.3-C.sub.5 cycloalkyl, wherein R.sup.25 is optionally
substituted with one or more halogen; or
[2136] (m) Formula (XI):
##STR00398##
[2137] or a pharmaceutically acceptable salt thereof, wherein:
[2138] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [2139]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [2140] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[2141] each R.sup.2 is independently H, halogen or C.sub.1-C.sub.4
straight or branched alkyl; [2142] R.sup.3 is H, --OH, or halogen;
[2143] R.sup.21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;
[2144] R.sup.22 is H, halogen, C.sub.1-C.sub.2 alkyl; and [2145]
R.sup.351 is C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or
C.sub.2 alkyl).
BRIEF DESCRIPTION OF THE DRAWINGS
[2146] FIG. 1 illustrates a correlation between FASN inhibition and
HCV inhibition.
[2147] FIG. 2 shows images of liver tissue samples stained with Oil
red O or Masson's taken from C57BL/6NCrSim mice treated with
vehicle or 10 mg/kg of Compound 364A. The results show that
treatment with FASN inhibitor Compound 364A inhibited the
development of steatosis.
[2148] FIG. 3 shows images of liver tissue samples stained with Oil
red O taken from C57BL/6J mice treated with vehicle for 28 days,
vehicle for 57 days or vehicle for 28 days followed by 10 mg/kg
Compound 364A for 29 days. The results show that treatment with
FASN inhibitor Compound 364A inhibited the development of hepatic
steatosis.
[2149] FIG. 4 is a graph showing IL-1.beta. levels in untreated
rats and in rats treated with vehicle, 60 mg/kg of Compound 6B, or
100 mg/kg of Compound 6B. The results show that treatment with
Compound 6B lowered IL-1.beta. beta levels in blood serum after
feeding fasted rats.
[2150] FIG. 5 is a graph showing IL-1.beta. levels in rats treated
with vehicle, 60 mg/kg of Compound 6B, or 100 mg/kg of Compound 6B.
The results show that treatment with Compound 6B lowered IL-1.beta.
beta levels in blood serum 22 hours after feeding fasted rats.
[2151] FIG. 6A is a graph showing IL-1.beta. levels in mice fed a
high fat diet for 14 days and then treated with vehicle, 3 mg/kg of
Compound 364A, or 10 mg/kg of Compound 364A. FIG. 6B is a graph
showing IL-1.beta. levels in mice fed a high fat diet for 37 days
and then treated with vehicle, 3 mg/kg of Compound 364A, or 10
mg/kg of Compound 364A. Mice treated with Compound 364A had reduced
levels of IL-1 beta at both 14 and 37 days, both before
reintroduction of food and after feeding, compared to mice which
received vehicle.
[2152] FIG. 7A is a graph showing secretion of IL-1.beta. levels
from human PBMC without stimulation or after 24 hours of
stimulation with lipopolysaccharide (LPS) or lipoteichoic acid
(LTA) when treated with vehicle or with 10 .mu.M of Compound 242A.
FIG. 7B is a graph showing secretion of IL-1.beta. levels from
human monocytes without stimulation or after 24 hours of
stimulation with lipopolysaccharide (LPS) or lipoteichoic acid
(LTA) when treated with vehicle or with 10 .mu.M of Compound 242A.
For monocytes, Compound 242A treatment reduced the level of IL-1
beta resulting from LTA stimulation whereas only a slight reduction
was observed after LPS stimulation. For PBMC, Compound 242A
treatment reduced the level of IL-1 beta resulting from both LTA
and LPS stimulation.
[2153] FIGS. 8A and 8B are plots showing the results of flow
cytometry analysis of mouse T cells treated with vehicle (DMSO) or
50 nM of Compound 364A. FASN inhibition of mouse CD4+ naive T cells
with 4 days of Th.sub.17 differentiation conditions inhibits
Th.sub.17 cell differentiation and stimulates T.sub.reg
differentiation.
[2154] FIGS. 9A and 9B are plots showing the results of flow
cytometry analysis of human T cells from Donor 1 treated with
vehicle (DMSO) or 50 nM of Compound 364A. FIGS. 9C and 9D are plots
showing the results of flow cytometry analysis of human T cells
from Donor 2 treated with vehicle (DMSO) or 50 nM of Compound 364A.
FASN inhibition with Compound 364A of human CD4+ naive T cells from
two different donors with 4 days of Th.sub.17 differentiation
conditions inhibits TH.sub.17 cell differentiation and stimulates
T.sub.reg differentiation.
[2155] FIGS. 10A and 10B are plots showing the results of flow
cytometry analysis of human T cells from Donor 1 treated with
vehicle (DMSO) or 50 nM of Compound 152. FIGS. 10C and 10D are
plots showing the results of flow cytometry analysis of human T
cells from Donor 2 treated with vehicle (DMSO) or 50 nM of Compound
152. FASN inhibition with Compound 152 of human CD4+ naive T cells
from two different donors with 4 days of Th.sub.17 differentiation
conditions inhibits TH.sub.17 cell differentiation and stimulates
T.sub.reg differentiation.
DETAILED DESCRIPTION
[2156] The present disclosure addresses the deficiencies in
treating conditions characterized by disregulation of the FASN
function in a subject, such as viral infection, cancer and
metabolic disorders, by providing novel heterocyclic modulators of
lipid synthesis.
[2157] In certain aspects, the present disclosure provides
compositions and methods for treatment of viral infections. In
general, the compositions and methods for treatment of viral
infections are directed toward modulation of the fatty acid
synthesis pathway. The fatty acid synthesis pathway is involved in
the replication of viruses into the host cells. The present
invention embodies methods for the treatment of viral infection,
such as hepatitis C infections, yellow fever infections, and human
rhinovirus infections, or any virus that targets the fatty acid
synthesis pathway.
[2158] In certain aspects, the present disclosure provides
compositions and methods for the treatment of cancer. Fatty acid
synthase is responsible for conversion of malonyl-CoA into
long-chain fatty acids, which is an early reaction in fatty acid
biosynthesis. Fatty acid synthase is overexpressed in many cancer
cells. Without being bound by any particular theory, it is
hypothesized that inhibition of fatty acid synthase expression or
fatty acid synthase activity selectivity suppresses proliferation
and induces cell death of cancer cells, with little toxicity
towards normal cells.
[2159] Further, the present disclosure provides compounds and
methods for modulating host cell targets that are targeted by
viruses. Such modulation of host cell targets can include either
activation or inhibition of the host cell targets. Accordingly,
compounds that modulate, e.g., inhibit, the activity of a non-viral
protein, e.g., a host cell protein, e.g., components of the fatty
acid synthesis pathway, can be used as antiviral pharmaceutical
agents.
Definitions
[2160] Chemical moieties referred to as univalent chemical moieties
(e.g., alkyl, aryl, etc.) also encompass structurally permissible
multivalent moieties, as understood by those skilled in the art.
For example, while an "alkyl" moiety generally refers to a
monovalent radical (e.g., CH.sub.3CH.sub.2--), in appropriate
circumstances an "alkyl" moiety can also refer to a divalent
radical (e.g., --CH.sub.2CH.sub.2--, which is equivalent to an
"alkylene" group). Similarly, under circumstances where a divalent
moiety is required, those skilled in the art will understand that
the term "aryl" refers to the corresponding divalent arylene
group.
[2161] All atoms are understood to have their normal number of
valences for bond formation (e.g., 4 for carbon, 3 for N, 2 for O,
and 2, 4, or 6 for S, depending on the atom's oxidation state). On
occasion a moiety can be defined, for example, as (A).sub.aB,
wherein a is 0 or 1. In such instances, when a is 0 the moiety is B
and when a is 1 the moiety is AB.
[2162] Where a substituent can vary in the number of atoms or
groups of the same kind (e.g., alkyl groups can be C.sub.1,
C.sub.2, C.sub.3, etc.), the number of repeated atoms or groups can
be represented by a range (e.g., C.sub.1-C.sub.6 alkyl) which
includes each and every number in the range and any and all sub
ranges. For example, C.sub.1-C.sub.3 alkyl includes C.sub.1,
C.sub.2, C.sub.3, C.sub.1-2, C.sub.1-3, and C.sub.2-3 alkyl.
[2163] "Alkanoyl" refers to a carbonyl group with a lower alkyl
group as a substituent.
[2164] "Alkylamino" refers to an amino group substituted by an
alkyl group.
[2165] "Alkoxy" refers to an O-atom substituted by an alkyl group
as defined herein, for example, methoxy [--OCH.sub.3, a
C.sub.1alkoxy]. The term "C.sub.1-6 alkoxy" encompasses C.sub.1
alkoxy, C.sub.2 alkoxy, C.sub.3 alkoxy, C.sub.4 alkoxy, C.sub.5
alkoxy, C.sub.6 alkoxy, and any sub-range thereof.
[2166] "Alkoxycarbonyl" refers to a carbonyl group with an alkoxy
group as a substituent.
[2167] "Alkyl," "alkenyl," and "alkynyl," refer to optionally
substituted, straight and branched chain aliphatic groups having
from 1 to 30 carbon atoms, or preferably from 1 to 15 carbon atoms,
or more preferably from 1 to 6 carbon atoms. Examples of alkyl
groups include, without limitation, methyl, ethyl, propyl,
isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vinyl,
allyl, isobutenyl, ethynyl, and propynyl. The term "heteroalkyl" as
used herein contemplates an alkyl with one or more heteroatoms.
[2168] "Alkylene" refers to an optionally substituted divalent
radical which is a branched or unbranched hydrocarbon fragment
containing the specified number of carbon atoms, and having two
points of attachment. An example is propylene
[--CH.sub.2CH.sub.2CH.sub.2--, a C.sub.3alkylene].
[2169] "Amino" refers to the group --NH.sub.2.
[2170] "Aryl" refers to optionally substituted aromatic groups
which have at least one ring having a conjugated pi electron system
and includes carbocyclic aryl, and biaryl groups, all of which can
be optionally substituted. Phenyl and naphthyl groups are preferred
carbocyclic aryl groups.
[2171] "Aralkyl" or "arylalkyl" refer to alkyl-substituted aryl
groups. Examples of aralkyl groups include butylphenyl,
propylphenyl, ethylphenyl, methylphenyl, 3,5-dimethylphenyl,
tert-butylphenyl.
[2172] "Carbamoyl" as used herein contemplates a group of the
structure
##STR00399##
where in R.sup.N is selected from the group consisting of hydrogen,
--OH, C.sub.1 to C.sub.12 alkyl, C.sub.1 to C.sub.12 heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl,
aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl,
sulfonate and sulfonamide. "Carbonyl" refers to a group of the
structure
##STR00400##
[2173] "Cycloalkyl" refers to an optionally substituted ring, which
can be saturated or unsaturated and monocyclic, bicyclic, or
tricyclic formed entirely from carbon atoms. An example of a
cycloalkyl group is the cyclopentenyl group (C.sub.5H.sub.7--),
which is a five carbon (C.sub.5) unsaturated cycloalkyl group.
[2174] "Heterocycle" refers to an optionally substituted 5- to
7-membered cycloalkyl ring system containing 1, 2 or 3 heteroatoms,
which can be the same or different, selected from N, O or S, and
optionally containing one double bond.
[2175] "Halogen" refers to a chloro, bromo, fluoro or iodo atom
radical. The term "halogen" also contemplates terms "halo" or
"halide."
[2176] "Heteroatom" refers to a non-carbon atom, where boron,
nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms,
with nitrogen, oxygen and sulfur being particularly preferred
heteroatoms in the compounds of the present disclosure.
[2177] "Heteroaryl" refers to optionally substituted aryl groups
having from 1 to 9 carbon atoms and the remainder of the atoms are
heteroatoms, and includes those heterocyclic systems described in
"Handbook of Chemistry and Physics," 49th edition, 1968, R. C.
Weast, editor; The Chemical Rubber Co., Cleveland, Ohio. See
particularly Section C, Rules for Naming Organic Compounds, B.
Fundamental Heterocyclic Systems. Suitable heteroaryls include
thienyl, pyrrolyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl,
oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl,
pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl, indolyl, isoindolyl,
indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,
benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl,
benzoxadiazolyl, thiadiazolyl, benzothiazolyl, benzothiadiazolyl,
and the like.
[2178] An "optionally substituted" moiety can be substituted with
from one to four, or preferably from one to three, or more
preferably one or two non-hydrogen substituents. Unless otherwise
specified, when the substituent is on a carbon, it is selected from
the group consisting of --OH, --CN, --NO.sub.2, halogen, C.sub.1 to
C.sub.12 alkyl, C.sub.1 to C.sub.12 heteroalkyl, cycloalkyl,
heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,
alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide
and amino, none of which are further substituted. Unless otherwise
specified, when the substituent is on a nitrogen, it is selected
from the group consisting of C.sub.1 to C.sub.12 alkyl, C.sub.1 to
C.sub.12 heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl,
aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl,
sulfonate and sulfonamide none of which are further
substituted.
[2179] The term "sulfonamide" as used herein contemplates a group
having the structure
##STR00401##
wherein R.sup.N is selected from the group consisting of hydrogen,
--OH, C.sub.1 to C.sub.12 alkyl, C.sub.1 to C.sub.12 heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl,
aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted
sulfonyl, sulfonate and sulfonamide.
[2180] The term "sulfonate" as used herein contemplates a group
having the structure
##STR00402##
wherein R.sup.s is selected from the group consisting of hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10
alkynyl, C.sub.1-C.sub.10 alkanoyl, or C.sub.1-C.sub.10
alkoxycarbonyl.
[2181] "Sulfonyl" as used herein alone or as part of another group,
refers to an SO.sub.2 group. The SO.sub.2 moiety is optionally
substituted.
[2182] Compounds of the present disclosure can exist as
stereoisomers, wherein asymmetric or chiral centers are present.
Stereoisomers are designated (R) or (S) depending on the
configuration of substituents around the chiral carbon atom. The
terms (R) and (S) used herein are configurations as defined in
IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30, hereby
incorporated by reference. The present disclosure contemplates
various stereoisomers and mixtures thereof and are specifically
included within the scope of the present disclosure. Stereoisomers
include enantiomers, diastereomers, and mixtures of enantiomers or
diastereomers. Individual stereoisomers of compounds of the present
disclosure can be prepared synthetically from commercially
available starting materials which contain asymmetric or chiral
centers or by preparation of racemic mixtures followed by
resolution well-known to those of ordinary skill in the art. These
methods of resolution are exemplified by (1) attachment of a
mixture of enantiomers to a chiral auxiliary, separation of the
resulting mixture of diastereomers by recrystallization or
chromatography and liberation of the optically pure product from
the auxiliary or (2) direct separation of the mixture of optical
enantiomers on chiral chromatographic columns.
[2183] Also, moieties disclosed herein which exist in multiple
tautomeric forms include all such forms encompassed by a given
tautomeric structure.
[2184] Individual atoms in the disclosed compounds may be any
isotope of that element. For example hydrogen may be in the form of
deuterium.
[2185] "Pharmaceutically acceptable" means approved or approvable
by a regulatory agency of the Federal or state government or listed
in the U.S. Pharmacopoeia or other generally recognized
pharmacopoeia for use in animals, and more particularly in humans.
It can be material which is not biologically or otherwise
undesirable, i.e., the material can be administered to an
individual without causing any undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained.
[2186] The term "pharmaceutically acceptable salt" of a compound
means a salt that is pharmaceutically acceptable and that possesses
the desired pharmacological activity of the parent compound. Such
salts include, for example, acid addition salts and base addition
salts.
[2187] "Acid addition salts" according to the present disclosure,
are formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like; or formed with organic acids such as acetic acid,
propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic
acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic
acid, maleic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 2-naphthalenesulfonic acid,
4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,
and the like.
[2188] "Base addition salts" according to the present disclosure
are formed when an acidic proton present in the parent compound
either is replaced by a metal ion, e.g., an alkali metal ion, an
alkaline earth ion, or an aluminum ion; or coordinates with an
organic base. Acceptable organic bases include ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
and the like. Acceptable inorganic bases include aluminum
hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate, sodium hydroxide, and the like. It should be understood
that a reference to a pharmaceutically acceptable salt includes the
solvent addition forms or crystal forms thereof, particularly
solvates or polymorphs. Solvates contain either stoichiometric or
non-stoichiometric amounts of a solvent, and are often formed
during the process of crystallization. Hydrates are formed when the
solvent is water, or alcoholates are formed when the solvent is
alcohol. Polymorphs include the different crystal packing
arrangements of the same elemental composition of a compound.
Polymorphs usually have different X-ray diffraction patterns,
infrared spectra, melting points, density, hardness, crystal shape,
optical and electrical properties, stability, and solubility.
Various factors such as the recrystallization solvent, rate of
crystallization, and storage temperature can cause a single crystal
form to dominate.
[2189] The term "treating" includes the administration of the
compounds or agents of the present invention to a subject to
prevent or delay, to alleviate, or to arrest or inhibit development
of the symptoms or conditions associated with fatty acid
synthase-associated disorders, e.g., tumor growth associated with
cancer. A skilled medical practitioner will know how to use
standard methods to determine whether a patient is suffering from a
disease associated with activity of fatty acid synthase, e.g., by
examining the patient and determining whether the patient is
suffering from a disease known to be associated with fatty acid
synthase activity or by assaying for fatty acid synthase levels in
blood plasma or tissue of the individual suspected of suffering
from fatty acid synthase associated disease and comparing fatty
acid synthase levels in the blood plasma or tissue of the
individual suspected of suffering from a fatty acid synthase
associated disease fatty acid synthase levels in the blood plasma
or tissue of a healthy individual. Increased securin levels are
indicative of disease. Accordingly, the present invention provides,
inter alia, methods of administering a compound of the present
invention to a subject and determining fatty acid synthase activity
in the subject. Fatty acid synthase activity in the subject can be
determined before and/or after administration of the compound.
[2190] A "therapeutically effective amount" or "pharmaceutically
effective amount" means the amount that, when administered to a
subject, produces effects for which it is administered. For
example, a "therapeutically effective amount," when administered to
a subject to inhibit fatty acid synthase activity, is sufficient to
inhibit fatty acid synthase activity. A "therapeutically effective
amount," when administered to a subject for treating a disease, is
sufficient to effect treatment for that disease.
[2191] Except when noted, the terms "subject" or "patient" are used
interchangeably and refer to mammals such as human patients and
non-human primates, as well as experimental animals such as
rabbits, rats, and mice, and other animals. Accordingly, the term
"subject" or "patient" as used herein means any mammalian patient
or subject to which the compounds of the invention can be
administered. In an exemplary aspect of the present invention, to
identify subject patients for treatment according to the methods of
the invention, accepted screening methods are employed to determine
risk factors associated with a targeted or suspected disease or
condition or to determine the status of an existing disease or
condition in a subject. These screening methods include, for
example, conventional work-ups to determine risk factors that are
associated with the targeted or suspected disease or condition.
These and other routine methods allow the clinician to select
patients in need of therapy using the methods and formulations of
the present invention.
[2192] FASN Pathway Modulators
[2193] One aspect of the present disclosure includes a method of
inhibiting viral infection or treating cancer by contacting a cell
with an agent that modulates the fatty acid synthesis pathway. This
method of inhibiting viral infection or treating cancer can be
performed in vitro by contacting virally infected/cancerous cells
with an agent that modulates the fatty acid synthesis pathway, or
in vivo by administering an agent that modulates the fatty acid
synthesis pathway to a subject infected with a virus/having cancer.
In one aspect, an agent can be an inhibitor of the fatty acid
synthesis pathway.
[2194] Examples of inhibitors of the fatty acid synthesis pathway
that can be used in the methods and compositions of the present
disclosure are described below.
[2195] Compounds of Structure (I)
[2196] In various aspects, the present disclosure provides for
compounds of Structure (I):
##STR00403##
[2197] or a pharmaceutically acceptable salt thereof, wherein:
[2198] X, Y, and Z are each independently CR or NR', wherein R is
hydrogen or C.sub.1-6 alkyl and R' is hydrogen, C.sub.1-6 alkyl, or
absent; [2199] A is CH or N; [2200] R.sub.1 is hydrogen, cyano,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2201] q is 0, 1, 2, 3,
or 4; [2202] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2203] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2204] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2205] R.sub.4 is hydrogen, heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6),
--N(R.sub.7)C(.dbd.O)R.sub.8, --N(R.sub.9R.sub.10), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, or R.sub.4 and
R.sub.11 taken together with the atoms to which they are attached
join together to form a heteroaryl; [2206] R.sub.11 is hydrogen,
halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[2207] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2208] R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9R.sub.10, R.sub.13, and R.sub.14 are each independently
hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, alkylamino, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [2209] R.sub.15 and R.sub.16 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, or alkylamino; [2210] R.sub.17 and
R.sub.18 are each independently hydrogen or alkyl or can optionally
join together to form a bond; [2211] n is 1 or 2; and [2212] m is 0
or 1.
[2213] In certain aspects of Structure (I), R.sub.3 is F.
[2214] In certain aspects of Structure (I), A is CH.
[2215] In certain aspects of Structure (I), A is N.
[2216] In certain aspects of Structure (I), X, Y, and Z are
NR'.
[2217] In certain aspects of Structure (I), R.sub.4 is heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.4
and R.sub.11 taken together with the atoms to which they are
attached join together to form a heteroaryl.
[2218] In certain aspects of Structure (I), R.sub.5 is hydrogen and
R.sub.6 is aryl or heteroaryl.
[2219] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-A) or (I-B):
##STR00404##
[2220] or a pharmaceutically acceptable salt thereof, wherein:
[2221] X, Y, and Z are each independently CR or NR', wherein R is
hydrogen or C.sub.1-6 alkyl and R' is hydrogen, C.sub.1-6 alkyl, or
absent; [2222] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2223] q is 0, 1, 2, 3,
or 4; [2224] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2225] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2226] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2227] R.sub.4 is hydrogen, heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2228] R.sub.11 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken
together with the atoms to which they are attached join together to
form a heteroaryl, or R.sub.11 and R.sub.12 taken together with the
atoms to which they are attached join together to form a
heteroaryl; [2229] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12
taken together with the atoms to which they are attached join
together to form a heteroaryl; [2230] R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9R.sub.10, R.sub.13, and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2231]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;
and [2232] R.sub.17 and R.sub.18 are each independently hydrogen or
alkyl or can optionally join together to form a bond.
[2233] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-C) or (I-D):
##STR00405##
[2234] or a pharmaceutically acceptable salt thereof, wherein:
[2235] X, Y, and Z are each independently CR or NR', wherein R is
hydrogen or C.sub.1-6 alkyl and R' is hydrogen, C.sub.1-6 alkyl, or
absent; [2236] R.sub.2 is hydrogen, halo, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, or R.sub.2 and R.sub.3 taken together with the
atoms to which they are attached form a 5-membered heterocyclyl;
[2237] R.sub.3 is hydrogen, hydroxyl, halo, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3 taken together with the
atoms to which they are attached form a 5-membered heterocyclyl;
[2238] R.sub.4 is hydrogen, heteroaryl, heterocyclyl,
--C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2239] R.sub.20 is hydrogen or C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14); [2240] R.sub.11 is
hydrogen, halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2241] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and
R.sub.10 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, alkylamino, or
--N(R.sub.15R.sub.16); and [2242] R.sub.15 and R.sub.16 are each
independently H, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, or alkylamino.
[2243] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-E), (I-F), (I-G), (I-H):
##STR00406##
[2244] or a pharmaceutically acceptable salt thereof, wherein:
[2245] R.sub.2 is hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-6
alkyl, or R.sub.2 and R.sub.3 taken together with the atoms to
which they are attached form a 5-membered heterocyclyl; [2246]
R.sub.3 is hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or R.sub.2 and R.sub.3 taken together with the atoms to
which they are attached form a 5-membered heterocyclyl; [2247]
R.sub.4 is hydrogen, heteroaryl, heterocyclyl,
--C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2248] R.sub.20 is hydrogen or C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14); [2249] R.sub.11 is
hydrogen, halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[2250] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2251] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.13, and R.sub.14 are each independently H,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, or --N(R.sub.15R.sub.16); and [2252] R.sub.15 and
R.sub.16 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, or alkylamino.
[2253] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-I), (I-J), or (I-K):
##STR00407##
[2254] or a pharmaceutically acceptable salt thereof, wherein:
[2255] X and Y are each independently CR or NR', wherein R is H or
C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2256]
R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2257] q is 0, 1, 2, 3,
or 4; [2258] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2259] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2260] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2261] R.sub.11 is hydrogen, halo, cyano,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2262] R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each independently H,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, or --N(R.sub.15R.sub.16); and [2263] R.sub.15 and
R.sub.16 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, or alkylamino.
[2264] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-L) or (I-M):
##STR00408##
[2265] or a pharmaceutically acceptable salt thereof, wherein:
[2266] X and Y are each independently CR or NR', wherein R is H or
C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2267]
R.sub.4 is hydrogen, heteroaryl, heterocyclyl,
--C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2268] R.sub.20 is hydrogen or C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14); [2269] R.sub.11 is
hydrogen, halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2270] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and
R.sub.10 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, alkylamino, or
--N(R.sub.15R.sub.16); and [2271] R.sub.15 and R.sub.16 are each
independently H, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, or alkylamino.
[2272] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-N) or (I-O):
##STR00409##
[2273] or a pharmaceutically acceptable salt thereof.
[2274] In certain aspects, the compounds of Structure (I) have the
following Structure (I-P):
##STR00410##
[2275] or a pharmaceutically acceptable salt thereof, wherein:
[2276] R.sub.2 is hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-6
alkyl, or R.sub.2 and R.sub.3 taken together with the atoms to
which they are attached form a 5-membered heterocyclyl; [2277]
R.sub.3 is hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or R.sub.2 and R.sub.3 taken together with the atoms to
which they are attached form a 5-membered heterocyclyl; [2278]
R.sub.4 is hydrogen, heteroaryl, heterocyclyl,
--C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2279] R.sub.20 is hydrogen or C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14); [2280] R.sub.11 is
hydrogen, halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[2281] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2282] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.13, and R.sub.14 are each independently H,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, or --N(R.sub.15R.sub.16); and [2283] R.sub.15 and
R.sub.16 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, or alkylamino.
[2284] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-Q), (I-R), or (I-S):
##STR00411##
[2285] or a pharmaceutically acceptable salt thereof.
[2286] In certain aspects, the compounds of Structure (I) have the
following Structure (I-T):
##STR00412##
[2287] or a pharmaceutically acceptable salt thereof, wherein:
[2288] X, Y, and Z are each independently CR or NR', wherein R is H
or C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2289]
R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2290] q is 0, 1, 2, 3,
or 4; [2291] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2292] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2293] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2294] R.sub.4 is hydrogen, heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6),
--N(R.sub.7)C(.dbd.O)R.sub.8, --N(R.sub.9R.sub.10), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, or R.sub.4 and
R.sub.11 taken together with the atoms to which they are attached
join together to form a heteroaryl; [2295] R.sub.11 is hydrogen,
halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[2296] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2297] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.13, and R.sub.14 are each independently H,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, or --N(R.sub.15R.sub.16); and [2298] R.sub.15 and
R.sub.16 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, or alkylamino.
[2299] In certain aspects, the compounds of Structure (I) have the
following Structure (I-U):
##STR00413##
[2300] or a pharmaceutically acceptable salt thereof.
[2301] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-V):
##STR00414##
[2302] or a pharmaceutically acceptable salt thereof, wherein:
[2303] X, Y, and Z are each independently CR or NR', wherein R is H
or C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2304]
R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2305] q is 0, 1, 2, 3,
or 4; [2306] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2307] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2308] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2309] R.sub.4 is hydrogen, heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2310] R.sub.11 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken
together with the atoms to which they are attached join together to
form a heteroaryl, or R.sub.11 and R.sub.12 taken together with the
atoms to which they are attached join together to form a
heteroaryl; [2311] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12
taken together with the atoms to which they are attached join
together to form a heteroaryl; [2312] R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.13, and R.sub.14 are each
independently H, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, alkylamino, or --N(R.sub.15R.sub.16); and [2313]
R.sub.15 and R.sub.16 are each independently H, C.sub.1-6 alkyl,
cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
[2314] In certain aspects, the compound of Structure (I) has the
following Structure (I-W):
##STR00415##
[2315] or a pharmaceutically acceptable salt thereof.
[2316] In certain aspects, the compounds of Structure (I) have one
of the following Structures (I-X), (I-Y), (I-Z), (I-AA), (I-AB),
(I-AC), (I-AD), (I-AF), (I-AG), or (I-AH):
##STR00416## ##STR00417##
[2317] or a pharmaceutically acceptable salt thereof.
[2318] Compounds of Structure (II)
[2319] In various aspects, the present disclosure provides for
compounds of Structure (II):
##STR00418##
[2320] or a pharmaceutically acceptable salt thereof, wherein:
[2321] X, Y, and Z are each independently CR or NR', wherein R is H
or C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2322]
L and D are each independently C or N; [2323] R.sub.1 is hydrogen,
cyano, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2324] q is 0, 1, 2, 3,
or 4; [2325] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2326] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2327] R.sub.3 is hydrogen, hydroxyl,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or R.sub.2 and R.sub.3
taken together with the atoms to which they are attached form a
5-membered heterocyclyl; [2328] R.sub.4 is hydrogen, heteroaryl,
heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2329] R.sub.11 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken
together with the atoms to which they are attached join together to
form a heteroaryl, or R.sub.11 and R.sub.12 taken together with the
atoms to which they are attached join together to form a
heteroaryl; [2330] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12
taken together with the atoms to which they are attached join
together to form a heteroaryl; [2331] R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.13, and R.sub.14 are each
independently H, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, alkylamino, or --N(R.sub.15R.sub.16); [2332] R.sub.15
and R.sub.16 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, or alkylamino; [2333] R.sub.17 and
R.sub.18 are each independently hydrogen or alkyl or can optionally
join together to form a bond; [2334] n is 1 or 2; and [2335] m is 0
or 1.
[2336] In certain aspects, the compounds of Structure (II) have the
following Structure (II-A):
##STR00419##
[2337] or a pharmaceutically acceptable salt thereof, wherein:
[2338] X, Y, and Z are each independently CR or NR', wherein R is H
or C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2339]
R.sub.2 is hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or
R.sub.2 and R.sub.3 taken together with the atoms to which they are
attached form a 5-membered heterocyclyl; [2340] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
R.sub.2 and R.sub.3 taken together with the atoms to which they are
attached form a 5-membered heterocyclyl; [2341] R.sub.4 is
hydrogen, heteroaryl, heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6),
--N(R.sub.7)C(.dbd.O)R.sub.8, --N(R.sub.9R.sub.10), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, or R.sub.4 and
R.sub.11 taken together with the atoms to which they are attached
join together to form a heteroaryl; [2342] R.sub.20 is hydrogen or
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14);
[2343] R.sub.11 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[2344] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2345] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.13, and R.sub.14 are each independently H,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, or --N(R.sub.15R.sub.16); and [2346] R.sub.15 and
R.sub.16 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, or alkylamino.
[2347] In certain aspects, the compounds of Structure (II) have the
following Structure (II-B):
##STR00420##
[2348] or a pharmaceutically acceptable salt thereof, wherein:
[2349] X and Y are each independently CR or NR', wherein R is H or
C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2350]
R.sub.2 is hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or
R.sub.2 and R.sub.3 taken together with the atoms to which they are
attached form a 5-membered heterocyclyl; [2351] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
R.sub.2 and R.sub.3 taken together with the atoms to which they are
attached form a 5-membered heterocyclyl; [2352] R.sub.4 is
hydrogen, heteroaryl, heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6),
--N(R.sub.7)C(.dbd.O)R.sub.8, --N(R.sub.9R.sub.10), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, or R.sub.4 and
R.sub.11 taken together with the atoms to which they are attached
join together to form a heteroaryl; [2353] R.sub.20 is hydrogen or
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14);
[2354] R.sub.11 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2355] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and
R.sub.10 are each independently H, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, alkylamino, or
--N(R.sub.15R.sub.16); and [2356] R.sub.15 and R.sub.16 are each
independently H, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, or alkylamino.
[2357] In certain aspects, the compounds of Structure (II) have one
of the following Structures (II-C), (II-D), or (II-E):
##STR00421##
[2358] or a pharmaceutically acceptable salt thereof, wherein:
[2359] X and Y are each independently CR or NR', wherein R is H or
C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2360]
R.sub.2 is hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or
R.sub.2 and R.sub.3 taken together with the atoms to which they are
attached form a 5-membered heterocyclyl; [2361] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
R.sub.2 and R.sub.3 taken together with the atoms to which they are
attached form a 5-membered heterocyclyl; [2362] R.sub.11 is
hydrogen, halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2363] R.sub.20 is hydrogen or C.sub.1-6
alkyl, C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14); [2364]
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are each
independently H, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, alkylamino, or --N(R.sub.15R.sub.16); and [2365]
R.sub.15 and R.sub.16 are each independently H, C.sub.1-6 alkyl,
cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.
[2366] In certain aspects, the compound of Structure (II) has the
following Structure (II-F):
##STR00422##
[2367] or a pharmaceutically acceptable salt thereof.
[2368] Compounds of Structure (III)
[2369] In various aspects, the present disclosure provides for
compounds of Structure (III):
##STR00423##
[2370] or a pharmaceutically acceptable salt thereof, wherein:
[2371] X, Y, and Z are each independently CR or NR', wherein R is H
or C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2372]
Q is C or N; [2373] R.sub.3 is hydrogen, hydroxyl, halo, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, or if Q is NR.sub.3 is absent; [2374]
R.sub.4 is hydrogen, heteroaryl, heterocyclyl,
--C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2375] R.sub.20 is hydrogen or C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or --N(R.sub.13)(R.sub.14); [2376] R.sub.11 is
hydrogen, halo, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, R.sub.4 and R.sub.11 taken together with
the atoms to which they are attached join together to form a
heteroaryl, or R.sub.11 and R.sub.12 taken together with the atoms
to which they are attached join together to form a heteroaryl;
[2377] R.sub.12 is hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or R.sub.11 and R.sub.12 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2378] R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.13, and R.sub.14 are each independently H,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, or --N(R.sub.15R.sub.16); [2379] R.sub.15 and R.sub.16
are each independently H, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, or alkylamino; [2380] R.sub.17 and
R.sub.18 are each independently hydrogen or alkyl or can optionally
join together to form a bond; [2381] R.sub.19 is aryl, heteroaryl,
cycloalkyl, or heterocyclyl; [2382] n is 0, 1, or 2; and [2383] m
is 0 or 1.
[2384] In certain aspects, the compounds of Structure (III) have
one of the following Structures (III-A), (III-B), or (III-C):
##STR00424##
[2385] or a pharmaceutically acceptable salt thereof, wherein:
[2386] X and Y are each independently CR or NR', wherein R is H or
C.sub.1-6 alkyl and R' is H, C.sub.1-6 alkyl, or absent; [2387]
R.sub.3 is hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6
alkoxy; [2388] R.sub.4 is hydrogen, heteroaryl, heterocyclyl,
--C(.dbd.O)N(R.sub.5R.sub.6), --N(R.sub.7)C(.dbd.O)R.sub.8,
--N(R.sub.9R.sub.10), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11 taken together
with the atoms to which they are attached join together to form a
heteroaryl; [2389] R.sub.11 is hydrogen, halo, cyano, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.13R.sub.14), CF.sub.3,
--OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, or R.sub.4 and R.sub.11
taken together with the atoms to which they are attached join
together to form a heteroaryl; [2390] R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, and R.sub.10 are each independently H, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or
--N(R.sub.15R.sub.16); and [2391] R.sub.15 and R.sub.16 are each
independently H, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, or alkylamino.
[2392] In certain aspects, the compounds of Structure (III) have
one of the following Structures (III-D), (III-E), or (III-F):
##STR00425##
[2393] or a pharmaceutically acceptable salt thereof.
[2394] Compounds of Structure (IV)
[2395] In certain aspects, the compounds of Structure (IV) have one
of the following Structures (IV-A), (IV-B), or (IV-C):
##STR00426##
[2396] or a pharmaceutically acceptable salt thereof, wherein:
[2397] L.sub.1, L.sub.2, L.sub.3, L.sub.4, and A are each
independently CH or N; [2398] R.sub.1 is hydrogen, cyano, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2399] q is 0, 1, 2, 3,
or 4; [2400] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2401] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2402] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2403] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2404] R.sub.23 is hydrogen,
--N(R.sub.13)(R.sub.14), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, is
absent if L.sub.1 is N, or R.sub.23 and R.sub.24 taken together
with the atoms to which they are attached join together to form a
heterocyclyl, heteroaryl, or cycloalkyl; [2405] R.sub.24 is
hydrogen, --N(R.sub.13)(R.sub.14), C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --(C.sub.1-6 alkoxy)(heterocyclyl), heterocyclyl, or
R.sub.23 and R.sub.24 taken together with the atoms to which they
are attached join together to form a heterocyclyl, heteroaryl, or
cycloalkyl; [2406] R.sub.26 is hydrogen, heteroaryl, heterocyclyl,
--N(R.sub.13)(R.sub.14), or --S(.dbd.O).sub.2R.sub.20; [2407]
R.sub.13 and R.sub.14 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
alkylamino, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
[2408] R.sub.25 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
and [2409] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, or alkylamino.
[2410] In certain aspects, the compounds of Structure (IV) have one
of the following Structures (IV-D) and (IV-E):
##STR00427##
[2411] or a pharmaceutically acceptable salt thereof. [2412]
R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2413] q is 0, 1, 2, 3,
or 4; [2414] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2415] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2416] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2417] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2418] R.sub.26 is hydrogen, heteroaryl,
heterocyclyl, --N(R.sub.13)(R.sub.14), or
--S(.dbd.O).sub.2R.sub.20; [2419] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2420]
R.sub.25 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; and
[2421] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, or alkylamino.
[2422] In certain aspects, the compounds of Structure (IV) have one
of the following Structures (IV-F) and (IV-G):
##STR00428##
[2423] or a pharmaceutically acceptable salt thereof, wherein:
[2424] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2425] q is 0, 1, 2, 3,
or 4; [2426] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2427] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2428] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2429] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2430] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2431]
R.sub.25 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2432]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, or alkylamino; [2433] s is 0, 1, or 2;
[2434] L.sub.5 is CH.sub.2, NH, S, or O; [2435] L.sub.6 is CH or N;
[2436] R.sub.27 is hydrogen, --C(.dbd.O)R'',
--S(.dbd.O).sub.2R.sub.20; [2437] R.sub.28 is hydrogen,
--C(.dbd.O)R'', --S(.dbd.O).sub.2R.sub.20, or is absent if L.sub.6
is O; and [2438] R'' is hydrogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14), or
--N(R.sub.13)(R.sub.14).
[2439] In certain aspects of Structure (IV), R.sub.1 is hydrogen,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[2440] In certain aspects of Structure (IV), R.sub.1 is cyano.
[2441] In certain aspects of Structure (IV), R.sub.2 is hydrogen or
halo; R.sub.2 is hydrogen.
[2442] In certain aspects of Structure (IV), R.sub.3 is
hydrogen.
[2443] In certain aspects of Structure (IV), R.sub.21 and R.sub.22
are each independently hydrogen or C.sub.1-6 alkyl.
[2444] In certain aspects of Structure (IV), R.sub.21 and R.sub.22
are each independently C.sub.1-6 alkyl.
[2445] In certain aspects of Structure (IV), R.sub.25 is
hydrogen.
[2446] In certain aspects of Structure (IV), L.sub.2 is N.
[2447] In certain aspects of Structure (IV), L.sub.1 is CH.
[2448] In certain aspects of Structure (IV), L.sub.3 is CH.
[2449] In certain aspects of Structure (IV), L.sub.4 is CH.
[2450] In certain aspects of Structure (IV), A is N.
[2451] In certain aspects of Structure (IV), A is CH.
[2452] In certain aspects of Structure (IV), R.sub.26 is
heterocyclyl.
[2453] In certain aspects of Structure (IV), R.sub.24 is
--N(R.sub.13)(R.sub.14).
[2454] In certain aspects of Structure (IV), L.sub.5 and L.sub.6
are each independently N. In certain aspects of Structure (IV), s
is 1.
[2455] In certain aspects of Structure (IV), s is 0.
[2456] In certain aspects, the compounds of Structure (IV) have one
of the following Structures (IV-H), (IV-I), (IV-J), (IV-K), (IV-L),
(IV-M), (IV-N), or (IV-O):
##STR00429## ##STR00430##
[2457] or a pharmaceutically acceptable salt thereof.
[2458] Compounds of Structure (V)
[2459] In various aspects, the present disclosure provides for
compounds of Structure (V):
##STR00431##
[2460] or a pharmaceutically acceptable salt thereof, wherein:
[2461] L.sub.7 is N or O, wherein R.sub.30 is absent if L.sub.7 is
O; [2462] A is CH or N; [2463] R.sub.1 is hydrogen, cyano, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2464] q is 0, 1, 2, 3,
or 4; [2465] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2466] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2467] R.sub.3 is halo,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2468] R.sub.21 and R.sub.22
are each independently hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2469] R.sub.29 and R.sub.30 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
hydroxyalkyl, heteroaryl, heterocyclyl, --N(R.sub.15R.sub.16),
--C(.dbd.O)R.sub.46, --R.sub.48C(.dbd.O)R.sub.47, or R.sub.29 and
R.sub.30 taken together with the atoms to which they are attached
join together to form a heteroaryl or heterocyclyl, wherein
R.sub.30 is absent if L.sub.7 is O; [2470] R.sub.46 and R.sub.47
are each independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [2471] R.sub.48 is alkyl or is absent;
[2472] R.sub.31 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2473] R.sub.13 and R.sub.14 are each independently hydrogen,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
hydroxyalkyl, alkylamino, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [2474] R.sub.15 and R.sub.16 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino; and [2475] v
is 0 or 1.
[2476] In certain aspects, the compounds of Structure (V) have one
of the following Structures (V-A), (V-B), (V-C), or (V-D):
##STR00432##
[2477] or a pharmaceutically acceptable salt thereof, wherein:
[2478] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2479] q is 0, 1, 2, 3,
or 4; [2480] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2481] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2482] R.sub.3 is halo,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2483] R.sub.21 and R.sub.22
are each independently hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2484] R.sub.30 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl,
--N(R.sub.15R.sub.16), --C(.dbd.O)R.sub.46, or
--R.sub.48C(.dbd.O)R.sub.47, wherein R.sub.30 is absent if L.sub.7
is O; [2485] R.sub.46 and R.sub.47 are each independently hydrogen,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
hydroxyalkyl, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
[2486] R.sub.48 is alkyl or is absent; [2487] R.sub.31 is hydrogen,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2488] R.sub.13 and R.sub.14
are each independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2489]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino; [2490] L.sub.8, L.sub.9, and L.sub.10 are each
independently CH.sub.2, NH, or O; [2491] L.sub.11 and L.sub.12 are
each independently CH or N; [2492] R.sub.32 and R.sub.33 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, --C(.dbd.O)R.sub.46, hydroxyalkyl,
hydroxyl, or are absent; [2493] u is 0, 1, or 2; and [2494] t is 0,
1, or 2.
[2495] In certain aspects of Structure (V), L.sub.7 is N.
[2496] In certain aspects of Structure (V), L.sub.7 is O.
[2497] In certain aspects of Structure (V), A is N.
[2498] In certain aspects of Structure (V), A is CH.
[2499] In certain aspects of Structure (V), R.sub.1 is hydrogen,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[2500] In certain aspects of Structure (V), R.sub.1 is cyano.
[2501] In certain aspects of Structure (V), R.sub.2 is hydrogen or
halo.
[2502] In certain aspects of Structure (V), R.sub.2 is
hydrogen.
[2503] In certain aspects of Structure (V), R.sub.3 is
fluorine.
[2504] In certain aspects of Structure (V), R.sub.21 and R.sub.22
are each independently hydrogen or C.sub.1-6 alkyl.
[2505] In certain aspects of Structure (V), R.sub.21 and R.sub.22
are each independently C.sub.1-6 alkyl.
[2506] In certain aspects of Structure (V), R.sub.31 is
hydrogen.
[2507] In certain aspects of Structure (V), R.sub.30 is
hydrogen.
[2508] In certain aspects of Structure (V), L.sub.8 is O.
[2509] In certain aspects of Structure (V), L.sub.9 is O.
[2510] In certain aspects of Structure (V), L.sub.10 is O and
L.sub.11 is N.
[2511] In certain aspects of Structure (V), L.sub.12 is N.
[2512] In certain aspects of Structure (V), R.sub.32 and R.sub.33
are each independently hydrogen.
[2513] In certain aspects, the compounds of Structure (V) have one
of the following Structures (V-I), (V-J), (V-K), (V-L), (V-M),
(V-N), or (V-O):
##STR00433## ##STR00434##
[2514] or a pharmaceutically acceptable salt thereof.
[2515] Compounds of Structure (VI)
[2516] In certain aspects, the compounds of Structure (VI) have one
of the following Structures (VI-A) or (VI-B):
##STR00435##
[2517] or a pharmaceutically acceptable salt thereof, wherein:
[2518] L.sub.13, L.sub.14, L.sub.15, and A are each independently
CH or N; [2519] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2520] q is 0, 1, 2, 3,
or 4; [2521] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2522] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2523] R.sub.3 is halo,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2524] R.sub.21 and R.sub.22
are each independently hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2525] R.sub.34 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl,
heterocyclyl, heteroaryl, alkylamino, CF.sub.3, --OCF.sub.3,
--S(.dbd.O).sub.2R.sub.20, or --N(R.sub.15R.sub.16); [2526]
R.sub.35 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2527]
R.sub.36 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--N(R.sub.15R.sub.16), heterocyclyl, or heteroaryl; [2528] R.sub.13
and R.sub.14 are each independently hydrogen, C.sub.1-6 alkyl,
cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
alkylamino, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
and [2529] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, or alkylamino.
[2530] In certain aspects, the compounds of Structure (VI) have one
of the following Structures (VI-C) or (VI-D):
##STR00436##
[2531] or a pharmaceutically acceptable salt thereof, wherein:
[2532] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2533] q is 0, 1, 2, 3,
or 4; [2534] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2535] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2536] R.sub.3 is halo,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2537] R.sub.21 and R.sub.22
are each independently hydrogen, halo, cyano, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2538] R.sub.35 is hydrogen, C.sub.1-6
alkyl, or C.sub.1-6 alkoxy; [2539] R.sub.36 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --N(R.sub.15R.sub.16), heterocyclyl, or
heteroaryl; [2540] R.sub.13 and R.sub.14 are each independently
hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl,
heteroaryl, hydroxyalkyl, alkylamino, --N(R.sub.15R.sub.16), or
--S(.dbd.O).sub.2R.sub.20; [2541] R.sub.15 and R.sub.16 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino; and [2542] R.sub.37 and R.sub.38 are each independently
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyalkyl,
heteroaryl, heterocyclyl, or R.sub.37 and R.sub.38 taken together
with the atoms to which they are attached join together to form a
heteroaryl or heterocyclyl.
[2543] In certain aspects of Structure (VI), R.sub.1 is hydrogen,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[2544] In certain aspects of Structure (VI), R.sub.1 is cyano.
[2545] In certain aspects of Structure (VI), R.sub.2 is hydrogen or
halo.
[2546] In certain aspects of Structure (VI), R.sub.2 is
hydrogen.
[2547] In certain aspects of Structure (VI), R.sub.3 is
fluorine.
[2548] In certain aspects of Structure (VI), R.sub.21 and R.sub.22
are each independently hydrogen or C.sub.1-6 alkyl.
[2549] In certain aspects of Structure (VI), R.sub.21 and R.sub.22
are each independently C.sub.1-6 alkyl.
[2550] In certain aspects of Structure (VI), R.sub.35 is
hydrogen.
[2551] In certain aspects of Structure (VI), R.sub.34 is
heteroaryl;
[2552] In certain aspects of Structure (VI), R.sub.34 is thienyl,
pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl,
isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl,
pyrrolinyl, pyridazinyl, triazolyl, indolyl, isoindolyl,
indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,
benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl,
benzoxadiazolyl, thiadiazolyl, benzothiazolyl, or
benzothiadiazolyl.
[2553] In certain aspects of Structure (VI), L.sub.13 is N.
[2554] In certain aspects of Structure (VI), L.sub.14 and L.sub.15
are each independently CH.
[2555] In certain aspects of Structure (VI), A is N.
[2556] In certain aspects of Structure (VI), A is CH.
[2557] In certain aspects, the compounds of Structure (VI) have one
of the following Structures (VI-E), (VI-F), (VI-G), (VI-H), or
(VI-I):
##STR00437##
[2558] or a pharmaceutically acceptable salt thereof.
[2559] In various aspects, the present disclosure provides for
compounds of Structure (VI-J):
##STR00438##
or a pharmaceutically acceptable salt thereof, wherein: [2560]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or branched
alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [2561] the C.sub.3-C.sub.5
cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
and [2562] when R.sup.1 is not H, --CN or halogen, it is optionally
substituted with one or more halogens; [2563] each R.sup.2 is
independently H, halogen or C.sub.1-C.sub.4 straight or branched
alkyl; [2564] R.sup.3 is H, --OH, or halogen; [2565] R.sup.21 is
cyclobutyl, azetidin-1-yl, or cyclopropyl; [2566] R.sup.22 is H,
halogen, or C.sub.1-C.sub.2 alkyl; [2567] R.sup.35 is
--C(O)--R.sup.351, --C(O)--NHR.sup.351, --C(O)--O--R.sup.351 or
S(O).sub.2R.sup.351; and [2568] R.sup.351 is C.sub.1-C.sub.6
straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or
heteroaryl, each of which is optionally substituted.
[2569] In some aspects of Structure (VI-J), R.sup.3 is H or
halogen.
[2570] In some aspects of Structure (VI-J), R.sup.1 is halogen,
--CN or C.sub.1-C.sub.2 haloalkyl.
[2571] In some aspects of Structure (VI-J), R.sup.22 is
C.sub.1-C.sub.2 alkyl.
[2572] In some aspects of Structure (VI-J), R.sup.21 is cyclobutyl
and R.sup.22 is C.sub.1-C.sub.2 alkyl.
[2573] In some aspects of Structure (VI-J), R.sup.21 is
cyclobutyl.
[2574] In some aspects of Structure (VI-J), R.sup.3 is H or F.
[2575] In some aspects of Structure (VI-J), R.sup.1 is --CN.
[2576] In some aspects of Structure (VI-J), R.sup.1 is
--CF.sub.3.
[2577] In some aspects of Structure (VI-J), R.sup.22 is H, methyl
or ethyl.
[2578] In some aspects of Structure (VI-J), R.sup.22 is H.
[2579] In some aspects of Structure (VI-J), R.sup.22 is methyl.
[2580] In some aspects of Structure (VI-J), R.sup.35 is
--C(O)--NHR.sup.351.
[2581] In some aspects of Structure (VI-J), R.sup.351 is isopropyl,
isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,
(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,
(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.
[2582] In some aspects of Structure (VI-J), R.sup.351 is
(R)-(tetrahydrofuran-2-yl)methyl or
(S)-(tetrahydrofuran-2-yl)methyl.
[2583] In some aspects of Structure (VI-J), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is H, R.sup.35 is --C(O)--NHR.sup.351 where
R.sup.351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,
(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,
(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or
(S)-tetrahydro-2H-pyran-3-yl.
[2584] In some aspects of Structure (VI-J), R.sup.35 is
--C(O)--O--R.sup.351.
[2585] In some aspects of Structure (VI-J), R.sup.351 is isopropyl,
isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,
(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,
(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
[2586] In some aspects of Structure (VI-J), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is H, R.sup.35 is --C(O)--O--R.sup.351 where
R.sup.351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,
(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,
(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or
(S)-tetrahydro-2H-pyran-3-yl.
[2587] In some aspects of Structure (VI-J), R.sup.351 is
(R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.
[2588] In some aspects of Structure (VI-J), compounds have a
structure selected from the group consisting of:
##STR00439## ##STR00440##
[2589] Compounds of Structure (VII)
[2590] In certain aspects, the compounds of Structure (VII) have
one of the following Structures (VII-A) or (VII-B):
##STR00441##
[2591] or a pharmaceutically acceptable salt thereof, wherein:
[2592] L.sub.16 is C or N, wherein R.sub.41 is absent if L.sub.16
is N; [2593] L.sub.17, L.sub.18, and A are each independently CH or
N; [2594] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2595] q is 0, 1, 2, 3,
or 4; [2596] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2597] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2598] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2599] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2600] R.sub.40, R.sub.42, and R.sub.43
are each independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--S(.dbd.O).sub.2R.sub.20, --C(.dbd.O)R, hydroxyalkyl, hydroxyl,
--N(R.sub.13R.sub.14), or R.sub.41 and R.sub.42 taken together with
the atoms to which they are attached join together to form a
heteroaryl or heterocyclyl; [2601] R.sub.41 is hydrogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --S(.dbd.O).sub.2R.sub.20, --C(.dbd.O)R,
hydroxyalkyl, hydroxyl, --N(R.sub.13R.sub.14), R.sub.41 is absent
if L.sub.16 is N, or R.sub.41 and R.sub.42 taken together with the
atoms to which they are attached join together to form a heteroaryl
or heterocyclyl; [2602] R is hydrogen, C.sub.1-6 alkyl, cycloalkyl,
aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2603]
R.sub.39 is hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; [2604]
R.sub.13 and R.sub.14 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,
alkylamino, --N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20;
and [2605] R.sub.15 and R.sub.16 are each independently hydrogen,
C.sub.1-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,
hydroxyalkyl, or alkylamino.
[2606] In certain aspects of Structure (VII), R.sub.1 is hydrogen,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[2607] In certain aspects of Structure (VII), R.sub.1 is cyano.
[2608] In certain aspects of Structure (VII), R.sub.2 is hydrogen
or halo.
[2609] In certain aspects of Structure (VII), R.sub.2 is
hydrogen.
[2610] In certain aspects of Structure (VII), R.sub.3 is
hydrogen.
[2611] In certain aspects of Structure (VII), R.sub.21 and R.sub.22
are each independently hydrogen or C.sub.1-6 alkyl.
[2612] In certain aspects of Structure (VII), R.sub.21 and R.sub.22
are each independently C.sub.1-6 alkyl.
[2613] In certain aspects of Structure (VII), R.sub.39 is
hydrogen.
[2614] In certain aspects of Structure (VII), R.sub.40 is
hydrogen.
[2615] In certain aspects of Structure (VII), L.sub.16 is N.
[2616] In certain aspects of Structure (VII), L.sub.17 is N.
[2617] In certain aspects of Structure (VII), L.sub.18 is CH.
[2618] In certain aspects of Structure (VII), L.sub.18 is N.
[2619] In certain aspects of Structure (VII), A is N.
[2620] In certain aspects of Structure (VII), A is CH.
[2621] In certain aspects of Structure (VII), R.sub.42 is C.sub.1-6
alkyl.
[2622] In certain aspects of Structure (VII), R.sub.41 is C.sub.1-6
alkyl.
[2623] In certain aspects, the compounds of Structure (VII) have
one of the following Structures (VII-C) or (VII-D):
##STR00442##
[2624] or a pharmaceutically acceptable salt thereof.
[2625] Compounds of Structure (VIII)
[2626] In certain aspects, the compounds of Structure (VIII) have
one of the following Structures (VIII-A), (VIII-B), or
(VIII-C):
##STR00443##
[2627] or a pharmaceutically acceptable salt thereof, wherein:
[2628] L.sub.19 and A are each independently CH or N; [2629]
R.sub.1 is hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2630] q is 0, 1, 2, 3,
or 4; [2631] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2632] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2633] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2634] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2635] R.sub.39 is hydrogen, C.sub.1-6
alkyl, or C.sub.1-6 alkoxy; [2636] R.sub.44 and R.sub.45 are each
independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
cycloalkyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, --S(.dbd.O).sub.2R.sub.20, --C(.dbd.O)R, or
--N(R.sub.13R.sub.14); and [2637] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; and [2638]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino.
[2639] In certain aspects of Structure (VIII), R.sub.1 is hydrogen,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)NN(R.sub.13)(R.sub.14).
[2640] In certain aspects of Structure (VIII), R.sub.1 is
cyano.
[2641] In certain aspects of Structure (VIII), R.sub.2 is hydrogen
or halo.
[2642] In certain aspects of Structure (VIII), R.sub.2 is
hydrogen.
[2643] In certain aspects of Structure (VIII), R.sub.3 is
hydrogen.
[2644] In certain aspects of Structure (VIII), R.sub.21 and
R.sub.22 are each independently hydrogen or C.sub.1-6 alkyl.
[2645] In certain aspects of Structure (VIII), R.sub.21 and
R.sub.22 are each independently C.sub.1-6 alkyl.
[2646] In certain aspects of Structure (VIII), R.sub.39 is
hydrogen.
[2647] In certain aspects of Structure (VIII), L.sub.19 is N.
[2648] In certain aspects of Structure (VIII), A is N.
[2649] In certain aspects of Structure (VIII), A is CH.
[2650] In certain aspects, the compounds of Structure (VIII) have
the following Structure (VIII-D):
##STR00444##
[2651] or a pharmaceutically acceptable salt thereof.
[2652] In various aspects, compounds of formula IX are
provided:
##STR00445##
[2653] or a pharmaceutically acceptable salt thereof, wherein:
[2654] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl) or
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [2655]
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [2656] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[2657] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [2658] R.sup.3 is H,
--OH, or halogen; [2659] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [2660] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [2661] R.sup.24 is H, C.sub.1-C.sub.4
straight or branched alkyl, --(C.sub.1-C.sub.4 alkyl).sub.t-OH,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5
cycloalkyl), or --(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [2662] t is 0 or 1; [2663] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [2664] L.sup.1 is CR.sup.23 or N; [2665]
L.sup.2 is CH or N; [2666] at least one of L.sup.1 or L.sup.2 is N;
and [2667] R.sup.23 is H or C.sub.1-C.sub.4 straight or branched
alkyl.
[2668] In some aspects of Structure (IX), R.sup.24 is
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or branched alkyl)
wherein t is 0 or 1.
[2669] In some aspects of Structure (IX), R.sup.21 is halogen,
C.sub.1-C.sub.4 straight or branched alkyl, C.sub.3-C.sub.5
cycloalkyl wherein the C.sub.3-C.sub.5 cycloalkyl optionally
includes an oxygen or nitrogen heteroatom,
--S(O).sub.u--(C.sub.1-C.sub.4 straight or branched alkyl) wherein
u is 0 or 2, or --S(O).sub.u--(C.sub.3-C.sub.5 cycloalkyl) wherein
u is 0 or 2;
[2670] In some aspects of Structure (IX), R.sup.3 is H or
halogen.
[2671] In some aspects of Structure (IX), R.sup.1 is halogen, --CN
or C.sub.1-C.sub.2 haloalkyl.
[2672] In some aspects of Structure (IX), both L.sup.1 and L.sup.2
are N.
[2673] In some aspects of Structure (IX), R.sup.21 is
C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is
C.sub.1-C.sub.2 alkyl.
[2674] In some aspects of Structure (IX), R.sup.21 is
C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[2675] In some aspects of Structure (IX), R.sup.24 is
--(C.sub.1-C.sub.2 alkyl).sub.t-O--(C.sub.1-C.sub.2 alkyl) wherein
t is 0 or 1.
[2676] In some aspects of Structure (IX), R.sup.21 is
C.sub.3-C.sub.5 cycloalkyl, R.sup.22 is C.sub.1-C.sub.2 alkyl and
R.sup.24 is C.sub.1-C.sub.2 alkyl.
[2677] In some aspects of Structure (IX), R.sup.21 is cyclobutyl,
R.sup.22 is C.sub.1-C.sub.2 alkyl and R.sup.24 is C.sub.1-C.sub.2
alkyl.
[2678] In some aspects of Structure (IX), R.sup.21 is
cyclobutyl.
[2679] In some aspects of Structure (IX), R.sup.3 is H or F.
[2680] In some aspects of Structure (IX), R.sup.1 is --CN.
[2681] In some aspects of Structure (IX), R.sup.1 is
--CF.sub.3.
[2682] In some aspects of Structure (IX), R.sup.22 is H, methyl or
ethyl.
[2683] In some aspects of Structure (IX), R.sup.22 is H.
[2684] In some aspects of Structure (IX), R.sup.22 is methyl.
[2685] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is hydrogen, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 and L.sup.2 are N, and
R.sup.24 is methyl, ethyl, hydroxymethyl, methoxymethyl,
2-methoxyethyl.
[2686] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 and L.sup.2 are N, and
R.sup.24 is methoxy or ethoxy.
[2687] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 is CH, L.sup.2 is N, and
R.sup.24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or
2-methoxyethyl.
[2688] In some aspects of Structure (IX), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 is N, L.sup.2 is CH, and
R.sup.24 is methyl, ethyl, hydroxymethyl, methoxymethyl, or
2-methoxyethyl.
[2689] In some aspects of Structure (IX), compounds have a
structure selected from the group consisting of:
##STR00446##
[2690] In various aspects, compounds of Structure (X) are
provided:
##STR00447##
[2691] or a pharmaceutically acceptable salt thereof, wherein:
[2692] R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or
branched alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl),
--O--(C.sub.1-C.sub.4 straight or branched alkyl) wherein: [2693]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; and [2694] when R.sup.1 is not H, --CN or
halogen, it is optionally substituted with one or more halogens;
[2695] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [2696] R.sup.3 is H,
--OH or halogen; [2697] L.sup.3 is C(R.sup.60).sub.2, O or
NR.sup.50; [2698] each R.sup.60 is independently H, --OH, --CN,
--O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl), or --C(O)--N(R.sup.601).sub.2 wherein:
[2699] t is 0 or 1, and [2700] the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom; [2701] each
R.sup.50 is independently H, --C(O)--O.sub.t--(C.sub.1-C.sub.4
straight or branched alkyl), --C(O)--O.sub.t--(C.sub.3-C.sub.5
cyclic alkyl), --C.sub.3-C.sub.5 cyclic alkyl optionally containing
an oxygen or nitrogen heteroatom, --C(O)--N(R.sup.501).sub.2,
C.sub.1-C.sub.4 straight or branched alkyl wherein: [2702] t is 0
or 1, and [2703] the C.sub.3-C.sub.5 cycloalkyl optionally includes
an oxygen or nitrogen heteroatom; [2704] n is 1, 2 or 3; [2705] m
is 1 or 2; [2706] R.sup.21 is H, halogen, C.sub.1-C.sub.4 straight
or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom [2707] R.sup.22 is H, halogen, C.sub.1-C.sub.2
alkyl; [2708] each R.sup.26 is independently --OH, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl), --C(O)--O.sub.t--(C.sub.1-C.sub.4 alkyl), or
--C(O)--N(R.sup.501).sub.2 wherein: [2709] t is 0 or 1, and [2710]
the C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [2711] s is 0, 1 or 2; [2712] each R.sup.601
and R.sup.501 is independently H or C.sub.1-C.sub.4 straight or
branched alkyl; and [2713] wherein two of R.sup.26, R.sup.60,
R.sup.50, R.sup.501 and R.sup.601 optionally join to form a ring
wherein the two of R.sup.26, R.sup.60, R.sup.5, R.sup.501 and
R.sup.601 may be two R.sup.26, two R.sup.60, two R.sup.50, two
R.sup.501 or two R.sup.601.
[2714] In some aspects of Structure (X), R.sup.21 is halogen,
C.sub.1-C.sub.4 straight or branched alkyl or C.sub.3-C.sub.5
cycloalkyl.
[2715] In some aspects of Structure (X), R.sup.3 is H or
halogen.
[2716] In some aspects of Structure (X), R.sup.1 is --CN or
C.sub.1-C.sub.2 haloalkyl.
[2717] In some aspects of Structure (X), R.sup.3 is H or F.
[2718] In some aspects of Structure (X), R.sup.1 is --CN.
[2719] In some aspects of Structure (X), R.sup.1 is-CF.sub.3.
[2720] In some aspects of Structure (X), n is 1.
[2721] In some aspects of Structure (X), n is 2.
[2722] In some aspects of Structure (X), m is 1
[2723] In some aspects of Structure (X), m is 2.
[2724] In some aspects of Structure (X), R.sup.21 is
C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is
C.sub.1-C.sub.2 alkyl.
[2725] In some aspects of Structure (X), R.sup.21 is
C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[2726] In some aspects of Structure (X), n is 2, m is 1, L.sup.3 is
--N--C(O)--O--(C.sub.1-C.sub.2 alkyl).
[2727] In some aspects of Structure (X), L.sup.3 is NR.sup.50;
R.sup.50 is C.sub.1-C.sub.2 alkyl; R.sup.21 is cyclobutyl; R.sup.22
is H or methyl; R.sup.3 is H; R.sup.1 is --CN; m is 2 and n is 1 or
2.
[2728] In some aspects of Structure (X), n is 2, m is 1, L.sup.3 is
O and s is 0.
[2729] In some aspects of Structure (X), R.sup.22 is H, methyl or
ethyl.
[2730] In some aspects of Structure (X), R.sup.22 is methyl.
[2731] In some aspects of Structure (X), R.sup.22 is H.
[2732] In some aspects of Structure (X), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, n is 2 and L.sup.3 is NR.sup.50
where R.sup.50 is methyl or ethyl.
[2733] In some aspects of Structure (X), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, n is 2 and L.sup.3 is O.
[2734] In some aspects of Structure (X), the compound has a
structure selected from the group consisting of:
##STR00448##
[2735] In various aspects, compounds of Structure (XI) are
provided:
##STR00449##
or a pharmaceutically acceptable salt thereof, wherein: [2736]
R.sup.1 is H, --CN, halogen, C.sub.1-C.sub.4 straight or branched
alkyl, --O--(C.sub.3-C.sub.5 cycloalkyl), --O--(C.sub.1-C.sub.4
straight or branched alkyl) wherein: [2737] the C.sub.3-C.sub.5
cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
and [2738] when R.sup.1 is not H, --CN or halogen, it is optionally
substituted with one or more halogens; [2739] each R.sup.2 is
independently H, halogen or C.sub.1-C.sub.4 straight or branched
alkyl; [2740] R.sup.3 is H, --OH, or halogen; [2741] R.sup.21 is
cyclobutyl, azetidin-1-yl, or cyclopropyl; [2742] R.sup.22 is H,
halogen, C.sub.1-C.sub.2 alkyl; and [2743] R.sup.351 is
C.sub.1-C.sub.2 alkyl or C.sub.2--O--(C.sub.1 or C.sub.2
alkyl).
[2744] In some aspects of Structure (XI), R.sup.3 is H or
halogen.
[2745] In some aspects of Structure (XI), R.sup.1 is halogen, --CN
or C.sub.1-C.sub.2 haloalkyl.
[2746] In some aspects of Structure (XI), R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[2747] In some aspects of Structure (XI), R.sup.21 is cyclobutyl
and R.sup.22 is C.sub.1-C.sub.2 alkyl.
[2748] In some aspects of Structure (XI), R.sup.21 is
cyclobutyl.
[2749] In some aspects of Structure (XI), R.sup.3 is H or F.
[2750] In some aspects of Structure (XI), R.sup.1 is --CN.
[2751] In some aspects of Structure (XI), R.sup.1 is
--CF.sub.3.
[2752] In some aspects of Structure (XI), R.sup.22 is H, methyl or
ethyl.
[2753] In some aspects of Structure (XI), R.sup.22 is H.
[2754] In some aspects of Structure (XI), R.sup.22 is methyl.
[2755] In some aspects of Structure (XI), R.sup.1 is --CN, each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is cyclobutyl, R.sup.22
is methyl and R.sup.351 is methyl or ethyl.
[2756] In some aspects of Structure (XI), the compound has a
structure selected from the group consisting of:
##STR00450##
[2757] In certain aspects, the present disclosure provides
compounds having any one of the structures found in Table 1.
According to the present disclosure, the compounds of Table 1 are
inhibitors of fatty acid synthase.
[2758] Synthesis of Compounds
[2759] Also described herein are methods of synthesizing the
compounds of the present disclosure. Compounds of the present
disclosure can be synthesized as indicated in SYNTHETIC SCHEMES
1-13 below.
##STR00451##
wherein: [2760] R'' is hydrogen or alkyl; [2761] R.sub.1 is
hydrogen, cyano, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2762] q is 0, 1, 2, 3,
or 4; [2763] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2764] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2765] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2766] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2767] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2768]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino; and [2769] R.sub.17 is hydrogen or alkyl.
##STR00452## ##STR00453##
[2770] wherein: [2771] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2772] q is 0, 1, 2, 3,
or 4; [2773] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2774] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2775] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2776] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2777] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2778]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino; [2779] R.sub.23 is hydrogen, --N(R.sub.13)(R.sub.14),
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, is absent if L.sub.1 is N, or
R.sub.23 and R.sub.24 taken together with the atoms to which they
are attached join together to form a heterocyclyl, heteroaryl, or
cycloalkyl; and [2780] R.sub.24 is hydrogen,
--N(R.sub.13)(R.sub.14), C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--(C.sub.1-6 alkoxy)(heterocyclyl), heterocyclyl, or R.sub.23 and
R.sub.24 taken together with the atoms to which they are attached
join together to form a heterocyclyl, heteroaryl, or
cycloalkyl.
##STR00454##
[2781] wherein: [2782] LG is a leaving group; [2783] Nu is a
nucleophile; [2784] L.sub.2, L.sub.3, L.sub.4, and L.sub.4' are
each independently CH or N; [2785] R.sub.1 is hydrogen, cyano,
halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
--C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2786] q is 0, 1, 2, 3,
or 4; [2787] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2788] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2789] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2790] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2791] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2792]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino; and [2793] R.sub.17 is hydrogen or alkyl.
##STR00455##
[2794] wherein: [2795] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2796] q is 0, 1, 2, 3,
or 4; [2797] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2798] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2799] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2800] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, Or
--S(.dbd.O).sub.2R.sub.20; [2801] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2802]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino; [2803] R.sub.17 is hydrogen or alkyl; and [2804]
R.sub.24 is hydrogen, --N(R.sub.13)(R.sub.14), C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --(C.sub.1-6 alkoxy)(heterocyclyl), or
heterocyclyl.
##STR00456## ##STR00457##
[2804] wherein: [2805] R.sub.1 is hydrogen, cyano, halo, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, --C(.dbd.O)N(R.sub.13)(R.sub.14),
--(CH.sub.2).sub.qC(.dbd.O)N(R.sub.13)(R.sub.14), CF.sub.3,
--OCF.sub.3, or --S(.dbd.O).sub.2R.sub.20; [2806] q is 0, 1, 2, 3,
or 4; [2807] R.sub.20 is hydrogen or C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or --N(R.sub.13)(R.sub.14); [2808] R.sub.2 is hydrogen,
halo, C.sub.1-6 alkoxy, or C.sub.1-6 alkyl; [2809] R.sub.3 is
hydrogen, hydroxyl, halo, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy;
[2810] R.sub.21 and R.sub.22 are each independently hydrogen, halo,
cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3, --OCF.sub.3, or
--S(.dbd.O).sub.2R.sub.20; [2811] R.sub.13 and R.sub.14 are each
independently hydrogen, C.sub.1-6 alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino,
--N(R.sub.15R.sub.16), or --S(.dbd.O).sub.2R.sub.20; [2812]
R.sub.15 and R.sub.16 are each independently hydrogen, C.sub.1-6
alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or
alkylamino; [2813] R.sub.17 is hydrogen or alkyl; [2814] R.sub.24
is hydrogen, --N(R.sub.13)(R.sub.14), C.sub.1-6 alkyl, C.sub.1-6
alkoxy, --(C.sub.1-6 alkoxy)(heterocyclyl), or heterocyclyl; [2815]
R.sub.29 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
hydroxyalkyl, heteroaryl, heterocyclyl, --N(R.sub.15R.sub.16),
--C(.dbd.O)R.sub.46, or --R.sub.48C(.dbd.O)R.sub.47; [2816]
R.sub.34 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
cycloalkyl, hydroxyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl,
alkylamino, CF.sub.3, --OCF.sub.3, --S(.dbd.O).sub.2R.sub.20, or
--N(R.sub.15R.sub.16); and [2817] m 0, 1, or 2.
[2818] Schemes 6-13 provides a synthesis for exemplary compounds of
formula IX wherein: [2819] R.sup.1 is H, --CN, halogen,
C.sub.1-C.sub.4 straight or branched alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O--(C.sub.1-C.sub.4 straight or branched alkyl)
wherein: [2820] C.sub.3-C.sub.5 cycloalkyl optionally includes an
oxygen or nitrogen heteroatom; and [2821] when R.sup.1 is not H,
--CN or halogen, it is optionally substituted with one or more
halogens; [2822] each R.sup.2 is independently hydrogen, halogen or
C.sub.1-C.sub.4 straight or branched alkyl; [2823] R.sup.3 is H,
--OH, or halogen; [2824] R.sup.21 is H, halogen, C.sub.1-C.sub.4
straight or branched alkyl, C.sub.3-C.sub.5 cycloalkyl wherein the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom; [2825] R.sup.22 is H, halogen, or
C.sub.1-C.sub.2 alkyl; [2826] R.sup.23 is H or C.sub.1-C.sub.4
straight or branched alkyl; and [2827] R.sup.24 is H,
C.sub.1-C.sub.4 straight or branched alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-OH, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.t--(C.sub.3-C.sub.5 cycloalkyl), or
--(C.sub.1-C.sub.4 alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or
branched alkyl) wherein: [2828] t is 0 or 1; and [2829] the
C.sub.3-C.sub.5 cycloalkyl optionally includes an oxygen or
nitrogen heteroatom.
##STR00458## ##STR00459##
##STR00460##
##STR00461## ##STR00462##
##STR00463##
##STR00464##
##STR00465##
##STR00466## ##STR00467##
##STR00468##
[2830] Additional methods for producing particular compounds
according to the present disclosure are provided in the EXAMPLES.
One skilled in the art will recognize that other compounds of
structures can be made by modifications to the specifically
disclosed schemes employing methods known to those of skill in the
art. Additional examples can be found in Table 1.
[2831] Many such techniques are well known in the art. However,
many of the known techniques are elaborated in Compendium of
Organic Synthetic Methods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3,
1977; Vol. 4, 1980; Vol. 5, 1984; and Vol. 6 as well as March in
Advanced Organic Chemistry (1985); Comprehensive Organic Synthesis.
Selectivity, Strategy & Efficiency in Modern Organic Chemistry.
In 9 Volumes (1993); Advanced Organic Chemistry Part B: Reactions
and Synthesis, Second Edition (1983); Advanced Organic Chemistry,
Reactions, Mechanisms, and Structure, Second Edition (1977);
Protecting Groups in Organic Synthesis, Second Edition; and
Comprehensive Organic Transformations (1999).
[2832] Viral Infection Pathways
[2833] The host cell targets inhibited by the present compounds and
methods play a role in the viral replication and/or infection
pathways. Targeting of such host cell targets modulates the
replication and/or infection pathways of the viruses. In preferred
aspects the identified host cell targets are directly or indirectly
modulated using the compositions of the present disclosure. The
modulation of such host cell targets can also be performed by
targeting entities in the upstream or downstream signaling pathways
of the host cell targets.
[2834] According to the present disclosure, viral infection can be
treated by targeting the fatty acid synthesis pathway, and in
particular fatty acid synthase. HRV is representative of viruses
that can be treated according to the present disclosure. Like other
viruses, the replication of HRV involves six phases; transmission,
entry, replication, biosynthesis, assembly, and exit. Entry occurs
by endocytosis, replication and vRNP assembly takes place in the
nucleus, and the virus buds from the plasma membrane. In the
infected patient, the virus targets airway epithelial cells. The
present compounds and methods target and modulate at least one host
cell targets involved in such pathways.
[2835] For some viruses a great deal of progress has been made in
the elucidation of the steps involved during infection of host
cells. For example, experiments initiated in the early 1980s showed
that influenza virus follows a stepwise, endocytic entry program
with elements shared with other viruses such as alpha- and
rhabdoviruses (Marsh and Helenius 1989; Whittaker 2006). The steps
include: 1) Initial attachment to sialic acid containing
glycoconjugates receptors on the cell surface; 2) signaling induced
by the virus particle; 3) endocytosis by clathrin-dependent and
clathrin-independent cellular mechanism; 4) acid-induced,
hemaglutinin (HA)-mediated penetration from late endosomes; 5)
acid-activated, M2 and matrix protein (M1) dependent uncoating of
the capsid; and, 6) intra-cytosolic transport and nuclear import of
vRNPs. These steps depend on assistance from the host cell in the
form of sorting receptors, vesicle formation machinery,
kinase-mediated regulation, organelle acidification, and, most
likely, activities of the cytoskeleton.
[2836] Influenza attachment to the cells surface occurs via binding
of the HA1 subunit to cell surface glycoproteins and glycolipids
that carry oligosaccharide moieties with terminal sialic acid
residues (Skehel and Wiley 2000). The linkage by which the sialic
acid is connected to the next saccharide contributes to species
specificity. Avian strains including H5N1 prefer an a-(2,3)-link
and human strains a-(2,6)-link (Matrosovich 2006). In epithelial
cells, binding occurs preferentially to microvilli on the apical
surface, and endocytosis occurs at base of these extensions (Matlin
1982). Whether receptor binding induces signals that prepare the
cell for the invasion is not yet known, but it is likely because
activation of protein kinase C and synthesis of
phopshatidylinositol-3-phosphate (PI3P) are required for efficient
entry (Sieczkarski et al. 2003; Whittaker 2006).
[2837] Endocytic internalization occurs within a few minutes after
binding (Matlin 1982; Yoshimura and Ohnishi 1984). In tissue
culture cells influenza virus makes use of three different types of
cellular processes; 1) preexisting clathrin coated pits, 2)
virus-induced clathrin coated pits, and 3) endocytosis in vesicles
without visible coat (Matlin 1982; Sieczkarski and Whittaker 2002;
Rust et al. 2004). Video microscopy using fluorescent viruses
showed the virus particles undergoing actin-mediated rapid motion
in the cell periphery followed by minus end-directed,
microtubule-mediated transport to the perinuclear area of the cell.
Live cell imaging indicated that the virus particles first entered
a subpopulation of mobile, peripheral early endosomes that carry
them deeper into the cytoplasm before penetration takes place
(Lakadamyali et al. 2003; Rust et al. 2004). The endocytic process
is regulated by protein and lipid kinases, the proteasome, as well
as by Rabs and ubiquitin-dependent sorting factors (Khor et al.
2003; Whittaker 2006).
[2838] The membrane penetration step is mediated by low pH-mediated
activation of the trimeric, metastable HA, and the conversion of
this Type I viral fusion protein to a membrane fusion competent
conformation (Maeda et al. 1981; White et al. 1982). This occurs
about 16 min after internalization, and the pH threshold varies
between strains in the 5.0-5.6 range. The target membrane is the
limiting membrane of intermediate or late endosomes. The mechanism
of fusion has been extensively studied (Kielian and Rey 2006).
Further it was observed that fusion itself does not seem to require
any host cell components except a lipid bilayer membrane and a
functional acidification system (Maeda et al. 1981; White et al.
1982). The penetration step is inhibited by agents such as
lysosomotropic weak bases, carboxylic ionophores, and proton pump
inhibitors (Matlin 1982; Whittaker 2006).
[2839] To allow nuclear import of the incoming vRNPs, the capsid
has to be disassembled. This step involves acidification of the
viral interior through the amantadine-sensitive M2-channels which
causes dissociation of M1 from the vRNPs (Bukrinskaya et al. 1982;
Martin and Helenius 1991; Pinto et al. 1992). Transport of the
individual vRNPs to the nuclear pore complexes and transfer into
the nucleus depends on cellular nuclear transport receptors
(O'Neill et al. 1995; Cros et al. 2005). Replication of the viral
RNAs (synthesis of positive and negative strands), and
transcription occurs in complexes tightly associated with the
chromatin in the nucleus. It is evident that, although many of the
steps are catalyzed by the viral polymerase, cellular factors are
involved including RNA polymerase activating factors, a chaperone
HSP90, hCLE, and a human splicing factor UAP56. Viral gene
expression is subject to complex cellular control at the
transcriptional level, a control system dependent on cellular
kinases (Whittaker 2006).
[2840] The final assembly of an influenza particle occurs during a
budding process at the plasma membrane. In epithelial cells,
budding occurs at the apical membrane domain only (Rodriguez-Boulan
1983). First, the progeny vRNPs are transported within the
nucleoplasm to the nuclear envelope, then from the nucleus to the
cytoplasm, and finally they accumulate in the cell periphery. Exit
from the nucleus is dependent on viral protein NEP and M1, and a
variety of cellular proteins including CRM1 (a nuclear export
receptor), caspases, and possibly some nuclear protein chaperones.
Phosphorylation plays a role in nuclear export by regulating M1 and
NEP synthesis, and also through the MAPK/ERK system (Bui et al.
1996; Ludwig 2006). G protein and protein kinase signaling is
involved in influenza virus budding from infected host cells (Hui
E. and Nayak D, 2002).
[2841] The three membrane proteins of the virus are synthesized,
folded and assembled into oligomers in the ER (Doms et al. 1993).
They pass through the Golgi complex; undergo maturation through
modification of their carbohydrate moieties and proteolytic
cleavage. After reaching the plasma membrane they associate with M1
and the vRNPs in a budding process that results in the inclusion of
all eight vRNPs and exclusion of most host cell components except
lipids.
[2842] Influenza infection is associated with activation of several
signaling cascades including the MAPK pathway (ERK, JNK, p38 and
BMK-1/ERK5), the IkB/NF-kB signaling module, the Raf/MEK/ERK
cascade, and programmed cell death (Ludwig 2006). These result in a
variety of effects that limit the progress of infection such as
transcriptional activation of IFNb, apoptotic cell death, and a
block in virus escape of from late endosomes (Ludwig 2006).
[2843] Most previous studies on virus-cell interactions were
performed in tissue culture using tissue culture- or egg-adapted
virus strains. The viruses in these examples were adapted in such a
manner that changes were induced that affected receptor binding and
tropism (Matrosovich 2006). Infection with wild-type pathogenic
strains is provides a more natural picture of viral interaction
with host proteins. It is known that in the human airways influenza
A and B primarily infect non ciliated epithelial cells in the upper
respiratory track carrying NeuSAc a-(2,6)-Gal, whereas avian
strains infect ciliated epithelial cell with a-(2,3)-linked sialic
acids deeper in the airways (Matrosovich et al. 2004a).
[2844] Additionally, progress has been made in the elucidation of
the steps involved during infection by HRV of host cells. Selected
events in rhinovirus infection of the normal human airway can be
regarded as occurring sequentially. Initial steps in rhinovirus
pathogenesis are believed to include viral entry through the nose,
mucociliary transport of virus to the posterior pharynx, and
initiation of infection in ciliated and non-ciliated epithelial
cells of the upper airway. Viral replication peaks on average
within 48 h of initiation of infection and persists for up to 3 wk.
Infection is followed by activation of several inflammatory
mechanisms, which can include release or generation of
interleukins, bradykinins, prostaglandins, and possibly histamine
and stimulation of parasympathetic reflexes. Pathophysiologic
processes are initiated, which include vasodilatation of nasal
blood vessels, transudation of plasma, glandular secretion, and
stimulation of nerve fibers, causing pain and triggering sneeze and
cough reflexes. The resultant clinical illness is a rhinosinusitis,
pharyngitis, and bronchitis, which, on average, lasts one week.
[2845] Changes in gene expression profiles during in vivo
rhinovirus infections have been identified (Proud D. et al. Am J
Respir Crit Care Med Vol 178. pp 962-968, 2008). Nasal epithelial
scrapings were obtained before and during experimental rhinovirus
infection, and gene expression was evaluated by microarray. Viperin
is identified as an antiviral protein induced by interferon (IFN),
viral infections, and pathogen-associated molecules. Naturally
acquired rhinovirus infections, cultured human epithelial cells,
and short interfering RNA knockdown were used to further evaluate
the role of viperin in rhinovirus infections. Symptom scores and
viral titers were measured in subjects inoculated with rhinovirus
or a sham control, and changes in gene expression were assessed 8
and 48 hours after inoculation. Rhinovirus-induced changes in gene
expression were not observed 8 hours after viral infection, but
11,887 gene transcripts were significantly altered in scrapings
obtained 2 days post-inoculation. Major groups of up-regulated
genes include chemokines, signaling molecules,
interferon-responsive genes, and antivirals. Rhinovirus infection
significantly alters the expression of many genes associated with
the immune response, including chemokines and antivirals. Some of
the genes markedly induced by HRV-16 infection include but are not
limited to CCL2, CCL8, CXCL11, CXCL10, CXCL13, CXCL9, CCL20, IFIT2,
GBP1, IFIT1, GIP2, IFIT4, IL28B, IRF7, CIG5, NOS2A, OAS3, OASL,
OAS2, OAS1, MX2, MX1, PLSCR1, SOCS1, SOCS2, MDA5, RIGI, SOCS3,
ICAM-1, HAPLN3, MMP12, EPSTI1, and TNC.
[2846] Fatty Acid Synthesis Pathway
[2847] Various aspects of the present disclosure relate to
compositions and methods that modulate the activity of the fatty
acid synthesis pathway to treat a viral infection or treat cancer.
The fatty acid synthesis pathway in humans can use four enzymes: 1)
acetyl-CoA carboxylase (ACC), which can synthesize malonyl-CoA; 2)
malic enzyme, which can produce NADPH; 3) citrate lyase, which can
synthesize acetyl-CoA; and 4) fatty acid synthase, which can
catalyze NADPH-dependent synthesis of fatty acids from acetyl-CoA
and malonyl-CoA. In various aspects, the present disclosure relates
to treatment of viral infections and cancer by modulating the
activity of the fatty acid synthase protein.
[2848] The final products of fatty acid synthase are free fatty
acids which can use separate enzymatic derivatization with
coenzyme-A for incorporation into other products. In humans, fatty
acid synthesis can occur in two sites: the liver, where palmitic
acid can be made (Roncari, (1974) Can. J. Biochem., 52:221-230) and
lactating mammary gland, where C.sub.10-C.sub.14 fatty acids can be
made (Thompson, et al., (1985) Pediatr. Res., 19:139-143).
[2849] Fatty acids can be synthesized in the cytoplasm from
acetyl-CoA. Acetyl-CoA can be generated from pyruvate by pyruvate
dehydrogenase (PDH) and by .beta.-oxidation of fatty acids in the
mitochondria. A "citrate shuttle" can transport acetyl-CoA from the
mitochondria to the cytoplasm. Acetyl-CoA can react with
oxaloacetate to yield citrate, and a tricarboxylate translocase can
transport citrate from the mitochondria to the cytosol. In the
cytoplasm, citrate can be cleaved back to oxaloacetate and
acetyl-CoA, a reaction that can be catalyzed by ATP-citrate lyase.
Oxaloacetate can be converted back to pyruvate for re-entry into
mitochondria.
[2850] Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA
carboxylase (ACC) is a complex multifunctional, biotin-containing,
enzyme system that can catalyze carboxylation of acetyl-CoA to
malonyl-CoA. This conversion is an irreversible, rate-limiting step
in fatty acid synthesis. ACC can carry out three functions: biotin
carboxyl carrier protein, biotin carboxylase and
carboxyltransferase. ATP-dependent carboxylation of biotin, a
prosthetic group (cofactor) can be followed by transfer of the
carboxyl group to acetyl-CoA.
HCO.sub.3.sup.-+ATP+acetyl-CoA->ADP+P.sub.i+malonyl-CoA
[2851] There are two ACC forms, alpha and beta, encoded by two
different genes ACC-alpha (also known as ACC, ACAC, ACCJ, ACCA, and
ACACA) can encode protein highly enriched in lipogenic tissues.
Multiple alternatively spliced transcript variants divergent in the
sequence and encoding distinct isoforms have been found for this
gene. ACC-beta (also known as ACC2, ACCB, HACC275, and ACACB) can
encode protein thought to control fatty acid oxidation by means of
the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA
transferase I, the rate-limiting step in fatty acid uptake and
oxidation by mitochondria. ACC-beta may be involved in the
regulation of fatty acid oxidation, rather than fatty acid
biosynthesis. There is evidence for the presence of two ACC-beta
isoforms.
[2852] ACC can be regulated by the
phosphorylation/dephosphorylation of targeted serine residues. For
example, AMP-activated kinase (AMPK) can phosphorylate ACC, and
this phosphorylation can inhibit the ability of ACC to produce
malonyl-CoA. On ACACA, AMPK can phosphorylate Ser79, Ser1200, and
Ser1215 (Park S. H. et al. (2002) J. Appl. Physiol. 92:2475-82).
AMPK can phosphorylate Ser218 on ACACB (Hardie D. G. (1992)
Biochim. Biophys. Acta 1123:231-8). Also, cAMP-dependent protein
kinase (Protein Kinase A, or PKA) can phosphorylate ACC.
[2853] ACC can be regulated by allosteric transformation by citrate
or palmitoyl-CoA. For example, citrate can be a positive effector
(i.e. citrate can allosterically activate ACC). Citrate
concentration can be high when there is adequate acetyl-CoA
entering the Krebs Cycle. Excess acetyl-CoA can then be converted
via malonyl-CoA to fatty acids. Palmitoyl-CoA can be a negative
effector. Palmitoyl-CoA, which is the product of Fatty Acid
Synthase (FASN), can promote the inactive conformation of ACC,
which can reduce production of malonyl-CoA (a feedback inhibition
process). AMP can regulate fatty acid synthesis by regulating the
availability of malonyl-CoA. Insulin binding a receptor can
activate a phosphatase to dephosphorylate ACC, which can remove the
inhibitory effect.
[2854] The fatty acid synthase gene (also known as FAS, OA-519,
SDR27X1; MGC14367; MGC15706; FASN) is involved in fatty acid
synthesis. The enzyme encoded by this gene is a multifunctional
protein of approximately 272 kDa with multiple domains, each with
distinct enzyme activities that can play a role in fatty acid
biosynthesis. FASN can catalyze the synthesis of palmitate from
acetyl-CoA and malonyl-CoA, in the presence of NADPH, into
long-chain saturated fatty acids. In some cancer cell lines, FASN
protein has been found to be fused with estrogen receptor-alpha
(ER-alpha), in which the N-terminus of FASN is fused in-frame with
the C-terminus of ER-alpha.
[2855] FASN protein can exist in the cytosol as a dimer of
identical subunits. FASN consists of three catalytic domains in the
N-terminal section (-ketoacyl synthase (KS),
malonyl/acetyltransferase (MAT), and dehydrase (DH)). The
N-terminal section is separated by a core region of about 600 amino
acids from four C-terminal domains (enoyl reductase (ER), -ketoacyl
reductase (KR), acyl carrier protein (ACP), and thioesterase (TE)).
The crystal structure of a mammalian fatty acid synthase has been
reported (Maier T. et al. (2008) Science 321: 1315-1322). Each of
the catalytic domains of FASN can be targeted in the methods of
treating viral infection of the provided invention.
[2856] The enzymatic steps of fatty acid synthesis can involve
decarboxylative condensation, reduction, dehydration, and another
reduction and can result in a saturated acyl moiety. NADPH can be
an electron donor in reductive reactions.
[2857] Antiviral Activity
[2858] In various aspects, the present disclosure provides methods
for treating viral infection in a subject, the method comprising
administering to a subject in need of such treatment an effective
amount of a compound of Structures (I), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1.
[2859] In various aspects, the disclosure provides methods for
treating a viral infection, the method comprising administering the
compounds of the present disclosure to a subject in need thereof
the agent.
[2860] The present disclosure contemplates the treatment of any
viral infection that targets the fatty acid synthesis pathway in a
host, and in particular by modulating the activity of fatty acid
synthase. For example, the present methods can be used to treat
influenza infection, adenovirus infection, respiratory syncytial
virus infection, poxvirus infection, poliomyelitis infection,
hepatitis C infection, yellow fever infection, dengue fever
infection, rhinovirus infection, and the like.
[2861] In various aspects, the present disclosure provides methods
for treating hepatitis C infection by administering to the subject
one or more compounds disclosed herein. In modulating the FASN
pathway in the subject, hepatitis C infection is treated. It has
been shown that expression of FASN is upregulated in human hepatoma
cell line Huh7 when these cells are infected with HCV. Inhibiting
FASN production with a FASN inhibitor reduced the production of
HCV. Thus administration to a subject of the compounds of the
present disclosure. (Yang, W. et al. (2008) Hepatology 48(5):
1396-1403). It is demonstrated in the EXAMPLES that FASN inhibition
correlates to inhibition of HCV.
[2862] In certain aspects, the methods of inhibiting viral
infection can be performed in vitro. In further aspects, the
methods of inhibiting viral infection can be performed in vivo.
[2863] In certain aspects the compounds of the present disclosure
may be used in combination with other antiviral treatments in the
treating of viral infection.
[2864] In various aspects, the viral infection is a human yellow
fever infection. In further aspects, the viral infection is a human
hepatitis C infection. In yet further aspects, the viral infection
is a human rhinoviral infection.
[2865] In various aspects the compounds of the present disclosure
can be used for the treatment of infection of an animal subject,
such as a human, by any of a plethora of viruses.
[2866] In certain aspects, the compounds of the present disclosure
can be used for the inhibition of a host by a respiratory virus.
Respiratory viruses are most commonly transmitted by airborne
droplets or nasal secretions and can lead to a wide spectrum of
illness. Respiratory viruses include the respiratory syncytial
virus (RSV), influenza viruses, coronaviruses such as SARS,
adenoviruses, parainfluenza viruses and rhinoviruses (HRV).
[2867] According to one aspect, the present disclosure can be used
to treat infection by HRV. The genus of rhinoviruses is a member of
the Picornaviridae family of viruses. Genera within the family
include the Genus Enterovirus, Rhinovirus, Cardiovirus,
Aphthovirus, Hepatovirus, Parechovirus, Erbovirus, Kobuvirus,
Teschovirus. Human rhinoviruses (HRV) include the most common
viruses that infect humans and can cause the common cold. HRV are
lytic in nature. Rhinoviruses have single-stranded positive sense
RNA genomes of between 7.2 and 8.5 kb in length. At the 5' end of
these genomes is a virus-encoded protein, and like mammalian mRNA,
there is also a 3' poly-A tail. The 5'-terminal UMP of the viral
RNA is covalently linked to the small viral protein VPg (Paul A V,
et al. Nature 1998, 393(6682):280-284). The 5'UTR contains two
structural elements. One is the 5'-cloverleaf structure involved in
the plus-strand RNA synthesis and in the process of switching from
translation to replication (Huang H, et al. Biochemistry 2001,
40(27):8055-8064). The other is the internal ribosomal entry site
(IRES) which promotes translation of the polyprotein. In addition,
species-specific internal cis-acting replication elements (cre)
have been identified in human enteroviruses (HEV), HRV-A and HRV-B
(Gerber K, Wimmer E, Paul A V, J Virol 2001, 75(22):10979-10990).
The viral particles themselves are not enveloped and are
icosahedral in structure. Rhinoviruses also grow best in
temperatures between 33-35.degree. C. They are also sensitive to
acidic environment.
[2868] HRV viral proteins are transcribed as a single long
polypeptide, which is cleaved into the viral structural and
nonstructural proteins. Rhinoviruses are composed of a capsid that
contains four viral proteins VP1, VP2, VP3 and VP4 (Rossmann M, et
al. 1985 Nature 317 (6033): 145-53; Smith T, et al. 1986, Science
233 (4770): 1286-93). The isometric nucleocapsids are 22-40 nm in
diameter. VP1, VP2, and VP3 form the major part of the protein
capsid. The much smaller VP4 protein has a more extended structure
and lies at interface between the capsid and the RNA genome. There
are 60 copies of each of these proteins assembled as an
icosahedron. Human antibodies that target epitopes lying on the
exterior regions of VP1-VP3 play a role in the immune response to
HRVs.
[2869] HRVs have two general modes of transmission: 1) via aerosols
of respiratory droplets and 2) from contaminated surfaces,
including direct person-to-person contact. The primary route of
entry for rhinoviruses is the upper respiratory tract. Afterwards,
an HRV binds to ICAM-1 (Inter-Cellular Adhesion Molecule 1) also
known as CD54 (Cluster of Differentiation 54) receptors on
respiratory epithelial cells. As the virus replicates and spreads,
infected cells release chemokines and cytokines, which in turn
activate inflammatory mediators. Infection occurs rapidly, with the
rhinovirus adhering to surface receptors within 15 minutes of
entering the respiratory tract. The incubation period is generally
8-10 hours before symptoms begin to occur. HRVs are the most
frequent cause of infection across all age groups of the human
population. Replication is often restricted to the upper
respiratory tract leading to self-limited illnesses such as the
common cold. However, HRV infections can also exacerbate
pre-existing airway disorders, invade the lower respiratory tract
and lead to serious complications.
[2870] In another aspect, the compounds of the present disclosure
can be used for the treatment of infection by the influenza virus
by targeting the pathways that the virus relies on for infection or
replication. Influenza viruses belong to Orthomyxoviridae family of
viruses. This family also includes Thogoto viruses and
Dhoriviruses. There are several types and subtypes of influenza
viruses known, which infect humans and other species. Influenza
type A viruses infect people, birds, pigs, horses, seals and other
animals, but wild birds are the natural hosts for these viruses.
Influenza type A viruses are divided into subtypes and named on the
basis of two proteins on the surface of the virus: hemagglutinin
(HA) and neuraminidase (NA). For example, an "H7N2 virus"
designates an influenza A subtype that has an HA 7 protein and an
NA 2 protein. Similarly an "H5N1" virus has an HA 5 protein and an
NA 1 protein. There are 16 known HA subtypes and 9 known NA
subtypes. Many different combinations of HA and NA proteins are
possible. Only some influenza A subtypes (i.e., H1N1, H1N2, and
H3N2) are currently in general circulation among people. Other
subtypes are found most commonly in other animal species. For
example, H7N7 and H3N8 viruses cause illness in horses, and H3N8
also has recently been shown to cause illness in dogs (see
www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).
[2871] Antiviral agents which target host cell proteins involved in
influenza infection can be used to protect high-risk groups
(hospital units, institutes caring for elderly, immuno-suppressed
individuals), and on a case by case basis. A potential use for
antiviral agents is to limit the spread and severity of the future
pandemics whether caused by avian H5N1 or other strains of
influenza virus. Avian influenza A viruses of the subtypes H5 and
H7, including H5N1, H7N7, and H7N3 viruses, have been associated
with high pathogenicity, and human infection with these viruses
have ranged from mild (H7N3, H7N7) to severe and fatal disease
(H7N7, H5N1). Human illness due to infection with low pathogenicity
viruses has been documented, including very mild symptoms (e.g.,
conjunctivitis) to influenza-like illness. Examples of low
pathogenicity viruses that have infected humans include H7N7, H9N2,
and H7N2 (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).
[2872] Influenza B viruses are usually found in humans but can also
infect seals. Unlike influenza A viruses, these viruses are not
classified according to subtype. Influenza B viruses can cause
morbidity and mortality among humans, but in general are associated
with less severe epidemics than influenza A viruses. Although
influenza type B viruses can cause human epidemics, they have not
caused pandemics. (see
www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).
[2873] Influenza type C viruses cause mild illness in humans and do
not cause epidemics or pandemics. These viruses can also infect
dogs and pigs. These viruses are not classified according to
subtype. (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).
[2874] Influenza viruses differ from each other in respect to cell
surface receptor specificity and cell tropism, however they use
common entry pathways. The compounds of the present disclosure
advantageously target pathways that are common to multiple viruses
giving rise to broader antiviral activity. Thus, the present
compounds can also prove useful against unrelated viruses that use
similar pathways. For example, the agents can protect airway
epithelial cells against a number of different viruses in addition
to influenza viruses.
[2875] In certain aspects, the compounds of the present disclosure
can be used for the treatment of infection by adenoviruses. Most
adenoviruses commonly cause respiratory illness; symptoms of
respiratory illness caused by adenovirus infection range from the
common cold syndrome to pneumonia, croup, and bronchitis. Patients
with compromised immune systems are especially susceptible to
severe complications of adenovirus infection. Acute respiratory
disease (ARD), first recognized among military recruits during
World War II, can be caused by adenovirus infections during
conditions of crowding and stress. Adenoviruses are medium-sized
(90-100 nm), nonenveloped icosohedral viruses containing
double-stranded DNA. There are 49 immunologically distinct types (6
subgenera: A through F) that can cause human infections.
Adenoviruses are unusually stable to chemical or physical agents
and adverse pH conditions, allowing for prolonged survival outside
of the body. Some adenoviruses, such as AD2 and Ad5 (species C) use
clathrin mediated endocytosis and macropinocytosis for infectious
entry. Other adenoviruses, such as Ad3 (species B) use dynamin
dependent endocytosis and macropinocytosis for infectious
entry.
[2876] In certain aspects, the compounds of the present disclosure
can be used for the treatment of infection by respiratory syncytial
virus (RSV). RSV is the most common cause of bronchiolitis and
pneumonia among infants and children under 1 year of age. Illness
begins most frequently with fever, runny nose, cough, and sometimes
wheezing. During their first RSV infection, between 25% and 40% of
infants and young children have signs or symptoms of bronchiolitis
or pneumonia, and 0.5% to 2% require hospitalization. Most children
recover from illness in 8 to 15 days. The majority of children
hospitalized for RSV infection are under 6 months of age. RSV also
causes repeated infections throughout life, usually associated with
moderate-to-severe cold-like symptoms; however, severe lower
respiratory tract disease can occur at any age, especially among
the elderly or among those with compromised cardiac, pulmonary, or
immune systems. RSV is a negative-sense, enveloped RNA virus. The
virion is variable in shape and size (average diameter of between
120 and 300 nm), is unstable in the environment (surviving only a
few hours on environmental surfaces), and is readily inactivated
with soap and water and disinfectants.
[2877] In certain aspects, the compounds of the present disclosure
can be used for the treatment of infection by human parainfluenza
virus (HPIV). HPIVs are second to respiratory syncytial virus (RSV)
as a common cause of lower respiratory tract disease in young
children. Similar to RSV, HPIVs can cause repeated infections
throughout life, usually manifested by an upper respiratory tract
illness (e.g., a cold and/or sore throat). HPIVs can also cause
serious lower respiratory tract disease with repeat infection
(e.g., pneumonia, bronchitis, and bronchiolitis), especially among
the elderly, and among patients with compromised immune systems.
Each of the four HPIVs has different clinical and epidemiologic
features. The most distinctive clinical feature of HPIV-1 and
HPIV-2 is croup (i.e., laryngotracheobronchitis); HPIV-1 is the
leading cause of croup in children, whereas HPIV-2 is less
frequently detected. Both HPIV-1 and -2 can cause other upper and
lower respiratory tract illnesses. HPIV-3 is more often associated
with bronchiolitis and pneumonia. HPIV-4 is infrequently detected,
possibly because it is less likely to cause severe disease. The
incubation period for HPIVs is generally from 1 to 7 days. HPIVs
are negative-sense, single-stranded RNA viruses that possess fusion
and hemagglutinin-neuraminidase glycoprotein "spikes" on their
surface. There are four serotypes types of HPIV (1 through 4) and
two subtypes (4a and 4b). The virion varies in size (average
diameter between 150 and 300 nm) and shape, is unstable in the
environment (surviving a few hours on environmental surfaces), and
is readily inactivated with soap and water.
[2878] In various aspects, the compounds of the present disclosure
can be used for the treatment of infection by coronavirus.
Coronavirus is a genus of animal virus belonging to the family
Coronaviridae. Coronaviruses are enveloped viruses with a
positive-sense single-stranded RNA genome and a helical symmetry.
The genomic size of coronaviruses ranges from approximately 16 to
31 kilobases, extraordinarily large for an RNA virus. The name
"coronavirus" is derived from the Latin corona, meaning crown, as
the virus envelope appears under electron microscopy to be crowned
by a characteristic ring of small bulbous structures. This
morphology is actually formed by the viral spike peplomers, which
are proteins that populate the surface of the virus and determine
host tropism. Coronaviruses are grouped in the order Nidovirales,
named for the Latin nidus, meaning nest, as all viruses in this
order produce a 3' co-terminal nested set of subgenomic mRNA's
during infection. Proteins that contribute to the overall structure
of all coronaviruses are the spike, envelope, membrane and
nucleocapsid. In the specific case of SARS a defined
receptor-binding domain on S mediates the attachment of the virus
to its cellular receptor, angiotensin-converting enzyme 2.
[2879] The present disclosure contemplates the treatment of any
viral infection that targets the fatty acid synthesis pathway in a
host, and in particular by modulating the activity of fatty acid
synthase. For example, the present methods can be used to treat
infections caused by Abelson leukemia virus, Abelson murine
leukemia virus, Abelson's virus, Acute laryngotracheobronchitis
virus, Adelaide River virus, Adeno associated virus group,
Adenovirus, African horse sickness virus, African swine fever
virus, AIDS virus, Aleutian mink disease parvovirus,
Alpharetrovirus, Alphavirus, ALV related virus, Amapari virus,
Aphthovirus, Aquareovirus, Arbovirus, Arbovirus C, arbovirus group
A, arbovirus group B, Arenavirus group, Argentine hemorrhagic fever
virus, Argentine hemorrhagic fever virus, Arterivirus, Astrovirus,
Ateline herpesvirus group, Aujezky's disease virus, Aura virus,
Ausduk disease virus, Australian bat lyssavirus, Aviadenovirus,
avian erythroblastosis virus, avian infectious bronchitis virus,
avian leukemia virus, avian leukosis virus, avian lymphomatosis
virus, avian myeloblastosis virus, avian paramyxovirus, avian
pneumoencephalitis virus, avian reticuloendotheliosis virus, avian
sarcoma virus, avian type C retrovirus group, Avihepadnavirus,
Avipoxvirus, B virus, B19 virus, Babanki virus, baboon herpesvirus,
baculovirus, Barmah Forest virus, Bebaru virus, Berrimah virus,
Betaretrovirus, Birnavirus, Bittner virus, BK virus, Black Creek
Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus,
Boma disease virus, border disease of sheep virus, borna virus,
bovine alphaherpesvirus 1, bovine alphaherpesvirus 2, bovine
coronavirus, bovine ephemeral fever virus, bovine immunodeficiency
virus, bovine leukemia virus, bovine leukosis virus, bovine
mammillitis virus, bovine papillomavirus, bovine papular stomatitis
virus, bovine parvovirus, bovine syncytial virus, bovine type C
oncovirus, bovine viral diarrhea virus, Buggy Creek virus, bullet
shaped virus group, Bunyamwera virus supergroup, Bunyavirus,
Burkitt's lymphoma virus, Bwamba Fever, CA virus, Calicivirus,
California encephalitis virus, camelpox virus, canarypox virus,
canid herpesvirus, canine coronavirus, canine distemper virus,
canine herpesvirus, canine minute virus, canine parvovirus, Cano
Delgadito virus, caprine arthritis virus, caprine encephalitis
virus, Caprine Herpes Virus, Capripox virus, Cardiovirus, caviid
herpesvirus 1, Cercopithecid herpesvirus 1, cercopithecine
herpesvirus 1, Cercopithecine herpesvirus 2, Chandipura virus,
Changuinola virus, channel catfish virus, Charleville virus,
chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, chub
reovirus, chum salmon virus, Cocal virus, Coho salmon reovirus,
coital exanthema virus, Colorado tick fever virus, Coltivirus,
Columbia SK virus, common cold virus, contagious ecthyma virus,
contagious pustular dermatitis virus, Coronavirus, Corriparta
virus, coryza virus, cowpox virus, coxsackie virus, CPV
(cytoplasmic polyhedrosis virus), cricket paralysis virus,
Crimean-Congo hemorrhagic fever virus, croup associated virus,
Cryptovirus, Cypovirus, Cytomegalovirus, cytomegalovirus group,
cytoplasmic polyhedrosis virus, deer papillomavirus,
deltaretrovirus, dengue virus, Densovirus, Dependovirus, Dhori
virus, diploma virus, Drosophila C virus, duck hepatitis B virus,
duck hepatitis virus 1, duck hepatitis virus 2, duovirus, Duvenhage
virus, Deformed wing virus DWV, eastern equine encephalitis virus,
eastern equine encephalomyelitis virus, EB virus, Ebola virus,
Ebola-like virus, echo virus, echovirus, echovirus 10, echovirus
28, echovirus 9, ectromelia virus, EEE virus, EIA virus, EIA virus,
encephalitis virus, encephalomyocarditis group virus,
encephalomyocarditis virus, Enterovirus, enzyme elevating virus,
enzyme elevating virus (LDH), epidemic hemorrhagic fever virus,
epizootic hemorrhagic disease virus, Epstein-Barr virus, equid
alphaherpesvirus 1, equid alphaherpesvirus 4, equid herpesvirus 2,
equine abortion virus, equine arteritis virus, equine encephalosis
virus, equine infectious anemia virus, equine morbillivirus, equine
rhinopneumonitis virus, equine rhinovirus, Eubenangu virus,
European elk papillomavirus, European swine fever virus, Everglades
virus, Eyach virus, felid herpesvirus 1, feline calicivirus, feline
fibrosarcoma virus, feline herpesvirus, feline immunodeficiency
virus, feline infectious peritonitis virus, feline leukemia/sarcoma
virus, feline leukemia virus, feline panleukopenia virus, feline
parvovirus, feline sarcoma virus, feline syncytial virus,
Filovirus, Flanders virus, Flavivirus, foot and mouth disease
virus, Fort Morgan virus, Four Corners hantavirus, fowl adenovirus
1, fowlpox virus, Friend virus, Gammaretrovirus, GB hepatitis
virus, GB virus, German measles virus, Getah virus, gibbon ape
leukemia virus, glandular fever virus, goatpox virus, golden
shinner virus, Gonometa virus, goose parvovirus, granulosis virus,
Gross' virus, ground squirrel hepatitis B virus, group A arbovirus,
Guanarito virus, guinea pig cytomegalovirus, guinea pig type C
virus, Hantaan virus, Hantavirus, hard clam reovirus, hare fibroma
virus, HCMV (human cytomegalovirus), hemadsorption virus 2,
hemagglutinating virus of Japan, hemorrhagic fever virus, hendra
virus, Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B
virus group, hepatitis C virus, hepatitis D virus, hepatitis delta
virus, hepatitis E virus, hepatitis F virus, hepatitis G virus,
hepatitis nonA nonB virus, hepatitis virus, hepatitis virus
(nonhuman), hepatoencephalomyelitis reovirus 3, Hepatovirus, heron
hepatitis B virus, herpes B virus, herpes simplex virus, herpes
simplex virus 1, herpes simplex virus 2, herpesvirus, herpesvirus
7, Herpesvirus ateles, Herpesvirus hominis, Herpesvirus infection,
Herpesvirus saimiri, Herpesvirus suis, Herpesvirus varicellae,
Highlands J virus, Hirame rhabdovirus, hog cholera virus, human
adenovirus 2, human alphaherpesvirus 1, human alphaherpesvirus 2,
human alphaherpesvirus 3, human B lymphotropic virus, human
betaherpesvirus 5, human coronavirus, human cytomegalovirus group,
human foamy virus, human gammaherpesvirus 4, human gammaherpesvirus
6, human hepatitis A virus, human herpesvirus 1 group, human
herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus 4
group, human herpesvirus 6, human herpesvirus 8, human
immunodeficiency virus, human immunodeficiency virus 1, human
immunodeficiency virus 2, human papillomavirus, human T cell
leukemia virus, human T cell leukemia virus I, human T cell
leukemia virus II, human T cell leukemia virus III, human T cell
lymphoma virus I, human T cell lymphoma virus II, human T cell
lymphotropic virus type 1, human T cell lymphotropic virus type 2,
human T lymphotropic virus I, human T lymphotropic virus II, human
T lymphotropic virus III, Ichnovirus, infantile gastroenteritis
virus, infectious bovine rhinotracheitis virus, infectious
haematopoietic necrosis virus, infectious pancreatic necrosis
virus, influenza virus A, influenza virus B, influenza virus C,
influenza virus D, influenza virus pr8, insect iridescent virus,
insect virus, iridovirus, Japanese B virus, Japanese encephalitis
virus, JC virus, Junin virus, Kaposi's sarcoma-associated
herpesvirus, Kemerovo virus, Kilham's rat virus, Klamath virus,
Kolongo virus, Korean hemorrhagic fever virus, kumba virus, Kysanur
forest disease virus, Kyzylagach virus, La Crosse virus, lactic
dehydrogenase elevating virus, lactic dehydrogenase virus, Lagos
bat virus, Langur virus, lapine parvovirus, Lassa fever virus,
Lassa virus, latent rat virus, LCM virus, Leaky virus, Lentivirus,
Leporipoxvirus, leukemia virus, leukovirus, lumpy skin disease
virus, lymphadenopathy associated virus, Lymphocryptovirus,
lymphocytic choriomeningitis virus, lymphoproliferative virus
group, Machupo virus, mad itch virus, mammalian type B oncovirus
group, mammalian type B retroviruses, mammalian type C retrovirus
group, mammalian type D retroviruses, mammary tumor virus, Mapuera
virus, Marburg virus, Marburg-like virus, Mason Pfizer monkey
virus, Mastadenovirus, Mayaro virus, ME virus, measles virus,
Menangle virus, Mengo virus, Mengovirus, Middelburg virus, milkers
nodule virus, mink enteritis virus, minute virus of mice, MLV
related virus, MM virus, Mokola virus, Molluscipoxvirus, Molluscum
contagiosum virus, monkey B virus, monkeypox virus,
Mononegavirales, Morbillivirus, Mount Elgon bat virus, mouse
cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis
virus, mouse K virus, mouse leukemia virus, mouse mammary tumor
virus, mouse minute virus, mouse pneumonia virus, mouse
poliomyelitis virus, mouse polyomavirus, mouse sarcoma virus,
mousepox virus, Mozambique virus, Mucambo virus, mucosal disease
virus, mumps virus, murid betaherpesvirus 1, murid cytomegalovirus
2, murine cytomegalovirus group, murine encephalomyelitis virus,
murine hepatitis virus, murine leukemia virus, murine nodule
inducing virus, murine polyomavirus, murine sarcoma virus,
Muromegalovirus, Murray Valley encephalitis virus, myxoma virus,
Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi
sheep disease virus, Nairovirus, Nanimavirus, Nariva virus, Ndumo
virus, Neethling virus, Nelson Bay virus, neurotropic virus, New
World Arenavirus, newborn pneumonitis virus, Newcastle disease
virus, Nipah virus, noncytopathogenic virus, Norwalk virus, nuclear
polyhedrosis virus (NPV), nipple neck virus, O'nyong'nyong virus,
Ockelbo virus, oncogenic virus, oncogenic viruslike particle,
oncomavirus, Orbivirus, Orf virus, Oropouche virus,
Orthohepadnavirus, Orthomyxovirus, Orthopoxvirus, Orthoreovirus,
Orungo, ovine papillomavirus, ovine catarrhal fever virus, owl
monkey herpesvirus, Palyam virus, Papillomavirus, Papillomavirus
sylvilagi, Papovavirus, parainfluenza virus, parainfluenza virus
type 1, parainfluenza virus type 2, parainfluenza virus type 3,
parainfluenza virus type 4, Paramyxovirus, Parapoxvirus,
paravaccinia virus, Parvovirus, Parvovirus B19, parvovirus group,
Pestivirus, Phlebovirus, phocine distemper virus, Picodnavirus,
Picornavirus, pig cytomegalovirus-pigeonpox virus, Piry virus,
Pixuna virus, pneumonia virus of mice, Pneumovirus, poliomyelitis
virus, poliovirus, Polydnavirus, polyhedral virus, polyoma virus,
Polyomavirus, Polyomavirus bovis, Polyomavirus cercopitheci,
Polyomavirus hominis 2, Polyomavirus maccacae 1, Polyomavirus muris
1, Polyomavirus muris 2, Polyomavirus papionis 1, Polyomavirus
papionis 2, Polyomavirus sylvilagi, Pongine herpesvirus 1, porcine
epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis
virus, porcine parvovirus, porcine transmissible gastroenteritis
virus, porcine type C virus, pox virus, poxvirus, poxvirus
variolae, Prospect Hill virus, Provirus, pseudocowpox virus,
pseudorabies virus, psittacinepox virus, quailpox virus, rabbit
fibroma virus, rabbit kidney vaculolating virus, rabbit
papillomavirus, rabies virus, raccoon parvovirus, raccoonpox virus,
Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus,
Rauscher's virus, recombinant vaccinia virus, recombinant virus,
reovirus, reovirus 1, reovirus 2, reovirus 3, reptilian type C
virus, respiratory infection virus, respiratory syncytial virus,
respiratory virus, reticuloendotheliosis virus, Rhabdovirus,
Rhabdovirus carpia, Rhadinovirus, Rhinovirus, Rhizidiovirus, Rift
Valley fever virus, Riley's virus, rinderpest virus, RNA tumor
virus, Ross River virus, Rotavirus, rougeole virus, Rous sarcoma
virus, rubella virus, rubeola virus, Rubivirus, Russian autumn
encephalitis virus, SA 11 simian virus, SA2 virus, Sabia virus,
Sagiyama virus, Saimirine herpesvirus 1, salivary gland virus,
sandfly fever virus group, Sandjimba virus, SARS virus, SDAV
(sialodacryoadenitis virus), sealpox virus, Semliki Forest Virus,
Seoul virus, sheeppox virus, Shope fibroma virus, Shope papilloma
virus, simian foamy virus, simian hepatitis A virus, simian human
immunodeficiency virus, simian immunodeficiency virus, simian
parainfluenza virus, simian T cell lymphotrophic virus, simian
virus, simian virus 40, Simplexvirus, Sin Nombre virus, Sindbis
virus, smallpox virus, South American hemorrhagic fever viruses,
sparrowpox virus, Spumavirus, squirrel fibroma virus, squirrel
monkey retrovirus, SSV 1 virus group, STLV (simian T lymphotropic
virus) type I, STLV (simian T lymphotropic virus) type II, STLV
(simian T lymphotropic virus) type III, stomatitis papulosa virus,
submaxillary virus, suid alphaherpesvirus 1, suid herpesvirus 2,
Suipoxvirus, swamp fever virus, swinepox virus, Swiss mouse
leukemia virus, TAC virus, Tacaribe complex virus, Tacaribe virus,
Tanapox virus, Taterapox virus, Tench reovirus, Theiler's
encephalomyelitis virus, Theiler's virus, Thogoto virus,
Thottapalayam virus, Tick borne encephalitis virus, Tioman virus,
Togavirus, Torovirus, tumor virus, Tupaia virus, turkey
rhinotracheitis virus, turkeypox virus, type C retroviruses, type D
oncovirus, type D retrovirus group, ulcerative disease rhabdovirus,
Una virus, Uukuniemi virus group, vaccinia virus, vacuolating
virus, varicella zoster virus, Varicellovirus, Varicola virus,
variola major virus, variola virus, Vasin Gishu disease virus, VEE
virus, Venezuelan equine encephalitis virus, Venezuelan equine
encephalomyelitis virus, Venezuelan hemorrhagic fever virus,
vesicular stomatitis virus, Vesiculovirus, Vilyuisk virus, viper
retrovirus, viral haemorrhagic septicemia virus, Visna Maedi virus,
Visna virus, volepox virus, VSV (vesicular stomatitis virus),
Wallal virus, Warrego virus, wart virus, WEE virus, West Nile
virus, western equine encephalitis virus, western equine
encephalomyelitis virus, Whataroa virus, Winter Vomiting Virus,
woodchuck hepatitis B virus, woolly monkey sarcoma virus, wound
tumor virus, WRSV virus, Yaba monkey tumor virus, Yaba virus,
Yatapoxvirus, yellow fever virus, and the Yug Bogdanovac virus.
[2880] Utility in Metabolic Disorders
[2881] In various aspects, the compounds of the present disclosure
have utility in the treating of metabolic diseases. FASN has been
demonstrated to be involved in regulation of glucose, lipids and
cholesterol metabolism. Mice with a liver-specific inactivation of
FASN have normal physiology unless fed a zero-fat diet, in which
case they develop hypoglycemia and fatty liver, both of which are
reversed with dietary fat. (Chakravarthy, M. V., et al. (2005) Cell
Metabolism 1:309-322). Db/+ mice fed a high fructose diet exhibit
reduced liver triglyceride levels and improved insulin sensitivity
when treated for 28 days with platensimycin, a covalent inhibitor
of FASN. (Wu, M. et al. (2011) PNAS 108(13):5378-5383). Ambient
glucose levels are also reduced in db/db mice following treatment
with platensimycin. These results provide evidence that inhibiting
FASN can yield therapeutically relevant benefits in animal models
of diabetes and related metabolic disorders. Thus the disclosed
FASN inhibitors are useful in the treatment of disorders
characterized by disregulation in these systems. Without
limitation, examples include steatosis and diabetes.
[2882] Non-alcoholic liver disease (NAFLD), a condition in which
the liver contains more than 5% fat by weight which is not caused
by alcohol consumption, is a disease which currently affects
.about.20-30% of the US and general western world population, and
is associated with a significant increased risk of morbidity
extending beyond the liver to cardiovascular disease, chronic
kidney disease and malignancy. Obesity and the metabolic syndrome
are two key risk factors for NAFLD which are characterized as an
imbalance in energy utilization and storage. This imbalance leads
to dysregulated metabolic pathways and inflammatory responses that
drive further changes leading to liver damage and comorbid
conditions. Along with the progression of metabolic syndrome, NAFLD
leads to more advanced liver disease starting with non-alcoholic
steatohepatitis (NASH) which can then progress to significant liver
diseases including cirrhosis and hepatocellular carcinoma.
[2883] The synthesis of fatty acids in the liver, a pathway termed
hepatic de novo lipogenesis (DNL), is increased in subjects with
metabolic syndrome and NAFLD. The DNL pathway not only produces
fatty acids that contribute to elevated liver stores of
triglycerides, but the fatty acids that are produced are saturated
fatty acid species, primarily palmitate (C.sub.16:0), which
contribute to signaling events that increase liver inflammation.
Free palmitate fatty acid has also been implicated in liver
inflammation processes such as macrophage recruitment and
activation of endoplasmic reticulum stress response.
[2884] Cardiovascular disease is closely linked to the progression
of metabolic syndrome. However, NAFLD is also a strong predictor of
cardiovascular disease, such as increased risk of carotid
atherosclerotic plaques and endothelial dysfunction, which is
independent of the existence of metabolic syndrome (Francis W. B.,
et. als., "De novo lipogenesis in the liver in health and disease:
more than just a shunting yard for glucose." Biol. Rev. (2016), 91,
pp. 452-468). NAFLD has also been implicated as an independent
factor contributing to the development of type II diabetes. The
rate of incidence of pre-diabetes or type II diabetes is 2.6 times
higher in individuals with NAFLD, suggesting an independent role in
the pathogenesis of type II diabetes beyond initial insulin
resistance (Francis W. B., Biol. Rev. (2016), pp. 452-468; Bae, J.
C., et. als., "Combined effect of nonalcoholic fatty liver disease
and impaired fasting glucose on the development of type 2
diabetes." Diabetes Care, 2011, 34, 727-729). Therefore DNL is an
important pathway for therapeutic intervention to reduce the
consequences associated with metabolic syndrome and NAFLD (Bae, J.
C., Diabetes Care, 2011, 727-729).
[2885] NAFLD and NASH have been associated with obesity and
diabetes in humans with high fat and high caloric diets. The
synthesis of fatty acids in the liver (i.e., synthesized via the
hepatic de novo lipogenesis (DNL) pathway), is increased in
subjects with metabolic syndrome and NAFLD. One of the key enzymes
in DNL is fatty acid synthase (FASN). While there are promising
associations between FASN, DNL and NAFLD, there is very little
evidence that direct inhibition of FASN is a competent mechanism
for treating NAFLD or controlling the progression of hepatic
steatosis. Some literature reports of direct intervention at FASN
by gene knock out or small molecule inhibitors give results which
suggest an exacerbation of liver steatosis; the exact opposite
effect needed to treat NAFLD or NASH. These results teach that FASN
inhibition would not be expected to reduce hepatic steatosis or be
a suitable mechanism to control the underlying metabolic
dysregulation or inflammation signaling which drive the progression
of fatty liver disease.
[2886] For example, liver-specific FASN knockout mice have been
shown to have normal livers when maintained on a standard diet.
Unexpectedly, when on a zero-fat/high carbohydrate diet, the mice
develop fatty livers (hepatic steatosis) and hypoglycemia showing
that complete inhibition of FASN in the liver of a mammal on a
fat-restricted diet results in the development of NAFLD, the
precursor of NASH (Chakravarthy, M. V., et al., "New hepatic fat
activates PPARalpha to maintain glucose, lipid, and cholesterol
homeostasis," Cell Metabol. 1(5), 2005, 309-322). When the knockout
mice are fed a normal diet, no effect on metabolism or development
of hepatic steatosis resulting from complete inhibition of FASN by
knockout is observed indicating that FASN inhibition in the liver
would either have no effect on a mammal consuming a fat-containing
diet or would induce a fatty liver state (leading to NAFLD and
NASH) in a mammal consuming a low fat/high carbohydrate diet,
providing the opposite effect needed for treating NASH.
[2887] Small molecule inhibitors of FASN have been used to assess
insulin resistance and hepatic steatosis. In a recent study in
obese insulin resistant Zucker rats (Type II diabetes model),
inhibition of de novo lipogenesis with a small molecule FASN
inhibitor did not improve insulin sensitivity and actually
increased the level of fat in the liver (i.e., hepatic steatosis).
FASN inhibitors have also been shown to inhibit hepatic de novo
lipogenesis, but resulted in increased hepatic steatosis or fat
deposits in the liver ("A Novel Fatty Acid Synthase Inhibitor
(FASi) Suppresses De Novo Lipogenesis but induces Hepatic
Steatosis, Dermatitis and does not enhance Insulin Sensitivity in
Obese Zucker Rats," Am. Diabetes Assoc. 68th Scientific Sessions,
June 6-10, 2008, San Francisco, Calif., poster 58LB; WO2008059214).
These studies show that direct inhibition of FASN reduces fat
synthesis in the liver, but results in acceleration in the
development of NAFLD and NASH in an obese diabetic mammal. Thus,
FASN inhibition would not be expected to have a therapeutic effect
on fatty liver disease in obese and diabetic individuals who have
the highest risk of developing NAFLD and NASH disease.
[2888] The FASN inhibitors of the present application were tested
for activity against NAFLD. Unexpectedly, the FASN inhibitors of
the present application have demonstrated efficacy in a rodent
model of NAFLD and lowering of pro-inflammatory IL-1beta
(IL-1.beta.) in rats on a high fat diet. The FASN inhibitors of the
present application have also demonstrated anti-inflammatory
activity in cells, specifically reduction of IL-1.beta. in human
peripheral blood mononuclear cells (PBMC) and monocytes cells, and
have been shown to modulate the differentiation of mouse and human
CD4+ naive T cells which resulted in a reduction of Th.sub.17
(pro-inflammatory T helper cells) and stimulation of T.sub.reg
(anti-inflammatory regulatory T) cells.
[2889] The FASN inhibitors of the present application are useful
for controlling NAFLD in rodents, reducing pro-inflammatory
cytokines, such as IL-1.beta., and modulating T cell
differentiation from pro-inflammatory cells, such as Th.sub.17
cells, to anti-inflammatory T.sub.reg cells. The FASN inhibitors of
the present application can be used to treat various aspects of
metabolic syndrome including non-alcoholic liver disease (NAFLD)
and the more advanced disease, non-alcoholic steatohepatitis
(NASH). If left untreated, these liver dysfunction disease states
can progress to significant liver diseases, including liver
cirrhosis, a state in which the liver shows steatosis,
inflammation, fibrosis, steatohepatitis, and may progress to liver
cancer (hepatocellular carcinoma). Liver cirrhosis can have direct
health consequences due to the liver dysfunction including spider
angiomata or spider nevi, palmar erythema, gynecomastia,
hypogonadism, ascites, fetor hepaticus, jaundice, portal
hypertension which causes splenomegaly, esophageal varices, caput
medusa, Hepatic encephalopathy, and acute kidney injury
(particularly hepatorenal syndrome). In some embodiments, the
compounds of the present disclosure can be used to treat metabolic
syndrome, non-alcoholic liver disease (NAFLD), non-alcoholic
steatohepatitis (NASH), liver cirrhosis, liver fibrosis, and/or
liver cancer (hepatocellular carcinoma).
[2890] The FASN inhibitor compounds of the present application can
also be used to treat inflammatory diseases by inducing changes in
inflammation inducing cytokines. Example of inflammatory diseases
that can be treated with FASN inhibitor compounds of the present
application, include, but are not limited to, inflammatory diseases
involving IL-1beta, such as diseases responsive to IL-1beta
blockade or associated with increased IL-1beta expression; Familial
Mediterranean fever (FMF); Pyogenic arthritis, pyoderma
gangrenosum, acne (PAPA); Cryopyrin-associated periodic syndromes
(CAPS); Hyper IgD syndrome (HIDS); Adult and juvenile Still
disease; Schnitzler syndrome; TNF receptor-associated periodic
syndrome (TRAPS); Blau syndrome; Sweet syndrome; Deficiency in IL-1
receptor antagonist (DIRA); Recurrent idiopathic pericarditis;
Macrophage activation syndrome (MAS); Urticarial vasculitis;
Antisynthetase syndrome; Relapsing chondritis; Behcet disease;
Erdheim-Chester syndrome (histiocytosis); Synovitis, acne,
pustulosis, hyperostosis, osteitis (SAPHO); Rheumatoid arthritis;
Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome
(PFAPA); Urate crystal arthritis (gout); Type 2 diabetes;
Smoldering multiple myeloma; Postmyocardial infarction heart
failure; Osteoarthritis; Transfusion-related acute lung injury;
Ventilator-induced lung injury; Pulmonary fibrosis including
Idiopathic; Chronic obstructive pulmonary disease (COPD); and
Asthma.
[2891] The FASN inhibitors of the present application can also be
used to treat disease or conditions associated with elevated levels
of inflammatory T cells and/or reduced or inadequate levels of
anti-inflammatory T cells, or to treat diseases or conditions in
which the modulation of differentiation of white blood cells (i.e.,
T cells) away from T helper cells and increasing anti-inflammatory
T regulatory (T.sub.reg) cells would be beneficial. T.sub.reg cells
are essential for immune tolerance and play a crucial role in the
limitation of excessive immune and inflammatory responses executed
by T helper cells (i.e., Th.sub.1, Th.sub.2, Th.sub.9, Th.sub.17,
etc.). Thus, shunting the differentiation of T helper cells to
regulatory T cells by FASN inhibition can be used to treat
inflammatory diseases.
[2892] Treatment with a FASN inhibitor of the present application
can inhibit the maturation of T cells to T helper inflammatory
cells (T-helper cells that can be inhibited include, but are not
limited to, Th.sub.1, Th.sub.2, Th.sub.9, and Th.sub.17) and
promotes their differentiation into T.sub.reg cells. Naive CD4+
cells differentiate into T helper and regulatory T cells to execute
their immunologic function. The differentiation depends on the
presence of cytokines. While T helper cells such as Th.sub.17 cells
play an important role in the protective immune response against
intracellular pathogens, excessive immune responses exerted by
these T helper cells also cause autoimmune and inflammatory
diseases. Examples of immune-mediated diseases that can be treated
by the FASN inhibitors of the present application include, but are
not limited to, psoriasis, rheumatoid arthritis, multiple
sclerosis, ankylosing spondylitis, inflammatory bowel disease
(IBD), Chronic obstructive pulmonary disease (COPD), asthma,
tumorigenesis, and transplant rejection. (Laura, A., et. al., "Th17
cells in human disease," Immunol. Rev. 223, 2008, 87-113; Lee, Y.,
et. al. "Unexpected targets and triggers of autoimmunity. J. Clin.
Immunol., 34 Suppl 1, 2014, S56-60)
[2893] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of disorders characterized by disregulation in
these systems including, but not limited to, nonalcoholic fatty
acid disease (NAFLD), non-alcoholic steatohepatitis (NASH),
steatosis and diabetes. In one embodiment, the present disclosure
relates to a method of treating non-alcoholic steatohepatitis
(NASH) with FASN inhibitor compounds of the disclosure (i.e., a
compound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)).
[2894] In another embodiment, the present disclosure relates to a
method of treating non-alcoholic steatohepatitis nonalcoholic fatty
acid disease (NAFLD) with FASN inhibitor compounds of the
disclosure (i.e., a compound of Formula (I), (II), (III), (IV),
(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII),
(XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).
[2895] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of metabolic syndrome. In one embodiment, the
present disclosure relates to a method of treating metabolic
syndrome with a compound of the disclosure (i.e., a compound of
Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)).
[2896] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of liver cirrhosis. In one embodiment, the present
disclosure relates to a method of treating liver cirrhosis with a
compound of the disclosure (i.e., a compound of Formula (I), (II),
(III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or
(XX)).
[2897] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of liver fibrosis. In one embodiment, the present
disclosure relates to a method of treating liver fibrosis with a
compound of the disclosure (i.e., a compound of Formula (I), (II),
(III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or
(XX)).
[2898] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of inflammation. In one embodiment, the present
disclosure relates to a method of treating inflammation with a
compound of the disclosure (i.e., a compound of Formula (I), (II),
(III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or
(XX)).
[2899] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of a disease or condition in which interleukin 1
beta (IL1.beta.) levels are elevated. In one embodiment, the
present disclosure relates to a method of treating a disease or
condition in which interleukin 1 beta (IL1.beta.) levels are
elevated with a compound of the disclosure (i.e., a compound of
Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)). In some embodiments, the disease or
condition in which interleukin 1 beta (IL1.beta.) levels are
elevated is selected from Familial Mediterranean fever (FMF),
Pyogenic arthritis, pyoderma gangrenosum, acne (PAPA),
Cryopyrin-associated periodic syndromes (CAPS), Hyper IgD syndrome
(HIDS), Adult and juvenile Still disease, Schnitzler syndrome, TNF
receptor-associated periodic syndrome (TRAPS), Blau syndrome; Sweet
syndrome, Deficiency in IL-1 receptor antagonist (DIRA), Recurrent
idiopathic pericarditis, Macrophage activation syndrome (MAS),
Urticarial vasculitis, Antisynthetase syndrome, Relapsing
chondritis, Behcet disease, Erdheim-Chester syndrome
(histiocytosis), Synovitis, acne, pustulosis, hyperostosis,
osteitis (SAPHO), Rheumatoid arthritis, Periodic fever, aphthous
stomatitis, pharyngitis, adenitis syndrome (PFAPA), Urate crystal
arthritis (gout), Type 2 diabetes, Smoldering multiple myeloma,
Postmyocardial infarction heart failure, Osteoarthritis,
Transfusion-related acute lung injury, Ventilator-induced lung
injury, Pulmonary fibrosis including Idiopathic, Chronic
obstructive pulmonary disease and Asthma.
[2900] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of a disease or condition in which t-helper
(T.sub.h) cell levels are elevated. In one embodiment, the present
disclosure relates to a method of treating a disease or condition
in which t-helper (T.sub.h) cell levels are elevated with a
compound of the disclosure (i.e., a compound of Formula (I), (II),
(III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX)).
In some embodiments, the disease or condition in which t-helper
(T.sub.h) cell levels are elevated is selected from Psoriasis,
Rheumatoid arthritis, Multiple sclerosis, Ankylosing spondylitis,
inflammatory bowel disease, asthma, tumorigenesis and transplant
rejection.
[2901] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of a disease or condition in which regulatory t
cells (T.sub.reg) are reduced or suppressed. In one embodiment, the
present disclosure relates to a method of treating a disease or
condition in which regulatory t cells (T.sub.reg) are reduced or
suppressed with a compound of the disclosure (i.e., a compound of
Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII), (VIII),
(IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)). In some embodiments, the disease or
condition in which regulatory t cells (T.sub.reg) are reduced or
suppressed is selected from Psoriasis, Rheumatoid arthritis,
Multiple sclerosis, Ankylosing spondylitis, inflammatory bowel
disease, asthma, tumorigenesis and transplant rejection.
[2902] In some embodiments, the disclosed FASN inhibitors (i.e., a
compound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)) may also be used in combination with one or
more other therapeutic agents in the treatment of a disease or
condition related to fatty liver or metabolic syndrome, including,
but not limited to, steatosis, glucose metabolism and lipogenesis.
Such therapeutic agents include, but are not limited to, (1)
Stearoyl-coenzyme A desaturase 1 enzyme (SCD1) inhibitors, e.g.,
Aramchol; (2) Fibroblast growth factors (FGFs) agonists, e.g.,
BMS-986036; (3) Peroxisome proliferator activated a/8 receptor
agonists, e.g., Elafibranor, aleglitazar, muraglitazar and
tesaglitazar; (4) Glucagon-like peptide-1 (GLP-1) agonists, e.g.,
Liraglutide, exenatide, lixisenatide, albiglutide, dulaglutide,
taspoglutide, and semaglutide; (5) Liver X receptor alpha
(LXR-.alpha.) inhibitors, e.g. Oltipraz; (6) Dipeptidyl peptidase
(DPP4) inhibitors, e.g., Sitagliptin; (7) Peroxisome
proliferator-activated receptor (PPAR)-.gamma. agonists, e.g.,
thiazolidinediones, Rosiglitazone, Pioglitazone, Lobeglitazone,
Ciglitazone, Darglitazone, Englitazone, Netoglitazone, and
Rivoglitazone; (8) Biguanides, e.g., Metformin, buformin, and
phenformin; (9) Statins or anti-absorbents, e.g., Atorvastatin,
Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin,
Pravastatin, Rosuvastatin, Simvastatin, Ezetimibe, SCH-48461,
Niacin, Taurine, and Orlistat; (10) Antihyperlipidemic agents and
fibrates e.g., Gemfibrozil, Bezafibrate, Ciprofibrate, Clofibrate,
Fenofibrate, Clinofibrate, pentoxifylline, and ursodiol; (11) Alpha
glucosidase inhibitors, e.g., Acarbose; (12) PPAR.alpha. ligands,
e.g., N-3 polyunsaturated fatty acids, Eicosapentaenoic acid (EPA),
and docosahexaenoic acid (DHA); (13) FXR agonists, e.g.,
Obeticholic acid (INT-747), and Px-104; (14) Sodium-dependent bile
acid transporters inhibitors, e.g., SHP626; (15) SGLT2 inhibitors
e.g., Remogliflozin, canagliflozin, dapagliflozin, and
empagliflozin; and (15) Acetyl-CoA Carboxylase (ACC) Inhibitors,
e.g., ND-630, ND-654, NDI-010976 (GS-0976), CP-640186, and
PF-05175157.
[2903] In some embodiments, the disclosed FASN inhibitors (i.e., a
compound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)) may also be used in combination with one or
more other therapeutic agents in the treatment of a disease or
condition related to fatty liver or metabolic syndrome. Such
therapeutic agents include, but are not limited to, (1) immune
signaling modulators; (2) TLR antagonists or TLR4 antagonists,
e.g., JKB-121, 2; (13) Inhibitors of the synthesis of TNF-.alpha.,
e.g., Pentoxifylline; (4) Angiotensin II type 1 blockers, e.g.,
telmisartan, losartan, Valsartan, Telmisartan, Irbesartan,
Azilsartan, and Olmesartan; and (5) Mediators of pro-inflammatory
signaling, e.g., IMM-124E, FGF19, and NGM282.
[2904] In some embodiments, the disclosed FASN inhibitors (i.e., a
compound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)) may also be used in combination with one or
more other therapeutic agents used to reduce oxidative stress for
the treatment of a disease or condition related to fatty liver or
metabolic syndrome. Such therapeutic agents include, but are not
limited to, (1) Apoptosis signal-regulating kinase (ASKI)
inhibitors which work to mitigate the profibrotic response to ROS
and (2) other mediators of oxidative stress, e.g., GS-4997 and
Vitamin E.
[2905] In some embodiments, the disclosed FASN inhibitors (i.e., a
compound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)) may also be used in combination with one or
more anti-fibrosis treatment agents in the treatment condition
related to fatty liver or metabolic syndrome. Such anti-fibrosis
treatment agents include, but are not limited to, (1) Inhibitors of
C--C chemokine receptors or dual inhibitor of C--C chemokine
receptor type 2 (CCR2) and C--C chemokine receptor type 5 (CCR5)
pathways, e.g., Cenicriviroc; (2) Galectin antagonists or
galectin-3 antagonist, e.g., GR-MD-02; (3) Angiotensin receptor
blockers (ARB) which disrupt the reninangiotensin system, e.g.,
Losartan; (4) Lysyloxidase-Like 2 (LOXL2) inhibitors, e.g.,
Simtuzumab; and (5) Mediators of fibrosis, e.g., Vitamin A, Vitamin
C, and Vitamin D.
[2906] In some embodiments, the disclosed FASN inhibitors (i.e., a
compound of Formula (I), (II), (III), (IV), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX) or (XX)) may also be used in combination with one or
more other apoptosis inhibitor agents in the treatment of a disease
or condition related to fatty liver or metabolic syndrome. Such
apoptosis inhibitor agents include, but are not limited to, (1)
Caspase inhibitors, e.g., GS-9450 or Emricasan; and (2) Galectin
protein inhibitors, e.g., GR-MD-02 or GCS-100.
[2907] Anticancer Activity
[2908] In various aspects, the present disclosure provides methods
for treating cancer in subject, the method comprising administering
to a subject in need of such treatment an effective amount of a
compound of Structures (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI) or as provided in Table 1. In further
aspects, compounds having Structure (I), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table 1 can
be used for the manufacture of a medicament for treating
cancer.
[2909] In certain aspects, the present disclosure provides a method
for inhibiting tumor cell growth in a subject, the method
comprising administering to a subject in need of such treatment an
effective amount of a compound of Structure (I), (II), (III), (IV),
(V), (VI), (VII), (VIII), (IX), (X), (XI) or as provided in Table
1. In further aspects, the tumor can be derived from ovary, breast,
lung, thyroid, lymph node, kidney, ureter, bladder, ovary, teste,
prostate, bone, skeletal muscle, bone marrow, stomach, esophagus,
small bowel, colon, rectum, pancreas, liver, smooth muscle, brain,
spinal cord, nerves, ear, eye, nasopharynx, oropharynx, salivary
gland, or heart tissue. In certain aspects, the present compounds
can be administered concurrently with one or more additional
anti-cancer treatments.
[2910] In various aspects, the disclosed FASN inhibitors are useful
in the treatment of liver cancer. In one embodiment, the present
disclosure related to a method of treating liver cancer with a
compound of the disclosure (i.e., a compound of Formula (I), (II),
(III), (IV), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI),
(XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or
(XX)).
[2911] Rapidly proliferating cancer cells activate the fatty acid
synthesis pathway to supply the high levels of lipids needed for
membrane assembly and oxidative metabolism. (Flavin, R. et al.
(2010) Future Oncology. 6(4):551-562) Inhibitors of fatty acid
synthesis have demonstrated in vivo activity in preclinical cancer
models. (Orita, H. et al. (2007) Clinical Cancer Research.
13(23):7139-7145 and Puig, T. et al. (2011) Breast Cancer Research,
13(6):R131) Additionally, fatty acid synthesis supports new blood
vessel formation and inhibitors of this pathway have activity in in
vitro models of angiogenesis. (Browne, C. D., et al. (2006) The
FASEB Journal, 20(12):2027-2035). The presently disclosed compounds
demonstrated the ability to selectively induce cell-cycle arrest in
HUVEC cells without causing general cell death by apoptosis. See
EXAMPLES.
[2912] The cancer treatment of the present invention includes an
anti-tumor effect that may be assessed by conventional means such
as the response rate, the time to disease progression and/or the
survival rate. Anti-tumor effects of the present invention include,
but are not limited to, inhibition of tumor growth, tumor growth
delay, regression of tumor, shrinkage of tumor, increased time to
regrowth of tumor on cessation of treatment and slowing of disease
progression. For example, it is expected that when the combination
of the present invention is administered to a warm-blooded animal
such as a human, in need of treatment for cancer involving a solid
tumor, such a method of treatment will produce an effect, as
measured by, for example, one or more of: the extent of the
anti-tumor effect, the response rate, the time to disease
progression and the survival rate.
[2913] Methods of Treatment
[2914] Also provided herein are pharmaceutical compositions
comprising the compounds of the present disclosure. The present
compositions and methods have antiviral and/or anticancer
activity.
[2915] In various aspects, the present disclosure provides
pharmaceutical compositions comprising any one of the compounds of
Structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
(X) or (XI) and a pharmaceutically acceptable carrier, excipient,
or diluent.
[2916] In certain aspects, the present disclosure provides
pharmaceutical compositions comprising any one of the compounds of
Table 1 and a pharmaceutically acceptable carrier, excipient, or
diluent.
[2917] Certain aspects of the present disclosure relates to methods
of using pharmaceutical compositions and kits comprising one or
more agents that inhibit the fatty acid synthesis pathway to
inhibit or decrease a viral infection or for the treatment of
cancer. Certain aspects of the present disclosure relates to
methods of using pharmaceutical compositions and kits comprising
one or more agents that inhibit fatty acid synthase to inhibit or
decrease a viral infection or for the treatment of cancer. Another
aspect of the present invention provides methods, pharmaceutical
compositions, and kits for the treatment of animal subjects having
a viral infection or cancer or at risk of developing a viral
infection or cancer. The term "subject" as used herein includes
humans as well as other mammals. The term "treating" as used herein
includes achieving a therapeutic benefit and/or a prophylactic
benefit. By therapeutic benefit is meant eradication or
amelioration of the underlying viral infection. Also, a therapeutic
benefit is achieved with the eradication or amelioration of one or
more of the physiological symptoms associated with the underlying
viral infection such that an improvement is observed in the animal
subject, notwithstanding the fact that the subject can still be
afflicted with the underlying virus.
[2918] In other aspects, the present invention relates to a method
of treating fatty liver disease in a subject in need thereof, the
method comprising administering to the subject a fatty acid
synthase inhibitor having Formula (I), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),
(XVI), (XVII), (XVIII), (XIX), or (XX).
[2919] In other aspects, the present invention relates to a method
of treating non-alcoholic steatohepatitis nonalcoholic fatty acid
disease (NAFLD) in a subject in need thereof, the method comprising
administering to the subject a fatty acid synthase inhibitor having
Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
(X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII),
(XIX), or (XX).
[2920] In other aspects, the present invention relates to a method
of treating non-alcoholic steatohepatitis (NASH) in a subject in
need thereof, the method comprising administering to the subject a
fatty acid synthase inhibitor having Formula (I), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII),
(XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX).
[2921] In other aspects, the present invention relates to a method
of treating liver cirrhosis in a subject in need thereof, the
method comprising administering to the subject a fatty acid
synthase inhibitor having Formula (I), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),
(XVI), (XVII), (XVIII), (XIX), or (XX).
[2922] In other aspects, the present invention relates to a method
of treating liver fibrosis in a subject in need thereof, the method
comprising administering to the subject a fatty acid synthase
inhibitor having Formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX), or (XX).
[2923] In other aspects, the present invention relates to a method
of treating inflammation in a subject in need thereof, the method
comprising administering to the subject a fatty acid synthase
inhibitor having Formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX), or (XX).
[2924] In other aspects, the present invention relates to a method
of treating of a disease or condition in which interleukin 1 beta
(IL1.beta.) levels are elevated in a subject in need thereof, the
method comprising administering to the subject a fatty acid
synthase inhibitor having Formula (I), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),
(XVI), (XVII), (XVIII), (XIX), or (XX).
[2925] In other aspects, the present invention relates to a method
of treating of a disease or condition in which t-helper (T.sub.h)
cell levels are elevated in a subject in need thereof, the method
comprising administering to the subject a fatty acid synthase
inhibitor having Formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX), or (XX).
[2926] In other aspects, the present invention relates to a method
of treating of a disease or condition in which regulatory t cells
(T.sub.reg) are reduced or suppressed in a subject in need thereof,
the method comprising administering to the subject a fatty acid
synthase inhibitor having Formula (I), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV),
(XVI), (XVII), (XVIII), (XIX), or (XX).
[2927] In other aspects, the present invention relates to a method
of treating liver cancer in a subject in need thereof, the method
comprising administering to the subject a fatty acid synthase
inhibitor having Formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX), or (XX).
[2928] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) wherein R.sub.3 is
F.
[2929] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compounds of Formula (I) wherein A is
CH.
[2930] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) wherein A is N.
[2931] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) wherein X, Y, and Z
are NR'.
[2932] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) wherein R.sub.4 is
heteroaryl, heterocyclyl, --C(.dbd.O)N(R.sub.5R.sub.6),
--N(R.sub.7)C(.dbd.O)R.sub.8, --N(R.sub.9R.sub.10), C.sub.1-6
alkyl, C.sub.1-6 alkoxy, or R.sub.4 and R.sub.11.
[2933] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-A).
[2934] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-B).
[2935] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-C).
[2936] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-D).
[2937] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-E).
[2938] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-F).
[2939] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-G).
[2940] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-H).
[2941] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-I).
[2942] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-J).
[2943] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-K).
[2944] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-L).
[2945] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-M).
[2946] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-N).
[2947] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-O).
[2948] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-P).
[2949] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-Q).
[2950] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-R).
[2951] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-S).
[2952] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-T).
[2953] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-U).
[2954] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-V).
[2955] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-W).
[2956] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-X).
[2957] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-Y).
[2958] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-Z).
[2959] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AA).
[2960] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AB).
[2961] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AC).
[2962] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AD).
[2963] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AE).
[2964] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AF).
[2965] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AG).
[2966] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (I) having a Formula
(I-AH).
[2967] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (II) having a Formula
(II-A).
[2968] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (II) having a Formula
(II-B).
[2969] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (II) having a Formula
(II-C).
[2970] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (II) having a Formula
(II-D).
[2971] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (II) having a Formula
(II-E).
[2972] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (II) having a Formula
(II-F).
[2973] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (III) having a Formula
(III-A).
[2974] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (III) having a Formula
(III-B).
[2975] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (III) having a Formula
(III-C).
[2976] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (III) having a Formula
(III-D).
[2977] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (III) having a Formula
(III-E).
[2978] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (III) having a Formula
(III-F).
[2979] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.1 is
hydrogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[2980] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.1 is
cyano.
[2981] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.2 is
hydrogen or halo; R.sub.2 is hydrogen.
[2982] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.3 is
hydrogen.
[2983] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.21
and R.sub.22 are each independently hydrogen or C.sub.1-6
alkyl.
[2984] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.21
and R.sub.22 are each independently C.sub.1-6 alkyl.
[2985] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.25
is hydrogen.
[2986] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein L.sub.2 is
N.
[2987] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein L.sub.1 is
CH.
[2988] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein L.sub.3 is
CH.
[2989] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein L.sub.4 is
CH.
[2990] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein A is
N.
[2991] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein A is
CH.
[2992] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.26
is heterocyclyl.
[2993] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein R.sub.24
is --N(R.sub.13)(R.sub.14).
[2994] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein L.sub.5
and L.sub.6 are each independently N.
[2995] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein s is
1.
[2996] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) wherein s is
0.
[2997] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-A).
[2998] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-B).
[2999] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-C).
[3000] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-D).
[3001] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-E).
[3002] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-F).
[3003] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-G).
[3004] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-H).
[3005] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-I).
[3006] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-J).
[3007] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-K).
[3008] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-L).
[3009] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-M).
[3010] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-N).
[3011] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IV) having a Formula
(IV-O).
[3012] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein L.sub.7 is
N.
[3013] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein L.sub.7 is
O.
[3014] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein A is N.
[3015] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein A is
CH.
[3016] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.1 is
hydrogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[3017] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.1 is
cyano.
[3018] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.2 is
hydrogen or halo.
[3019] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.2 is
hydrogen.
[3020] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.3 is
fluorine.
[3021] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.21
and R.sub.22 are each independently hydrogen or C.sub.1-6
alkyl.
[3022] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.21
and R.sub.22 are each independently C.sub.1-6 alkyl.
[3023] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.31 is
hydrogen.
[3024] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.30 is
hydrogen.
[3025] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein L.sub.8 is
O.
[3026] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein L.sub.9 is
O.
[3027] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein L.sub.10 is
O and L.sub.11 is N.
[3028] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein L.sub.12 is
N.
[3029] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) wherein R.sub.32
and R.sub.33 are each independently hydrogen.
[3030] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-A).
[3031] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-B).
[3032] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-C).
[3033] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-D).
[3034] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-I).
[3035] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-K).
[3036] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-L).
[3037] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-M).
[3038] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-N).
[3039] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (V) having a Formula
(V-O).
[3040] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.1 is
hydrogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[3041] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.1 is
cyano.
[3042] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.2 is
hydrogen or halo.
[3043] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.2 is
hydrogen.
[3044] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.3 is
fluorine.
[3045] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.21
and R.sub.22 are each independently hydrogen or C.sub.1-6
alkyl.
[3046] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.21
and R.sub.22 are each independently C.sub.1-6 alkyl.
[3047] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.35
is hydrogen.
[3048] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.34
is heteroaryl;
[3049] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein R.sub.34
is thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl,
pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl,
tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl, indolyl,
isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,
indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl,
benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl, or
benzothiadiazolyl.
[3050] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein L.sub.13
is N.
[3051] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein L.sub.14
and L.sub.15 are each independently CH.
[3052] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein A is
N.
[3053] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) wherein A is
CH.
[3054] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-A).
[3055] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-B).
[3056] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-C).
[3057] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-D).
[3058] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-E).
[3059] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-F).
[3060] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-G).
[3061] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-H).
[3062] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VI) having a Formula
(VI-I).
[3063] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.1
is hydrogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)N(R.sub.13)(R.sub.14).
[3064] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.1
is cyano.
[3065] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.2
is hydrogen or halo.
[3066] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.2
is hydrogen.
[3067] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.3
is hydrogen.
[3068] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.21
and R.sub.22 are each independently hydrogen or C.sub.1-6
alkyl.
[3069] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.21
and R.sub.22 are each independently C.sub.1-6 alkyl.
[3070] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.39
is hydrogen.
[3071] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.40
is hydrogen.
[3072] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein L.sub.16
is N.
[3073] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein L.sub.17
is N.
[3074] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein L.sub.18
is CH.
[3075] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein L.sub.18
is N.
[3076] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein A is
N.
[3077] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein A is
CH.
[3078] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.42
is C.sub.1-6 alkyl.
[3079] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) wherein R.sub.41
is C.sub.1-6 alkyl.
[3080] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) having a Formula
(VII-A).
[3081] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) having a Formula
(VII-B).
[3082] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) having a Formula
(VII-C).
[3083] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VII) having a Formula
(VII-D).
[3084] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.1
is hydrogen, cyano, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or
--C(.dbd.O)NN(R.sub.13)(R.sub.14).
[3085] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.1
is cyano.
[3086] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.2
is hydrogen or halo.
[3087] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.2
is hydrogen.
[3088] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.3
is hydrogen.
[3089] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.21
and R.sub.22 are each independently hydrogen or C.sub.1-6
alkyl.
[3090] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.21
and R.sub.22 are each independently C.sub.1-6 alkyl.
[3091] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein R.sub.39
is hydrogen.
[3092] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein L.sub.19
is N.
[3093] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein A is
N.
[3094] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) wherein A is
CH.
[3095] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) having a Formula
(VIII-A).
[3096] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) having a Formula
(VIII-B).
[3097] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) having a Formula
(VIII-C).
[3098] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VIII) having a Formula
(VIII-D).
[3099] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.24
is C.sub.1-C.sub.4 straight or branched alkyl or --(C.sub.1-C.sub.4
alkyl).sub.t-O--(C.sub.1-C.sub.4 straight or branched alkyl),
wherein t is 0 or 1.
[3100] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.21
is halogen, C.sub.1-C.sub.4 straight or branched alkyl or
C.sub.3-C.sub.5 cycloalkyl wherein the C.sub.3-C.sub.5 cycloalkyl
optionally includes an oxygen or nitrogen heteroatom.
[3101] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.3 is
H or halogen.
[3102] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.1 is
halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3103] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein both
L.sup.1 and L.sup.2 are N.
[3104] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl and R.sup.22
is C.sub.1-C.sub.2 alkyl.
[3105] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.21
is C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[3106] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.24
is --(C.sub.1-C.sub.2 alkyl).sub.t-O--(C.sub.1-C.sub.2 alkyl)
wherein t is 0 or 1.
[3107] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.21
is C.sub.3-C.sub.5 cycloalkyl, R.sup.22 is C.sub.1-C.sub.2 alkyl
and R.sup.24 is C.sub.1-C.sub.2 alkyl.
[3108] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.21
is cyclobutyl, R.sup.22 is C.sub.1-C.sub.2 alkyl and R.sup.24 is
C.sub.1-C.sub.2 alkyl.
[3109] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.21
is cyclobutyl.
[3110] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.3 is
H or F.
[3111] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.1 is
--CN.
[3112] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.1 is
--CF.sub.3.
[3113] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.22
is H, methyl or ethyl.
[3114] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.22
is H.
[3115] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.22
is methyl.
[3116] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein each
R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is C.sub.3-C.sub.4
cycloalkyl, R.sup.22 is methyl, L.sup.1 and L.sup.2 are N, and
R.sup.24 is methyl, ethyl, hydroxymethyl, methoxymethyl,
2-methoxyethyl.
[3117] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.1 is
--CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl, R.sup.22 is methyl, L.sup.1 and L.sup.2
are N, and R.sup.24 is methoxy or ethoxy.
[3118] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.1 is
--CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl, R.sup.22 is methyl, L.sup.1 is CH,
L.sup.2 is N, and R.sup.24 is methyl, ethyl, hydroxymethyl,
methoxymethyl, or 2-methoxyethyl.
[3119] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein R.sup.1 is
--CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl, R.sup.22 is methyl, L.sup.1 is N,
L.sup.2 is CH, and R.sup.24 is methyl, ethyl, hydroxymethyl,
methoxymethyl, or 2-methoxyethyl.
[3120] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (IX) wherein the
compound selected from:
##STR00469##
[3121] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.21 is
halogen, C.sub.1-C.sub.4 straight or branched alkyl or
C.sub.3-C.sub.5 cycloalkyl.
[3122] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.3 is
H or halogen.
[3123] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.1 is
--CN or C.sub.1-C.sub.2 haloalkyl.
[3124] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.3 is
H or F.
[3125] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.1 is
--CN.
[3126] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.1 is
--CF.sub.3.
[3127] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein n is 1.
[3128] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein n is 2.
[3129] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein m is 1.
[3130] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein m is 2.
[3131] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.21 is
C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is
C.sub.1-C.sub.2 alkyl.
[3132] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.21 is
C.sub.3-C.sub.5 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[3133] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein n is 2, m
is 1, L.sup.3 is --N--C(O)--O--(C.sub.1-C.sub.2 alkyl).
[3134] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein L.sup.3 is
NR.sup.50; R.sup.50 is C.sub.1-C.sub.2 alkyl; R.sup.21 is
cyclobutyl; R.sup.22 is H or methyl; R.sup.3 is H; R.sup.1 is --CN;
m is 2 and n is 1 or 2.
[3135] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein n is 2, m
is 1, L.sup.3 is O and s is 0.
[3136] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.22 is
H, methyl or ethyl.
[3137] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.22 is
methyl.
[3138] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.22 is
H.
[3139] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.1 is
--CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl, R.sup.22 is methyl, n is 2 and L.sup.3
is NR.sup.50 wherein R.sup.50 is methyl or ethyl.
[3140] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein R.sup.1 is
--CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl, R.sup.22 is methyl, n is 2 and L.sup.3
is O.
[3141] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (X) wherein the
compound selected from:
##STR00470##
[3142] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.3
is H or halogen.
[3143] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.1
is halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3144] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.22
is C.sub.1-C.sub.2 alkyl.
[3145] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.21
is cyclobutyl and R.sup.22 is C.sub.1-C.sub.2 alkyl.
[3146] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.21
is cyclobutyl.
[3147] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.3
is H or F.
[3148] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.1
is --CN.
[3149] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.1
is --CF.sub.3.
[3150] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.22
is H, methyl or ethyl.
[3151] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.22
is H.
[3152] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.22
is methyl.
[3153] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.35
is --C(O)--NHR.sup.351.
[3154] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein
R.sup.351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,
(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,
(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or
(S)-tetrahydro-2H-pyran-3-yl.
[3155] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein
R.sup.351 is (R)-(tetrahydrofuran-2-yl)methyl or
(S)-(tetrahydrofuran-2-yl)methyl.
[3156] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.1
is --CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl, R.sup.22 is H, R.sup.35 is
--C(O)--NHR.sup.351 where R.sup.351 is isopropyl, isobutyl,
(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,
(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,
(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
[3157] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.35
is --C(O)--O--R.sup.351.
[3158] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein
R.sup.351 is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,
(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,
(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or
(S)-tetrahydro-2H-pyran-3-yl.
[3159] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein
R.sup.351 is (R)-3-tetrahydrofuranyl or
(S)-3-tetrahydrofuranyl.
[3160] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein R.sup.1
is --CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is
C.sub.3-C.sub.4 cycloalkyl, R.sup.22 is H, R.sup.35 is
--C(O)--O--R.sup.351 where R.sup.351 is isopropyl, isobutyl,
(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,
(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,
(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
[3161] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (VJ-I) wherein the
compound selected from:
##STR00471## ##STR00472##
[3162] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.3 is
H or halogen.
[3163] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.1 is
halogen, --CN, or C.sub.1-C.sub.2 haloalkyl.
[3164] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.21
is C.sub.3-C.sub.4 cycloalkyl and R.sup.22 is C.sub.1-C.sub.2
alkyl.
[3165] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.21
is cyclobutyl and R.sup.22 is C.sub.1-C.sub.2 alkyl.
[3166] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.21
is cyclobutyl.
[3167] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.3 is
H or F.
[3168] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.1 is
--CN.
[3169] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.1 is
--CF.sub.3.
[3170] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.22
is H, methyl or ethyl.
[3171] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.22
is H.
[3172] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.22
is methyl.
[3173] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein R.sup.1 is
--CN, each R.sup.2 is H, R.sup.3 is H or F, R.sup.21 is cyclobutyl,
R.sup.22 is methyl and R.sup.351 is methyl or ethyl.
[3174] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XI) wherein the
compound selected from:
##STR00473##
[3175] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein L-Ar
is
##STR00474##
Ar is not
##STR00475##
[3177] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein L-Ar
is
##STR00476##
and Ar is
##STR00477##
[3179] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein L-Ar
is
##STR00478##
and Ar is
##STR00479##
[3181] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein Ar is
##STR00480##
[3182] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.1
is halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3183] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.1
is --CN.
[3184] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.2
is H.
[3185] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.21
is halogen, C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.5
cycloalkyl.
[3186] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.21
is C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.5 cycloalkyl.
[3187] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl.
[3188] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl.
[3189] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.21
is --CH.sub.3.
[3190] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.22
is H or C.sub.1-C.sub.2 alkyl.
[3191] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.22
is H or --CH.sub.3.
[3192] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.22
is --CH.sub.3.
[3193] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is H, --CN, --(C.sub.1-C.sub.4 alkyl)-CN, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4
alkyl).
[3194] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is H, C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.6 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl) t-O.sub.u-(4- to 6-membered heterocycle)
or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl).
[3195] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is C.sub.1-C.sub.4 alkyl or --(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl).
[3196] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is --(C.sub.1-C.sub.2 alkyl)-O--(C.sub.1-C.sub.2 alkyl).
[3197] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is --CH.sub.2--O--CH.sub.3.
[3198] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is C.sub.1-C.sub.2 alkyl.
[3199] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is --CH.sub.3.
[3200] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is C.sub.3-C.sub.6 cycloalkyl.
[3201] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is --CN or --(C.sub.1-C.sub.2 alkyl)-CN.
[3202] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is --CN.
[3203] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is --(C.sub.1-C.sub.2 alkyl)-CN.
[3204] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is H, --CH.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--(CH.sub.2).sub.2OH, --(CH.sub.2).sub.2OCH.sub.3 or
--(CH.sub.2).sub.2N(CH.sub.3).sub.2.
[3205] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is methyl, isopropyl, cyclopropyl, --CN, or --(C.sub.1-C.sub.2
alkyl)-CN.
[3206] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is substituted with one or more substituents selected from
C.sub.1-C.sub.2 alkyl, oxo, --CN, halogen, alkanoyl,
alkoxycarbonyl, --OH and C.sub.1-C.sub.2 alkoxy.
[3207] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is substituted with one or more substituents selected from methyl,
--F, methoxy, --C(.dbd.O)CH.sub.3 and --C(.dbd.O)--OCH.sub.3.
[3208] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is substituted with two substituents that are the same or
different.
[3209] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.24
is substituted with three substituents that are the same or
different.
[3210] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is halogen, --CN, C.sub.1-C.sub.2 alkyl or cyclopropyl.
[3211] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is halogen, C.sub.1-C.sub.2 alkyl or cyclopropyl.
[3212] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is --CN, --Cl or --CH.sub.3.
[3213] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is --Cl.
[3214] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is --CH.sub.3.
[3215] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is substituted with one or more substituents selected from --OH,
halogen, C.sub.1-C.sub.2 alkyl and alkylcarbonyloxy.
[3216] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is substituted with one or more substituents selected from --F,
methyl and --O--C(.dbd.O)--CH.sub.3.
[3217] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is substituted with two substituents that are the same or
different.
[3218] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XII) wherein R.sup.25
is substituted with three substituents that are the same or
different.
[3219] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein the
compound is not:
##STR00481##
[3220] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein when
L-Ar is
##STR00482##
Ar is not
##STR00483##
[3222] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein L-Ar
is
##STR00484##
and Ar is
##STR00485##
[3224] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein L-Ar
is
##STR00486##
and Ar is
##STR00487##
[3226] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein Ar
is
##STR00488##
[3227] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.1
is halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3228] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.1
is --CN.
[3229] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.2
is H.
[3230] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.21
is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4-
to 6-membered heterocycle.
[3231] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.21
is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle.
[3232] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl.
[3233] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl.
[3234] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.21
is --CH.sub.3.
[3235] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.22
is H or C.sub.1-C.sub.2 alkyl.
[3236] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.22
is H or --CH.sub.3.
[3237] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.22
is --CH.sub.3.
[3238] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein each
R.sup.24 and R.sup.25 is independently H, --CN, C.sub.1-C.sub.4
alkyl, --(C.sub.1-C.sub.4 alkyl)-OH, --(C.sub.1-C.sub.4
alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4
alkyl).
[3239] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein each
R.sup.24 and R.sup.25 is independently H, C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4
alkyl).
[3240] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is H, C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4 alkyl)-OH,
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.241).sub.2, --(C.sub.1-C.sub.4
alkyl).sub.t-O.sub.u--(C.sub.3-C.sub.5 cycloalkyl),
--(C.sub.1-C.sub.4 alkyl).sub.t-O.sub.u-(4- to 6-membered
heterocycle) or --(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4
alkyl).
[3241] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is --CN, --Cl, C.sub.1-C.sub.4 alkyl or --(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl).
[3242] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is C.sub.1-C.sub.4 alkyl or --(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl).
[3243] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is --(C.sub.1-C.sub.2 alkyl)-O--(C.sub.1-C.sub.2 alkyl).
[3244] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is C.sub.1-C.sub.4 alkyl.
[3245] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is --CH.sub.3.
[3246] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is hydrogen.
[3247] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is substituted with one or more substituents selected from halogen,
C.sub.3-C.sub.5 cycloalkyl and C.sub.1-C.sub.2 alkoxy.
[3248] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is substituted with one or more substituents selected from --F,
cyclopropyl and --OCH.sub.3.
[3249] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is substituted with two substituents that are the same or
different.
[3250] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.24
is substituted with three substituents that are the same or
different.
[3251] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is halogen, methyl, ethyl or cyclopropyl.
[3252] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is --CN, --Cl, C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4
alkyl).sub.t-O--(C.sub.3-C.sub.5 cycloalkyl) or --(C.sub.1-C.sub.4
alkyl).sub.t-O--(C.sub.1-C.sub.4 alkyl).
[3253] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is --CN, --Cl, --CH.sub.3, --O--(C.sub.3-C.sub.5 cycloalkyl) or
--O--(C.sub.1-C.sub.2 alkyl).
[3254] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is --CN, --Cl or C.sub.1-C.sub.4 alkyl.
[3255] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is --CH.sub.3.
[3256] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is --Cl.
[3257] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is substituted with one or more halogen.
[3258] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is substituted with one or more --F.
[3259] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is substituted by two substituents.
[3260] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIII) wherein R.sup.25
is substituted by three substituents.
[3261] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein L-Ar
is
##STR00489##
and Ar is
##STR00490##
[3263] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein L-Ar
is
##STR00491##
and Ar is
##STR00492##
[3265] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein Ar is
##STR00493##
[3266] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.1
is halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3267] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.1
is --CN.
[3268] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.2
is H.
[3269] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.21
is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4-
to 6-membered heterocycle.
[3270] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.21
is H, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4- to
6-membered heterocycle.
[3271] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl.
[3272] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl.
[3273] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.21
is C.sub.3-C.sub.5 cycloalkyl.
[3274] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.22
is H or C.sub.1-C.sub.2 alkyl.
[3275] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.22
is H.
[3276] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.22
is C.sub.1-C.sub.2 alkyl.
[3277] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.22
is --CH.sub.3.
[3278] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.24
is C.sub.1-C.sub.4 alkyl or --(C.sub.1-C.sub.4
alkyl).sub.t-O--(C.sub.1-C.sub.4 alkyl).
[3279] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIV) wherein R.sup.24
is --(C.sub.1-C.sub.2 alkyl).sub.t-O--(C.sub.1-C.sub.2 alkyl).
[3280] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein L-Ar
is
##STR00494##
and Ar is
##STR00495##
[3282] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein L-Ar
is
##STR00496##
and Ar is
##STR00497##
[3284] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.1 is
H, --CN, --C.sub.1-C.sub.4 alkyl, --O--(C.sub.3-C.sub.5
cycloalkyl), --O-(4- to 6-membered heterocycle) or
--O--(C.sub.1-C.sub.4 alkyl) wherein when R.sup.1 is not H or --CN,
R.sup.1 is optionally substituted with one or more halogens.
[3285] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.1 is
halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3286] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.1 is
--CN or C.sub.1-C.sub.2 haloalkyl.
[3287] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.1 is
--CN.
[3288] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.1 is
--Cl.
[3289] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.2 is
H.
[3290] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.21
is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4-
to 6-membered heterocycle.
[3291] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl.
[3292] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.21
is C.sub.3-C.sub.5 cycloalkyl.
[3293] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.22
is H or C.sub.1-C.sub.2 alkyl.
[3294] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.22
is H.
[3295] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.22
is C.sub.1-C.sub.2 alkyl.
[3296] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein R.sup.22
is --CH.sub.3.
[3297] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein L.sup.3 is
--N(CH.sub.3)--.
[3298] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein n is 2 and
m is 2.
[3299] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein n is 1 or
2.
[3300] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XV) wherein n is 1 and
m is 2.
[3301] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVI) wherein L-Ar
is
##STR00498##
Ar is not
##STR00499##
[3303] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVI) wherein L-Ar
is
##STR00500##
and Ar is
##STR00501##
[3305] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVI) wherein L-Ar
is
##STR00502##
and Ar is
##STR00503##
[3307] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVI) wherein R.sup.1
is halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3308] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVI) wherein R.sup.21
is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4-
to 6-membered heterocycle.
[3309] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVI) wherein R.sup.21
is --CH.sub.3.
[3310] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVI) wherein R.sup.22
is H.
[3311] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein L-Ar
is
##STR00504##
and Ar is
##STR00505##
[3313] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.1
is halogen, --CN or C.sub.1-C.sub.2 haloalkyl.
[3314] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.1
is --CN.
[3315] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.2
is H.
[3316] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.21
is halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl or 4-
to 6-membered heterocycle.
[3317] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.5 cycloalkyl.
[3318] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.21
is C.sub.1-C.sub.2 alkyl.
[3319] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.21
is C.sub.3-C.sub.5 cycloalkyl.
[3320] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.22
is H or C.sub.1-C.sub.2 alkyl.
[3321] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.22
is H.
[3322] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.22
is C.sub.1-C.sub.2 alkyl.
[3323] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.22
is --CH.sub.3.
[3324] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.24
is C.sub.1-C.sub.4 alkyl or --(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl).
[3325] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVII) wherein R.sup.24
is --(C.sub.1-C.sub.2 alkyl)-O--(C.sub.1-C.sub.2 alkyl).
[3326] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVIII) wherein L-Ar
is
##STR00506##
Ar is not
##STR00507##
[3328] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVIII) wherein L.sup.2
is --NHR.sup.35.
[3329] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XVIII) wherein L.sup.2
is --C(O)NHR.sup.351.
[3330] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIX) wherein Ar is
##STR00508##
[3331] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIX) wherein Y is
--CR.sup.26-- wherein R.sup.26 is --N(R.sup.27).sub.2.
[3332] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XIX) wherein X is
--N--.
[3333] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein the
compound is not:
##STR00509##
[3334] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein L-Ar
is
##STR00510##
[3335] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein L-Ar
is
##STR00511##
[3336] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein L-Ar
is
##STR00512##
[3337] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.3 is
H.
[3338] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.1 is
--CN or --O--(C.sub.1-C.sub.4 alkyl), wherein when R.sup.1 is not
--CN, R.sup.1 is optionally substituted with one or more
halogen.
[3339] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.1 is
--CN.
[3340] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.1 is
--O--(C.sub.1-C.sub.4 alkyl) optionally substituted with one or
more halogen.
[3341] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein each
R.sup.2 is hydrogen.
[3342] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.21
is C.sub.1-C.sub.4 alkyl.
[3343] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.22
is H or C.sub.1-C.sub.2 alkyl.
[3344] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.24
is --O--(C.sub.1-C.sub.4 alkyl) optionally substituted with one or
more hydroxyl or halogen.
[3345] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.24
is --O--(C.sub.1-C.sub.4 alkyl) optionally substituted with one or
more hydroxyl.
[3346] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein R.sup.25
is --CH.sub.3.
[3347] In some embodiments of the methods above, the fatty acid
synthase inhibitor is a compound of Formula (XX) wherein the
compound selected from:
##STR00513## ##STR00514## ##STR00515## ##STR00516##
##STR00517##
[3348] For aspects where a prophylactic benefit is desired, a
pharmaceutical composition of the invention can be administered to
a patient at risk of developing viral infection such as HRV, or
HIV, or to a patient reporting one or more of the physiological
symptoms of a viral infection, even though a diagnosis of the
condition may not have been made. Administration can prevent the
viral infection from developing, or it can reduce, lessen, shorten
and/or otherwise ameliorate the viral infection that develops. The
pharmaceutical composition can modulate the fatty acid synthesis
pathway, e.g., FASN gene expression or FASN protein activity.
Wherein, the term modulate includes inhibition of the fatty acid
synthesis pathway, e.g., FASN gene expression or FASN protein
activity or alternatively activation of the fatty acid synthesis
pathway, e.g., FASN gene expression or FASN protein activity.
[3349] Reducing the activity of the fatty acid synthesis pathway,
e.g., FASN gene expression or FASN protein activity, is also
referred to as "inhibiting" the fatty acid synthesis pathway, e.g.,
FASN gene expression or FASN protein activity. The term "inhibits"
and its grammatical conjugations, such as "inhibitory," do not
require complete inhibition, but refer to a reduction in fatty acid
synthesis activity, e.g., FASN gene expression or FASN protein
activity. In another aspect, such reduction is by at least 50%, at
least 75%, at least 90%, and can be by at least 95% of the activity
of the enzyme in the absence of the inhibitory effect, e.g., in the
absence of an inhibitor. Conversely, the phrase "does not inhibit"
and its grammatical conjugations refer to situations where there is
less than 20%, less than 10%, and can be less than 5%, of reduction
in enzyme activity in the presence of the agent. Further the phrase
"does not substantially inhibit" and its grammatical conjugations
refer to situations where there is less than 30%, less than 20%,
and in some aspects less than 10% of reduction in enzyme activity
in the presence of the agent.
[3350] Increasing the activity of the fatty acid synthesis pathway,
e.g., FASN gene expression or FASN protein activity, is also
referred to as "activating" the fatty acid synthesis pathway, e.g.,
FASN gene expression or FASN protein activity. The term "activated"
and its grammatical conjugations, such as "activating," do not
require complete activation, but refer to an increase in fatty acid
synthesis pathway activity, e.g., FASN gene expression or FASN
protein activity. In another aspect such increase is by at least
50%, at least 75%, at least 90%, and can be by at least 95% of the
activity of the enzyme in the absence of the activation effect,
e.g., in the absence of an activator. Conversely, the phrase "does
not activate" and its grammatical conjugations refer to situations
where there is less than 20%, less than 10%, and can be less than
5%, of an increase in enzyme activity in the presence of the agent.
Further the phrase "does not substantially activate" and its
grammatical conjugations refer to situations where there is less
than 30%, less than 20%, and in another aspect less than 10% of an
increase in enzyme activity in the presence of the agent.
[3351] The ability to reduce enzyme activity is a measure of the
potency or the activity of an agent, or combination of agents,
towards or against the enzyme. Potency can be measured by cell
free, whole cell and/or in vivo assays in terms of IC50, K.sub.i
and/or ED50 values. An IC50 value represents the concentration of
an agent required to inhibit enzyme activity by half (50%) under a
given set of conditions. A K.sub.i value represents the equilibrium
affinity constant for the binding of an inhibiting agent to the
enzyme. An ED50 value represents the dose of an agent required to
effect a half-maximal response in a biological assay. Further
details of these measures will be appreciated by those of ordinary
skill in the art, and can be found in standard texts on
biochemistry, enzymology, and the like.
[3352] The present invention also includes kits that can be used to
treat viral infections or treat cancer. These kits comprise an
agent or combination of agents that inhibit the fatty acid
synthesis pathway, e.g., FASN gene expression or FASN protein
activity, and optionally instructions teaching the use of the kit
according to the various methods and approaches described herein.
Such kits can also include information, such as scientific
literature references, package insert materials, clinical trial
results, and/or summaries of these and the like, which indicate or
establish the activities and/or advantages of the agent. Such
information can be based on the results of various studies, for
example, studies using experimental animals involving in vivo
models and studies based on human clinical trials. Kits described
herein can be provided, marketed and/or promoted to health
providers, including physicians, nurses, pharmacists, formulary
officials, and the like.
[3353] Formulations, Routes of Administration, and Effective
Doses
[3354] Yet another aspect of the present invention relates to
formulations, routes of administration and effective doses for
pharmaceutical compositions comprising an agent or combination of
agents of the instant invention. Such pharmaceutical compositions
can be used to treat viral infections as described above.
[3355] Compounds of the invention can be administered as
pharmaceutical formulations including those suitable for oral
(including buccal and sub-lingual), rectal, nasal, topical,
transdermal patch, pulmonary, vaginal, suppository, or parenteral
(including intramuscular, intraarterial, intrathecal, intradermal,
intraperitoneal, subcutaneous and intravenous) administration or in
a form suitable for administration by aerosolization, inhalation or
insufflation. General information on drug delivery systems can be
found in Ansel et al., Pharmaceutical Dosage Forms and Drug
Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md.
(1999).
[3356] In various aspects, the pharmaceutical composition includes
carriers and excipients (including but not limited to buffers,
carbohydrates, mannitol, proteins, polypeptides or amino acids such
as glycine, antioxidants, bacteriostats, chelating agents,
suspending agents, thickening agents and/or preservatives), water,
oils including those of petroleum, animal, vegetable or synthetic
origin, such as peanut oil, soybean oil, mineral oil, sesame oil
and the like, saline solutions, aqueous dextrose and glycerol
solutions, flavoring agents, coloring agents, detackifiers and
other acceptable additives, adjuvants, or binders, other
pharmaceutically acceptable auxiliary substances as required to
approximate physiological conditions, such as pH buffering agents,
tonicity adjusting agents, emulsifying agents, wetting agents and
the like. Examples of excipients include starch, glucose, lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium
stearate, glycerol monostearate, talc, sodium chloride, dried skim
milk, glycerol, propylene, glycol, water, ethanol and the like. In
another aspect, the pharmaceutical preparation is substantially
free of preservatives. In another aspect, the pharmaceutical
preparation can contain at least one preservative. General
methodology on pharmaceutical dosage forms is found in Ansel et
al., Pharmaceutical Dosage Forms and Drug Delivery Systems
(Lippencott Williams & Wilkins, Baltimore Md. (1999)). It will
be recognized that, while any suitable carrier known to those of
ordinary skill in the art can be employed to administer the
compositions of this invention, the type of carrier will vary
depending on the mode of administration.
[3357] Compounds can also be encapsulated within liposomes using
well-known technology. Biodegradable microspheres can also be
employed as carriers for the pharmaceutical compositions of this
invention. Suitable biodegradable microspheres are disclosed, for
example, in U.S. Pat. Nos. 4,897,268; 5,075,109; 5,928,647;
5,811,128; 5,820,883; 5,853,763; 5,814,344 and 5,942,252.
[3358] The compound can be administered in liposomes or
microspheres (or microparticles). Methods for preparing liposomes
and microspheres for administration to a patient are well known to
those of skill in the art. U.S. Pat. No. 4,789,734, the contents of
which are hereby incorporated by reference, describes methods for
encapsulating biological materials in liposomes. Essentially, the
material is dissolved in an aqueous solution, the appropriate
phospholipids and lipids added, along with surfactants if required,
and the material dialyzed or sonicated, as necessary. A review of
known methods is provided by G. Gregoriadis, Chapter 14,
"Liposomes," Drug Carriers in Biology and Medicine, pp.
2.sup.87-341 (Academic Press, 1979).
[3359] Microspheres formed of polymers or proteins are well known
to those skilled in the art, and can be tailored for passage
through the gastrointestinal tract directly into the blood stream.
Alternatively, the compound can be incorporated and the
microspheres, or composite of microspheres, implanted for slow
release over a period of time ranging from days to months. See, for
example, U.S. Pat. Nos. 4,906,474, 4,925,673 and 3,625,214, and
Jein, TIPS 19:155-157 (1998), the contents of which are hereby
incorporated by reference.
[3360] The concentration of drug can be adjusted, the pH of the
solution buffered and the isotonicity adjusted to be compatible
with intravenous injection, as is well known in the art.
[3361] The compounds of the invention can be formulated as a
sterile solution or suspension, in suitable vehicles, well known in
the art. The pharmaceutical compositions can be sterilized by
conventional, well-known sterilization techniques, or can be
sterile filtered. The resulting aqueous solutions can be packaged
for use as is, or lyophilized, the lyophilized preparation being
combined with a sterile solution prior to administration. Suitable
formulations and additional carriers are described in Remington
"The Science and Practice of Pharmacy" (20.sup.th Ed., Lippincott
Williams & Wilkins, Baltimore Md.), the teachings of which are
incorporated by reference in their entirety herein.
[3362] The agents or their pharmaceutically acceptable salts can be
provided alone or in combination with one or more other agents or
with one or more other forms. For example a formulation can
comprise one or more agents in particular proportions, depending on
the relative potencies of each agent and the intended indication.
For example, in compositions for targeting two different host
targets, and where potencies are similar, about a 1:1 ratio of
agents can be used. The two forms can be formulated together, in
the same dosage unit e.g., in one cream, suppository, tablet,
capsule, aerosol spray, or packet of powder to be dissolved in a
beverage; or each form can be formulated in a separate unit, e.g.,
two creams, two suppositories, two tablets, two capsules, a tablet
and a liquid for dissolving the tablet, two aerosol sprays, or a
packet of powder and a liquid for dissolving the powder, etc.
[3363] The term "pharmaceutically acceptable salt" means those
salts which retain the biological effectiveness and properties of
the agents used in the present invention, and which are not
biologically or otherwise undesirable. For example, a
pharmaceutically acceptable salt does not interfere with the
beneficial effect of an agent of the invention in inhibiting the
fatty acid synthesis pathway, e.g., inhibiting FASN gene expression
or FASN protein activity.
[3364] Typical salts are those of the inorganic ions, such as, for
example, sodium, potassium, calcium, magnesium ions, and the like.
Such salts include salts with inorganic or organic acids, such as
hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,
sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic
acid, fumaric acid, succinic acid, lactic acid, mandelic acid,
malic acid, citric acid, tartaric acid or maleic acid. In addition,
if the agent(s) contain a carboxy group or other acidic group, it
can be converted into a pharmaceutically acceptable addition salt
with inorganic or organic bases. Examples of suitable bases include
sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine,
dicyclohexyl-amine, ethanolamine, diethanolamine, triethanolamine,
and the like.
[3365] A pharmaceutically acceptable ester or amide refers to those
which retain biological effectiveness and properties of the agents
used in the present invention, and which are not biologically or
otherwise undesirable. For example, the ester or amide does not
interfere with the beneficial effect of an agent of the invention
in inhibiting the fatty acid synthesis pathway, e.g., inhibiting
FASN gene expression or FASN protein activity. Typical esters
include ethyl, methyl, isobutyl, ethylene glycol, and the like.
Typical amides include unsubstituted amides, alkyl amides, dialkyl
amides, and the like.
[3366] In another aspect, an agent can be administered in
combination with one or more other compounds, forms, and/or agents,
e.g., as described above. Pharmaceutical compositions comprising
combinations of a fatty acid synthesis pathway inhibitor e.g., an
inhibitor or FASN gene expression or FASN protein activity with one
or more other active agents can be formulated to comprise certain
molar ratios. For example, molar ratios of about 99:1 to about 1:99
of a fatty acid synthesis pathway inhibitor e.g., an inhibitor of
FASN gene expression or FASN protein activity, to the other active
agent can be used. In some subset of the aspects, the range of
molar ratios of fatty acid synthesis pathway inhibitor e.g., an
inhibitor of FASN gene expression or FASN protein activity: other
active agent is selected from about 80:20 to about 20:80; about
75:25 to about 25:75, about 70:30 to about 30:70, about 66:33 to
about 33:66, about 60:40 to about 40:60; about 50:50; and about
90:10 to about 10:90. The molar ratio of a fatty acid synthesis
pathway inhibitor e.g., an inhibitor of FASN gene expression or
FASN protein activity: other active agent can be about 1:9, and in
another aspect can be about 1:1. The two agents, forms and/or
compounds can be formulated together, in the same dosage unit e.g.,
in one cream, suppository, tablet, capsule, or packet of powder to
be dissolved in a beverage; or each agent, form, and/or compound
can be formulated in separate units, e.g., two creams,
suppositories, tablets, two capsules, a tablet and a liquid for
dissolving the tablet, an aerosol spray a packet of powder and a
liquid for dissolving the powder, etc.
[3367] If necessary or desirable, the agents and/or combinations of
agents can be administered with still other agents. The choice of
agents that can be co-administered with the agents and/or
combinations of agents of the instant invention can depend, at
least in part, on the condition being treated. Agents of particular
use in the formulations of the present invention include, for
example, any agent having a therapeutic effect for a viral
infection, including, e.g., drugs used to treat inflammatory
conditions. For example, in treatments for HRV, in some aspects
formulations of the instant invention can additionally contain one
or more conventional anti-inflammatory drugs, such as an NSAID,
e.g., ibuprofen, naproxen, acetaminophen, ketoprofen, or aspirin.
In some alternative aspects for the treatment of influenza
formulations of the instant invention can additionally contain one
or more conventional influenza antiviral agents, such as
amantadine, rimantadine, zanamivir, and oseltamivir. In treatments
for retroviral infections, such as HIV, formulations of the instant
invention can additionally contain one or more conventional
antiviral drug, such as protease inhibitors (lopinavir/ritonavir
(Kaletra), indinavir (Crixivan), ritonavir (Norvir), nelfinavir
(Viracept), saquinavir hard gel capsules (Invirase), atazanavir
(Reyataz), amprenavir (Agenerase), fosamprenavir (Telzir),
tipranavir (Aptivus)), reverse transcriptase inhibitors, including
non-Nucleoside and Nucleoside/nucleotide inhibitors (AZT
(zidovudine, Retrovir), ddI (didanosine, Videx), 3TC (lamivudine,
Epivir), d4T (stavudine, Zerit), abacavir (Ziagen), FTC
(emtricitabine, Emtriva), tenofovir (Viread), efavirenz (Sustiva)
and nevirapine (Viramune)), fusion inhibitors T20 (enfuvirtide,
Fuzeon), integrase inhibitors (MK-0518 and GS-9137), and maturation
inhibitors (PA-457 (Bevirimat)). As another example, formulations
can additionally contain one or more supplements, such as vitamin
C, E or other anti-oxidants.
[3368] In certain aspects, the compounds of the present disclosure
can be administered in combination with a known cancer therapeutic.
For example, the compounds can be administered in combination with
paclitaxel (commercially available as Taxol, Bristol-Myers Squibb),
doxorubicin (also known under the trade name Adriamycin),
vincristine (known under the trade names Oncovin, Vincasar PES, and
Vincrex), actinomycin D, altretamine, asparaginase, bleomycin,
busulphan, capecitabine, carboplatin, carmustine, chlorambucil,
cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin,
epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine,
hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine,
melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone,
oxaliplatin, procarbazine, steroids, streptozocin, taxotere,
tamozolomide, thioguanine, thiotepa, tomudex, topotecan,
treosulfan, UFT (uracil-tegufur), vinblastine, and vindesine, or
the like.
[3369] The agent(s) (or pharmaceutically acceptable salts, esters
or amides thereof) can be administered per se or in the form of a
pharmaceutical composition wherein the active agent(s) is in an
admixture or mixture with one or more pharmaceutically acceptable
carriers. A pharmaceutical composition, as used herein, can be any
composition prepared for administration to a subject.
Pharmaceutical compositions for use in accordance with the present
invention can be formulated in conventional manner using one or
more physiologically acceptable carriers, comprising excipients,
diluents, and/or auxiliaries, e.g., which facilitate processing of
the active agents into preparations that can be administered.
Proper formulation can depend at least in part upon the route of
administration chosen. The agent(s) useful in the present
invention, or pharmaceutically acceptable salts, esters, or amides
thereof, can be delivered to a patient using a number of routes or
modes of administration, including oral, buccal, topical, rectal,
transdermal, transmucosal, subcutaneous, intravenous, and
intramuscular applications, as well as by inhalation.
[3370] For oral administration, the agents can be formulated
readily by combining the active agent(s) with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
agents of the invention to be formulated as tablets, including
chewable tablets, pills, dragees, capsules, lozenges, hard candy,
liquids, gels, syrups, slurries, powders, suspensions, elixirs,
wafers, and the like, for oral ingestion by a patient to be
treated. Such formulations can comprise pharmaceutically acceptable
carriers including solid diluents or fillers, sterile aqueous media
and various non-toxic organic solvents. A solid carrier can be one
or more substances which can also act as diluents, flavoring
agents, solubilizers, lubricants, suspending agents, binders,
preservatives, tablet disintegrating agents, or an encapsulating
material. In powders, the carrier generally is a finely divided
solid which is a mixture with the finely divided active component.
In tablets, the active component generally is mixed with the
carrier having the necessary binding capacity in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain from about one (1) to about
seventy (70) percent of the active compound. Suitable carriers
include but are not limited to magnesium carbonate, magnesium
stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose, a low
melting wax, cocoa butter, and the like. Generally, the agents of
the invention will be included at concentration levels ranging from
about 0.5%, about 5%, about 10%, about 20%, or about 30% to about
50%, about 60%, about 70%, about 80% or about 90% by weight of the
total composition of oral dosage forms, in an amount sufficient to
provide a desired unit of dosage.
[3371] Aqueous suspensions for oral use can contain agent(s) of
this invention with pharmaceutically acceptable excipients, such as
a suspending agent (e.g., methyl cellulose), a wetting agent (e.g.,
lecithin, lysolecithin and/or a long-chain fatty alcohol), as well
as coloring agents, preservatives, flavoring agents, and the
like.
[3372] In another aspect, oils or non-aqueous solvents can be
required to bring the agents into solution, due to, for example,
the presence of large lipophilic moieties. Alternatively,
emulsions, suspensions, or other preparations, for example,
liposomal preparations, can be used. With respect to liposomal
preparations, any known methods for preparing liposomes for
treatment of a condition can be used. See, for example, Bangham et
al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc. Natl
Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein by
reference. Ligands can also be attached to the liposomes to direct
these compositions to particular sites of action. Agents of this
invention can also be integrated into foodstuffs, e.g., cream
cheese, butter, salad dressing, or ice cream to facilitate
solubilization, administration, and/or compliance in certain
patient populations.
[3373] Pharmaceutical preparations for oral use can be obtained as
a solid excipient, optionally grinding a resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as sugars,
including lactose, sucrose, mannitol, or sorbitol; flavoring
elements, cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone (PVP). If
desired, disintegrating agents can be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. The agents can also be formulated
as a sustained release preparation.
[3374] Dragee cores can be provided with suitable coatings. For
this purpose, concentrated sugar solutions can be used, which can
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments can be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active agents.
[3375] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active agents can be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers can be added. All formulations for oral administration
should be in dosages suitable for administration.
[3376] Other forms suitable for oral administration include liquid
form preparations including emulsions, syrups, elixirs, aqueous
solutions, aqueous suspensions, or solid form preparations which
are intended to be converted shortly before use to liquid form
preparations. Emulsions can be prepared in solutions, for example,
in aqueous propylene glycol solutions or can contain emulsifying
agents, for example, such as lecithin, sorbitan monooleate, or
acacia. Aqueous solutions can be prepared by dissolving the active
component in water and adding suitable colorants, flavors,
stabilizers, and thickening agents. Aqueous suspensions can be
prepared by dispersing the finely divided active component in water
with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other
well-known suspending agents. Suitable fillers or carriers with
which the compositions can be administered include agar, alcohol,
fats, lactose, starch, cellulose derivatives, polysaccharides,
polyvinylpyrrolidone, silica, sterile saline and the like, or
mixtures thereof used in suitable amounts. Solid form preparations
include solutions, suspensions, and emulsions, and can contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[3377] A syrup or suspension can be made by adding the active
compound to a concentrated, aqueous solution of a sugar, e.g.,
sucrose, to which can also be added any accessory ingredients. Such
accessory ingredients can include flavoring, an agent to retard
crystallization of the sugar or an agent to increase the solubility
of any other ingredient, e.g., as a polyhydric alcohol, for
example, glycerol or sorbitol.
[3378] When formulating compounds of the invention for oral
administration, it can be desirable to utilize gastroretentive
formulations to enhance absorption from the gastrointestinal (GI)
tract. A formulation which is retained in the stomach for several
hours can release compounds of the invention slowly and provide a
sustained release that can be used in methods of the invention.
Disclosure of such gastro-retentive formulations are found in
Klausner, E. A.; Lavy, E.; Barta, M.; Cserepes, E.; Friedman, M.;
Hoffman, A. 2003 "Novel gastroretentive dosage forms: evaluation of
gastroretentivity and its effect on levodopa in humans." Pharm.
Res. 20, 1466-73, Hoffman, A.; Stepensky, D.; Lavy, E.; Eyal, S.
Klausner, E.; Friedman, M. 2004 "Pharmacokinetic and
pharmacodynamic aspects of gastroretentive dosage forms" Int. J.
Pharm. 11, 141-53, Streubel, A.; Siepmann, J.; Bodmeier, R.; 2006
"Gastroretentive drug delivery systems" Exp. Opin. Drug Deliver. 3,
217-3, and Chavanpatil, M. D.; Jain, P.; Chaudhari, S.; Shear, R.;
Vavia, P. R. "Novel sustained release, swellable and bioadhesive
gastroretentive drug delivery system for olfoxacin" Int. J. Pharm.
2006 epub March 24. Expandable, floating and bioadhesive techniques
can be utilized to maximize absorption of the compounds of the
invention.
[3379] The compounds of the invention can be formulated for
parenteral administration (e.g., by injection, for example bolus
injection or continuous infusion) and can be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
can take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, for example solutions in aqueous polyethylene
glycol.
[3380] For injectable formulations, the vehicle can be chosen from
those known in art to be suitable, including aqueous solutions or
oil suspensions, or emulsions, with sesame oil, corn oil,
cottonseed oil, or peanut oil, as well as elixirs, mannitol,
dextrose, or a sterile aqueous solution, and similar pharmaceutical
vehicles. The formulation can also comprise polymer compositions
which are biocompatible, biodegradable, such as
poly(lactic-co-glycolic)acid. These materials can be made into
micro or nanospheres, loaded with drug and further coated or
derivatized to provide superior sustained release performance.
Vehicles suitable for periocular or intraocular injection include,
for example, suspensions of therapeutic agent in injection grade
water, liposomes and vehicles suitable for lipophilic substances.
Other vehicles for periocular or intraocular injection are well
known in the art.
[3381] In a preferred aspect, the composition is formulated in
accordance with routine procedures as a pharmaceutical composition
adapted for intravenous administration to human beings. Typically,
compositions for intravenous administration are solutions in
sterile isotonic aqueous buffer. Where necessary, the composition
can also include a solubilizing agent and a local anesthetic such
as lidocaine to ease pain at the site of the injection. Generally,
the ingredients are supplied either separately or mixed together in
unit dosage form, for example, as a dry lyophilized powder or water
free concentrate in a hermetically sealed container such as an
ampoule or sachette indicating the quantity of active agent. Where
the composition is to be administered by infusion, it can be
dispensed with an infusion bottle containing sterile pharmaceutical
grade water or saline. Where the composition is administered by
injection, an ampoule of sterile water for injection or saline can
be provided so that the ingredients can be mixed prior to
administration.
[3382] When administration is by injection, the active compound can
be formulated in aqueous solutions, specifically in physiologically
compatible buffers such as Hanks solution, Ringer's solution, or
physiological saline buffer. The solution can contain formulatory
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active compound can be in powder form for
constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use. In another aspect, the pharmaceutical
composition does not comprise an adjuvant or any other substance
added to enhance the immune response stimulated by the peptide. In
another aspect, the pharmaceutical composition comprises a
substance that inhibits an immune response to the peptide. Methods
of formulation are known in the art, for example, as disclosed in
Remington's Pharmaceutical Sciences, latest edition, Mack
Publishing Co., Easton P.
[3383] In addition to the formulations described previously, the
agents can also be formulated as a depot preparation. Such long
acting formulations can be administered by implantation or
transcutaneous delivery (for example subcutaneously or
intramuscularly), intramuscular injection or use of a transdermal
patch. Thus, for example, the agents can be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[3384] In another aspect, pharmaceutical compositions comprising
one or more agents of the present invention exert local and
regional effects when administered topically or injected at or near
particular sites of infection. Direct topical application, e.g., of
a viscous liquid, solution, suspension, dimethylsulfoxide
(DMSO)-based solutions, liposomal formulations, gel, jelly, cream,
lotion, ointment, suppository, foam, or aerosol spray, can be used
for local administration, to produce for example local and/or
regional effects. Pharmaceutically appropriate vehicles for such
formulation include, for example, lower aliphatic alcohols,
polyglycols (e.g., glycerol or polyethylene glycol), esters of
fatty acids, oils, fats, silicones, and the like. Such preparations
can also include preservatives (e.g., p-hydroxybenzoic acid esters)
and/or antioxidants (e.g., ascorbic acid and tocopherol). See also
Dermatological Formulations: Percutaneous absorption, Barry (Ed.),
Marcel Dekker Incl, 1983. In another aspect, local/topical
formulations comprising a fatty acid synthesis pathway inhibitor
e.g., an inhibitor of FASN gene expression or FASN protein
activity, are used to treat epidermal or mucosal viral
infections.
[3385] Pharmaceutical compositions of the present invention can
contain a cosmetically or dermatologically acceptable carrier. Such
carriers are compatible with skin, nails, mucous membranes, tissues
and/or hair, and can include any conventionally used cosmetic or
dermatological carrier meeting these requirements. Such carriers
can be readily selected by one of ordinary skill in the art. In
formulating skin ointments, an agent or combination of agents of
the instant invention can be formulated in an oleaginous
hydrocarbon base, an anhydrous absorption base, a water-in-oil
absorption base, an oil-in-water water-removable base and/or a
water-soluble base. Examples of such carriers and excipients
include, but are not limited to, humectants (e.g., urea), glycols
(e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids
(e.g., oleic acid), surfactants (e.g., isopropyl myristate and
sodium lauryl sulfate), pyrrolidones, glycerol monolaurate,
sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes,
alkanols, water, calcium carbonate, calcium phosphate, various
sugars, starches, cellulose derivatives, gelatin, and polymers such
as polyethylene glycols.
[3386] Ointments and creams can, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions can be formulated with an aqueous or
oily base and will in general also containing one or more
emulsifying agents, stabilizing agents, dispersing agents,
suspending agents, thickening agents, or coloring agents. The
construction and use of transdermal patches for the delivery of
pharmaceutical agents is well known in the art. See, e.g., U.S.
Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be
constructed for continuous, pulsatile, or on demand delivery of
pharmaceutical agents.
[3387] Lubricants which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, calcium stearate, magnesium stearate, mineral oil,
light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures
thereof. Additional lubricants include, for example, a syloid
silica gel, a coagulated aerosol of synthetic silica, or mixtures
thereof. A lubricant can optionally be added, in an amount of less
than about 1 weight percent of the pharmaceutical composition.
[3388] The compositions according to the present invention can be
in any form suitable for topical application, including aqueous,
aqueous-alcoholic or oily solutions, lotion or serum dispersions,
aqueous, anhydrous or oily gels, emulsions obtained by dispersion
of a fatty phase in an aqueous phase (O/W or oil in water) or,
conversely, (W/O or water in oil), microemulsions or alternatively
microcapsules, microparticles or lipid vesicle dispersions of ionic
and/or nonionic type. These compositions can be prepared according
to conventional methods. Other than the agents of the invention,
the amounts of the various constituents of the compositions
according to the invention are those conventionally used in the
art. These compositions in particular constitute protection,
treatment or care creams, milks, lotions, gels or foams for the
face, for the hands, for the body and/or for the mucous membranes,
or for cleansing the skin. The compositions can also consist of
solid preparations constituting soaps or cleansing bars.
[3389] Compositions of the present invention can also contain
adjuvants common to the cosmetic and dermatological fields, such as
hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic
active agents, preserving agents, antioxidants, solvents,
fragrances, fillers, sunscreens, odor-absorbers and dyestuffs. The
amounts of these various adjuvants are those conventionally used in
the fields considered and, for example, are from about 0.01% to
about 20% of the total weight of the composition. Depending on
their nature, these adjuvants can be introduced into the fatty
phase, into the aqueous phase and/or into the lipid vesicles.
[3390] In another aspect, ocular viral infections can be
effectively treated with ophthalmic solutions, suspensions,
ointments or inserts comprising an agent or combination of agents
of the present invention. Eye drops can be prepared by dissolving
the active ingredient in a sterile aqueous solution such as
physiological saline, buffering solution, etc., or by combining
powder compositions to be dissolved before use. Other vehicles can
be chosen, as is known in the art, including but not limited to:
balance salt solution, saline solution, water soluble polyethers
such as polyethylene glycol, polyvinyls, such as polyvinyl alcohol
and povidone, cellulose derivatives such as methylcellulose and
hydroxypropyl methylcellulose, petroleum derivatives such as
mineral oil and white petrolatum, animal fats such as lanolin,
polymers of acrylic acid such as carboxypolymethylene gel,
vegetable fats such as peanut oil and polysaccharides such as
dextrans, and glycosaminoglycans such as sodium hyaluronate. If
desired, additives ordinarily used in the eye drops can be added.
Such additives include isotonizing agents (e.g., sodium chloride,
etc.), buffer agent (e.g., boric acid, sodium monohydrogen
phosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g.,
benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.),
thickeners (e.g., saccharide such as lactose, mannitol, maltose,
etc.; e.g., hyaluronic acid or its salt such as sodium hyaluronate,
potassium hyaluronate, etc.; e.g., mucopolysaccharide such as
chondroitin sulfate, etc.; e.g., sodium polyacrylate, carboxyvinyl
polymer, crosslinked polyacrylate, polyvinyl alcohol, polyvinyl
pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,
hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl
cellulose or other agents known to those skilled in the art).
[3391] The solubility of the components of the present compositions
can be enhanced by a surfactant or other appropriate co-solvent in
the composition. Such cosolvents include polysorbate 20, 60, and
80, Pluronic F68, F-84 and P-103, cyclodextrin, or other agents
known to those skilled in the art. Such co-solvents can be employed
at a level of from about 0.01% to 2% by weight.
[3392] The compositions of the invention can be packaged in
multidose form. Preservatives can be preferred to prevent microbial
contamination during use. Suitable preservatives include:
benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben,
propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid,
Onamer M, or other agents known to those skilled in the art. In the
prior art ophthalmic products, such preservatives can be employed
at a level of from 0.004% to 0.02%. In the compositions of the
present application the preservative, preferably benzalkonium
chloride, can be employed at a level of from 0.001% to less than
0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% by
weight. It has been found that a concentration of benzalkonium
chloride of 0.005% can be sufficient to preserve the compositions
of the present invention from microbial attack.
[3393] In another aspect, viral infections of the ear can be
effectively treated with otic solutions, suspensions, ointments or
inserts comprising an agent or combination of agents of the present
invention.
[3394] In another aspect, the agents of the present invention are
delivered in soluble rather than suspension form, which allows for
more rapid and quantitative absorption to the sites of action. In
general, formulations such as jellies, creams, lotions,
suppositories and ointments can provide an area with more extended
exposure to the agents of the present invention, while formulations
in solution, e.g., sprays, provide more immediate, short-term
exposure.
[3395] In another aspect relating to topical/local application, the
pharmaceutical compositions can include one or more penetration
enhancers. For example, the formulations can comprise suitable
solid or gel phase carriers or excipients that increase penetration
or help delivery of agents or combinations of agents of the
invention across a permeability barrier, e.g., the skin. Many of
these penetration-enhancing compounds are known in the art of
topical formulation, and include, e.g., water, alcohols (e.g.,
terpenes like methanol, ethanol, 2-propanol), sulfoxides (e.g.,
dimethyl sulfoxide, decylmethyl sulfoxide, tetradecylmethyl
sulfoxide), pyrrolidones (e.g., 2-pyrrolidone,
N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone),
laurocapram, acetone, dimethylacetamide, dimethylformamide,
tetrahydrofurfuryl alcohol, L-.alpha.-amino acids, anionic,
cationic, amphoteric or nonionic surfactants (e.g., isopropyl
myristate and sodium lauryl sulfate), fatty acids, fatty alcohols
(e.g., oleic acid), amines, amides, clofibric acid amides,
hexamethylene lauramide, proteolytic enzymes, .alpha.-bisabolol,
d-limonene, urea and N,N-diethyl-m-toluamide, and the like.
Additional examples include humectants (e.g., urea), glycols (e.g.,
propylene glycol and polyethylene glycol), glycerol monolaurate,
alkanes, alkanols, ORGELASE, calcium carbonate, calcium phosphate,
various sugars, starches, cellulose derivatives, gelatin, and/or
other polymers. In another aspect, the pharmaceutical compositions
will include one or more such penetration enhancers.
[3396] In another aspect, the pharmaceutical compositions for
local/topical application can include one or more antimicrobial
preservatives such as quaternary ammonium compounds, organic
mercurials, p-hydroxy benzoates, aromatic alcohols, chlorobutanol,
and the like.
[3397] Gastrointestinal viral infections can be effectively treated
with orally- or rectally delivered solutions, suspensions,
ointments, enemas and/or suppositories comprising an agent or
combination of agents of the present invention.
[3398] Respiratory viral infections can be effectively treated with
aerosol solutions, suspensions or dry powders comprising an agent
or combination of agents of the present invention. Administration
by inhalation is particularly useful in treating viral infections
of the lung, such as an HRV infection. The aerosol can be
administered through the respiratory system or nasal passages. For
example, one skilled in the art will recognize that a composition
of the present invention can be suspended or dissolved in an
appropriate carrier, e.g., a pharmaceutically acceptable
propellant, and administered directly into the lungs using a nasal
spray or inhalant. For example, an aerosol formulation comprising a
fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN
gene expression or FASN protein activity, can be dissolved,
suspended or emulsified in a propellant or a mixture of solvent and
propellant, e.g., for administration as a nasal spray or inhalant.
Aerosol formulations can contain any acceptable propellant under
pressure, such as a cosmetically or dermatologically or
pharmaceutically acceptable propellant, as conventionally used in
the art.
[3399] An aerosol formulation for nasal administration is generally
an aqueous solution designed to be administered to the nasal
passages in drops or sprays. Nasal solutions can be similar to
nasal secretions in that they are generally isotonic and slightly
buffered to maintain a pH of about 5.5 to about 6.5, although pH
values outside of this range can additionally be used.
Antimicrobial agents or preservatives can also be included in the
formulation.
[3400] An aerosol formulation for inhalations and inhalants can be
designed so that the agent or combination of agents of the present
invention is carried into the respiratory tree of the subject when
administered by the nasal or oral respiratory route. Inhalation
solutions can be administered, for example, by a nebulizer.
Inhalations or insufflations, comprising finely powdered or liquid
drugs, can be delivered to the respiratory system as a
pharmaceutical aerosol of a solution or suspension of the agent or
combination of agents in a propellant, e.g., to aid in
disbursement. Propellants can be liquefied gases, including
halocarbons, for example, fluorocarbons such as fluorinated
chlorinated hydrocarbons, hydrochlorofluorocarbons, and
hydrochlorocarbons, as well as hydrocarbons and hydrocarbon
ethers.
[3401] Halocarbon propellants useful in the present invention
include fluorocarbon propellants in which all hydrogens are
replaced with fluorine, chlorofluorocarbon propellants in which all
hydrogens are replaced with chlorine and at least one fluorine,
hydrogen-containing fluorocarbon propellants, and
hydrogen-containing chlorofluorocarbon propellants. Halocarbon
propellants are described in Johnson, U.S. Pat. No. 5,376,359,
issued Dec. 27, 1994; Byron et al., U.S. Pat. No. 5,190,029, issued
Mar. 2, 1993; and Purewal et al., U.S. Pat. No. 5,776,434, issued
Jul. 7, 1998. Hydrocarbon propellants useful in the invention
include, for example, propane, isobutane, n-butane, pentane,
isopentane and neopentane. A blend of hydrocarbons can also be used
as a propellant. Ether propellants include, for example, dimethyl
ether as well as the ethers. An aerosol formulation of the
invention can also comprise more than one propellant. For example,
the aerosol formulation can comprise more than one propellant from
the same class, such as two or more fluorocarbons; or more than
one, more than two, more than three propellants from different
classes, such as a fluorohydrocarbon and a hydrocarbon.
Pharmaceutical compositions of the present invention can also be
dispensed with a compressed gas, e.g., an inert gas such as carbon
dioxide, nitrous oxide or nitrogen.
[3402] Aerosol formulations can also include other components, for
example, ethanol, isopropanol, propylene glycol, as well as
surfactants or other components such as oils and detergents. These
components can serve to stabilize the formulation and/or lubricate
valve components.
[3403] The aerosol formulation can be packaged under pressure and
can be formulated as an aerosol using solutions, suspensions,
emulsions, powders and semisolid preparations. For example, a
solution aerosol formulation can comprise a solution of an agent of
the invention such as a fatty acid synthesis pathway inhibitor
e.g., an inhibitor of FASN gene expression or FASN protein
activity, in (substantially) pure propellant or as a mixture of
propellant and solvent. The solvent can be used to dissolve the
agent and/or retard the evaporation of the propellant. Solvents
useful in the invention include, for example, water, ethanol and
glycols. Any combination of suitable solvents can be use,
optionally combined with preservatives, antioxidants, and/or other
aerosol components.
[3404] An aerosol formulation can also be a dispersion or
suspension. A suspension aerosol formulation can comprise a
suspension of an agent or combination of agents of the instant
invention, e.g., a fatty acid synthesis pathway inhibitor, e.g., an
inhibitor of FASN gene expression or FASN protein activity, and a
dispersing agent. Dispersing agents useful in the invention
include, for example, sorbitan trioleate, oleyl alcohol, oleic
acid, lecithin and corn oil. A suspension aerosol formulation can
also include lubricants, preservatives, antioxidant, and/or other
aerosol components.
[3405] An aerosol formulation can similarly be formulated as an
emulsion. An emulsion aerosol formulation can include, for example,
an alcohol such as ethanol, a surfactant, water and a propellant,
as well as an agent or combination of agents of the invention,
e.g., a fatty acid synthesis pathway, e.g., an inhibitor of FASN
gene expression or FASN protein activity. The surfactant used can
be nonionic, anionic or cationic. One example of an emulsion
aerosol formulation comprises, for example, ethanol, surfactant,
water and propellant. Another example of an emulsion aerosol
formulation comprises, for example, vegetable oil, glyceryl
monostearate and propane.
[3406] The compounds of the invention can be formulated for
administration as suppositories. A low melting wax, such as a
mixture of triglycerides, fatty acid glycerides, Witepsol S55
(trademark of Dynamite Nobel Chemical, Germany), or cocoa butter is
first melted and the active component is dispersed homogeneously,
for example, by stirring. The molten homogeneous mixture is then
poured into convenient sized molds, allowed to cool, and to
solidify.
[3407] The compounds of the invention can be formulated for vaginal
administration. Pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[3408] It is envisioned additionally, that the compounds of the
invention can be attached releasably to biocompatible polymers for
use in sustained release formulations on, in or attached to inserts
for topical, intraocular, periocular, or systemic administration.
The controlled release from a biocompatible polymer can be utilized
with a water soluble polymer to form a instillable formulation, as
well. The controlled release from a biocompatible polymer, such as
for example, PLGA microspheres or nanospheres, can be utilized in a
formulation suitable for intra ocular implantation or injection for
sustained release administration, as well. Any suitable
biodegradable and biocompatible polymer can be used.
[3409] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredients are
present in an effective amount, i.e., in an amount effective to
achieve therapeutic and/or prophylactic benefit in a host with at
least one viral infection or in a subject having cancer. The actual
amount effective for a particular application will depend on the
condition or conditions being treated, the condition of the
subject, the formulation, and the route of administration, as well
as other factors known to those of skill in the art. Determination
of an effective amount of a fatty acid synthesis pathway inhibitor
e.g., an inhibitor of FASN gene expression or FASN protein
activity, is well within the capabilities of those skilled in the
art, in light of the disclosure herein, and will be determined
using routine optimization techniques.
[3410] The effective amount for use in humans can be determined
from animal models. For example, a dose for humans can be
formulated to achieve circulating, liver, topical and/or
gastrointestinal concentrations that have been found to be
effective in animals. One skilled in the art can determine the
effective amount for human use, especially in light of the animal
model experimental data described herein. Based on animal data, and
other types of similar data, those skilled in the art can determine
the effective amounts of compositions of the present invention
appropriate for humans.
[3411] The effective amount when referring to an agent or
combination of agents of the invention will generally mean the dose
ranges, modes of administration, formulations, etc., that have been
recommended or approved by any of the various regulatory or
advisory organizations in the medical or pharmaceutical arts (e.g.,
FDA, AMA) or by the manufacturer or supplier.
[3412] Further, appropriate doses for a fatty acid synthesis
pathway inhibitor e.g., an inhibitor of FASN gene expression or
FASN protein activity, can be determined based on in vitro
experimental results. For example, the in vitro potency of an agent
in inhibiting a fatty acid synthesis pathway component, e.g., FASN
gene expression or FASN protein activity, provides information
useful in the development of effective in vivo dosages to achieve
similar biological effects.
[3413] In another aspect, administration of agents of the present
invention can be intermittent, for example administration once
every two days, every three days, every five days, once a week,
once or twice a month, and the like. In another aspect, the amount,
forms, and/or amounts of the different forms can be varied at
different times of administration.
[3414] A person of skill in the art would be able to monitor in a
patient the effect of administration of a particular agent. For
example, HIV viral load levels can be determined by techniques
standard in the art, such as measuring CD4 cell counts, and/or
viral levels as detected by PCR. Other techniques would be apparent
to one of skill in the art.
[3415] Having now generally described various aspects and aspects
of the invention, the same will be more readily understood through
reference to the following examples which are provided by way of
illustration, and are not intended to be limiting, unless
specified.
EXAMPLES
Example--Synthesis of Compounds of the Present Disclosure
[3416] General: All reactions and manipulations described were
carried out in well ventilated fume-hoods. Operations and reactions
carried out at elevated or reduced pressure were carried out behind
blast shields. Abbreviations: ACN, acetonitrile; AcOH, acetic acid;
AIBN, azobisisobutyronitrile; BuLi, butyl lithium; CDI,
1,1'-Carbonyldiimidazole; DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene;
DCE, 1,2-dichloroethane; DCM, dichloromethane or methylene
chloride; DIEA, N,N-Diisopropylethylamine; DMAP,
4-dimethylaminopyridine; DMF, N,N-dimethylformamide; DMSO,
dimethylsulfoxide; EDC,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EtOAc,
ethyl acetate; EtOH, Ethanol; HATU,
2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate; HBTU,
O-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate
or 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium
hexafluorophosphate; HMPA, hexamethylphosphoramide; HOAc, acetic
acid; HOBT, 1-Hydroxybenzotriazole; LDA, lithium diisopropylamine;
MeOH, methanol; MsCl, methanesulfonyl chloride; MsOH,
methanesulfonic acid; NBS, N-bromosuccinimide; NIS,
N-iodosuccinimide; PE, petroleum ether; PTAT,
phenyltrimethylammonium tribromide; PTSA, p-toluenesulfonic acid;
Py, pyridine; Pyr, pyridine; TEA, triethylamine; TFA,
trifluoroacetic acid; THF, tetrahydrofuran; TMSC1,
chlorotrimethylsilane; TsOH, p-toluenesulfonic acid.
##STR00518##
Compound 1.1. tert-Butyl
4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate
[3417] To a stirred solution of 1-bromo-4-iodobenzene (93.7 g,
331.21 mmol, 1.10 equiv) in tetrahydrofuran (800 mL) under nitrogen
at -78.degree. C. was added dropwise of a solution of butyllithium
(150 mL, 2.43 M in THF, 1.05 equiv) during 30 min. The resulting
solution was stirred for 2 h at -78.degree. C. To this was then
added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (60 g,
301.13 mmol, 1.00 equiv) in tetrahydrofuran (800 mL) dropwise with
stirring at -78.degree. C. during 30 min. After stirring for 1 h at
-78.degree. C., reaction was carefully quenched with 350 mL of
H.sub.2O. The resulting mixture was extracted with 2.times.400 mL
of ethyl acetate and the combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
residue was purified using silica gel column chromatography with
ethyl acetate/petroleum ether (1:200-1:10) as eluent to yield 91 g
(85%) of the title compound as a yellow oil.
##STR00519##
Compound 1.2. tert-Butyl
4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate
[3418] A solution of tert-butyl
4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 1.1,
36 g, 101.05 mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (11.7 g, 10.12
mmol, 0.05 equiv), and Zn(CN).sub.2 (17.9 g, 152.44 mmol, 1.51
equiv) in DMF (400 mL) under nitrogen was stirred overnight at
80.degree. C. After reaching ambient temperature, the reaction was
then quenched by the addition of 600 mL of FeSO.sub.4 (aq., sat.)
and diluted with ethyl acetate. The resulting mixture was stirred
vigorously then filtered through celite and washed with 1 M
FeSO.sub.4, water, and ethyl acetate. The layers were separated and
the aqueous phase was extracted with 2.times.300 mL of ethyl
acetate. The combined organic layers were washed with 1.times.200
mL of potassium carbonate (aq., sat.) followed by 1.times.200 mL of
brine, dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:200-1:5) as
eluent to yield 23 g (75%) of the title compound as a white
solid.
##STR00520##
Compound 1.3. tert-Butyl
4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate
[3419] Into a round-bottom flask, was placed a solution of
tert-butyl 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate
(compound 1.2, 2 g, 6.61 mmol, 1.00 equiv) in pyridine (40 mL).
POCl.sub.3 (10.16 g, 66.26 mmol, 10.02 equiv) was carefully added.
The resulting mixture was stirred under nitrogen overnight at room
temperature and then concentrated under vacuum. The residue was
taken up in 20 mL of DCM, washed with 2.times.20 mL of sodium
bicarbonate (aq), dried (Na.sub.2SO.sub.4), and concentrated under
reduced pressure. The residue was purified using silica gel column
chromatography with PE/EtOAc (100:1-30:1) as eluent to yield 1.4 g
(74%) of the title compound as a white solid.
##STR00521##
Compound 1.4. tert-Butyl
4-(4-cyanophenyl)piperidine-1-carboxylate
[3420] Around-bottom flask, containing a solution of tert-butyl
4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (compound
1.3, 500 mg, 1.76 mmol, 1.00 equiv) in ethyl acetate (20 mL) was
purged with nitrogen gas. To the solution was then added palladium
on carbon (0.1 g, 10%, 60% water) and the flask was then further
purged with nitrogen. The atmosphere was then changed to hydrogen
and the mixture was stirred overnight at room temperature. After
purging the system with nitrogen, the solids were removed by
filtration and the filtrate was concentrated under reduced pressure
to yield 0.2 g (40%) of the title compound as a yellow oil.
##STR00522##
Compound 1.5. 4-(Piperidin-4-yl)benzonitrile hydrochloride
[3421] Into a 100-mL 3-necked round-bottom flask, was placed a
solution of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate
(compound 1.4, 4 g, 13.99 mmol, 1.00 equiv) in ethyl acetate (60
mL). Hydrogen chloride (gas) was bubbled through the solution and
the resulting mixture was stirred for 1 h at room temperature. The
formed precipitate was collected by filtration and dried to yield
2.2 g (71%) of the title compound as a white solid. m/z (ES+) 187
(M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.72 (d,
J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 3.54 (d with fine structure,
J=12.6 Hz, 2H), 3.18 (t with fine structure, J=12.2 Hz, 2H),
3.12-1.97 (m, 1H), 2.11 (d with fine structure, J=14.1 Hz, 2H),
2.04-1.84 (m, 2H).
##STR00523##
Compound 1.6. Methyl 3-bromo-4-methylbenzoate
[3422] A solution of 3-bromo-4-methylbenzoic acid (20 g, 93.00
mmol, 1.00 equiv) and sulfuric acid (20 mL) in methanol (100 mL)
was stirred overnight at 80.degree. C. The mixture was then
concentrated under reduced pressure and the residue was diluted
with 500 mL of ethyl acetate. The resulting mixture was washed with
3.times.200 mL of water, 1.times.200 mL of sodium bicarbonate (aq),
followed by 1.times.200 mL of brine. The organic phase was dried
over anhydrous sodium sulfate, concentrated under reduced pressure,
and dried to yield 20 g (94%) of the title compound as a dark red
oil.
##STR00524##
Compound 1.7. Methyl 3-cyano-4-methylbenzoate
[3423] A mixture of methyl 3-bromo-4-methylbenzoate (compound 1.6,
18 g, 78.58 mmol, 1.00 equiv), Zn(CN).sub.2 (11.1 g, 94.87 mmol,
1.20 equiv), and Pd(PPh.sub.3).sub.4 (7.3 g, 6.32 mmol, 0.08 equiv)
in N,N-dimethylformamide (250 mL) was stirred under a nitrogen
atmosphere at 100.degree. C. overnight. After cooling to room
temperature, the reaction was then quenched by careful addition of
200 mL of FeSO.sub.4 (aq., sat.) and diluted with ethyl acetate.
The resulting mixture was stirred vigorously then filtered through
celite and washed with 1 M FeSO.sub.4, water, and ethyl acetate.
The layers were separated and the aqueous phase was extracted with
2.times.500 mL of ethyl acetate. The combined organic layers were
washed with 3.times.200 mL of brine, dried over (Na.sub.2SO.sub.4),
and concentrated under reduced pressure. The residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:50) as eluent to yield 11 g (76%) of the title compound as
an off-white solid.
##STR00525##
Compound 1.8. Methyl
3-(N'-hydroxycarbamimidoyl)-4-methylbenzoate
[3424] A mixture of methyl 3-cyano-4-methylbenzoate (compound 1.7,
8 g, 43.38 mmol, 1.00 equiv, 95%), NH.sub.2OH.HCl (3.785 g, 54.86
mmol, 1.20 equiv), and N,N-Diisopropylethylamine (DIEA, 17.7 g,
136.95 mmol, 3.00 equiv) in tetrahydrofuran (100 mL) was stirred
overnight at 70.degree. C. After cooling to room temperature, the
mixture was concentrated under reduced pressure. The residue was
taken up in water and the pH was adjusted to 2-3 with hydrogen
chloride (aqueous, 1 M). After washing the mixture with 3.times.40
mL of ethyl acetate, the pH of the aqueous layer was adjusted to
8-9 with NaOH (aqueous, 2 M) followed by extraction with 3.times.30
mL of ethyl acetate. The combined organic layers were dried over
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to yield
2.76 g (29%) of the title compound as a white solid.
##STR00526##
Compound 1.9. Methyl 3-carbamimidoyl-4-methylbenzoate
[3425] A round-bottom flask, containing a solution of methyl
3-(N'-hydroxycarbamimidoyl)-4-methylbenzoate (compound 1.8, 8 g,
36.50 mmol, 1.00 equiv, 95%) in methanol (150 mL) was purged with
nitrogen gas. To the solution was added palladium on carbon (9 g,
10%, 60% water) and the flask was then further purged with nitrogen
gas. The atmosphere was then changed to hydrogen and the mixture
was stirred overnight at 25.degree. C. under a balloon. After
purging the system with nitrogen, the solids were removed by
filtration and the filtrate was concentrated under reduced pressure
to yield 4 g (54%) of the title compound as a brown solid.
##STR00527##
Compound 1.10.1 3-Bromodihydro-2H-pyran-4(3H)-one
[3426] To a mixture of dihydro-2H-pyran-4(3H)-one (10 g, 99.88
mmol, 1.00 equiv) and NH.sub.4OAc (3.56 g, 46.23 mmol) in
tetrahydrofuran (100 mL) at 0.degree. C. under nitrogen was added
in several batches N-bromosuccinimide (17.8 g, 100.00 mmol, 1.00
equiv). The resulting mixture was stirred overnight at 30.degree.
C. under nitrogen. The reaction mixture was then filtered and the
filtrate was concentrated. The residue was purified using silica
gel column chromatography with ethyl acetate/petroleum ether
(1/10-1/5) as eluent to yield 15 g (50%) of the title compound as a
brown oil.
##STR00528##
Compound 1.10. Methyl
4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate
[3427] A mixture of methyl 3-carbamimidoyl-4-methylbenzoate
(compound 1.9, 400 mg, 1.98 mmol, 1.00 equiv, 95%),
3-bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 750 mg, 2.09
mmol, 1.00 equiv), and potassium carbonate (580 mg, 4.20 mmol, 2.00
equiv) in CH.sub.3CN (15 mL) was stirred overnight at 80.degree. C.
under nitrogen. After cooling to ambient temperature, the reaction
mixture was concentrated under reduced pressure. The residue was
dissolved in 50 mL of ethyl acetate and washed with 2.times.10 mL
of H.sub.2O. The organic phase was dried over (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. The residue was purified
using silica gel column chromatography and purified using ethyl
acetate/petroleum ether (1/3) to yield 0.21 g (37%) of the title
compound as a white solid.
##STR00529##
Compound 1.11.
4-Methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic
Acid
[3428] A mixture of methyl
4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate
(compound 1.10, 210 mg, 0.73 mmol, 1.00 equiv, 95%) and sodium
hydroxide (92.65 mg, 2.32 mmol, 3.00 equiv) in 12 mL
methanol/H.sub.2O (2:1) was stirred for at 60.degree. C. in an oil
bath. After 2 h, the reaction mixture was concentrated under
reduced pressure and the residue was taken up in 5 mL of H.sub.2O.
The resulting mixture was washed with 3.times.10 mL of ethyl
acetate and the pH of the aqueous layer was then adjusted to 2-3
using hydrogen chloride (aq., 2 M). The resulting mixture was
extracted with 3.times.30 mL of ethyl acetate. The combined organic
layers were dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to yield 0.21 g (89%) of the title compound as a white
solid.
##STR00530##
Compound 1. Methyl
4-(1-(4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)pi-
peridin-4-yl)benzonitrile
[3429] A mixture of
4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic
acid (compound 1.11, 60 mg, 0.22 mmol, 1.00 equiv, 95%), EDCI (88.4
mg, 0.46 mmol, 2.00 equiv), DMAP (85.12 mg, 0.70 mmol, 3.00 equiv),
and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 52
mg, 0.23 mmol, 1.00 equiv) in DMF was stirred at room temperature.
After 3 h, the reaction mixture was diluted with 40 mL of DCM and
washed with 2.times.10 mL of NH.sub.4Cl (aq.sat.) followed by
2.times.10 mL of brine. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
crude product (.about.100 mg) was purified by Prep-HPLC with the
following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire
Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and
CH.sub.3CN (15.0% CH.sub.3CN up to 42.0% in 12 min, up to 100.0% in
1 min); Detector, uv 254/220 nm. The fractions containing pure
compound were combined and lyophilized to yield 32.9 mg (34%) of
the title compound as a white solid. m/z (ES+) 427 (M+H).sup.+.
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.73-7.65 (m, 4H), 7.61
(d, J=5.7 Hz, 1H), 7.50 (d, J=6.0 Hz, 2H), 4.89-4.78 (1H partially
obscured by water peak), 4.81 (s, 2H), 4.10 (t, J=4.1 Hz, 2H),
3.94-3.81 (m, 1H), .about.3.35 (1H partially obscured by methanol
solvent peak), 3.08-1.95 (m, 2H), 2.92 (t, J=4.1 Hz, 2H), 2.52 (s,
3H), 2.08-1.92 (m, 1H), 1.92-1.65 (m, 3H). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.63 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz,
2H), 7.30 (s, 1H) 7.50 (m, 2H), 4.89 (d, J=13.0 Hz, 1H), 4.81 (s,
2H), 4.05 (t, J=5.2 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 3.30 (t,
J=13.0 Hz, 1H), 3.01-2.84 (m, 4H), 2.34 (s, 3H), 2.06 (d, J=13.7
Hz, 1H), 1.86 (d, J=12.9 Hz, 1H), 1.76 (q, J=12.8 Hz, 1H), 1.57 (q,
J=11.7 Hz, 1H).
##STR00531##
Compound 2.1. 5-Iodo-2,4-dimethylbenzoic Acid
[3430] A solution of 2,4-dimethylbenzoic acid (20 g, 133.18 mmol,
1.00 equiv), sodium periodate (14.27 g, 66.72 mmol, 0.50 equiv),
iodine (37.25 g, 146.76 mmol, 1.10 equiv), and sulfuric acid (1.96
g, 19.98 mmol, 0.15 equiv) in acetic acid (150 mL) was stirred at
110.degree. C. in an oil bath. After 6 h, the reaction mixture was
allowed to reach ambient temperature and was then diluted with 1.2
L of water. To this was carefully added 800 mL of aq
Na.sub.2S.sub.2O.sub.3 (aq., sat.). The resulting solids were
collected by filtration, dissolved in 1.2 L of ethyl acetate, and
washed with 1.times.300 mL of Na.sub.2S.sub.2O.sub.3 (aq., sat.)
followed by 1.times.400 mL of brine. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
crude residue was re-crystallized from ethanol:H.sub.2O (2:1) to
yield 30 g (82%) of the title compound as a white solid.
##STR00532##
Compound 2.2. Methyl 5-iodo-2,4-dimethylbenzoate
[3431] A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1,
10 g, 32.60 mmol, 1.00 equiv, 90%) and sulfuric acid (10 mL) in
methanol (100 mL) was stirred overnight at 80.degree. C. After
cooling to room temperature, the mixture was concentrated under
reduced pressure and the residue was diluted with 200 mL of ethyl
acetate. The resulting mixture was washed with 3.times.50 mL of
water, 2.times.50 mL of sodium bicarbonate (aq. sat.), followed by
2.times.50 mL of brine. The organic phase was dried over anhydrous
sodium sulfate and concentrated under reduced pressure to yield 9.2
g (88%) of the title compound as a yellow oil.
##STR00533##
Compound 2.3. Methyl 5-cyano-2,4-dimethylbenzoate
[3432] A solution of methyl 5-iodo-2,4-dimethylbenzoate (compound
2.2, 9.2 g, 31.71 mmol, 1.00 equiv), Zn(CN).sub.2 (4.46 g, 38.12
mmol, 1.20 equiv), and Pd(PPh.sub.3).sub.4 (2.93 g, 2.54 mmol, 0.08
equiv) in N,N-dimethylformamide (120 mL) was stirred under a
nitrogen atmosphere at 100.degree. C. overnight. After cooling to
room temperature, the reaction was then quenched by careful
addition of 100 mL of FeSO.sub.4 (aq., sat.) and diluted with ethyl
acetate. The resulting mixture was stirred vigorously then filtered
through celite and washed with 1 M FeSO.sub.4, water, and ethyl
acetate. The layers were separated and the aqueous phase was
extracted with 2.times.100 mL of ethyl acetate. The combined
organic layers were washed with 2.times.20 mL of brine, dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure. The
residue was purified using silica gel column chromatography with
ethyl acetate/petroleum ether (1:5) as eluent to yield 6.2 g (93%)
of the title compound as a white solid.
##STR00534##
Compound 2.4. Methyl
5-(N'-hydroxycarbamimidoyl)-2,4-dimethylbenzoate
[3433] A solution of methyl 5-cyano-2,4-dimethylbenzoate (compound
2.3, 6 g, 28.54 mmol, 1.00 equiv, 90%) and NH.sub.2OH (10 mL, 5.00
equiv, 50% in water) in EtOH (20 mL) was stirred at 100.degree. C.
in an oil bath. After 2 h, the mixture was cooled to room
temperature and concentrated under reduced pressure. The residue
was diluted with 100 mL of ethyl acetate, washed with 2.times.20 mL
of brine, dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure to yield 4.66 g (66%) of the title compound as a white
solid.
##STR00535##
Compound 2.5. Methyl 5-carbamimidoyl-2,4-dimethylbenzoate
hydrochloride
[3434] A solution of methyl
5-(N'-hydroxycarbamimidoyl)-2,4-dimethylbenzoate (compound 2.4,
4.66 g, 18.87 mmol, 1.00 equiv, 90%) and Ac.sub.2O (2.36 g, 23.09
mmol, 1.10 equiv) in AcOH (21 mL) was stirred at room temperature.
After 5 minutes, the flask was purged with nitrogen and HCOOK (8.8
g, 104.76 mmol, 5.00 equiv) and palladium on carbon (10%, 2.33 g)
were added. The flask was purged with nitrogen followed by
hydrogen. The mixture was stirred under a hydrogen atmosphere
(balloon) at room temperature for 4 h. After purging the system
with nitrogen, the solids were removed by filtration, and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in 50 mL of ethanol and the pH was adjusted to 5-6 with
hydrogen chloride (aq., 5 M). The resulting solids were removed by
filtration and the filtrate was concentrated under reduced pressure
to yield 4 g of the title compound as a white solid.
##STR00536##
Compound 2.6. tert-Butyl
2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]p-
yridine-5(4H)-carboxylate
[3435] A mixture of methyl methyl
5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5,
500 mg, 90%), tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (860
mg, 2.78 mmol), and potassium carbonate (570 mg, 4.12 mmol) in
CH.sub.3CN (15 mL) was stirred overnight under nitrogen at
80.degree. C. After cooling to ambient temperature, the reaction
mixture was concentrated under reduced pressure. The residue was
dissolved in 25 mL of ethyl acetate and washed with 2.times.10 mL
of H.sub.2O. The organic phase was dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. The crude product thus
obtained was purified using silica gel column chromatography with
ethyl acetate/petroleum ether (1:3) as eluent to yield 0.3 g of the
title compound as a white solid.
##STR00537##
Compound 2.7.
5-(5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2--
yl)-2,4-dimethylbenzoic Acid
[3436] A mixture of tert-butyl
2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]p-
yridine-5 (4H)-carboxylate (compound 2.6, 300 mg, 0.70 mmol, 1.00
equiv, 90%) and sodium hydroxide (62 mg, 1.55 mmol, 2.00 equiv) in
15 mL methanol/H.sub.2O (2:1) was stirred for at 40.degree. C. in
an oil bath. After 2 h, the reaction mixture was concentrated to
about 1/3 of the volume under reduced pressure. The pH value of the
remaining mixture was adjusted to 3-4 with hydrogen chloride (aq.,
1 M). The resulting solids were collected by filtration and dried
in an oven under reduced pressure to yield 0.2 g (69%) of the title
compound as a yellow solid.
##STR00538##
Compound 2.8. tert-Butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dih-
ydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3437] A solution of compound 2.7 (125 mg, 0.30 mmol, 1.00 equiv,
90%), DIEA (130.5 mg, 1.01 mmol, 3.00 equiv), HBTU (256.2 mg, 0.68
mmol, 2.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride
(compound 1.5, 75 mg, 0.30 mmol, 1.00 equiv) in DMF (5 mL) was
stirred overnight at room temperature. The reaction mixture was
then diluted with 50 mL of ethyl acetate, washed with 2.times.20 mL
of brine, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified using silica gel
column chromatography and purified using ethyl acetate/petroleum
ether (1:1) to yield 0.1 g (55%) of the title compound as a yellow
solid.
##STR00539##
Compound 2.9.
4-(1-(2,4-Dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3438] To a solution of tert-butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dih-
ydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 2.8, 100
mg, 0.17 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) was added
trifluoroacetic acid (1 mL). The resulting mixture was stirred at
room temperature. After 2 h, the reaction mixture was concentrated
under reduced pressure. The residue was taken up in dichloromethane
and washed with sodium bicarbonate (aq., sat.). The organic phase
was dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to yield 0.1 g (68%) of the title compound as a yellow
solid.
##STR00540##
Compound 2.
4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-d-
imethylbenzoyl)piperidin-4-yl)benzonitrile
[3439] To a stirred mixture of
4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 20 mg, 0.02 mmol,
1.00 equiv, 50%) in DMF (2 mL) under nitrogen was added a solution
of Ac.sub.2O (2.4 mg, 0.02 mmol, 1.00 equiv) in DMF (0.2 mL)
dropwise at 0.degree. C. The resulting solution was stirred for 1 h
at 0-3.degree. C. in a water/ice bath. The reaction mixture was
then diluted with 50 mL of ethyl acetate and washed with 2.times.20
mL of brine. The organic phase was dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. The crude residue (50 mg) was
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-006(Waters)): Column, xbridge C18; mobile phase, WATER
WITH 0.05% NH.sub.3.H.sub.2O and CH.sub.3CN (hold 5% CH.sub.3CN in
2 min, up to 20%-46% in 10 min, up to 100% in 12 min, down to 20%
in 14 min); Detector, UV 254/220 nm. The fractions containing pure
compound were combined and lyophilized to yield 5.5 mg of the title
compound as a white solid. m/z (ES+) 482 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD): .delta. 7.69 (d, J=8.1 Hz, 2H), 7.48 (d,
J=8.1 Hz, 2H), 7.39-7.28 (m, 2H), 4.90 (m, 1H, partially obscured
by the solvent peak), 4.67 and 4.62 (2 singlets, acetamide
rotamers, MeCONCH.sub.2-imidazole, 2H), 3.92 (m, 2H), 3.66 (m, 1H),
3.23 (m, 1H), 3.00 (m, 2H), 2.85-2.76 (m, 2H), 2.48 (s, 3H), 2.41
and 2.31 (2 singlets, aryl amide rotamers, ArCH.sub.3, 3H), 2.25
and 2.22 (2 singlets, acetamide rotamers, CH.sub.3CON, 3H), 2.04
(m, 1H), 1.92-1.20 (m, 3H).
##STR00541##
Compound 3.
4-(1-(3-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-met-
hylbenzoyl)piperidin-4-yl)benzonitrile
[3440] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 468 (M+H).sup.+.
##STR00542##
Compound 4.
4-(1-(4-Methyl-3-(5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]-
pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3441] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 504 (M+H).sup.+.
##STR00543##
Compound 5.
4-(1-(5-(5-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[3442] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 546 (M+H).sup.+.
##STR00544##
Compound 6.
4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoy-
l)piperidin-4-yl)-2-fluorobenzonitrile
[3443] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 459 (M+H).sup.+.
##STR00545##
Compound 7.
2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dim-
ethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-sulfonamide
[3444] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 547 (M+H).sup.+.
##STR00546##
Compound 8.
(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(-
4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone
[3445] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 484 (M+H).sup.+.
##STR00547##
Compound 9.
2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methy-
l-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxamide
[3446] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 496 (M+H).sup.+.
##STR00548##
Compound 11.1. tert-Butyl
4-(4-cyanophenyl)-4-fluoropiperidine-1-carboxylate
[3447] To a stirred solution of compound 1.2 (5 g, 16.54 mmol, 1.00
equiv) in dichloromethane (250 mL) under nitrogen at -78.degree. C.
was added dropwise Deoxo-Fluor.RTM. (4.4 g, 19.89 mmol, 1.20
equiv). The resulting mixture was stirred for 1 h at -78.degree. C.
The reaction mixture was then carefully quenched by the addition of
50 mL of sodium bicarbonate (aq.sat.) and extracted with
3.times.100 mL of dichloromethane. The combined organic layers were
washed with 150 mL of brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:30) as eluent to yield 2.5 g (35%) of
the title compound as a white solid.
##STR00549##
Compound 11.2. 4-(4-Fluoropiperidin-4-yl)benzonitrile
[3448] To a stirred solution of compound 11.1 (620 mg, 1.02 mmol,
1.00 equiv, 50%) in DCM (40 mL) was added dropwise trifluoroacetic
acid (6 g, 52.62 mmol, 51.66 equiv). After stirring at ambient
temperature for 2 h, the mixture was concentrated under reduced
pressure. The residue was taken up in DCM and treated with aqueous
sodium bicarbonate. The phases were separated and the aqueous layer
was extracted with 2.times.50 mL DCM. The combined organic layers
were dried over anhydrous magnesium sulfate and concentrated under
reduced pressure to yield 0.4 g of the title compound as a light
yellow solid. m/z (ES+) 205 (M+H).sup.+.
##STR00550##
Compound 11.2 HCl Salt. 4-(4-Fluoropiperidin-4-yl)benzonitrile
hydrochloride
[3449] The title compound was prepared using standard chemical
manipulations and a procedure similar to that used for the
preparation of compound 1.5 and using compound 11.1 in place of
compound 1.4. m/z (ES+) 205 (M+H).sup.+. .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 7.83 (d, J=6.3 Hz, 2H), 7.68 (d, J=6.3 Hz,
2H), 3.55-3.32 (m, 4H), 2.58-2.40 (m, 2H), 2.28-2.22 (m, 2H).
##STR00551##
Compound 11.
4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoy-
l)-4-fluoropiperidin-4-yl)benzonitrile
[3450] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2 and using compound 11.2 in place
of compound 1.5. m/z (ES+) 459 (M+H).sup.+.
##STR00552##
Compound 12.
(4-(4-Chlorophenyl)piperidin-1-yl)(2,4-dimethyl-5-(3,4,6,7-tetrahydropyra-
no[3,4-d]imidazol-2-yl)phenyl)methanone
[3451] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 450 (M+H).sup.+.
##STR00553##
Compound 13.
2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methy-
l-1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carboxamide
[3452] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 482 (M+H).sup.+.
##STR00554##
Compound 14.
4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoy-
l)piperidin-4-yl)benzonitrile
[3453] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 441 (M+H).sup.+.
##STR00555##
Compound 15.
(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(-
4-(trifluoromethoxy)phenyl)piperidin-1-yl)methanone
[3454] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2. m/z (ES+) 500 (M+H).sup.+.
##STR00556##
Compound 16.1.
N.sup.2-(2-Methoxyethyl)-N.sup.2-methyl-5-nitropyridine-2,4-diamine
[3455] A solution of 2-chloro-5-nitropyridin-4-amine (500 mg, 2.88
mmol, 1.00 equiv), triethylamine (1.167 g, 11.53 mmol, 4.00 equiv),
and (2-methoxyethyl)(methyl)amine (514 mg, 5.77 mmol, 2.00 equiv)
in DMF (20 mL) was stirred in a sealed tube at 55.degree. C. behind
a blast shield overnight. After cooling to room temperature, the
mixture was diluted with 100 mL of water and extracted with
3.times.150 mL of ethyl acetate. The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
yield 723 mg (crude) of the title compound as a dark red oil.
##STR00557##
Compound 16.2.
N.sup.2-(2-Methoxyethyl)-N.sup.2-methylpyridine-2,4,5-triamine
[3456] Around-bottom flask, containing a solution of compound 16.1
(400 mg, 1.77 mmol, 1.00 equiv)) in methanol (30 mL) was purged
with nitrogen gas. To the solution was then added palladium on
carbon (40 mg, 10%, 60% water). The flask was purged further with
nitrogen and the atmosphere was then changed to hydrogen. The
mixture was stirred at room temperature under a balloon with
hydrogen for 4 h. After purging the system with nitrogen, the
solids were removed by filtration and the filtrate was concentrated
under reduced pressure to yield 300 mg (86%) of the title compound
as a light brown solid. The crude product was found to be unstable
and used immediately.
##STR00558##
Compound 16.3. 5-Formyl-2,4-dimethylbenzoic Acid
[3457] To a stirred solution of 5-iodo-2,4-dimethylbenzoic acid
(compound 2.1, 5 g, 18.11 mmol, 1.00 equiv) in tetrahydrofuran (150
mL) under nitrogen at -78.degree. C. was added n-BuLi (2.5 M in
THF, 18 mL, 2.50 equiv) dropwise. After stirring at -78.degree. C.
for 1 h, DMF (5 g, 68.4 mmol, 3.80 equiv) was added dropwise. The
resulting mixture was stirred at -78.degree. C. for an additional
0.5 h and then carefully quenched by slow addition of 50 mL of
water. The pH was then adjusted to .about.3-4 using aqueous HCl
(aq., 6 M). The mixture was extracted with 3.times.200 mL of ethyl
acetate. The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. The residue thus obtained
was purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:10-1:5) as gradient to yield 2.4 g (74%)
of the title compound as a white solid.
##STR00559##
Compound 16.4.
4-(1-(5-Formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[3458] To a stirred solution of 5-formyl-2,4-dimethylbenzoic acid
(compound 16.3, 950 mg, 5.33 mmol, 1.10 equiv) in DMF (15 mL) was
added DIEA (2.48 g, 19.19 mmol, 4.00 equiv) followed by HBTU (3.67
g, 9.68 mmol, 2.00 equiv), and 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.00 equiv). After
stirring overnight at ambient temperature, the reaction was
quenched by the addition of 60 mL of water. The resulting mixture
was extracted with 3.times.150 mL of ethyl acetate and the organic
layers were combined, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified using
silica gel column chromatography with ethyl acetate/petroleum ether
(1:10-1:3) as eluent to yield 1.4 g (84%) of the title compound as
a brown oil.
##STR00560##
Compound 16.
4-(1-(5-(6-((2-Methoxyethyl)(methyl)amino)-3H-imidazo[4,5-c]pyridin-2-yl)-
-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[3459] A solution of compound 16.2 (300 mg, 1.53 mmol, 1.30 equiv),
compound 16.4 (407 mg, 1.17 mmol, 1.00 equiv), and ammonium acetate
(362 mg, 4.70 mmol, 4.00 equiv) in ethanol (20 mL) was stirred
overnight at 70.degree. C. in an oil bath. The resulting mixture
was then concentrated under vacuum and the residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:10-2:1) as eluent to yield -200 mg of product which was
further purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, WATER WITH 0.05% TFA and CH.sub.3CN (hold 5.0%
CH.sub.3CN in 2 min, up to 25.0% in 1 min, up to 55.0% in 12 min,
up to 100.0% in 1 min); Detector, UV 254/220 nm. The fractions
containing pure compound were combined and lyophilized to yield 150
mg (24%) of the title compound as a white solid. m/z (ES+) 523
(M+H).sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.57-8.38
(m, 1H), 7.78-7.53 (m, 4H), 7.34 (d, J=7.5 Hz, 2H), 7.28-7.12 (m,
2H), 5.06-4.88 (m, 1H), 3.71 (app s, 5H), 3.50 (s, 3H), 3.41-3.05
(m, 4H), 3.01-2.75 (m, 2H), 2.68 (s, 3H), 2.42 & 2.31 (2
singlets, amide rotamers, ArCH.sub.3, 3H), 2.12-1.93 (m, 1H),
1.93-1.39 (m, 3H).
##STR00561##
Compound 17.
4-(1-(2,4-Dimethyl-5-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-
piperidin-4-yl)benzonitrile
[3460] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 521 (M+H).sup.+.
##STR00562##
Compound 18.
4-(1-(2,4-Dimethyl-5-(6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-
-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3461] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 534 (M+H).sup.+. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): 8.73 (s, 1H), 7.76 (d, J=7.5 Hz, 2H), 7.66 &
7.56 (2 singlets, amide rotamers, Ar--H, 1H), 7.49 (d, J=8.1 Hz,
2H), 7.37 (s, 1H), 7.12 (s, 1H), 4.81-4.67 (m, 1H), 4.30 (br s,
2H), 3.70-3.37 (m, 3H), 3.37-3.05 (m, 5H), 3.05-1.80 (m, 5H), 2.60
(s, 3H), 2.37 & 2.27 (2 singlets, amide rotamers, Ar--CH.sub.3,
3H), 2.02-1.87 (m, 1H), 1.87-2.40 (m, 3H).
##STR00563##
Compound 19.
4-(1-(2,4-Dimethyl-5-(6-(piperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3462] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 519 (M+H).sup.+.
##STR00564##
Compound 20.1. 5-Nitro-2-(pyrrolidin-1-yl)pyridin-4-amine
[3463] A 500 mL round bottom flask equipped with a reflux condenser
was charged with 2-chloro-5-nitropyridin-4-amine (2.00 g, 11.5
mmol, 1.0 equiv), pyrrolidine (2.86 mL, 34.6 mmol, 3.0 equiv),
potassium carbonate (4.78 g, 34.6 mmol, 3.0 equiv) and acetonitrile
(50 mL). The mixture was heated at 70.degree. C. overnight under
nitrogen then cooled to room temperature. The yellow solids were
collected by filtration and washed with acetonitrile, water and
hexanes. The solids were dried to obtain the title compound as a
bright yellow solid (1.43 g, 1.sup.st crop). The solvents from the
filtrate were removed and the aqueous was extracted with ethyl
acetate. The organic extracts was dried (Na.sub.2SO.sub.4),
filtered and removed in vacuo to obtain additional product as an
orange/yellow solid (820 mg, 2.sup.nd crop). The 2.sup.nd crop of
product was triturated with ethyl acetate (3 mL) and then filtered
and washed with ethyl acetate (2.times.1 mL) and diethyl ether (3
mL) to obtain a bright yellow solid (751 mg). The total yield of
5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine obtained was 2.18 g
(91%). m/z (ES+) 209.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.79 (s, 1H), 7.39 (br s, 2H), 5.63 (s, 1H),
3.40 (br s, 4H), 1.93 (br s, 4H).
##STR00565##
Compound 20.2. 6-(Pyrrolidin-1-yl)pyridine-3,4-diamine
[3464] To a 100 mL round bottom flask was added
5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine (compound 20.1, 800 mg,
3.84 mmol, 1.0 equiv) and Pd on carbon (10 wt % Pd, 400 mg, 0.38
mmol, 0.1 equiv). The system was purged with nitrogen and charged
with methanol (19 mL) followed by hydrogen. The mixture was stirred
at room temperature under hydrogen for 4 hours then purged with
nitrogen. The mixture was filtered though celite and washed
extensively with MeOH. The solvents were removed in vacuo to obtain
the title compound as a purple solid (641 mg, 94%). m/z (ES+) 179.3
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.27 (s,
1H), 5.62 (s, 1H), 5.14 (br s, 2H), 3.67 (br s, 2H), 3.23-3.13 (m,
4H), 1.91-1.79 (m, 4H).
##STR00566##
Compound 20.
4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile
[3465] To a 100 mL round bottom flask was added
6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 20.2, 641 mg,
3.60 mmol, 1.0 equiv),
4-(1-(5-formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
(compound 16.4, 1.25 g, 3.60 mmol, 1.0 equiv), sodium metabisulfite
(890 mg, 4.68 mmol, 1.3 equiv) and DMF (36 mL). The mixture was
heated at 100.degree. C. under air for 22 hours then allowed to
cool to room temperature. Water (80 mL) was added slowly to the
stirred solution until no further product precipitated. The solids
were filtered and washed with water (2.times.15 mL) and dried to a
brown solid (1.42 g). Additional product precipitated from the
filtrate upon standing which was filtered and washed with water
(2.times.10 mL) to obtain an off white solid (241 mg). The above
reaction was repeated a second time in the exact manner and
quantities as described to yield additional product (1.26 g of
brown solid upon initial precipitation, plus 288 mg of off white
solid from additional precipitation). The aqueous filtrates from
the two reactions were combined and aqueous NaHCO.sub.3 was added
to adjust the pH to 7. The aqueous was extracted with DCM/2% MeOH
(300 mL), dried (Na.sub.2SO.sub.4), filtered and evaporated to
obtain a brown solid (547 mg). All products obtained were combined
and purified by silica gel chromatography (DCM/MeOH) to obtain the
title compound as a yellow solid (2.37 g, 65% based on the
theoretical yield for the two reactions). m/z (ES+) 505.1
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.41 (br
s, 1H), 8.52 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.66 & 7.56 (2 br
singlets, amide rotamers, ArH, 1H), 7.49 (s, J=8.2 Hz, 2H), 7.29
(s, 1H), 6.31 (br s, 1H), 4.79-4.67 (m, 1H), 3.54-3.34 (m, 5H),
3.17 (app t, J=11.8, 1H), 2.99-2.82 (m, 2H), 2.63 (s, 3H), 2.33
& 2.24 (2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.03-1.87
(m, 5H), 1.82-1.38 (m, 3H). Elemental analysis
(C.sub.31H.sub.32N.sub.6O.1.3H.sub.2O, 528.04), found (calcd), C:
70.66 (70.51); H: 6.54 (6.60); N: 15.78 (15.92).
##STR00567##
Compound 20 HCl salt.
4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile hydrochloride
[3466] Dichloromethane (.about.50 mL) was added to
4-(1-(2,4-dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile (compound 20 free base, 2.31 g,
4.58 mmol) until it completely dissolved and then 4M HCl in dioxane
(5 mL, 20 mmol, 4.3 equiv) was added. The solvents were removed and
the residue was dissolved in DCM and removed in vacuo. The
resulting hydrochloride salt was recrystallized from boiling
ethanol (180 mL) and allowed to cool to room temperature slowly.
The mixture sat at room temperature overnight and then placed in
the freezer for 4 hours. The resulting solids were filtered and
washed with cold ethanol (25 mL) followed by diethyl ether (25 mL).
The solids were dried to obtain an off white to light grey solid
(1.82 g, 73%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 13.59
& 13.46 (2 br singlets, imidazole NH tautomers, 1H), 13.29 (br
s, 1H), 8.62 (br s, 1H), 7.83 & 7.67 (2 singlets, amide
rotamers, ArH, 1H), 7.78 (d, J=7.8 Hz, 2H), 7.58-7.45 (m, 2H), 7.37
(s, 1H), 6.71 (br s, 1H), 4.80-4.68 (m, 1H), 3.65-3.38 (m, 5H),
3.25-3.12 (m, 1H), 3.00-2.82 (m, 2H), 2.66 (s, 3H), 2.37 & 2.27
(2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.13-2.01 (m, 4H),
1.98-1.87 (m, 1H), 1.82-1.40 (m, 3H). Elemental analysis
(C.sub.31H.sub.32N.sub.6O.1.0 HCl.2.4H.sub.2O, 584.32), found
(calcd), C: 63.80 (63.72); H: 6.32 (6.52); N: 14.25 (14.38).
##STR00568##
Compound 20 MsOH Salt.
4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile methanesulfonate
[3467]
4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin--
2-yl)benzoyl)piperidin-4-yl)benzonitrile hydrochloride (compound 20
HCl salt, 1.82 g, 3.36 mmol) was added to water (100 mL) plus
saturated NaHCO.sub.3 (50 mL) and extracted with 1:1 DCM/EtOAc (500
mL) plus MeOH (25 mL). Once the entire product completely
dissolved, the layers were separated and the aqueous was extracted
with additional 1:1 DCM/EtOAc (100 mL). The combined organics was
dried (Na.sub.2SO.sub.4), filtered and evaporated to a light yellow
powder (1.68 g, 3.33 mmol). The free base material was dissolved in
hot acetonitrile (10 mL), then a 1.0 M aqueous methanesulfonic acid
solution (3.33 mL, 3.33 mmol, 1.0 equiv) was added and mixed well.
Additional water (6 mL) was added and the mixture was frozen and
dried on the lyophilizer to obtain a yellow powder (1.99 g, 99%).
m/z (ES+) 505.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 13.29 (br s, 1H), 13.10 (br s, 1H), 8.65 (br s, 1H), 7.78
(d, J=8.2 Hz, 2H), 7.74 & 7.64 (2 singlets, amide rotamers,
ArH, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.37 (s, 1H), 6.74 (br s, 1H),
4.80-4.68 (m, 1H), 3.65-3.38 (m, 5H), 3.26-3.12 (m, 1H), 3.01-2.83
(m, 2H), 2.64 (s, 3H), 2.37 & 2.27 (2 singlets, amide rotamers,
ArCH.sub.3, 3H), 2.32 (s, 3H) 2.12-2.00 (m, 4H), 1.98-1.88 (m, 1H),
1.82-1.39 (m, 3H). Elemental analysis (C.sub.31H.sub.32N.sub.6O.1.0
MsOH.1.7H.sub.2O, 631.36), found (calcd), C: 60.96 (60.88); H: 6.14
(6.29); N: 13.21 (13.31); S: 5.08 (5.08).
##STR00569##
Compound 21.
4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylben-
zoyl)piperidin-4-yl)benzonitrile
[3468] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 491 (M+H).sup.+.
##STR00570##
Compound 22.
4-(1-(2,4-Dimethyl-5-(6-(methylsulfonyl)-3H-imidazo[4,5-c]pyridin-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3469] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 514 (M+H).sup.+.
##STR00571##
Compound 23.
4-(1-(2,4-Dimethyl-5-(6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3470] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 514 (M+H).sup.+. .sup.1H NMR (300 MHz,
DMSO-d.sub.6+D20): .delta. 8.87 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1
Hz, 1H), 7.74 (d, J=7.5 Hz, 2H), 7.66 & 7.56 (2 singlets, amide
rotamers, Ar--H, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.38 (br s, 1H),
4.76-4.63 (m, 1H), 3.57-3.38 (m, 1H), 3.31 (s, 3H), 3.28-3.13 (m,
1H), 3.03-2.85 (m, 2H), 2.60 (s, 3H), 2.35 & 2.27 (2 singlets,
amide rotamers, Ar--CH.sub.3, 3H), 2.00-1.85 (m, 1H), 1.85-1.32 (m,
3H).
##STR00572##
Compound 24.
4-(1-(5-(5-(Azetidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethylben-
zoyl)piperidin-4-yl)benzonitrile
[3471] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16 but using 6-chloro-3-nitropyridin-2-amine and
azetidine hydrochloride in place of 2-chloro-5-nitropyridin-4-amine
and (2-methoxyethyl)(methyl)amine respectively. m/z (ES+) 491
(M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 8.06 (d,
J=9.0 Hz, 1H), 7.70-7.42 (m, 6H), 6.60 (d, J=9.0 Hz, 1H), 4.90 (m,
1H, partially obscured by the solvent peak), 4.32 (m, 4H), 3.65 (m,
1H), 3.03 (m, 1H), 2.62 (s, 3H), 2.57 (m, 3H), 2.48 and 2.38 (2
singlets, amide rotamers, ArCH.sub.3, 3H), 2.04 (m, 1H), 1.96-1.68
(m, 4H).
##STR00573##
Compound 25.
4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylben-
zoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3472] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16 and using compound 11.2 in place of compound 1.5.
m/z (ES+) 509 (M+H).sup.+.
##STR00574##
Compound 26.1. tert-Butyl
4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate
[3473] To a stirred solution of 2,5-dibromopyridine (10 g, 42.19
mmol, 1.00 equiv) in toluene (1000 mL) under nitrogen at
-78.degree. C. was added dropwise n-BuLi (18 mL, 2.5 M in toluene).
After 1 h at -78.degree. C., a solution of tert-butyl
4-oxopiperidine-1-carboxylate (10 g, 50.25 mmol, 1.19 equiv) in
toluene (200 mL) was added dropwise while stirring. After an
additional 2 h of stirring at -78.degree. C., the reaction was then
carefully quenched by the addition of 300 mL of water. The
resulting mixture was extracted with 3.times.500 mL of ethyl
acetate. The combined organic layers were washed with 1.times.300
mL of brine, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether
(1:100-1:5) to yield 6.5 g (42%) of the title compound as a yellow
oil.
##STR00575##
Compound 26.2. tert-Butyl
4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate
[3474] A mixture of tert-butyl
4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound
26.1, 1 g, 2.80 mmol, 1.00 equiv), zinc cyanide (400 mg, 3.42 mmol,
1.22 equiv), Pd(PPh.sub.3).sub.4 (200 mg, 0.17 mmol, 0.06 equiv) in
DMF (50 mL) was stirred under nitrogen for 2 h at 100.degree. C.
After cooling to room temperature, the reaction was then quenched
by careful addition of 300 mL of FeSO.sub.4 (aq., sat.) and diluted
with ethyl acetate. The resulting mixture was stirred vigorously
then filtered through celite and washed with 1 M FeSO.sub.4, water,
and ethyl acetate. The layers were separated and the aqueous phase
was extracted with 2.times.100 mL of ethyl acetate. The combined
organic layers were washed with 1.times.100 mL of brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified using silica gel column chromatography
with ethyl acetate/petroleum ether (1:100-1:4) yield 0.5 g (58%) of
the title compound as a yellow oil.
##STR00576##
Compound 26.3. tert-Butyl
4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate
[3475] To a solution of tert-butyl
4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound
26.2, 1 g, 3.13 mmol, 1.00 equiv, 95%) in dichloromethane (50 mL)
under nitrogen at -78.degree. C. was added dropwise a solution of
bis(2-methoxyethyl)aminosulfur trifluoride (830 mg, 3.75 mmol, 1.20
equiv) in dichloromethane (10 mL) during the course of 1 min. The
resulting mixture was stirred for 1 h at -78.degree. C. The
reaction was then carefully quenched by dropwise addition of water
and washed with 2.times.20 mL of sodium bicarbonate(aq) followed by
3.times.20 mL of brine. The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The crude
residue was purified using silica gel column chromatography with
ethyl acetate/petroleum ether (1:10) to yield 0.38 g (38%) of the
title compound as a white solid.
##STR00577##
Compound 26.4. 6-(4-Fluoropiperidin-4-yl)nicotinonitrile
trifluoroacetate
[3476] To a stirred solution of tert-butyl
4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate (compound
26.3, 1 g, 3.11 mmol, 1.00 equiv, 95%) in dichloromethane (20 mL)
was added dropwise TFA (3.75 g, 32.89 mmol, 10.57 equiv). After
stirring for 1 h at 25.degree. C., the mixture was concentrated
under reduced pressure to yield 0.5 g of the title compound as a
brown oil.
##STR00578##
Compound 26.
6-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylben-
zoyl)-4-fluoropiperidin-4-yl)nicotinonitrile
[3477] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16 but using compound 26.4 in place of compound 1.5.
m/z (ES+) 509 (M+H).sup.+.
##STR00579##
Compound 27.
4-(1-(4-Methyl-3-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzo-
yl)piperidin-4-yl)benzonitrile
[3478] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16 but using 3-bromo-4-methylbenzoic acid in place of
5-iodo-2,4-dimethylbenzoic acid. m/z (ES+) 491 (M+H).sup.+.
##STR00580##
Compound 28.
4-(1-(3-(1H-Imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)be-
nzonitrile
[3479] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compounds 16 and 27. m/z (ES+) 422 (M+H).sup.+. .sup.1H NMR (300
MHz, CD.sub.3OD): .delta. 9.35 (s, 1H), 8.60 (d, J=6.6 Hz, 1H),
8.19 (d, J=6.6 Hz, 1H), 7.92 (s, 1H), 7.73-7.58 (m, 4H), 7.50 (d,
J=8.1 Hz, 1H), .about.4.9 (1H, partially obscured by water peak),
4.06-3.87 (m, 1H), 3.13-2.95 (m, 3H), 2.73 (s, 3H), 2.11-1.63 (m,
4H).
##STR00581##
Compound 29.
4-(1-(3-(1H-Benzo[d]imidazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzoni-
trile
[3480] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compounds 16 and 27. m/z (ES+) 421 (M+H).sup.+. .sup.1H NMR (300
MHz, CD.sub.3OD): .delta. 7.87-7.77 (m, 3H), 7.75-7.60 (m, 4H),
7.60-7.47 (m, 4H), .about.4.85 (1H, partially obscured by water
peak), 4.04-3.89 (m, 1H), 3.13-2.95 (m, 3H), 2.61 (s, 3H),
2.11-1.69 (m, 4H).
##STR00582##
Compound 30.
4-(1-(3-(6-Chloro-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidi-
n-4-yl)benzonitrile
[3481] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compounds 16 and 27. m/z (ES+) 456 (M+H).sup.+.
##STR00583##
Compound 31.
4-(1-(2-Methyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzo-
yl)piperidin-4-yl)benzonitrile
[3482] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16 but using 5-bromo-2-methylbenzoic acid in place of
5-iodo-2,4-dimethylbenzoic acid (compound 2.1). m/z (ES+) 491
(M+H).sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.63 (br
s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.01 & 7.91 (2 singlets, amide
rotamers, Ar--H, 1H), 7.81 (d, J=6.6 Hz, 2H), 7.58-7.42 (m, 3H),
6.31 (s, 1H), 4.85 (m, 1H), 3.57-3.35 (m, 5H), 3.30-3.13 (m, 1H),
3.07-1.85 (m, 2H), 2.39 & 2.29 (2 singlets, amide rotamers,
Ar--CH.sub.3, 3H), 2.10-1.89 (m, 5H), 1.87-1.40 (m, 3H).
##STR00584##
Compound 32.
4-(1-(2-Methoxy-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benz-
oyl)piperidin-4-yl)benzonitrile
[3483] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 507 (M+H).sup.+.
##STR00585##
Compound 33.
2-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-(6-(pyrrolidin-1-yl)-3H-imid-
azo[4,5-c]pyridin-2-yl)benzonitrile
[3484] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 502 (M+H).sup.+.
##STR00586##
Compound 34.
4-(1-(2-Chloro-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzo-
yl)piperidin-4-yl)benzonitrile
[3485] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 511 (M+H).sup.+.
##STR00587##
Compound 35.
4-(1-(5-(6-(Pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2-(trifluorom-
ethoxy)benzoyl)piperidin-4-yl)benzonitrile
[3486] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 561 (M+H).sup.+.
##STR00588##
Compound 36.
4-(1-(3-(6-(Pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperi-
din-4-yl)benzonitrile
[3487] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 477 (M+H).sup.+. .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 8.44 (s, 1H), 8.25-8.17 (m, 2H), 7.77-7.63 (m,
4H), 7.51 (d, J=8.1 Hz, 2H), 6.59 (s, 1H), .about.4.85 (1H,
partially obscured by water peak), 3.98-3.83 (m, 1H), 3.61-3.48 (m,
4H), .about.3.4 (1H, partially obscured by methanol solvent peak),
3.12-2.96 (m, 2H), 2.22-2.09 (m, 4H), 2.09-1.95 (m, 1H), 1.95 (m,
3H).
##STR00589##
Compound 37.
4-(1-(3-(6-(Isopropylamino)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperid-
in-4-yl)benzonitrile
[3488] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 16. m/z (ES+) 465 (M+H).sup.+.
##STR00590##
Compound 38.1. Methyl tetrahydrofuran-3-carboxylate
[3489] A solution of tetrahydrofuran-3-carboxylic acid (540 mg,
4.65 mmol, 1.00 equiv) and TsOH (10 mg, 0.06 mmol, 0.01 equiv) in
methanol (40 mL) was stirred at 66.degree. C. in an oil bath. After
16 h, the resulting mixture was cooled to room temperature and
concentrated under reduced pressure. The residue was dissolved in
10 mL of ether, washed with 1.times.20 mL of NaHCO.sub.3 (aq.,
sat.) followed by 3.times.20 mL of brine, and concentrated under
reduced pressure to yield 0.40 g (66%) of the title compound as a
colorless oil.
##STR00591##
Compound 38.2. Tetrahydrofuran-3-carbohydrazide
[3490] Into around-bottom flask, was placed hydrazine hydrate (20
mL). To this was added methyl tetrahydrofuran-3-carboxylate
(compound 38.1, 390 mg, 3.00 mmol, 1.00 equiv) dropwise with
stirring. The resulting mixture was stirred at 50.degree. C. in an
oil bath. After 3 h, the reaction mixture was concentrated and
dried under reduced pressure to yield 0.29 g (74%) of the title
compound as a colorless oil.
##STR00592##
Compound 38.3. Methyl 3-carbamothioyl-4-methylbenzoate
[3491] A solution of methyl 3-cyano-4-methylbenzoate (compound 1.7,
880 mg, 5.02 mmol, 1.00 equiv) and O,O'-diethyl dithiophosphate
(1.41 g, 8.29 mmol, 1.50 equiv) in THF/H.sub.2O (40 mL) was stirred
at 80.degree. C. (CAUTION: significant gas evolution occurs--this
and all other reactions described herein should be carried out in
well ventilated fume hoods). After 3 h, the organic solvent was
removed under reduced pressure and the residual aqueous phase was
extracted with 3.times.20 mL of ethyl acetate. The combined organic
layers were concentrated under reduced pressure to yield 0.85 g
(79%) of the title compound as a light yellow solid.
##STR00593##
Compound 38.4. Methyl
3-(imino(methylthio)methyl)-4-methylbenzoate
[3492] To a stirred solution of methyl
3-carbamothioyl-4-methylbenzoate (compound 38.3, 2.10 g, 9.85 mmol,
1.00 equiv) in tetrahydrofuran (30 mL) was added iodomethane (2.8
g, 19.73 mmol, 2.00 equiv) dropwise. The resulting mixture was
stirred at room temperature. After 3 h, the reaction mixture was
concentrated under reduced pressure and the residue was dried under
vacuum to yield 1.6 g (73%) of the title compound as a light yellow
solid.
##STR00594##
Compound 38.5. Methyl
4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoate
[3493] A solution of tetrahydrofuran-3-carbohydrazide (compound
38.2, 195 mg, 1.50 mmol, 1.50 equiv) and compound 38.4 (223 mg,
1.00 mmol, 1.00 equiv) in AcOH (30 mL) was stirred at 80.degree. C.
After 4 h, the reaction mixture was concentrated under reduced
pressure and the residue was dried under high-vacuum to yield 153
mg (53%) of the title compound as yellow oil.
##STR00595##
Compound 38.6.
4-Methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoic
Acid
[3494] To a stirred solution of compound 38.5 (57 mg, 0.20 mmol,
1.00 equiv) in methanol (20 mL) was added sodium hydroxide
(aqueous, 1 M, 0.2 mL) dropwise. The resulting mixture was stirred
at room temperature. After 4 h, the organic solvent was removed
under reduced pressure. The residual aqueous layer was washed with
2.times.20 mL of ethyl acetate. The pH of the aqueous phase was
then adjusted to 4 with hydrogen chloride (aq., 1 M) and the
resulting solids were collected by filtration and dried to yield 23
mg (42%) of the title compound as a light yellow solid.
##STR00596##
Compound 38.
4-(1-(4-Methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)-
piperidin-4-yl)benzonitrile
[3495] A mixture of compound 38.6 (137 mg, 0.50 mmol, 1.00 equiv),
HBTU (228 mg, 0.60 mmol, 1.20 equiv), DIEA (162 mg, 1.25 mmol, 2.50
equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 111
mg, 0.50 mmol, 1.00 equiv) in DMF (20 mL) was stirred at room
temperature. After 1 h, the reaction was quenched by the addition
of 20 mL of water and resulting mixture was extracted with
3.times.20 mL of ethyl acetate. The combined organic phases were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure.
The residue was purified using silica gel column chromatography
with ethyl acetate/petroleum ether (1:100-1:3) to yield 35 mg (16%)
of the title compound as a brown solid. m/z (ES+) 442
(M+H).sup.+.
##STR00597##
Compound 39.1. 3-Formyl-4-methylbenzoic Acid
[3496] To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14
g, 10.00 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) under
nitrogen at -78.degree. C. was added n-BuLi (10 mL, 2.5 M in THF,
2.50 equiv) dropwise. After stirring for 1 h below -70.degree. C.,
DMF (5 mL) was slowly added. The resulting solution was warmed
slowly to room temperature and stirred for 1 h. After carefully
quenching the reaction by slowly adding 50 mL of water, the pH was
adjusted to .about.3-4 using aqueous HCl (6 M). The resulting
mixture was extracted with 2.times.50 mL of ethyl acetate and the
combined organic layers were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to yield 1.6 g (98%) of the
title compound as a yellow solid.
##STR00598##
Compound 39.2.
4-(1-(3-Formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile
[3497] A mixture of 3-formyl-4-methylbenzoic acid (compound 39.1,
660 mg, 4.02 mmol, 1.00 equiv), HBTU (2 g, 5.28 mmol, 1.30 equiv)
in N,N-dimethylformamide (20 mL) was stirred at room temperature.
After 1 h, 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 890
mg, 4.01 mmol, 1.00 equiv) and DIEA (1.03 g, 7.98 mmol, 2.00 equiv)
were added. The resulting mixture was stirred for 5 h at room
temperature and then overnight at 60.degree. C. in. After cooling
to ambient temperature, the reaction mixture was diluted with 100
mL of EtOAc and washed with 2.times.50 mL of NH.sub.4Cl (aq., sat.)
followed by 2.times.50 mL of sodium bicarbonate (aq., sat.). The
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to yield 1 g (75%) of the title
compound as a brown oil.
##STR00599##
Compound 39.3.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic Acid
[3498] To a stirred mixture of
4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile
(compound 39.2, 600 mg, 1.81 mmol, 1.00 equiv) in THF (5 mL) was
added dropwise a solution of KMnO.sub.4 (1 g) in water (10 mL). The
resulting mixture was stirred overnight at 60.degree. C. in an oil
bath. After cooling to ambient temperature, the solids were removed
by filtration and the pH of the filtrate was adjusted to .gtoreq.10
with sodium hydroxide (aqueous, 1 M). The resulting mixture was
washed with 20 mL of ethyl acetate. Aqueous 1 M HCl was then
employed to adjust the pH of the aqueous layer to .about.4. The
resulting aqueous phase was extracted with 2.times.100 mL of ethyl
acetate and the combined organic layers were dried over anhydrous
sodium sulfate and concentrated under reduced pressure to yield 500
mg (80%) of the title compound as light yellow oil.
##STR00600##
Compound 39.4. Methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoate
[3499] To a stirred mixture of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic acid
(compound 39.3, 1.392 g, 4.00 mmol, 1.00 equiv) in methanol (50 mL)
was added sulfuric acid (784 mg, 7.99 mmol, 2.00 equiv), dropwise.
The resulting mixture was heated to reflux overnight in an oil
bath. After cooling to ambient temperature, the organic solvent was
removed under reduced pressure. The residue was diluted with 20 mL
of EtOAc and was washed with 1.times.100 mL of saturated sodium
bicarbonate(aq) followed by 1.times.100 mL of brine. The organic
layer was dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to yield 1.303 g (90%) of the title compound as a white
solid.
##STR00601##
Compound 39.5.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylbenzohydrazide
[3500] A solution of compound 39.4 (1.503 g, 4.15 mmol, 1.00 equiv)
and hydrazine hydrate (10 mL) in ethanol (50 mL) was heated at
reflux in an oil bath. After 2 h, the mixture was concentrated
under reduced pressure and the residue was dissolved in 20 mL of
EtOAc. The resulting mixture was washed with 1.times.50 mL of
H.sub.2O and 1.times.50 mL of brine. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to yield
1.353 g (90%) of the title compound as a white solid
##STR00602##
Compound 39.6.
4-(1-(3-(5-Amino-1,3,4-oxadiazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)ben-
zonitrile
[3501] A mixture of compound 39.5 (380 mg, 1.05 mmol, 1.00 equiv)
and sodium bicarbonate (105.8 mg, 1.26 mmol, 1.20 equiv) in
dioxane/H.sub.2O (1:1) (50 mL) was stirred at room temperature.
After 5 minutes, cyanogen bromide (212 mg, 2.00 mmol, 2.00 equiv)
was added. The resulting mixture was stirred for 3 h at room
temperature. The resulting solution was stirred for 3 h at room
temperature, then quenched with 30 mL of FeSO.sub.4 (aq., sat.) and
diluted with ethyl acetate. The resulting mixture was stirred
vigorously then filtered through celite and washed with 1 M
FeSO.sub.4, water, and ethyl acetate. The layers were separated and
the aqueous phase was extracted with 2.times.50 mL of ethyl
acetate. The combined organic layers were washed with 2.times.50 mL
of brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. This resulted in 397 mg (98%) of an off-white solid.
##STR00603##
Compound 39.
4-(1-(3-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)b-
enzonitrile
[3502] A mixture of compound 39.6 (397 mg, 1.02 mmol, 1.00 equiv)
and potassium hydroxide (287 mg, 5.12 mmol, 5.00 equiv) in ethanol
(25 mL) was heated at reflux overnight. After cooling the reaction
mixture to room temperature with a water bath, the pH was adjusted
to .about.7 with acetic acid. The resulting mixture was
concentrated under reduced pressure. The residue was taken up in
ethyl acetate and washed with water. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated. The crude residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:5-1:0). The product was further purified by Prep-HPLC with
the following conditions (1#-Pre-HPLC-006(Waters)): Column, SunFire
Prep C18, 5 um, 19*150 mm; mobile phase, WATER WITH 0.05% TFA and
CH.sub.3CN (hold 5.0% CH.sub.3CN in 2 min, up to 30.0% in 1 min, up
to 59.0% in 12 min, up to 100.0% in 2 min); Detector, UV 254/220
nm. The fractions containing pure compound were combined and
lyophilized to yield 51.9 mg (12%) of the title compound as a white
solid. m/z (ES+) 416 (M+H).sup.+.
##STR00604##
Compound 40.1. tert-Butyl
4-(4-cyanophenyl)-4-hydroxyazepane-1-carboxylate
[3503] A solution of 4-iodobenzonitrile (510 mg, 2.22 mmol, 1.1
equiv) in THF (3 mL) was added to a 10 mL round-bottom flask and
the system purged with nitrogen. The mixture was cooled to
-40.degree. C. then isopropylmagnesium chloride (1.16 mL of a 2.0 M
soln in THF, 2.32 mmol, 1.15 equiv) was added dropwise over 20
minutes. The resulting mixture was stirred at -40.degree. C. for 2
hours then tert-butyl 4-oxoazepane-1-carboxylate (431 mg, 2.02
mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise over 15
minutes. The resulting mixture was stirred at -40.degree. C. for 1
hour then diluted into ethyl acetate (15 mL) and washed with 0.2 M
HCl (10 mL), 0.1 M HCl (5 mL), saturated sodium bicarbonate (5 mL)
then brine (5 mL). The organics were dried (Na.sub.2SO.sub.4),
filtered and evaporated. To remove remaining ketone and aldol
by-product, the residue was dissolved in acetonitrile (3 mL) then
hydrazine (0.2 mL) was added and heated at 60.degree. C. for 4
hours. The mixture was diluted with EtOAc (20 mL) and washed with
water (20 mL), followed by 0.5 M phosphoric acid (3.times.20 mL),
saturated sodium bicarbonate (10 mL) and brine (10 mL). The
organics were dried (Na.sub.2SO.sub.4), filtered and evaporated.
The residue was purified by silica column chromatography
(hexanes/ethyl acetate) to obtain the title compound as a pink oil
which solidified upon standing (303 mg, 47%). m/z (ES+) 317
(M+H).sup.+.
##STR00605##
Compound 40.2. tert-Butyl
4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate and
tert-butyl
5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate
[3504] In a vial containing tert-butyl
4-(4-cyanophenyl)-4-hydroxyazepane-1-carboxylate (compound 40.1,
200 mg, 0.63 mmol, 1.0 equiv) was added pyridine (3 mL) and
phosphorus oxychloride (438 .mu.L, 4.7 mmol, 7.5 equiv) and the
mixture was stirred at room temperature for 45 hours. The solvents
were removed in vacuo and the residue was dissolved in DCM (5 mL)
and washed with water (10 mL). The aqueous layer was extracted with
DCM (5 mL) and the combined organics were washed with saturated
sodium bicarbonate (2.times.10 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated to obtain a mixture of the title
compounds as a pale yellow oil (167 mg, 89%). m/z (ES+) 299
(M+H).sup.+.
##STR00606##
Compound 40.3. tert-Butyl
4-(4-cyanophenyl)azepane-1-carboxylate
[3505] To a 25 mL round bottom flask containing a mixture of
tert-butyl
4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate and
tert-butyl
5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate
(compound 40.2, 167 mg, 0.56 mmol) was added 10% palladium on
carbon (40 mg) and ethyl acetate (6 mL). The system was purged with
nitrogen then charged with hydrogen and stirred at room
temperature. After purging the system with nitrogen, the mixture
was filtered through celite and the filtrate was concentrated. The
residue was purified by preparative TLC to obtain a colorless wax
(77 mg, 45%). m/z (ES+) 245 (M minus t-butyl+H).sup.+.
##STR00607##
Compound 40.4. 4-(Azepan-4-yl)benzonitrile
[3506] To a vial containing tert-butyl
4-(4-cyanophenyl)azepane-1-carboxylate (compound 40.3, 77 mg, 0.257
mmol, 1.0 equiv) was added DCM (500 .mu.L) and trifluoroacetic acid
(198 .mu.L, 2.57 mmol, 10 equiv) and the mixture was stirred vented
for 90 min. The mixture was diluted into ethyl acetate (5 mL) and
washed with saturated sodium bicarbonate (5 mL). The aqueous was
adjusted to pH 10-11 and extracted with addition ethyl acetate
until no product remained. The combined organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated to obtain the title
compound as a yellow oil (51 mg, theoretical). m/z (ES+) 201
(M+H).sup.+.
##STR00608##
Compound 40.5.
4-(1-(3-Amino-4-methylbenzoyl)azepan-4-yl)benzonitrile
[3507] To a 4-mL vial was added 3-amino-4-methylbenzoic acid (27
mg, 0.18 mmol, 1.0 equiv), 4-(azepan-4-yl)benzonitrile (compound
40.4, 40 mg, 0.2 mmol, 1.1 equiv), hydroxybenzotriazole (39 mg of
20 wt % H2O, 0.23 mmol, 1.3 equiv),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (44 mg, 0.23 mmol,
1.3 equiv), DMF (1 mL) and N,N-diisopropylethylamine (93 .mu.L,
0.54 mmol, 3.0 equiv). The mixture was stirred at room temperature
for 4 hours then diluted into ethyl acetate (10 mL) and washed with
brine (10 mL). The aqueous was extracted with ethyl acetate (3 mL)
and the combined organics were washed with brine (10 mL), 1 M
NaH.sub.2PO.sub.4 (5 mL) and brine (10 mL). The organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated to obtain the title
compound as a brown solid (45 mg, 74%). m/z (ES+) 334
(M+H).sup.+.
##STR00609##
Compound 40.6.
N-(5-(4-(4-Cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-fluoronicoti-
namide
[3508] To a 4-mL vial containing
4-(1-(3-amino-4-methylbenzoyl)azepan-4-yl)benzonitrile (compound
40.5, 44 mg, 0.13 mmol, 1.0 equiv) was added dichloromethane (1 mL)
and N,N-diisopropylethylamine (35 .mu.L, 0.20 mmol, 1.5 equiv). A
solution of 6-fluoronicotinoyl chloride (22 mg, 0.14 mmol, 1.05
equiv) in dichloromethane (1 mL) was added dropwise over about 2
minutes. The resulting mixture was stirred at room temperature for
19 hours then diluted with dichloromethane (5 mL) and washed with 1
M NaH.sub.2PO.sub.4 (3 mL), saturated sodium bicarbonate (3 mL) and
brine (3 mL). The organics were dried (Na.sub.2SO.sub.4), filtered
and concentrated to obtain the title compound as a brown wax (64
mg, theoretical). m/z (ES+) 457 (M+H).sup.+.
##STR00610##
Compound 40.
N-(5-(4-(4-Cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-(isopropylam-
ino)nicotinamide
[3509] To a vial containing
N-(5-(4-(4-cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-fluoronicoti-
namide (compound 40.6, 61 mg, 0.13 mmol) was added
dimethylsulfoxide (1 mL) and isopropylamine (1 mL). The mixture was
stirred at 35.degree. C. for 2 hours then at room temperature for
16 hours followed by 35.degree. C. for an additional 4 hours. The
excess isopropyl amine was removed in vacuo and the remaining
solution was purified by preparative HPLC to yield the product as
an off white powder (TFA salt, 39 mg, 49%). m/z (ES+) 496
(M+H).sup.+.
##STR00611##
Compound 41.1. 5-Nitro-2-(pyrrolidin-1-yl)pyridine
[3510] A mixture of 2-chloro-5-nitropyridine (1.58 g, 10.00 mmol,
1.00 equiv), pyrrolidine (710 mg, 10.00 mmol, 1.00 equiv) and
potassium carbonate (2.76 g, 20.00 mmol, 2.00 equiv) in CH.sub.3CN
(20 mL) was stirred at 60.degree. C. in an oil bath. After 2 h, the
reaction mixture was allowed to reach ambient temperature. The
solids were filtered off and the filtrate was concentrated under
reduced pressure. The residue was triturated with 1.times.20 mL of
petroleum ether to yield 1.8 g (93%) of the title compound as a
yellow solid.
##STR00612##
Compound 41.2. 6-(Pyrrolidin-1-yl)pyridin-3-amine
[3511] Around-bottom flask, containing a solution of
5-nitro-2-(pyrrolidin-1-yl)pyridine (compound 40.1, 1.93 g, 10.00
mmol, 1.00 equiv) in ethanol (30 mL) was purged with nitrogen.
Palladium on carbon (0.4 g, 10%, 60% water) was added. After
further purging the system with nitrogen, the atmosphere was
changed to hydrogen and the resulting mixture was stirred overnight
at room temperature. After purging the system with nitrogen, the
solids were filtered off and the filtrate was concentrated under
reduced pressure and dried to yield 1.6 g (98%) of the title
compound as a brown solid.
##STR00613##
Compound 41.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methyl-N-(6-(pyrrolidin-1-yl-
)pyridin-3-yl)benzamide
[3512] A mixture of compound 39.3 (528 mg, 1.52 mmol, 1.00 equiv)
and HBTU (635 mg, 2.28 mmol, 1.50 equiv) in DMF (30 mL) was stirred
for 30 min at room temperature. To this was added
6-(pyrrolidin-1-yl)pyridin-3-amine (compound 41.2, 299 mg, 1.82
mmol, 1.20 equiv) and DIEA (50 mg). The resulting mixture was
stirred overnight at 60.degree. C. in an oil bath. After cooling to
room temperature, the reaction mixture was diluted with 50 mL of
EtOAc and washed with 2.times.30 mL of NH.sub.4Cl (aq., sat.)
followed by 2.times.30 mL of sodium bicarbonate (aq., sat.). The
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The crude product was purified
by Prep-HPLC with the following conditions
(1#-Pre-HPLC-016(Waters)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, Water with 50 mmol NH.sub.4HCO.sub.3 and
CH.sub.3CN (10% CH.sub.3CN up to 32% in 3 min, up to 51% in 20 min,
up to 100% in 1 min, down to 10% in 1 min); Detector, UV 220 NMnm.
The fractions containing pure compound were combined and
lyophilized to yield 50 mg (7%) of the title compound as a solid.
m/z (ES+) 494 (M+H).sup.+.
##STR00614##
Compound 42.1. 5-Amino-2,4-dimethylbenzoic Acid
[3513] A mixture of methyl 5-amino-2,4-dimethylbenzoate (1.2 g,
6.70 mmol, 1.00 equiv) and sodium hydroxide (1.5 g, 37.50 mmol,
5.60 equiv) in methanol/H.sub.2O (20/20 mL) was stirred overnight
at 50.degree. C. After cooling to ambient temperature, the organic
phase was removed under reduced pressure. The pH of the remaining
aqueous layer was adjusted to .about.4-5 with hydrogen chloride
(aq., 2 M). The resulting solids were collected by filtration and
dried to yield 1.0 g of a yellow solid.
##STR00615##
Compound 42.2.
4-(1-(5-Amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3514] A mixture of 5-amino-2,4-dimethylbenzoic acid (compound
42.1, 2.264 g, 13.71 mmol, 1.00 equiv), HBTU (7.803 g, 20.59 mmol,
1.50 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2,
2.8 g, 13.71 mmol, 1.00 equiv), and DIEA (3.541 g, 27.45 mmol, 2.00
equiv) in DMF (50 mL) was stirred at room temperature. After 1 h,
the mixture was diluted with 100 mL of EtOAc and washed with
1.times.100 mL of water followed by 1.times.100 mL of brine. The
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to yield 3.51 g (73%) of the
title compound as a white solid.
##STR00616##
Compound 42.3.
6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimet-
hylphenyl)nicotinamide
[3515] To a mixture of compound 42.2 (3.51 g, 9.99 mmol, 1.00
equiv) and triethylamine (2.02 g, 19.96 mmol, 2.00 equiv) in DCM
(50 mL) under nitrogen at 0.degree. C. was added dropwise a
solution of 6-chloropyridine-3-carbonyl chloride (1.936 g, 11.00
mmol, 1.10 equiv) in DCM (50 mL). After stirring for 1 h at
0.degree. C., the reaction mixture was quenched by careful addition
of 50 mL of water and extracted with 2.times.50 mL of
dichloromethane. The combined organic layers were washed with
2.times.50 mL of brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to yield 4.41 g (90%) of the
title compound as a yellow solid.
##STR00617##
Compound 42.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl-
)-6-(isopropylamino)nicotinamide
[3516] A mixture of compound 42.3 (392 mg, 0.80 mmol, 1.00 equiv),
propan-2-amine (472 mg, 7.99 mmol, 10.00 equiv), potassium
carbonate (221 mg, 1.60 mmol, 2.01 equiv), KI (66.4 mg, 0.40 mmol,
0.50 equiv) in DMSO (10 mL) was heated at 100.degree. C. in a
sealed tube behind a blast shield. After 48, the mixture was
allowed to reach ambient temperature and was then diluted with 20
mL of EtOAc. The mixture was washed with 1.times.20 mL of water
followed by 1.times.20 mL of brine. The organic phase was dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The crude product (.about.300 mg) was purified by
Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)):
Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH
0.05% TFA and CH3CN (15.0% CH3CN up to 40.0% in 6 min, up to 100.0%
in 2 min, down to 15.0% in 2 min); Detector, uv 220&254 nm. The
fractions containing pure compound were combined and lyophilized to
yield 158 mg (39%) of the title compound as an off-white solid. m/z
(ES+) 514 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD, ppm):
.delta. 8.49 (s, 1H), 8.32 (d, J=9.9 Hz, 1H), 7.79 (d, J=8.1 Hz,
2H), 7.67 (d, J=7.5 Hz, 2H), 7.40-7.22 (m, 2H), 7.07 (d, J=9.6 Hz,
1H), 4.85 (m, 1H), 4.03 (m, 1H), 3.80-3.42 (m, 2H), 3.29 (m, 1H),
2.48-2.03 (m, 9H), 1.95 (m, 1H), 1.39 (d, J=6.3 Hz, 6H).
##STR00618##
Compound 43.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl-
)-6-morpholinonicotinamide
[3517] A mixture of compound 42.3 (392 mg, 0.80 mmol, 1.00 equiv),
morpholine (348 mg, 3.99 mmol, 5.00 equiv), and potassium carbonate
(221 mg, 1.60 mmol, 2.01 equiv) in DMSO (10 mL) was stirred
overnight at 100.degree. C. in a sealed tube behind a blast shield.
After cooling to ambient temperature, the reaction mixture was
diluted with 20 mL of EtOAc and was washed with 1.times.20 mL of
water followed by 1.times.20 mL of brine. The organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The crude product (300 mg) was purified by Prep-HPLC with
the following conditions (1#-Pre-HPLC-002(Agilent)): Column,
1#-PrepC-005(XBridge C18 19*150 186002979 170130047113 03), n;
mobile phase, WATER WITH 0.05% TFA and CH.sub.3CN (15.0% CH.sub.3CN
up to 50.0% in 10 min, up to 100.0% in 1 min, hold 100.0% in 1 min,
down to 15.0% in 2 min); Detector, uv 220&254 nm. The fractions
containing pure compound were combined and lyophilized to yield 106
mg (25%) of the title compound as a white solid m/z (ES+) 542
(M+H).sup.+.
##STR00619##
Compound 44.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl-
)-6-((2-methoxyethyl)(methyl)amino)nicotinamide
[3518] The title compound was synthesized in a similar manner to
that described for compound 43 to yield a white solid (219 mg,
50%). m/z (ES+) 544 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 8.56 (s with fine structure, 1H), 8.41 (d with fine
structure, J=9.9 Hz, 1H), 7.79 (br d, J=8.1 Hz, 2H), 7.67 (br d,
J=6.9 Hz, 2H), 7.44-7.19 (m, 3H), 4.88-4.73 (m, 1H), 3.94 (t, J=5.0
Hz, 2H), 3.73 (t, J=5.0 Hz, 2H), 3.70-3.47 (m, 2H), 3.39 (s, 3H),
3.36 (s, 3H), 3.36-3.21 (m, 1H), 2.46-2.22 (m, 6H), 2.22-1.85 (m,
4H).
##STR00620##
Compound 45.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl-
)-6-(4-methylpiperazin-1-yl)nicotinamide
[3519] The title compound was synthesized in a similar manner to
that described for compound 43 to yield a white solid (180 mg,
44%). m/z (ES+) 555 (M+H).sup.+.
##STR00621##
Compound 46.
6-(Azetidin-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)--
2,4-dimethylphenyl)nicotinamide
[3520] The title compound was synthesized in a similar manner to
that described for compound 43 to yield a white solid (180 mg,
44%). m/z (ES+) 512 (M+H).sup.+.
##STR00622##
Compound 47.1.
6-(1-(5-Amino-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)nicotinonit-
rile
[3521] The title compound was synthesized in a similar manner to
that described for 42.2 and using compound 26.4 in place of
compound 1.5 to yield a brown oil (280 mg, 89%).
##STR00623##
Compound 47.2.
6-Chloro-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-e-
thyl-4-methylphenyl)nicotinamide
[3522] The title compound was synthesized in a similar manner to
that described for compound 42.3 to yield a brown oil (350 mg,
91%).
##STR00624##
Compound 47.
6-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carb-
onyl)-2-ethyl-4-methylphenyl)nicotinamide
[3523] The title compound was synthesized in a similar manner to
that described for compound 43 to yield a white solid (187 mg,
54%). m/z (ES+) 527 (M+H).sup.+. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 9.88 (s, 1H), 9.06 (s, 1H), 8.59 (d, J=1.8
Hz, 1H), 8.43 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 8.23 (d, J=9.3 Hz, 1H),
7.81 (d, J=8.1 Hz, 1H), 7.22 (s, 1H), 7.17 (br s, 1H), 6.74 (d,
J=9.0 Hz, 1H), 4.68-4.53 (m, 1H), 4.23 (t, J=7.7 Hz, 4H), 3.54-3.32
(m, 2H), 3.22-3.05 (m, 1H), 2.59 (q, J=7.5 Hz, 2H), 2.50-2.38 (m,
2H), 2.35-1.80 (m, 7H), 1.14 (t, 3H).
##STR00625##
Compound 48.1. Methyl 2-ethyl-4-methylbenzoate
[3524] To a stirred mixture of ZnBr.sub.2 (13 g, 57.72 mmol, 2.00
equiv) in THF (230 mL) under nitrogen at 0.degree. C. was added
dropwise EtMgBr (19.5 mL, 3 M in THF). After 30 minutes at
0.degree. C., the temperature was lowered to -78.degree. C. and
Pd(dppf)Cl.sub.2 (2 g, 2.73 mmol, 0.09 equiv) was added followed by
dropwise addition of a solution of methyl 2-bromo-4-methylbenzoate
(6.6 g, 28.81 mmol, 1.00 equiv) in tetrahydrofuran (200 mL). The
resulting mixture was allowed to slowly reach ambient temperature
and stirred under nitrogen overnight. The reaction mixture was
quenched by the careful addition of 20 mL NH.sub.4Cl (aq., sat.)
and extracted with 3.times.100 mL of ethyl acetate. The combined
organic layers were washed with 1.times.200 mL of brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified using silica gel column chromatography
with ethyl acetate/petroleum ether (1:30) as eluent to yield 3.7 g
(72%) of the title compound as a colorless oil.
##STR00626##
Compound 48.2. 2-Ethyl-4-methylbenzoic Acid
[3525] A mixture of compound 48.1, 3.7 g, 20.76 mmol, 1.00 equiv)
and sodium hydroxide (4 g, 100.01 mmol, 4.82 equiv) in
methanol/H.sub.2O (30/20 mL was stirred overnight at 50.degree. C.
After cooling to ambient temperature, the organic solvent was
removed under reduced pressure. The pH of the residual aqueous
layer was adjusted to 3-4 with hydrogen chloride (aq., 1 M). The
resulting precipitate was collected by filtration and dried to
yield in 3.0 g (83%) of the title compound as a white solid.
##STR00627##
Compound 48.3. 2-Ethyl-4-methyl-5-nitrobenzoic Acid
[3526] To a stirred mixture of 2-ethyl-4-methylbenzoic acid
(compound 48.2, 2 g, 12.18 mmol, 1.00 equiv) in sulfuric acid (30
mL) at -10.degree. C. was added dropwise a solution of nitric acid
(1.6 g, 16.50 mmol, 2.08 equiv) in sulfuric acid (10 mL). After
stirring for 30 min at -10.degree. C., 200 mL of H.sub.2O/ice was
carefully added and the resulting mixture was extracted with 50 mL
of ethyl acetate. The organic phase was washed with 2.times.50 mL
of brine, dried over sodium sulfate, and concentrated under reduced
pressure. The crude product was purified by re-crystallization from
ethyl acetate/petroleum ether in the ratio 1:10 to yield 1.0 g
(37%) of 2-ethyl-4-methyl-5-nitrobenzoic acid as a light-yellow
solid.
##STR00628##
Compound 48.4. 5-Amino-2-ethyl-4-methylbenzoic Acid
[3527] The title compound was synthesized from 48.3 (1 g, 4.78
mmol) using a procedure similar to that described for the
preparation of 1.9 to yield the title compound as a light pink
solid (900 mg, 97%).
##STR00629##
Compound 48.5.
4-(1-(5-Amino-2-ethyl-4-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitril-
e
[3528] A mixture of 5-amino-2-ethyl-4-methylbenzoic acid (compound
48.4, 100 mg, 0.56 mmol, 1.00 equiv), 4-(4-fluoropiperidin-4-yl)
benzonitrile (compound 11.2, 140 mg, 0.69 mmol, 1.23 equiv), HBTU
(320 mg, 0.84 mmol, 1.51 equiv), and DIEA (150 mg, 1.16 mmol, 2.08
equiv) in DMF (20 mL) was stirred for 48 h at room temperature.
Water (30 mL) was added and the resulting mixture was extracted
with 3.times.20 mL of ethyl acetate. The combined organic layers
were washed with 1.times.50 mL of brine, dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
residue was purified using silica gel column chromatography with
PE:EtOAc (1:1) to yield 130 mg (38%) of the title compound as a
light yellow solid.
##STR00630##
Compound 48.6.
6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-
-methylphenyl)nicotinamide
[3529] The title compound was synthesized in a similar manner to
that described for compound 42.3 and using compound 48.5 in place
of compound 42.2 to yield a light yellow solid (200 mg, 87%).
##STR00631##
Compound 48.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylph-
enyl)-6-(isopropylamino)nicotinamide
[3530] The title compound was synthesized in a similar manner to
that described for compound 43 and using compound 48.6 in place of
compound 42.3 to yield an off-white solid (32 mg, 30%). m/z (ES+)
528 (M+H).sup.+.
##STR00632##
Compound 49.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-6--
(isopropylamino)nicotinamide
[3531] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43.
m/z (ES+) 500 (M+H).sup.+.
##STR00633##
Compound 50.1. tert-Butyl
5-cyano-5',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate
[3532] To a stirred mixture of tert-butyl
4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound
26.2, 500 mg, 1.65 mmol, 1.00 equiv) in pyridine (20 mL) was added
dropwise phosphoryl trichloride (2.5 g, 16.34 mmol, 9.90 equiv) at
10-15.degree. C. The resulting solution was stirred for 18 h at
15-20.degree. C. The reaction was then carefully quenched by the
addition of 20 mL of water and extracted with 3.times.100 mL of
ethyl acetate. The combined organic phases were washed with
2.times.50 mL of aqueous HCl (1 M) followed by 1.times.100 mL of
brine. The organic layer was dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:100 to 1:7) as eluent to yield 0.3 g (64%) of the title
compound as a yellow solid.
##STR00634##
Compound 50.2. tert-butyl
4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate
[3533] Around-bottom flask, containing a solution of compound 50.1
(300 mg, 1.05 mmol, 1.00 equiv) in ethyl acetate (20 mL), was
purged with nitrogen gas. To the solution was then added palladium
on carbon (40 mg, 10%) and the flask was purged further with
nitrogen gas. The atmosphere was then changed to hydrogen and the
mixture was stirred for 16 h at 15-20.degree. C. After purging the
system with nitrogen, the solids were removed by filtration and the
filtrate was concentrated under reduced pressure to yield 0.2 g
(66%) of the title compound as a yellow oil.
##STR00635##
Compound 50.3. 6-(Piperidin-4-yl)nicotinonitrile hydrochloride
[3534] Through a solution of tert-butyl
4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate (compound 50.2, 200
mg, 0.70 mmol, 1.00 equiv) in ethyl acetate (20 mL) was bubbled HCl
gas. The resulting mixture was stirred for 40 min at 5-10.degree.
C. The resulting precipitate was collected by filtration and dried
to yield 150 mg (97%) of the title compound as a white solid.
##STR00636##
Compound 50.
N-(5-(4-(5-Cyanopyridin-2-yl)piperidine-1-carbonyl)-2-methylphenyl)-6-(is-
opropylamino)nicotinamide
[3535] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43
but using compound 50.3 in place of compound 11.2. m/z (ES+) 483
(M+H).sup.+.
##STR00637##
Compound 51.1. tert-Butyl
4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate
[3536] To a solution of 2,5-dibromopyridine (10 g, 42.55 mmol, 1.00
equiv) in tetrahydrofuran (400 mL) under nitrogen at -78.degree. C.
was added dropwise n-BuLi (19 mL, 2.4 M in THF). After 1 h at
-78.degree. C., a solution of tert-butyl
4-oxopiperidine-1-carboxylate (9.5 g, 47.74 mmol, 1.12 equiv) in
tetrahydrofuran (100 mL) was added dropwise. The resulting mixture
was stirred for an additional hour at -78.degree. C. The reaction
was then warmed to -30.degree. C. and carefully quenched by the
addition of 300 mL of water. The resulting mixture was extracted
with 3.times.200 mL of ethyl acetate and the combined organic
layers were washed with 1.times.200 mL of brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified using silica gel column chromatography
with ethyl acetate/petroleum ether (1:3) as eluent to yield 5 g
(33%) of the title compound as a yellow solid.
##STR00638##
Compound 51.2. tert-Butyl
4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate
[3537] To a mixture of tert-butyl
4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound
51.1, 1 g, 2.81 mmol, 1.00 equiv) in DMF (50 mL) under nitrogen at
50.degree. C. was added Zn(CN).sub.2 (400 mg, 3.42 mmol, 1.22
equiv) at 50.degree. C. followed by Pd(PPh.sub.3).sub.4 (200 mg,
0.17 mmol, 0.06 equiv) at 80.degree. C. The resulting mixture was
then stirred for 1 h at 120.degree. C. After cooling to ambient
temperature, the reaction was quenched by the addition of 200 mL of
FeSO.sub.4 (aq., sat.) and diluted with ethyl acetate. The
resulting mixture was stirred vigorously then filtered through
celite and washed with 1 M FeSO.sub.4, water, and ethyl acetate.
The layers were separated and the aqueous phase was extracted with
2.times.100 mL of ethyl acetate. The combined organic layers were
washed with 1.times.200 mL of brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:5-1:3) as eluent to yield 0.6 g (70%) of
the title compound as a light yellow oil.
##STR00639##
Compound 51.3. tert-Butyl
6-cyano-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate
[3538] To solution of tert-butyl
4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound
51.2, 600 mg, 1.98 mmol, 1.00 equiv) in pyridine (15 mL) under
nitrogen at 10-15.degree. C. was carefully added POCl.sub.3 (3 g,
19.74 mmol, 9.97 equiv). After stirring overnight under nitrogen in
a water/ice bath, the mixture was concentrated and the residue was
dissolved in 50 mL of ethyl acetate. The organic phase was washed
with 1.times.50 mL of hydrogen chloride (aq. 1M) followed by
1.times.50 mL of sodium bicarbonate (aq.sat.). The organic layer
was then dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:10) as the
eluent to yield 0.26 g (46%) of the title compound as a white
solid.
##STR00640##
Compound 51.4. tert-Butyl
4-(6-cyanopyridin-3-yl)piperidine-1-carboxylate
[3539] A round-bottom flask, containing a solution of compound 51.3
(260 mg, 0.91 mmol, 1.00 equiv) in ethyl acetate (40 mL) was purged
with nitrogen gas. To the solution was then added palladium on
carbon (0.1 g, 10%, 60% water) and the flask was purged further
with nitrogen gas. The atmosphere was then changed to hydrogen and
the mixture was stirred for 16 h at 15-20.degree. C. After purging
the system with nitrogen, the solids were removed by filtration and
the filtrate was concentrated under reduced pressure. The crude
residue was purified using silica gel column chromatography with
ethyl acetate/petroleum ether (1:5). This resulted in 0.18 g (69%)
of the title compound as a colorless oil.
##STR00641##
Compound 51.5. 5-(Piperidin-4-yl)picolinonitrile hydrochloride
[3540] Into a cooled (5-10.degree. C.) solution of tert-butyl
4-(6-cyanopyridin-3-yl)piperidine-1-carboxylate (51.4, 180 mg, 0.63
mmol, 1.00 equiv) in ethyl acetate (30 mL) was bubbled hydrogen
chloride gas. The mixture was stirred for 30 min at 5-10.degree. C.
and the resulting solids were collected by filtration and dried to
yield 0.11 g (78%) of 5-(piperidin-4-yl)picolinonitrile
hydrochloride as a white solid.
##STR00642##
Compound 51.
N-(5-(4-(6-Cyanopyridin-3-yl)piperidine-1-carbonyl)-2-methylphenyl)-6-(is-
opropylamino)nicotinamide
[3541] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43
but using compound 51.5 in place of compound 11.2. m/z (ES+) 483
(M+H).sup.+.
##STR00643##
Compound 52.
N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridazin-3-yl)-6-(isopropyl-
amino)nicotinamide
[3542] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43.
m/z (ES+) 470 (M+H).sup.+.
##STR00644##
Compound 53.
2-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)piperidine-1-carbonyl)-2-m-
ethylphenyl)pyrimidine-5-carboxamide
[3543] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 50.
m/z (ES+) 482 (M+H).sup.+.
##STR00645##
Compound 54.
2-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carb-
onyl)-2-methylphenyl)pyrimidine-5-carboxamide
[3544] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 47.
m/z (ES+) 500 (M+H).sup.+.
##STR00646##
Compound 55.
6-(Azetidin-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)--
2-ethylphenyl)nicotinamide
[3545] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43.
m/z (ES+) 512 (M+H).sup.+.
##STR00647##
Compound 56.
6-(Azetidin-1-yl)-N-(5-(4-fluoro-4-(5-methoxypyridin-2-yl)piperidine-1-ca-
rbonyl)-2-methylphenyl)nicotinamide
[3546] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43.
m/z (ES+) 504 (M+H).sup.+.
##STR00648##
Compound 57.
6-(Azetidin-1-yl)-N-(2-chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-c-
arbonyl)phenyl)nicotinamide
[3547] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43.
m/z (ES+) 518 (M+H).sup.+.
##STR00649##
Compound 58.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylph-
enyl)-6-morpholinonicotinamide
[3548] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43.
m/z (ES+) 556 (M+H).sup.+.
##STR00650##
Compound 60.
N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylph-
enyl)-6-((2-methoxyethyl)(methyl)amino)nicotinamide
[3549] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 43.
m/z (ES+) 558 (M+H).sup.+.
##STR00651##
Compound 61.
N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethyl-
phenyl)-2-morpholinopyrimidine-5-carboxamide
[3550] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 47.
m/z (ES+) 544 (M+H).sup.+.
##STR00652##
Compound 62.
N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-me-
thylphenyl)-2-morpholinopyrimidine-5-carboxamide
[3551] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 47.
m/z (ES+) 558 (M+H).sup.+.
##STR00653##
Compound 63.
N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-me-
thylphenyl)-6-morpholinonicotinamide
[3552] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 47.
m/z (ES+) 557 (M+H).sup.+.
##STR00654##
Compound 64.
(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylph-
enyl)-3-((tetrahydrofuran-2-yl)methyl)urea
[3553] A mixture of
4-(1-(5-amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile
(compound 42.2, 150 mg, 0.43 mmol, 1.00 equiv), DIEA (560 mg, 4.33
mmol, 10.15 equiv), and CO(OCCl.sub.3).sub.2 (160 mg, 0.54 mmol,
1.26 equiv) in DCM (50 mL) was stirred under nitrogen at room
temperature. After 0.5 h, (R)-(tetrahydrofuran-2-yl)methanamine (52
mg, 0.51 mmol, 1.20 equiv) was added. After stirring for 2 h at
room temperature, the mixture was washed with 2.times.50 mL of
water and 1.times.50 mL of brine. The organic phase was
concentrated under reduced pressure and the residue (.about.200 mg)
was purified by prep-HPLC with the following conditions
(1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, WATER WITH 0.05% TFA and CH.sub.3CN (hold 5.0%
CH.sub.3CN in 2 min, up to 35.0% in 1 min, up to 65.0% in 12 min,
up to 100.0% in 1 min); Detector, UV 254/220 nm. The fractions
containing pure compound were combined and lyophilized to yield 110
mg (54%) of the title compound as a light yellow solid. m/z (ES+)
479 (M+H).sup.+. .sup.1H NMR (300 MHz, DMSO, ppm): .delta. 7.91 (d,
J=8.1 Hz, 2H), 7.77-7.69 (m, 4H), 7.04 (s, 1H), 6.68 (s, 1H), 4.64
(m, 1H), 3.89-3.82 (m, 2H), 3.71 (m, 1H), 3.33-3.23 (m, 3H),
3.11-3.09 (m, 2H), 2.18-2.03 (m, 8H), 1.97-1.84 (m, 4H), 1.57 (m,
1H).
##STR00655##
Compound 65.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl-
)-3-(tetrahydro-2H-pyran-3-yl)urea
[3554] The title compound was synthesized in a similar manner to
that described for compound 64 to yield a yellow solid (111 mg,
53%). m/z (ES+) 479 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 7.80 (d, J=8.1 Hz, 2H), 7.78-7.50 (m, 3H), 7.13 (s, 1H),
4.88-4.72 (m, 1H), 3.94-8.82 (m, 1H), 3.82-3.68 (m, 2H), 3.68-3.33
(m, 3H), 3.33-3.19 (m, 2H), 2.42-2.08 (m, 8H), 2.08-1.74 (m, 4H),
1.74-1.54 (m, 2H).
##STR00656##
Compound 66.
(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylph-
enyl)-3-(tetrahydrofuran-3-yl)urea
[3555] The title compound was synthesized in a similar manner to
that described for compound 64 to yield a light yellow solid (105
mg, 53%). m/z (ES+) 465 (M+H).sup.+.
##STR00657##
Compound 67.
(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-meth-
ylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea
[3556] The title compound was synthesized in a similar manner to
that described for compound 64 but using compound 48.5 in place of
compound 42.2. m/z (ES+) 493 (M+H).sup.+.
##STR00658##
Compound 68.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylph-
enyl)-3-(tetrahydro-2H-pyran-3-yl)urea
[3557] The title compound was synthesized in a similar manner to
that described for compound 64 but using compound 48.5 in place of
compound 42.2. m/z (ES+) 493 (M+H).sup.+.
##STR00659##
Compound 69.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3--
(tetrahydro-2H-pyran-4-yl)urea
[3558] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 465 (M+H).sup.+.
##STR00660##
Compound 70.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3--
(tetrahydro-2H-pyran-3-yl)urea
[3559] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 465 (M+H).sup.+.
##STR00661##
Compound 71.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3--
cyclopentylurea
[3560] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 449 (M+H).sup.+.
##STR00662##
Compound 72.
(R)-1-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-methyl-
phenyl)-3-(tetrahydrofuran-3-yl)urea
[3561] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 452 (M+H).sup.+.
##STR00663##
Compound 73.
(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl-
)-3-(tetrahydrofuran-3-yl)urea
[3562] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 451 (M+H).sup.+.
##STR00664##
Compound 74.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methoxyphenyl)-3-
-(tetrahydrofuran-3-yl)urea
[3563] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 467 (M+H).sup.+.
##STR00665##
Compound 75.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-fluorophenyl)-3--
(tetrahydrofuran-3-yl)urea
[3564] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 455 (M+H).sup.+.
##STR00666##
Compound 76.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethylphenyl)-3-(-
tetrahydrofuran-3-yl)urea
[3565] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 465 (M+H).sup.+.
##STR00667##
Compound 77.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-(trifluoromethyl-
)phenyl)-3-(tetrahydrofuran-3-yl)urea
[3566] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 505 (M+H).sup.+.
##STR00668##
Compound 78.
(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl-
)-3-((tetrahydrofuran-2-yl)methyl)urea
[3567] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 465 (M+H).sup.+.
##STR00669##
Compound 79.
1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3--
(2-methoxyethyl)urea
[3568] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 64.
m/z (ES+) 439 (M+H).sup.+.
##STR00670##
Compound 80.1. (R)-Tetrahydrofuran-3-yl
1H-imidazole-1-carboxylate
[3569] A solution of (R)-tetrahydrofuran-3-ol (500 mg, 5.68 mmol,
1.00 equiv) and CDI (2 g, 12.33 mmol, 2.17 equiv) in
tetrahydrofuran (50 mL) was stirred overnight under nitrogen at
60.degree. C. After cooling to room temperature, the mixture was
concentrated under reduced pressure. The residue was dissolved in
30 mL of DCM and washed with 1.times.50 mL of H.sub.2O. The organic
layer was dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. The crude residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:1) to yield
0.95 g (92%) of the title compound as a white solid.
##STR00671##
Compound 80. (R)-Tetrahydrofuran-3-yl
(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)c-
arbamate
[3570] A mixture of compound 42.2 (200 mg, 0.57 mmol, 1.00 equiv),
(R)-tetrahydrofuran-3-yl 1H-imidazole-1-carboxylate (80.1, 124 mg,
0.68 mmol, 1.20 equiv), and DBU (2.6 mg, 0.02 mmol, 0.03 equiv) in
DMF (50 mL) was stirred for 16 h under nitrogen at 120.degree. C.
After cooling to ambient temperature, the reaction was quenched by
the addition of 200 mL of water. The resulting mixture was
extracted with 3.times.100 mL of ethyl acetate. The combined
organic layers were washed with 1.times.100 mL of brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue (200 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire Prep C18,
19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH.sub.3CN
(40.0% CH.sub.3CN up to 45.0% in 8 min, hold 45.0% in 2 min, up to
100.0% in 1 min, down to 40.0% in 2 min); Detector, uv 220 254 nm.
47.4 mg product was obtained. The fractions containing pure
compound were combined and lyophilized to yield 47.4 mg (18%) of
the title compound as a white solid. m/z (ES+) 466 (M+H).sup.+.
##STR00672##
Compound 81. 1-Acetylpyrrolidin-3-yl
(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)c-
arbamate
[3571] The title compound was synthesized in a similar manner to
that described for compound 80 to yield a white solid (113 mg,
39%). m/z (ES+) 507 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 7.80 (d, J=8.1 Hz, 2H), 7.77-7.61 (m, 2H), 7.52 & 7.33
(2 br singlets, amide rotamers, Ar--H, 1H), 7.17 (s, 1H), 5.41-5.28
(m, 1H), 4.87-4.72 (m, 1H), 3.88-3.42 (m, 6H), 3.33-3.19 (m, 1H),
2.42-1.82 (m, 15H).
##STR00673##
Compound 82. (R)-Tetrahydrofuran-3-yl
(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)carba-
mate
[3572] The title compound was synthesized using readily available
reagents and procedures similar to those described for compound 80.
m/z (ES+) 452 (M+H).sup.+.
[3573] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compounds 1 and 2:
TABLE-US-00001 Cmpnd m/z # Compound Name Compound Structure (ES+)
83 2-(5-(4-(4- cyanophenyl)piperidine- 1-carbonyl)-2,4-
dimethylphenyl)- N,N-dimethyl-6,7- dihydro-3H- imidazo[4,5-
c]pyridine-5(4H)- carboxamide ##STR00674## 511 (M + H).sup.+ 84
4-(1-(2,4-dimethyl- 5-(3,4,6,7- tetrahydropyrano [3,4-d]imidazol-2-
yl)benzoyl) piperidin-4-yl)-N,N- dimethylbenzamide ##STR00675## 487
(M + H).sup.+ 85 (2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano
[3,4-d]imidazol-2- yl)phenyl)(4-(4- fluorophenyl) piperidin-1-yl)
methanone ##STR00676## 434 (M + H).sup.+ 86 (2,4-dimethyl-5-
(3,4,6,7- tetrahydropyrano [3,4-d]imidazol-2- yl)phenyl)(4-(4-
(methylsulfonyl) phenyl)piperidin-1- yl)methanone ##STR00677## 494
(M + H).sup.+ 87 (2,4-dimethyl-5 (3,4,6,7- tetrahydropyrano
[3,4-d]imidazol-2- yl)phenyl)(4-(4- methoxyphenyl) piperidin-1-
yl)methanone ##STR00678## 446 (M + H).sup.+ 88 1-(2-(2,4-dimethyl-
5-(4-(4- (trifluoromethyl) phenyl)piperidine-1- carbonyl)phenyl)-
6,7-dihydro-3H- imidazo[4,5- c]pyridin-5(4H)- yl)ethanone
##STR00679## 525 (M + H).sup.+ 89 4-(1-(5-(5-
(cyclopropanecarbonyl)- 4,5,6,7- tetrahydro-3H- imidazo[4,5-
c]pyridin-2-yl)-2,4- dimethylbenzoyl) piperidin-4- yl)benzonitrile
##STR00680## 508 (M + H).sup.+ 90 1-(2-(5-(4-(4- fluorophenyl)
piperidine-1- carbonyl)-2,4- dimethylphenyl)- 6,7-dihydro-3H-
imidazo[4,5- c]pyridin-5(4H)- yl)ethanone ##STR00681## 475 (M +
H).sup.+ 91 4-(1-(4-methoxy-2- methyl-5-(3,4,6,7- tetrahydropyrano
[3,4-d]imidazol-2- yl)benzoyl)piperidin- 4-yl)benzonitrile
##STR00682## 457 (M + H).sup.+ 92 (4-(4- fluorophenyl)
piperidin-1-yl)(5-(5- (isopropylsulfonyl)- 4,5,6,7-tetrahydro-
3H-imidazo[4,5- c]pyridin-2-yl)-2,4- dimethylphenyl) methanone
##STR00683## 539 (M + H).sup.+ 93 1-(2-(5-(4-(4- fluorophenyl)
piperidine-1-carbonyl)- 2,4-dimethylphenyl)- 6,7-dihydro-3H-
imidazo[4,5- c]pyridin-5(4H)-yl)- 2-methylpropan-1- one
##STR00684## 503 (M + H).sup.+ 94 (2,4-dimethyl-5- (3,4,6,7-
tetrahydropyrano [3,4-d]imidazol-2- yl)phenyl)(4-
phenylpiperidin-1- yl)methanone ##STR00685## 416 (M + H).sup.+ 95
methyl 2-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-
2,4-dimethylphenyl)- 6,7-dihydro-3H- imidazo[4,5- c]pyridine-5(4H)-
carboxylate ##STR00686## 498 (M + H).sup.+ 96 4-(1-(2,4-dimethyl-
5-(5-propionyl- 4,5,6,7-tetrahydro- 3H-imidazo[4,5- c]pyridin-2-
yl)benzoyl) piperidin-4-yl) benzonitrile ##STR00687## 496 (M +
H).sup.+ 97 4-(1-(5-(5- isobutyryl-4,5,6,7- tetrahydro-3H-
imidazo[4,5- c]pyridin-2-yl)-2,4- dimethylbenzoyl) piperidin-4-
yl)benzonitrile ##STR00688## 510 (M + H).sup.+ 98 (2,4-dimethyl-5-
(3,4,6,7- tetrahydropyrano [3,4-d]imidazol-2- yl)phenyl)(4-(p-
tolyl)piperidin-1- yl)methanone ##STR00689## 430 (M + H).sup.+ 99
4-(1-(2,4-dimethyl- 5-(4,5,6,7- tetrahydro-1H- benzo[d]imidazol-2-
yl)benzoyl)piperidin- 4-yl)benzonitrile ##STR00690## 439 (M +
H).sup.+ 100 4-(1-(2,3-dimethyl- 5-(3,4,6,7- tetrahydropyrano
[3,4-d]imidazol-2- yl)benzoyl)piperidin- 4-yl)benzonitrile
##STR00691## 441 (M + H).sup.+ 101 4-(1-(2-chloro-3- (3,4,6,7-
tetrahydropyrano [3,4-d]imidazol-2- yl)benzoyl)piperidin-
4-yl)benzonitrile ##STR00692## 447 (M + H).sup.+ 102
4-(1-(3-(5-isopropyl- 4,5,6,7-tetrahydro- 3H-imidazo[4,5-
c]pyridin-2-yl)-4- methylbenzoyl) piperidin-4- yl)benzonitrile
##STR00693## 468 (M + H).sup.+ 103 methyl 2-(5-(4-(4- cyanophenyl)
piperidine-1-carbonyl)-2- methylphenyl)-6,7- dihydro-3H-
imidazo[4,5- c]pyridine-5(4H)- carboxylate ##STR00694## 484 (M +
H).sup.+ 104 (2,4-dimethyl-5-(5- methyl-4,5,6,7- tetrahydro-3H-
imidazo[4,5- c]pyridin-2- yl)phenyl)(4-(4- (trifluoromethyl)
phenyl)piperidin- 1-yl)methanone ##STR00695## 497 (M + H).sup.+
##STR00696##
Compound 105.
4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)b-
enzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3574] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 20, except compound 11.2 HCl salt was used
in place of compound 1.5. m/z (ES+) 523 (M+H).sup.+.
##STR00697##
Compound 106.
4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-4-fluoro-2-meth-
ylbenzoyl)piperidin-4-yl)benzonitrile
[3575] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 20, except 4-fluoro-2-methylbenzoic acid
and azetidine were used in place of 2,4-dimethylbenzoic acid and
pyrrolidine respectively. m/z (ES+) 495 (M+H).
[3576] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compound 20:
TABLE-US-00002 Cmpnd m/z # Compound Name Compound Structure (ES+)
107 2-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-
2,4-dimethylphenyl)- 1H-benzo[d] imidazole-5- carboxylic acid
##STR00698## 479 (M + H).sup.+ 108 4-(1-(5-(3H- imidazo[4,5-
c]pyridin-2-yl)- 2,4-dimethylbenzoyl) piperidin-4- yl)benzonitrile
##STR00699## 436 (M + H).sup.+ 109 2-(5-(4-(4- cyanophenyl)
piperidine-1-carbonyl)- 2,4-dimethylphenyl)- N,N-dimethyl-1H-
benzo[d]imidazole- 5-carboxamide ##STR00700## 506 (M + H).sup.+ 110
2-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-
2,4-dimethylphenyl)- 1H-benzo[d]imidazole- 5-carboxamide
##STR00701## 478 (M + H).sup.+ 111 2-(5-(4-(4- cyanophenyl)
piperidine-1-carbonyl)- 2,4-dimethylphenyl)- 1H-benzo[d]imidazole-
5-carbonitrile ##STR00702## 460 (M + H).sup.+ 112
4-(1-(2,4-dimethyl- 5-(4-(oxetan-3-yl)- 3H-imidazo[4,5-
c]pyridin-2- yl)benzoyl)piperidin- 4-yl)benzonitrile ##STR00703##
492 (M + H).sup.+ 113 4-(1-(5-(4- methoxy-3H- imidazo[4,5-
c]pyridin-2-yl)- 2,4-dimethylbenzoyl) piperidin-4- yl)benzonitrile
##STR00704## 466 (M + H).sup.+ 114 4-(1-(2,4-dimethyl-
5-(4-oxo-4,5- dihydro-3H- imidazo[4,5- c]pyridin-2- yl)benzoyl)
piperidin-4-yl) benzonitrile ##STR00705## 452 (M + H).sup.+ 115
4-(1-(5-(4- (azetidin-1-yl)-3H- imidazo[4,5- c]pyridin-2-yl)-2,4-
dimethylbenzoyl) piperidin-4- yl)benzonitrile ##STR00706## 491 (M +
H).sup.+ 116 4-(1-(2,4-dimethyl- 5-(6-(oxetan-3- yloxy)-3H-
imidazo[4,5- c]pyridin-2- yl)benzoyl) piperidin-4-yl) benzonitrile
##STR00707## 508 (M + H).sup.+ 117 4-(1-(2,4-dimethyl-
5-(4-(pyrrolidin-1- yl)-3H-imidazo[4,5- c]pyridin-2- yl)benzoyl)
piperidin-4- yl)benzonitrile ##STR00708## 505 (M + H).sup.+
Compound 118.1. Tetramethyl
2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylate
[3577] A mixture of
(E)-N-(4-methoxybenzylidene)-4-methylbenzenesulfonamide (2.89 g, 10
mmol), dimethyl malonate (3.43 mL, 30 mmol), t-BuOK (2.24 g, 20
mmol) in anhydrous t-BuOH (20 mL) was heated at 50.degree. C. for 4
h. After cooling to room temperature, the reaction mixture was
poured into saturated aqueous NH.sub.4Cl and extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organic layer was dried
over MgSO.sub.4, filtered, and then concentrated. The residue was
purified by flash column chromatography with EtOAc in hexane (10%,
20%, 30%, then 40%) to give the title compound as a clear oil
(3.255 g, 85% yield).
##STR00709##
Compound 118.2. 3-(4-Methoxyphenyl)pentanedioic acid and
3-(4-hydroxyphenyl)pentanedioic Acid
[3578] A mixture of tetramethyl
2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylate (compound
118.1, 6.0 g, 15.7 mmol) in concentrated HCl (37%, 80 mL) was
heated under reflux overnight. After cooling to room temperature,
the suspension was filtered. The filtrate was washed with water and
dried under vacuum to give 2.66 g product as a mixture of
3-(4-methoxyphenyl)pentanedioic acid (major, LCMS observed
[M-H].sup.- 237) and 3-(4-hydroxyphenyl)pentanedioic acid (minor,
LCMS observed [M-H].sup.- 223).
##STR00710##
Compound 118.3. Dimethyl 3-(4-methoxyphenyl)pentanedioate
[3579] A mixture of the product (compound 118.2) obtained from the
previous step (2.66 g), K.sub.2CO.sub.3 (6.56 g, 47.5 mmol) and
CH.sub.3I (3 mL, 47.5 mmol) in DMF (10 mL) was heated at 50.degree.
C. in a pressure tube overnight. After cooling to room temperature,
the reaction mixture was poured into saturated aqueous NaHCO.sub.3
and extracted with EtOAc (3.times.). The combined organic extract
was dried over MgSO.sub.4, filtered and concentrated. The residue
was purified by flash column chromatography with EtOAc in hexane
(20%, 30%, 40%, then 50%) to give the title compound as a clear oil
(2.0 g, 48% yield over two steps).
##STR00711##
Compound 118.4. Dimethyl
3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate
[3580] To a solution of LDA (18.8 mmol) in THF (60 mL) at
-78.degree. C. was added a solution of dimethyl
3-(4-methoxyphenyl)pentanedioate (2.0 g, 7.52 mmol) in THF (10 mL)
dropwise. After stirring at -78.degree. C. for 1 h, the dry
ice-acetone bath was removed. The reaction mixture was stirred for
30 min before being cooled to -78.degree. C. Solid AgCl (2.2 g,
15.4 mmol) was added all at once. The reaction mixture was stirred
at -78.degree. C. for 1 h and then room temperature overnight.
Saturated aqueous NH.sub.4Cl was added. The mixture was vigorously
stirred for 10 min. The suspension was filtered through celite. The
filtrate was extracted with EtOAc (3.times.). The combined organic
extract was dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by flash column chromatography with EtOAc in
hexane (10%, 15%, 20%, then 30%) to give the title compound as a
pale yellow solid (0.87 g, 44% yield). .sup.1HNMR (CDCl.sub.3, 400
Hz) .delta. 7.09 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.82
(s, 3H), 3.77 (s, 6H), 3.17 (t, J=7.6 Hz, 1H), 2.36 (d, J=7.6 Hz,
2H).
##STR00712##
Compound 118.5. 3-(4-Methoxyphenyl)cyclopropane-1,2-dicarboxylic
Acid
[3581] A mixture of dimethyl
3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate (0.88 g, 3.33
mmol) and LiOH (2M in H.sub.2O, 10 mL) in THF (30 mL) was stirred
at 55.degree. C. overnight. After cooling to room temperature, the
reaction mixture was poured into 1N HCl and extracted with EtOAc
(3.times.). The combined organic extract was dried over MgSO.sub.4,
filtered, and concentrated to give the title compound as a light
yellow solid.
##STR00713##
Compound 118.6.
6-(4-Methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione
[3582] A mixture of
3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid (crude
product from the previous step) in Ac.sub.2O (20 mL) was heated
under reflux for 1 h. Excess Ac.sub.2O was removed under reduced
pressure. The crude product was used in the next step without
further purification.
##STR00714##
Compound 118.7.
3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dio-
ne
[3583] A mixture of
6-(4-Methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione (crude
product from the previous step) and (4-methoxyphenyl)methanamine
was heated at 180.degree. C. for 1.5 h. After cooling to room
temperature, the reaction mixture was dissolved in CH.sub.2Cl.sub.2
and purified by flash column chromatography with EtOAc in hexane
(20%, 30%, then 40%) to give the title compound as a yellow solid
(0.71 g, 63% yield over three steps). MS [M+H].sup.+: 338.
##STR00715##
Compound 118.8.
3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane
[3584] A mixture of
3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dio-
ne (0.86 g, 2.6 mmol), NaBH.sub.4 (0.296 g, 7.8 mmol) and BF.sub.3
etherate (1.0 mL, 7.8 mmol) in THF was heated under reflux
overnight. After cooling to 0.degree. C., a solution of piperazine
(2 g) in H.sub.2O (20 mL) was added. The mixture was stirred at
room temperature for 2 h, poured into H.sub.2O and extracted with
EtOAc (3.times.). The combined organic extract was dried over
MgSO.sub.4, filtered and then concentrated. The residue was
purified by flash column chromatography with EtOAc in hexane (10%,
20%, then 30%) to give a white solid. To a suspension of the solid
in THF (20 mL) and H.sub.2O (10 mL) was added piperazine (3 g).
After heating the mixture under reflux overnight, it was poured
into brine and extracted with EtOAc (3.times.). The combined
organic extract was dried over MgSO.sub.4, filtered and
concentrated to give the title compound as white solid (0.51 g, 65%
yield). MS [M+H].sup.+: 310.
##STR00716##
Compound 118.9. 6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane
[3585] To a solution of
(1R,5S,6S)-3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hex-
ane (0.5 g, 1.6 mmol) in DCE (30 mL) at 0.degree. C. was added
1-chloroethyl chloroformate (0.21 mL, 1.9 mmol, 1.2 equiv). The
reaction mixture was stirred at 0.degree. C. for 30 min, heated
under reflux for 1 h and then concentrated under reduced pressure.
MeOH (20 mL) was added. The resulting mixture was heated under
reflux for 40 min and then concentrated. The residue was purified
by preparative TLC to give the title compound as a white
crystalline solid (155 mg, 51% yield). MS [M+H].sup.+: 190.
##STR00717##
Compound 118.10.
(3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-y-
l)methanone
[3586] A mixture of 6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane
(0.124 g, 0.82 mmol), 3-amino-4-methylbenzoic acid (0.155 g, 0.82
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDCI, 0.172 g, 0.90 mmol), 1-hydroxybenzotriazole (.about.20%
H.sub.2O, 0.122 g, 0.90 mmol) and diisopropylethylamine (0.71 mL,
4.1 mmol) in DMF (3 mL) was stirred at room temperature overnight.
The reaction mixture was poured into saturated aqueous NaHCO.sub.3
and extracted with EtOAc (3.times.). The combined organic extract
was dried over MgSO.sub.4, filtered and concentrated. The residue
was purified by flash column chromatography with EtOAc in hexane
(60%, then 100%) to give the title compound as a white foam (0.15
g, 57% yield).
##STR00718##
Compound 118.11.
6-Chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)--
2-methylphenyl)nicotinamide
[3587] To a solution of
(3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-y-
l)methanone (150 mg, 0.47 mmol) and Et.sub.3N (0.25 mL, 1.8 mmol)
in CH.sub.2Cl.sub.2 (4 mL) at 0.degree. C. was added
6-chloronicotinoyl chloride (106 mg, 0.6 mmol). The ice bath was
removed after the addition. The reaction mixture was stirred at
room temperature for 1.5 h and then purified by flash column
chromatography with EtOAc in hexane (60%, then 100%) to give the
title compound as a white foam (0.172 g, 80% yield). MS
[M+H].sup.+: 462, 464.
##STR00719##
Compound 118.
6-(Isopropylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3--
carbonyl)-2-methylphenyl)nicotinamide
[3588] A mixture of
6-chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)--
2-methylphenyl)nicotinamide (compound 118.11, 0.107 g, 0.23 mmol)
and isopropylamine (1.5 mL) in DMSO (1.5 mL) was heated at
120.degree. C. in a sealed pressure tube overnight. After cooling
to room temperature, the reaction mixture was poured into saturated
aqueous NaHCO.sub.3 and extracted with EtOAc (3.times.). The
combined organic extract was dried over MgSO.sub.4, filtered and
concentrated. The residue was triturated with hexane to give the
title compound as a white powder (40 mg, 36% yield). MS
[M+H].sup.+: 485. .sup.1H-NMR (DMSO-d.sub.6, 400 Hz) .delta. 9.63
(s, 1H), 8.69 (d, J=3 Hz, 1H), 7.95-7.90 (m, 1H), 7.55-7.51 (m,
1H), 7.39-7.30 (m, 2H), 7.10-7.03 (m, 3H), 6.84 (d, J=9.2 Hz, 2H),
6.52 (d, J=9.2 Hz, 1H), 4.17-4.07 (m, 2H), 3.85-3.77 (m, 1H), 3.74
(s, 3H), 3.65-3.51 (m, 2H), 2.30 (s, 3H), 1.87 (s, 2H), 1.69 (t,
J=3.7 Hz, 1H), 1.20 (d, J=7.2 Hz, 6H).
##STR00720##
Compound 119.
6-(Ethylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carb-
onyl)-2-methylphenyl)nicotinamide
[3589] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 118. MS [M+H].sup.+: 471. .sup.1HNMR
(DMSO-d.sub.6, 400 Hz) .delta. 9.62 (s, 1H), 8.66 (d, J=2.4 Hz,
1H), 7.91 (dd, J=2.4, 9.0 Hz, 1H), 7.50 (s, 1H), 7.34-7.24 (m, 2H),
7.18 (t, J=6.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz,
2H), 6.50 (d, J=9.2 Hz, 1H), 4.08 (d, J=12.4 Hz, 1H), 3.81-3.75 (m,
1H), 3.70 (s, 3H), 3.59 (d, J=11.2 Hz, 1H), 3.52 (d, J=13.2 Hz,
1H), 3.37-3.30 (m, 2H), 2.26 (s, 3H), 1.84 (s, 2H), 1.66 (t, J=3.2
Hz, 1H), 1.16 (t, J=8.4 Hz, 3H).
##STR00721##
Compound 120.
1-(5-(6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylp-
henyl)-3-(tetrahydrofuran-3-yl)urea
[3590] The title compound was prepared using readily available
reagents and procedures similar to those used for the preparation
of compounds 64 and 118. m/z (ES+) 436 (M+H).sup.+.
##STR00722##
Compound 121.1.
4-(1-(3-Amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile
[3591] A solution of 3-amino-4-methylbenzoic acid (1.36 g, 9.0
mmol), (4-(piperidin-4-yl)benzonitrile HCl salt (compound 1.5, 2.0
g, 9.0 mmol), EDCI (1.89 g, 9.9 mmol), HOBT (1.66 g, 9.9 mmol, with
20% H.sub.2O) and DIEA (3.13 ml, 18.0 mmol) in DMF (50 ml) was
stirred at room temperature overnight. The reaction mixture was
poured into cold water (300 ml) and off white solids precipitated.
The precipitate was filtered, washed with water and dried under
reduced pressure in an oven to yield 2.88 g (100%) of the title
compound. m/z (ES+) 320 (M+H).sup.+.
##STR00723##
Compound 121.
6-((5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)amino)-N-is-
opropylnicotinamide
[3592] A mixture of 6-chloro-N-isopropylnicotinamide (0.055 g, 0.26
mmol), 4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile
(121.1, 0.1 g, 0.31 mmol), K.sub.2CO.sub.3 (0.171 g, 1.24 mmol),
Pd(OAc).sub.2 (6.7 mg, 0.03 mmol) and the ligand (10.2 mg, 0.03
mmol) in toluene (5 mL) was heated at 90.degree. C. under argon for
3 h. After cooling to room temperature, the reaction mixture was
diluted with H.sub.2O and extracted with EtOAc. The combined
organic extract was dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by flash column
chromatography with EtOAc in hexane (60%, 80%, then 100%) to give
the title compound as an off-white powder after lyophilization from
CH.sub.3CN/H.sub.2O (11.2 mg, 9% yield). m/z (ES+) 482
(M+H).sup.+.
##STR00724##
Compound 122.
4-(1-(4-Methyl-3-((5-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)amino)be-
nzoyl)piperidin-4-yl)benzonitrile
[3593] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 121 replacing K.sub.2CO.sub.3 with t-BuONa.
m/z (ES+) 524 (M+H).
##STR00725##
Compound 123.
N-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)-6-(pyrrolidin--
1-yl)nicotinamide
[3594] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 43 and using 2-aminoisonicotinic acid in
place of 3-amino-4-methylbenzoic acid. m/z (ES+) 481
(M+H).sup.+.
##STR00726##
Compound 124.
1-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)-3-isobutylurea
[3595] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 64 and using 2-aminoisonicotinic acid in
place of 3-amino-4-methylbenzoic acid. m/z (ES+) 406
(M+H).sup.+.
##STR00727##
Compound 125.
N-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)pyrrolidine-1-c-
arboxamide
[3596] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 64 and using 2-aminoisonicotinic acid in
place of 3-amino-4-methylbenzoic acid. m/z (ES+) 404
(M+H).sup.+.
##STR00728##
Compound 126.
N-(3-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl-
)-6-(isopropylamino)nicotinamide
[3597] The title compound was prepared using readily available
reagents and procedures similar to those used for the preparation
of compound 43 and using 3-amino-2,6-dimethylbenzoic acid in place
of 3-amino-4-methylbenzoic acid. m/z (ES+) 514 (M+H).sup.+.
##STR00729##
Compound 127.
4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2-ethyl-4-methylbenzoyl)piperidi-
n-4-yl)benzonitrile
[3598] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 39. m/z (ES+) 445 (M+H).sup.+.
##STR00730##
Compound 128.
4-(1-(3-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperid-
in-4-yl)benzonitrile
[3599] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)-
piperidin-4-yl)benzonitrile (compound 38). m/z (ES+) 416
(M+H).sup.+.
##STR00731##
Compound 129.
4-(1-(3-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)b-
enzonitrile
[3600] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 38. m/z (ES+) 402 M+H).sup.+.
##STR00732##
Compound 130.1. Methyl 5-carbamothioyl-2,4-dimethylbenzoate
[3601] To a round-bottom flask was added a solution of methyl
5-cyano-2,4-dimethylbenzoate (compound 2.3, 1.78 g, 9.41 mmol, 1.00
equiv) in tetrahydrofuran/H.sub.2O (30/3 mL). O,O'-diethyl
dithiophosphate (3.30 g, 17.7 mmol, 2.00 equiv) was added and the
resulting mixture was stirred for 2 days at 85.degree. C. (CAUTION:
significant gas evolution occurs--this and all other reactions
described herein should be carried out in well ventilated fume
hoods). After cooling to ambient temperature, the mixture was
extracted with 2.times.50 mL of ethyl acetate. The combined organic
layers were dried over sodium sulfate and concentrated in vacuo.
The crude residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:10) as eluent
to furnish 1.20 g (57%) of the title compound as a yellow
solid.
##STR00733##
Compound 130.2. Methyl
5-(imino(methylthio)methyl)-2,4-dimethylbenzoate
[3602] To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate
(compound 130.1, 3.10 g, 12.5 mmol, 1.00 equiv, 90%) in
tetrahydrofuran (30 mL) was added CH.sub.3I (3.95 g, 27.8 mmol,
2.00 equiv) and the resulting mixture was stirred overnight at
25.degree. C. The organic layer was washed with 2.times.30 mL of
Na.sub.2S.sub.2O.sub.4 (aq.) and 1.times.30 mL of brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo. This resulted
in 2.10 g (64%) of methyl
5-(imino(methylthio)methyl)-2,4-dimethylbenzoate as a yellow
oil.
##STR00734##
Compound 130.3. Methyl 2-(tetrahydrofuran-3-yl)acetate
[3603] A mixture of 2-(tetrahydrofuran-3-yl)acetic acid (2.00 g,
15.4 mmol, 1.00 equiv) and sulfuric acid (2 mL) in methanol (20 mL)
was stirred for 3 h at 80.degree. C. in an oil bath. After cooling
to ambient temperature, the mixture was diluted with 50 mL of ether
and washed with 2.times.20 mL of water, 2.times.20 mL of sodium
bicarbonate (aq., sat. Note: gas evolution), and 2.times.20 mL of
brine. The organic phase was then dried over anhydrous sodium
sulfate and concentrated in vacuo to yield 1.50 g (68%) of the
title compound as a yellow oil.
##STR00735##
Compound 130.4. 2-(Tetrahydrofuran-3-yl)acetohydrazide
[3604] To a round-bottom flask was added a solution of methyl
2-(tetrahydrofuran-3-yl)acetate (compound 130.3, 1.50 g, 10.4 mmol,
1.00 equiv) and NH.sub.2NH.sub.2.H.sub.2O (1.04 g, 20.8 mmol, 2.00
equiv) in methanol (15 mL). The resulting mixture was stirred
overnight at 80.degree. C. in an oil bath. After cooling to ambient
temperature, the mixture was concentrated in vacuo to yield 1.20 g
(80%) of the title compound as a yellow oil.
##STR00736##
Compound 130.5. Methyl
2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)be-
nzoate
[3605] To a round-bottom flask was added a solution of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4, 1.20 g,
8.32 mmol, 1.50 equiv) in acetic acid (4 mL). Methyl
2,4-dimethyl-5-(methylsulfanyl) carboximidoylbenzoate (compound
130.2, 1.30 g, 5.48 mmol, 1.00 equiv) was added and the resulting
mixture was stirred overnight at 100.degree. C. in an oil bath.
After cooling to ambient temperature, the mixture was concentrated
in vacuo. The residue was diluted with 50 mL of ethyl acetate, then
washed with 2.times.20 mL of water and 2.times.20 mL of brine. The
organic phase was dried over anhydrous sodium sulfate and
concentrated in vacuo. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether
(0:1-1:10-1:1) as eluent to furnish 0.600 g (35%) of the title
compound as a yellow solid.
##STR00737##
Compound 130.6.
2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)be-
nzoic Acid
[3606] To a round-bottom flask was added a solution of methyl
2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)be-
nzoate (compound 130.5, 600 mg, 1.90 mmol, 1.00 equiv) in methanol
(10 mL). A solution of sodium hydroxide (381 mg, 9.53 mmol, 5.00
equiv) in water (5 mL) was added and the resulting mixture was
stirred for 3 h at 70.degree. C. in an oil bath. After cooling to
room temperature, the organic solvent was then removed under
reduced pressure and the pH of the remaining aqueous phase was
adjusted to 3-4 with hydrogen chloride (aq., 1 M). The resulting
solids were collected via filtration and dried in an oven under
reduced pressure to yield 0.500 g (87%) of the title compound as a
yellow solid.
##STR00738##
Compound 130.
4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile
[3607] A mixture of compound 130.6 (200 mg, 0.660 mmol, 1.00
equiv), EDCI (253 mg, 1.32 mmol, 2.00 equiv), DMAP (243 mg, 1.99
mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride
(compound 1.5, 148 mg, 0.660 mmol, 1.00 equiv) in DMF (5 mL) was
stirred for 3 h at 25.degree. C., then diluted with 50 mL of ethyl
acetate. The organic layer was washed with 2.times.10 mL of water,
2.times.10 mL of brine, dried over anhydrous sodium sulfate and
concentrated in vacuo. The crude product (.about.300 mg) was
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (28%
CH.sub.3CN up to 52% in 8 min, up to 100% in 1 min, down to 28% in
1 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield 168
mg (52%) of the title compound as a white solid. m/z (ES+) 470
(M+H).sup.+. .sup.1H-NMR (400 Hz, CD.sub.3OD): .delta. 7.68 (d,
J=8.0 Hz, 2H), 7.61 (s, 1H), 7.50-7.49 (m, 2H), 7.33-7.31 (m, 1H),
4.90-4.88 (m, 1H), 3.95-3.92 (m, 2H), 3.90-3.81 (m, 1H), 3.79-3.77
(m, 1H), 3.69-3.55 (m, 1H), 3.28-3.25 (m, 1H), 3.03-2.94 (m, 4H),
2.81-2.73 (m, 1H), 2.53 (s, 3H), 2.43 and 2.33 (2 s, amide
rotamers, ArCH.sub.3, 3H), 2.19-2.15 (m, 1H), 2.13-2.05 (m, 1H),
1.94-1.68 (m, 4H).
##STR00739##
Compound 131.
4-(1-(5-(5-(2-Methoxyethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)pi-
peridin-4-yl)benzonitrile
[3608] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
3-methoxypropanehydrazide (compound 143.1) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
444 (M+H).sup.+.
##STR00740##
Compound 132.
4-(1-(5-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)pip-
eridin-4-yl)benzonitrile
[3609] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
2-methoxyacetohydrazide (compound 190.6) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
430 (M+H).sup.+.
##STR00741##
Compound 133.1. (R)-Tetrahydrofuran-2-carbohydrazide
[3610] A mixture of (R)-tetrahydrofuran-2-carboxylic acid (5.00 g,
43.1 mmol, 1.00 equiv), EDCI (12.4 g, 64.6 mmol, 1.50 equiv) and
HOBt (8.70 g, 64.4 mmol, 1.50 equiv) in dichloromethane (100 mL)
was stirred for 30 min at 25.degree. C. To the mixture was then
added hydrazine (2.00 g, 62.4 mmol, 1.50 equiv) dropwise. The
resulting mixture was stirred overnight at 25.degree. C. The solids
were removed by filtration, and the filtrate was concentrated in
vacuo to furnish 25.0 g (crude) of
(R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
##STR00742##
Compound 133.
(R)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)-
benzoyl)piperidin-4-yl)benzonitrile
[3611] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
(R)-tetrahydrofuran-2-carbohydrazide (compound 133.1) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
446 (M+H).sup.+.
##STR00743##
Compound 134.1. Ethyl 2-hydrazinyl-2-oxoacetate
[3612] To a round-bottom flask was added a solution of diethyl
oxalate (10.0 g, 68.4 mmol, 1.00 equiv) in ethanol (100 mL).
Hydrazine hydrate (2.75 g, 85.8 mmol, 1.00 equiv) was added and the
resulting mixture was stirred for 3 h at 80.degree. C. After
cooling to ambient temperature, the solids were removed via
filtration and the filtrate was concentrated in vacuo to yield 8.00
g (80%) of the title compound as a colorless oil.
##STR00744##
Compound 134.2. 2-Hydrazinyl-N-methyl-2-oxoacetamide
[3613] To a round-bottom flask was added a solution of ethyl
2-hydrazinyl-2-oxoacetate (compound 134.1, 300 mg, 2.04 mmol, 1.00
equiv, 90%) in methanol (10 mL). Methyl amine (10 mL, 40% in water)
was added and the resulting mixture was stirred overnight at
70.degree. C. After cooling to ambient temperature, the solids were
collected by filtration and dried to yield 250 mg (94%) of the
title compound as a white solid.
##STR00745##
Compound 134.
5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methy-
l-4H-1,2,4-triazole-3-carboxamide
[3614] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 130, using compound 134.2 instead of
compound 130.4. m/z (ES+) 443 (M+H).sup.+. .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 7.69 (d, J=8.1 Hz, 2H), 7.62-7.43 (m, 3H),
7.32 (s, 1H), .about.4.9 (1H partially obscured by water peak),
3.73-3.58 (m, 1H), 3.32-3.18 (m, 1H partially obscured by methanol
solvent peak), 3.07-1.91 (m, 5H), 2.58 (s, 3H), 2.43 & 2.33 (2
singlets, amide rotamers, Ar--CH.sub.3, 3H), 2.10-1.93 (m, 1H),
1.93-1.52 (m, 3H).
##STR00746##
Compound 135.1. 2-Hydrazinyl-N,N-dimethyl-2-oxoacetamide
[3615] To a round-bottom flask was added ethyl
2-hydrazinyl-2-oxoacetate (compound 134.1, 2.00 g, 13.6 mmol, 1.00
equiv, 90%). Dimethylamine (10 mL) was added to the reaction, and
then the reaction was stirred overnight at 70.degree. C. in an oil
bath. The mixture was cooled to room temperature and concentrated
in vacuo to yield 1.50 g (76%) of the title compound as a colorless
oil.
##STR00747##
Compound 135.
5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dim-
ethyl-4H-1,2,4-triazole-3-carboxamide
[3616] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
2-hydrazinyl-N,N-dimethyl-2-oxoacetamide (compound 135.1) instead
of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z
(ES+) 457 (M+H).sup.+.
##STR00748##
Compound 136.1. (S)-Tetrahydrofuran-2-carbohydrazide
[3617] To a round-bottom flask was added a solution of
(S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 23.3 mmol, 1.00
equiv, 90%) in dichloromethane (40 mL). NH.sub.2NH.sub.2 (2 mL,
2.00 equiv), HOBt (5.20 g, 38.5 mmol, 1.50 equiv), and EDCI (7.50
g, 39.1 mmol, 1.50 equiv) were added and the resulting mixture was
stirred overnight at 25.degree. C. The solids were removed by
filtration, and the filtrate was concentrated in vacuo to furnish
2.50 g (74%) of (S)-tetrahydrofuran-2-carbohydrazide as a yellow
oil.
##STR00749##
Compound 136.
(S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)-
benzoyl)piperidin-4-yl)benzonitrile
[3618] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
(S)-tetrahydrofuran-2-carbohydrazide (compound 136.1) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
456 (M+H).sup.+.
##STR00750##
Compound 137.1. Methyl tetrahydro-2H-pyran-4-carboxylate
[3619] To a solution of tetrahydro-2H-pyran-4-carboxylic acid (520
mg, 4.00 mmol, 1.00 equiv) in methanol (50 mL) was added PTSA (35.0
mg, 0.200 mmol). The resulting mixture was stirred overnight at
80.degree. C. in an oil bath, then cooled to ambient temperature
and concentrated in vacuo. The residue was diluted with 30 mL of
water and extracted with 3.times.30 mL of DCM. The combined organic
layers were dried over anhydrous magnesium sulfate and concentrated
in vacuo. This resulted in 500 mg (87%) of methyl
tetrahydro-2H-pyran-4-carboxylate as a colorless oil.
##STR00751##
Compound 137.2. Tetrahydro-2H-pyran-4-carbohydrazide
[3620] To a round-bottom flask was added a solution of methyl
tetrahydro-2H-pyran-4-carboxylate (compound 137.1, 5.00 g, 31.2
mmol, 1.00 equiv, 90%) in methanol (50 mL). Hydrazine hydrate (5.20
g, 83.2 mmol, 3.00 equiv) was added and the resulting mixture was
stirred overnight at 40.degree. C. in an oil bath. After cooling to
ambient temperature, the mixture was concentrated in vacuo to yield
4.00 g (80%) of tetrahydro-2H-pyran-4-carbohydrazide as a white
solid.
##STR00752##
Compound 137.
4-(1-(2,4-Dimethyl-5-(5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)-
benzoyl)piperidin-4-yl)benzonitrile
[3621] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
tetrahydro-2H-pyran-4-carbohydrazide (compound 137.2) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
470 (M+H).sup.+.
##STR00753##
Compound 138.1. 2-(Tetrahydrofuran-2-yl)acetohydrazide
[3622] To a round-bottom flask was added a solution of ethyl
2-(tetrahydrofuran-2-yl)acetate (2.00 g, 12.6 mmol, 1.00 equiv) in
ethanol (20 mL). NH.sub.2NH.sub.2.H.sub.2O (1.27 g, 25.4 mmol, 2.00
equiv) was added to the reaction. The resulting solution was
stirred overnight at 80.degree. C. in an oil bath, then cooled to
room temperature and concentrated in vacuo. This resulted in 2.10 g
(92%) of 2-(tetrahydrofuran-2-yl)acetohydrazide as a yellow
oil.
##STR00754##
Compound 138.
4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-2-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile
[3623] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
2-(tetrahydrofuran-2-yl)acetohydrazide (compound 138.1) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
470 (M+H).sup.+.
##STR00755##
Compound 139.1. 2-Cyanoacetohydrazide
[3624] To a solution of NH.sub.2NH.sub.2.H.sub.2O (3.50 g, 70.0
mmol, 1.00 equiv) in a solvent mixture of ethanol and Et.sub.2O
(35/35 mL) at 0.degree. C. was added dropwise a solution of methyl
2-cyanoacetate (7.00 g, 70.6 mmol, 1.00 equiv) in ethanol (5 mL).
The resulting mixture was stirred for 3 h at room temperature, then
washed with 2.times.30 mL of ether. The solids were collected by
filtration to yield 5.00 g (68%) of 2-cyanoacetohydrazide as a
white solid.
##STR00756##
Compound 139.
4-(1-(5-(5-(cyanomethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piper-
idin-4-yl)benzonitrile
[3625] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
2-cyanoacetohydrazide (compound 139.1) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
425 (M+H).sup.+. .sup.1H-NMR (300 Hz, CD.sub.3OD): .delta. 7.70 (d,
J=8.4 Hz, 2H), 7.54-7.42 (m, 3H), 7.35 (s, 1H), 4.87-4.80 (m, 1H),
4.12 (s, 2H), 3.77-3.65 (m, 1H), 3.27-3.23 (m, 1H), 3.09-2.99 (m,
2H), 2.55 (s, 3H), 2.43 and 2.33 (2 singlets, amide rotamers,
ArCH.sub.3, 3H), 2.05-2.00 (m, 1H), 1.83-1.76 (m, 3H).
##STR00757##
Compound 140.1. 3-cyanopropanehydrazide
[3626] To a round-bottom flask was added a solution of
NH.sub.2NH.sub.2.H.sub.2O (1.25 g, 25.1 mmol, 1.00 equiv) in
ether/EtOH (8/8 mL). To this was added methyl 3-cyanopropanoate
(2.84 g, 25.1 mmol, 1.00 equiv) dropwise. The resulting solution
was stirred for 2 h at room temperature, then concentrated in
vacuo. This resulted in 1.40 g (49%) of 3-cyanopropanehydrazide as
a colorless oil.
##STR00758##
Compound 140.
4-(1-(5-(5-(2-cyanoethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)pipe-
ridin-4-yl)benzonitrile
[3627] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using
3-cyanopropanehydrazide (compound 140.1) instead of
2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)
439 (M+H).sup.+. .sup.1H-NMR (300 Hz, CD.sub.3OD): .delta. 7.68 (d,
2H), 7.58-4.47 (m, 3H), 7.30 (s, 1H), 4.89-4.80 (m, 1H), 3.65-3.62
(m, 1H), 3.32-3.30 (m, 1H), 3.15 (t, 2H), 3.03-2.95 (m, 4H), 2.50
(s, 3H), 2.42 and 2.32 (2 singlets, amide rotamers, ArCH.sub.3,
3H), 2.03-2.00 (m, 1H), 1.83-1.78 (m, 3H).
##STR00759##
Compound 141.
4-(1-(2,4-Dimethyl-5-(5-(oxetan-3-ylmethyl)-4H-1,2,4-triazol-3-yl)benzoyl-
)piperidin-4-yl)benzonitrile
[3628] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-
-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130). m/z (ES+)
456 (M+H).sup.+.
##STR00760##
Compound 142.1. Methyl 4-cyclopropyl-2-methylbenzoate
[3629] To a solution of methyl 4-bromo-2-methylbenzoate (5.00 g,
20.7 mmol, 1.00 equiv, 95%) in a mixture of toluene and H.sub.2O
(20 mL/1 mL) were added potassium carbonate (6.10 g, 44.1 mmol,
2.00 equiv), cyclopropylboronic acid (2.30 g, 26.8 mmol, 1.20
equiv), Pd(dppf)Cl.sub.2 (900 mg, 1.23 mmol, 0.05 equiv), and
Pd(OAc).sub.2 (250 mg, 1.12 mmol, 0.05 equiv). The reaction mixture
was purged with nitrogen and stirred at 80.degree. C. overnight.
After cooling to room temperature, the mixture was then
concentrated in vacuo. The resulting residue was purified via
silica gel column chromatography with ethyl acetate/petroleum ether
(1:50) as eluent to yield 2.68 g (61%) of methyl
4-cyclopropyl-2-methylbenzoate as a colorless oil.
##STR00761##
Compound 142.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate
[3630] To a solution of methyl 4-cyclopropyl-2-methylbenzoate
(compound 142.1, 2.68 g, 13.4 mmol, 1.00 equiv, 95%) in AcOH (50
mL) were added NaIO.sub.4 (1.51 g, 7.08 mmol, 0.50 equiv), 12 (3.58
g, 14.1 mmol, 1.00 equiv), and sulfuric acid (201 mg, 2.01 mmol,
0.15 equiv, 98%). The reaction mixture was stirred at 110.degree.
C. overnight. After cooling to ambient temperature, 100 mL of water
was added. The resulting mixture was diluted with 100 mL of ethyl
acetate, then washed with 3.times.30 mL of Na.sub.2S.sub.2O.sub.3
(aq., sat.) and 1.times.30 mL of brine. The organic phase was dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified via silica gel column chromatography with
ethyl acetate/petroleum ether (1/50) as eluent to yield 2.00 g
(45%) of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate as a
colorless oil.
##STR00762##
Compound 142.3. Methyl 5-cyano-4-cyclopropyl-2-methylbenzoate
[3631] To a solution of methyl
4-cyclopropyl-5-iodo-2-methylbenzoate (compound 142.2, 2.00 g, 6.01
mmol, 1.00 equiv, 95%) in DMF (16 mL) was added Zn(CN).sub.2 (890
mg, 7.58 mmol, 1.27 equiv) and Pd(PPh.sub.3).sub.4 (731 mg, 0.630
mmol, 0.11 equiv). The resulting solution was stirred at
100.degree. C. under nitrogen overnight. After cooling to ambient
temperature, the reaction was then quenched by the addition of 100
mL of FeSO.sub.4 (aq., sat.) and diluted with ethyl acetate. The
resulting mixture was stirred vigorously then filtered through
celite and washed with 1 M FeSO.sub.4, water, and ethyl acetate.
The layers were separated and the aqueous phase was extracted with
2.times.100 mL of ethyl acetate. The combined organic phases were
dried over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified via silica gel column chromatography with
ethyl acetate/petroleum ether (1/50) as eluent to yield 1.10 g
(81%) of methyl 5-cyano-4-cyclopropyl-2-methylbenzoate as a light
yellow oil.
##STR00763##
Compound 142.4. Methyl
5-carbamothioyl-4-cyclopropyl-2-methylbenzoate
[3632] To a solution of methyl
5-cyano-4-cyclopropyl-2-methylbenzoate (compound 142.3, 1.65 g,
7.28 mmol, 1.00 equiv, 95%) in a mixture of tetrahydrofuran and
H.sub.2O (20 mL/5 mL) was added O,O'-diethylphosphorodithioate
(3.79 g, 22.3 mmol, 2.00 equiv). The resulting mixture was stirred
at 80.degree. C. overnight (CAUTION: significant gas evolution
occurs--this and all other reactions described herein should be
carried out in well ventilated fume hoods). After cooling to
ambient temperature, the reaction was quenched with 100 mL of
water. The resulting solution was extracted with 100 mL of ethyl
acetate. The combined organic layers were washed with 3.times.30 mL
of brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified via silica gel column
chromatography with ethyl acetate/petroleum ether (1/5) as eluent
to furnish 0.880 g (46%) of methyl
5-carbamothioyl-4-cyclopropyl-2-methylbenzoate as a white
solid.
##STR00764##
Compound 142.5. Methyl
4-cyclopropyl-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate
[3633] To a round-bottom flask was added a solution of methyl
5-carbamothioyl-4-cyclopropyl-2-methylbenzoate (compound 142.4, 880
mg, 3.35 mmol, 1.00 equiv, 95%) in tetrahydrofuran (10 mL).
Iodomethane (1.00 g, 7.05 mmol, 2.00 equiv) was added and the
resulting mixture and stirred at room temperature overnight. The
mixture was then concentrated in vacuo to yield 0.800 g (86%) of
methyl
4-cyclopropyl-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate as a
colorless liquid.
##STR00765##
Compound 142.6. Methyl 3-(dimethylamino)propanoate
hydrochloride
[3634] To a round-bottom flask was added a solution of
3-(dimethylamino)propanoic acid (2.00 g, 17.1 mmol, 1.00 equiv) in
methanol (60 mL). Hydrogen chloride (g) was bubbled into the
reaction mixture and the resulting solution was stirred for 4 h at
25.degree. C. Concentration of the reaction mixture in vacuo
afforded 2.00 g of title compound as a colorless oil.
##STR00766##
Compound 142.7. 3-(Dimethylamino)propanehydrazide
[3635] To a solution of methyl 3-(dimethylamino)propanoate
hydrochloride (compound 142.6, 2.00 g, 15.3 mmol, 1.00 equiv) in
methanol (40 mL) was added hydrazine hydrate (6 mL, 6.00 equiv).
The reaction mixture was stirred at 70.degree. C. for 3 h. The
mixture was concentrated in vacuo and then dissolved in 50 mL of
H.sub.2O and washed with 2.times.10 mL of ethyl acetate. The
aqueous layers were combined and concentrated in vacuo to afford
1.30 g (65%) of 3-(dimethylamino)propanehydrazide as a colorless
oil.
##STR00767##
Compound 142.8. Methyl
4-cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-meth-
ylbenzoate
[3636] A solution of 3-(dimethylamino)propanehydrazide (compound
142.7, 1.20 g, 9.15 mmol, 5.00 equiv) and methyl
4-cyclopropyl-2-methyl-5-(methylsulfanyl) carboximidoylbenzoate
(compound 142.5, 600 mg, 2.28 mmol, 1.00 equiv) in AcOH (30 mL) was
stirred at 80.degree. C. overnight. After cooling to ambient
temperature, the pH was adjusted to 8-9 with sodium hydroxide (aq.,
1 M). The resulting mixture was extracted with 2.times.100 mL of
ethyl acetate and the combined organic layers were concentrated in
vacuo. The residue was purified via silica column chromatography
with dichloromethane/methanol (10/1) as eluent to give 504 mg (67%)
of the title compound as a white solid.
##STR00768##
Compound 142.9.
4-Cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-meth-
ylbenzoic Acid
[3637] To a solution of compound 142.8 (200 mg, 0.610 mmol, 1.00
equiv) in a mixture of methanol and H.sub.2O (6 mL/3 mL) was added
sodium hydroxide (97.6 mg, 2.44 mmol, 4.00 equiv) in water (1 mL).
After stirring at 60.degree. C. overnight, the organic solvent was
removed under reduced pressure. The residual aqueous layer was
washed with 20 mL of ethyl acetate. The pH was then adjusted to 4-5
with HCl (aq., 3 M), and the resulting mixture was extracted with
ethyl acetate (3.times.20 mL). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to afford 280 mg
(73%) of the title compound as a brown solid.
##STR00769##
Compound 142.
4-(1-(4-Cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)--
2-methylbenzoyl)piperidin-4-yl)benzonitrile
[3638] To a solution of compound 2661.9 (250 mg, 0.800 mmol, 1.00
equiv) in N,N-dimethylformamide (3 mL) were added
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 175 mg,
0.790 mmol, 1.00 equiv), EDCI (302 mg, 1.58 mmol, 2.00 equiv), and
DMAP (194 mg, 1.59 mmol, 2.00 equiv). The resulting mixture was
stirred at 25.degree. C. overnight and then diluted with water. The
mixture was extracted with 3.times.50 mL of ethyl acetate. The
combined organic layers were washed with 2.times.20 mL of
NH.sub.4Cl (aq) and 2.times.20 mL of brine, dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified
via silica gel column chromatography with dichloromethane/methanol
(10/1) as eluent. The product (.about.150 mg) was further purified
by Prep-HPLC with the following conditions
[(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um,
19*150 mm; mobile phase, water with 0.03% NH.sub.3.H.sub.2O and
CH.sub.3CN (32.0% CH.sub.3CN up to 47.0% in 7 min, up to 100.0% in
1 min, down to 32.0% in 1 min); Detector, Waters 2489 254&220
nm]. The fractions containing pure compound were combined and
lyophilized to yield 70.3 mg (18%) of the title compound as a white
solid. m/z (ES+) 483 (M+H).sup.+.
##STR00770##
Compound 143.1. 3-Methoxypropanehydrazide
[3639] A mixture of methyl 3-methoxypropanoate (5.0 g, 42.33 mmol)
and hydrazine (1.36 g, 42.33 mmol) was heated at 50.degree. C. for
two hours. The mixture was concentrated and dried under reduced
pressure to give the product as a clear oil. Yield: 5.0 g, 100%.
m/z (ES+) 119 (M+H).sup.+. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 7.86 (br, 1H), 4.05-3.71 (m, 2H), 3.63 (t, 2H), 3.34 (s,
3H), 2.42 (t, 2H).
##STR00771##
Compound 143.
4-(1-(4-Cyclopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methyl-
benzoyl)piperidin-4-yl)benzonitrile
[3640] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 142 and using compound 143.1 in place of
142.7. m/z (ES+) 471 (M+H).sup.+.
##STR00772##
Compound 144.
4-(1-(4-Cyclopropyl-5-(5-((dimethylamino)methyl)-4H-1,2,4-triazol-3-yl)-2-
-methylbenzoyl)piperidin-4-yl)benzonitrile
[3641] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 142. m/z (ES+) 469 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD): .delta. 7.69 (d, J=6.3 Hz, 2H), 7.49 (d,
J=6.0 Hz, 2H), 7.47 & 7.39 (2 singlets, amide rotamers, Ar--H,
1H), 7.03 (s, 1H), .about.4.9 (1H partially obscured by water
peak), 3.74 (s, 2H), 3.72-3.57 (m, 1H), 3.32-3.22 (m, 1H partially
obscured by methanol solvent peak), 3.00 (t with fine structure,
J=8.9 Hz, 2H), 2.49-2.27 (m, 2H), 2.10-1.98 (m, 2H), 1.93-1.51 (m,
3H), 1.05-0.90 (m, 2H), 0.79-0.64 (m, 2H).
##STR00773##
Compound 145.
4-(1-(5-(5-(Azetidin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-m-
ethylbenzoyl)piperidin-4-yl)benzonitrile
[3642] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 142. m/z (ES+) 481 (M+H).sup.+.
##STR00774##
Compound 146.
2-(5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-methylph-
enyl)-4H-1,2,4-triazol-3-yl)-N,N-dimethylacetamide
[3643] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 142. m/z (ES+) 497 (M+H).sup.+.
##STR00775##
Compound 147.1. Methyl 4-ethyl-2-methylbenzoate
[3644] To a stirred mixture of ZnBr.sub.2 (4.50 g, 20.0 mmol, 2.00
equiv) in tetrahydrofuran (50 mL) under nitrogen at 0.degree. C.
was added EtMgBr (6.6 mL, 2.00 equiv, 3M in THF) dropwise. After
stirring for 30 min at 0.degree. C., the temperature was lowered to
-78.degree. C. and Pd(dppf)Cl.sub.2 (1.08 g, 1.48 mmol, 0.30 equiv)
was added followed by a solution of methyl 4-bromo-2-methylbenzoate
(compound 152.1, 2.30 g, 10.0 mmol, 1.00 equiv) in tetrahydrofuran
(20 mL). The resulting mixture was stirred for 30 min at
-78.degree. C., warmed to room temperature, and stirred overnight.
The reaction mixture was carefully quenched with 60 mL of
NH.sub.4Cl (aq.) and extracted with 3.times.50 mL of ethyl acetate.
The combined organic phases were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether
(1:100-1:5) as eluent to furnish 1.50 g (84%) of methyl
4-ethyl-2-methylbenzoate as a brown oil.
##STR00776##
Compound 147.2.
4-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
Acid
[3645] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 142.9 and using compounds 147.1 and 143.1
instead of compounds 142.1. and 142.7.
##STR00777##
Compound 147.
4-(1-(4-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoy-
l)piperidin-4-yl)benzonitrile
[3646] To a solution of compound (147.2, 100 mg, 0.350 mmol, 1.00
equiv) in DMF (10 mL) under nitrogen were added EDCI (132 mg, 0.690
mmol, 2.00 equiv) and DMAP (85.0 mg, 0.700 mmol, 2.00 equiv). The
resulting mixture was stirred 30 min at 25.degree. C. followed by
the addition of 4-(piperidin-4-yl)benzonitrile (compound 1.5, 129
mg, 2.77 mmol, 2.00 equiv). The reaction mixture was stirred for 25
h at 25.degree. C., then quenched with 40 mL of ice water, and
extracted with 3.times.50 mL of ethyl acetate. The combined organic
layers were washed with 1.times.50 mL of brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo. The residue
was purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:100-1:1) as eluent. The crude product
(50 mg) was purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150
mm; mobile phase, water with 0.03% NH.sub.3H.sub.2O and CH.sub.3CN
(33% CH.sub.3CN up to 52% in 10 min, up to 100% in 1 min, down to
33% in 1 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield
20.2 mg (12%) of the title compound as a white solid. m/z (ES+) 458
(M+H).sup.+.
##STR00778##
Compound 148.
4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoy-
l)-4-fluoropiperidin-4-yl)benzonitrile
[3647] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation compound 147 and using compound 11.2 HCl salt instead
compound 1.5. m/z (ES+) 476 (M+H).sup.+.
##STR00779##
Compound 149.
4-(1-(5-(5-(Ethoxymethyl)-4H-1,2,4-triazol-3-yl)-4-ethyl-2-methylbenzoyl)-
-4-fluoropiperidin-4-yl)benzonitrile
[3648] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 147 and 148. m/z (ES+) 476
(M+H).sup.+.
##STR00780##
Compound 150.
4-(1-(4-Ethyl-2-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)-
benzoyl)piperidin-4-yl)benzonitrile
[3649] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoy-
l)piperidin-4-yl)benzonitrile (compound 147). m/z (ES+) 470
(M+H).sup.+.
##STR00781##
Compound 151.
4-(1-(4-Ethyl-5-(5-(isopropoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenz-
oyl)-4-fluoropiperidin-4-yl)benzonitrile
[3650] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 147 and 148. m/z (ES+) 490 (M+H).sup.+.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.78 (d, 2H), 7.69-7.34
(m, 4H), 4.82-4.78 (m, 1H), 4.72 (s, 2H), 3.80 (quintet, 1H),
3.57-3.55 (m, 2H), 3.30-3.25 (m, 1H), 2.94 (q, 2H), 2.46 and 2.35
(2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.35-2.1 (m, 3H),
2.0-1.95 (m, 1H), 1.30 (d, 6H), 1.14 (t, 3H).
##STR00782##
Compound 152.1. Methyl 4-bromo-2-methylbenzoate
[3651] To a solution of 4-bromo-2-methylbenzoic acid (5.11 g, 23.8
mmol, 1.0 equiv) in methanol (25 mL) was added dropwise sulfuric
acid (2.0 mL) over about 3 minutes (mildly exothermic). The
resulting mixture was refluxed for 4 hours. After cooling to room
temperature, the reaction mixture was carefully quenched into
saturated aqueous NaHCO.sub.3 (100 mL) (note--significant gas
evolution) and extracted with dichloromethane (200 mL.times.1 then
50 mL.times.1). The combined organic phases were washed with a
mixture of brine/saturated NaHCO.sub.3 (9:1)(50 mL), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure to
obtain the title compound as a colorless oil (5.28 g, 97%). .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 7.78 (d, J=8.0 Hz, 1H), 7.42 (d,
J=1.6 Hz, 1H), 7.38 (dd, J=1.6 Hz, 1H), 3.89 (s, 3H), 2.58 (s,
3H).
##STR00783##
Compound 152.2. Methyl 4-cyclobutyl-2-methylbenzoate
[3652] Cyclobutylzinc(II) bromide (50 ml, 0.5 M in THF, 25.0 mmol)
was added to a mixture of methyl 4-bromo-2-methylbenzoate (compound
152.1, 5.2 g, 22.7 mmol) and PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 (1.85
g, 2.27 mmol). The mixture was degassed and the flask was filled
with argon through a balloon. The mixture was heated at 65.degree.
C. under argon for 24 hours. The mixture was cooled to 0.degree. C.
and quenched with water (10 ml). The mixture was diluted with EtOAc
(200 ml), washed with water then with brine. The EtOAc layer was
dried (Na.sub.2SO.sub.4), concentrated under reduced pressure, and
purified using column (silica gel) chromatography (hexanes:EtOAc
30:1 to 20:1). Yield: 4.1 g, clear oil, 89.1%. .sup.1H NMR (400
MHz, Chloroform-d) .delta. 7.86 (d, 1H), 7.12-7.02 (m, 2H), 3.88
(s, 3H), 3.59-3.48 (m, 1H), 2.59 (s, 3H), 2.35 (m, 2H), 2.22-1.96
(m, 3H), 1.86-1.84 (m, 1H).
##STR00784##
Compound 152.3. Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate
[3653] N-Iodosuccinimide (3.52 g, 15.6 mmol) was added portionwise
to a solution of methyl 4-cyclobutyl-2-methylbenzoate (compound
152.2, 3.2 g, 15.6 mmol) in concentrated sulfuric acid (25 ml) at
0.degree. C. The mixture was stirred at 0.degree. C. for 30 min and
at RT for 2 hours. The mixture turned very thick. The mixture was
cooled to 0.degree. C. again and MeOH (30 ml) was added. The
mixture was heated at 60.degree. C. for 2 hours. The methanol was
removed under reduced pressure and the residue was poured into ice
water (100 ml). The mixture was extracted with EtOAc (2.times.).
The combined organic layers were washed with brine, then aq. 1N
NaHCO.sub.3 (note-significant gas evolution), dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified using
column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1).
Yield: 4.17 g, light yellow oil, 81%. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.33 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H),
3.67-3.54 (m, 1H), 2.57 (s, 3H), 2.51-2.40 (m, 2H), 2.14-1.97 (m,
3H), 1.82-1.79 (m, 1H).
##STR00785##
Compound 152.4. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate
[3654] A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate
(compound 152.3, 4.17 g, 12.64 mmol), Zn(CN).sub.2 (2.96 g, 25.21
mmol) and Pd(PPh.sub.3).sub.4 (0.73 g, 0.63 mmol) in DMF (30 ml)
was degassed and the flask was filled with argon through a balloon.
The mixture was heated at 100.degree. C. under argon overnight.
After cooling to ambient temperature, the mixture was quenched with
saturated aq. FeSO.sub.4 (20 ml) and diluted with EtOAc (200 ml).
The greenish solid was removed by filtration through celite. The
filtrate was partitioned between water and EtOAc. The EtOAc layer
was washed with brine, dried (Na.sub.2SO.sub.4), and concentrated.
The residue was purified using column (silica gel) chromatography
(hexanes:EtOAc 30:1 to 20:1). Yield: 2.55 g, white solid, 88%.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 8.16 (s, 1H), 7.28 (s,
1H), 3.90 (s, 3H), 3.86-3.82 (m, 1H), 2.68 (s, 3H), 2.55-2.45 (m,
2H), 2.27-2.04 (m, 3H), 1.89-1.87 (m, 1H).
##STR00786##
Compound 152.5. Methyl
5-carbamothioyl-4-cyclobutyl-2-methylbenzoate
[3655] To a round-bottom flask were added methyl
5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4, 3.63 g,
0.015 mol), O,O'-diethyl dithiophosphate (10 mL) and water (1 mL).
The reaction mixture was heated to 80.degree. C. for 3 hours
(CAUTION: significant gas evolution occurs--this and all other
reactions described herein should be carried out in well ventilated
fume hoods). After cooling to room temperature, the reaction
mixture was partitioned between ethyl acetate (50 mL) and water (50
mL). The combined organic layers were washed successively with
saturated aqueous NaHCO.sub.3 (50 mL) and brine (50 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. Purification by
SiO.sub.2 flash chromatography (hexanes/ethyl acetate=80/20 to
50/50) afforded methyl
5-carbamothioyl-4-cyclobutyl-2-methylbenzoate as a yellow solid
(3.06 g, 78% yield). m/z (ES+) 264 (M+H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.93 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H),
6.92 (s, 1H), 4.19 (m, 1H), 3.89 (s, 3H), 2.64 (s, 3H), 2.40 (m,
2H), 2.29-2.15 (m, 2H), 2.12-2.00 (m, 1H), 1.95-1.84 (m, 1H).
##STR00787##
Compound 152.6. Methyl
4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate
[3656] To a round-bottom flask was added methyl
5-carbamothioyl-4-cyclobutyl-2-methylbenzoate (compound 152.5, 861
mg, 3.27 mmol) in THF (10 mL). Iodomethane (912 mg, 6.42 mmol) was
added dropwise and the reaction mixture was stirred at room
temperature for 7 hours. The reaction mixture was concentrated in
vacuo and purified by SiO.sub.2 flash chromatography (ethyl acetate
to ethyl acetate/methanol=95/5) to afford methyl
4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate as a
yellowish oil (807 mg, 89% yield). m/z (ES+) 278 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.67 (s, 1H), 7.40 (s,
1H), 3.88-3.71 (m, 4H), 2.57 (s, 3H), 2.44 (s, 3H), 2.22-2.19 (m,
2H), 2.12 (m, 2H), 1.98-1.86 (m, 1H), 1.82-1.70 (m, 1H).
##STR00788##
Compound 152.7. Methyl
4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate
[3657] To a round-bottom flask were added methyl
4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate (compound
152.6, 556 mg, 0.002 mol) and acetohydrazide (223 mg, 0.003 mol) in
6 mL acetic acid. The reaction mixture was heated to 90.degree. C.
for 3 hours. After cooling to room temperature, the reaction
mixture was partitioned between water (50 mL) and ethyl acetate (50
mL). The organic layer was washed with brine (2.times.50 mL), dried
over Na.sub.2SO.sub.4, and concentrated in vacuo. Purification via
SiO.sub.2 flash chromatography (hexanes/ethyl acetate=50/50 to
30/70) afforded the title compound as a white solid (243 mg, 43%
yield). m/z (ES+) 286 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.23 (s, 1H), 7.32 (s, 1H), 4.24-4.05 (m, 1H),
3.89 (s, 3H), 2.69 (s, 3H), 2.54 (s, 3H), 2.23-2.20 (m, 2H),
2.16-2.05 (m, 2H), 2.05-1.88 (m, 1H), 1.88-1.71 (m, 1H).
##STR00789##
Compound 152.8.
4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic
Acid
[3658] To a solution of methyl
4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate
(compound 152.7, 240 mg, 0.842 mmol) in methanol (5 mL) was added
aqueous NaOH (6 mL, 1M). The resulting mixture was heated to
50.degree. C. for 6 hours. After cooling to ambient temperature,
the reaction mixture was acidified with 1N HCl to pH 2 and
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo to afford
4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic
acid (260 mg, quantitative) as a white solid. m/z (ES+) 272
(M+H).sup.+.
##STR00790##
Compound 152.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile
[3659] To a solution of
4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic
acid (compound 152.8, 260 mg, 0.95 mmol) in DMF (4 mL) were added
4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5,
232 mg, 1.045 mmol), EDC (272 mg, 1.425 mmol), HOBt (39 mg, 0.285
mmol), and DIEA (367.7 mg, 2.85 mmol). The resulting mixture was
stirred at room temperature for 16 hours. The mixture was quenched
with saturated aqueous NaHCO.sub.3 (20 mL) and extracted with ethyl
acetate (2.times.50 mL). The combined organic layers were washed
with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. Purification via SiO.sub.2 column
chromatography (dichloromethane/methanol=95/5) afforded
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile as a white solid (193 mg, 44% yield). m/z
(ES+) 440 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
7.69 (d, J=5.4 Hz. 2H), 7.56-7.30 (m, 4H), 1 proton obscured by
methanol solvent peak, 4.10-3.98 (m, 1H), 3.64 (t, J=10.7 Hz, 1H),
3.33-3.21 (m, 1H), 3.00 (t, J=8.9 Hz, 2H), 2.58 (s, 3H), 2.48 and
2.38 (2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.28-1.92 (m,
6H), 1.92-1.55 (m, 4H). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 13.66 (s, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.62-7.34 (m, 4H),
4.78-4.63 (m, 1H), 4.31 (br s, 1H), 3.45 (br s, 1H), 3.15 (app t,
J=12.3 Hz, 1H), 2.99-2.78 (m, 2H), 2.44-1.80 (m, 12H), 1.80-1.37
(m, 4H).
##STR00791##
Compound 153.
4-(1-(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylb-
enzoyl)piperidin-4-yl)benzonitrile
[3660] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152), but using
3-methoxypropanehydrazide (compound 143.1) in place of
acetohydrazide. m/z (ES+) 484 (M+H).sup.+, 967 (2M+H).sup.+.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 11.50-11.33 (br s, 1H),
7.66-7.44 (m, 3H), 7.33-7.27 (m, 3H), 4.98 (d, 1H), 4.24-4.12 (m,
1H), 3.78 (t, 2H), 3.70 (d, 1H), 3.44 (s, 3H), 3.14-3.03 (m, 3H),
2.90-2.75 (m, 2H), 2.42 and 2.34 (2 singlets, amide rotamers,
ArCH.sub.3, 3H), 2.17 (d, 2H), 2.08-1.88 (m, 3H), 1.84-1.51 (m,
5H).
##STR00792##
Compound 154.
4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbe-
nzoyl)piperidin-4-yl)benzonitrile
[3661] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152) but using
2-methoxyacetohydrazide (compound 190.6) in place of
acetohydrazide. m/z (ES+) 470 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 12.15 (br s, 1H), 7.64-7.57 (m, 2H), 7.43
& 7.33 (2 singlets, amide rotamers, Ar--H, 1H), 7.30 (d, J=8.4
Hz, 2H), 7.20 (s, 1H), 5.04-4.92 (m, 1H), 4.65 (s, 2H), 4.18-4.03
(m, 1H), 3.63 (br d, J=13.2 Hz, 1H), 3.51 (s, 3H), 3.08 (t with
fine structure, J=12.8 Hz, 1H), 2.93-2.77 (m, 2H), 2.38 & 2.30
(2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.25-1.84 (m, 6H),
1.84-1.43 (m, 4H).
##STR00793##
Compound 155.
4-(1-(4-Cyclobutyl-5-(5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbe-
nzoyl)piperidin-4-yl)benzonitrile
[3662] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152 but using 2-hydroxyacetohydrazide in
place of acetohydrazide. m/z (ES+) 456 (M+H).sup.+.
##STR00794##
Compound 156.
4-(1-(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylb-
enzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3663] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylb-
enzoyl)piperidin-4-yl)benzonitrile (compound 153), using
4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride salt (compound
11.2 HCl salt) instead of 4-(piperidin-4-yl)benzonitrile
hydrochloride salt (compound 1.5). m/z (ES+) 501.8 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 11.46 (br s, 1H),
7.75-7.45 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 4.89 (br
d, J=13.2 Hz, 1H), 4.28-4.15 (m, 1H), 3.79 (t, J=6.0 Hz, 2H),
3.70-3.45 (m, 2H), 3.46 (s, 3H), 3.31-3.17 (m, 1H), 3.13 (t, J=6.0
Hz, 2H), 2.45 & 2.38 (2 br singlets, amide rotamers,
Ar--CH.sub.3, 3H), 2.30-1.68 (m, 10H).
##STR00795##
Compound 157.
(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylphenyl-
)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone
[3664] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylb-
enzoyl)piperidin-4-yl)benzonitrile (compound 153), using
4-(4-(trifluoromethyl)phenyl)piperidine hydrochloride salt instead
of 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound
1.5). m/z (ES+) 527 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 11.30-11.10 (br, 1H), 7.60-7.47 (m, 3H),
7.35-7.28 (m, 3H), 5.10-4.93 (m, 1H), 4.24-4.13 (m, 1H), 3.78 (t,
2H), 3.70 (d, 1H), 3.45 (s, 3H), 3.12 t, 2H), 3.15-3.05 (m, 1H),
2.90-2.75 (m, 2H), 2.44 and 2.35 (2 singlets, amide rotamers,
ArCH.sub.3, 3H), 2.25-2.13 (m, 2H), 2.13-1.85 (m, 4H), 1.87-1.66
(m, 4H).
##STR00796##
Compound 158.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4--
fluoropiperidin-4-yl)benzonitrile
[3665] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152), using compound 11.2 HCl
salt instead of compound 1.5. m/z (ES+) 458 (M+H).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 13.66 (s, 1H), 7.66 (d, 2H),
7.51 (d, 3H), 7.38 (s, 1H), 4.72 (d, 1H), 4.30 (br s, 1H), 3.46 (br
s, 1H), 3.16 (dd, 1H), 3.04-2.78 (m, 2H), 2.38 and 2.36 (2
singlets, amide rotamers, ArCH.sub.3, 3H), 2.35-2.27 (m, 3H),
2.22-1.82 (m, 6H), 1.81-1.56 (m, 3H).
##STR00797##
Compound 159.
(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)(4-(4-(tr-
ifluoromethyl)phenyl)piperidin-1-yl)methanone
[3666] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152). m/z (ES+) 483
(M+H).sup.+.
##STR00798##
Compound 160.
4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pipe-
ridin-4-yl)benzonitrile
[3667] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152 and using propionohydrazide instead of
acetohydrazide. m/z (ES+) 454 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.75-7.43 (m, 3H), 7.40-7.17 (m, 3H),
5.18-4.81 (m, 1H), 4.30-3.91 (m, 1H), 3.84-3.55 (m, 1H), 3.21-2.99
(m, 1H), 2.92-2.69 (m, 4H), 2.40 and 2.32 (2 singlets, amide
rotamers, ArCH.sub.3, 3H), 2.25-1.84 (m, 7H), 1.83-1.42 (m, 3H),
1.32 (t, 3H).
##STR00799##
Compound 161.
4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-f-
luoropiperidin-4-yl) benzonitrile
[3668] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152). m/z (ES+) 472 (M+H).sup.+.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.79-7.57 (m, 2H),
7.57-7.18 (m, 4H), 4.86 (dd, 1H), 4.14 (s, 1H), 3.62-3.40 (m, 4H),
3.22 (t, 1H), 2.77 (q, 2H), 2.31 & 2.41 (2 singlets, amide
rotamers, 3H), 2.29-1.47 (m, 8H), 1.30 (t, 3H).
##STR00800##
Compound 162.
4-(1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-
piperidin-4-yl)benzonitrile
[3669] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152). m/z (ES+) 468 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sup.6) .delta. 13.67 (s, 1H), 7.77 (d,
2H), 7.49-7.47 (m, 3H), 7.36 (s, 1H), 4.72 (d, 1H), 4.29 (s, 1H),
3.46 (d, 1H), 3.12 (m, 2H), 2.98-2.75 (m, 2H), 2.31 (d, 3H),
2.23-1.81 (m, 6H), 1.83-1.36 (m, 4H), 1.31 (d, 6H).
##STR00801##
Compound 163.
4-(1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-
-4-fluoropiperidin-4-yl)benzonitrile
[3670] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152). m/z (ES+) 486
(M+H).sup.+.
##STR00802##
Compound 164.1.
4-(1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-
-4-fluoropiperidin-4-yl)benzonitrile
[3671] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152.7 and using propionohydrazide instead
of acetohydrazide.
##STR00803##
Compound 164.2. Methyl
4-cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate
[3672] Methyl
4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate
(compound 164.1, 87 mg, 0.29 mmol) was dissolved in methanol and
dichloromethane (1:1 v/v) (6 ml). ((Trimethylsilyl) methyl)
diazomethane (2.0 M in ether) (220 ul, 0.44 mmol) was added. The
mixture was stirred for 16 hours and quenched with HOAc (300 ul).
The volatiles were removed in vacuo to afford an oil (85 mg). The
residue was carried as crude onto the next step without further
purification. m/z (ES+) 314 (M+H).sup.+.
##STR00804##
Compound 164.
4-(1-(4-Cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylben-
zoyl) piperidin-4-yl) benzonitrile
[3673] The title compound (mixture of N-methyl isomers) was
prepared using standard chemical manipulations and procedures
similar to those used for preparation of compound 152 and using
compound 164.2 instead of compound 152.7. m/z (ES+) 468
(M+H).sup.+.
##STR00805##
Compound 165.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-
benzoyl)piperidin-4-yl)benzonitrile
[3674] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152). m/z (ES+) 494.0
(M+H).sup.+.
##STR00806##
Compound 166.
4-(1-(4-Cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylb-
enzoyl) piperidin-4-yl) benzonitrile
[3675] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152). m/z (ES+) 476
(M+H).sup.+.
##STR00807##
Compound 167.
4-(1-(4-Cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylb-
enzoyl)-4-fluoropiperidin-4-yl) benzonitrile
[3676] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-[1-[4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl]-4--
piperidyl]benzonitrile (compound 152). m/z (ES+) 494
(M+H).sup.+.
##STR00808##
Compound 168.1. Methyl 4-cyclobutylbenzoate
[3677] To a stirred mixture of ZnBr.sub.2 (83.0 g, 368.53 mmol,
4.00 equiv) in THF (500 mL) under nitrogen at 0.degree. C. was
added a solution of bromo(cyclobutyl)magnesium (242 mL, 364 mmol,
1.5 M in THF) dropwise during 20 min. To the resulting mixture were
added Pd(dppf)Cl.sub.2 (2.00 g, 0.10 equiv) and methyl
4-bromobenzoate (20 g, 93.00 mmol, 1.00 equiv) at -40.degree. C.
The resulting mixture was stirred at -40.degree. C. for 1 h under
nitrogen, and then carefully quenched with 500 mL of NH.sub.4Cl
(aq., sat.). The mixture was extracted with 3.times.500 mL of ethyl
acetate. The combined organic layers were washed with 3.times.500
mL of brine, then dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to yield 18.0 g (crude) of the
title compound as a light yellow oil.
##STR00809##
Compound 168.2. Methyl 4-cyclobutyl-3-iodobenzoate
[3678] To a solution of methyl 4-cyclobutylbenzoate (168.1, 2.00 g,
10.5 mmol, 1.00 equiv) in acetic acid (30 mL) were carefully added
sodium periodate (1.00 g, 4.68 mmol, 0.50 equiv), iodine (3.00 g,
11.8 mmol, 1.10 equiv) and sulfuric acid (0.15 g, 0.15 equiv). The
resulting mixture was stirred overnight at 100.degree. C. After
cooling to room temperature, the reaction was then quenched by
carefully adding 30 mL of Na.sub.2S.sub.2O.sub.3 (aq., sat.) and
the resulting mixture was extracted with 3.times.20 mL of ethyl
acetate. The combined organic layers were washed with 3.times.20 mL
of brine, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure to yield 1.50 g (45%) of the title compound
as a yellow oil.
##STR00810##
Compound 168.3. Methyl 3-cyano-4-cyclobutylbenzoate
[3679] The title compound (2.60 g (95%), white solid) was prepared
using standard chemical manipulations and a procedure similar to
that used for the preparation of compound 152.4 and using compound
168.2 (4.00 g, 12.7 mmol) in place of compound 152.3.
##STR00811##
Compound 168.
4-(1-(4-Cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropipe-
ridin-4-yl)benzonitrile
[3680] The title compound was prepared using procedures similar to
those used for preparation of compound 152 and using 168.3 in place
of 152.4. m/z (ES+) 458 (M+H).
##STR00812##
Compound 169.
4-(1-(4-Cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-y-
l)benzonitrile
[3681] The title compound was prepared using procedures similar to
those used for preparation of compound 152 and using 168.3 in place
of 152.4. m/z (ES+) 440 (M+H).sup.+. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.88 (d, 2H), 7.67-7.50 (m, 3H), 7.47 (d, 2H),
4.89-4.75 (m, 1H), 4.25-3.73 (m, 2H), 3.35-3.25 (m, 1H), 3.16-2.75
(m, 4H), 2.30-1.94 (m, 6H), 1.93-1.56 (m, 4H), 1.51-1.32 (m,
3H).
##STR00813##
Compound 170.
4-(1-(4-Cyclobutyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropip-
eridin-4-yl)benzonitrile
[3682] The title compound was prepared using procedures similar to
those used for preparation of compound 152 and using compounds
168.3 and 11.2 HCl salt in place of compounds 152.4 and 1.5
respectively. m/z (ES+) 444 (M+H).sup.+.
##STR00814##
Compound 171.
4-(1-(4-Cyclobutyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-
-fluoropiperidin-4-yl)benzonitrile
[3683] The title compound was prepared using procedures similar to
those used for preparation of compounds 152 and 156 and using 168.3
in place of 152.4. m/z (ES+) 488 (M+H).sup.+.
##STR00815##
Compound 172.1. (S)-Tetrahydrofuran-2-carbohydrazide
[3684] To a round-bottom flask was added a solution of
(S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00
equiv) in dichloromethane (40 mL). EDC.HCl (7.50 g, 39.1 mmol, 1.50
equiv), HOBT (5.20 g, 38.5 mmol, 1.50 equiv), and hydrazine hydrate
(2 mL, 2.00 equiv, 99%) were added to the reaction. The resulting
solution was stirred overnight at room temperature. The solids were
removed by filtration and the filtrate was concentrated in vacuo to
furnish 5.38 g (80%) of the title compound as a yellow oil.
##STR00816##
Compound 172.
(S)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-tria-
zol-3-yl)benzoyl)piperidin-4-yl)benzonitrile
[3685] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152), using
(S)-tetrahydrofuran-2-carbohydrazide (compound 172.1) in place of
acetohydrazide. m/z (ES+) 496 (M+H).sup.+.
##STR00817##
Compound 173.
(S)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-tria-
zol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3686] The title compound was prepared using procedures similar to
those used for the preparation of compound 172 and using compound
11.2 HCl salt in place of compound 1.5. m/z (ES+) 514
(M+H).sup.+.
##STR00818##
Compound 174.1. (R)-Tetrahydrofuran-2-carbohydrazide
[3687] To a round-bottom flask was added a solution of
(R)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00
equiv) in dichloromethane (60 mL). EDC-HCl (7.37 g, 38.5 mmol, 1.50
equiv), HOBt (5.24 g, 38.8 mmol, 1.50 equiv), and hydrazine hydrate
(2.60 g, 51.9 mmol, 2.00 equiv) were added to the reaction. The
resulting solution was stirred overnight at 25.degree. C. The
solids were removed with filtration. The filtrate was concentrated
in vacuo to yield 2.00 g (59%) of
(R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
##STR00819##
Compound 174.
(R)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-tria-
zol-3-yl)benzoyl)piperidin-4-yl)benzonitrile
[3688] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 152), using
(R)-tetrahydrofuran-2-carbohydrazide (compound 174.1) in place of
acetohydrazide. m/z (ES+) 496 (M+H).sup.+. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.70 (d, 2H), 7.49-7.41 (m, 4H), 5.15 (t, 1H),
4.89-4.80 (m, 1H), 4.14-3.92 (m, 3H), 3.65-3.51 (m, 1H), 3.33-3.27
(m, 1H), 3.03-2.95 (m, 2H), 2.47-2.37 (m, 4H), 2.24-1.91 (m, 9H),
1.83-1.71 (m, 4H).
##STR00820##
Compound 175.1.
4-Cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic
Acid
[3689] The title compound was synthesized using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152.8 and using bromo(cyclopentyl)magnesium
in place of bromo(cyclobutyl)magnesium.
##STR00821##
Compound 175.
4-(1-(4-Cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)pi-
peridin-4-yl)benzonitrile
[3690] The title compound was synthesized using a procedure similar
to that used for the preparation of compound 152 and using compound
175.1 in place of compound 152.8. m/z (ES+) 495 (M+H).sup.+.
##STR00822##
Compound 176.1. tert-Butyl
4-(4-bromophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate
[3691] The title compound was synthesized using a procedure similar
to that used for the preparation of compound 1.1 and using
tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate in place of
tert-butyl 4-oxopiperidine-1-carboxylate.
##STR00823##
Compound 176.2. tert-Butyl
4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate
[3692] The title compound was synthesized using procedures similar
to those used for the preparation of compound 1.4 and using
compound 176.1 in place of compound 1.1.
##STR00824##
Compound 176.3. 4-(2-Methylpiperidin-4-yl)benzonitrile
[3693] To a solution of tert-butyl
4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate (compound 176.2,
500 mg, 1.50 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) was
added TFA dropwise (1 mL). The resulting mixture was stirred for
1.5 h at room temperature, then diluted with 30 mL of
dichloromethane. The resulting mixture was washed with sodium
bicarbonate (aq., 1 M. Note: significant gas evolution). The
aqueous phase was extracted with 2.times.50 mL of dichloromethane
and the combined organic layers were dried (Na.sub.2SO.sub.4), and
concentrated in vacuo. The residue was purified using silica gel
column chromatography with methanol/dichloromethane (1:50-1:20) as
eluent to yield 280 mg (93%) of
4-(2-methylpiperidin-4-yl)benzonitrile as a colorless oil.
##STR00825##
Compound 176.4. tert-Butyl
4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate
[3694] The title compound was synthesized using a procedure similar
to that used for the preparation of compound 152.8 and using
compound 164.1 in place of compound 152.7.
##STR00826##
Compound 176.
4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-2-m-
ethylpiperidin-4-yl)benzonitrile
[3695] To a round-bottom flask was added a solution of
4-(2-methylpiperidin-4-yl)benzonitrile (compound 176.3, 210 mg,
0.940 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL).
EDC.HCl (404 mg, 2.11 mmol, 2.00 equiv), 4-dimethylaminopyridine
(257 mg, 2.10 mmol, 2.00 equiv), and
4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid
(compound 176.4, 300 mg, 1.05 mmol, 1.00 equiv) were added to the
reaction mixture. The resulting solution was stirred for 4 h at
25.degree. C., then diluted with 50 mL of ethyl acetate. The
resulting mixture was washed with 2.times.30 mL of NH.sub.4Cl (aq.,
sat.) and 2.times.30 mL of brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The residue was purified using
silica gel column chromatography with dichloromethane/methanol
(20:1) as eluent. The crude product (.about.20 mg) was further
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (48%
CH.sub.3CN up to 49% in 8 min, up to 100% in 3 min, down to 48% in
2 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield 3.8
mg (1%) of the title compound as a white solid. m/z (ES+) 468
(M+H).sup.+.
##STR00827##
Compound 177.1. 4-Chloro-5-iodo-2-methylbenzoic Acid
[3696] To a round-bottom flask was added a solution of
4-chloro-2-methylbenzoic acid (30.0 g, 176 mmol, 1.00 equiv) in
acetic acid (300 mL). NaIO.sub.4 (19.0 g, 88.8 mmol, 0.50 equiv),
12 (49.0 g, 193 mmol, 1.10 equiv), and sulfuric acid (3 mL) were
added to the reaction. The resulting mixture was stirred overnight
at 110.degree. C. After cooling to ambient temperature, the
reaction was carefully quenched with 500 mL of
Na.sub.2S.sub.2O.sub.3 (aq., sat.). The resulting solids were
collected by filtration and then dissolved in 500 mL of ethyl
acetate. The organic phase was washed with 2.times.200 mL of brine,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. This resulted in 20.0 g (38%) of
4-chloro-5-iodo-2-methylbenzoic acid as a white solid.
##STR00828##
Compound 177.2. Methyl 4-chloro-5-iodo-2-methylbenzoate
[3697] To a solution of 4-chloro-5-iodo-2-methylbenzoic acid
(compound 177.1, 20.0 g, 67.5 mmol, 1.00 equiv) in methanol (100
mL) was added sulfuric acid (5 mL) dropwise. The resulting mixture
was stirred overnight at 75.degree. C. After cooling to ambient
temperature, the methanol was removed under reduced pressure. The
pH value of the remaining aqueous layer was carefully adjusted to 7
with sodium bicarbonate (aq., 1 M. Note: significant gas
evolution). The aqueous phase was extracted with 2.times.200 mL of
ethyl acetate and the combined organic layers were washed with
2.times.100 mL of brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was purified using silica
gel column chromatography with ethyl acetate/petroleum ether (1:50)
as eluent to furnish 20.0 g (95%) of methyl
4-chloro-5-iodo-2-methylbenzoate as a light yellow liquid.
##STR00829##
Compound 177.3.
4-Chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
Acid
[3698] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152.8 but using compounds 177.2 and 143.1
instead of compound 152.3 and acetohydrazide respectively.
##STR00830##
Compound 177.
4-(1-(4-Chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2
methylbenzoyl)piperidin-4-yl)benzonitrile
[3699] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152 but using compound 177.3 instead of
compound 152.8. m/z (ES+) 464 (M+H).sup.+.
##STR00831##
Compound 178.1. 2-Bromo-4-chlorobenzoate
[3700] The title compound (17.0 g light yellow solid, 80%) was
prepared using a procedure similar to that used for the preparation
of compound 177.2 but using 2-bromo-4-chlorobenzoic acid (20.0 g)
in place of compound 177.1.
##STR00832##
Compound 178.2. Methyl 4-chloro-2-ethylbenzoate
[3701] The title compound (2.20 g light colorless liquid, 55%) was
prepared using a procedure similar to that used for the preparation
of compound 48.1 but using compound 178.1 (5.00 g) in place of
methyl 2-bromo-4-methylbenzoate.
##STR00833##
Compound 178.3.
4-Chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic
Acid
[3702] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152.8 using compound 178.2 and
3-methoxypropanehydrazide (compound 143.1) instead of compound
152.2 and acetohydrazide respectively
##STR00834##
Compound 178.
4-(1-(4-Chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoy-
l)piperidin-4-yl)benzonitrile
[3703] The title compound was prepared using a procedure similar to
that used for the preparation of compound 152 but using compound
178.3 in place of compound 152.8. m/z (ES+) 478 (M+H).
##STR00835##
Compound 179.
4-(1-(4-Chloro-2-ethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)-
benzoyl)piperidin-4-yl)benzonitrile
[3704] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 38 and 178. m/z (ES+) 490 (M+H).sup.+.
##STR00836##
Compound 180.1. Methyl 4-bromo-2-fluorobenzoate
[3705] To a 500-mL three neck round-bottom flask was added a
solution of 4-bromo-2-fluorobenzoic acid (30.0 g, 137 mmol, 1.00
equiv) in methanol (200 mL). SOCl.sub.2 (24.0 g, 202 mmol, 1.50
equiv) was added dropwise at 0.degree. C. The resulting solution
was stirred for 10 min at 0.degree. C., for 30 min at 25.degree.
C., and then for 3 h at 50.degree. C. After cooling to room
temperature, the resulting mixture was concentrated under reduced
pressure. The residue was partitioned between water (100 mL) and
ethyl acetate (100 mL). The aqueous phase was extracted with 100 mL
of ethyl acetate. The combined organic layers were washed with
1.times.100 mL of water, 1.times.100 mL of sodium bicarbonate (aq.
sat.) and 1.times.100 mL of brine. The organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced pressure to
yield 30.0 g (94%) of the title compound as a light yellow
solid.
##STR00837##
Compound 180.2. Methyl 4-ethyl-2-fluorobenzoate
[3706] The title compound (3.80 g light colorless oil, 97%) was
prepared using a procedure similar to that used for the preparation
of compound 48.1 but using compound 180.1 (5.00 g) in place of
methyl 2-bromo-4-methylbenzoate.
##STR00838##
Compound 180.3.
4-Ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic
Acid
[3707] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152.8 using compounds 180.2 and 143.1
instead of compound 152.2 and acetoydrazide respectively.
##STR00839##
Compound 180.
4-(1-(4-Ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoy-
l)piperidin-4-yl)benzonitrile
[3708] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152 but using compound 180.3 in place of
compound 152.8. m/z (ES+) 462 (M+H).sup.+.
##STR00840##
Compound 181.1. 4-Bromo-2-ethylbenzoic Acid
[3709] To a 1 L three neck round-bottom flask, which was purged and
maintained with a nitrogen atmosphere, was added
4-bromo-2-fluorobenzoic acid (50.0 g, 228 mmol, 1.00 equiv) in
tetrahydrofuran (500 mL). A solution of ethylmagnesium bromide (250
mL, 3 M in THF) was added dropwise at 0.degree. C. The resulting
solution was stirred for 3-4 h at 0.degree. C. The mixture was then
carefully quenched by dropwise addition of water at 0.degree. C.
After complete quench of the reaction, additional water was added
and the pH was adjusted to 2-3 with hydrogen chloride (aqueous, 2
M). The mixture was extracted with 2.times.200 mL of ethyl acetate
and the organic layers were combined. Sodium hydroxide (2N, aq.)
was employed to adjust the pH to 7-8. The resulting mixture was
washed with 2.times.200 mL of ethyl acetate. The pH value of the
aqueous solution was adjusted to 2-3 with 2N hydrogen chloride,
then extracted with 2.times.200 mL of ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated in vacuo. This resulted in 30.0 g (57%) of
4-bromo-2-ethylbenzoic acid as a yellow solid.
##STR00841##
Compound 181.2. Methyl 4-bromo-2-ethylbenzoate
[3710] The title compound (25.0 g light yellow liquid, 79%) was
prepared using a procedure similar to that used for the preparation
of compound 177.2 but using compound 181.1 (30.0 g) in place of
compound 177.1.
##STR00842##
Compound 181.3. Methyl 4-cyclobutyl-2-ethylbenzoate
[3711] To a stirred mixture of ZnBr.sub.2 (33.5 g, 149 mmol, 4.00
equiv) in THF (350 mL) under nitrogen at 0.degree. C. was added
dropwise a solution of cyclobutylmagnesium bromide (148 mmol in 50
mL THF). After stirring at 0.degree. C. for 0.5 h, the temperature
was lowered to -78.degree. C. and Pd(dppf)Cl.sub.2 (2.00 g, 2.73
mmol, 0.07 equiv) was added followed by the addition of a solution
of methyl 4-bromo-2-ethylbenzoate (compound 181.2, 9.00 g, 37.0
mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise at the same
temperature. The reaction mixture was slowly allowed to reach
ambient temperature and then stirred overnight. The reaction was
carefully quenched with a saturated NH.sub.4Cl aqueous solution
(100 mL). The resulting mixture was extracted with 500 mL of ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate
and concentrated in vacuo. The residue was purified by silica gel
chromatography with ethyl acetate/petroleum ether (1:50) to furnish
8.00 g (99%) of the desired product as a light yellow oil.
##STR00843##
Compound 181.4. Methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate
[3712] To a solution of methyl 4-cyclobutyl-2-ethylbenzoate
(compound 181.3, 7.70 g, 35.3 mmol, 1.00 equiv) in acetic acid (80
mL) was added iodine (8.98 g, 35.4 mmol, 1.00 equiv), NaIO.sub.4
(3.78 g, 17.7 mmol, 0.50 equiv), and sulfuric acid (0.870 g, 8.87
mmol, 0.25 equiv). The reaction mixture was stirred at 60.degree.
C. overnight. After cooling to room temperature, the reaction was
slowly quenched with Na.sub.2S.sub.2O.sub.3 (aq., sat.). The
mixture was extracted with 200 mL of ethyl acetate and the organic
layer was dried over anhydrous sodium sulfate and concentrated in
vacuo. The residue was purified by silica gel chromatography with
ethyl acetate/petroleum ether (1:50) to furnish 10.5 g (86%) of the
desired product as a colorless solid.
##STR00844##
Compound 181.5. Methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate
[3713] To a round-bottom flask, which was purged and maintained
with a nitrogen atmosphere, was added a solution of methyl
4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 5.50 g, 16.0
mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). Zinc cyanide
(2.78 g, 23.7 mmol, 1.50 equiv) and Pd(PPh.sub.3).sub.4 (1.83 g,
1.59 mmol, 0.10 equiv) were added to the reaction mixture. The
resulting solution was stirred at 100.degree. C. for 15 h under
nitrogen. After cooling to ambient temperature, the reaction was
carefully quenched with 300 mL of FeSO.sub.4 (aq., sat.) and
diluted with ethyl acetate. The resulting mixture was stirred
vigorously then filtered through celite and washed with 1 M
FeSO.sub.4, water, and ethyl acetate. The layers were separated and
the aqueous phase was extracted with 2.times.300 mL of ethyl
acetate. The combined organic layers were washed with 2.times.300
mL of brine, dried over anhydrous sodium sulfate, and concentrated
in vacuo. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:100-1:50) as
eluent to furnish 3.20 g (82%) of methyl
5-cyano-4-cyclobutyl-2-ethylbenzoate as a light yellow oil.
##STR00845##
Compound 181.6. Methyl
5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate
[3714] To a round-bottom flask was added a solution of methyl
5-cyano-4-cyclobutyl-2-ethylbenzoate (compound 181.5, 3.00 g, 12.3
mmol, 1.00 equiv) in a solvent mixture of tetrahydrofuran and
H.sub.2O (80 mL/40 mL). To this was added O,O'-diethyl
dithiophosphate (6.69 g, 35.9 mmol, 3.00 equiv) dropwise with
stirring. The resulting solution was stirred at 85.degree. C. for
48 h (CAUTION: significant gas evolution occurs--this and all other
reactions described herein should be carried out in well ventilated
fume hoods). After cooling to ambient temperature, the mixture was
then concentrated in vacuo. The crude product was purified by
re-crystallization from petroleum ether to furnish 1.30 g (38%) of
methyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate as a light
yellow solid.
##STR00846##
Compound 181.7. Methyl
4-cyclobutyl-2-ethyl-5-(imino(methylthio)methyl)benzoate
[3715] To a round-bottom flask was added a solution of methyl
5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate (compound 181.6, 1.50
g, 5.41 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). This was
followed by the addition of iodomethane (3.80 g, 26.8 mmol, 5.00
equiv) dropwise with stirring. The resulting solution was stirred
at 25.degree. C. for 15 h, then concentrated in vacuo. This
resulted in 1.80 g (97%) of the title compound as a yellow oil.
##STR00847##
Compound 181.8. Methyl
4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate
[3716] To a round-bottom flask was added a solution of methyl
4-cyclobutyl-2-ethyl-5-(methylsulfanyl)carboximidoylbenzoate
(compound 181.7, 900 mg, 3.09 mmol, 1.00 equiv) in AcOH (20 mL).
Propionohydrazide (880 mg, 9.99 mmol, 3.00 equiv) was added and the
resulting mixture was stirred at 90.degree. C. for 2 h. After
cooling to ambient temperature, the mixture was then concentrated
in vacuo. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:50-1:3) as
eluent to give 0.360 g (37%) of the title compound as a clear
oil.
##STR00848##
Compound 181.9.
4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic
Acid
[3717] To a round-bottom flask was added a solution of methyl
4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate
(compound 181.8, 360 mg, 1.15 mmol, 1.00 equiv) in methanol (20
mL). A solution of sodium hydroxide (460 mg, 11.5 mmol, 10.0 equiv)
in water (10 mL) was added to the reaction mixture. The resulting
solution was stirred at 25.degree. C. for 15 h. The organic solvent
was then removed under reduced pressure. The pH value of the
remaining aqueous phase was adjusted to 2-3 with hydrogen chloride
(aq., 2 M). The resulting precipitate was collected by filtration
and dried under high-vacuum to yield 320 mg (93%) of the title
compound as a white solid.
##STR00849##
Compound 181.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piper-
idin-4-yl)benzonitrile
[3718] To a solution of
4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid
(compound 181.9, 160 mg, 0.530 mmol, 1.00 equiv) in
N,N-dimethylformamide (20 mL) were added EDCI (113 mg, 0.590 mmol,
1.11 equiv), DMAP (197 mg, 1.62 mmol, 3.03 equiv), and HOBT (87.5
mg, 0.650 mmol, 1.21 equiv). After 5 min,
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 110 mg,
0.590 mmol, 1.10 equiv) was added. The resulting mixture was
stirred at 25.degree. C. for 15 h, then quenched with 100 mL of ice
water. The mixture was extracted with 2.times.150 mL of ethyl
acetate. The combined organic layers were washed with 3.times.150
mL of brine, dried over anhydrous sodium sulfate, and concentrated.
The crude product (.about.150 mg) was purified by Prep-HPLC with
the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,
SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%
TFA and CH.sub.3CN (47% CH.sub.3CN up to 61% in 6 min, up to 100%
in 1.5 min, down to 47% in 1.5 min); Detector, Waters 2489
254&220 nm. The fractions containing pure compound were
combined and lyophilized to yield 99.5 mg (40%) of the title
compound as a white solid m/z (ES+) 468 (M+H).sup.+. .sup.1H-NMR
(300 MHz, CD.sub.3OD): .delta. 7.71-7.69 (m, 2H), 7.50-7.32 (m,
4H), 4.03-3.99 (m, 1H), 3.65-3.5 (m, 1H), 3.32-3.20 (m, 1H),
2.90-2.95 (m, 4H), 2.70-2.74 (m, 2H), 2.20-1.98 (m, 6H), 1.98-1.79
(m, 4H), 1.41 (t, 3H), 1.39-1.28 (m, 3H).
##STR00850##
Compound 182.
4-(1-(4-Cyclopropyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)b-
enzoyl)piperidin-4-yl)benzonitrile
[3719] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 143 and 181. m/z (ES+) 484 (M+H).sup.+.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.67 (d, 2H), 7.49-7.37
(m, 3H), 7.11-7.05 (m, 1H), 4.89-4.80 (m, 1H), 3.81 (t, 2H),
3.77-3.60 (m, 1H), 3.4 (s, 3H), 3.37-3.32 (m, 1H), 3.14 (t, 2H),
3.15-2.9 (m, 2H), 2.92-2.5 (m, 2H), 2.39-2.36 (m, 1H), 2.02-1.85
(m, 1H), 1.85-1.69 (m, 3H), 1.32-1.21 (m, 3H), 1.0-0.95 (m, 2H),
0.77-0.69 (m, 2H).
##STR00851##
Compound 183.
4-(1-(4-Cyclopropyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3720] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 143 and 181. m/z (ES+) 470
(M+H).sup.+.
##STR00852##
Compound 184.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)ben-
zoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3721] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 143 and 181 and using compound 11.2 HCl
salt in place of compound 1.5. m/z (ES+) 502 (M+H).sup.+.
##STR00853##
Compound 185.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)ben-
zoyl)piperidin-4-yl)benzonitrile
[3722] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 143 and 181. m/z (ES+) 484
(M+H).sup.+.
##STR00854##
Compound 186.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fl-
uoropiperidin-4-yl)benzonitrile
[3723] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 181 and using compound 11.2 HCl salt in
place of compound 1.5. m/z (ES+) 486 (M+H).sup.+.
##STR00855##
Compound 187.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)be-
nzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3724] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 143 and 181 and using compound 11.2 HCl
salt in place of compound 1.5. m/z (ES+) 516 (M+H).sup.+.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.77 (d, 2H), 7.66-7.47
(m, 2H), 7.47-7.35 (m, 2H), 4.89-4.83 (m, 1H), 4.08-4.03 (t, 1H),
3.79 (t, 2H), 3.55 (t, 2H), 3.33 (s, 3H), 3.28-3.20 (m, 1H), 3.12
(t, 2H), 2.80-2.68 (m, 2H), 2.27-1.68 (m, 10H), 1.27 (t, 3H).
##STR00856##
Compound 188.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3725] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 143 and 181. m/z (ES+) 498 (M+H).sup.+.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.67 (d, 2H), 7.44-7.31
(m, 4H), 4.89 (s, 1H), 4.04-3.98 (m, 1H), 3.79 (t, 2H), 3.66-3.60
(m, 1H), 3.33 (s, 3H), 3.23-3.12 (m, 1H), 3.10 (t, 2H), 3.02 (t,
2H), 2.77-2.66 (m, 2H), 2.19-2.04 (m, 6H), 1.80-1.68 (m, 4H),
1.31-1.26 (m, 3H).
##STR00857##
Compound 189.1. Methyl 4-(cyclobutylmethyl)-2-methylbenzoate
[3726] The title compound (4.00 g, yellow oil, 84%) was prepared
using a procedure similar to that used for the preparation of
compound 181.3 using compound 152.1 (5.00 g) and
cyclobutylmethylmagnesium bromide in place of compound 181.2 and
cyclobutylmagnesium bromide respectively.
##STR00858##
Compound 189.2. Methyl
4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate
[3727] To a round-bottom flask was added a solution of methyl
4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.1, 8.40 g, 38.5
mmol, 1.00 equiv) in AcOH (150 mL). NaIO.sub.4 (5.00 g, 23.4 mmol,
0.50 equiv), iodine (10.0 g, 39.4 mmol, 1.00 equiv), and sulfuric
acid (0.3 mL) were added to the reaction mixture. The resulting
solution was stirred at 60.degree. C. for 12 h. After cooling to
room temperature, the reaction was quenched with 200 mL of
NaHSO.sub.3 (aq). The mixture was extracted with 2.times.200 mL of
ethyl acetate, and the combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (20:1) as eluent to furnish 8.00 g (60%) of
methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate as a white
solid.
##STR00859##
Compound 189.3. methyl
5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate
[3728] The title compound (5.0 g, light yellow oil, 88%) was
prepared using a procedure similar to that used for the preparation
of compound 181.5 using compound 189.2 (8.00 g) in place of
compound 181.4.
##STR00860##
Compound 189.4. Methyl
5-carbamothioyl-4-(cyclobutylmethyl)-2-methylbenzoate
[3729] To a round-bottom flask was added a solution of methyl
5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.3, 5.00
g, 20.6 mmol, 1.00 equiv) in a solvent mixture of THF and H.sub.2O
(50 mL/25 mL). O,O'-diethyl dithiophosphate (15.0 g, 80.5 mmol,
4.00 equiv) was added to the reaction flask. The resulting solution
was stirred at 80.degree. C. for 48 h (CAUTION: significant gas
evolution occurs--this and all other reactions described herein
should be carried out in well ventilated fume hoods). After cooling
to ambient temperature, the reaction was carefully quenched with 50
mL of brine. The mixture was extracted with 3.times.50 mL of ethyl
acetate and the combined organic layers were dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:4) as eluent to furnish 1.20 g (21%) of the title compound
as a yellow oil.
##STR00861##
Compound 189.5. Methyl
4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate
[3730] To a round-bottom flask was added a solution of methyl
5-carbamothioyl-4-(cyclobutylmethyl)-2-methylbenzoate (compound
189.4, 1.20 g, 4.33 mmol, 1.00 equiv) in tetrahydrofuran (25 mL).
Iodomethane (5.00 g, 35.2 mmol, 8.00 equiv) was added to the
reaction mixture. The resulting solution was stirred at 20.degree.
C. for 12 h, and then concentrated in vacuo. This resulted in 1.10
g (87%) of methyl
4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate
as a yellow oil.
##STR00862##
Compound 189.6. Methyl
4-(cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate
[3731] To a round-bottom flask was added a solution of methyl
4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate
(compound 189.5, 1.00 g, 3.43 mmol, 1.00 equiv) in AcOH (25 mL).
Propionohydrazide (1.20 g, 13.6 mmol, 4.00 equiv) was added and the
resulting mixture was stirred at 100.degree. C. for 1 h. After
cooling to ambient temperature, the mixture was concentrated in
vacuo. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:5) as eluent
to furnish 300 mg (28%) of the title compound as a white solid.
##STR00863##
Compound 189.7.
4-(Cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
Acid
[3732] The title compound (260 mg, white solid, 91%) was prepared
using a procedure similar to that used for the preparation of
compound 181.9 using compound 189.6 (300 mg) in place of compound
181.8.
##STR00864##
Compound 189.
4-(1-(4-(Cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenz-
oyl)piperidin-4-yl)benzonitrile
[3733] The title compound (28 mg, white solid, 18%) was prepared
using a procedure similar to that used for the preparation of
compound 181 using compound 189.7 (100 mg) in place of compound
181.9. m/z (ES+) 468 (M+H).sup.+. .sup.1H-NMR (300 MHz,
CD.sub.3OD): .delta. 7.67 (d, 2H), 7.52-7.47 (m, 3H), 7.26 (s, 1H),
3.66-3.22 (m, 1H), 3.33-3.22 (m, 1H), 3.05-2.99 (m, 4H), 2.97 (q,
2H), 2.53-2.47 (m, 1H), 2.47 and 2.45 (2 singlets, amide rotamers,
ArCH.sub.3, 3H) 2.00-1.50 (m, 10H), 1.41 (t, 3H).
##STR00865##
Compound 190.1. Methyl 2-bromo-5-iodo-4-methylbenzoate
[3734] To a round-bottom flask was added a mixture of methyl
2-bromo-4-methylbenzoate (2.00 g, 7.86 mmol, 1.00 equiv) in AcOH
(20 mL). 12 (2.45 g, 9.65 mmol, 1.10 equiv), NaIO.sub.4 (950 mg,
4.42 mmol, 0.50 equiv), and sulfuric acid (0.1 mL, 0.15 equiv) were
added and the resulting mixture was stirred at 100.degree. C.
overnight. After cooling to ambient temperature, the reaction was
carefully quenched with Na.sub.2S.sub.2O.sub.3 (aq., sat.). The
resulting mixture was extracted with 2.times.50 mL of ethyl
acetate. The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo to yield 2.50 g (81%) of the title
compound as an off-white solid.
##STR00866##
Compound 190.2. Methyl 2-bromo-5-cyano-4-methylbenzoate
[3735] The title compound (1.10 g, white solid, 61%) was prepared
using a procedure similar to that used for the preparation of
compound 181.5 using compound 190.1 (2.50 g) in place of compound
181.4.
##STR00867##
Compound 190.3. Methyl 5-cyano-2-cyclopropyl-4-methylbenzoate
[3736] To a solution of methyl 2-bromo-5-cyano-4-methylbenzoate
(compound 190.2, 600 mg, 2.13 mmol, 1.00 equiv, 90%) in toluene (20
mL) under nitrogen were added cyclopropylboronic acid (552 mg, 6.43
mmol, 2.00 equiv), a solution of potassium carbonate (876 mg, 6.34
mmol, 2.00 equiv) in water (1 mL), Pd(dppf)Cl.sub.2 (252 mg, 0.10
equiv), and Pd(OAc).sub.2 (70 mg, 0.10 equiv). The resulting
mixture was stirred under nitrogen at 100.degree. C. overnight.
After cooling to ambient temperature, the mixture was diluted with
20 mL of H.sub.2O, then extracted with 3.times.50 mL of ethyl
acetate. The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo to furnish 450 mg (89%) of methyl
5-cyano-2-cyclopropyl-4-methylbenzoate as a white solid.
##STR00868##
Compound 190.4. Methyl
5-carbamothioyl-2-cyclopropyl-4-methylbenzoate
[3737] To a round-bottom flask, was added a solution of methyl
5-cyano-2-cyclopropyl-4-methylbenzoate (compound 190.3, 220 mg,
0.920 mmol, 1.00 equiv, 90%) in tetrahydrofuran (6 mL). A solution
of O,O'-diethyl dithiophosphate (300 mg, 1.61 mmol, 2.00 equiv) in
water (1.5 mL) was added to the solution, and the resulting mixture
was stirred overnight at 80.degree. C. in an oil bath (CAUTION:
significant gas evolution occurs--this and all other reactions
described herein should be carried out in well ventilated fume
hoods). After cooling to ambient temperature, the mixture was
concentrated in vacuo. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether (5:1) as
eluent. The collected fractions were combined and concentrated in
vacuo to furnish 100 mg (39%) of methyl
5-carbamothioyl-2-cyclopropyl-4-methylbenzoate as a yellow
solid.
##STR00869##
Compound 190.5. Methyl 2-cyclopropyl-4-methyl-5-(methylsulfanyl)
carboximidoylbenzoate
[3738] To a solution of methyl
5-carbamothioyl-2-cyclopropyl-4-methylbenzoate (compound 190.4, 600
mg, 2.17 mmol, 1.00 equiv, 90%) in THF (55 mL) was added dropwise
iodomethane (1 mL). The resulting mixture was stirred overnight at
25.degree. C., then concentrated and dried under reduced pressure
to yield 400 mg (56%) of the title compound as a yellow solid.
##STR00870##
Compound 190.6. 2-Methoxyacetohydrazide
[3739] To a round-bottom flask, was added a solution of ethyl
2-methoxyacetate (10.0 g, 76.2 mmol, 1.00 equiv, 90%) and
NH.sub.2NH.sub.2.H.sub.2O (12 mL, 3.00 equiv) in ethanol (100 mL).
The resulting solution was stirred for 3 h at 80.degree. C. in an
oil bath, then concentrated and dried under reduced pressure to
yield 6 g (68%) of 2-methoxyacetohydrazide as a white solid.
##STR00871##
Compound 190.7. Methyl
2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoat-
e
[3740] A solution of methyl
2-cyclopropyl-4-methyl-5-(methylsulfanyl)carboximidoylbenzoate
(compound 190.5, 400 mg, 1.37 mmol, 1.00 equiv, 90%) and
2-methoxyacetohydrazide (compound 190.6, 889 mg, 7.69 mmol, 5.00
equiv) in AcOH (25 mL) was stirred overnight at 90.degree. C. After
cooling to room temperature, the mixture was concentrated in vacuo.
The residue was purified using silica gel column chromatography
with ethyl acetate/petroleum ether (2:1) as eluent. The collected
fractions were combined and concentrated in vacuo to furnish 200 mg
(44%) of methyl
2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoat-
e as a white solid.
##STR00872##
Compound 190.8.
2-Cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic
Acid
[3741] To a round-bottom flask was added a solution of methyl
2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoat-
e (compound 190.7, 200 mg, 0.600 mmol, 1.00 equiv, 90%) in methanol
(4 mL). A solution of sodium hydroxide (106 mg, 2.65 mmol, 4.00
equiv) in water (2 mL) was added to the reaction mixture. The
resulting solution was stirred for 2 h at 60.degree. C. After
cooling to ambient temperature, the organic solvent was removed
under reduced pressure and the pH the remaining aqueous layer was
adjusted to 2-3 with hydrogen chloride (aq, 6 M). The resulting
solids were collected by filtration and dried to yield 170 mg (89%)
of the title compound as a white solid.
##STR00873##
Compound 190.
4-(1-(2-Cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylb-
enzoyl)piperidin-4-yl)benzonitrile
[3742] The title compound (115.5 mg, white solid, 51%) was prepared
using a procedure similar to that used for the preparation of
compound 181 using compound 190.8 (150 mg) in place of compound
181.9. m/z (ES+) 456 (M+H).sup.+.
##STR00874##
Compound 191.1.
2-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic
Acid
[3743] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 190.8.
##STR00875##
Compound 191.
4-(1-(2-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoy-
l)piperidin-4-yl)benzonitrile
[3744] The title compound (74.8 mg, white solid, 33%) was prepared
using a procedure similar to that used for the preparation of
compound 181 using compound 191.1 (145 mg) in place of compound
181.9. m/z (ES+) 458 (M+H).sup.+.
##STR00876##
Compound 192.
4-(1-(2-Ethyl-4-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)-
benzoyl)piperidin-4-yl)benzonitrile
[3745] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 191. m/z (ES+) 470 (M+H).sup.+.
##STR00877##
Compound 193.
4-(1-(2-Ethyl-5-(5-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)-4-methyl-
benzoyl)piperidin-4-yl)benzonitrile
[3746] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 191. m/z (ES+) 472 (M+H).sup.+.
##STR00878##
Compound 194.
4-(1-(2-Ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl-
)piperidin-4-yl)benzonitrile
[3747] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 191. m/z (ES+) 444 (M+H).sup.+.
##STR00879##
Compound 195.
4-(1-(2-Cyclobutyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbe-
nzoyl)piperidin-4-yl)benzonitrile
[3748] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 190. m/z (ES+) 470 (M+H).sup.+.
##STR00880##
Compound 196.1. Methyl 2-isopropyl-4-methylbenzoate
[3749] To a stirred mixture of dibromozinc (39.0 g, 173 mmol, 4.00
equiv) in THF (500 mL) under nitrogen at -48.degree. C. was added
dropwise isopropylmagnesium bromide (3 M in THF, 170 mmol) over a
period of 30 min. Pd(dppf)Cl.sub.2 (0.5 g, 0.05 equiv) and methyl
2-bromo-4-methylbenzoate (10.0 g, 43.7 mmol, 1.00 equiv) were added
to the above reaction mixture. After stirring for 1 h at
-48.degree. C., the reaction mixture was quenched by the careful
addition of 500 mL of NH.sub.4Cl (aq.). The resulting mixture was
extracted with 3.times.500 mL of ethyl acetate. The combined
organic layers were washed with 3.times.500 mL of brine and
concentrated in vacuo. The residue was purified using silica gel
column chromatography with petroleum ether (1:1) as eluent. This
resulted in 6.50 g 77%) of methyl 2-isopropyl-4-methylbenzoate as a
yellow oil.
##STR00881##
Compound 196.2. Methyl 5-iodo-2-isopropyl-4-methylbenzoate
[3750] To a round-bottom flask, was added a solution of methyl
2-isopropyl-4-methylbenzoate (compound 196.1, 6.50 g, 33.8 mmol,
1.00 equiv) in acetic acid (60 mL). Iodide (9.50 g, 37.4 mmol, 1.10
equiv), sodium periodate (3.60 g, 16.8 mmol, 0.50 equiv), and
sulfuric acid (0.500 g, 0.15 equiv) were added to the reaction
mixture. The resulting solution was stirred overnight at
100.degree. C. After cooling to room temperature, the reaction was
quenched with Na.sub.2S.sub.2O.sub.3 (aq., sat.). The mixture
extracted with 3.times.100 mL of ethyl acetate. The combined
organic layers were washed with 3.times.100 mL of brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo. This resulted
in 6.00 g (56%) of methyl 5-iodo-2-isopropyl-4-methylbenzoate as a
yellow oil.
##STR00882##
Compound 196.3. Methyl 5-cyano-2-isopropyl-4-methylbenzoate
[3751] The title compound (0.8 g, white solid, 37%) was prepared
using a procedure similar to that used for the preparation of
compound 181.5 using compound 196.2 (3.20 g) in place of compound
181.4.
##STR00883##
Compound 196.4. Methyl
5-carbamothioyl-2-isopropyl-4-methylbenzoate
[3752] To a round-bottom flask was added a solution of methyl
5-cyano-2-isopropyl-4-methylbenzoate (compound 196.3, 800 mg, 3.68
mmol, 1.00 equiv) in tetrahydrofuran/H.sub.2O (10/5 mL).
0,0'-diethyl dithiophosphate (2.05 g, 11.0 mmol, 3.00 equiv) was
added to the reaction mixture. The resulting solution was stirred
for 15 h at 85.degree. C. in an oil bath (CAUTION: significant gas
evolution occurs--this and all other reactions described herein
should be carried out in well ventilated fume hoods). After cooling
to ambient temperature, the mixture was extracted with 2.times.100
mL of ethyl acetate. The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:100-1:50-1:0) as eluent to furnish 0.800
g (86%) of methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate as a
yellow oil.
##STR00884##
Compound 196.5. Methyl
5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate
[3753] The title compound (0.800 g, yellow oil, 92%) was prepared
using a procedure similar to that used for the preparation of
compound 181.7 using compound 196.4 (820 mg) in place of compound
181.6.
##STR00885##
Compound 196.6. Methyl
2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate
[3754] A solution of methyl
5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate (compound
196.5, 800 mg, 3.01 mmol, 1.00 equiv) and 2-methoxyacetohydrazide
(compound 190.6, 1.90 g, 18.3 mmol, 5.00 equiv) in acetic acid (30
mL) was stirred for 2 h at 80.degree. C. in an oil bath, then
concentrated in vacuo. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether (1:50-1:2)
as eluent to yield 250 mg (27%) of methyl
2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbe-
nzoate as a clear oil.
##STR00886##
Compound 196.7.
2-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic
Acid
[3755] The title compound (0.20 g, white solid, 84%) was prepared
using a procedure similar to that used for the preparation of
compound 181.9 using compound 196.6 (250 mg) in place of compound
181.8.
##STR00887##
Compound 196.
4-(1-(2-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylben-
zoyl)piperidin-4-yl)benzonitrile and Compound 197.
4-(1-(5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methyl-2-propylbenzoy-
l)piperidin-4-yl)benzonitrile
[3756] To a solution of
2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoic
acid (compound 196.7, 200 mg, 0.690 mmol, 1.00 equiv) in DMF (20
mL) were added EDCI (200 mg, 1.04 mmol, 1.51 equiv), DMAP (250 mg,
2.05 mmol, 2.96 equiv), and HOBT (110 mg, 0.810 mmol, 1.18 equiv).
After stirring for 30 min at room temperature compound 1.5, 142 mg,
0.640 mmol, 0.92 equiv was added and the resulting solution was
stirred for 15 h at 25.degree. C., then quenched with 100 mL of ice
water. The resulting mixture was extracted with 2.times.200 mL of
ethyl acetate. The combined organic layers were washed with
2.times.100 mL of brine, then dried over anhydrous sodium sulfate
and concentrated in vacuo. The residue was purified using silica
gel column chromatography with ethyl acetate/petroleum ether
(1:50-1:1-1:0) as eluent. The crude product (.about.120 mg) was
further purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (40.0%
CH.sub.3CN up to 55.0% in 8 min, up to 100.0% in 1 min, down to
40.0% in 1 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 57.4 mg (18%) of compound 196 and 11.7 mg (4%) of compound
197 as white solids. Compound 196. m/z (ES+) 458 (M+H).sup.+.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.65-7.62 (m, 2H),
7.55-7.28 (m, 4H), 4.61 (s, 2H), 3.67-3.62 (m, 1H), 3.44 (s, 3H),
3.27-3.20 (m, 1H), 3.04-2.86 (m, 3H), 2.51 (s, 3H), 1.99-1.68 (m,
5H), 1.31-1.26 (m, 6H). Compound 197. m/z (ES+) 458 (M+H).sup.+.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.66-7.63 (m, 2H), 7.55
(s, 1H), 7.46-7.37 (m, 2H), 7.28 (m, 1H), 4.61 (s, 2H), 3.62-3.58
(m, 1H), 3.44 (s, 3H), 3.19-3.05 (m, 2H), 3.04-2.91 (m, 2H),
2.73-2.45 (m, 5H), 1.98-1.54 (m, 6H), 1.05-0.85 (m, 3H).
##STR00888##
Compound 198.1. Methyl 4-isopropyl-2-methylbenzoate
[3757] A dried round bottom flask with stir bar was purged with
nitrogen and charged with diisopropyl zinc (25 mL of a 1 M solution
in THF, 25 mmol, 2.0 equiv). Methyl 4-bromo-2-methylbenzoate
(compound 152.1, 2.86 g, 12.5 mmol, 1.0 equiv) in 1,4-dioxane (25
mL) was added followed by addition of Pd(dppf).sub.2Cl.sub.2.DCM
(1.02 g, 1.25 mmol, 0.1 equiv) (exothermic upon catalyst addition).
The system was purged with additional nitrogen then argon and
heated to 100.degree. C. for 4 hours then stirred at room
temperature for 12 hours. The mixture was carefully quenched with
1M HCl (ag., 12 mL) (some bubbling) and then diluted with water
(100 mL) and ethyl acetate (150 mL) and mixed. The mixture was
filtered through celite and washed with water and ethyl acetate
(2.times.25 mL each). The layers were separated and the aqueous was
extracted with addition ethyl acetate (50 mL). The combined
organics were washed with brine (50 mL), dried (Na.sub.2SO.sub.4),
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (hexanes to 6% ethyl
acetate) to obtain the title compound as a colorless oil (2.31 g,
96%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.86 (d with fine
str, J=8.8 Hz, 1H), 7.12-7.07 (m, 2H), 3.87 (s, 3H), 2.90 (septet,
J=6.8 Hz, 1H), 2.59 (s, 3H), 1.25 (d, J=6.8 Hz, 6H).
##STR00889##
Compound 198.2. Methyl 5-iodo-4-isopropyl-2-methylbenzoate
[3758] To methyl 4-isopropyl-2-methylbenzoate (compound 198.1, 2.31
g, 12.0 mmol, 1.0 equiv) in a 100 mL round bottom flask was
carefully added TFA (24 mL) and the mixture was cooled to 0.degree.
C. N-Iodosuccinimide (2.70 g, 12.0 mmol, 1.0 equi) was added
portionwise over 2 minutes and the resulting mixture was added
under nitrogen and stirred at 0.degree. C. for 20 min then at room
temperature for 15 hours. The mixture was carefully diluted To a
mixture of dichloromethane (50 mL) and added to saturated aqueous
disodium phosphate to maintain a pH above 3 (total disodium
phosphate about 500 mL). The mixture was shaken well, separated and
the aqueous was extracted with additional DCM (5.times.25 mL). The
combined organics was washed with a mix of saturated sodium sulfite
(10 mL) plus water (40 mL) followed by brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered and removed in vacuo. The crude
product was purified by silica column chromatography (hexanes to 3%
ethyl acetate) to obtain the title compound as a light tan oil
(3.59 g, 94%). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.35 (s,
1H), 7.08 (s, 1H), 3.87 (s, 3H), 3.17 (septet, J=6.8 Hz, 1H), 2.59
(s, 3H), 1.23 (d, J=6.8 Hz, 6H).
##STR00890##
Compound 198.3. Methyl 5-cyano-4-isopropyl-2-methylbenzoate
[3759] To a dried round bottom flask was added methyl
5-iodo-4-isopropyl-2-methylbenzoate (compound 198.2, 2.00 g, 6.29
mmol, 1.0 equiv), zinc cyanide (1.48 g, 12.6 mmol, 2.0 equiv), DMF
(20 mL) and Pd(PPh.sub.3).sub.4 (364 mg, 0.315 mmol, 0.05 equiv).
The system was purged with nitrogen followed by argon and the
mixture was heated at 100.degree. C. for 15 hours. The reaction was
allowed to cool to room temperature then diluted with ethyl acetate
(50 mL) and quenched with 1 M FeSO.sub.4 (25 mL). The mixture was
stirred vigorously for 40 minutes then filtered through celite and
washed with 1 M FeSO.sub.4 (15 mL), water (50 mL) and ethyl acetate
(150 mL). The layers were separated and the aqueous phase was
extracted with ethyl acetate (50 mL). The combined organic layers
were washed with brine (4.times.100 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The product was purified by
silica column chromatography (hexanes to 8% ethyl acetate) to
obtain the title compound (1.14 g, 83%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.19 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H), 3.37
(septet, J=6.8 Hz, 1H), 2.67 (s, 3H), 1.32 (d, J=6.8 Hz, 6H).
##STR00891##
Compound 198.4. Methyl
5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate
[3760] Methyl 5-cyano-4-isopropyl-2-methylbenzoate (compound 198.3,
1.12 g, 5.16 mmol, 1.0 equiv), O,O'-diethyl dithiophosphate (90%)
(2.0 mL, 10.7 mmol, 2.1 equiv) and water (200 .mu.L) were added to
a 16 mL vial and the mixture was heated with the cap loose at
80.degree. C. for 85 hours (CAUTION: significant gas evolution
occurs--this and all other reactions described herein should be
carried out in well ventilated fume hoods). Note that additional
O,O'-diethyl dithiophosphate (0.5 mL, 2.7 mmol, 0.5 equiv) and
water (50 .mu.L) was added at 6 hours and 14 hours. The
intermediate thioamide is also observed by LC/MS during the
reaction and is heated until the conversion to the desired product
is complete. The reaction mixture was diluted with ethyl acetate
(75 mL) and washed with saturated aqueous NaHCO.sub.3 (20 mL)
followed by 1 M NaH.sub.2PO.sub.4 (10 mL) and brine (10 mL). The
organics were dried (Na.sub.2SO.sub.4), filtered and removed in
vacuo. The crude product was purified by silica column
chromatography (hexanes to 25% ethyl acetate) to obtain a colorless
oil (1.12 g, 78%). m/z (ES+) 280 (M+H).sup.+.
##STR00892##
Compound 198.5. Methyl
4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate
[3761] Methyl
5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate (compound
198.4, 33 mg, 0.12 mmol, 1.0 equiv), 3-methoxypropanehydrazide
(compound 143.1, 21 mg, 0.18 mmol, 1.5 equiv) and acetic acid (1.2
mL) were added to a 4-mL vial and heated at 80.degree. C. with a
loose cap for 4 hours. The solvent was removed in vacuo and the
residue was dissolved in DCM (10 mL) and washed with saturated
NaHCO.sub.3 (5 mL) then brine (5 mL), dried (Na.sub.2SO.sub.4),
filtered and evaporated to a colorless oil (theoretical yield). m/z
(ES+) 318 (M+H).sup.+.
##STR00893##
Compound 198.6.
4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
Acid
[3762] To crude methyl
4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate
(compound 198.5, 0.12 mmol, 1.0 equiv) from the previous step in a
4-mL vial was added lithium hydroxide monohydrate (10.1 mg, 0.24
mmol, 2.0 equiv), methanol (0.9 mL) and water (0.3 mL). The
resulting mixture was stirred at room temperature for 3 hours
followed by 50.degree. C. for 3 hours and 40.degree. C. for 17
hours. The solvents were removed in vacuo and the residue was
diluted with water (7 mL) plus saturated NaHCO.sub.3 (1 mL) and the
aqueous was washed with diethyl ether (2 mL). The organic was back
extracted with a mix of water (2 mL) plus saturated NaHCO.sub.3
(0.5 mL). The combined aqueous was acidified to pH=3 with 1 M
H.sub.3PO.sub.4 and extracted with dichlormethane (3.times.5 mL).
The organics were dried (Na.sub.2SO.sub.4), filtered and removed in
vacuo to obtain the title compound as a white waxy solid (31.5 mg,
88% over 2 steps). m/z (ES+) 304 (M+H).sup.+.
##STR00894##
Compound 198.
4-(1-(4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbe-
nzoyl)piperidin-4-yl)benzonitrile
[3763] To a 4-mL vial was added
4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
acid (compound 198.6, 31 mg, 0.10 mmol, 1.0 equiv),
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 23 mg,
0.10 mmol, 1.0 equiv), 1-hydroxybenzotriazole hydrate (20 wt %
water) (22 mg, 0.13 mmol, 1.25 equiv),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (21.5
mg, 0.11 mmol, 1.1 equiv), DMF (1 mL) and DIEA (71 .mu.L, 0.41
mmol, 4 equiv). The mixture was stirred at room temperature for 24
hours then diluted with ethyl acetate (10 mL) and washed with brine
(10 mL). The aqueous was back extracted with ethyl acetate (3 mL)
and the combined organics was washed with saturated NaHCO.sub.3 (5
mL), 1 M NaH.sub.2PO.sub.4 (5 mL), and brine (5 mL). The organics
were dried (Na.sub.2SO.sub.4), filtered and removed in vacuo. The
crude residue was purified by preparative TLC (DCM/8% MeOH) to
obtain the title compound as an off white solid (23 mg, 48%). m/z
(ES+) 472 (M+H).sup.+.
##STR00895##
Compound 199.
4-(1-(4-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylben-
zoyl)piperidin-4-yl)benzonitrile
[3764] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbe-
nzoyl)piperidin-4-yl)benzonitrile (compound 198). m/z (ES+) 458
(M+H).sup.+.
##STR00896##
Compound 200.
4-(1-(4-Isopropyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile
[3765] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbe-
nzoyl)piperidin-4-yl)benzonitrile (compound 198). m/z (ES+) 458
(M+H).sup.+.
##STR00897##
Compound 201.
4-(1-(4-Isopropyl-3-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)pipe-
ridin-4-yl)benzonitrile
[3766] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbe-
nzoyl)piperidin-4-yl)benzonitrile (compound 198). m/z (ES+) 444
(M+H).sup.+.
##STR00898##
Compound 202.1. Methyl
5-carbamoyl-4-cyclobutyl-2-methylbenzoate
[3767] To an 8-mL vial was added methyl
5-cyano-4-cyclobutyl-2-methylbenzoate (152.4, 100 mg, 0.436 mmol,
1.0 equiv), potassium carbonate (181 mg, 1.31 mmol, 3.0 equiv) and
DMSO (2.2 mL) and stirring was initiated. Hydrogen peroxide (50 wt
%) (176 .mu.L, 3.05 mmol, 7.0 equiv) was added over about 1 minute.
The mixture was stirred at room temperature for 29 hours then
diluted into brine (10 mL) plus 1 M H.sub.3PO.sub.4 (1.5 mL). The
mixture was extracted with ethyl acetate (10 mL.times.1, 3
mL.times.1). The combined organic layers were washed with brine (10
mL) plus a few drops of 1 M H.sub.3PO.sub.4 followed by a mixture
of water (10 mL) plus saturated NaHCO.sub.3 (1 mL) and finally
brine (5 mL). The organics was dried (Na.sub.2SO.sub.4), filtered
and evaporated to obtain the title compound as a white solid (59
mg, 55%). m/z (ES+) 248.0 (M+H).sup.+.
##STR00899##
Compound 202.2. Methyl
4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate
[3768] To a vial was added methyl
5-carbamoyl-4-cyclobutyl-2-methylbenzoate (compound 202.1, 59 mg,
0.24 mmol, 1.0 equiv) and N,N-dimethylformamide dimethyl acetal (1
mL) was added. The mixture was heated at 80.degree. C. for 5 hours
then the solvents were removed in vacuo. To the residue was added
acetic acid (400 .mu.L) and a solution of anhydrous hydrazine (8.2
.mu.L, 0.26 mmol, 1.1 equiv) in acetic acid (100 .mu.L). To the
resulting thick suspension was added additional acetic acid (500
.mu.L) and the mixture was stirred at 80.degree. C. for 1.5 hours
then the solvents removed in vacuo. Ethyl acetate (5 mL) and DCM (5
mL) was added (some undissolved solids). The organics was washed
with saturated NaHCO.sub.3 (10 mL) and brine (5 mL) and removed in
vacuo to obtain the title compound as a white solid (theoretical
yield). m/z (ES+) 272 (M+H).sup.+.
##STR00900##
Compound 202.3.
4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic Acid
[3769] To crude methyl
4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate (compound
202.2, 0.24 mmol, 1.0 equiv) from the previous step in a 4-mL vial
was added methanol (1.5 mL) and water (0.5 mL) and lithium
hydroxide monohydrate (20 mg, 0.48 mmol, 2.0 equiv), The resulting
mixture was stirred at 40.degree. C. for 42 hours. The reaction
mixture was diluted into water (5 mL), acidified to pH 3 with 1M
H.sub.3PO.sub.4 and extracted with DCM (3.times.5 mL). The organics
were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo
to obtain the title compound as a white solid (61 mg, 98% over 2
steps). m z (ES+) 258 (M+H).sup.+.
##STR00901##
Compound 202.
4-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4--
yl)benzonitrile
[3770] To a 4-mL vial was added
4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid
(compound 202.3, 31 mg, 0.12 mmol, 1.0 equiv),
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 27 mg,
0.12 mmol, 1.0 equiv), 1-hydroxybenzotriazole hydrate (20 wt %
water) (25 mg, 0.15 mmol, 1.25 equiv),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (25
mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83 .mu.L, 0.48
mmol, 4 equiv). The mixture was stirred at room temperature for 4
hours then diluted with ethyl acetate (10 mL) and washed with 1 M
NaH.sub.2PO.sub.4 (5 mL). The aqueous was back extracted with ethyl
acetate (3 mL) and the combined organics was washed with brine (5
mL), saturated NaHCO.sub.3 (5 mL) and brine (5 mL). The organics
were dried (Na.sub.2SO.sub.4), filtered and removed in vacuo. The
crude residue was purified by preparative TLC (DCM/8% MeOH) to
obtain the title compound as a white solid (23 mg, 46%). m/z (ES+)
426 (M+H).sup.+.
##STR00902##
Compound 203.
4-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropip-
eridin-4-yl)benzonitrile
[3771] To a 4-mL vial was added
4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid
(compound 202.3, 31 mg, 0.12 mmol, 1.0 equiv),
4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 31 mg, 0.13
mmol, 1.1 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water)
(25 mg, 0.15 mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (25 mg, 0.13 mmol, 1.1 equiv), DMF (0.6
mL) and DIEA (83 .mu.L, 0.48 mmol, 4 equiv). The mixture was
stirred at room temperature for 4 hours then diluted with ethyl
acetate (10 mL) and washed with 1 M NaH.sub.2PO.sub.4 (5 mL). The
aqueous was back extracted with ethyl acetate (3 mL) and the
combined organics was washed with brine (5 mL), saturated
NaHCO.sub.3 (5 mL) and brine (5 mL). The organics were dried
(Na.sub.2SO.sub.4), filtered and removed in vacuo. The crude
residue was purified by preparative TLC (DCM/8% MeOH) to obtain the
title compound as a white solid (30 mg, 56%). m/z (ES+) 444
(M+H).sup.+.
##STR00903##
Compound 204.1. Methyl 2,4-dibromobenzoate
[3772] A solution of 2,4-dibromobenzoic acid (52.0 g, 176 mmol,
1.00 equiv, 95%) and sulfuric acid (20 mL) in methanol (400 mL) was
stirred at 90.degree. C. overnight. After cooling to room
temperature, the mixture was concentrated under reduced pressure.
The residue was diluted with 500 mL of ethyl acetate and washed
with 3.times.100 mL of H.sub.2O followed by 1.times.100 mL of
NaHCO.sub.3 (aq., sat. Note: gas evolution occurs). The organic
layer was dried over anhydrous sodium sulfate and concentrated in
vacuo. This resulted in 45.0 g (78%) of methyl 2,4-dibromobenzoate
as a yellow oil.
##STR00904##
Compound 204.2. Methyl 2,4-diethylbenzoate
[3773] To stirred mixture of ZnBr.sub.2 (40.0 g, 176 mmol, 5.44
equiv, 99%) in THF (100 mL) under nitrogen at 0.degree. C. was
added dropwise EtMgBr (60 mL, 3 M in THF). After 0.5 h at 0.degree.
C., the temperature was lowered to -78.degree. C. and
PdCl.sub.2(dppf) (3.72 g, 5.03 mmol, 0.16 equiv, 99%) was added
followed by the dropwise addition of a solution of methyl
2,4-dibromobenzoate (compound 204.1, 10.0 g, 32.3 mmol, 1.00 equiv,
95%) in THF (200 mL). The reaction was stirred overnight at room
temperature, then carefully quenched with water followed by HCl
(aq., 1 M). The resulting mixture was extracted with 3.times.500 mL
of ethyl acetate, and the combined organic layers were washed with
3.times.50 mL of brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether (1:60) as
eluent to furnish 6.30 g (96%) of methyl 2,4-diethylbenzoate as a
colorless oil
##STR00905##
Compound 204.3. Methyl 2,4-diethyl-5-iodobenzoate
[3774] The title compound (4.0 g, light yellow oil, 69%) was
prepared using a procedure similar to that used for the preparation
of compound 181.4 using compound 204.2 (3.50 g) in place of
compound 181.3.
##STR00906##
Compound 204.4. 2,4-Diethyl-5-iodobenzoic Acid
[3775] The title compound (3.24 g, white solid, 85%) was prepared
using a procedure similar to that used for the preparation of
compound 181.9 using compound 204.3 (4.00 g) in place of compound
181.8.
##STR00907##
Compound 204.5. 2,4-Diethyl-5-(methoxycarbonyl)benzoic Acid
[3776] To a stirred solution of 2,4-diethyl-5-iodobenzoic acid
(compound 204.4, 500 mg, 1.64 mmol, 1.00 equiv, 90%) in
tetrahydrofuran (20 mL) at -78.degree. C. under nitrogen was added
dropwise a solution of n-BuLi (1.73 mL, 4.10 mmol, 2.36 M in THF).
After 5 minutes, a solution of methyl chloroformate (0.315 mL, 4.10
mmol, 2.50 equiv) in THF (5 mL) was added dropwise to the reaction
at -78.degree. C. over 5 minutes. The reaction was stirred for
another 5 min at -78.degree. C., and then carefully quenched with
10 mL of water. The pH was adjusted to 1-2 with hydrochloric acid
(6 M) and the resulting mixture was extracted with ethyl acetate
(2.times.30 mL). The combined organic layers were washed with 20 mL
of brine, then dried over anhydrous sodium sulfate, and
concentrated in vacuo. The residue was purified by silica gel
column chromatograph with ethyl acetate-petroleum ether (1:20) as
eluent to yield 96 mg (25%) of the title compound as an off-white
solid.
##STR00908##
Compound 204.6. Methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzoate
[3777] To a round-bottom flask, were added a solution of
2,4-diethyl-5-(methoxycarbonyl)benzoic acid (compound 204.5, 500
mg, 2.12 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 470 mg, 2.12 mmol, 1 equiv), EDC-HCl
(810 mg, 4.24 mmol, 2.00 equiv), and 4-dimethylaminopyridine (520
mg, 4.24 mmol, 2 equiv) in N,N-dimethylformamide (15 mL). The
reaction was stirred overnight at 25.degree. C. Upon reaction
completion, the reaction mixture was diluted with 30 mL of ethyl
acetate, then washed with 1.times.20 mL of NH.sub.4Cl (aq.) and
1.times.20 mL of brine. The organic phase was dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified
by silica gel chromatography with a solvent mixture of ethyl
acetate and petroleum ether (1:1) to yield 500 mg (60%) of the
title compound as a pale yellow solid.
##STR00909##
Compound 204.7.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide
[3778] To a solution of compound 204.6 (500 mg, 1.05 mmol, 1.00
equiv, 85%) in ethanol (6 mL) was added hydrazine hydrate (3 mL).
The resulting solution was stirred overnight at 90.degree. C. After
cooling to ambient temperature, the mixture was concentrated in
vacuo. The residue was diluted with 20 mL of ethyl acetate, then
washed with 1.times.5 mL of brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The residue was purified by
silica gel column chromatography with dichloromethane-methanol
(20:1) as eluent to yield 260 mg (55%) of the desired compound as a
yellow solid.
##STR00910##
Compound 204.8.
4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)-
benzonitrile
[3779] To a round-bottom flask was added a solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide
(compound 204.7, 100 mg, 0.220 mmol, 1.00 equiv, 90%) in a solvent
mixture of water (2 mL) and dioxane (3 mL). Sodium bicarbonate (62
mg, 0.740 mmol, 3.00 equiv) was added to the reaction mixture at
room temperature, and stirred for 5 minutes. BrCN (75 mg, 0.740
mmol, 3.00 equiv) was then added to the reaction at room
temperature. The resulting solution was stirred for 2 h at room
temperature, then quenched with 30 mL of FeSO.sub.4 (aq., sat.) and
diluted with ethyl acetate. The resulting mixture was stirred
vigorously then filtered through celite and washed with 1 M
FeSO.sub.4, water, and ethyl acetate. The layers were separated and
the aqueous phase was extracted with 2.times.50 mL of ethyl
acetate. The combined organic layers were washed with 2.times.50 mL
of brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. This resulted in 100 mg (89%) of the title compound as a
yellow solid. The compound was used in the next step reaction
without further purification.
##STR00911##
Compound 204.9.
4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-y-
l)benzamide
[3780] A mixture of compound 204.8 (100 mg, 0.200 mmol, 1.00 equiv,
85%) and potassium hydroxide (132 mg, 2.35 mmol, 10.0 equiv) in
ethanol (10 mL) was stirred at 85.degree. C. overnight. After
cooling to ambient temperature, the pH was adjusted to 7 with
acetic acid and the resulting solution was concentrated in vacuo.
The residue was diluted with 50 mL of ethyl acetate, washed with
2.times.20 mL of brine, then concentrated in vacuo. The crude
product was dried in a vacuum oven, before it was charged onto a
silica gel column, and purified with dichloromethane-methanol
(20:1) to afford 100 mg (85%) of the title compound as a yellow
solid.
##STR00912##
Compound 204.
4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-y-
l)benzonitrile
[3781] To a round-bottom flask was added a solution of
4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-y-
l)benzamide (compound 204.9, 100 mg, 0.170 mmol, 1.00 equiv) in
dichloromethane (10 mL). Triethylamine (170 mg, 1.68 mmol, 8.00
equiv) was added to the reaction at room temperature, followed by
dropwise addition of a solution of (CF.sub.3CO).sub.2O (160 mg,
0.760 mmol, 4.50 equiv) in dichloromethane (0.5 mL) at 0 to
5.degree. C. The resulting solution was stirred at room temperature
for another 2 hours. The mixture was diluted with 60 mL of ethyl
acetate, then washed with 3.times.20 mL of brine. The organic layer
was dried over anhydrous sodium sulfate, and concentrated in vacuo.
The residue was purified by prep-HPLC (SunFire Prep C18, 19*150 mm
5 um, water with 0.05% TFA and CH.sub.3CN (53.0% CH.sub.3CN up to
65.0% in 8 min, up to 100.0% in 2 min, down to 53.0% in 1 min). The
fractions containing pure compound were combined and lyophilized to
yield 50 mg (50%) of the title compound as a white solid. m/z (ES+)
458 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.63
(d, 2H), 7.45-7.30 (m, 4H), 4.89-4.80 (m, 1H, overlapped), 4.36 (q,
2H), 3.60-3.57 (m, 1H), 3.29-3.23 (m, 1H), 3.19-2.85 (m, 4H),
2.74-2.56 (m, 2H), 2.00-1.82 (m, 1H), 1.77-1.66 (m, 3H), 1.40 (t,
3H), 1.30-1.21 (m, 3H), 1.11 (t, 3H).
##STR00913##
Compound 205.
4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4--
yl)benzonitrile
[3782] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-y-
l)benzonitrile (compound 204). m/z (ES+) 430 (M+H).sup.+. .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.69 (d, 2H), 7.52-7.47 (m, 3H),
7.29 (s, 1H), 4.89-4.80 (m, 1H, overlapped), 4.42-4.40 (m, 2H),
3.64-3.61 (m, 1H), 3.02-2.96 (m, 2H), 2.51 (s, 3H), 2.41 and 2.31
(2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.05-2.02 (m, 1H),
1.77-1.46 (m, 3H), 1.45 (t, 3H).
##STR00914##
Compound 206.
4-(1-(5-(5-(2-Methoxyethoxy)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)p-
iperidin-4-yl)benzonitrile
[3783] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation
4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-y-
l)benzonitrile (compound 204). m/z (ES+) 460 (M+H).sup.+.
##STR00915##
Compound 207.
4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)oxy)-4H-1,2,4-triazol-3-yl-
)benzoyl)piperidin-4-yl)benzonitrile
[3784] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-y-
l)benzonitrile (compound 204). m/z (ES+) 472 (M+H).sup.+. .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.69 (d, J=6.0 Hz, 2H),
7.58-7.37 (m, 3H), 7.30 (br s, 1H), 5.40 (br s, 1H), .about.4.9 (1H
partially obscured by water peak), 4.08-3.96 (m, 3H), 3.96-3.88 (m,
1H), 3.71-3.58 (m, 1H), 3.33-3.22 (m, 1H), 3.00 (t with fine
structure, J=9.0 Hz, 2H), 2.52 (s, 3H), 2.42 & 2.32 (2
singlets, amide rotamers, Ar--CH.sub.3, 3H), 2.38-2.20 (m, 2H),
2.08-1.97 (m, 1H), 1.93-1.55 (m, 3H).
##STR00916##
Compound 208.
4-(1-(2,4-Diethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4--
yl)benzonitrile
[3785] To a round-bottom flask was added a solution of
4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)-
benzonitrile (compound 204.8, 80.0 mg, 0.150 mmol, 1.00 equiv, 80%)
and potassium hydroxide (104 mg, 1.85 mmol, 10.00 equiv) in
methanol (10 mL). The resulting mixture was stirred at room
temperature overnight, then concentrated in vacuo. The residue was
purified using silica gel column chromatography with
dichloromethane/methanol (20:1) as eluent. The crude product (50
mg) was further purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (40%
CH.sub.3CN up to 64% in 8 min, up to 100% in 1 min, down to 40% in
1 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield 1.7
mg (3%) of the title compound as a white solid. m/z (ES+) 444
(M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.63 (d,
J=5.7 Hz, 2H), 7.45-7.30 (m, 4H), 4.85-4.80 (m, 1H), 4.02 (s, 3H),
3.65-3.62 (m, 1H), 3.15-3.10 (m, 1H), 2.90-2.84 (m, 4H), 2.72-2.60
(m, 2H), 2.02-2.00 (m, 1H), 1.72-1.65 (m, 3H), 1.30-1.25 (m, 3H),
1.11 (t, 3H).
##STR00917##
Compound 209.1.
2,4-Diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic
Acid
[3786] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 198.6), but using methyl
2,4-diethyl-5-iodobenzoate (compound 204.3) instead compound 198.2
as the starting material.
##STR00918##
Compound 209.
4-(1-(2,4-Diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile
[3787] To a round-bottom flask was added a solution of
2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic
acid (compound 209.1, 300 mg, 0.940 mmol, 1.00 equiv, 95%) in
N,N-dimethylformamide (20 mL). 4-(Piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 243 mg, 1.09 mmol, 1.10 equiv),
EDC-HCl (380 mg, 1.98 mmol, 2.00 equiv), and
4-dimethylaminopyridine (240 mg, 1.96 mmol, 2.09 equiv) were added
to the reaction mixture. The resulting solution was stirred
overnight at room temperature, then diluted with 100 mL of ethyl
acetate. The organic layer was washed with 3.times.15 mL of brine,
dried over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified using silica gel column chromatography with
ethyl acetate as eluent. The crude product (300 mg) was purified by
Prep-HPLC with the following conditions (1#-Pre-HPLC-001
(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile
phase, water with 0.05% TFA and CH.sub.3CN (35% CH.sub.3CN up to
60% in 8 min, up to 100% in 1 min, down to 35% in 1 min); Detector,
Waters 2489 254&220 nm. The fractions containing pure compound
were combined and lyophilized to yield 188 mg (42%) of the title
compound as a white solid. m/z (ES+) 472 (M+H).sup.+.
##STR00919##
Compound 210.
4-(1-(2,4-Diethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzo-
yl)piperidin-4-yl)benzonitrile
[3788] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile (compound 209) but using
tetrahydrofuran-3-carbohydrazide (compound 38.2) instead of
3-methoxypropanehydrazide (compound 143.1). m/z (ES+) 484.05
(M+H).sup.+.
##STR00920##
Compound 211.2. Methyl 2-ethyl-5-iodo-4-methylbenzoate
[3789] To a round-bottom flask was added a solution of methyl
2-ethyl-4-methylbenzoate (compound 48.1, 12.5 g, 70.1 mmol, 1.00
equiv) in AcOH (100 mL). NaIO.sub.4 (7.51 g, 35.1 mmol, 0.50 equiv)
and 12 (21.4 g, 84.3 mmol, 1.20 equiv) were added in portions at
25.degree. C. Sulfuric acid (1.60 g, 16.3 mmol, 0.20 equiv) was
then added to the reaction mixture dropwise at 25.degree. C. The
resulting solution was stirred for 12 h at 110.degree. C. in an oil
bath, and then cooled to ambient temperature. The reaction was
quenched with 150 mL of Na.sub.2S.sub.2O.sub.3 (aq., sat.). The
aqueous phase was extracted with 2.times.200 mL of ethyl acetate.
The combined organic layers were washed with 3.times.300 mL of
sodium bicarbonate (aq.) and 1.times.150 mL of brine. The mixture
was dried over anhydrous sodium sulfate and concentrated in vacuo.
This resulted in 20.0 g (94%) of methyl
2-ethyl-5-iodo-4-methylbenzoate as a yellow oil.
##STR00921##
Compound 211.3. 2-Ethyl-5-iodo-4-methylbenzoic Acid
[3790] To a round-bottom flask, was added a solution of methyl
2-ethyl-5-iodo-4-methylbenzoate (compound 211.2, 10.0 g, 32.9 mmol,
1.00 equiv) in methanol (40 mL). A solution of NaOH (5.26 g, 132
mmol, 4.00 equiv) in water (20 mL) was added dropwise. After
stirring for 12 h at 40.degree. C., the organic solvent was removed
under reduced pressure. The pH of the remaining aqueous phase was
adjusted to 4 with hydrogen chloride (aq., 6 M), then extracted
with 2.times.100 mL of ethyl acetate. The combined organic layers
were dried over anhydrous sodium sulfate and concentrated in vacuo.
This resulted in 9.30 g (97%) of 2-ethyl-5-iodo-4-methylbenzoic
acid as a white solid.
##STR00922##
Compound 211.4. 2-Ethyl-5-formyl-4-methylbenzoic Acid
[3791] To a stirred solution of 2-ethyl-5-iodo-4-methylbenzoic acid
(compound 211.3, 5.00 g, 17.2 mmol, 1.00 equiv) in tetrahydrofuran
(100 mL) at -78.degree. C. under nitrogen was added dropwise n-BuLi
(17 mL, 2 M in THF, 2.00 equiv). After 1 h at -78.degree. C., DMF
(7.00 g, 95.8 mmol, 3.00 equiv) was added dropwise at -78.degree.
C. The resulting solution was slowly warmed up to 25.degree. C.,
then carefully quenched with water followed by the addition of 10
mL of HCl (aq., 6 M). The aqueous phase was extracted with
3.times.100 mL of ethyl acetate. The combined organic layers were
dried over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified using silica gel column chromatography with
ethyl acetate/petroleum ether (2:1) as eluent to furnish 450 mg
(14%) of 2-ethyl-5-formyl-4-methylbenzoic acid as a yellow
solid.
##STR00923##
Compound 211.5.
4-(1-(2-Ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile
[3792] To a round-bottom flask was added a solution of
2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 450 mg, 2.34
mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). DIEA (907 mg,
7.02 mmol, 3.00 equiv) and HBTU (1.30 g, 3.43 mmol, 1.50 equiv)
were added to the reaction mixture. The resulting solution was
stirred for 30 min at 25.degree. C.
[3793] A solution of 4-(piperidin-4-yl)benzonitrile hydrochloride
(compound 1.5, 624 mg, 2.80 mmol, 1.20 equiv) in DIEA (2 mL) was
added dropwise. The resulting solution was stirred for 30 min at
25.degree. C., then quenched with 20 mL of water. The aqueous phase
was extracted with 3.times.30 mL of ethyl acetate. The combined
organic layers were washed with 1.times.50 mL of brine, dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (5:1) as eluent to furnish 720 mg (85%) of
the title compound as a yellow solid.
##STR00924##
Compound 211.6.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic
Acid
[3794] To a round-bottom flask was added a solution of
4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile
(compound 211.5, 720 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran
(20 mL). A solution of KMnO.sub.4 (640 mg, 4.05 mmol, 2.00 equiv)
in water (20 mL) was added dropwise. The resulting solution was
stirred for 15 h at 60.degree. C. then cooled to rt with a water
bath. The solids were removed with filtration. The filtrate was
extracted with 3.times.30 mL of ethyl acetate. The combined organic
layers were dried over anhydrous sodium sulfate and concentrated in
vacuo. This resulted in 600 mg (80%) of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic
acid as a light yellow solid.
##STR00925##
Compound 211.7. Methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate
[3795] To a round-bottom flask was added a solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic
acid (compound 211.6, 600 mg, 1.59 mmol, 1.00 equiv) in methanol
(30 mL). To this was added sulfuric acid (500 mg, 5.10 mmol, 3.20
equiv) dropwise. The resulting solution was stirred for 15 h at
60.degree. C. After cooling to ambient temperature, the mixture was
concentrated in vacuo. The residue was diluted with 20 mL of
H.sub.2O. The aqueous phase was extracted with 3.times.20 mL of
ethyl acetate. The combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo. This resulted
in 500 mg (80%) of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate
as a yellow oil.
##STR00926##
Compound 211.8.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide
[3796] To a round-bottom flask was added a solution of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate
(compound 211.7, 500 mg, 1.28 mmol, 1.00 equiv) in ethanol (20 mL).
Hydrazine (4 mL) was added to the reaction mixture. The resulting
solution was stirred for 15 h at 80.degree. C., then concentrated
in vacuo. The residue was partitioned between water and ethyl
acetate. The aqueous layer was extracted with ethyl acetate
(2.times.). The combined organic layers were dried over anhydrous
sodium sulfate and concentrated in vacuo to yield 400 mg (80%) of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide
as a light yellow solid.
##STR00927##
Compound 211.9. N-(Morpholine-4-carbonothioyl)benzamide
[3797] To a 50-mL three neck round-bottom flask, which was purged
and maintained with an inert atmosphere of nitrogen, was added a
solution of morpholine (1.00 g, 11.5 mmol, 1.00 equiv) in acetone
(10 mL). TEA (1.74 g, 17.2 mmol, 1.50 equiv) was added to the
reaction, and the resulting solution was stirred for 30 min at
25.degree. C. Benzoyl isothiocyanate (1.87 g, 11.5 mmol, 2.00
equiv) was added dropwise to the reaction at 0.degree. C. The
resulting solution was stirred for 30 min at 0.degree. C., then
quenched with 20 mL of water. The mixture was extracted with
2.times.30 mL of ethyl acetate. The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:10-1:3) as eluent to furnish 2.30 g
(80%) of N-(morpholine-4-carbonothioyl)benzamide as a yellow
solid.
##STR00928##
Compound 211.10. Morpholine-4-carbothioamide
[3798] To a round-bottom flask was added a solution of
N-(morpholine-4-carbonothioyl)benzamide (compound 211.9, 3.00 g,
12.0 mmol, 1.00 equiv) in methanol (20 mL). A solution of sodium
hydroxide (1.44 g, 36.0 mmol, 3.00 equiv) in water (20 mL) was
added to the reaction. The resulting solution was stirred overnight
at 60.degree. C. After cooling to ambient temperature, the organic
solvent was removed under reduced pressure. The residue was
extracted with 2.times.20 mL of ethyl acetate/petroleum ether
(1:1). The combined organic layers were dried over anhydrous sodium
sulfate and concentrated in vacuo. This resulted in 430 mg (25%) of
morpholine-4-carbothioamide as a yellow solid.
##STR00929##
Compound 211.11. 4-(Methylsulfanyl)carboximidoylmorpholine
[3799] A solution of morpholine-4-carbothioamide (compound 211.10,
430 mg, 2.94 mmol, 1.00 equiv) and iodomethane (1.25 g, 8.81 mmol,
3.00 equiv) in tetrahydrofuran (10 mL) was stirred for 4 h at
25.degree. C., then concentrated in vacuo. This resulted in 471 mg
(100%) of 4-(methylsulfanyl)carboximidoylmorpholine as a yellow
solid.
##STR00930##
Compound 211.
4-(1-(2-Ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)pipe-
ridin-4-yl)benzonitrile
[3800] To a 20-mL sealed tube was added solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide
(compound 211.8, 225 mg, 0.580 mmol, 1.00 equiv) in pyridine (10
mL). 4-(Methylsulfanyl) carboximidoylmorpholine (compound 211.11,
200 mg, 1.25 mmol, 1.00 equiv) was added to the reaction mixture.
The resulting solution was stirred for 3 days at 100.degree. C.
behind a blast shield. After cooling to room temperature, the
mixture was then concentrated in vacuo. The residue was purified
using silica gel column chromatography with chloroform/methanol
(30:1) as eluent. The crude product (.about.100 mg) was purified by
Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150
mm; mobile phase, water with 0.03% NH.sub.3H.sub.2O and CH.sub.3CN
(32% CH.sub.3CN up to 55% in 8 min, up to 100% in 2 min, down to
32% in 1 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield
67.7 mg (24%) of the title compound as a white solid. m/z (ES+) 485
(M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.69 (d,
2H), 7.49-7.31 (m, 4H), 4.90-4.80 (m, 1H), 3.83-3.81 (m, 4H),
3.79-3.65 (m, 1H), 3.60-3.41 (m, 4H), 3.40-3.31 (m, 1H), 3.08-2.97
(m, 2H), 2.76-2.71 (m, 2H), 2.51 (s, 3H), 2.02-1.98 (m, 1H),
1.85-1.80 (m, 3H), 1.33-1.30 (m, 3H).
##STR00931##
Compound 212.
4-(1-(5-(5-((2-Methoxyethyl)(methyl)amino)-4H-1,2,4-triazol-3-yl)-2,4-dim-
ethylbenzoyl)piperidin-4-yl)benzonitrile
[3801] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)pipe-
ridin-4-yl)benzonitrile (compound 211). m/z (ES+) 473
(M+H).sup.+.
##STR00932##
Compound 213.
4-(1-(2,4-Dimethyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidi-
n-4-yl)benzonitrile
[3802] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)pipe-
ridin-4-yl)benzonitrile (compound 211). m/z (ES+) 471
(M+H).sup.+.
##STR00933##
Compound 214.
4-(1-(2,4-Dimethyl-5-(5-(pyrrolidin-1-yl)-4H-1,2,4-triazol-3-yl)benzoyl)p-
iperidin-4-yl)benzonitrile
[3803] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)pipe-
ridin-4-yl)benzonitrile (compound 211). m/z (ES+) 455
(M+H).sup.+.
##STR00934##
Compound 215.3. 4-Cyclobutyl-2-ethyl-5-iodobenzoic Acid
[3804] To a round-bottom flask, was added a solution of methyl
4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 10.3 g, 30.0
mmol, 1.00 equiv) in methanol (100 mL). A solution of sodium
hydroxide (3.60 g, 3.00 equiv) in water (10 mL) was added dropwise
to the stirred reaction mixture. The resulting mixture was stirred
for 2 h at 60.degree. C. After cooling to ambient temperature, the
volatiles were removed under reduced pressure. The pH of the
remaining aqueous mixture was adjusted to .about.4 using HCl (aq.,
1 M). The resulting precipitate was collected by filtration and
dried to yield 9.00 g (91%) of 4-cyclobutyl-2-ethyl-5-iodobenzoic
acid as a white solid.
##STR00935##
Compound 215.4. 4-Cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic
Acid
[3805] To a solution of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid
(compound 215.3, 3.30 g, 10.0 mmol, 1.00 equiv) in THF (40 mL) was
added n-BuLi (2.5 M, 9.50 mL, 2.38 equiv) dropwise at -78.degree.
C. under nitrogen atmosphere. The resulting solution was stirred
for another 20 min at the same temperature, followed by the
addition of a solution of dimethyl carbonate (2.70 g, 30.0 mmol,
3.00 equiv) in tetrahydrofuran (2 mL) dropwise. The reaction
temperature was slowly raised to 25.degree. C. and stirred for
another 1 h, then slowly quenched with 50 mL of water. The pH was
adjusted to .about.4 with HCl (aq., 1 M) and the resulting mixture
was extracted with 100 mL of ethyl acetate. The combined organic
layers were dried over anhydrous sodium sulfate and concentrated in
vacuo. The residue was purified by silica gel chromatography with
ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.80 g
(69%) of the desired product as a white solid.
##STR00936##
Compound 215.5. Methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate
[3806] To a round-bottom flask were added a solution of
4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound
215.4, 1.15 g, 4.38 mmol, 1.00 equiv),
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g,
4.80 mmol, 1.10 equiv), HBTU (2.50 g, 6.59 mmol, 1.50 equiv), and
DIEA (1.07 g, 8.28 mmol, 3.00 equiv) in N,N-dimethylformamide (10
mL). The resulting solution was stirred for 1 h at 25.degree. C.
The reaction was then quenched by the addition of 20 mL of water.
The resulting mixture was extracted with 2.times.50 mL of ethyl
acetate. The combined organic layers were dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:3) to yield 1.80 g (95%) of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate
as a yellow solid.
##STR00937##
Compound 215.6.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydra-
zide
[3807] To a solution of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate
(compound 215.5, 2.15 g, 4.99 mmol, 1.00 equiv) in methanol (20
mL), was added hydrazine hydrate (80%, 15 mL) batchwise. The
reaction was stirred at 80.degree. C. overnight. After cooling to
ambient temperature, the mixture was concentrated under reduced
pressure. The residue was extracted with dichloromethane
(2.times.100 mL). The combined organic layers were dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The residue
was purified by silica gel chromatography with
dichloromethane/methanol (100:1) to furnish 1.13 g (53%) of the
desired product as a pinkish solid.
##STR00938##
Compound 215.7.
4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperi-
din-4-yl)benzonitrile
[3808] To a solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydra-
zide (compound 215.6, 600 mg, 1.39 mmol, 1.00 equiv) in 1,4-dioxane
(10 mL) was added 10 mL of an aqueous solution of sodium
bicarbonate (350 mg, 4.17 mmol, 1.00 equiv). Cyanogen bromide (220
mg, 2.08 mmol, 1.50 equiv) was added to the reaction mixture
dropwise. The reaction mixture was stirred at 25.degree. C. for 2
h, then quenched with 20 mL of FeSO.sub.4 (aq., sat.) and diluted
with DCM. The resulting mixture was stirred vigorously then
filtered through celite and washed with 1 M FeSO.sub.4, water, and
ethyl acetate. The layers were separated and the aqueous phase was
extracted with 2.times.50 mL of DCM. The combined organic layers
were dried over anhydrous sodium sulfate and concentrated in vacuo.
This resulted in 600 mg (95%) of
4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperi-
din-4-yl)benzonitrile as an off-white solid.
##STR00939##
Compound 215.8.
4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pipe-
ridin-4-yl)benzamide
[3809] To a 10-mL sealed tube, which was purged and maintained with
an inert atmosphere of nitrogen, was added a solution of
4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperi-
din-4-yl)benzonitrile (compound 215.7, 228 mg, 0.500 mmol, 1.00
equiv) in ethanol (5 mL). This was followed by the addition of
potassium hydroxide (280 mg, 4.99 mmol, 10.0 equiv) in portions.
The resulting solution was stirred for 5 h at 80.degree. C. behind
a blast shield. After cooling to ambient temperature, the reaction
was then quenched by the addition of 15 mL of water and extracted
with 2.times.20 mL of ethyl acetate. The combined organic layers
were dried over anhydrous sodium sulfate and concentrated in vacuo.
This resulted in 200 mg (80%) of
4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pipe-
ridin-4-yl)benzamide as a yellow solid.
##STR00940##
Compound 215.
4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pipe-
ridin-4-yl)benzonitrile
[3810] To a round-bottom flask was added a solution of compound
215.8 (251 mg, 0.500 mmol, 1.00 equiv) in dichloromethane (5 mL).
This was followed by the addition of (CF.sub.3CO).sub.2O (158 mg,
1.50 equiv) dropwise with stirring. Triethylamine (101 mg, 1.00
mmol, 2.00 equiv) was added dropwise with stirring. The resulting
mixture was stirred at 25.degree. C. for 1 h, then concentrated in
vacuo. The residue was purified using silica gel column
chromatography with dichloromethane/methanol (20:1) as eluent. The
crude product (120 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18,
19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH.sub.3CN
(54.0% CH.sub.3CN up to 64.0% in 6 min, up to 100.0% in 1 min, down
to 54.0% in 1 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 60 mg (25%) of the title compound as a white solid. m/z (ES+)
484 (M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.64
(d, 2H), 7.45-7.21 (m, 4H), 4.37 (q, 2H), 4.02-3.96 (m, 1H),
3.60-3.53 (m, 1H), 3.29-3.19 (m, 2H), 2.98-2.90 (m, 2H), 2.76-2.61
(m, 2H), 2.15-2.12 (m, 2H), 2.07-1.92 (m, 4H), 1.80-1.68 (m, 4H),
1.35 (t, 3H), 1.29-1.20 (m, 3H).
##STR00941##
Compound 216.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)pip-
eridin-4-yl)benzonitrile
[3811] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pipe-
ridin-4-yl)benzonitrile (compound 215). m/z (ES+) 470 (M+H).sup.+.
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.64 (d, 2H), 7.45-7.38
(m, 3H), 7.32 and 7.21 (2 singlets, amide rotamers, 1H), 4.0 (s,
3H), 4.00-3.95 (m, 1H), 3.63-3.56 (m, 1H), 3.29-3.19 (m, 2H), 2.98
(app t, 2H), 2.76-2.61 (m, 2H), 2.17-1.89 (m, 6H), 1.80-1.64 (m,
4H), 1.32-1.20 (m, 3H).
##STR00942##
Compound 217.1. Methyl
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylb-
enzoate
[3812] To a round-bottom flask was added a solution of
4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound
215.4, 70.0 mg, 0.270 mmol, 1.00 equiv) in N,N-dimethylformamide (5
mL). HBTU (210 mg, 0.550 mmol, 2.07 equiv), DIEA (150 mg, 1.16
mmol, 4.35 equiv) were added to the reaction mixture at 0.degree.
C., and stirred for 30 min. This was followed by the addition of
4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2
HCl salt, 80.0 mg, 0.330 mmol, 1.20 equiv). The resulting solution
was stirred for 15 h at 25.degree. C., and then quenched with 20 mL
of ice-water. The mixture was extracted with 2.times.50 mL of ethyl
acetate. The combined organic layers were washed with 1.times.50 mL
of brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:100-1:5) as
eluent to yield 100 mg (84%) of methyl
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-
-ethylbenzoate as a white solid.
##STR00943##
Compound 217.2.
5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylb-
enzohydrazide
[3813] To a round-bottom flask was added a solution of methyl
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylb-
enzoate (compound 217.1, 1.10 g, 2.45 mmol, 1.00 equiv) in ethanol
(40 mL). Hydrazine hydrate (20 mL) was added to the reaction
mixture, and the reaction was stirred 80.degree. C. for 15 h. After
cooling to ambient temperature, the mixture was concentrated in
vacuo, then diluted with 50 mL of H.sub.2O. The resulting mixture
was extracted with 3.times.50 mL of dichloromethane. The combined
organic layers were washed with 2.times.50 mL of brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo. The residue
was purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:1-1:0) as eluent to yield 900 mg (82%)
of
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-
-4-ethylbenzohydrazide as a white solid.
##STR00944##
Compound 217.3.
4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-flu-
oropiperidin-4-yl)benzonitrile
[3814] To a round-bottom flask was added a solution of
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylb-
enzohydrazide (compound 217.2, 450 mg, 1.00 mmol, 1.00 equiv) in
1,4-dioxane (10 mL). A solution of sodium bicarbonate (252 mg, 3.00
mmol, 2.99 equiv) in water (10 mL) and BrCN (128 mg, 1.21 mmol,
1.20 equiv) were added to the reaction mixture. The resulting
solution was stirred for 3 h at room temperature, then quenched
with 30 mL of FeSO.sub.4 (aq., sat.) and diluted with ethyl
acetate. The resulting mixture was stirred vigorously then filtered
through celite and washed with 1 M FeSO.sub.4, water, and ethyl
acetate. The layers were separated and the aqueous phase was
extracted with 2.times.50 mL of ethyl acetate. The combined organic
layers were washed with 2.times.50 mL of brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo. This resulted
in 400 mg (84%) of
4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4--
fluoropiperidin-4-yl)benzonitrile as a light brown solid.
##STR00945##
Compound 217.
4-(1-(4-Cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4--
fluoropiperidin-4-yl)benzonitrile
[3815] To a round-bottom flask, which was purged and maintained
with a nitrogen atmosphere, was added a solution of
4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-flu-
oropiperidin-4-yl)benzonitrile (compound 217.3, 200 mg, 0.420 mmol,
1.00 equiv) in methanol (20 mL). Potassium hydroxide (237 mg, 4.22
mmol, 10.0 equiv) was added to the reaction mixture. The resulting
solution was stirred for 15 h at 70.degree. C. After cooling to
ambient temperature, the organic solvent was removed under reduced
pressure. The residue was diluted with 30 mL of H.sub.2O, then
extracted with 2.times.50 mL of ethyl acetate. The combined organic
layers were washed with 2.times.50 mL of brine, dried over
anhydrous sodium sulfate and concentrated in vacuo. The crude
product (50 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18,
19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH.sub.3CN
(49.0% CH.sub.3CN up to 63.0% in 8 min, up to 100.0% in 1 min, down
to 49.0% in 1 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 20 mg (10%) of the title compound as a white. m/z (ES+) 488
(M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.72 (d,
2H), 7.64-7.61 (m, 2H), 7.39-7.25 (m, 2H), 4.85-4.78 (m, 1H),
4.00-3.93 (m, 4H), 3.54-3.49 (m, 2H), 3.28-3.22 (m, 1H), 2.80-2.65
(m, 2H), 2.26-1.84 (m, 10H), 1.45-1.27 (m, 3H).
##STR00946##
Compound 218.
4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4-f-
luoropiperidin-4-yl)benzonitrile
[3816] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pipe-
ridin-4-yl)benzonitrile (compound 215) and using compound 11.2 HCl
salt in place of compound 1.5. m/z (ES+) 502 [M+H].sup.+, 543
[M+CH.sub.3CN+H].sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.
7.73 (d, 2H), 7.64-7.58 (m, 2H), 7.39-7.26 (m, 2H), 4.89-4.82 (m,
1H), 4.35 (q, 2H), 4.10-3.95 (m, 1H), 3.50-3.38 (m, 2H), 3.30-3.27
(m, 1H), 2.75-2.65 (m, 2H), 2.22-1.86 (m, 10H), 1.41 (t, 3H),
1.35-1.20 (m, 3H).
##STR00947##
Compound 219.1 Methyl 2-bromo-4-methylbenzoate
[3817] To a solution of 2-bromo-4-methylbenzoic acid (10 g) in MeOH
(50 ml) was added dropwise concentrated sulfuric acid (10 ml) at
0.degree. C. The mixture was heated at 70.degree. C. for 2 hours.
After cooling to ambient temperature, the methanol was removed
under reduced pressure. The residue was poured into ice-water (100
ml). The mixture was extracted with EtOAc (.times.2). The combined
organic layers were washed with NaHCO.sub.3 (aq. sat. Note: gas
evolution), brine, dried over MgSO.sub.4, filtered, and
concentrated to give the product as a clear oil. Yield: 10.5 g,
99%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.73 (d, 1H), 7.50
(d, 1H), 7.19-7.11 (m, 1H), 3.92 (s, 3H), 2.36 (s, 3H).
##STR00948##
Compound 219.2 Methyl 2-cyclobutyl-4-methylbenzoate
[3818] Cyclobutylzinc(II) bromide (50 ml, 0.5M in THF, 25.0 mmol)
was added to a mixture of methyl 2-bromo-4-methylbenzoate (219.1,
5.0 g, 21.8 mmol) and PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 (1.78 g,
2.20 mmol). The mixture was degassed and the flask was filled with
argon through a balloon. After the mixture was heated at 65.degree.
C. under argon for 24 hours, it was cooled to 0.degree. C. and
quenched with water (10 ml). The mixture was diluted with EtOAc
(200 ml), washed with water then with brine. The EtOAc layer was
dried (Na.sub.2SO.sub.4), concentrated, and purified using column
(silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield:
3.6 g, 81%. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.68 (d,
1H), 7.23-7.17 (s, 1H), 7.03 (d, 1H), 4.16 (m, 1H), 3.86 (s, 3H),
2.39 (s, 3H), 2.34 (m, 2H), 2.16-1.96 (m, 3H), 1.80 (m, 1H).
##STR00949##
Compound 219.3 Methyl 2-cyclobutyl-5-iodo-4-methylbenzoate
[3819] N-Iodosuccinimide (5.25 g, 23.3 mmol) was added portionwise
to a solution of methyl 2-cyclobutyl-4-methylbenzoate (219.2, 4.77
g, 23.3 mmol) in concentrated sulfuric acid (100 ml) at 0.degree.
C. The mixture turned very thick after it was stirred at 0.degree.
C. for 30 min and at RT for 2 hours. The mixture was cooled to
0.degree. C. again and MeOH (100 ml) was added. The mixture was
heated at 60.degree. C. for 2 hours. The methanol was removed under
reduced pressure and the residue was poured into ice water (200
ml). The mixture was extracted with EtOAc (2.times.). The combined
organic layers were washed with brine, then aq. 1N NaHCO.sub.3,
dried (Na.sub.2SO.sub.4), and concentrated. The residue was
purified using column (silica gel) chromatography (hexanes:EtOAc
30:1 to 20:1). Yield: 5.0 g, clear oil, 65%. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 8.19 (s, 1H), 7.24 (s, 1H), 4.17-4.04 (m,
1H), 3.86 (s, 3H), 2.48-2.44 (s, 3H), 2.40-2.28 (m, 2H), 2.13-1.92
(m, 3H), 1.85-1.75 (m, 1H).
##STR00950##
Compound 219.4 Methyl 5-cyano-2-cyclobutyl-4-methylbenzoate
[3820] A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate
(219.3, 3.0 g, 9.1 mmol), Zn(CN).sub.2 (2.3 g, 19.6 mmol) and
Pd(PPh.sub.3).sub.4 (0.55 g, 0.47 mmol) in DMF (50 ml) was degassed
and the flask was filled with argon through a balloon. The mixture
was heated at 100.degree. C. under argon overnight. After cooling
to ambient temperature, the reaction was quenched with saturated
aq. FeSO.sub.4 (20 ml) and diluted with EtOAc (200 ml). The mixture
was stirred vigorously then filtered through celite and washed with
1 M FeSO.sub.4, water and ethyl acetate. The layers were separated
and the aqueous phase was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified
using column (silica gel) chromatography (hexanes:EtOAc 30:1 to
20:1). Yield: 2.0 g, 96%. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 8.03 (s, 1H), 7.34 (s, 1H), 4.26-4.13 (m, 1H), 3.89 (s,
3H), 2.59 (s, 3H), 2.46-2.32 (m, 2H), 2.16-1.98 (m, 3H), 1.90-1.78
(m, 1H).
##STR00951##
Compound 219.5. 5-Cyano-2-cyclobutyl-4-methylbenzohydrazide
[3821] To a solution of methyl
5-cyano-2-cyclobutyl-4-methylbenzoate (219.4, 2.0 g, 8.73 mmol) in
EtOH (10 ml) was added anhydrous hydrazine (2 ml, excess) at room
temperature. The mixture was heated at 90.degree. C. overnight.
After cooling to ambient temperature, the mixture was partitioned
between water (60 ml) and EtOAc (200 ml). The EtOAc layer was
washed with water (.times.2), brine, dried with Na.sub.2SO.sub.4,
and concentrated to give the product as a white solid. Yield: 1.9
g, 95%. m/z (ES+) 230 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.52 (s, 1H), 7.32 (s, 1H), 6.91 (br, 1H),
4.08 (br, 2H), 3.89 (m, 1H), 2.61-2.52 (m, 3H), 2.42-2.28 (m, 2H),
2.18-1.98 (m, 3H), 1.91-1.78 (m, 1H).
##STR00952##
Compound 219.6.
5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile
[3822] The title compound (0.55 g, white solid, 100%) was prepared
using a procedure similar to that used for the preparation of
compound 217.3 and using compound 219.5 (0.50 g) in place of
compound 217.2. m/z (ES+) 255 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.93 (s, 1H), 7.45 (s, 1H), 5.10 (br, 2H),
4.38 (m, 1H), 2.61 (s, 3H), 2.48-2.34 (m, 2H), 2.17-1.98 (m, 3H),
1.91-1.79 (m, 1H).
##STR00953##
Compound 219.7.
4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile
[3823] To a solution of
5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile
(219.6, 0.5 g, 2.0 mmol) in EtOH (40 ml) was added KOH (1.11 g,
20.0 mmol). The mixture was heated at 85.degree. C. overnight.
After cooling to ambient temperature, the mixture was neutralized
to pH 7 with 1N HCl at 0.degree. C. and then extracted with EtOAc
(.times.2). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified using
column (silica gel) chromatography (hexanes:EtOAc 1:1 to EtOAc).
Yield: 0.2 g, white solid, 34%. m/z (ES+) 283 (M+H).sup.+. .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 7.84 (s, 1H), 7.35 (s, 1H),
4.48 (t, 2H), 4.19-4.10 (m, 1H), 2.58 (s, 3H), 2.30-2.19 (m, 2H),
2.11-1.95 (m, 3H), 1.85-1.76 (m, 1H), 1.45 (t, 3H).
##STR00954##
Compound 219.8.
4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide
[3824] To a solution of
4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile
(219.7, 0.15 g, 0.53 mmol) in EtOH (10 ml) was added NH.sub.4OH
(0.18 ml, 2.66 mmol, 14.8 N in H.sub.2O) followed by H.sub.2O.sub.2
(1.8 ml, 26.6 mmol, 50% in H.sub.2O). The mixture was stirred at
room temperature overnight. The mixture was cooled to 0.degree. C.
and quenched carefully with 1N Na.sub.2S.sub.2O.sub.3 solution (26
ml). The mixture was extracted with EtOAc (.times.2) and the
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified with prep-TLC (5% MeOH
in CH.sub.2Cl.sub.2). Yield: 0.1 g, white solid, 62.5%. m/z (ES-)
299 (M-H).sup.-.
##STR00955##
Compound 219.9.
4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
Acid
[3825] To a solution of
4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide
(219.8, 0.1 g, 0.33 mmol) in TFA (5 ml) was added NaNO.sub.2 (0.046
g, 0.66 mmol) at 0.degree. C. The mixture was stirred at 0.degree.
C. for 1 hour then at room temperature for 2 hours. The mixture was
concentrated under reduced pressure. The residue was partitioned
between EtOAc and brine. The aqueous layer was extracted with
EtOAc. The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated to give a clear oil. Yield: 0.1 g, 100%. m/z (ES-)
300 (M-H).sup.-.
##STR00956##
Compound 219.
4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pip-
eridin-4-yl)benzonitrile
[3826] A solution of
4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
acid (compound 219.9, 40 mg, 0.13 mmol), DIEA (0.07 ml, 0.39 mmol),
HOBT (34 mg, 0.19 mmol, with 20% water), EDCI (38 mg, 0.19 mmol),
and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 36
mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was stirred
overnight at room temperature. The reaction mixture was then
diluted with 50 mL of ethyl acetate and washed with 2.times.20 mL
of brine. The mixture was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was applied onto a
silica gel prep-TLC plate and developed using ethyl acetate/hexanes
(1:1) to yield 0.1 g (68%) of the title compound as a white solid.
m/z (ES+) 470 (M+H).sup.+.
##STR00957##
Compound 220.
4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4--
fluoropiperidin-4-yl)benzonitrile
[3827] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pip-
eridin-4-yl)benzonitrile (compound 219), using compound 11.2 HCl
salt in place of compound 1.5. m/z (ES+) 488 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 11.10 (br s, 1H), 7.72-7.63 (m,
2H), 7.47 (d, J=8.4 Hz, 2H), 7.42 & 7.33 (2 singlets, amide
rotamers, Ar--H, 1H), 7.25 (s, 1H), 4.86 (br d, J=11.2 Hz, 1H),
4.41 (q, J=7.1 Hz, 2H), 4.17-4.03 (m, 1H), 3.61-3.38 (m, 2H),
3.29-3.14 (m, 1H), 2.46-1.70 (m, 13H), 1.45 (t, J=7.2 Hz, 3H).
##STR00958##
Compound 221.
(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluoro-
-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone
[3828] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pip-
eridin-4-yl)benzonitrile (compound 219). m/z (ES+) 531 (M+H).
##STR00959##
Compound 222.1.
4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile
[3829] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound
4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonit-
rile (compound 219.7), except MeOH was used as the solvent instead
of EtOH. m/z (ES+) 269 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 10.96 (br, 1H), 7.82 (s, 1H), 7.35 (s, 1H),
4.11 (s, 3H), 4.15-4.05 (m, 1H), 2.59 (s, 3H), 2.31-2.16 (m, 2H),
2.14-1.89 (m, 3H), 1.87-1.71 (m, 1H).
##STR00960##
Compound 222.2.
4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide
[3830] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide
(compound 219.8) but using compound 222.1 in place of compound
219.7. m/z (ES+) 287 (M+H).sup.+. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.50 (s, 1H), 7.33 (s, 1H), 4.03 (s, 3H),
3.95-4.05 (m, 1H), 2.51 (s, 3H), 2.23-2.11 (m, 2H), 2.11-1.88 (m,
3H), 1.83-1.71 (m, 1H).
##STR00961##
Compound 222.3.
4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
Acid
[3831] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
acid (compound 219.9) but using compound 222.2 in place of compound
219.8. m/z (ES+) 287 (M+H).sup.+.
##STR00962##
Compound 222.
4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pi-
peridin-4-yl)benzonitrile
[3832] A solution of
4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic
acid (compound 222.3, 60 mg, 0.21 mmol), DIEA (0.11 ml, 0.63 mmol),
HOBT (53 mg, 0.32 mmol, with 20% water), EDCI (60 mg, 0.32 mmol)
and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 47
mg, 0.21 mmol) in N,N-dimethylformamide (3 mL) was stirred
overnight at room temperature. The reaction mixture was then
diluted with 50 mL of ethyl acetate and washed with 2.times.20 mL
of brine. The mixture was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was applied onto a
silica gel prep-TLC plate and developed using ethyl acetate/hexanes
(1:1) to yield 21.0 mg (22%) of the title compound as a white
solid. m/z (ES+) 456 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta.11.54-10.86 (br s, 1H), 7.60 (d, 2H),
7.38-7.20 (m, 4H), 5.04-4.92 (m, 1H), 4.06 (s, 3H), 4.14-4.00 (m,
1H), 3.62 (d, 1H), 3.15-3.03 (m, 1H), 2.93-2.76 (m, 2H), 2.38 and
2.30 (2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.34-2.22 (m,
1H), 2.20-2.06 (m, 2H), 2.05-1.84 (m, 3H), 1.61-1.45 (m, 1H).
##STR00963##
Compound 223.
4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-
-fluoropiperidin-4-yl)benzonitrile
[3833] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pi-
peridin-4-yl)benzonitrile (compound 222) but using compound 11.2
HCl salt in place of compound 1.5. m/z (ES+) 474 (M+H).sup.+.
##STR00964##
Compound 224.
(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-(4-(t-
rifluoromethyl)phenyl)piperidin-1-yl)methanone
[3834] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pi-
peridin-4-yl)benzonitrile (222). m/z (ES+) 499 (M+H).sup.+.
##STR00965##
Compound 225.
(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluor-
o-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone
[3835] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)pi-
peridin-4-yl)benzonitrile (Compound 222). m z (ES+) 517
(M+H).sup.+.
##STR00966##
Compound 226.3. Methyl 4-cyclopropyl-2-ethylbenzoate
[3836] To a stirred mixture of ZnBr.sub.2 (37.0 g, 164 mmol, 3.99
equiv) in tetrahydrofuran (150 mL) under nitrogen was added
bromo(cyclopropyl)magnesium (3.28 M in THF, 50 mL, 4.00 equiv)
dropwise at 0.degree. C. After stirring at 15 minutes at 0.degree.
C., the temperature was lowered to -30.degree. C. followed by the
dropwise addition of a solution of Pd(dppf)Cl.sub.2 (2.00 g, 2.73
mmol, 0.07 equiv) in tetrahydrofuran (50 mL) and a solution of
methyl 4-bromo-2-ethylbenzoate (compound 181.2, 10.0 g, 41.1 mmol,
1.00 equiv) in tetrahydrofuran (50 mL). The resulting solution was
warmed slowly to 25.degree. C. and stirred for 15 h, then carefully
quenched by slow addition of 100 mL of NH.sub.4Cl (aq.sat.). The
mixture was extracted with 2.times.100 mL of ethyl acetate and the
combined organic layers were dried over anhydrous sodium sulfate
and concentrated in vacuo. The residue was purified using silica
gel column chromatography with ethyl acetate/petroleum ether (1:30)
as eluent to yield 7.50 g (89%) of methyl
4-cyclopropyl-2-ethylbenzoate as a light yellow oil.
##STR00967##
Compound 226.4. Methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate
[3837] To a round-bottom flask was added a solution of methyl
4-cyclopropyl-2-ethylbenzoate (compound 226.3, 5.00 g, 24.5 mmol,
1.00 equiv) in AcOH (40 mL). 12 (6.80 g, 26.8 mmol, 1.10 equiv),
NaIO.sub.4 (2.60 g, 12.2 mmol, 0.50 equiv), and sulfuric acid (400
mg, 4.08 mmol, 0.15 equiv) were added to the reaction. The
resulting solution was stirred for 2 h at 50.degree. C. After
cooling to ambient temperature, the reaction was carefully quenched
with Na.sub.2S.sub.2O.sub.3 (aq., sat.). The mixture was extracted
with 2.times.100 mL of ethyl acetate, and the combined organic
layers were dried over sodium sulfate and concentrated in vacuo.
The residue was purified using silica gel column chromatography
with petroleum ether/ethyl acetate (20:1) as eluent to furnish 4.00
g (49%) of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate as a yellow
oil.
##STR00968##
Compound 226.5. 4-Cyclopropyl-2-ethyl-5-iodobenzoic Acid
[3838] To a solution of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate
(compound 226.4, 2.50 g, 7.57 mmol, 1.00 equiv) in methanol (40 mL)
was added aqueous sodium hydroxide (3.10 g, 77.5 mmol, 10.0 equiv,
in 10 mL water). The resulting mixture was stirred for 15 h at
60.degree. C. in an oil bath. After cooling to ambient temperature,
the organic solvent was removed under reduced pressure and pH of
the remaining aqueous layer was adjusted to 4 with hydrogen
chloride (aq, 1 M). The solids were collected by filtration and
dried in an oven under reduced pressure to yield 2.20 g (92%) of
4-cyclopropyl-2-ethyl-5-iodobenzoic acid as a white solid.
##STR00969##
Compound 226.6. 4-Cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic
Acid
[3839] To a solution of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid
(compound 226.5, 500 mg, 1.58 mmol, 1.00 equiv) in THF/Et.sub.2O
(10/10 mL) under nitrogen at -78.degree. C. was added dropwise
n-butyllithium (2.5 M, 1.88 mL, 3.00 equiv) over 3 min. After
stirring for 10 min at -78.degree. C., methyl chloroformate (230
mg, 2.43 mmol, 1.50 equiv) was added dropwise at -78.degree. C. The
resulting solution was stirred for 40 min at -78.degree. C., then
warmed slowly to -35.degree. C. The reaction was carefully quenched
with 2 mL of water. The pH was adjusted to .about.4-5 with hydrogen
chloride (aq., 1 M). The resulting mixture was extracted with
3.times.20 mL of ethyl acetate and the combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
yield 400 mg the title compound as a yellow solid.
##STR00970##
Compound 226.7. Methyl
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethyl-
benzoate
[3840] To a solution of
4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound
226.6, 150 mg, 0.600 mmol, 1.00 equiv) in N,N-dimethylformamide (15
mL) were added 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride
(compound 11.2, 150 mg, 0.620 mmol, 1.00 equiv), DIPEA (450 mg,
3.49 mmol, 6.00 equiv), and HBTU (300 mg, 0.790 mmol, 1.30 equiv).
The resulting solution was stirred for 4 h at 20.degree. C., then
quenched by the addition of 20 mL of brine. The resulting mixture
was extracted with 4.times.30 mL of ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated in vacuo. The residue was purified via silica gel
column with ethyl acetate/petroleum ether (1:3) as eluent. This
resulted in 0.200 g (76%) of methyl
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethyl-
benzoate as a light yellow solid.
##STR00971##
Compound 226.8.
5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethyl-
benzohydrazide
[3841] To a solution of methyl
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethyl-
benzoate (compound 226.7, 200 mg, 0.460 mmol, 1.00 equiv) in
ethanol (15 mL) was added hydrazine hydrate (80%, 5 mL). The
resulting solution was stirred at 80.degree. C. for 15 h. After
cooling to ambient temperature, the reaction was quenched with 50
mL of water, then extracted with 3.times.50 mL of dichloromethane.
The combined organic layers were dried over anhydrous sodium
sulfate and concentrated in vacuo to yield 150 mg (75%) of
5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropy-
l-4-ethylbenzohydrazide as a colorless oil.
##STR00972##
Compound 226.9.
4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclopropyl-2-ethylbenzoyl)-4-fl-
uoropiperidin-4-yl)benzonitrile
[3842] The title compound (50 mg, white solid, 95%) was prepared
using a procedure similar to that used for the preparation of
compound 217.3 and using compound 226.8 (50 mg) in place of
compound 217.2.
##STR00973##
Compound 226.
4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-
-fluoropiperidin-4-yl)benzonitrile
[3843] The title compound (50 mg, white solid, 95%) was prepared
using a procedure similar to that used for the preparation of
compound 219.7 and using compound 226.9 (300 mg) in place of
compound 219.6. The crude product (.about.30 mg) was purified by
Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (46.0%
CH.sub.3CN up to 57.0% in 8 min, up to 100.0% in 1 min, down to
46.0% in 1 min); Detector, Waters 2489 254 & 220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 15 mg of the title compound as a white solid. m/z (ES+) 474
(M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD, ppm): .delta. 7.73
(d, 2H), 7.65-7.57 (m, 2H), 7.46-7.32 (m, 1H), 7.03 (s, 1H),
4.85-4.73 (m, 1H), 4.00 (s, 3H), 3.48-3.32 (m, 2H), 3.28-3.21 (m,
1H), 2.71-2.62 (m, 2H), 2.28-2.14 (m, 2H), 2.10-1.80 (m, 3H),
1.28-1.20 (m, 3H), 0.97-0.94 (m, 2H), 0.75-0.50 (m, 2H).
##STR00974##
Compound 227.
4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4--
fluoropiperidin-4-yl)benzonitrile
[3844] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of
4-(1-(4-cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-
-fluoropiperidin-4-yl)benzonitrile (compound 226). m/z (ES+) 488
(M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta.7.80-7.78
(m, 2H), 7.70-7.63 (m, 2H), 7.51 (m, 1H), 7.07 (s, 1H), 4.89-4.82
(m, 1H), 4.40 (app t, 2H), 3.57-3.52 (m, 2H), 3.28-3.25 (m, 1H),
2.80-2.50 (m, 2H), 2.40-2.10 (m, 4H), 1.95-1.80 (m, 1H), 1.45 (t,
3H), 1.32-1.22 (m, 3H), 1.01-0.99 (m, 2H), 0.73-0.73 (m, 2H).
##STR00975##
Compound 228.1. Methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate
[3845] To a round-bottom flask, which was purged and maintained
with a nitrogen atmosphere, was added a solution of
4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound
226.6, 500 mg, 2.01 mmol, 1.00 equiv) in N,N-dimethylformamide (20
mL). HBTU (1.53 g, 4.03 mmol, 2.00 equiv), DIEA (780 mg, 6.04 mmol,
3.00 equiv) were added to the reaction solution, and it was stirred
for 5 min at 25.degree. C. 4-(piperidin-4-yl)benzonitrile (compound
1.5, 410 mg, 2.20 mmol, 1.10 equiv) was added to the above mixture.
After stirring for 15 h at 25.degree. C., the reaction was quenched
by the addition of water. The mixture was extracted with 100 mL of
ethyl acetate and the combined organic layers were washed with
4.times.40 mL of brine, dried over anhydrous sodium sulfate and
concentrated in vacuo. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether (4:1) as
eluent to furnish 0.830 g (99%) of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbe-
nzoate as a colorless oil.
##STR00976##
Compound 228.2.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydr-
azide
[3846] To a round-bottom flask was added a solution of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate
(compound 228.1, 830 mg, 1.99 mmol, 1.00 equiv) in ethanol (15 mL).
Hydrazine (5 mL, 100 equiv) was added to the reaction. The
resulting solution was stirred for 15 h at 100.degree. C., then
concentrated in vacuo. The residue was extracted with 100 mL of
dichloromethane and the combined organic layers were washed with
1.times.30 mL of brine, dried over anhydrous sodium sulfate and
concentrated in vacuo. This resulted in 0.800 g (96%) of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydr-
azide as a white solid.
##STR00977##
Compound 228.3.
4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclopropyl-2-ethylbenzoyl)piper-
idin-4-yl)benzonitrile
[3847] The title compound (750 mg, light brown solid, 94%) was
prepared using a procedure similar to that used for the preparation
of compound 217.3 and using compound 228.2 (750 mg) in place of
compound 217.2.
##STR00978##
Compound 228.4.
4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pip-
eridin-4-yl)benzamide
[3848] The title compound (80 mg, yellow solid, 36%) was prepared
using a procedure similar to that used for the preparation of
compound 219.7 and using compound 228.3 (200 mg) in place of
compound 219.6.
##STR00979##
Compound 228.
4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pip-
eridin-4-yl)benzonitrile
[3849] To a round-bottom flask, which was purged and maintained
with a nitrogen atmosphere, was added a solution of
4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)pip-
eridin-4-yl)benzamide (compound 228.4, 80.0 mg, 0.160 mmol, 1.00
equiv) in dichloromethane (10 mL). Trifluoroacetic anhydride (34.0
mg, 0.160 mmol, 1.00 equiv) and triethylamine (33.0 mg, 0.330 mmol,
2.00 equiv) were added dropwise to the stirred mixture. The
resulting solution was stirred for 2 h at 25.degree. C., then
washed with 1.times.10 mL of brine. The aqueous layer was extracted
with 2.times.20 mL of dichloromethane and the combined organic
layers were dried over anhydrous sodium sulfate and concentrated in
vacuo. The crude product (30 mg) was purified by Prep-HPLC with the
following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire
Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and
CH.sub.3CN (42% CH.sub.3CN up to 57% in 8 min, up to 100% in 1.5
min, down to 42% in 1 min); Detector, Waters 2489 254&220 nm.
The fractions containing pure compound were combined and
lyophilized to yield 15 mg (20%) of the title compound as a an
off-white solid. m/z (ES+) 470 (M+H).sup.+. .sup.1H-NMR (300 MHz,
CD.sub.3OD, ppm): .delta. 7.64 (d, 2H), 7.46-7.28 (m, 3H),
7.02-7.01 (m, 1H), 4.89-4.80 (m, 1H), 4.40-4.33 (m, 2H), 3.58-3.56
(m, 1H), 3.27-3.25 (m, 1H), 3.04-2.90 (m, 2H), 2.73-2.58 (m, 2H),
2.31-2.29 (m, 1H), 1.94-1.96 (m, 1H), 1.82-1.78 (m, 3H), 1.45 (t,
3H), 1.32-1.12 (m, 3H), 0.98-0.88 (m, 2H), 0.71-0.68 (m, 2H).
##STR00980##
Compound 229.
4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)pi-
peridin-4-yl)benzonitrile
[3850] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 228. m/z (ES+) 456 (M+H).sup.+. .sup.1H-NMR
(300 MHz, CD.sub.3OD, ppm): .delta. 7.64 (d, 2H), 7.43-7.27 (m,
3H), 7.03-7.02 (m, 1H), 4.0 (s, 3H), 3.59-3.55 (m, 1H), 3.28-3.27
(m, 1H), 3.04-2.98 (m, 2H), 2.97-2.56 (m, 2H), 2.53-2.29 (m, 1H),
2.0-1.98 (m, 1H), 1.76-1.42 (m, 3H), 1.30-1.16 (m, 3H), 0.99-0.94
(m, 2H), 0.70-0.64 (m, 2H).
##STR00981##
Compound 230.1. 4-Cyclobutyl-5-iodo-2-methylbenzoic Acid
[3851] To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate
(compound 152.3, 35.0 g, 106 mmol, 1.00 equiv) in methanol (200 mL)
at 0-5.degree. C. was added dropwise aqueous sodium hydroxide (12.7
g, 318 mmol, 3.00 equiv in 100 mL water). The resulting mixture was
stirred for 3 h at 60.degree. C. After cooling to ambient
temperature, the organic solvent was then removed under reduced
pressure. The pH of the remaining aqueous phase was adjusted to
.about.4 with hydrogen chloride (aqueous, 2 M). The resulting
solids were collected by filtration and dried in an oven under
reduced pressure to yield 31.0 g (93%) of the title compound as a
white solid.
##STR00982##
Compound 230.2. 4-Cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic
Acid
[3852] To a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid
(compound 230.1, 3.00 g, 9.49 mmol, 1.00 equiv) in THF (40 mL)
under nitrogen at -78.degree. C. was added dropwise n-BuLi (9.5 mL,
2.50 equiv, 2.5 M in THF). After 10 minutes, a solution of dimethyl
carbonate (2.56 g, 28.4 mmol, 3.00 equiv) in THF (10 mL) was added
dropwise at -78.degree. C. The resulting solution was stirred for 1
h at -78.degree. C., then carefully quenched by slow addition of 50
mL of water. The pH was adjusted to .about.4 with hydrogen chloride
(aq., 1 M). The resulting mixture was extracted with 2.times.80 mL
of ethyl acetate, the combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:10-1:2) as eluent to furnish 1.30 g
(55%) of 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid as a
white solid.
##STR00983##
Compound 230.3. Methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate
[3853] To a round-bottom flask was added a solution of
4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound
230.2, 2.10 g, 8.46 mmol, 1.00 equiv) in N,N-dimethylformamide (10
mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,
1.88 g, 8.44 mmol, 1.00 equiv), EDC.HCl (3.22 g, 16.8 mmol, 2.00
equiv), and 4-dimethylaminopyridine (3.10 g, 25.4 mmol, 3.00 equiv)
were added to the reaction. The resulting solution was stirred
overnight at 25.degree. C., then diluted with 100 mL of ethyl
acetate. The mixture was washed with 2.times.30 mL of NH.sub.4Cl
(aq., sat.) and 2.times.30 mL of brine, dried over anhydrous sodium
sulfate and concentrated in vacuo. The residue was purified using
silica gel column chromatography with ethyl acetate/petroleum ether
(0:1-1:3) as eluent to yield 3.20 g (91%) of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbe-
nzoate as a white solid.
##STR00984##
Compound 230.4.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydr-
azide
[3854] The title compound (660 mg, white solid, 66%) was prepared
using a procedure similar to that used for the preparation of
compound 219.5 and using compound 230.3 (1.00 g) in place of
compound 219.4.
##STR00985##
Compound 230.
4-(1-(4-Cyclobutyl-5-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-methylbenzoyl)piper-
idin-4-yl)benzonitrile
[3855] To a round-bottom flask was added a solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydr-
azide (compound 230.4, 150 mg, 0.360 mmol, 1.00 equiv) in dioxane
(5 mL). MeSO.sub.3H (7 mg, 0.07 mmol, 0.20 equiv), and
1,1,1-triethoxypropane (190 mg, 1.08 mmol, 3.00 equiv) were added
to the reaction. The resulting solution was stirred for 20 min at
110.degree. C., then cooled to room temperature and diluted with 50
mL of ethyl acetate. The organic layer was washed with 2.times.20
mL of water, dried over anhydrous sodium sulfate and concentrated
in vacuo. The crude product (200 mg) was purified by Prep-HPLC with
the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,
SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%
TFA and CH.sub.3CN (64.0% CH.sub.3CN up to 76.0% in 6 min, up to
100.0% in 4 min, down to 64.0% in 1 min); Detector, Waters 2489
254&220 nm. The fractions containing pure compound were
combined and lyophilized to yield 129 mg (79%) of the title
compound as a white solid. m/z (ES+) 455 (M+H).sup.+. .sup.1H-NMR
(300 MHz, CD.sub.3OD, ppm): .delta. 7.73-7.67 (m, 3H), 7.52-7.48
(m, 3H), 5-4.94 (m, 1H), 4.25-4.20 (m, 1H), 3.60-3.58 (m, 1H),
3.33-3.24 (m, 1H), 3.05-2.97 (m, 4H), 2.49 and 2.30 (2 singlets,
amide rotamers, CH.sub.3, 3H), 2.39-2.34 (m, 2H), 2.19-1.91 (m,
4H), 1.88-1.66 (m, 4H), 1.49-1.42 (t, 3H).
##STR00986##
Compound 231.1. Methyl 4-ethenyl-2-methylbenzoate
[3856] To a round-bottom flask, which was purged and maintained
with a nitrogen atmosphere, was added a solution of methyl
4-bromo-2-methylbenzoate (compound 152.1, 14.0 g, 61.1 mmol, 1.00
equiv) in N,N-dimethylformamide (150 mL). Tributyl(ethenyl)stannane
(29.3 g, 92.4 mmol, 2.00 equiv) and Pd(PPh.sub.3).sub.4 (7.10 g,
6.14 mmol, 0.10 equiv) were added to the reaction. The resulting
mixture was stirred overnight at 100.degree. C. in an oil bath.
After cooling to room temperature, the mixture was diluted with 400
mL of ethyl acetate. The organic layer was washed with 2.times.400
mL of NH.sub.4Cl (aq.) and 2.times.400 mL of brine, dried over
anhydrous sodium sulfate, then concentrated in vacuo. The crude
product was purified by CombiFlash with the following conditions
(IntelFlash-1): mobile phase, petroleum ether/ethyl acetate=1:0
increasing to petroleum ether/ethyl acetate=100:1 within 20 min;
Detector, UV 254 nm. This resulted in 6.81 g (63%) of methyl
4-ethenyl-2-methylbenzoate as a colorless oil.
##STR00987##
Compound 231.2. Methyl 2-methyl-4-(3-oxocyclobutyl)benzoate
[3857] To a solution of N,N-dimethylacetamide (5.5 mL) in DCE (20
mL) under nitrogen at -15.degree. C. was added a solution of
trifluoromethanesulfonic anhydride (10 mL) in DCE (50 mL) dropwise.
The mixture was then stirred for 10 min at -15.degree. C. to make
solution A. To another flask was added methyl
4-ethenyl-2-methylbenzoate (compound 231.1, 5.30 g, 0.03 mol, 1.00
equiv). A solution of 2,4,6-trimethylpyridine (5.5 mL) in DCE (80
mL) was added dropwise at -15.degree. C. The resulting mixture was
added into solution A dropwise under an inert atmosphere of
nitrogen. The resulting solution was stirred overnight at
80.degree. C. After cooling to ambient temperature, the mixture was
carefully quenched with water. The resulting mixture was extracted
with 2.times.200 mL of ethyl acetate, and the combined organic
layers were washed with 3.times.400 mL of brine, dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:50-1:5) as eluent to furnish 2.95 g
(45%) of methyl 2-methyl-4-(3-oxocyclobutyl)benzoate as a brown
oil.
##STR00988##
Compound 231.3. Methyl
4-(3,3-difluorocyclobutyl)-2-methylbenzoate
[3858] To a round-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was added a solution of
methyl 2-methyl-4-(3-oxocyclobutyl)benzoate (compound 231.2, 3.00
g, 13.8 mmol, 1.00 equiv) in dichloromethane (100 mL). DAST (22.2
g, 137 mmol, 10.00 equiv) was added to the reaction mixture. The
resulting solution was stirred overnight at 25.degree. C., then
carefully quenched by slowly adding (dropwise at first) 500 mL of
sodium bicarbonate (aq.) and ice. The mixture was extracted with
300 mL of ethyl acetate and the combined organic layers were washed
with 2.times.300 mL of sodium bicarbonate (aq.) and 2.times.300 mL
of brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:20) as eluent
to furnish 3.00 g (91%) of methyl
4-(3,3-difluorocyclobutyl)-2-methylbenzoate as a brown oil.
##STR00989##
Compound 231.4. Methyl
4-(3,3-difluorocyclobutyl)-5-iodo-2-methylbenzoate
[3859] The title compound (3.02 g, yellow solid, 66%) was prepared
using a procedure similar to that used for the preparation of
compound 181.4 and using compound 231.3 (3.00 g) in place of
compound 181.3.
##STR00990##
Compound 231.5.
4-(3,3-Difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenz-
oic Acid
[3860] The title compound was synthesized using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 164.1 using compound 231.4 in place of
compound 152.3.
##STR00991##
Compound 231.
4-(1-(4-(3,3-Difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-meth-
ylbenzoyl)piperidin-4-yl)benzonitrile
[3861] To a round-bottom flask was added a solution of
4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenz-
oic acid (compound 231.5, 211 mg, 0.660 mmol, 1.00 equiv) in
N,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 146 mg, 0.660 mmol, 1.00 equiv),
EDC-HCl (252 mg, 1.31 mmol, 2.00 equiv) and 4-dimethylaminopyridine
(160 mg, 1.31 mmol, 2.00 equiv) were added to the reaction. The
resulting solution was stirred for 3 h at 30.degree. C. in an oil
bath, then diluted with 30 mL of ethyl acetate. The mixture was
washed with 3.times.40 mL of brine, dried over anhydrous sodium
sulfate and concentrated in vacuo. The crude product (448 mg) was
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (48.0%
CH.sub.3CN up to 62.0% in 6 min, up to 100.0% in 4 min, down to
48.0% in 2 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 186 mg (58%) of the title compound as a white solid. m/z
(ES+) 490 (M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD, ppm):
.delta. 7.68 (d, J=8 Hz, 2H), 7.59-7.44 (m, 4H), 4.89-4.80 (m, 1H),
4.03-3.98 (m, 1H), 3.67-3.61 (m, 1H), 3.28-3.24 (m, 1H), 3.04-3.00
(m, 2H), 2.97-2.89 (m, 2H), 2.87-2.83 (m, 2H), 2.62-2.60 (m, 2H),
2.48 and 2.38 (2 singlets, amide rotamers, ArCH.sub.3, 3H),
2.05-2.00 (m, 1H), 1.88-1.58 (m, 3H), 1.41 (t, 3H).
##STR00992##
Compound 232.1. Methyl
5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate
[3862] A mixture of 3-bromo-N,N-dimethyl-2-oxopropanamide (246 mg),
methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound
2.5, 237 mg), and potassium carbonate (311 mg) in acetonitrile (12
ml) was heated to reflux for 48 hours. After cooling to ambient
temperature the mixture was concentrated. The residue was dissolved
in EtOAc and washed with brine, dried over MgSO.sub.4,
concentrated, and purified by flash chromatography (SiO.sub.2;
EtOAc) to give 88 mg of the title compound. m/z (ES+) 302
(M+H).sup.+.
##STR00993##
Compound 232.2.
5-(5-(Dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic
Acid
[3863] Methyl
5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate
(compound 232.1, 113 mg, 0.37 mmol) was dissolved in 2N LiOH
aqueous (1 ml) and tetrahydrofuran (THF) (5 ml) and heated to
50.degree. C. for 16 hours. After cooling to ambient temperature,
the organic solvent was removed in vacuo. The pH of the remaining
aqueous layer was adjusted with 2N HCl to pH 3-4. The resulting
precipitate was collected by filtration and dried to afford 56 mg
of 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic
acid (53%). m/z (ES+) 288 (M+H).sup.+.
##STR00994##
Compound 232.
2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dim-
ethyl-1H-imidazole-5-carboxamide
[3864] A mixture of above acid (compound 232.2, 56 mg, 0.2 mmol),
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 45 mg,
0.2 mmol), HBTU (152 mg, 0.4 mmol), and DIEA (105 ul, 0.6 mmol) in
DMF (2 ml) was stirred at room temperature for 16 hours. The
reaction was diluted with brine and extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO.sub.4 and
concentrated. The residue was purified by flash chromatography
(SiO.sub.2; 4% Methanol in EtOAc) to yield 44 mg of a foam (48%).
m/z (ES+) 456 (M+H).sup.+.
##STR00995##
Compound 233.
4-(1-(2,4-Dimethyl-5-(5-(morpholine-4-carbonyl)-1H-imidazol-yl)benzoyl)pi-
peridin-4-yl)benzonitrile
[3865] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dim-
ethyl-1H-imidazole-5-carboxamide (compound 232). m/z (ES+) 498
(M+H).sup.+.
##STR00996##
Compound 234.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoic
Acid
[3866] To a solution of methyl
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate
(compound 230.3, 1.50 g, 3.60 mmol, 1.00 equiv) in methanol (10 mL)
was added aqueous sodium hydroxide (577 mg, 14.4 mmol, in 5 mL
water) dropwise at 0.degree. C. The resulting solution was stirred
for 2 h at 60.degree. C. in an oil bath. After cooling to ambient
temperature, the organic solvent was removed under reduced
pressure. The pH of the remaining aqueous layer was adjusted to 3-4
with hydrogen chloride (aq., 2 M). The resulting solids were
collected by filtration and dried in an oven under reduced pressure
to yield 1.20 g (83%) of the title compound as a white solid. m/z
(ES+) 403 (M+H).sup.+.
##STR00997##
Compound 235.1.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoyl
chloride
[3867] To a round-bottom flask was added a solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoic
acid (compound 234, 500 mg, 1.24 mmol, 1.00 equiv) in
dichloromethane (5 mL). Oxalyl chloride (317 mg, 2.50 mmol, 2.00
equiv) and N,N-dimethylformamide (.about.5 mg) were added dropwise
to the mixture. The resulting solution was stirred for 1 h at
40.degree. C., then concentrated and dried under reduced pressure
to yield 480 mg (92%) of the title compound as a light yellow
oil.
##STR00998##
Compound 235.2.
4-(1-(5-(2-Bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzo-
nitrile
[3868] To a solution of TMSCHN.sub.2 (2 M in hexane) (0.476 mL,
2.00 equiv) in dichloromethane (10 mL) under nitrogen at 0.degree.
C. was added dropwise a solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoyl
chloride (compound 235.1, 200 mg, 0.480 mmol, 1.00 equiv) in
dichloromethane (3 mL). The resulting mixture was stirred overnight
at 25.degree. C. HBr (40%) (0.154 mL, 1.50 equiv) was then added
dropwise at 0.degree. C. and the mixture was stirred for another 2
h at 0.degree. C., then diluted with 50 mL of dichloromethane. The
organic layer was washed with 2.times.20 mL of water and 1.times.20
mL of brine, dried over anhydrous sodium sulfate and concentrated
in vacuo. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (0:1-1:50-1:5) as
eluent to furnish 200 mg (88%) of
4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)be-
nzonitrile as a yellow oil.
##STR00999##
Compound 235.
4-(1-(4-Cyclobutyl-5-(2-ethyl-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-
-4-yl)benzonitrile
[3869] To a round-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was added a solution of
4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzo-
nitrile (compound 235.2, 100 mg, 0.210 mmol, 1.00 equiv) in
CH.sub.3CN (5 mL). Propionimidamide hydrochloride (22.8 mg, 1.00
equiv) and potassium carbonate (86.6 mg, 0.63 mmol, 3.00 equiv)
were added to the reaction. The resulting solution was stirred for
3 h at 80.degree. C., then cooled to room temperature and
concentrated in vacuo. The residue was dissolved in 20 mL of water.
The mixture was extracted with 2.times.20 mL of ethyl acetate and
the combined organic layers were dried over anhydrous sodium
sulfate and concentrated in vacuo. The crude product (.about.100
mg) was purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (29.0%
CH.sub.3CN up to 43.0% in 7 min, up to 100.0% in 3 min, down to
29.0% in 2 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 43 mg (44%) of the title compound as a white solid. m/z (ES+)
453 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.68 (d
with fine structure, J=7.8 Hz, 2H), 7.56-7.53 (m, 4H), 7.30 and
7.20 (2 singlets, amide rotamers, Ar--H, 1H), .about.4.9 (1H
partially obscured by water peak), 3.84-3.70 (m, 1H), 3.70-3.53 (m,
1H), 3.33-3.19 (m, 1H partially obscured by methanol solvent peak),
3.13-2.92 (m, 4H), 2.48 & 2.38 (2 singlets, amide rotamers,
Ar--CH.sub.3, 3H), 2.29-2.11 (m, 4H), 2.11-1.93 (m, 2H), 1.93-1.72
(m, 3H), 1.72-1.53 (m, 1H), 1.45 (t, 3H).
##STR01000##
Compound 236.1.
4-(1-(5-(2-Bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-
-yl)benzonitrile
[3870] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzo-
nitrile (compound 235.2) but using compound 11.2 HCl salt instead
of compound 1.5.
##STR01001##
Compound 236.
4-(1-(4-Cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluor-
opiperidin-4-yl)benzonitrile
[3871] To a round-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was added a solution of
4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-
-yl)benzonitrile (compound 236.1, 40 mg, 0.08 mmol, 1.00 equiv) in
CH.sub.3CN (10 mL). Acetimidamide hydrochloride (7.6 mg, 0.08 mmol,
1.00 equiv) and potassium carbonate (33.4 mg, 0.24 mmol, 3.00
equiv) were added to the reaction. The resulting solution was
stirred for 2 h at 80.degree. C. in an oil bath, then cooled to
ambient temperature and concentrated under reduced pressure. The
residue was dissolved in 50 mL of ethyl acetate. The organic layer
was washed with 2.times.20 mL of water, 2.times.20 mL of brine,
dried over anhydrous sodium sulfate and concentrated under vacuum.
The crude product (.about.50 mg) was purified by Prep-HPLC with the
following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire
Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and
CH.sub.3CN (29.0% CH.sub.3CN up to 43.0% in 8 min, up to 100.0% in
2 min, down to 29.0% in 2 min); Detector, Waters 2489 254&220
nm. The fractions containing pure compound were combined and
lyophilized to yield 13 mg (35%) of the title compound as a white
solid. m/z (ES+) 457 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.78 (d, 2H), 7.65 (d, 2H), 7.50-7.46 (m, 2H),
7.35 and 7.23 (2 s, amide rotamers, 1H), 4.91-4.83 (m, 1H),
3.76-3.63 (m, 1H), 3.54-3.49 (m, 2H), 3.32-3.30 (m, 1H), 2.70 (s,
3H), 2.49 and 2.39 (2 singlets, amide rotamers, ArCH.sub.3, 3H),
2.34-2.28 (m, 7H), 1.98-1.80 (m, 3H).
##STR01002##
Compound 237.1. N'-Hydroxy-3-methoxypropanimidamide
[3872] Into a round-bottom flask, was placed a solution of
3-methoxypropanenitrile (10.0 g, 118 mmol, 1.00 equiv) in ethanol
(20 mL). NH.sub.2OH (50% in H.sub.2O) (10 mL) was added to the
reaction. The resulting solution was stirred overnight at
90.degree. C. in an oil bath, then cooled to ambient temperature
and concentrated under reduced pressure. The residue was diluted
with 30 mL of H.sub.2O and washed with 2.times.20 mL of ethyl
acetate. The aqueous layers were combined and concentrated under
reduced pressure to yield 10.0 g (65%) of the title compound as a
colorless oil.
##STR01003##
Compound 237.2. 3-Methoxypropanimidamide hydrochloride
[3873] Into a round-bottom flask, was placed a solution of
N'-hydroxy-3-methoxypropanamidine (compound 237.1, 10.0 g, 76.2
mmol, 1.00 equiv, 90%) in AcOH (50 mL). Acetic anhydride (9.50 g,
93.1 mmol, 1.10 equiv) was added dropwise and the resulting mixture
was stirred for 30 min at room temperature. After purging the flask
with nitrogen, palladium on carbon (10%, 60% water, 5 g) was added.
The flask was carefully purged with nitrogen again and the
atmosphere was then changed to hydrogen. The mixture was stirred
overnight at 20.degree. C. under atmospheric pressure of hydrogen.
After purging the system with nitrogen, the solids were then
removed by filtration and the filtrate was concentrated under
reduced pressure. The residue was diluted with 50 mL of H.sub.2O.
The pH value of the solution was adjusted to 2-3 with hydrogen
chloride (12 mol/L), then washed with 2.times.30 mL of ethyl
acetate. The aqueous layers were combined and concentrated under
reduced pressure to furnish 5.00 g (40%) of the title compound as
an off-white solid.
##STR01004##
Compound 237.
4-(1-(4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoy-
l)-4-fluoropiperidin-4-yl)benzonitrile
[3874] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluor-
opiperidin-4-yl)benzonitrile (compound 236) and using 237.2 in
place of acetimidamide hydrochloride. m/z (ES+) 501
(M+H).sup.+.
##STR01005##
Compound 238.1. Methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate
[3875] To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate
(152.3, 5.00 g, 15.1 mmol, 1.00 equiv) in DMSO (50 mL) under
nitrogen were added 1-(ethenyloxy)butane (3.03 g, 30.3 mmol, 2.00
equiv), DPPP (624 mg, 1.51 mmol, 0.10 equiv), Pd(OAc).sub.2 (324
mg, 1.51 mmol, 0.10 equiv), and TEA (3.06 g, 30.2 mmol, 2.00
equiv). The resulting mixture was stirred overnight at 120.degree.
C. under nitrogen, then cooled to ambient temperature and diluted
with water. The pH was adjusted to 1 with hydrogen chloride (aq., 6
M). The resulting mixture was diluted with 200 mL of ethyl acetate,
washed with brine (3.times.200 mL), dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure. The residue was purified using
silica gel column chromatography with ethyl acetate/petroleum ether
(1:30) as eluent to furnish 2.28 g (61%) of the title compound as a
yellow oil.
##STR01006##
Compounds 238.2 and 238.3. Methyl
5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoate and methyl
4-cyclobutyl-5-(2,2-dibromoacetyl)-2-methylbenzoate
[3876] To a solution of methyl
5-acetyl-4-cyclobutyl-2-methylbenzoate (238.1, 500 mg, 1.83 mmol,
1.00 equiv, 90%) in chloroform (5 mL) was added dropwise Br.sub.2
(325 mg, 2.03 mmol, 1.00 equiv)(CAUTION: exotherm reaction with
significant evolution of HBr). The resulting mixture was stirred
for 3 h at 25.degree. C., and then quenched by the addition of 5 mL
of H.sub.2O. The mixture was then extracted with 50 mL of ethyl
acetate. The organic phase was washed with 2.times.10 mL of
Na.sub.2S.sub.2O.sub.3 (aq., sat.) followed by 1.times.20 mL of
brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure to yield 500 mg of a mixture of the title
compounds as a yellow oil.
##STR01007##
Compound 238.4. Methyl
4-cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoate
[3877] Into around-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was placed a solution of a
mixture of compounds 238.2 and 238.3 (500 mg, .about.0.6 mmol,
80%), potassium carbonate (640 mg, 3.00 equiv),
3-methoxypropanimidamide hydrochloride (compound 237.2, 213 mg,
1.54 mmol) in acetonitrile. The resulting solution was stirred
overnight at 80.degree. C. in an oil bath, then cooled to ambient
temperature and concentrated under reduced pressure. The residue
was diluted with 60 mL of ethyl acetate. The organic layer was
washed with 2.times.25 mL of water, 2.times.25 mL of brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (2:1) as eluent
to furnish 90 mg (43%) of the title compound as a yellow solid.
##STR01008##
Compound 238.5.
4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoic
Acid
[3878] A mixture of compound 238.4, 90 mg, 0.25 mmol, 1.00 equiv,
90%) and aqueous sodium hydroxide (44 mg, 1.10 mmol, 4.00 equiv in
1 mL of water) in methanol (3 mL) was stirred for 2 h at 60.degree.
C. After cooling to ambient temperature, the methanol was removed
under reduced pressure. The pH of the residual aqueous layer was
adjusted to 3-4 with hydrogen chloride (aqueous, 2 M). The
resulting mixture was concentrated under reduced pressure to yield
80 mg (crude) of the title compound as a yellow solid.
##STR01009##
Compound 238.
4-(1-(4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoy-
l)piperidin-4-yl)benzonitrile
[3879] Into around-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was placed a solution of
compound 238.5 (80 mg, 0.23 mmol, 1.00 equiv, 90%) in
N,N-dimethylformamide (2 mL). 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 54 mg, 0.24 mmol, 1.00 equiv), EDC-HCl
(93 mg, 0.49 mmol, 2.00 equiv), and 4-dimethylaminopyridine (59 mg,
0.48 mmol, 2.00 equiv) were added to the solution. The resulting
mixture was stirred for 3 h at 30.degree. C., then diluted with 50
mL of ethyl acetate. The organic layer was washed with 2.times.20
mL of water, 2.times.20 mL of brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified using silica gel column chromatography with
chloroform/methanol (20:1) as eluent. The product (.about.50 mg)
was further purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (29%
CH.sub.3CN up to 43% in 8 min, up to 100% in 6 min, down to 29% in
1 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield
20.6 mg (19%) of the title compound as a white solid. m/z (ES+) 483
(M+H).sup.+.
[3880] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compounds 236, 237, and 238:
TABLE-US-00003 Cmpnd m/z # Compound Name Compound Structure (ES+)
239 4-(1-(4-cyclobutyl- 5-(2-(methoxymethyl)- 1H-imidazol-5-yl)-
2-methylbenzoyl)- 4-fluoropiperidin- 4-yl)benzonitrile ##STR01010##
487 (M + H).sup.+ 240 4-(1-(4-cyclobutyl- 5-(2-(methoxymethyl)-
1H-imidazol-5-yl)- 2-methylbenzoyl) piperidin-4- yl)benzonitrile
##STR01011## 469 (M + H).sup.+ 241 4-(1-(4-cyclobutyl-
3-(2-methyl-1H- imidazol-5- yl)benzoyl) piperidin-4-yl)
benzonitrile ##STR01012## 425 (M + H).sup.+ 242 4-(1-(4-cyclobutyl-
2-methyl-5-(2- methyl-1H- imidazol-5- yl)benzoyl) piperidin-4-yl)
benzonitrile ##STR01013## 439 (M + H).sup.+ 243 4-(1-(4-cyclobutyl-
3-(2-(2- methoxyethyl)-1H- imidazol-5- yl)benzoyl)-4-
fluoropiperidin-4- yl)benzonitrile ##STR01014## 487 (M + H).sup.+
244 4-(1-(4-cyclobutyl- 3-(2-(2- methoxyethyl)-1H- imidazol-5-
yl)benzoyl) piperidin-4-yl) benzonitrile ##STR01015## 469 (M +
H).sup.+
##STR01016##
Compound 245.1. Methyl
5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride
[3881] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of methyl 5-(N'-hydroxycarbamimidoyl)-2,4-dimethylbenzoate
(compound 2.4) and methyl 5-carbamimidoyl-2,4-dimethylbenzoate
hydrochloride (compound 2.5) using methyl
5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4) instead of
methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3).
##STR01017##
Compound 245.2. Methyl
4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate
[3882] To a round-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was added a solution of
methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride
(compound 245.1, 350 mg, 1.11 mmol, 1.00 equiv, 90%) in ACN (50
mL). 1-Bromobutan-2-one (186 mg, 1.23 mmol, 1.00 equiv) and
potassium carbonate (513 mg, 3.53 mmol, 3.00 equiv, 95%) were added
to the reaction. The resulting solution was stirred overnight at
80.degree. C. After cooling to ambient temperature, the mixture was
diluted with ethyl acetate and washed with 3.times.30 mL of brine,
dried over anhydrous sodium sulfate, and concentrated in vacuo. The
residue was purified using silica gel column chromatography with
ethyl acetate/petroleum ether (1:5) as eluent to furnish 290 mg
(83%) of methyl
4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate as a
yellow solid.
##STR01018##
Compound 245.3.
4-Cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic Acid
[3883] A mixture of methyl
4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate
(compound 245.2, 200 mg, 0.600 mmol, 1.00 equiv, 90%) and sodium
hydroxide (107 mg, 2.68 mmol, 4.00 equiv) in a solvent mixture of
methanol and water (4/2 mL) was stirred for 3 h at 60.degree. C.
After cooling to ambient temperature, the pH was adjusted to 3-4
with hydrogen chloride (aq., 6 M). The resulting mixture was
concentrated in vacuo to yield 150 mg of a white solid.
##STR01019##
Compound 245.
4-(1-(4-Cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-
-4-yl)benzonitrile
[3884] To a round-bottom flask was added a solution of
4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid
(compound 245.3, 153 mg, 0.480 mmol, 1.00 equiv, 90%) in
N,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 132 mg, 0.590 mmol, 1.10 equiv),
EDC-HCl (204 mg, 1.01 mmol, 2.00 equiv, 95%) and
4-dimethylaminopyridine (131 mg, 1.02 mmol, 2.00 equiv, 95%) were
added to the reaction. The resulting solution was stirred overnight
at room temperature, then concentrated in vacuo. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (2:1) as eluent. The crude product
(.about.150 mg) was further purified by Prep-HPLC with the
following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire
Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and
CH.sub.3CN (28% CH.sub.3CN up to 43% in 7 min, up to 100% in 2 min,
down to 28% in 2 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 62 mg (29%) of the title compound as a white solid. m/z (ES+)
453 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.75-7.67 (m, 2H), 7.49-7.34 (m, 5H), 4.89-4.80 (m, 1H), 3.75-3.72
(m, 1H), 3.64-3.59 (m, 1H), 3.27-3.23 (m, 1H), 3.05-2.90 (m, 2H),
2.83 (q, 2H), 2.40 and 2.30 (2 singlets, amide rotamers,
ArCH.sub.3, 3H), 2.27-1.97 (m, 6H), 1.90-1.70 (m, 4H), 1.40 (t,
3H).
##STR01020##
Compound 246.1. 2-Methoxyacetyl chloride
[3885] To a solution of 2-methoxyacetic acid (2.00 g, 22.2 mmol,
1.00 equiv) in dichloromethane (20 mL) was added dropwise
(COCl).sub.2 (5.65 g, 2.00 equiv) in N,N-dimethylformamide (0.1 mL)
(gas evolution observed). The reaction was stirred for 1 h at
40.degree. C. The resulting mixture was then concentrated under
reduced pressure to yield 2.10 g (70%) of 2-methoxyacetyl chloride
as a yellow oil.
##STR01021##
Compound 246.2. 1-Bromo-3-methoxypropan-2-one
[3886] To a solution of TMSCHN.sub.2 (2 M in hexane) (16 mL, 2.00
equiv) in dichloromethane (40 mL) was added 2-methoxyacetyl
chloride (compound 246.1, 2.10 g, 15.5 mmol, 1.00 equiv, 80%)
dropwise at 0.degree. C. After stirring for 20 min, HBr (48%, 2 mL)
was added to the reaction. The resulting solution was stirred for
30 min at 25.degree. C. The mixture was washed with 1.times.20 mL
of brine, dried over anhydrous sodium sulfate and concentrated in
vacuo. This resulted in 2.30 g (71%) of
1-bromo-3-methoxypropan-2-one as a yellow oil.
##STR01022##
Compound 246.3. Methyl
4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate
[3887] To a round-bottom flask was added a solution of
1-bromo-3-methoxypropan-2-one (compound 246.2, 505 mg, 1.81 mmol,
1.00 equiv, 60%) in CH.sub.3CN (16 mL). Methyl
5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride
(compound 245.1, 450 mg, 1.59 mmol, 1.00 equiv) and potassium
carbonate (554 mg, 3.61 mmol, 3.00 equiv, 90%) were added to the
reaction. The resulting solution was stirred overnight at
80.degree. C. under nitrogen. After cooling to ambient temperature,
the reaction was carefully quenched by the addition of water. The
resulting mixture was extracted with 2.times.50 mL of ethyl
acetate. The combined organic layers were dried (Na.sub.2SO.sub.4),
and concentrated in vacuo. The residue was purified using silica
gel column chromatography with ethyl acetate/petroleum ether (1:2)
as eluent to furnish 170 mg (24%) of methyl
4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate
as a white solid.
##STR01023##
Compound 246.4.
4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic
Acid
[3888] A solution of methyl
4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate
(compound 246.3, 150 mg, 0.430 mmol, 1.00 equiv, 90%) and aqueous
sodium hydroxide (76.0 mg, 1.90 mmol, 4.00 equiv in 2 mL water) in
methanol (4 mL) was stirred for 2 h at 60.degree. C. After cooling
to ambient temperature, the organic solvent was removed under
reduced pressure. The pH value of the remaining aqueous phase was
adjusted to .about.4 with hydrogen chloride (aq., 4 M). The
resulting mixture was extracted with 2.times.50 mL of ethyl
acetate, and the combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. This resulted in 120
mg (84%) of
4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic
acid as a white solid.
##STR01024##
Compound 246.
4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile
[3889] To a round-bottom flask was added a solution of
4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic
acid (compound 246.4, 50.0 mg, 0.150 mmol, 1.00 equiv, 90%) in
N,N-dimethylformamide (3 mL). 4-(Piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 41.0 mg, 0.170 mmol, 1.10 equiv),
EDC-HCl (64.0 mg, 0.330 mmol, 2.00 equiv), and
4-dimethylaminopyridine (41.0 mg, 0.340 mmol, 2.00 equiv) were
added to the reaction. The resulting solution was stirred for 3 h
at 25.degree. C., then quenched with water and extracted with
2.times.30 mL of ethyl acetate. The combined organic layers were
concentrated in vacuo. The crude product (.about.50 mg) was
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (26.0%
CH.sub.3CN up to 42.0% in 7 min, up to 100.0% in 2 min, down to
26.0% in 1 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 18 mg (25%) of the title compound as a white solid. m/z (ES+)
469 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
7.73-7.64 (m, 3H), 7.52-7.32 (m, 4H), .about.4.9 (1H partially
obscured by water peak), 4.60 (s, 2H), 3.81-3.68 (m, 1H), 3.68-3.52
(m, 1H), 3.46 (s, 3H), 3.35-3.22 (m, 1H partially obscured by
methanol solvent peak), 3.09-2.95 (m, 2H), 2.52 & 2.41 (2
singlets, amide rotamers, Ar--CH.sub.3, 3H), 2.16-1.97 (m, 6H),
1.94-1.58 (m, 4H).
##STR01025##
Compound 247.
4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)-4-fluoropiperidin-4-yl)benzonitrile
[3890] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile (compound 246), using
4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2
HCl salt) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride
(compound 1.5). m/z (ES+) 487 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 7.79-7.67 (m, 2H), 7.66 (d, 3H), 7.53-7.39 (m,
2H), 4.99-4.93 (m, 1H), 4.85 (s, 2H), 3.76-3.56 (m, 3H), 3.50 (s,
3H), 2.42 and 2.34 (2 singlets, amide rotamers, ArCH.sub.3, 3H),
2.27-1.97 (m, 8H), 1.92-1.81 (m, 2H), 1.35-1.26 (m, 1H).
##STR01026##
Compound 248.
4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-4-methyl-1H-imidazol-2-yl)-2-meth-
ylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3891] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile (compound 246). m/z (ES+) 501
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.79-7.77
(m, 2H), 7.66 (d, 2H), 7.52-7.38 (m, 2H), 4.87-4.80 (m, 1H), 4.55
(s, 2H), 3.78-3.74 (m, 1H), 3.62-3.56 (m, 2H), 3.50 (s, 3H),
3.44-3.32 (m, 1H), 2.52 and 2.42 (2 singlets, amide rotamers,
ArCH.sub.3, 3H), 2.44 (s, 3H), 2.11-1.99 (m, 8H), 1.93-1.83 (m,
2H).
##STR01027##
Compound 249.
4-(1-(4-Cyclobutyl-5-(4,5-dimethyl-1H-imidazol-2-yl)-2-methylbenzoyl)pipe-
ridin-4-yl)benzonitrile
[3892] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile (compound 246). m/z (ES+) 453
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.68 (d,
2H), 7.51 (d, 2H), 7.31 (d, 1H), 7.32 and 7.30 (2 singlets, amide
rotamers, ArH, 1H), 4.90-4.88 (m, 1H), 3.96-3.87 (m, 1H), 3.70-3.62
(m, 1H), 3.32-3.29 (m, 1H), 3.02 (t, 2H), 2.44 and 2.33 (2
singlets, amide rotamers, ArCH.sub.3, 3H), 2.20 (s, 6H), 2.18-1.90
(m, 7H), 1.88-1.78 (m, 3H).
##STR01028##
Compound 250.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-1H-imidazol-2-yl)benzoyl)piperidi-
n-4-yl)benzonitrile
[3893] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile (compound 246). m/z (ES+) 439
(M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 7.68 (d,
2H), 7.49-7.39 (m, 4H), 7.36 and 7.34 (2 singlets, amide rotamers,
ArH, 1H), 4.90-4.86 (m, 1H), 3.75-3.70 (m, 1H), 3.63-3.55 (m, 1H),
3.33-3.24 (m, 1H), 3.04-2.99 (m, 2H), 2.51 and 2.41 (2 singlets,
amide rotamers, ArCH.sub.3, 3H), 2.44 (s, 3H), 2.28-1.96 (m, 6H),
1.89-1.81 (m, 3H), 1.77-1.74 (m, 1H).
##STR01029##
Compound 251.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-1H-imidazol-2-yl)benzo-
yl)piperidin-4-yl)benzonitrile
[3894] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile (compound 246). m/z (ES+) 493
(M+H).sup.+.
##STR01030##
Compound 252.
4-(1-(5-(5-Chloro-1H-imidazol-2-yl)-4-cyclobutyl-2-methylbenzoyl)piperidi-
n-4-yl)benzonitrile
[3895] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile (compound 246). m/z (ES+) 459
(M+H).sup.+.
##STR01031##
Compound 253.
2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl-
)-1H-imidazole-5-carbonitrile
[3896] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 246. m/z (ES+) 450 (M+H).sup.+.
##STR01032##
Compound 254.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenza-
mide
[3897] To a solution of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoic
acid (compound 234, 50 mg, 0.124 mmol) in DMF (2 mL) were added
EDCI (36 mg, 0.186 mmol), HOBt (10 mg, 0.5 mmol), diisopropylethyl
amine (54 mg, 0.434 mmol), and methyl amine (125 ul, 2.5 M in THF).
The reaction mixture was stirred for 12 hours at room temperature
and quenched with saturated aqueous NaHCO.sub.3 (50 mL). After
extraction with ethyl acetate (2.times.50 mL), the combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated
in vacuo. Purification via SiO.sub.2 flash chromatography with
ethyl acetate to ethyl acetate/methanol=98/2 afforded
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenza-
mide (28.3 mg, 55% yield) as a white solid. m/z (ES+) 416
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.13 (q,
J=4.5 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.55-7.45 (m, 2H), 7.26 (br
s, 1H), 7.12 & 6.99 (2 singlets, amide rotamers, Ar--H, 1H),
4.70 (br d, J=11.9 Hz, 1H), 3.86-3.72 (m, 1H), 3.50-3.35 (m, 1H),
3.13 (t with fine structure, J=12.3 Hz, 1H), 2.99-2.78 (m, 2H),
2.72 (d, J=4.6 Hz, 3H), 2.39-2.17 (m, 5H), 2.17-1.98 (m, 2H),
1.98-1.81 (m, 2H), 1.81-1.35 (m, 4H).
##STR01033##
Compound 255.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N-(2-methoxyethyl-
)-4-methylbenzamide
[3898] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenza-
mide (compound 254). m/z (ES+) 460 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.27 (t, 1H), 7.78 (d, 2H), 7.49 (d,
2H), 7.26 (s, 1H), 7.12 and 6.98 (2 singlets, amide rotamers, 1H),
4.70 (d, 1H), 3.85-3.75 (m, 1H), 3.44 (t, 3H), 3.39-3.33 (m, 2H),
3.30 (s, 3H), 3.19-3.03 (m, 1H), 3.02-2.71 (m, 2H), 2.32 and 2.26
(2 singlets, amide rotamers, ArCH.sub.3, 3H), 2.38-2.17 (m, 2H),
2.15-2.00 (m, 2H), 1.98-1.81 (m, 2H), 1.83-1.47 (m, 4H).
##STR01034##
Compound 256.
5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N-ethyl-4-methylb-
enzamide
[3899] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenza-
mide (compound 254). m/z (ES+) 430 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.21 (t, 1H), 7.78 (d, 2H), 7.56-7.45
(m, 2H), 7.31-7.20 (m, 1H), 7.11 and 6.98 (2 singlets, amide
rotamers, 1H), 4.74-4.65 (m, 1H), 3.85-3.74 (m, 1H), 3.50-3.37 (m,
1H), 3.22 (q, 2H), 3.20-3.05 (m, 2H), 2.32 and 2.22 (2 singlets,
amide rotamers, ArCH.sub.3, 3H), 3.01-2.76 (m, 2H), 2.38-2.17 (m,
2H), 2.18-1.97 (m, 2H), 1.98-1.84 (m, 2H), 1.81-1.38 (m, 3H), 1.10
(t, 3H).
##STR01035##
Compound 257.1. (S)-Tetrahydrofuran-2-carbonyl chloride
[3900] To a round-bottom flask was added a solution of
(S)-tetrahydrofuran-2-carboxylic acid (4.64 g, 40.0 mmol, 1.00
equiv) in dichloromethane (25 mL). N,N-dimethylformamide (0.05 mL,
0.05 equiv) and (COCl).sub.2 (5.2 mL, 1.50 equiv) were added
dropwise to the reaction. The resulting solution was stirred for 1
h at 25.degree. C., then concentrated in vacuo to yield 5.00 g
(93%) of (S)-tetrahydrofuran-2-carbonyl chloride as a yellow
oil.
##STR01036##
Compound 257.2. (S)-2-Bromo-1-(tetrahydrofuran-2-yl)ethanone
[3901] To a 250-mL three neck round-bottom flask, which was purged
and maintained with an inert atmosphere of nitrogen, was added a
solution of (diazomethyl)trimethylsilane (20 mL, 2 M in hexane) in
ether (150 mL). A solution of (S)-tetrahydrofuran-2-carbonyl
chloride (compound 257.1, 5.00 g, 37.2 mmol, 1.00 equiv) in
ether/DCM (25/10 mL) was added dropwise at 0.degree. C. and stirred
for 20 min at 0.degree. C. Hydrogen bromide (48%) (8 mL, 1.50
equiv) was added dropwise. The resulting solution was stirred for
30 min at 10.degree. C., then washed with 2.times.100 mL of water
and 1.times.50 mL of brine. The mixture was dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:50) as eluent to furnish 2.50 g (35%) of
(S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone as a yellow oil.
##STR01037##
Compound 257.3. (S)-Methyl
2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate
[3902] To a round-bottom flask was added a solution of methyl
5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5,
1.30 g) in CH.sub.3CN (30 mL).
(S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone (compound 257.2, 1.92
g, 9.95 mmol) and potassium carbonate (4.20 g, 30.4 mmol) were
added to the reaction. The resulting solution was stirred for 3
days at 75.degree. C. under nitrogen. After cooling to ambient
temperature, the solids were removed by filtration. The filtrate
was concentrated in vacuo and diluted with 30 mL of H.sub.2O. The
aqueous phase was extracted with 3.times.50 mL of ethyl acetate and
the combined organic layers were dried over anhydrous sodium
sulfate, then concentrated in vacuo. The mixture was purified using
silica gel column chromatography with ethyl acetate/petroleum ether
(1:2) as eluent to yield 400 mg (25%) of (S)-methyl
2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate
as a light yellow solid.
##STR01038##
Compound 257.4.
(S)-2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoic
Acid
[3903] To a round-bottom flask was added a solution of (S)-methyl
2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate
(compound 257.3, 400 mg, 1.33 mmol, 1.00 equiv) and sodium
hydroxide (300 mg, 7.50 mmol, 5.63 equiv) in a solvent mixture of
methanol and H.sub.2O (20/10 mL). The resulting solution was
stirred for 2 h at 70.degree. C. After cooling to ambient
temperature, the organic solvent was removed under reduced
pressure. The residual aqueous layer was washed with 2.times.50 mL
of ethyl acetate. The pH of the aqueous layer was adjusted to 5-6
with hydrogen chloride (aq., 6 M), then extracted with 3.times.50
mL of ethyl acetate. The combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo. This resulted
in 340 mg (90%) of (S)-methyl
2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate
as a yellow solid.
##STR01039##
Compound 257.
(S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzo-
yl)piperidin-4-yl)benzonitrile
[3904] To a round-bottom flask was added a solution of (S)-methyl
2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate
(compound 257.4, 143 mg, 0.500 mmol, 1.00 equiv) in
N,N-dimethylformamide (10 mL). HBTU (285 mg, 0.750 mmol, 1.50
equiv) was added to the reaction, and it was stirred for 30 min at
25.degree. C. To this was added 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 133 mg, 0.600 mmol, 1.20 equiv) and
DIEA (390 mg, 3.02 mmol, 6.04 equiv) dropwise. The resulting
solution was stirred for 30 min at 25.degree. C., then quenched
with 20 mL of water. The mixture was extracted with 3.times.25 mL
of ethyl acetate and the combined organic layers were dried over
anhydrous sodium sulfate and concentrated in vacuo. The residue was
purified using silica gel column chromatography with methanol/ethyl
acetate (1:30) as eluent. The product (.about.100 mg) was further
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150
mm; mobile phase, water with 0.03% NH.sub.3H.sub.2O and CH.sub.3CN
(35% CH.sub.3CN up to 52% in 8 min, up to 100% in 1 min, down to
35% in 1 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield
34.6 mg (15%) of the title compound as a white solid. m/z (ES+) 455
(M+H).sup.+.
##STR01040##
Compound 258.1.
5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic Acid
[3905] The title compound was synthesized using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 152.8 using 4-fluoro-2-methylbenzoic acid
instead of 4-bromo-2-methylbenzoic acid and propionohydrazide
instead of acetohydrazide.
##STR01041##
Compound 258.2.
4-(1-(5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidi-
n-4-yl)benzonitrile
[3906] To a round-bottom flask was added a solution of
5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid
(compound 258.1, 125 mg, 0.500 mmol, 1.00 equiv) in DMF (10 mL).
EDC.HCl (143 mg, 0.750 mmol, 1.50 equiv),
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 122 mg,
0.550 mmol, 1.10 equiv), and 4-dimethylaminopyridine (183 mg, 1.50
mmol, 3.00 equiv) were added in portions. The resulting solution
was stirred for 1 h at 40.degree. C. in an oil bath, then quenched
with 50 mL of NH.sub.4Cl (aq.sat.). The mixture was extracted with
40 mL of ethyl acetate and the combined organic layers were washed
with 3.times.30 mL of NH.sub.4Cl (aq.sat.), dried over anhydrous
sodium sulfate and concentrated under vacuum. This resulted in 180
mg (86%) of
4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidi-
n-4-yl)benzonitrile as a white solid.
##STR01042##
Compound 258.
4-(1-(4-(Azetidin-1-yl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl-
)piperidin-4-yl)benzonitrile
[3907] To a 10-mL sealed tube was added a solution of
4-(1-[[5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylphenyl]carbonyl-
]piperidin-4-yl)benzonitrile (compound 258.2, 83.5 mg, 0.200 mmol,
1.00 equiv) in 1,4-dioxane (5 mL). Azetidine hydrochloride (93.0
mg, 0.990 mmol, 5.00 equiv) was added to the reaction in portions.
Potassium carbonate (276 mg, 2.00 mmol, 10.0 equiv) was also added
to the above mixture. The resulting solution was stirred overnight
at 105.degree. C. behind a blast shield, then cooled to rt. The
reaction was quenched with 20 mL of water. The mixture was
extracted with 30 mL of ethyl acetate and the organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The product (80 mg) was further purified by Prep-HPLC
with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,
SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 50 mL
NH.sub.4CO.sub.3 and CH.sub.3CN (41.0% CH.sub.3CN up to 43.0% in 8
min, up to 100.0% in 2 min, down to 41.0% in 2 min); Detector,
Waters 2489 254&220 nm. The fractions containing pure compound
were combined and lyophilized to yield 18.0 mg (20%) of the title
compound as a white solid. m/z (ES+) 455 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD): .delta. 7.68 (d, J=6.3 Hz, 2H), 7.48 (d,
J=5.7 Hz, 2H), 7.24 & 7.13 (2 singlets, amide rotamers, Ar--H,
1H), 6.52 (s, 1H), 4.91-7.77 (m, 1H partially obscured by water
peak), 3.81-3.67 (m, 1H), 3.68 (t, J=5.6 Hz, 4H), 3.32-3.18 (m,
1H), 3.05-1.91 (m, 2H), 2.84 (q, J=5.8 Hz, 2H), 2.45-2.19 (m, 5H),
2.09-1.91 (m, 1H), 1.91-1.49 (m, 3H), 1.39 (t, J=5.7 Hz, 3H).
##STR01043##
Compound 259.
4-(1-(5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-2-methyl-4-(methylthio)benzoyl)pi-
peridin-4-yl)benzonitrile
[3908] To a round-bottom flask was added a solution of
4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidi-
n-4-yl)benzonitrile (compound 258.2, 20 mg, 0.050 mmol, 1.0 equiv)
in N,N-dimethylformamide (3 mL). Sodium thiomethoxide (70 mg, 0.10
mmol, 2.0 equiv) was added to the reaction. The resulting mixture
was stirred for 15 h at 110.degree. C. in an oil bath, and then
cooled to ambient temperature and quenched with 100 mL of ice
water. The mixture was extracted with 50 mL of ethyl acetate and
the combined organic layers were washed with 2.times.50 mL of
brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The product (50 mg) was further purified by
Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (37%
CH.sub.3CN up to 49% in 7 min, up to 100% in 3 min, down to 37% in
2 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield 4
mg (19%) of the title compound as a white solid. m/z (ES+) 446
(M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.69 (d,
J=8.4 Hz, 2H), 7.61-7.43 (m, 3H), 7.35 (br s, 1H), .about.4.85 (1H
partially obscured by water peak), 3.77-3.60 (m, 1H), .about.3.3
(1H partially obscured by methanol solvent peak), 3.08-2.94 (m,
2H), 2.91 (q, J=7.7 Hz, 2H), 2.51 (s, 3H), 2.47 & 2.37 (2
singlets, amide rotamers, Ar--CH.sub.3, 3H), 2.10-1.97 (m, 1H),
1.88-1.55 (m, 3H), 1.40 (t, 3H).
[3909] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compound
5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenza-
mide (compound 254):
TABLE-US-00004 Cmpnd Compound m/z # Name Compound Structure (ES+)
260 5-(4-(4- methoxyphenyl) piperidine-1- carbonyl)-2- methyl-N-(6-
(pyrrolidin-1- yl)pyridin-3- yl)benzamide ##STR01044## 499 (M +
H).sup.+ 261 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-
2-methyl-N- ((tetrahydrofuran- 2-yl)methyl) benzamide ##STR01045##
432 (M + H).sup.+ 262 5-(4-(4- cyanophenyl) piperidine-1-
carbonyl)- 2-methyl-N- (tetrahydrofuran- 3-yl)benzamide
##STR01046## 418 (M + H).sup.+ 263 3-(4-(4- cyanophenyl)
piperidine-1- carbonyl)- N-(6-(pyrrolidin- 1-yl)pyridin-3-
yl)benzamide ##STR01047## 480 (M + H).sup.+ 264 5-(4-(4-
cyanophenyl) piperidine-1- carbonyl)- 2-methyl-N- (piperidin-4-
ylmethyl) benzamide ##STR01048## 445 (M + H).sup.+ 265 5-(4-(4-
cyanophenyl) piperidine-1- carbonyl)- 2-methyl-N-((1-
methylpiperidin- 4-yl)methyl) benzamide ##STR01049## 459 (M +
H).sup.+ 266 5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-
2-methyl-N- ((tetrahydrofuran- 3-yl)methyl) benzamide ##STR01050##
432 (M + H).sup.+ 267 2-methyl-5-(4- (pyridin-4- yl)piperidine-1-
carbonyl)-N-(6- (pyrrolidin-1- yl)pyridin-3- yl)benzamide
##STR01051## 470 (M + H).sup.+ 268 5-(4-(4- cyanophenyl)
piperidine-1- carbonyl)- N-(6-((2- hydroxyethyl) (methyl)amino)
pyridin-3-yl)-2- methylbenzamide ##STR01052## 499 (M + H).sup.+ 269
5-(4-(4- cyanophenyl) piperidine-1- carbonyl)- N-(6-(3-
hydroxyazetidin- 1-yl)pyridin-3-yl)- 2-methylbenzamide ##STR01053##
497 (M + H).sup.+ 270 5-(4-(4- cyanophenyl) piperidine-1-
carbonyl)- 2-methyl-N-(6-(4- methylpiperazin- 1-yl)pyridin-3-
yl)benzamide ##STR01054## 524 (M + H).sup.+
[3910] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compounds 27, 38, and 211:
TABLE-US-00005 Preparation similar to Cmpnd compound #(s) #
Compound Name Compound Structure [m/z (ES+)] 271 4-(1-(4-methyl-
3-(6-(4- methylpiperazin- 1-yl)-3H- imidazo[4,5- c]pyridin-2-
yl)benzoyl)piper- idin-4- yl)benzonitrile ##STR01055## 27 [520 (M +
H).sup.+] 272 4-(1-(3-(6-(3- hydroxyazetidin- 1-yl)-3H-
imidazo[4,5- c]pyridin-2-yl)- 4- methylbenzoyl) piperidin-4-
yl)benzonitrile ##STR01056## 27 [493 (M + H).sup.+] 273
4-(1-(3-(6-((2- hydroxyethyl) (methyl)amino)- 3H-imidazo[4,5-
c]pyridin-2-yl)- 4- methylbenzoyl) piperidin-4- yl)benzonitrile
##STR01057## 27 [495 (M + H).sup.+] 274 4-(1-(3-(5- isopropyl-4H-
1,2,4-triazol-3- yl)-4- methylbenzoyl) piperidin-4- yl)benzonitrile
##STR01058## 38 [414 (M + H).sup.+] 275 4-(1-(3-(5- ethyl-4H-1,2,4-
triazol-3-yl)-4- methylbenzoyl) piperidin-4- yl)benzonitrile
##STR01059## 38 [400 (M + H).sup.+] 276 (S)-4-(1-(4- methyl-3-(5-
((tetrahydro- furan-3- yl)amino)-4H- 1,2,4-triazol-3-
yl)benzoyl)pi- peridin-4- yl)benzonitrile ##STR01060## 211 [457 (M
+ H).sup.+] 277 (R)-4-(1-(4- methyl-3-(5- ((tetrahydro- furan-3-
yl)amino)-4H- 1,2,4-triazol-3- yl)benzoyl)pi- peridin-4-
yl)benzonitrile ##STR01061## 211 [457 (M + H).sup.+] 278 (R)-4-(4-
fluoro-1-(4- methyl-3-(5- ((tetrahydro- furan-3- yl)amino)-4H-
1,2,4-triazol-3- yl)benzoyl)pi- peridin-4- yl)benzonitrile
##STR01062## 211 [475 (M + H).sup.+] 279 4-(1-(2,4- dimethyl-5-(5-
((tetrahydro- furan-3- yl)amino)-4H- 1,2,4-triazol-3-
yl)benzoyl)pi- peridin-4- yl)benzonitrile ##STR01063## 211 [471 (M
+ H).sup.+]
##STR01064##
Compound 280.1.
N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-isonicoti-
noylhydrazinecarboxamide
[3911] A solution of
4-(1-(3-Amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound
121.1, 0.1 g, 0.31 mmol) and triethyl amine (0.09 ml, 0.62 mmol) in
DCM (5 ml) was added to a solution of phosgene (20% in toluene,
0.31 ml, 0.62 mmol) in DCM (5 ml) at 0.degree. C. After the
resulting reaction mixture was stirred at room temperature for 1.5
hours, all solvents were removed under reduced pressure. The
residue was dried under high-vacuum for 30 minutes then was
re-dissolved in EtOH (5 ml). Isonicotinohydrazide (0.05 g, 0.34
mmol) was added. The mixture was heated at 80.degree. C. over
night. The ethanol was removed and the residue was purified using
prep.-TLC (10% MeOH in DCM) to give the product as a light brown
solid. Yield: 0.14 g, 93%. m/z (ES+) 483.2 (M+H).sup.+.
##STR01065##
Compound 280.
4-(1-(4-Methyl-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)benzoyl)piperidin-
-4-yl)benzonitrile
[3912] To a solution of
N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-isonicoti-
noylhydrazinecarboxamide (compound 280.1, 0.14 g, 0.29 mmol) and
PPh.sub.3 (0.09 g, 0.35 mmol) in DCM (10 ml) was added triethyl
amine (0.061 ml, 0.43 mmol) followed with CCl.sub.4 (0.08 ml, 0.87
mmol). The mixture was refluxed for 3 hours. TLC and LCMS showed
that the reaction was complete. The mixture was cooled to room
temperature, diluted with DCM (100 ml), and washed with water (20
ml). The organic layer was dried with Na.sub.2SO.sub.4,
concentrated and purified using prep.-TLC (5% MeOH in
CH.sub.2Cl.sub.2) to yield 54 mg (42%) of a white solid. m/z (ES+)
465.0 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.00 (br, 1H), 8.77 (d, 2H), 7.92 (s, 1H), 7.81-7.73 (m, 4H), 7.50
(d, 2H), 7.33 (d, 1H), 7.14 (d, 1H), 4.64 (m, 1H), 3.81 (m, 1H),
3.17 (m, 1H), 3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.95-1.57 (m,
4H).
##STR01066##
Compound 281.1.
N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazol-
e-1-carbothioamide
[3913] To a solution of
4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (121.1,
0.1 g, 0.32 mmol) in DMF (3 ml) was added 1,1'-thio-CDI (0.056 g,
0.32 mmol). The mixture was stirred at room temperature for 3
hours. LCMS showed the reaction was complete. The mixture was
carried to the next step in one pot without work up or
purification. m/z (ES+) 430 (M+H).sup.+.
##STR01067##
Compound 281.2.
1-(4-Aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-m-
ethylphenyl)thiourea
[3914] To a solution of
N-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazol-
e-1-carbothioamide (281.1) in DMF continued from the prior step was
added pyridine-3,4-diamine (0.034, 0.32 mmol). The mixture was
stirred at room temperature for 3 hours. LCMS showed the reaction
was complete. The reaction was carried to the next step without
workup or purification. m/z (ES+) 471 (M+H).sup.+.
##STR01068##
Compound 281.
4-(1-(3-((1H-Imidazo[4,5-c]pyridin-2-yl)amino)-4-methylbenzoyl)piperidin--
4-yl)benzonitrile
[3915] To a solution of
1-(4-aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-m-
ethylphenyl)thiourea (281.2) in DMF continued from the prior step
was added EDCI (0.12 g, 0.64 mmol). The mixture was stirred at room
temperature overnight. The DMF was removed under high vacuum and
the residue was purified using prep.-TLC (5% MeOH in EtOAc) to
yield 76 mg (56% for 3 steps) of a white powder. m/z (ES+) 437
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.84 (br,
1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.08 (d, 1H), 7.78 (d, 2H), 7.53
(d, 2H), 7.29 (d, 2H), 7.05 (d, 1H), 4.65 (m, 1H), 3.91 (m, 1H),
3.17 (m, 1H), 3.04-3.72 (m, 2H), 2.36 (s, 3H), 1.97-1.60 (m,
4H).
##STR01069##
Compound 282.1.
N-((5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)carbamothio-
yl)isobutyramide
[3916] Into around-bottom flask, was placed a solution of
NH.sub.4SCN (72 mg, 0.95 mmol, 2.00 equiv) in acetone (10 mL). A
solution of 2-methylpropanoyl chloride (50 mg, 0.47 mmol, 1.00
equiv) in acetone was added (5 mL) dropwise at 25.degree. C. and
the reaction was stirred overnight at 40.degree. C. in an oil bath.
To this was added
4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound
121.1, 150 mg, 0.42 mmol, 1.00 equiv) at 25.degree. C. The
resulting solution was stirred for 2 h at 25.degree. C., then
concentrated under reduced pressure. The residue was diluted with
100 mL of ethyl acetate. The organic layer was washed with
2.times.30 mL of brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified using
silica gel column chromatography with dichloromethane/methanol
(20:1) as eluent to furnish 150 mg (64%) of the title compound as a
brown oil.
##STR01070##
Compound 282.
4-(1-(3-((5-Isopropyl-4H-1,2,4-triazol-3-yl)amino)-4-methylbenzoyl)piperi-
din-4-yl)benzonitrile
[3917] Into a 10-mL sealed tube, was placed a solution of
N-((5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)carbamothio-
yl)isobutyramide (compound 282.1, 200 mg, 0.40 mmol, 1.00 equiv,
90%) in ethanol (3 mL). NH.sub.2NH.sub.2HCl (234 mg, 2.23 mmol,
5.00 equiv) and potassium carbonate (185 mg, 1.34 mmol, 3.00 equiv)
were added to the reaction. The resulting solution was stirred
overnight at 80.degree. C. in an oil bath behind a blast shield.
After cooling to ambient temperature, the mixture was concentrated
under reduced pressure. The residue was partitioned between ethyl
acetate and water. The organic phase was washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated. The crude product (.about.50
mg) was purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 5 um, 19*150
mm; mobile phase, water with 0.05% TFA and CH.sub.3CN (hold 5.0%
CH.sub.3CN in 2 min, up to 30.0% in 1 min, up to 60.0% in 12 min,
up to 100.0% in 1 min); Detector, UV 254/220 nm. The fractions
containing pure compound were combined and lyophilized to yield
10.3 mg (6%) of the title compound as a white solid. m/z (ES+) 429
(M+H).sup.+.
[3918] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compounds 280, 121, 281, and 282:
TABLE-US-00006 Preparation similar to Cmpnd compound #(s) #
Compound Name Compound Structure [m/z (ES+)] 283 4-(1-(4-methyl-
3-((5-(pyridin- 3-yl)-1,3,4- oxadiazol-2- yl)amino)benzo-
yl)piperidin-4- yl)benzonitrile ##STR01071## 280 [465 (M +
H).sup.+] 284 4-(1-(3-((5- ethyl-1,3,4- oxadiazol-2- yl)amino)-4-
methylbenzoyl) piperidin-4- yl)benzonitrile ##STR01072## 280 [416
(M + H).sup.+] 285 4-(1-(3-((1H- imidazo[4,5- b]pyridin-2-
yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile
##STR01073## 281 [437 (M + H).sup.+] 286 4-(1-(3-((1H- imidazol-2-
yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile
##STR01074## 281 [386 (M + H).sup.+] 287 4-(1-(3-((5-
(dimethylamino)- 1H- imidazo[4,5- b]pyridin-2- yl)amino)-4-
methylbenzoyl) piperidin-4- yl)benzonitrile ##STR01075## 281 [480
(M + H).sup.+] 288 4-(1-(3-((5- (isobutylamino)- 1H- imidazo[4,5-
b]pyridin-2- yl)amino)-4- methylbenzoyl) piperidin-4-
yl)benzonitrile ##STR01076## 281 [508 (M + H).sup.+] 289
4-(1-(3-((5-(iso- propylamino)- 1H- imidazo[4,5- b]pyridin-2-
yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile
##STR01077## 281 [494 (M + H).sup.+] 290 5-((5-(4-(4-
cyanophenyl)pi- peridine-1- carbonyl)-2- methylphenyl)a- mino)-N-
isopropylnicotin- amide ##STR01078## 121 [482 (M + H).sup.+] 291
2-((5-(4-(4- cyanophenyl)pi- peridine-1- carbonyl)-2-
methylphenyl)a- mino)-N- cyclopropyliso- nicotinamide ##STR01079##
121 [480 (M + H).sup.+] 292 6-((5-(4-(4- cyanophenyl)pi-
peridine-1- carbonyl)-2- methylphenyl)a- mino)-N- cyclopropylni-
cotinamide ##STR01080## 121 [480 (M + H).sup.+] 293 2-((5-(4-(4-
cyanophenyl)pi- peridine-1- carbonyl)-2- methylphenyl)a- mino)-N-
ethylisonicotin- amide ##STR01081## 121 [468 (M + H).sup.+] 294
6-((5-(4-(4- cyanophenyl)pi- peridine-1- carbonyl)-2-
methylphenyl)a- mino)-N- ethylnicotin- amide ##STR01082## 121 [468
(M + H).sup.+] 295 4-(1-(4-methyl- 3-((4-(4- methylpiper- azine-1-
carbonyl)pyridin- 2- yl)amino)benzo- yl)piperidin-4-
yl)benzonitrile ##STR01083## 121 [523 (M + H).sup.+] 296
4-(1-(3-((5- ethyl-4H-1,2,4- triazol-3- yl)amino)-4- methylbenzoyl)
piperidin-4- yl)benzonitrile ##STR01084## 282 [415 (M +
H).sup.+]
[3919] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compounds 26, 43, 48, 50, 51, 64, and 80:
TABLE-US-00007 Preparation similar to Cmpnd compound #(s) #
Compound Name Compound Structure [m/z (ES+)] 297 1-(5-(4-(4-
cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2- methylphenyl)-
3-isobutylurea ##STR01085## 64 [437 (M + H).sup.+] 298 N-(5-(4-(5-
cyanopyridin-2- yl)piperidine-1- carbonyl)-2- methylphen-
yl)pyrrolidine-1- carboxamide ##STR01086## 50 and 64 [418 (M +
H).sup.+] 299 N-(5-(4-(6- cyanopyridin-3- yl)piperidine-1-
carbonyl)-2- methylphen- yl)pyrrolidine-1- carboxamide ##STR01087##
51 and 64 [418 (M + H).sup.+] 300 1-(5-(4-(6- cyanopyridin-3-
yl)piperidine-1- carbonyl)-2- methylphenyl)- 3-(2-methoxy-
ethyl)urea ##STR01088## 51 and 64 [422 (M + H).sup.+] 301
1-(5-(4-(5- cyanopyridin-2- yl)piperidine-1- carbonyl)-2-
methylphenyl)- 3-(2-methoxy- ethyl)urea ##STR01089## 50 and 64 [422
(M + H).sup.+] 302 1-(5-(4-(4- cyanophenyl)pi- peridine-1-
carbonyl)pyrid- azin-3-yl)-3-(2- methoxy- ethyl)urea ##STR01090##
64 [409 (M + H).sup.+] 303 N-(5-(4-(5- cyanopyridin-2-
yl)piperidine-1- carbonyl)-2- methylphenyl)- 6-(ethylamino)
nicotinamide ##STR01091## 50 [469 (M + H).sup.+] 304 6-(azetidin-1-
yl)-N-(5-(4-(5- cyanopyridin-2- yl)piperidine-1- carbonyl)-2-
methylphenyl) nicotinamide ##STR01092## 50 [481 (M + H).sup.+] 305
1-(5-(4-(4- cyanophenyl)pi- peridine-1- carbonyl)pyrid-
azin-3-yl)-3- isobutylurea ##STR01093## 64 [407 (M + H).sup.+] 306
1-(5-(4-(5- cyanopyridin-2- yl)piperidine-1- carbonyl)-2-
methylphenyl)- 3-isopropylurea ##STR01094## 50 and 64 [406 (M +
H).sup.+] 307 1-(5-(4-(5- cyanopyridin-2- yl)piperidine-1-
carbonyl)-2- methylphenyl)- 3-cyclobutylurea ##STR01095## 50 and 64
[418 (M + H).sup.+] 308 1-(5-(4-(5- cyanopyridin-2-
yl)piperidine-1- carbonyl)-2- methylphenyl)- 3- cyclopentylurea
##STR01096## 50 and 64 [432 (M + H).sup.+] 309 1-(5-(4-(5-
cyanopyridin-2- yl)piperidine-1- carbonyl)-2- methylphenyl)-
3-(oxetan-3- yl)urea ##STR01097## 50 and 64 [420 (M + H).sup.+] 310
1-(5-(4-(5- cyanopyridin-2- yl)piperidine-1- carbonyl)-2-
methylphenyl)- 3-(tetrahydro- 2H-pyran-4- yl)urea ##STR01098## 50
and 64 [448 (M + H).sup.+] 311 1-(5-(4-(5- cyanopyridin-2-
yl)piperidine-1- carbonyl)-2- methylphenyl)- 3-(tetrahydro-
2H-pyran-3- yl)urea ##STR01099## 50 and 64 [448 (M + H).sup.+] 312
6-(azetidin-1-yl)- N-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-
1-carbonyl)-2- methylphenyl) nicotinamide ##STR01100## 43 [498 (M +
H).sup.+] 313 1-(5-(4-(5- cyanopyridin-2- yl)piperidine-1-
carbonyl)-2- methylphenyl)- 3- (tetrahydrofuran- 3-yl)urea
##STR01101## 50 and 64 [434 (M + H).sup.+] 314 2-(azetidin-1-
yl)-N-(5-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphen- yl)pyrimidine-5- carboxamide ##STR01102## 43 [499 (M +
H).sup.+] 315 1-(5-(4-(5- cyanopyridin-2- yl)-4- fluoropiperidine-
1-carbonyl)-2- methylphenyl)- 3- (tetrahydrofuran- 3-yl)urea
##STR01103## 26 and 64 [452 (M + H).sup.+] 316 (S)-1-(5-(4-(5-
cyanopyridin-2- yl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphenyl)- 3- (tetrahydrofuran- 3-yl)urea ##STR01104## 26 and
64 [452 (M + H).sup.+] 317 1-(5-(4-(5- cyanopyridin-2- yl)-4-
fluoropiperidine- 1-carbonyl)-2- methylphenyl)- 3- (tetrahydro-2H-
pyran-4-yl)urea ##STR01105## 26 and 64 [466 (M + H).sup.+] 318
1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphenyl)- 3- (tetrahydrofuran- 3-yl)urea ##STR01106## 64 [451
(M + H).sup.+] 319 (S)-1-(5-(4-(4- cyanophenyl)-4-
fluoropiperidine- 1-carbonyl)-2- methylphenyl)- 3-
(tetrahydrofuran- 3-yl)urea ##STR01107## 64 [451 (M + H).sup.+] 320
1-(5-(4-(5- cyanopyridin-2- yl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphenyl)- 3-(oxetan-3- yl)urea ##STR01108## 26 and 64 [438 (M
+ H).sup.+] 321 1-(2-chloro-5-(4- (4-cyanophenyl)- 4-
fluoropiperidine- 1- carbonyl)phenyl)- 3- (tetrahydrofuran-
3-yl)urea ##STR01109## 26 and 64 [471 (M + H).sup.+] 322
6-(azetidin-1-yl)- N-(5-(4-(5- cyanopyridin-2- yl)-4-
fluoropiperidine- 1-carbonyl)-2- methylphenyl) nicotinamide
##STR01110## 26 and 43 [499 (M + H).sup.+] 323 N-(5-(4-(5-
cyanopyridin-2- yl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphenyl)-6- (isopropylamino) nicotinamide ##STR01111## 26 and
43 [501 (M + H).sup.+] 324 1-(5-(4-fluoro-4- (5- methoxypyridin-
2-yl)piperidine- 1-carbonyl)-2- methylphenyl)-3- (tetrahydrofuran-
3-yl)urea ##STR01112## 1, 11, and 64 [457 (M + H).sup.+] 325
1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphenyl)- 3-((1- methylpiperidin- 4-yl)methyl)urea
##STR01113## 64 [492 (M + H).sup.+] 326 6-(azetidin-1-yl)-
N-(2-methyl-5- (4-(pyridin-4- yl)piperidine-1- carbonyl)phenyl)
nicotinamide ##STR01114## 43 [492 (M + H).sup.+] 327 1-(5-(4-(4-
cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2- methylphenyl)-
3-(piperidin-4- ylmethyl)urea ##STR01115## 64 [492 (M + H).sup.+]
328 6-(azetidin-1-yl)- N-(5-(4-(4- cyanophenyl)-4-
fluoropiperidine- 1-carbonyl)-2- fluorophenyl) nicotinamide
##STR01116## 43 [502 (M + H).sup.+] 329 3-(5-(4-(4- cyanophenyl)-4-
fluoropiperidine- 1-carbonyl)-2- methylphenyl)- 1-(2-
methoxyethyl)- 1-methylurea ##STR01117## 64 [453 (M + H).sup.+] 330
6-(azetidin-1- yl)-N-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-
1-carbonyl)-2- (trifluoromethyl) phenyl)nicotin- amide ##STR01118##
43 [552 (M + H).sup.+] 331 6-(azetidin-1-yl)- N-(5-(4-(4-
cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2- methoxyphenyl)
nicotinamide ##STR01119## 43 [514 (M + H).sup.+] 332
(S)-1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphenyl)- 3-((tetrahydro- furan-2- yl)methyl)urea ##STR01120##
64 [465 (M + H).sup.+] 333 (R)-1-(2-chloro- 5-(4-(4-
cyanophenyl)-4- fluoropiperidine- 1- carbonyl)phenyl)- 3-
(tetrahydrofuran- 3-yl)urea ##STR01121## 64 [471 (M + H).sup.+] 334
N-(5-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2,4-
dimethylphenyl)- 6-(piperazin-1- yl)nicotinamide ##STR01122## 43
[541 (M + H).sup.+] 335 (R)-1-(5-(4-(4- cyanophenyl)-4-
fluoropiperidine- 1-carbonyl)-2- ethyl-4- methylphenyl)-3-
(tetrahydrofuran- 3-yl)urea ##STR01123## 64 [479 (M + H).sup.+] 336
(R)- tetrahydrofuran- 3-yl (3-(4-(4- cyanophenyl)-4-
fluoropiperidine- 1-carbonyl)-4- methylphenyl) carbamate
##STR01124## 80 [452 (M + H).sup.+] 337 1- acetylpyrrolidin- 3-yl
(3-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-4-
methylphenyl) carbamate ##STR01125## 80 [493 (M + H).sup.+] 338
(R)-1-(5-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2-
ethyl-4- methylphenyl)- 3-((tetrahydro- furan-2- yl)methyl)urea
##STR01126## 64 [493 (M + H).sup.+] 339 (S)- tetrahydrofuran- 3-yl
(5-(4-(4- cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-2-
methylphenyl) carbamate ##STR01127## 80 [452 (M + H).sup.+] 340
6-(azetidin-1-yl)- N-(5-(4-(4- cyanophenyl)-4- fluoropiperidine-
1-carbonyl)-2- ethyl-4- methylphenyl) nicotinamide ##STR01128## 43
[526 (M + H).sup.+] 341 N-(5-(4-(4- cyanophenyl)-4-
fluoropiperidine- 1-carbonyl)-4- ethyl-2- methylphenyl)-
6-((2-methoxy- ethyl)(methyl)a- mino)nicotin- amide ##STR01129## 43
and 48 [558 (M + H).sup.+] 342 N-(5-(4-(4- cyanophenyl)-4-
fluoropiperidine- 1-carbonyl)-2- ethyl-4- methylphenyl)-6-
(isopropylamino) nicotinamide ##STR01130## 43 [528 (M + H)+] 343
N-(5-(4-(5- cyanopyridin-2- yl)-4- fluoropiperidine-
1-carbonyl)-2,4- dimethylphenyl)- 6-morpholino- nicotinamide
##STR01131## 26 and 43 [543 (M + H).sup.+] 344 (R)-
tetrahydrofuran- 3-yl (5-(4-(4- cyanophenyl)-4- fluoropiperidine-
1-carbonyl)-4- ethyl-2- methylphenyl) carbamate ##STR01132## 48 and
80 [480 (M + H).sup.+] 345 (S)- tetrahydrofuran- 3-yl (5-(4-(4-
cyanophenyl)-4- fluoropiperidine- 1-carbonyl)-4- ethyl-2-
methylphenyl) carbamate ##STR01133## 48 and 80 [480 (M +
H).sup.+]
##STR01134##
Compound 346.1. 2-(1-Benzyl-4-hydroxypiperidin-4-yl)-5-bromobenzoic
Acid
[3920] To a stirred solution of 2,5-dibromobenzoic acid (27.8 g,
100 mmol, 1.00 equiv) in THF/Et.sub.2O (450/50 mL) under nitrogen
at -78.degree. C. was added dropwise n-BuLi (2.5M) (88 mL, 2.20
equiv). After 2 h at -78.degree. C., was added
1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equiv). The
resulting solution was stirred for 0.5 h at -78.degree. C. and then
warmed to room temperature, and stirred overnight. The reaction was
quenched by carefully adding 200 mL of water. The pH of the mixture
was adjusted to 2-3 with hydrogen chloride (aq., 2 M). The aqueous
phase was extracted with 3.times.500 mL of ethyl acetate and
3.times.500 mL of tetrahydrofuran. The combined organic layers were
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to yield 38.9 g (crude) of the title compound as a yellow
solid.
##STR01135##
Compound 346.2.
1'-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4'-piperidin]-3-one
[3921] Into a round-bottom flask, was placed a solution of crude
compound 346.1 (38.9 g, 100 mmol, 1.00 equiv) in tetrahydrofuran
(800 mL). To this was added sulfuric acid (8 mL) dropwise. The
resulting solution was stirred overnight at reflux in an oil bath.
The pH value of the solution was slowly adjusted to 10 with LiOH
(aq.sat.). The aqueous phase was extracted with 3.times.500 mL of
ethyl acetate and the combined organic layers were dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:8.about.1:5) as eluent to furnish 8.00 g
(22%) of the title compound as a white solid.
##STR01136##
Compound 346.3.
1'-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4'-piperidine]
[3922] To a solution of compound 346.2 (10.0 g, 26.9 mmol, 1.00
equiv) in tetrahydrofuran (150 mL) under nitrogen at -10.degree. C.
was added dropwise BH.sub.3-THF (135 mL, 5.00 equiv). The resulting
solution was stirred for 30 min at room temperature and then heated
at reflux temperature overnight. After cooling to -10.degree. C.,
hydrogen chloride (aq., 6 M, 60 mL) was added dropwise at
-10.degree. C. The resulting solution was heated to reflux for 5 h
in an oil bath. The reaction mixture was cooled and the pH of the
solution was adjusted to 10 with potassium hydroxide (aq., 1 M).
The aqueous phase was extracted with 2.times.200 mL of ethyl
acetate and the combined organic layers were washed with
2.times.300 mL of brine, dried over sodium sulfate, and
concentrated under reduced pressure to yield 15.0 g (crude) of the
tile compound as a yellow oil.
##STR01137##
Compound 346.4.
1'-Benzyl-3H-spiro[isobenzofuran-1,4'-piperidine]-5-carbonitrile
[3923] Into a three neck round-bottom flask, which was purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of compound 346.3 (12.0 g, 33.6 mmol, 1.00 equiv) in
N,N-dimethylformamide (150 mL). Zn(CN).sub.2 (4.50 g, 38.5 mmol,
1.14 equiv) and Pd(PPh.sub.3).sub.4 (4.00 g) were added to the
reaction. The resulting solution was stirred overnight at
90.degree. C. in an oil bath. The reaction mixture was cooled to
rt, then quenched with 200 mL of FeSO.sub.4 (aq. sat.) and diluted
with ethyl acetate. The resulting mixture was stirred vigorously
then filtered through celite and washed with 1 M FeSO.sub.4, water,
and ethyl acetate. The layers were separated and the aqueous phase
was extracted with 2.times.200 mL of ethyl acetate. The combined
organic layers were washed with 2.times.100 mL of sodium chloride
(aq. sat.), dried over sodium sulfate, and concentrated under
reduced pressure. The residue was purified using silica gel column
chromatography with petroleum ether/ethyl acetate (10:1.about.5:1)
as eluent to yield 9.12 g (89%) of the title compound as a yellow
oil.
##STR01138##
Compound 346.5.
3H-Spiro[isobenzofuran-1,4'-piperidine]-5-carbonitrile
[3924] To a solution of 346.4 (9.12 g, 30.0 mmol, 1.00 equiv) in
DCE (150 mL) 0.degree. C. was added dropwise 1-chloroethyl
chloroformate (8.52 g, 60.0 mmol, 2.00 equiv). After stirring at
ambient temperature for 30 min, triethylamine (9.09 g, 3.00 equiv)
was carefully added to the mixture. The resulting solution was
heated to reflux for 2 h in an oil bath, then concentrated under
reduced pressure. The residue was dissolved in 100 mL of methanol
and then heated to reflux for 1 h in an oil bath. The resulting
mixture was concentrated under reduced pressure and the residue was
taken up in water (100 mL). The pH of the mixture was adjusted to
10 with sodium hydroxide (aqueous, 1 M). The aqueous phase was
extracted with 3.times.200 mL of ethyl acetate and the combined
organic layers were washed with 2.times.100 mL of brine, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified using silica gel column chromatography
with ethyl acetate/methanol (100:0 to 3:1) as eluent to furnish
3.50 g (46%) of the title compound as a yellow solid.
##STR01139##
Compound 346.
N-(5-(5-Cyano-3H-spiro[isobenzofuran-1,4'-piperidin]-1'-ylcarbonyl)-2-met-
hylphenyl)-6-(pyrrolidin-1-yl)nicotinamide
[3925] The title compound was prepared using procedures similar to
those used for the preparation of compound 43 and using compound
346.5 was in place of compound 11.2. m/z (ES+) 522 (M+H).sup.+.
##STR01140##
Compound 347.1. tert-Butyl
4-(4-cyanophenyl)-2-oxopiperidine-1-carboxylate
[3926] Into a round-bottom flask, was placed a solution of
tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.4,
515 mg, 1.80 mmol, 1.00 equiv) in ethyl acetate (5 mL). A solution
of NaIO.sub.4 (963 mg, 4.50 mmol, 2.50 equiv) in water (5 mL) and
RuCl.sub.3 (74.7 mg, 0.36 mmol, 0.20 equiv) was carefully added.
The resulting mixture was stirred overnight at room temperature.
The solids were removed by filtration and the filtrate was washed
with 2.times.20 mL of water, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure to yield 432 mg (80%) of
the title compound as a light yellow oil.
##STR01141##
Compound 347.2. 4-(2-Oxopiperidin-4-yl)benzonitrile
[3927] Into a round-bottom flask, was placed a solution of compound
347.1 (432 mg, 1.44 mmol, 1.00 equiv) in ethyl acetate (10 mL).
Hydrogen chloride gas was bubbled through the solution and the
resulting mixture was stirred for 0.5 h at room temperature. The
solids were collected by filtration, then dissolved in 50 mL of
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure to yield 254 mg
(88%) of the title compound as a white solid.
##STR01142##
Compound 347.3.
4-(6-Methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile
[3928] Into a round-bottom flask, was placed a solution of
4-(2-oxopiperidin-4-yl)benzonitrile (347.2, 220 mg, 1.10 mmol, 1.00
equiv) in dichloromethane (10 mL). Trimethyloxonium
tetrafluoroborate (244.2 mg, 1.65 mmol, 1.50 equiv) was slowly
added and the resulting mixture was stirred for 2 h at room
temperature. The pH was carefully adjusted to 8 with sodium
bicarbonate (aq.). The organic layer was washed with 2.times.20 mL
of H.sub.2O, dried over anhydrous sodium sulfate and concentrated
under reduced pressure to yield 212 mg (90%) of the title compound
as a white solid.
##STR01143##
Compound 347.4. 3-Amino-4-methylbenzohydrazide
[3929] Into a round-bottom flask, was placed a solution of methyl
3-amino-4-methylbenzoate (6.60 g, 40.0 mmol, 1.00 equiv) in ethanol
(100 mL). Hydrazine hydrate (10.0 g, 200 mmol, 5.00 equiv) was
added to the reaction. The resulting solution was stirred for 2 h
at 100.degree. C. in an oil bath. After cooling to ambient
temperature, the mixture was concentrated under reduced pressure.
The residue was partitioned between water and ethyl acetate (20
mL). The aqueous layer was extracted with 4.times.20 mL of ethyl
acetate and the combined organic layers were dried over anhydrous
sodium sulfate, concentrated under reduced pressure, and dried
under high-vacuum to yield 4.60 g (70%) of the title compound as a
brown solid.
##STR01144##
Compound 347.5.
4-(3-(3-Amino-4-methylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]py-
ridin-7-yl)benzonitrile
[3930] To a solution of
4-(6-methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile (compound
347.3, 5.00 g, 23.36 mmol, 1.00 equiv) in 1,2-dichlorobenzene (100
mL) was added 3-amino-4-methylbenzohydrazide (compound 347.4, 4.63
g, 28.0 mmol, 1.20 equiv). The resulting solution was stirred
overnight at 150.degree. C. in an oil bath. After cooling to
ambient temperature, the resulting mixture was purified using
silica gel column chromatography with dichloromethane/methanol
(1:0.about.100:1) as eluent to furnish 2.40 g (31%) of the title
compound as a white solid.
##STR01145##
Compound 347.
N-(5-(7-(4-Cyanophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin--
3-yl)-2-methylphenyl)-6-(isopropylamino)nicotinamide
[3931] The title compound was prepared using procedures similar to
those used for the preparation of compound 43 and using compound
347.5 was in place of compound 42.2. m/z (ES+) 492 (M+H).sup.+.
##STR01146##
Compound 348.1. 2-Hydroxy-6-methyl-5-nitronicotinic Acid
[3932] To a solution of 2-hydroxy-6-methylnicotinic acid (14.0 g,
91.5 mmol, 1.00 equiv) in sulfuric acid (conc.) (140 mL) at
0.degree. C. was added dropwise a solution of HNO.sub.3 (12.0 g,
190 mmol, 2.00 equiv) in sulfuric acid (conc.) (10 mL). The
resulting mixture was then stirred for 2 h at 90.degree. C., cooled
to ambient temperature, and then quenched with 250 mL of ice water.
The resulting solids were collected by filtration and dried in an
oven under reduced pressure to yield 15.8 g (87%) of the title
compound as a yellow solid.
##STR01147##
Compound 348.2. Methyl 2-chloro-6-methyl-5-nitronicotinate
[3933] To a solution of 2-hydroxy-6-methyl-5-nitronicotinic acid
(compound 348.1, 15.0 g, 75.8 mmol, 1.00 equiv) in chlorobenzene
(150 mL) were carefully added phosphoryl trichloride (45.0 g, 296
mmol, 4.00 equiv) and N,N-dimethylformamide (1.5 mL, 0.10 equiv).
The resulting mixture was stirred for 2 h at 135.degree. C., and
then concentrated under reduced pressure. The residue was dissolved
in 20 mL of DCM. To this was added methanol (20 mL) dropwise. The
resulting solution was stirred for 3 h at 25.degree. C., and then
concentrated under reduced pressure. To the residue was carefully
added 100 mL of water and the pH of the resulting mixture was
slowly adjusted to 8 with sodium bicarbonate (aq.). The aqueous
phase was extracted with 2.times.200 mL of ethyl acetate. The
combined organic layers were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to yield 17.6 g (crude) of
the title compound as a yellow solid.
##STR01148##
Compound 348.3. Methyl 5-amino-6-methylnicotinate
[3934] A round-bottom flask, containing a solution of methyl
2-chloro-6-methyl-5-nitronicotinate (12.8 g, 55.5 mmol, 1.00 equiv)
in methanol (120 mL) was purged with nitrogen. Triethylamine (15.0
g, 149 mmol, 2.68 equiv) and palladium on carbon (1.30 g) were
added. After further purging the flask with nitrogen, the
atmosphere was changed to hydrogen and the resulting solution was
stirred for 2 days at room temperature under atmospheric pressure.
After purging the system with nitrogen, the solids were removed by
filtration and the filtrate was concentrated under reduced
pressure. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:50-1:5) as
eluent to furnish 3.50 g (38%) of the title compound as a yellow
solid.
##STR01149##
Compound 348.4. 5-Amino-6-methylnicotinic Acid
[3935] Into a round-bottom flask, was placed a solution of methyl
5-amino-6-methylnicotinate (5.00 g, 30.1 mmol, 1.00 equiv) and
sodium hydroxide (20 g) in MeOH/H.sub.2O (80/200 mL). The resulting
solution was heated at reflux overnight. After cooling to ambient
temperature, the methanol was removed under reduced pressure. The
pH of the remaining aqueous phase was adjusted to 4 with aqueous
hydrogen chloride (2 M). The resulting mixture was then
concentrated under reduced pressure to yield 5.00 g (crude) of the
title compound as a yellow solid.
##STR01150##
Compound 348.
N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylpyridin-3-yl)-6-(py-
rrolidin-1-yl)nicotinamide
[3936] The title compound was prepared using procedures similar to
those used for the preparation of compound 43 and using compounds
348.4 and 1.5 in place of 5-amino-2,4-dimethylbenzoic acid and
compound 11.2 respectively. m/z (ES+) 495 (M+H).sup.+.
##STR01151##
Compound 349.1. 2-Bromo-5-methylpyridine 1-oxide
[3937] Into a round-bottom flask, was placed a solution of
2-bromo-5-methylpyridine (10.0 g, 58.1 mmol, 1.00 equiv) in
dichloromethane (250 mL). mCPBA (15.0 g, 86.9 mmol, 1.50 equiv) was
added in several batches at room temperature. The resulting
solution was stirred overnight at 30.degree. C., then diluted with
50 mL of 2N sodium hydroxide (aq.). The pH value of the solution
was adjusted to 10 with 2N sodium hydroxide (aq.). The aqueous
phase was extracted with 3.times.100 mL of dichloromethane and the
combined organic layers were dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to yield 11.0 g (91%) of
2-bromo-5-methylpyridin-1-ium-1-olate as a yellow solid.
##STR01152##
Compound 349.2. 2-Bromo-5-methyl-4-nitropyridine 1-oxide
[3938] Into a round-bottom flask, was placed HNO.sub.3 (15 mL),
sulfuric acid (20 mL). To this was added compound 349.1 (11.0 g,
52.7 mmol, 1.00 equiv, 90%) in several batches at room temperature.
The resulting mixture was stirred overnight at 100.degree. C., then
cooled to ambient temperature and quenched with 50 mL of ice water.
The pH was slowly adjusted to 2-3 with sodium hydroxide (aq. 2 M)
and the resulting mixture was extracted with 3.times.50 mL of
dichloromethane. The combined organic layers were dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:2) as eluent
to furnish 3.00 g (23%) of the title compound as a yellow
solid.
##STR01153##
Compound 349.3. Methyl 4-amino-5-methylpicolinate
[3939] Into a 250-mL autoclave (30 atm, CAUTION: Carry out behind a
blast shield) purged and maintained with an inert atmosphere of
nitrogen, was placed a solution of 2-bromo-5-methyl-4-nitropyridine
1-oxide (compound 349.2, 3.00 g, 12.9 mmol, 1.00 equiv) in methanol
(120 mL). Triethylamine (2.60 g, 25.7 mmol, 2.00 equiv) and
Pd(dppf)Cl.sub.2 (600 mg, 0.82 mmol, 0.06 equiv) were added to the
reaction. The autoclave was purged and the mixture was then stirred
overnight under 30 atm of CO (g) at 90.degree. C. After cooling to
ambient temperature, the mixture was concentrated under reduced
pressure. The residue was purified using silica gel column
chromatography with ethyl acetate:methanol (20:1) as eluent to
furnish 1.50 g (67%) of methyl
4-amino-5-methylpyridine-2-carboxylate as a yellow solid.
##STR01154##
Compound 349.4. 4-Amino-5-methylpicolinic Acid
[3940] A solution of methyl 4-amino-5-methylpicolinate (compound
349.3, 1.50 g, 8.12 mmol, 1.00 equiv, 90%) and 5N sodium hydroxide
(aq., 15 mL) in methanol (15 mL) was stirred overnight at room
temperature, then concentrated under reduced pressure. The residue
was diluted with 20 mL of H.sub.2O and the pH was adjusted to 3-4
with 2 M aqueous hydrogen chloride. The resulting precipitate was
collected by filtration and dried to yield 0.8 g (58%) of the title
compound as a yellow solid.
##STR01155##
Compound 349.
N-(2-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-5-methylpyridin-4-yl)-6-(is-
opropylamino)nicotinamide
[3941] The title compound was prepared using procedures similar to
those used for the preparation of compound 43 and using compounds
349.4 and 1.5 in place of 5-amino-2,4-dimethylbenzoic acid and
compound 11.2 respectively. m/z (ES+) 483 (M+H).sup.+.
##STR01156##
Compound 350.1. 2-Bromo-3-methylpyridine 1-oxide
[3942] The title compound was prepared (8.00 g, 85%) using a
procedure similar to that used for the preparation of compound
349.1 and using 2-bromo-3-methylpyridine (8.60 g) in place of
2-bromo-5-methylpyridine.
##STR01157##
Compound 350.2. 6-Bromo-5-methylpicolinonitrile
[3943] To a solution of 2-bromo-3-methylpyridine 1-oxide (compound
350.1, 5.65 g, 30.1 mmol, 1.00 equiv) in acetonitrile (50 mL) were
added triethylamine (6.10 g, 60.3 mmol, 2.00 equiv) and TMSCN (8.90
g, 3.00 equiv). The resulting solution was heated to reflux and
stirred overnight in an oil bath, then cooled to ambient
temperature and concentrated under reduced pressure. The residue
was purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:5) as eluent to yield 2.00 g (34%) of
the title compound as a yellow solid.
##STR01158##
Compound 350.3. 6-Bromo-5-methylpicolinimidamide
[3944] Into a 50-mL sealed tube, was placed a solution of
6-bromo-5-methylpicolinonitrile (compound 350.2, 900 mg, 4.57 mmol,
1.00 equiv) in methanol (40 mL). NH.sub.3 (g) was bubbled through
the solution and the resulting solution was stirred overnight at
95.degree. C. in an oil bath behind a blast shield. After cooling
to ambient temperature, the mixture concentrated under reduced
pressure to yield 800 mg (82%) of the title compound as a light
brown solid.
##STR01159##
Compound 350.4. 6-Amino-5-methylpicolinamide
[3945] Into a 50-mL sealed tube, was placed a solution of
6-bromo-5-methylpicolinimidamide (compound 350.3, 800 mg, 3.74
mmol, 1.00 equiv) and CuSO.sub.4 (80 mg) in NH.sub.3.H.sub.2O (40
mL). The resulting mixture was stirred overnight at 80.degree. C.
behind a blast shield. After cooling to ambient temperature, the
mixture was then extracted with 2.times.50 mL of ethyl acetate. The
combined organic layers were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to yield 750 mg (crude) of
the title compound as a brown solid.
##STR01160##
Compound 350.5. 6-Amino-5-methylpicolinic Acid hydrochloride
[3946] Into around-bottom flask was placed a solution of
6-amino-5-methylpicolinamide (compound 350.4, 500 mg, 3.31 mmol,
1.00 equiv) in hydrogen chloride (conc., 15 mL). The resulting
solution was heated to reflux overnight in an oil bath, then
concentrated under reduced pressure to yield 600 mg (crude) of the
title compound as a light yellow solid.
##STR01161##
Compound 350.
N-(6-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-3-methylpyridin-2-yl)-6-(is-
opropylamino)nicotinamide
[3947] The title compound was prepared using procedures similar to
those used for the preparation of compound 43 and using compounds
350.5 and 1.5 in place of 5-amino-2,4-dimethylbenzoic acid and
compound 11.2 respectively. m/z (ES+) 483 (M+H).sup.+.
##STR01162##
Compound 351.1. Methyl 5-nitro-1H-pyrazole-3-carboxylate
[3948] Into a round-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was placed a solution of
5-nitro-1H-pyrazole-3-carboxylic acid (5.00 g, 31.9 mmol, 1.00
equiv) in methanol (150 mL). To this was added thionyl chloride
(5.60 g, 47.8 mmol, 1.50 equiv) dropwise at 0.degree. C. The
resulting solution was stirred for 18 h at 30.degree. C. in an oil
bath, then concentrated under reduced pressure. The residue was
purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:30-1:10) as eluent to furnish 5.00 g
(78%) of the title compound as a brown solid.
##STR01163##
Compound 351.2 and 351.3. Methyl
1-methyl-5-nitro-1H-pyrazole-3-carboxylate and methyl
1-methyl-3-nitro-1H-pyrazole-5-carboxylate
[3949] Into a round-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was placed a solution of
methyl 5-nitro-1H-pyrazole-3-carboxylate (3.00 g, 17.5 mmol, 1.00
equiv) in N,N-dimethylformamide (30 mL). Potassium carbonate (4.84
g, 35.0 mmol, 2.00 equiv) and CH.sub.3I (2.98 g, 21.0 mmol, 1.20
equiv) were added at 0.degree. C. The resulting solution was
stirred for 2 h at 40.degree. C. in an oil bath. After cooling to
ambient temperature, the solids were removed by filtration followed
by the addition of 120 mL of ice water. The mixture was extracted
with 3.times.100 mL of ethyl acetate and the combined organic
layers were dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude product was purified by re-crystallization
from ether. This resulted in 1.10 g (34%) of methyl
1-methyl-3-nitro-1H-pyrazole-5-carboxylate as a white solid. m/z
(ES+) 186 (M+H).sup.+. .sup.1H-NMR, (300 MHz, DMSO-d.sub.6, ppm):
.quadrature. 7.57 (s, 1H), 4.22 (s, 3H), 3.91 (s, 3H). The filtrate
was concentrated under vacuum and the crude product (2 g) was
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (10%
CH.sub.3CN up to 56.5% in 10 min); Detector, uv 254 nm. The
fractions containing pure compound were combined and concentrated
to yield 470 mg (15%) of methyl
1-methyl-5-nitro-1H-pyrazole-3-carboxylate as a white solid. m/z
(ES+) 186 (M+H).sup.+. .sup.1H-NMR, (300 MHz, DMSO-d.sub.6, ppm):
.quadrature..quadrature.7.64 (1H, s), 4.24 (3H, s), 3.87 (3H,
s).
##STR01164##
Compound 351.4. Methyl
5-amino-1-methyl-1H-pyrazole-3-carboxylate
[3950] To a solution of methyl
1-methyl-5-nitro-1H-pyrazole-3-carboxylate (351.2, 0.48 g, 2.60
mmol) in MeOH (15 ml) under nitrogen was added palladium on carbon
(10%, 0.25 g). The flask was further degassed with nitrogen and
filled with H.sub.2 through a balloon. The mixture was stirred at
room temperature for 1.5 hours. After purging the system with
nitrogen, the reaction mixture was filtered through a Celite cake
and concentrated to give 363 mg (90%) of a white solid. m/z (ES+)
156 (M+H).sup.+.
##STR01165##
Compound 351.5. Methyl
5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate
[3951] To a solution of methyl
5-amino-1-methyl-1H-pyrazole-3-carboxylate (compound 351.4, 0.088
g, 0.57 mmol) in THF (5 ml) was added triphosgene (0.084 g, 0.28
mmol) followed by DIEA (0.2 ml, 1.14 mmol). After the mixture was
stirred at room temperature for 2 hours, isobutyl amine (0.225 ml,
2.28 mmol) was added. The resulting mixture was stirred at room
temperature over night. The mixture was partitioned between water
and EtOAc. The EtOAc layer was washed with 1 M aqueous
NaH.sub.2PO.sub.4 solution followed by brine, dried with
Na.sub.2SO.sub.4, and concentrated to give 120 mg (83%) of a light
yellow solid. m/z (ES+) 255 (M+H).sup.+.
##STR01166##
Compound 351.6.
5-(3-Isobutylureido)-1-methyl-1H-pyrazole-3-carboxylic Acid
[3952] To a solution of methyl
5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate (compound
351.5, 0.12 g, 0.47 mmol) in MeOH (5 ml) was added 1 M LiOH in
H.sub.2O (1.42 ml, 1.42 mmol). The mixture was stirred at room
temperature for 5 hours. TLC showed the reaction was complete. The
mixture was acidified to pH 3-4 at 0.degree. C. and then was
extracted with EcOAc (2.times.50 ml). The combined organic layers
were dried with Na.sub.2SO.sub.4, filtered, and concentrated to
give 110 mg (100%) of a clear oil. m/z (ES+) 241 (M+H).sup.+.
##STR01167##
Compound 351.
1-(3-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)-3-
-isobutylurea
[3953] A solution of
5-(3-Isobutylureido)-1-methyl-1H-pyrazole-3-carboxylic acid
(compound 351.6, 0.11 g, 0.46 mmol), 4-(piperidin-4-yl)benzonitrile
HCl salt (compound 1.5, 0.097 g, 0.4 6 mmol), EDCI (0.090 g, 0.51
mmol), HOBT (0.065 g, 0.51 mmol, with 20% H.sub.2O) and DIEA (0.22
ml, 1.38 mmol) in DMF (5 ml) was stirred at room temperature
overnight. The reaction mixture was then diluted with 50 ml of
ethyl acetate and washed with 2.times.20 ml of brine. The organic
phase was dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified using prep.-TLC
and developed using neat ethyl acetate to yield 25 mg of the title
compound as an off-white solid. m/z (ES+) 409 (M+H).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.8.46 (s, 1H), 7.76 (d, 2H), 7.49
(d, 2H), 6.48 (t, 1H), 6.37 (s, 1H), 4.84 (d, 1H), 4.63 (d, 1H),
3.65 (s, 3H), 3.14 (m, 1H), 2.92 (t, 3H), 2.79 (m, 2H), 1.85 (m,
1H), 1.67 (m, 1H), 1.57 (m, 2H), 0.87 (d, 6H).
[3954] The compounds in the following table were prepared using
standard chemical manipulations, readily available starting
materials, and procedures similar to those used for the preparation
of compounds 346, 347, 348, 349, 350, and 351:
TABLE-US-00008 Preparation similar to compound Cmpnd Compound #(s)
# name Compound Structure [m/z (ES+)] 352 1-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 3- isobutylurea ##STR01168## 346 and 64 [447 (M +
H).sup.+] 353 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'-
piperidin]-1'- ylcarbonyl)-2- methylphenyl) pyrrolidine-1-
carboxamide ##STR01169## 346 and 64 [445 (M + H).sup.+] 354
1-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'- piperidin]-1'-
ylcarbonyl)-2- methylphenyl)- 3-(2- methoxyethyl) urea ##STR01170##
346 and 64 [449 (M + H).sup.+] 355 N-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 6- (isopropyl- amino) nicotinamide ##STR01171## 346
[510 (M + H).sup.+] 356 3-(5-(5-cyano- 3H- spiro[isobenzo
furan-1,4'- piperidin]-1'- ylcarbonyl)-2- methylphenyl)- 1-(2-
methoxyethyl)- 1-methylurea ##STR01172## 346 and 64 [463 (M +
H).sup.+] 357 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'-
piperidin]-1'- ylcarbonyl)-2- methylphenyl)- 6-(4- methylpiperazin-
1- yl)nicotinamide ##STR01173## 346 [551 (M + H).sup.+] 358
N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'- piperidin]-1'-
ylcarbonyl)-2- methylphenyl)- 6-(piperazin-1- yl)nicotinamide
##STR01174## 346 [537 (M + H).sup.+] 359 N-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 6-((2- methoxyethyl) (methyl)amino) nicotinamide
##STR01175## 346 [540 (M + H).sup.+] 360 N-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 6-((2- methoxyethyl) amino) nicotinamide
##STR01176## 346 [526 (M + H).sup.+] 361 N-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 6-((2- hydroxyethyl) amino) nicotinamide
##STR01177## 346 [512 (M + H).sup.+] 362 N-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 6-((2- hydroxyethyl) (methyl)amino) nicotinamide
##STR01178## 346 [526 (M + H).sup.+] 363 (S)-1-(5-(5- cyano-3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 3- ((tetrahydro- furan-2- yl)methyl) urea
##STR01179## 346 and 64 [475 (M + H).sup.+] 364 1-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylpyridin- 3-yl)-3- isobutylurea ##STR01180## 346, 348, and 64
[448 (M + H).sup.+] 365 1-(5-(5-cyano- 3H- spiro[isobenzo
furan-1,4'- piperidin-1'- ylcarbonyl)-2- methylphenyl)- 3-(1-
methylpiperidin- 4-yl)urea ##STR01181## 346 and 64 [488 (M +
H).sup.+] 366 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'-
piperidin]-1'- ylcarbonyl)-2- methylpyridin- 3-yl)-6-
(pyrrolidin-1- yl)nicotinamide ##STR01182## 346 and 348 [523 (M +
H).sup.+] 367 1-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'-
piperidin]-1'- ylcarbonyl)-2- methylpyridin- 3-yl)-3-(2-
methoxyethyl) urea ##STR01183## 346, 348, and 64 [450 (M +
H).sup.+] 368 1-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'-
piperidin]-1'- ylcarbonyl)-2- methylphenyl)- 3-((tetrahydro-
furan-3- yl)methyl)urea ##STR01184## 346 and 64 [475 (M + H).sup.+]
369 N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'- piperidin]-1,4'-
ylcarbonyl)-2- methylpyridin- 3-yl)-6- (isopropylamino)
nicotinamide ##STR01185## 346 and 348 [511 (M + H).sup.+] 370
N-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'- piperidin]-1'-
ylcarbonyl)-2- methylpyridin- 3-yl)-6- (dimethylamino) nicotinamide
##STR01186## 346 and 348 [497 (M + H).sup.+] 371 6-(azetidin-1-
yl)-N-(5-(5- cyano-3H- spiro[isobenzo furan-1,4'- piperidin]-1'-
ylcarbonyl)-2- methylpyridin- 3- yl)nicotinamide ##STR01187## 346
and 348 [509 (M + H).sup.+] 372 N-(5-(5-cyano- 3H- spiro[isobenzo
furan-1,4'- piperidin]-1'- ylcarbonyl)-2- methylpyridin-
3-yl)-6-((2- methoxyethyl) amino) nicotinamide ##STR01188## 346 and
348 [527 (M + H).sup.+] 373 N-(5-(7-(4- cyanophenyl)- 5,6,7,8-
tetrahydro- [1,2,4]triazolo[4,3- a]pyridin-3- yl)-2- methylphenyl)
pyrrolidine-1- carboxamide ##STR01189## 347 and 64 [427 (M +
H).sup.+] 374 1-(5-(7-(4- cyanophenyl)- 5,6,7,8- tetrahydro-
[1,2,4]triazolo [4,3-a] pyridin-3-yl)-2- methylphenyl)- 3-(2-
methoxyethyl) urea ##STR01190## 347 and 64 [431 (M + H).sup.+] 375
1-(5-(7-(4- cyanophenyl)- 5,6,7,8- tetrahydro- [1,2,4]triazolo
[4,3-a]pyridin-3- yl)-2- methylphenyl)- 3- isobutylurea
##STR01191## 347 and 64 [429 (M + H).sup.+] 376 1-(5-(4-(4-
cyanophenyl) piperidine-1- carbonyl)-2- methylpyridin- 3-yl)-3-
isobutylurea ##STR01192## 348 and 64 [420 (M + H).sup.+] 377
1-(5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2- methylpyridin-
3-yl)-3-(2- methoxyethyl) urea ##STR01193## 348 and 64 [422 (M +
H).sup.+] 378 N-(5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-2-
methylpyridin-3- yl)pyrrolidine- 1-carboxamide ##STR01194## 348 and
64 [418 (M + H).sup.+] 379 N-(5-(4-(4- cyanophenyl) piperidine-1-
carbonyl)-2- methylpyridin- 3-yl)-6- (isopropylamino) nicotinamide
##STR01195## 348 [483 (M + H).sup.+] 380 1-(5-(5-cyano- 3H-
spiro[isobenzo furan-1,4'- piperidin]-1'- ylcarbonyl)-2-
methylphenyl)- 3-(piperidin- 4-yl)urea ##STR01196## 348 and 64 [474
(M + H).sup.+] 381 3-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4'-
piperidin]-1'- ylcarbonyl)-2- methylphenyl)- 1-methyl-1-
((tetrahydrofuran-3- yl)methyl)urea ##STR01197## 348 and 64 [489 (M
+ H).sup.+] 382 1-(2-(4-(4- cyanophenyl) piperidine-1- carbonyl)-5-
methylpyridin- 4-yl)-3- (tetrahydrofuran- 3-yl)urea ##STR01198##
349 and 64 [434 (M + H).sup.+] 383 1-(6-(4-(4- cyanophenyl)
piperidine-1- carbonyl)-3- methylpyridin- 2-yl)-3-
(tetrahydrofuran- 3-yl)urea ##STR01199## 321 and 64 [434 (M +
H).sup.+] 384 N-(5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-1-
methyl-1H- pyrazol-3-yl)- 6- (isobutylamino) nicotinamide
##STR01200## 351 and 43 [486 (M + H).sup.+] 385 N-(5-(4-(4-
cyanophenyl) piperidine-1- carbonyl)-1- methyl-1H- pyrazol-3-yl)-
6- (isopropylamino) nicotinamide ##STR01201## 351 and 43 [472 (M +
H).sup.+] 386 N-(3-(4-(4- cyanophenyl) piperidine-1- carbonyl)-1H-
pyrazol-5-yl)- 6- (isobutylamino) nicotinamide ##STR01202## 351 and
43 [472 (M + H).sup.+] 387 N-(3-(4-(4- cyanophenyl) piperidine-1-
carbonyl)-1H pyrazol-5-yl)- 6- (isopropylamino) nicotinamide
##STR01203## 351 and 43 [458 (M + H).sup.+] 388 1-(5-(4-(4-
cyanophenyl) piperidine-1- carbonyl)-1- methyl-1H- pyrazol-3-yl)-
3-isobutylurea ##STR01204## 351 and 64 [409 (M + H).sup.+] 389
1-(5-(4-(4- cyanophenyl) piperidine-1- carbonyl)-1- methyl-1H-
pyrazol-3-yl)- 3- isopropylurea ##STR01205## 351 and 64 [395 (M +
H).sup.+] 390 1-(3-(4-(4- cyanophenyl) piperidine-1- carbonyl)-1-
methyl-1H- pyrazol-5-yl)- 3- isopropylurea ##STR01206## 351 and 64
[395 (M + H).sup.+] 391 N-(3-(4-(4- cyanophenyl) piperidine-1-
carbonyl)-1- methyl-1H- pyrazol-5-yl)- 6- (isobutylamino)
nicotinamide ##STR01207## 351 and 43 [486 (M + H).sup.+]
##STR01208##
Compound 392.1. 4-Cyclobutyl-5-formyl-2-methylbenzoic Acid
[3955] Into a three neck round-bottom flask, which was purged and
maintained with an inert atmosphere of nitrogen, was placed a
solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound
230.1, 5.00 g, 12.7 mmol, 1.00 equiv, 80%) in a solvent mixture of
tetrahydrofuran and Et.sub.2O (50/50 mL). This was followed by the
addition of butyllithium (15 mL, 2.50 equiv, 95%) dropwise with
stirring at -78.degree. C. To this was added N,N-dimethylformamide
(2.50 g, 32.5 mmol, 2.00 equiv). The resulting solution was stirred
for 1 h at -78.degree. C. and then carefully quenched by slow
addition of 50 mL of NH.sub.4Cl (aq.). The pH was adjusted to 1-2
with hydrogen chloride (6 M). The resulting solution was diluted
with 100 mL of ethyl acetate, then washed with 4.times.50 mL of
brine. The organic layer was dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue was purified using
silica gel column chromatography with ethyl acetate/petroleum ether
(1:1) as eluent to furnish 1.62 g (41%) of
4-cyclobutyl-5-formyl-2-methylbenzoic acid as a white solid.
##STR01209##
Compound 392.2.
4-(1-(4-Cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile
[3956] Into a round-bottom flask, was placed a solution of
4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 392.1, 490 mg,
1.57 mmol, 1.00 equiv, 70%) in N,N-dimethylformamide (8 mL).
Compound 1.5 (500 mg, 1.57 mmol, 1.00 equiv), EDC-HCl (860 mg, 4.26
mmol, 2.00 equiv, 95%) and 4-dimethylaminopyridine (550 mg, 4.28
mmol, 2.00 equiv, 95%) were added to the reaction mixture. The
resulting solution was stirred overnight at room temperature, and
then diluted with 30 mL of ethyl acetate. The resulting mixture was
washed with 4.times.30 mL of brine, then dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue
was purified using silica gel column chromatography with ethyl
acetate/petroleum ether (1:2) as eluent to yield 560 mg (74%) of
the title compound as a white solid.
##STR01210##
Compound 392.
4-(1-(4-Cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile
[3957] Into around-bottom flask, was placed a solution of
4-[1-[(4-cyclobutyl-5-formyl-2-methylphenyl)carbonyl]piperidin-4-yl]benzo-
nitrile (392.2, 300 mg, 0.74 mmol, 1.00 equiv, 95%) in
N,N-dimethylformamide (10 mL). 3-Bromodihydro-2H-pyran-4(3H)-one
(compound 1.10.1, 210 mg, 1.17 mmol, 1.00 equiv), ammonia (82 mg,
0.59 mmol, 3.00 equiv, 25% aq.), and NH.sub.4OAc (270 mg, 2.81
mmol, 4.50 equiv, 80%) were added and the resulting mixture was
stirred overnight at 130.degree. C. under nitrogen. After cooling
to room temperature, the mixture was diluted with 50 mL of ethyl
acetate, washed with 4.times.50 mL of brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The
residue was purified using silica gel column chromatography with
ethyl acetate as eluent. The crude product (.about.80 mg) was
further purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (26%
CH.sub.3CN up to 41% in 7 min, up to 100% in 3 min, down to 26% in
2 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield
24.6 mg (7%) of the title compound as a white solid. m/z (ES+) 481
(M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.67 (d,
J=7.8 Hz, 2H), 4.47 (d, J=8.1 Hz, 2H), 7.33 (br s, 1H), 7.26 &
7.15 (2 singlets, amide rotamers, Ar--H, 1H), .about.4.9 (1H
partially obscured by water peak), 4.68 (s, 2H), 4.06-3.88 (m, 3H),
3.73-3.58 (m, 1H), 3.33-3.18 (m, 1H), 3.07-2.92 (m, 2H), 2.83-2.73
(m, 2H), 2.44 & 2.34 (2 singlets, amide rotamers, Ar--CH.sub.3,
3H), 2.25-1.91 (m, 6H), 1.91-1.50 (m, 4H). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.64 (m, 2H), 7.34 (m, 2H), 7.13-6.93 (m, 2H),
4.99 (m, 1H), 4.75 (s, 2H), 3.98 (m, 2H), 3.73 (m, 1H), 3.53 (m,
1H), 3.31-2.83 (m, 5H), 2.41 (m, 1H), 2.37-1.61 (m, 11H), 1.44 (m,
1H).
##STR01211##
Compound 393.
4-(1-(2-Ethyl-4-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3958] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2 but compound 211.2 was used in
place of compound 2.2. m/z (ES+) 455 (M+H).sup.+.
##STR01212##
Compound 394.
4-(1-(4-Ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile
[3959] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 393 but compound 152.1 was used in place of
methyl 2-bromo-4-methylbenzoate. m/z (ES+) 455 (M+H).sup.+.
##STR01213##
Compound 395.
4-(1-(4-Ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)be-
nzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3960] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 394 but compound 11.2 HCl salt was used in
place of compound 1.5. m/z (ES+) 473 (M+H).sup.+.
##STR01214##
Compound 396.
4-(1-(2,4-Diethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl-
)-4-fluoropiperidin-4-yl)benzonitrile
[3961] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2 except compounds 204.3 and 11.2
were used in place of compounds 2.2 and 1.5 respectively. m/z (ES+)
487 (M+H).sup.+.
##STR01215##
Compound 397.
4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-d-
iethylbenzoyl)piperidin-4-yl)benzonitrile
[3962] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2 except compound 204.3 was used in
place of compound 2.2. m/z (ES+) 510 (M+H).sup.+.
##STR01216##
Compound 398.
4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-eth-
yl-2-methylbenzoyl)piperidin-4-yl)benzonitrile
[3963] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1, 2, and 394. m/z (ES+) 496
(M+H).sup.+.
##STR01217##
Compound 399.
4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-eth-
yl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3964] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1, 2, and 394, but using compound 11.2 HCl
salt in place of compound 1.5. m/z (ES+) 514 (M+H).sup.+.
##STR01218##
Compound 400.1. 3-Methyldihydro-2H-pyran-4(3H)-one
[3965] A 1-L three neck round-bottom flask was purged and
maintained with a nitrogen atmosphere and a solution of LDA (2 M
THF, 132 mL, 1.20 equiv) in tetrahydrofuran (300 mL). The mixture
was cooled to -78.degree. C., then a solution of
dihydro-2H-pyran-4(3H)-one (22.0 g, 220 mmol, 1.00 equiv) in
hexamethylphosphoramide (40 mL, 230 mmol, 1.05 equiv) was added
drop-wise followed by drop-wise addition of methyliodide (34 mL,
550 mmol, 2.5 equiv) at -78.degree. C. The resulting solution was
stirred at -78.degree. C. for 5 min, then at 25.degree. C. for 5
min. The reaction was carefully quenched with saturated aqueous
NH.sub.4Cl (80 mL) and extracted with ether (2.times.100 mL). The
combined organics was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography with PE/Et.sub.2O (5:1) as the eluent to obtain the
title compound as a yellow oil (6.00 g, 24%).
##STR01219##
Compound 400.2. 3-Bromo-5-methyldihydro-2H-pyran-4(3H)-one
[3966] A 250-mL three neck round-bottom flask was purged and
maintained with a nitrogen atmosphere. LDA (2.0 M in THF)(6 mL, 12
mmol, 1.20 equiv) and tetrahydrofuran (30 mL) were added. The
solution was cooled to -78.degree. C. and then TMSC1 (7 mL, 55
mmol) was added drop-wise and stirred at -78.degree. C. for 5 min.
A solution of 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1,
1.14 g, 9.99 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was added
drop-wise and the resulting mixture was stirred at -78.degree. C.
for 10 min. The mixture was carefully quenched with a mixture of
triethylamine (15 mL) and saturated aqueous NaHCO.sub.3 (100 mL).
The aqueous was extracted with ether (2.times.50 mL), and the
combined organics was washed with aqueous citric acid (3.times.100
mL), dried (K.sub.2CO.sub.3), filtered and concentrated in vacuo to
obtain the intermediate enol silyl ether as a colorless oil. The
enol silyl ether was dissolved in tetrahydrofuran (20 mL) and the
system was purged with nitrogen. The mixture was cooled to
0.degree. C., and then N-bromosuccinimide (1.95 g, 11.0 mmol, 1.10
equiv) was added portion-wise. The resulting mixture was stirred at
25.degree. C. for 1 h, then quenched with saturated aqueous
NaHCO.sub.3 (30 mL). The aqueous was extracted with ether
(2.times.30 mL), and the combined organics was dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography with PE/Et.sub.2O (5:1)
as the eluent to obtain the title compound as a colorless oil (1.00
g, 52%).
##STR01220##
Compound 400.3.
2-Ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl-
)benzoic Acid
[3967] Into around-bottom flask, was placed a solution of
3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2, 800 mg,
4.14 mmol, 1.6 equiv) in N,N-dimethylformamide (5 mL). Ammonium
hydroxide (25% NH.sub.3 in H.sub.2O) (530 mg, 7.8 mmol, 3.0 equiv),
NH.sub.4OAc (904 mg, 11.7 mmol, 4.50 equiv) and
2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 500 mg, 2.60
mmol, 1.00 equiv) were added to the flask. The resulting mixture
was stirred at 130.degree. C. for 2 h, then concentrated in vacuo.
The residue was purified by silica gel chromatography with
dichloromethane/methanol (70/1) as the eluent to obtain the title
compound as a white solid (30.0 mg, 2%).
##STR01221##
Compound 400.
4-(1-(2-Ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazo-
l-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3968] Into around-bottom flask, was placed a solution of
2-ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl-
)benzoic acid (compound 400.3, 30 mg, 0.10 mmol, 1.0 equiv) in
DMF/DCM (5/5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride
(compound 1.5, 50 mg, 0.22 mmol, 2.2 equiv), EDC (40 mg, 2.0 equiv)
and 4-dimethylaminopyridine (28 mg, 2.0 equiv) were added. The
resulting solution was stirred overnight at 25.degree. C., then
quenched with water (10 mL). The mixture was extracted with ethyl
acetate (3.times.5 mL), and the combined organic layers was dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography with ethyl
acetate/petroleum ether (2:1) as the eluent to obtain the title
compound as a light yellow solid (3.2 mg, 7%). m/z (ES+) 469
(M+H).sup.+.
##STR01222##
Compound 401.
4-(1-(4-Cyclopropyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-
-yl)benzoyl)piperidin-4-yl)benzonitrile
[3969] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 392 but compound 142.2 was used in place of
compound 152.3. m/z (ES+) 467 (M+H).sup.+.
##STR01223##
Compound 402.
4-(1-(4-Cyclopropyl-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2--
yl)benzoyl)piperidin-4-yl)benzonitrile
[3970] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 392 but compound 226.5 was used in place of
compound 230.1. m/z (ES+) 481 (M+H).sup.+.
##STR01224##
Compound 403. Methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-methylpheny-
l)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3971] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2 but compound 142.2 and dimethyl
dicarbonate/DIEA were used in place of compound 2.2. and acetic
anhydride respectively. m/z (ES+) 524 (M+H).sup.+.
##STR01225##
Compound 404.
4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyc-
lopropyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile
[3972] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compounds 1 and 2 but using compound 142.2 was used
in place of compound 2.2. m/z (ES+) 508 (M+H).sup.+.
##STR01226##
Compound 405.
4-(1-(4-Cyclobutyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2--
yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3973] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 392, except compound 11.2 HCl salt was used
in place of compound 1.5. m/z (ES+) 499 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.97 (m, 2H), 7.97 (m, 2H), 7.67-7.53
(m, 2H), 4.80 (s, 2H), 4.10 (m, 2H), 3.75 (m, 1H), 3.55 (m, 2H),
3.27 (m, 1H), 2.90 (m, 2H), 2.53 and 2.43 (2 singlets, amide
rotamers, ArCH.sub.3, 3H), 2.38-1.80 (m, 10H).
##STR01227##
Compound 406.1.
5-(5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2--
yl)-4-cyclobutyl-2-methylbenzoic Acid
[3974] To a solution of 4-cyclobutyl-5-formyl-2-methylbenzoic acid
(compound 392.1, 2.00 g, 9.16 mmol, 1.00 equiv) in
N,N-dimethylformamide (15 mL) were added tert-butyl
3-bromo-4-oxopiperidine-1-carboxylate (9.00 g, 16.2 mmol, 2.00
equiv), ammonium hydroxide (3.84 g, 27.4 mmol, 3.00 equiv, 25%),
and NH.sub.4OAc (3.18 g, 41.3 mmol, 4.50 equiv). The resulting
mixture was stirred overnight at 130.degree. C. under nitrogen.
After cooling to ambient temperature, the mixture was diluted with
50 mL of ethyl acetate, washed with 3.times.30 mL of brine, dried
over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified using silica gel column
chromatography with dichloromethane/methanol (20:1) as eluent to
furnish 2.00 g (27%) of the title compound as a brown solid.
##STR01228##
Compound 406.2. tert-Butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl-
)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3975] To a solution of
5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2--
yl)-4-cyclobutyl-2-methylbenzoic acid (compound 406.1, 1.00 g, 1.22
mmol, 1.00 equiv, 50%) in N,N-dimethylformamide (5 mL) were added
4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5,
270 mg, 1.21 mmol, 1.00 equiv), EDC-HCl (460 mg, 2.40 mmol, 2.00
equiv), and 4-dimethylaminopyridine (296 mg, 2.42 mmol, 2.00
equiv). The resulting mixture was stirred at 25.degree. C.
overnight. The mixture was then diluted with 30 mL of ethyl
acetate, washed with 3.times.30 mL of brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to yield
890 mg (63%) of the title compound as a brown solid.
##STR01229##
Compound 406.3.
4-(1-(4-Cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3976] A solution of tert-butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl-
)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (406.2,
600 mg, 0.620 mmol, 1.00 equiv, 60%) in dichloromethane (3 mL) and
trifluoroacetic acid (1.5 mL) was stirred for 3 h at 25.degree. C.,
then diluted with 5 mL of hydrochloric acid (3 mol/L) and 10 mL of
water. The resulting mixture was washed with 3.times.20 mL of ethyl
acetate and the pH was then adjusted to .about.9 with sodium
hydroxide (aq, 3 M). The resulting mixture was extracted with
4.times.20 mL of dichloromethane. The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
yield 140 mg (37%) of the title compound as a brown solid.
##STR01230##
Compound 406.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-
-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3977] To a solution of
4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 190 mg, 0.30
mmol, 1.00 equiv, 75%) in tetrahydrofuran (10 mL) were added
NaBH(OAc).sub.3 (252 mg, 1.13 mmol, 3.00 equiv, 95%) and HCHO (37%)
(2.2 mL, 2.00 equiv). The resulting mixture was stirred for 2 h at
40.degree. C. in an oil bath and then concentrated under reduced
pressure. The residue was diluted with dichloromethane and washed
with aqueous saturated sodium bicarbonate and brine. The organic
layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude
product (.about.80 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5
um, 19*150 mm; mobile phase, water with 0.03% NH.sub.3H.sub.2O and
CH.sub.3CN (36% CH.sub.3CN up to 48% in 8 min, up to 100% in 1 min,
down to 36% in 1.5 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 23.4 mg (16%) of the title compound as a white solid. m/z
(ES+) 494 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
7.69 (d, J=6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 7.37-7.31 (m, 1H),
7.26 & 7.15 (2 singlets, amide rotamers, Ar--H, 1H), .about.4.9
(1H partially obscured by water peak), 4.02-3.90 (m, 1H), 3.73-3.57
(m, 1H), 3.57 (s, 2H), 3.34-3.21 (m, 1H), 3.06-2.94 (m, 2H),
2.90-2.77 (m, 4H), 2.54 (s, 3H), 2.45 & 2.34 (2 singlets, amide
rotamers, ArCH.sub.3, 3H), 2.11-1.86 (m, 6H), 1.86-1.54 (m,
4H).
##STR01231##
Compound 407.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-
-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3978] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 406, except compound 11.2 HCl salt was used
in place of compound 1.5. m/z (ES+) 512 (M+H).sup.+.
##STR01232##
Compound 408.
4-(1-(4-Methyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2--
yl)benzoyl)piperidin-4-yl)benzonitrile
[3979] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 406 except 3-iodo-4-methylbenzoic acid was
used in place of compound 230.1. m/z (ES+) 440 (M+H).sup.+.
##STR01233##
Compound 409.
4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-
-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3980] To a solution of
4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 180 mg, 0.300
mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (5 mL) were added
dimethyl dicarbonate (176 mg, 1.31 mmol, 5.00 equiv) and DIEA (169
mg, 1.31 mmol, 5.00 equiv). The resulting solution was stirred
overnight at 25.degree. C. and then quenched with 20 mL of
methanol. The resulting mixture was concentrated under reduced
pressure and the crude product was purified by Prep-HPLC using the
following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire
Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and
CH.sub.3CN (28% CH.sub.3CN up to 43% in 8 min, up to 100% in 3 min,
down to 28% in 2 min); Detector, Waters 2489 254&220 nm. The
fractions containing pure compound were combined and lyophilized to
yield 29.9 mg (19%) of the title compound as a white solid. m/z
(ES+) 538 (M+H).sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.
7.70 (m, 2H), 7.50-7.35 (m, 4H), 4.90 (m, 1H), 4.70 (s, 2H), 4.00
(m, 2H), 3.80 (m, 4H), 3.60 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H),
2.85 (m, 2H), 2.50 and 2.40 (2 singlets, amide rotamers,
ArCH.sub.3, 3H), 2.16-2.00 (m, 6H), 1.86-1.64 (m, 4H).
##STR01234##
Compound 410. Methyl
2-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-met-
hylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3981] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 409, except compound 11.2 was used in place
of compound 1.5. m/z (ES+) 556 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.78 (m, 2H), 7.67 (m, 2H), 7.35-7.20 (m, 2H),
4.80 (m, 1H), 4.55 (s, 2H), 4.00 (m, 1H), 4.84 (m, 2H), 3.77 (s,
3H), 3.60 (m, 1H), 3.28 (m, 1H), 2.80 (s, 2H), 2.47 and 2.36 (2
singlets, amide rotamers, ArCH.sub.3, 3H), 2.30-1.80 (m, 9H), 1.62
(m, 1H), 1.32 (m, 1H).
##STR01235##
Compound 411. Methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylphenyl-
)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3982] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 409, except compound 226.5 was used in
place of compound 230.1. m/z (ES+) 538 (M+H).sup.+.
##STR01236##
Compound 412.
4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-
-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3983] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 406, except compound 226.5 was used in
place of compound 230.1. m/z (ES+) 494 (M+H).sup.+.
##STR01237##
Compound 413.1. 4-Cyclobutyl-3-iodobenzoic Acid
[3984] A solution of compound 168.2 (11.0 g, 34.8 mmol, 1.00 equiv)
and sodium hydroxide (4.00 g, 100 mmol, 3.00 equiv) in methanol
(.about.100 mL) was stirred at 50.degree. C. overnight. After
cooling to ambient temperature, the mixture was concentrated to
dryness. The residue was taken up in water (50 mL) equiv and washed
with ethyl acetate. The pH of the aqueous layer was adjusted to 3-4
with 6 M aqueous hydrogen chloride. The resulting precipitate was
collected by filtration and dried to yield 8.60 g (82%) of the
title compound as a white solid.
##STR01238##
Compound 413.
4-(1-(4-Cyclobutyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoy-
l)piperidin-4-yl)benzonitrile
[3985] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 392, except compound 413.1 was used as in
place of compound 230.1. m/z (ES+) 477 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.76-7.65 (m, 5H), 7.48 (m, 2H), 5.00
(m, 1H), 4.80 (s, 2H), 4.10 (m, 2H), 3.80 (m, 2H), 3.45 (m, 1H),
3.04 (m, 2H), 2.90 (m, 2H), 2.18-1.95 (m, 6H), 1.85-1.77 (m,
4H).
##STR01239##
Compound 414.
4-(1-(4-Cyclobutyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoy-
l)-4-fluoropiperidin-4-yl)benzonitrile
[3986] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 413, except compound 11.2 HCl salt was used
in place of compound 1.5. m/z (ES+) 485 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.82-7.77 (m, 3H), 7.68-7.65 (m, 4H),
4.80 (m, 3H), 4. 90 (m, 2H), 3.83-3.46 (m, 3H), 2.90 (m, 2H), 2.29
(m, 1H), 2.18-1.83 (m, 1OH).
##STR01240##
Compound 415.
4-(1-(4-Cyclobutyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2--
yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3987] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 414, except
3-methyldihydro-2H-pyran-4(3H)-one was used in place of
dihydro-2H-pyran-4(3H)-one. m/z (ES+) 499 (M+H).sup.+.
##STR01241##
Compound 416.
4-(1-(4-Cyclopropyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-
-yl)benzoyl)piperidin-4-yl)benzonitrile
[3988] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 413, except bromo(cyclopropyl)magnesium and
3-methyldihydro-2H-pyran-4(3H)-one were used in place of
bromo(cyclobutyl)magnesium and dihydro-2H-pyran-4(3H)-one
respectively. m/z (ES+) 467 (M+H).sup.+.
##STR01242##
Compound 417.
4-(1-(4-Cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3989] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 406, except compound 413.1 was used in
place of compound 230.1. m/z (ES+) 480 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.72-7.63 (m, 4H), 7.56 (s, 1H), 7.49
(m, 2H), 4.82 (m, 1H), 4.56 (s, 2H), 3.89 (m, 2H), 3.80 (m, 2H),
3.08 (m, 2H), 3.04 (s, 3H), 2.99 (m, 2H), 2.18-1.66 (m, 11H).
##STR01243##
Compound 418.
4-(1-(4-Cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[3990] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 417, except compound 11.2 HCl salt was used
in place of compound 1.5. m/z (ES+) 498 (M+H).sup.+. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.79 (m, 2H), 7.74-7.59 (m, 5H), 4.73
(br s, 1H), 4.54 (br s, 2H), 3.94 (m, 2H), 3.76 (br s, 2H), 3.61
(br s, 1H), 3.20 (br s, 2H), 3.16 (s, 3H), 2.39-1.96 (m, 10H), 1.79
(m, 1H).
##STR01244##
Compound 419. Methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dih-
ydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3991] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 409, except compound 413.1 was used in
place of compound 230.1. m/z (ES+) 524 (M+H).
##STR01245##
Compound 420. Methyl
2-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylphenyl-
)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3992] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 409, except compounds 413.1 and 11.2 were
used in place of compounds 230.1 and 1.5 respectively. m/z (ES+)
542 (M+H).
##STR01246##
Compound 421. Ethyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dih-
ydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3993] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 409, except compound 413.1 and diethyl
dicarbonate were used in place of compound 230.1 and dimethyl
dicarbonate respectively. m/z (ES+) 538 (M+H).
##STR01247##
Compound 422. Methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropylphenyl)-6,7-di-
hydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate
[3994] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 421, except bromo(cyclopropyl)magnesium and
dimethyl diethyl dicarbonate were used in place of
bromo(cyclobutyl)magnesium and diethyl dicarbonate respectively.
m/z (ES+) 510 (M+H).
##STR01248##
Compound 423.
4-(1-(2,4-Dimethyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c-
]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3995] A mixture of
4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 62 mg),
oxetan-3-one (18 al), sodium cyanotrihydroborate (18 mg), and
acetic acid (80 .mu.l) in MeOH/THF (1:1 v/v) was stirred for 16
hours. The reaction was then diluted with dichloromethane, washed
with saturated sodium bicarbonate solution followed by brine. The
organic layer was dried (MgSO.sub.4) and concentrated. The residue
was purified by preparative TLC at 8% MeOH in DCM to give 42 mg
white solid (60%). m/z (ES+) 496 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.63 (d, 2H), 7.32 (d, 2H), 7.27 and 7.20 (2
singlet, amide rotamers, 1H), 7.02 (s, 1H), 4.96 (s, 1H), 4.74 (m,
4H), 3.88-3.77 (m, 1H), 3.63 (d, 1H), 3.49 (d, 2H), 3.08 (t, 1H),
2.97-2.62 (m, 6H), 2.45 (d, 3H), 2.31 and 2.22 (2 singlets, amide
rotamers, 3H), 2.11-1.40 (m, 4H).
##STR01249##
Compound 424.
4-(1-(5-(5-Cyclopropyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)--
2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[3996] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 423. m/z (ES+) 480 (M+H).sup.+. .quadrature..sup.1H NMR
(400 MHz, Chloroform-d) .delta. 10.58, 7.61 (d, 2H), 7.33 (d, 2H),
7.23 and 7.15 (2 singlet, amide rotamers, 1H), 6.97 (s, 1H), 4.93
(s, 1H), 3.80-3.66 (m, 2H), 3.64-3.49 (m, 1H), 3.02 (m, 3H),
2.91-2.64 (m, 4H), 2.41 (d, 3H), 2.28 and 2.18 (2 singles, amide
rotamers, 3H), 2.07-1.86 (m, 2H), 1.84-1.37 (m, 2H), 0.66-0.40 (m,
4H).
##STR01250##
Compound 425.
4-(1-(2,4-Dimethyl-5-(5-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[3997] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 406 but using compound 2.9 in place of compound 406.3.
m/z (ES+) 454 (M+H).sup.+.
##STR01251##
Compound 426.
4-(1-(5-(5-Ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-di-
methylbenzoyl)piperidin-4-yl)benzonitrile
[3998] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 423. m/z (ES+) 468 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.63 (d, 2H), 7.40-7.19 (m, 3H), 7.04 (s,
1H), 4.95 (s, 1H), 3.75-3.51 (m, 3H), 3.09 (m, 1H), 2.95-2.77 (m,
6H), 2.71 (m, 2H), 2.46 (s, 3H), 2.30 and 2.21 (2 singlets, amide
rotamers, 3H), 2.12-1.89 (m, 1H), 1.85-1.43 (m, 3H), 1.22 (m,
3H).
##STR01252##
Compound 427.
4-(1-(5-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2--
yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[3999] A mixture of
4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)be-
nzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 88 mg),
1-bromo-2-fluoroethane (150 .mu.l), potassium iodide (50 mg), and
triethyl amine (140 .mu.l) in DMF (2 ml) was stirred for 48 hours.
The reaction mixture was then diluted with dichloromethane and
washed with brine. The organic layer was dried (MgSO.sub.4) and
concentrated. The residue was purified by prep. TLC using 8% MeOH
in DCM to give 51 mg of a white solid (52%). m/z (ES+) 486
(M+H).sup.+. .sup.1H NMR (400 MHz, Chloroform-d) 7.63 (d, 2H), 7.32
(d, 2H), 7.28 and 7.20 (2 singlets, amide rotamers, 1H), 7.00 (s,
1H), 4.93 (m, 1H), 4.67 (dt, J.sub.1=47.6 Hz, J.sub.2=4.9 Hz, 2H),
3.71 (d, 2H), 3.62 (d, 1H), 3.03-2.71 (m, 8H), 2.43 (d, 3H), 2.29
and 2.19 (2 singlets, amide rotamers, 3H), 2.08-1.89 (m, 2H),
1.85-1.49 (m, 2H), 3.18-3.05 (m, 1H).
##STR01253##
Compound 428.
4-(4-Fluoro-1-(5-(5-(2-fluoroethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]p-
yridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[4000] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 427 but using compound 11.2 HCl salt instead of
compound 1.5. m/z (ES+) 504 (M+H).sup.+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.70 (d, 2H), 7.50 (d, 2H), 7.28 and 7.21 (2
singlet, amide rotamers, 1H), 7.00 (s, 1H), 4.92-4.77 (m, 1H), 4.66
(dt, J.sub.1=47.7 Hz, J.sub.2=4.8 Hz, 2H), 3.68 (d, 2H), 3.58-3.35
(m, 2H), 3.33-3.11 (m, 1H), 2.95 (dt, 4H), 2.76 (d, 2H), 2.42 (s,
3H), 2.28 and 2.20 (2 singlets, amide rotamers, 3H), 2.16-1.72 (m,
4H).
##STR01254##
Compound 429.1. 1-tert-Butyl 4-ethyl
5-oxoazepane-1,4-dicarboxylate
[4001] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate
(20.0 g, 100 mmol, 1.00 equiv) in ether (60 mL) -30.degree. C. was
added dropwise a solution of BF.sub.3.Et.sub.2O (16.0 mL, 1.30
equiv) in ether (20 mL). After stirring 30 min at -30.degree. C., a
solution of ethyl 2-diazoacetate (16.0 g, 140 mmol, 1.30 equiv) in
ether (20 mL) was added dropwise to the reaction at -30.degree. C.
The resulting solution was stirred for 1 h at -30.degree. C., then
warmed to 25.degree. C. and stirred for 2 h. The reaction was then
quenched with 100 mL of 30% aqueous potassium carbonate. The
resulting mixture was extracted with 2.times.250 mL of ethyl
acetate, and the combined organic layers were washed with
2.times.50 mL of brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography with ethyl acetate/petroleum ether (1/10)
as eluent to furnish 19.0 g (66%) of the title compound as a light
yellow oil.
##STR01255##
Compound 429.2. tert-Butyl 4-oxoazepane-1-carboxylate
[4002] To a solution 1-tert-butyl 4-ethyl
5-oxoazepane-1,4-dicarboxylate (429.1, 19.0 g, 66.6 mmol, 1.00
equiv) in 1,4-dioxane (190 mL) was added dropwise sodium hydroxide
(4.00 g, 100 mmol, 1.50 equiv) in water (100 mL). The resulting
mixture was stirred at room temperature overnight. The pH was then
adjusted to 4-5 with hydrogen chloride (aq. 3 M) and the resulting
solution was extracted with 2.times.50 mL of ethyl acetate. The
combined organic layers were washed with 2.times.10 mL of brine,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The crude residue was purified by silica gel
chromatography using ethyl acetate/petroleum ether (1:3) as eluent
to furnish 11.0 g (77%) of the title compound as a yellow oil.
##STR01256##
Compound 429.3. tert-Butyl 4-bromo-5-oxoazepane-1-carboxylate
[4003] To a solution tert-butyl 4-oxoazepane-1-carboxylate (429.2,
11.0 g, 51.6 mmol, 1.00 equiv) in chloroform (220 mL) 0.degree. C.
was added dropwise solution of Br.sub.2 (12.4 g, 77.6 mmol, 1.50
equiv) in chloroform (110 mL). The resulting mixture was stirred at
room temperature overnight. The formed solids were collected by
filtration and taken up in 200 mL of dichloromethane. Et.sub.3N
(12.2 g) and (Boc).sub.2O (8.70 g, 40.3 mmol, 1.00 equiv) were
added to the mixture at 0.degree. C. The resulting solution was
stirred for 3 h at room temperature, and then concentrated under
pressure. The crude residue was purified by silica gel
chromatography using ethyl acetate/petroleum ether (1:10) as eluent
to give 4.00 g (27%) of the title compound as a yellow oil.
##STR01257##
Compound 429.4. tert-Butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-
-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate
[4004] To a solution of tert-butyl
4-bromo-5-oxoazepane-1-carboxylate (429.3, 844 mg, 2.89 mmol, 2.00
equiv) in N,N-dimethylformamide (5 mL) were added compound 16.4
(500 mg, 1.44 mmol, 1.00 equiv), NH.sub.4OH (606 mg, 4.33 mmol,
3.00 equiv, 25%), and NH.sub.4OAc (500 mg, 6.49 mmol, 4.50 equiv).
The resulting mixture was stirred overnight at 130.degree. C. under
nitrogen. After cooling to ambient temperature, 30 mL of ethyl
acetate was added. The resulting mixture was washed with 3.times.20
mL of brine, dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography with ethyl acetate as eluent to yield 343 mg (43%)
of the title compound as a brown solid.
##STR01258##
Compound 429.5.
4-(1-(5-(1,4,5,6,7,8-Hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenz-
oyl)piperidin-4-yl)benzonitrile trifluoroacetate
[4005] To a solution of compound 429.4 (550 mg, 0.990 mmol, 1.00
equiv) in DCM (3 mL) was added trifluoroacetic acid (1.3 mL). After
stirring at 25.degree. C. for 4 h, the mixture was concentrated
under reduced pressure and dried to yield 400 mg (71%) of the title
compound as a brown solid.
##STR01259##
Compound 429.
4-(1-(5-(6-Acetyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dim-
ethylbenzoyl)piperidin-4-yl)benzonitrile
[4006] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 2, except compound 429.5 was used in place
of compound 2.9. m/z (ES+) 496 (M+H).sup.+. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.65 (d, J=8.1 Hz, 2H), 7.44-7.32 (m, 4H), 4.90
(m, 1H), 3.86 (m, 2H), 3.60 (m, 1H), 3.20 (m, 2H), 3.00 (m, 6H),
2.40-2.31 (m, 6H), 2.20 (s, 3H), 2.00-1.60 (m, 5H).
##STR01260##
Compound 430. Methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-
-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate
[4007] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 409, except compound 429.5 was used in
place of compound 406.3. m/z (ES+) 496 (M+H).sup.+.
##STR01261##
Compound 431.
4-(1-(5-(6-Isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4--
dimethylbenzoyl)piperidin-4-yl)benzonitrile
[4008] To a solution of
4-(1-(5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenz-
oyl)piperidin-4-yl)benzonitrile trifluoroacetate (429.5, 80.0 mg,
0.140 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) were added
2-iodopropane (270 mg, 1.59 mmol, 9.00 equiv) and DIEA (205 mg,
1.59 mmol, 9.00 equiv). The resulting solution was stirred
overnight at 80.degree. C. in an oil bath. After cooling to ambient
temperature, the mixture was diluted with 50 mL of ethyl acetate,
washed with 3.times.20 mL of brine, dried (Na.sub.2SO.sub.4), and
concentrated. The residue was purified using silica gel column
chromatography with ethyl acetate/petroleum ether (1:10) as eluent.
The product (50 mg) was further purified by Prep-HPLC with the
following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, Xbridge
Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03%
NH.sub.3H.sub.2O and CH.sub.3CN (38.0% CH.sub.3CN up to 51.0% in 8
min, up to 100.0% in 2 min, down to 38.0% in 1 min); Detector,
Waters 2489 254&220 nm. The fractions containing pure compound
were combined and lyophilized to yield 15.0 mg (21%) of the title
compound as a white solid. m/z (ES+) 496 (M+H).sup.+. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.69 (d, J=8.0 Hz, 2H), 7.49 (m, 2H),
7.33-7.23 (m, 2H), 4.86 (m, 1H), 3.65 (m, 1H), 3.30 (m, 1H), 3.15
(m, 1H), 2.99 (m, 6H), 2.80 (m, 4H), 2.45 (s, 3H), 2.40 and 2.29 (2
singlets, amide rotamers, 3H), 2.10 (m, 1H), 1.70 (m, 3H), 1.15 (d,
J=6.8 Hz, 6H).
##STR01262##
Compound 432.
4-(1-(5-(5-Ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-di-
methylbenzoyl)piperidin-4-yl)benzonitrile
[4009] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 431 except compound 2.9 was used in place of compound
429.5. m/z (ES+) 482 (M+H).sup.+.
##STR01263##
Compound 433.
4-(1-(4-Cyclopropyl-5-(5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]py-
ridin-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile
[4010] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 431, except compound 142.2 and tert-butyl
3-bromo-4-oxopiperidine-1-carboxylate were used in place of
compound 152.3 and tert-butyl 4-ethyl
5-oxoazepane-1,4-dicarboxylate (429.2) respectively. m/z (ES+) 508
(M+H).sup.+.
##STR01264##
Compounds 434 and 435.
4-(1-(2,4-Dimethyl-5-(4,5,7,8-tetrahydro-1H-oxepino[4,5-d]imidazol-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile and
4-(1-(2,4-dimethyl-5-(4,6,7,8-tetrahydro-1H-oxepino[3,4-d]imidazol-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile
[4011] The title compounds were prepared as a separable mixture
using standard chemical manipulations and procedures similar to
those used for the preparation of compound 429, except oxepan-4-one
was used in place of compound tert-butyl 4-oxoazepane-1-carboxylate
(429.2). 434: m/z (ES+) 455 (M+H).sup.+. 435: m/z (ES+) 455
(M+H).sup.+.
##STR01265##
Compound 436.
4-(1-(5-(6-(2-Fluoroethyl)-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl-
)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[4012] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 427, except compound 429.5 was used in
place of compound 2.9. m/z (ES+) 500 (M+H).sup.+. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.64 (d, J=8.1 Hz, 2H), 7.43 (m, 2H),
7.28-7.20 (m, 2H), 4.86 (m, 1H), 4.60 (dt, J.sub.1=47.7 Hz,
J.sub.2=4.8 Hz, 2H), 3.60 (m, 1H), 3.20 (m, 1H), 3.00 (m, 8H), 2.80
(m, 4H), 2.40 (s, 3H), 2.35 and 2.24 (2 singlets, amide rotamers,
3H), 1.99 (m, 1H), 1.70 (m, 3H).
##STR01266##
Compound 437.
4-(1-(4-Cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin--
2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[4013] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 418, except compound 429.3 was used in
place of compound tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate.
m/z (ES+) 512 (M+H).sup.+.
##STR01267##
Compound 438.
4-(1-(4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5--
d]azepin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[4014] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 407, except compound 429.3 was used in
place of compound tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate.
m/z (ES+) 526 (M+H).sup.+.
##STR01268##
Compound 439.
4-(1-(4-Cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin--
2-yl)benzoyl)piperidin-4-yl)benzonitrile
[4015] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 417, except compound 429.3 was used in
place of compound tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate.
m/z (ES+) 494 (M+H).sup.+.
##STR01269##
Compound 440.
4-(1-(4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5--
d]azepin-2-yl)benzoyl)piperidin-4-yl)benzonitrile
[4016] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 406, except compound 429.3 was used in
place of compound tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate.
m/z (ES+) 508 (M+H).sup.+.
##STR01270##
Compound 441.
(R)-1-(2-Chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-eth-
ylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea
[4017] The title compound was prepared using readily available
reagents and procedures similar to those used for the preparation
of compound 67 and using compound 178.2 in place of compound 48.1.
m/z (ES+) 513 (M+H).sup.+.
##STR01271##
Compound 442.
(R)-1-(2-Chloro-4-ethyl-5-(4-fluoro-4-(4-fluorophenyl)piperidine-1-carbon-
yl)phenyl)-3-((tetrahydrofuran-2-yl)methyl)urea
[4018] The title compound was prepared using readily available
reagents and procedures similar to those used for the preparation
of compound 67 and using compound 178.2 in place of compound 48.1.
m/z (ES+) 506 (M+H).sup.+.
##STR01272##
Compound 443.1. Methyl 4-cyclobutyl-3-nitrobenzoate
[4019] To a solution of methyl 4-cyclobutylbenzoate (compound
168.1, 3.80 g, 20.0 mmol, 1.00 equiv) in acetic anhydride (12 mL)
0.degree. C. was added dropwise fuming HNO.sub.3 (5 mL, 97%). The
resulting mixture was stirred at 30.degree. C. in an oil bath.
After 2 h, 30 mL of water was carefully added and the mixture was
extracted with 2.times.30 mL of ethyl acetate. The combined organic
layers were washed with aqueous saturated NaHCO.sub.3 (note: gas
evolution), dried over anhydrous sodium sulfate, and concentrated
under reduced pressure. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether (1:25) as
eluent to furnish 3.00 g (64%) of the title compound as a light
yellow oil.
##STR01273##
Compound 443.2. Methyl 3-amino-4-cyclobutylbenzoate
[4020] A flask containing a solution of methyl
4-cyclobutyl-3-nitrobenzoate (compound 443.1, 2.50 g, 10.6 mmol,
1.00 equiv) in methanol (30 mL) was purged with nitrogen. Palladium
on carbon (10%, 60% water, 1.2 g) was added and the flask was
carefully purged further with nitrogen. The atmosphere was then
changed to hydrogen and the mixture was stirred overnight at
20.degree. C. After purging the system with nitrogen, the solids
were then removed by filtration and the filtrate was concentrated
under reduced pressure. The residue was purified using silica gel
column chromatography with ethyl acetate/petroleum ether (1:5) as
eluent to yield 1.60 g (73%) of the title compound as a white
solid.
##STR01274##
Compound 443.3. 3-Amino-4-cyclobutylbenzoic Acid
[4021] Into around-bottom flask, was placed a solution of methyl
3-amino-4-cyclobutylbenzoate (1.00 g, 4.87 mmol, 1.00 equiv) and
sodium hydroxide (compound 443.2, 800 mg, 20.0 mmol, 4.00 equiv) in
a solvent mixture of methanol and H.sub.2O (20/10 mL). The
resulting solution was stirred for 8 h at 20.degree. C. After
cooling to ambient temperature, the organic solvent was removed
under reduced pressure. The pH of the remaining aqueous layer was
adjusted to .about.4-5 with HCl (aqueous, 1 M). The resulting
precipitate was then collected by filtration and dried to furnish
500 mg (54%) of the title compound as a white solid.
##STR01275##
Compound 443.4.
4-(1-(3-Amino-4-cyclobutylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[4022] The title compound was prepared using a procedure similar to
that used for the preparation of compound 42.2, but using compound
443.3 in place of compound 42.1.
##STR01276##
Compound 443.
(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylph-
enyl)-3-(tetrahydrofuran-3-yl)urea
[4023] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 64, using compound 443.4 and
(R)-tetrahydrofuran-3-amine in place of compound 42.2 and
(R)-(tetrahydrofuran-2-yl)methanamine respectively. m/z (ES+) 491
(M+H).sup.+.
##STR01277##
Compound 444.
(S)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylph-
enyl)-3-(tetrahydrofuran-3-yl)urea
[4024] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 443, using (S)-tetrahydrofuran-3-amine in
place of (R)-tetrahydrofuran-3-amine. m/z (ES+) 491 (M+H).sup.+.
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.83-7.77 (m, 3H), 7.69
(d, J=8.4 Hz, 2H), 7.38 (d, J=8.1 Hz, 1H), 7.22 (dd, J=7.8 Hz,
J=1.5 Hz, 1H), 4.80-4.62 (m, 1H), 4.39-4.31 (m, 1H), 4.02-3.78 (m,
4H), 3.72-3.49 (m, 3H), .about.3.3 (1H partially obscured by
methanol solvent peak), 2.50-2.37 (m, 2H), 2.37-1.78 (m, 10H).
##STR01278##
Compound 445.1. Methyl
4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate
[4025] To a solution of methyl
5-acetyl-4-cyclobutyl-2-methylbenzoate (compound 238.1, 500 mg,
2.03 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) at 0.degree. C.
was added dropwise a solution of LiHMDS (680 mg, 4.06 mmol, 2.00
equiv) in tetrahydrofuran (5 mL). After 30 min of stirring at
0.degree. C., a solution of propanoyl chloride (280 mg, 3.03 mmol,
1.50 equiv) in tetrahydrofuran (5 mL) was added dropwise. The
resulting mixture was stirred for 3 h at 15.degree. C., and then
concentrated under reduced pressure. The residue was diluted with
40 mL of ethyl acetate, washed with of brine (3.times.40 mL), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure. This
resulted in 500 mg (crude) of the title compound as a brown
oil.
##STR01279##
Compound 445.2. Methyl
4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoate
[4026] To a solution of methyl
4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate (compound 445.1,
300 mg, 0.990 mmol, 1.00 equiv) in methanol (15 mL) was added
NH.sub.2NH.sub.2.H.sub.2O. The resulting solution was stirred for
1.5 h at 80.degree. C. in an oil bath, and then concentrated under
reduced pressure. The residue was diluted with 100 mL of ethyl
acetate, then washed with 3.times.100 mL of brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified using silica gel column chromatography
with ethyl acetate/petroleum ether (1:5) as eluent to yield 188 mg
(64%) of the title compound as a yellow oil.
##STR01280##
Compound 445.3.
4-Cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic Acid
[4027] To a solution of methyl
4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoate (compound
445.2, 188 mg, 0.630 mmol, 1.00 equiv) in methanol (6 mL) was added
aqueous sodium hydroxide (76.0 mg, 1.90 mmol, 3.00 equiv in 3 mL
water). The resulting solution was stirred for 2 h at 70.degree. C.
in an oil bath. After cooling to ambient temperature, the mixture
was concentrated under reduced pressure. The residue was diluted
with 20 mL of H.sub.2O. The pH of the mixture was adjusted to
.about.4 with aqueous HCl (2 M). The mixture was then extracted
with 3.times.20 mL of ethyl acetate. The combined organic layers
were washed with 3.times.20 mL of brine, dried (Na.sub.2SO.sub.4),
and concentrated under reduced pressure. This resulted in 0.180 g
(crude) of the title compound as a yellow oil.
##STR01281##
Compound 445.
4-(1-(4-Cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoyl)piperidin--
4-yl)benzonitrile
[4028] To a solution of
4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic acid
(compound 445.3, 130 mg, 0.460 mmol, 1.00 equiv) in
N,N-dimethylformamide (5 mL) were added
4-(Piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg, 0.460
mmol, 1.00 equiv), EDCI (176 mg, 0.920 mmol, 2.00 equiv), and
4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equiv). The
resulting solution was stirred for 2 h at 30.degree. C., and then
diluted with 40 mL of ethyl acetate. The mixture was washed with
3.times.40 mL of brine, dried (Na.sub.2SO.sub.4), and concentrated
under reduced pressure. The crude product was purified by Prep-HPLC
with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,
SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%
TFA and CH.sub.3CN (59.0% CH.sub.3CN up to 73.0% in 6 min, up to
100.0% in 7 min, down to 59.0% in 1 min); Detector, Waters 2489
254&220 nm. The fractions containing pure compound were
combined and lyophilized to yield 150 mg (72%) of the title
compound as a white solid. m/z (ES+) 453 (M+H).sup.+.
##STR01282##
Compound 446.1 Methyl
4-cyclobutyl-2-methyl-5-((trimethylsilyl)ethynyl)benzoate
[4029] A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate
(compound 152.3, 1.32 g, 4 mmol), trimethylsilylacetylene (663
.mu.l, 4.8 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (85 mg, 0.12 mmol)
and copper iodide (CuI, 46 mg, 0.24 mmol) in THF (8 ml) and
triethylamine (2 ml) was degassed and then heated to 80.degree. C.
for 1.5 hours under nitrogen. After cooling to ambient temperature,
the reaction was filtered through celite and concentrated. The
residue was dissolved in ethyl acetate (EtOAc), washed with brine,
dried over MgSO.sub.4 and concentrated. The residue was purified by
flash chromatography (SiO.sub.2; 3% EtOAc in Hexane) to give 1.17 g
(97%) of the title compound as a liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.01 (s, 1H), 7.15 (s, 1H), 4.01-3.75 (m, 4H),
2.63 (s, 3H), 2.54-2.31 (m, 2H), 2.27-2.12 (m, 2H), 2.12-1.98 (m,
1H), 1.94-1.80 (m, 1H), 0.28 (s, 9H).
##STR01283##
Compound 446.2. Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate
[4030] To a solution of compound 446.1 (1.17 g, 3.9 mmol) in THF (6
ml) at -20.degree. C. was added 4.1 ml TBAF (1.0 M in THF). The
mixture was stirred for 30 minutes at this temperature and was then
diluted with water (15 ml) and extracted with EtOAc twice. The
combined organic phases were washed with brine, dried (MgSO.sub.4),
and concentrated. The residue was purified by flash chromatography
(SiO.sub.2; 2% EtOAc in Hexane) to give 816 mg (91%) of the title
compound as a liquid. m/z (ES-) 227 (M-H).sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.05 (s, 1H), 7.20 (s, 1H), 4.02-3.80 (m,
4H), 3.25 (s, 1H), 2.64 (s, 3H), 2.52-2.38 (m, 2H), 2.29-2.13 (m,
2H), 2.12-1.98 (m, 1H), 1.93-1.79 (m, 1H).
##STR01284##
Compound 446.3. Methyl
4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl) benzoate
[4031] Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate (compound
446.2, 180 mg, 0.69 mmol) was dissolved in TMSN.sub.3 (1 ml) in
sealed tube. The reaction was heated to 170.degree. C. for 24 hours
behind a blast shield then cooled down to 0.degree. C. EtOAc (10
ml) and water (20 ml) were added. The resulting mixture was stirred
at RT for 1 hr. The organic phase was then washed with brine, dried
(MgSO.sub.4), and concentrated. The residue was purified by flash
chromatography (SiO.sub.2; 0-30% EtOAc in Hexane) to give 92 mg
(49%) of the title compound as a liquid. m/z (ES+) (272)
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04 (s,
1H), 7.83 (s, 1H), 7.35 (s, 1H), 3.90 (s, 4H), 2.69 (s, 3H),
2.27-2.15 (m, 2H), 2.13-2.03 (m, 2H), 1.99-1.90 (m, 1H), 1.86-1.76
(m, 1H).
##STR01285##
Compound 446.4. 4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)
benzoic Acid
[4032] A solution of methyl
4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate (compound
446.3, 92 mg, 0.34 M) in 2N NaOH (1.5 ml) and methanol (MeOH) (4
ml) was heated at 50.degree. C. for 16 hours. After cooling to room
temperature, the methanol was removed under reduced pressure. The
residue was neutralized with 2N HCl to pH 3-4 and extracted with
EtOAc. The organic phase was then washed with brine, dried
(MgSO.sub.4), and concentrated to yield 83 mg of a white solid that
was used without further purification. m/z (ES-) 256
(M-H).sup.+.
##STR01286##
Compound 446. 4-(1-(4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)
benzoyl) piperidin-4-yl) benzonitrile
[4033] A mixture of the above acid (compound 446.4, 44 mg, 0.17
mmol), compound 1.5 (42 mg, 0.19 M), EDCI (49 mg, 0.26 mmol), HOBt
(33 mg, 0.19 mmol) and DIEA (120 01, 0.68 mmol) in DMF (1 ml) was
stirred at room temperature for 2.5 hours. The reaction was then
diluted with water and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO.sub.4, and concentrated. The
residue was purified by flash chromatography (SiO.sub.2; 8%
Methanol in dichloromethane) and to yield 46 mg foam of the title
compound (70%). m/z (ES+) 426 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 12.20 (s, 1H), 7.70 (d, 1H), 7.66-7.49 (m, 2H),
7.44-7.21 (m, 4H), 5.01 (d, 1H), 3.83 (p, 1H), 3.72 (d, 1H),
3.27-3.06 (m, 1H), 2.91 (m, 2H), 2.46 (2 singlets, amide rotamers,
3H), 2.27-1.89 (m, 3H), 1.86-1.43 (m, 7H).
##STR01287##
Compound 447. 4-(1-(4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)
benzoyl)-4-fluoropiperidin-4-yl) benzonitrile
[4034] The title compound was prepared using procedures similar to
those used for preparation of compound 446 and using compound 11.2
HCl salt in place of compound 1.5. m/z (ES+) (444) (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.00 (s, 1H), 7.77 (s,
1H), 7.67 (m, 2H), 7.49 (d, 2H), 7.37 (m, 2H), 4.92 (d, 1H), 3.85
(t, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 3.25 (m, 1H), 2.45 (2
singlets, amide rotamers, 3H), 2.28-1.89 (m, 8H), 1.85 (m, 2H).
##STR01288##
Compound 448.1. Methyl
5-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoate
[4035] To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate
(compound 130.1, 500 mg, 2.24 mmol, 1.00 equiv) in ethanol (5 mL)
was added sodium bicarbonate (396 mg, 4.71 mmol, 1.00 equiv) and
3-bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 186 mg, 1.04
mmol, 1.00 equiv). The resulting solution was stirred overnight at
80.degree. C. under nitrogen. After cooling to room temperature the
mixture was concentrated under reduced pressure. The residue was
taken up 10 mL of water and ethyl acetate. The aqueous phase was
extracted with 2.times.20 mL of ethyl acetate and the combined
organic layers were dried (MgSO.sub.4), and concentrated under
reduced pressure to yield 400 mg (56%) of the title compound as a
yellow solid.
##STR01289##
Compound 448.2.
5-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoic
Acid
[4036] A solution of compound 448.1 (304 mg, 1.00 mmol) and sodium
hydroxide (aqueous, 280 mg, 7.00 mmol in 3 mL water) in methanol (5
mL) was stirred for 1 h at 56.degree. C. in an oil bath. After
cooling to ambient temperature, the methanol was removed under
reduced pressure. The pH of the remaining aqueous layer was
adjusted to 3-4 with hydrogen chloride (aq., 2 M). The resulting
precipitate was collected by filtration and dried in an oven under
reduced pressure to yield 230 mg (79%) of the title compound as a
yellow solid.
##STR01290##
Compound 448.
4-(1-(5-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoyl)pi-
peridin-4-yl)benzonitrile
[4037] A solution of compound 448.2 (100 mg, 0.35 mmol, 1.00 equiv)
in N,N-dimethylformamide (3 mL), DIEA (140 mg, 1.08 mmol, 3.00
equiv), and HBTU (197 mg, 0.52 mmol, 1.50 equiv) was stirred for
0.5 h at 25.degree. C. A solution of 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 92.2 mg, 0.41 mmol, 1.10 equiv) in
DIEA (1 mL) was added dropwise. The resulting solution was stirred
for 0.5 h at 25.degree. C., then quenched with 10 mL of water. The
aqueous phase was extracted with 2.times.20 mL of ethyl acetate and
the combined organic layers were washed with 1.times.20 mL of
water, 1.times.20 mL of brine, dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified
using silica gel column chromatography with ethyl acetate/petroleum
ether (1:1) as eluent. The product was further purified by
Prep-HPLC using the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (25%
CH.sub.3CN up to 80% in 7 min, up to 100% in 1 min, down to 25% in
1 min); Detector, Waters 2489 254&220 nm. The fractions
containing pure compound were combined and lyophilized to yield
134.9 mg (85%) of the title compound as a white solid. m/z (ES+)
458 (M+H).sup.+.
##STR01291##
Compound 449.1 and Compound 400.1.
3,3-Dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) and
3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1)
[4038] To a solution of LDA (2.0 M in heptanes/THF/ethylbenzene)
(28 mL, 55 mmol) was added dihydro-2H-pyran-4(3H)-one (4.612 g, 46
mmol) in THF (50 mL) drop-wise under argon at -78.degree. C. The
mixture was stirred at -78.degree. C. for 5 minutes, then
iodomethane (14 mL, 225 mmol) in THF (500 ml) was added. The
resulting mixture was allowed to warm to 0.degree. C. and stirred
for 2 hours at 0.degree. C. The reaction was allowed to warm to
room temperature for 5 min, then cooled back to 0.degree. C. and
quenched with saturated ammonium chloride (30 mL) and the mixture
was extracted with ether (2.times.50 mL). The combined organics was
washed with brine (50 mL), dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography (15% ethyl acetate in hexanes) to yield
3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) as an oil
(694 mg, 13%) and 3-methyldihydro-2H-pyran-4(3H)-one (compound
400.1) as an oil (860 mg, 16%).
##STR01292##
Compound 449.2. 5-Bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one
[4039] A solution of lithium diisopropylamine (2.0 M in
heptanes/THF/ethylbenzene) (2.5 ml, 5.1 mmol) diluted with THF (10
mL) under argon was cooled to -78.degree. C. Chlorotrimethylsilane
(2.5 mL, 19.5 mmol) was added followed by
3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1, 500 mg, 3.9
mmol) in THF (5 mL) and triethylamine (8.0 mL, 57 mmol). The
resulting mixture was stirred at -78.degree. C. for 5 minutes and
then quenched with saturated NaHCO.sub.3 (20 mL). The mixture was
extracted with ether (30 mL) and the organics was washed with 1M
citric acid (50 mL), dried (K.sub.2CO.sub.3), filtered and
concentrated in vacuo. The residue was dissolved in THF (5 mL) and
cooled to 0.degree. C. N-Bromosuccinimide (694 mg, 3.9 mmol) was
added and the resulting mixture was stirred at room temperature for
2 hrs and then quenched with saturated NaHCO.sub.3 (10 mL). The
mixture was extracted with ether (2.times.20 mL) and the organics
was washed with brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography (8% ethyl acetate in hexane) to yield the title
compound as an oil (150 mg, 18%).
##STR01293##
Compound 449.3. Methyl
5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethy-
lbenzoate
[4040] A mixture of 5-bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one
(compound 449.2, 150 mg, 0.72 mmol), methyl
5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5,
135 mg, 0.55 mmol), and potassium carbonate (228 mg, 1.65 mmol) in
acetonitrile (8 mL) was heated at 100.degree. C. for 48 hrs. The
mixture was concentrated in vacuo and the residue was dissolved in
ethyl acetate (10 mL) and washed with brine (20 mL), dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by silica gel chromatography (50% ethyl acetate in
hexanes) to yield the title compound as a white solid (27 mg,
15%).
##STR01294##
Compound 449.4.
5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethy-
lbenzoic Acid
[4041] To methyl
5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethy-
lbenzoate (compound 449.3, 27 mg, 0.086 mmol) in THF (3 mL) was
added 2 M lithium hydroxide (430 .mu.l, 0.86 mmol) and the mixture
was heated at 50.degree. C. for 16 hrs. The volatile solvents were
removed in vacuo and the resulting residue was neutralized with 2M
HCl to pH=3 and concentrated in vacuo to give a white solid and
used in the next reaction without doing further purification. m/z
(ES-) 299 (M-H).sup.-.
##STR01295##
Compound 449.
4-(1-(5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-d-
imethylbenzoyl)piperidin-4-yl)benzonitrile
[4042] Crude
5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethy-
lbenzoic acid (compound 449.4, 0.086 mmol) was dissolved in DMF (1
mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 19
mg, 0.086 mmol),
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate(V) (HBTU) (65 mg, 0.17 mmol) and DIEA (45
.mu.l, 0.26 mmol) were added and the mixture was stirred at room
temperature for 16 hrs. The mixture was then diluted with ethyl
acetate (10 mL) and washed with brine (10 mL), dried (MgSO.sub.4),
filtered and concentrated in vacuo. The residue was purified by
silica gel chromatography (ethyl acetate) to obtain the title
compound as a solid foam (15 mg, 30%). m/z (ES+) 469
(M+H).sup.+.
##STR01296##
Compound 450.
4-(1-(2,4-Dimethyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2--
yl)benzoyl)piperidin-4-yl)benzonitrile
[4043] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for preparation
of compound 449, except 3-methyldihydro-2H-pyran-4(3H)-one
(compound 400.1) was used in place of
3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z (ES+)
455 (M+H).sup.+.
##STR01297##
Compound 451.1 and compound 451.2. tert-Butyl
3-methyl-4-oxopiperidine-1-carboxylate and tert-butyl
3,3-dimethyl-4-oxopiperidine-1-carboxylate
[4044] Sodium hydride (60% in mineral oil)(1.27 g, 31.8 mmoL), was
suspended in THF (80 mL) under an atmosphere of nitrogen.
tert-Butyl 4-oxopiperidine-1-carboxylate (6.0 g, 30 mmol) was added
portion-wise at room temperature. The mixture was stirred at room
temperature for 1.5 hours and then methyl iodide (3.8 mL, 6.1 mmol)
was added. The mixture was stirred at room temperature overnight
and then cooled to 0.degree. C. and carefully quenched with water
(20 mL). The mixture was extracted with ethyl acetate (100 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
crude product was purified by silica gel chromatography (10:1
hexane/ethyl acetate) to obtain compound 451.1 as a clear oil (1.7
g, 27%) and compound 451.2 as a crystalline solid (963 mg,
14%).
##STR01298##
Compound 451.3. tert-Butyl
5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate
[4045] tert-Butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (0.963
g, 4.24 mmol) as dissolved in THF (10 mL) and then
phenyltrimethylammonium tribromide (PTAT) (1.59 g, 4.24 mmol) was
added. The mixture was stirred at room temperature for 2 hours then
water (20 mL) was added and mixture was extracted with ethyl
acetate (100 mL). The organics was dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The crude product was purified
by silica gel chromatography (10:1 hexane/ethyl acetate) to obtain
compound 451.3 as a white crystalline solid (0.94 g, 73%).
##STR01299##
Compound 451.
4-(4-(5-(5-Acetyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)-2,4-dimethylbenzoyl)cyclohexyl)benzonitrile
[4046] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 2, except tert-butyl
5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate (compound 451.3)
was used in place of tert-butyl
3-bromo-4-oxopiperidine-1-carboxylate. m/z (ES+) 510
(M+H).sup.+.
##STR01300##
Compound 452.
4-(1-(5-(5-Isopropyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyr-
idin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[4047]
4-(1-(5-(7,7-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-
-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (0.12 g, 0.26
mmol) (intermediate prepared in the synthesis of compound 451), DMF
(4 mL), acetic acid (69 .mu.L, 1.21 mmol), sodium
triacetoxyborohydride (0.11 g, 0.52 mmol) and acetone (0.50 mL, 6.8
mmol) were mixed and stirred at room temperature for 2 hours. The
reaction was carefully quenched with water (10 mL) and the mixture
was extracted with ethyl acetate (60 mL) and the organics was dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude
product was purified by preparative TLC (DCM/10% MeOH) followed by
a second preparative TLC (ethyl acetate/5% MeOH) to obtain the
title compound as a white powder (4.1 mg, 8.1%). m/z (ES+) 510
(M+H).sup.+.
##STR01301##
Compound 454.1. Phenyl
4-methoxy-2-methylpyridine-1(2H)-carboxylate
[4048] A 3-L four neck round-bottom flask was purged and maintained
with a nitrogen atmosphere and a solution of 4-methoxypyridine
(30.0 g, 275 mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) was
added. The mixture was cooled to -40.degree. C. and phenyl
chloroformate (45.0 g, 287 mmol, 1.05 equiv) was added dropwise.
The resulting solution was stirred for 1 h at -40.degree. C., then
methylmagnesium bromide (3M, 110 mL, 1.20 equiv) was added to the
reaction mixture while maintaining the temperature at -40.degree.
C. The resulting solution was warmed slowly to 5-10.degree. C. and
stirred for 2 h, then carefully quenched with ice water (100 mL).
The resulting mixture was extracted with ethyl acetate (2.times.1
L) and the combined organics was washed with brine (1.times.300
mL), dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo
to yield the title compound as a light brown oil (71.0 g,
>theoretical).
##STR01302##
Compound 454.2. tert-Butyl
2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate
[4049] A 3-L four neck round-bottom flask was purged and maintained
with a nitrogen atmosphere and a solution of phenyl
4-methoxy-2-methylpyridine-1 (2H)-carboxylate (454.1, 70. 0 g, 285
mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) was added. The
solution was cooled to -78.degree. C. then potassium tert-butoxide
(128 g, 1.14 mol, 4.00 equiv) was added portion-wise. The resulting
mixture was stirred at 10-15.degree. C. for 20 h then concentrated
in vacuo. The residue was dissolved in EtOAc (1.5 L), then
carefully quenched with ice water (200 mL). The layers were
separated and the aqueous was extracted with additional ethyl
acetate (100 mL). The combined organics was washed with aqueous
sodium hydroxide (1.5 M, 3.times.100 mL), aqueous hydrochloric acid
(1 M, 2.times.100 mL), and brine (200 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography (ethyl acetate/petroleum
ether, 1:200-1:20) as the eluent to obtain the title compound as a
light yellow oil (31.0 g, 51%).
##STR01303##
Compound 453.1 and compound 454.3. tert-Butyl
6-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate
(453.1) and tert-butyl
2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate
(454.3)
[4050] A 500-mL three neck round-bottom flask was purged and
maintained with a nitrogen atmosphere and a solution of tert-butyl
2-methyl-4-oxo-3,4-dihydropyridine-1 (2H)-carboxylate (compound
454.2, 10.5 g, 49.5 mmol, 1.00 equiv) in tetrahydrofuran (300 mL)
was added. The solution was cooled to -78.degree. C. and
L-Selectride (1 M in THF, 60 mL, 1.20 equiv) was added drop-wise.
The resulting solution was stirred for 2 h at -78.degree. C. then
chlorotrimethylsilane (6.96 g, 64.1 mmol, 1.30 equiv) was added
drop-wise with stirring. The resulting solution was stirred for 16
h at 10-15.degree. C., and then concentrated in vacuo. The residue
was diluted with n-hexane (500 mL) and the solids were filtered
away. The filtrate was concentrated in vacuo and the residue
purified by silica gel chromatography ethyl acetate/petroleum ether
(1:100-1:20) as the eluent to obtain a mixture of the title
compounds as a light yellow solid (10.0 g, 71%).
##STR01304##
Compound 453.2 and compound 454.4. tert-Butyl
5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (453.2) and
tert-butyl 3-bromo-2-methyl-4-oxopiperidine-1-carboxylate
(454.4)
[4051] Into a round-bottom flask, was placed a solution of a
mixture of tert-butyl
6-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate
and tert-butyl
2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate
(compound 453.1 and compound 454.2, 4.00 g, 12.5 mmol, 1.00 equiv,
89% combined purity) in tetrahydrofuran (250 mL). The mixture was
cooled to 0-5.degree. C. and N-bromosuccinimide (4.97 g, 27.9 mmol,
2.2 equiv) was added to the reaction mixture in portions. The
resulting mixture was stirred at 25.degree. C. for 2 h, then
concentrated in vacuo. The residue was purified by silica gel
chromatography with ethyl acetate/petroleum ether (1:100-1:10) as
the eluent to obtain a mixture of the title compounds as a yellow
oil (2.50 g, 69%).
##STR01305##
Compound 453.3 and compound 454.5.
5-(5-(tert-Butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]p-
yridin-2-yl)-2,4-dimethylbenzoic Acid (453.3) and
5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]p-
yridin-2-yl)-2,4-dimethylbenzoic Acid (454.5)
[4052] Into a 50-mL sealed tube, was placed a solution of a mixture
of tert-Butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate and
tert-butyl 3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound
453.2 and compound 454.4, 1.60 g, 5.48 mmol, 1.00 equiv) in
N,N-dimethylformamide (10 mL). 5-Formyl-2,4-dimethylbenzoic acid
(compound 16.3, 978 mg, 5.49 mmol, 1.00 equiv), ammonium acetate
(1.90 g, 24.7 mmol, 4.50 equiv), and ammonium hydroxide (2.88 g,
16.4 mmol, 3.00 equiv, 20%) were added and the resulting mixture
was stirred for 2 h at 130.degree. C. The mixture was cooled to
10-15.degree. C. then quenched with ice water (50 mL). The
resulting solution was extracted with ethyl acetate (2.times.50 mL)
and the organics were combined. The pH of the aqueous was adjusted
to 6 with hydrogen chloride (2 M) and extracted with ethyl acetate
(2.times.150 mL) and all organic extracts were combined, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography with ethyl
acetate/petroleum ether (1:4-2:1) as the eluent to obtain a mixture
of the title compounds as a light yellow oil (480 mg, 23%).
##STR01306##
Compound 453.4 and compound 454.6. tert-Butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (Compound
453.4) and tert-butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (Compound
454.6)
[4053] Into around-bottom flask, was placed a solution of a mixture
of
5-(5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]p-
yridin-2-yl)-2,4-dimethylbenzoic acid and
5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]p-
yridin-2-yl)-2,4-dimethylbenzoic acid (compound 453.3 and compound
454.5, 480 mg, 1.25 mmol, 1.00 equiv) in N,N-dimethylformamide (10
mL). DIEA (643 mg, 4.98 mmol, 4.00 equiv), EDC (476 mg, 2.48 mmol,
2.00 equiv), and 1-hydroxybenzotrizole (337 mg, 2.50 mmol, 2.00
equiv) were added and the resulting solution was stirred at
25.degree. C. for 20 min. 4-(Piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 276 mg, 1.24 mmol, 1.00 equiv) was
then added in portions at 0.degree. C. The resulting solution was
stirred at 25.degree. C. for 16 h, and then quenched with of ice
water (40 mL). The resulting solids were collected by filtration,
and then dissolved in ethyl acetate (100 mL). The resulting
organics was washed with brine (2.times.30 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to obtain a
mixture of the title compounds as a light yellow oil (440 mg,
64%).
##STR01307##
Compound 453.5 and compound 454.7.
4-(1-(2,4-Dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate
(Compound 453.5) and
4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate
(Compound 454.7)
[4054] Into around-bottom flask, was placed a solution of a mixture
of tert-butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate and
tert-butyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound
453.4 and compound 454.6, 440 mg, 0.790 mmol, 1.00 equiv) in
dichloromethane (10 mL) and trifluoroacetic acid (3 mL). The
resulting solution was stirred at 25.degree. C. for 20 h, then
concentrated in vacuo to obtain a mixture of the title compounds as
a yellow oil (450 mg, 99%).
##STR01308##
Compounds 453 and 454. Methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (Compound
453) and methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (Compound
454)
[4055] Into an 8-mL sealed tube, was placed a mixture of
4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate
and
4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile 2,2,2-trifluoroacetate
(compound 453.5 and compound 454.7, 100 mg, 0.176 mmol, 1.00 equiv)
in dichloromethane (6 mL). DIEA (114 mg, 0.880 mmol, 5.00 equiv)
was added and the mixture was cooled to 0.degree. C. Dimethyl
dicarbonate (29.6 mg, 0.220 mmol, 1.25 equiv) was added drop-wise
with stirring at 0.degree. C., and then the resulting solution was
stirred for 2.5 h at 0-5.degree. C. The resulting mixture was
concentrated in vacuo and the residue was purified by prep-HPLC
(1#-Pre-HPLC-001 (SHIMADZU)): Column, Xbridge Prep C18, 5 um,
19*150 mm; mobile phase, water with 0.03% NH.sub.3H.sub.2O and
CH.sub.3CN (39.0% CH.sub.3CN up to 52.0% in 7 min, up to 100.0% in
1 min, down to 39.0% in 1 min); Detector, Waters 2489 254 & 220
nm. The title compounds were obtained from the prep-HPLC as a
mixture of isomers (30 mg). The isomeric mixture was purified by
chiral-prep-HPLC (2#-Gilson Gx 281(HPLC-09)): Column, Chiralpak IA,
2*25 cm, 5 um; mobile phase, Hex (0.1% DEA) and ethanol (0.2% TEA)
(hold 50.0% ethanol (0.2% TEA) in 10 min); Detector, UV 220/254 nm.
The chiral-prep-HPLC fractions containing pure, separated products
were appropriately combined and lyophilized to obtain methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound
453) as a white solid (14.2 mg, 13%) and methyl
2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methy-
l-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound
454) as white solid (11.8 mg, 10%). Compound 453: m/z (ES+) 512
(M+H).sup.+. Compound 454: m/z (ES+) 512 (M+H).sup.+.
##STR01309##
Compounds 455 & 456.
4-(1-(5-(5,6-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2-
,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (Compound 455) and
4-(1-(5-(4,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2-
,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (Compound 456)
[4056] Into a 10-mL sealed tube, was placed a solution of a mixture
of
4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile trifluoroacetate and
4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridi-
n-2-yl)benzoyl)piperidin-4-yl)benzonitrile trifluoroacetate
(compound 453.5 and compound 454.7, (100 mg, 0.22 mmol, 1.00 equiv)
in tetrahydrofuran (5 mL). Formaldehyde (1 mL, 37 wt %) and sodium
triacetoxyborohydride (162 mg, 0.760 mmol, 3.5 equiv) were added to
the mixture and stirred for 2.5 h at 40.degree. C. The mixture was
concentrated in vacuo and the residue was purified by Prep-HPLC
with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,
Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03%
NH.sub.3H.sub.2O and CH.sub.3CN (32% CH.sub.3CN up to 42% in 8 min,
up to 100% in 2 min, down to 32% in 1 min); Detector, Waters 2489
254 nm & 220 nm. The title compounds were obtained from the
prep-HPLC as a mixture of isomers (50 mg). The isomeric mixture was
purified by chiral-prep-HPLC with the following conditions
(2#-Gilson Gx 281(HPLC-09)): Column, Chiralpak IC, 2*25 cm, 5 um;
mobile phase, Hex (0.2% TEA) and ethanol (0.2% TEA) (hold 50.0%
ethanol (0.2% TEA) in 27 min); Detector, UV 220/254 nm. The
chiral-prep-HPLC fractions containing pure, separated products were
appropriately combined and lyophilized to obtain
4-(1-(5-(5,6-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2-
,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 455) as a
white solid (13.5 mg, 13%) and
4-(1-(5-(4,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2-
,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 456) as a
white solid (6.8 mg, 7%). Compound 455: m/z (ES+) 468 (M+H).sup.+.
Compound 456: m/z (ES+) 468 (M+H).sup.+.
##STR01310##
Compound 457.1 and compound 457.2. tert-Butyl
3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (Compound 457.1) and
tert-butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (Compound
457.2)
[4057] Into a 1-L four neck round-bottom flask, which was purged
and maintained with an inert atmosphere of nitrogen, was placed a
solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (5.00
g, 23.4 mmol, 1.00 equiv) in ether (700 mL). Ammonium acetate (904
mg, 11.7 mmol, 0.50 equiv) and azobisisobutyronitrile (AIBN) (192
mg, 1.17 mmol, 0.05 equiv) were added. The mixture was cooled to
0.degree. C., then N-bromosuccinimide (4.15 g, 23.5 mmol, 1.00
equiv) was added in portions. The resulting mixture was stirred for
4 h at 25.degree. C., then concentrated in vacuo. The residue was
purified by silica gel chromatography with ethyl acetate/petroleum
ether (1:100-1:10) as the eluent to obtain a mixture of the title
compounds as a light yellow oil (4.10 g, 60%).
##STR01311##
Compound 457.
4-(1-(5-(5-Acetyl-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2--
yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[4058] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 400 and compound 2, except a mixture of
tert-butyl 3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound
457.1) and tert-butyl
5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound 457.2) was
used in place of 3-bromo-5-methyldihydro-2H-pyran-4(3H)-one
(compound 400.2). The product contains about 10% of the other
methyl regioisomer
4-(1-(5-(5-acetyl-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2--
yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile. m/z (ES+) 496
(M+H).sup.+.
##STR01312##
Compound 458.
4-(1-(5-(5'-Acetyl-3',4',5',6'-tetrahydrospiro[cyclopropane-1,7'-imidazo[-
4,5-c]pyridin]-2'-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile
[4059] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 449 and compound 2, except tert-butyl
8-oxo-5-azaspiro[2.5]octane-5-carboxylate (Remen, L. et al. Bioorg.
andMed. Chem. Lett., 2009, 32, 351-357) was used in place of
3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z (ES+)
508 (M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.71
(d, J=8.1 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.37-7.20 (m, 2H), 4.77
and 4.71 (2 singlets, acetyl amide rotamers, CH.sub.2, 2H), 3.77
and 3.72 ((2 singlets, acetyl amide rotamers, CH.sub.2, 2H),
3.71-3.67 (m, 1H), 3.30-3.18 (m, 1H), 2.99 (t, J=11.6 Hz, 2H),
2.48-2.27 (m, 6H), 2.24 and 2.21 (2 singlets, acetyl amide
rotamers, acetyl CH.sub.3, 3H), 2.10-1.95 (m, 1H), 1.92-1.52 (m,
3H), 1.18-0.96 (m, 4H).
##STR01313##
Compound 459.
4-(1-(5-(6-Methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimet-
hylbenzoyl)piperidin-4-yl)benzonitrile
[4060] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 449, except 4-methoxycyclohexanone (Kaiho,
T. et al. J. Med. Chem., 1989, 32, 351-357) was used in place of
3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z (ES+)
469 (M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.69
(d, J=8.1 Hz, 2H), 7.53-7.44 (m, 2H), 7.37-7.21 (m, 2H), one proton
estimated under methanol (1H), 3.84-3.75 (m, 1H), 3.73-3.57 (m,
1H), 3.45 (s, 3H), 3.27-3.19 (m, 1H), 3.05-2.91 (m, 3H), 2.79-2.58
(m, 3H), 2.46 (s, 3H), 2.40 and 2.29 (2 singlets, amide rotamers,
3H), 2.17-1.92 (m, 3H), 1.92-1.67 (m, 3H).
##STR01314##
Compound 460.
4-(1-(5-(6-Hydroxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimet-
hylbenzoyl)piperidin-4-yl)benzonitrile
[4061] Into around-bottom flask, was placed a solution of
4-(1-(5-(6-methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimet-
hylbenzoyl)piperidin-4-yl)benzonitrile (compound 459, 80 mg, 0.17
mmol, 1.0 equiv) in a solvent mixture of acetonitrile and
dichloromethane (10/10 mL). Tetrachlorosilane (32 mg, 0.19 mmol,
1.1 equiv) and sodium iodide (28 mg, 0.19 mmol, 1.1 equiv) were
added to the reaction and the resulting mixture was stirred
overnight at 20.degree. C. The reaction was quenched with aqueous
sodium bicarbonate (10 mL) and the aqueous was extracted with ethyl
acetate (3.times.10 mL). The combined organics was dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo and the
residue was purified by silica gel chromatography with ethyl
acetate as the eluent to obtain the title compound as a yellow
solid (7.1 mg, 9%). m/z (ES+) 455 (M+H).sup.+.
##STR01315##
Compound 461.1. 4-Methoxyhepta-1,6-diene
[4062] Into a round-bottom flask, was placed a solution of
hepta-1,6-dien-4-ol (2.00 g, 17.8 mmol, 1.00 equiv) and iodomethane
(5.00 g, 35.2 mmol, 2.00 equiv) in tetrahydrofuran (30 mL). The
solution was cooled to 0.degree. C. and sodium hydride (1.00 g,
25.0 mmol, 1.50 equiv, 60% in mineral oil) was added to the
reaction in portions. The resulting mixture was stirred overnight
at room temperature, then carefully quenched with water (5 mL) and
diluted with of ether (30 mL). The organics was washed with brine
(2.times.20 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to obtain the title compound as a colorless
oil (2.00 g, 84%).
##STR01316##
Compound 461.2. 4-Methoxycyclopent-1-ene
[4063] Into around-bottom flask, which was purged and maintained
with an inert atmosphere of nitrogen, was placed a solution of
4-methoxyhepta-1,6-diene (compound 461.1, 200 mg, 1.43 mmol, 1.00
equiv, 90%) in dichloromethane (25 mL). Grubbs II catalyst (55 mg,
0.06 mmol, 0.04 equiv) was added and the resulting solution was
stirred overnight at room temperature. The mixture was concentrated
in vacuo to obtain the title compound as a colorless oil (100 mg,
57%).
##STR01317##
Compound 461.3. 2-Bromo-4-methoxycyclopentanol
[4064] Into a round-bottom flask, was added a solution of
4-methoxycyclopent-1-ene (compound 461.2, 1.00 g, 8.66 mmol, 1.00
equiv, 85%) in dichloromethane (100 mL) and a solution of
1N-bromosuccinirmide (2.00 g, 11.3 mmol, 1.00 equiv) in water (20
mL). The reaction mixture was stirred at room temperature for 3
hours and then the resulting mixture was washed with water (20 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to
obtain the title compound as a colorless oil (1.00 g, 36%).
##STR01318##
Compound 461.4. 2-Bromo-4-methoxycyclopentanone
[4065] Into a round-bottom flask, was placed a solution of
2-Bromo-4-methoxycyclopentanol (compound 461.3, 1.00 g, 3.08 mmol,
1.00 equiv, 60%) in dichloromethane (100 mL). Dess-Martin
periodinane (2.00 g, 4.72 mmol, 1.10 equiv) was added in portions
and the mixture was stirred overnight at room temperature. The
mixture was then diluted with water (20 mL) and quenched with
Na.sub.2S.sub.2O.sub.4 (4 g). The aqueous was extracted with
dichloromethane (100 mL) and the combined organics was washed with
brine (30 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo to obtain the title compound as a brown oil (800 mg,
81%).
##STR01319##
Compound 461.5. Methyl
5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-yl-
)-2,4-dimethylbenzoate
[4066] Into around-bottom flask, was placed a solution of
2-bromo-4-methoxycyclopentanone (compound 461.4, 600 mg, 1.86 mmol,
60%) in ACN (15 mL). Methyl 5-carbamimidoyl-2,4-dimethylbenzoate
hydrochloride (compound 2.5, 320 mg) and potassium carbonate (430
mg, 3.11 mmol) were added and the mixture was stirred overnight at
80.degree. C. The mixture was concentrated in vacuo and the residue
was diluted with ethyl acetate (50 mL) and then washed with brine
(2.times.20 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography with dichloromethane/methanol (10:1) as the eluent
to obtain the title compound as a brown oil (200 mg, 27%).
##STR01320##
Compound 461.6. Methyl
5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbe-
nzoate
[4067] Into around-bottom flask, was placed a solution of methyl
5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-yl-
)-2,4-dimethylbenzoate (compound 461.5, 200 mg, 0.38 mmol, 1.00
equiv, 60%) in N,N-dimethylformamide (mL). p-Toluenesulfonic acid
(20 mg, 0.12 mmol, 0.18 equiv) was added and the resulting solution
was stirred overnight at 80.degree. C., then concentrated in vacuo.
The residue was purified by silica gel chromatography with
dichloromethane/methanol (10:1) as the eluent to obtain the title
compound as a brown oil (100 mg, 66%).
##STR01321##
Compound 461.7.
5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbe-
nzoic Acid
[4068] Into around-bottom flask, was placed a solution of methyl
5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbe-
nzoate (compound 461.6, 100 mg, 0.270 mmol, 1.00 equiv, 80%) in
methanol (3 mL). A solution of sodium hydroxide (67.0 mg, 1.68
mmol, 5.00 equiv) in water (3 mL) was added and the resulting
mixture was stirred overnight at 70.degree. C., then concentrated
in vacuo. The residue was diluted with water (3 mL) and the pH of
the solution was adjusted to 2-3 with aqueous hydrogen chloride (12
M). The mixture was extracted ethyl acetate (3.times.10 mL), and
the combined organics was concentrated in vacuo to obtain the title
compound as a brown solid (80 mg, 84%).
##STR01322##
Compound 461.
4-(1-(5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dime-
thylbenzoyl)piperidin-4-yl)benzonitrile
[4069] Into around-bottom flask, was placed a solution of
5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbe-
nzoic acid (compound 461.7, 60 mg, 0.17 mmol, 1.00 equiv, 80%) in
N,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 46 mg, 0.20 mmol, 1.00 equiv),
4-dimethylaminopyridine (52 mg, 0.43 mmol, 2.00 equiv), and EDC-HCl
(80 mg, 0.42 mmol, 2.00 equiv) were added and the mixture was
stirred overnight at room temperature. The resulting solution was
diluted with ethyl acetate (30 mL) and washed with brine
(3.times.10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue (40 mg) was purified by
preparative-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5
um; mobile phase, water with 0.05% TFA and CH.sub.3CN (15.0%
CH.sub.3CN up to 55.0% in 7 min, up to 100.0% in 1 min, down to
15.0% in 1 min); Detector, Waters 2489 254 & 220 nm. The
fractions containing pure product were combined and lyophilized to
obtain the title compound as a white solid (8.9 mg, 11%). m/z (ES+)
455 (M+H).sup.+.
##STR01323##
Compound 462.1. 5-Bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one
[4070] Into around-bottom flask, was placed a solution of
2,2-dimethyloxan-4-one (1.00 g, 7.80 mmol, 1.00 equiv) in ether (20
mL). N-Bromrosuccinimide (1.50 g, 25.5 mmol, 3.26 equiv) was added
in portions, followed by the addition of ammonium acetate (60.0 mg,
0.78 mmol, 0.10 equiv). The resulting mixture was stirred overnight
at 25.degree. C., then diluted with ethyl acetate (20 mL). The
resulting mixture was washed brine (2.times.40 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography with ethyl
acetate/petroleum ether (1:30) as the eluent to obtain the title
compound as a yellow oil (508 mg, 31%).
##STR01324##
Compound 462.
4-(1-(5-(6,6-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-d-
imethylbenzoyl)piperidin-4-yl)benzonitrile
[4071] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 461, except
5-bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one (compound 462.1) was
used in place of 2-bromo-4-methoxycyclopentanone (compound 461.4).
m/z (ES+) 469 M+H).
##STR01325##
Compound 463.1.
Trimethyl((4-(trimethylsilyl)but-3-yn-1-yl)oxy)silane
[4072] Into a 1-L three neck round-bottom flask, was placed a
solution of but-3-yn-1-ol (20.0 g, 285 mmol, 1.00 equiv) in
tetrahydrofuran (300 mL) and the mixture was purged with nitrogen.
The mixture was cooled to -78.degree. C., then n-butyllithium (2.5
M in THF) (270 mL, 2.40 equiv) was added drop-wise followed by the
addition of chlorotrimethylsilane (67.9 g, 625 mmol, 2.20 equiv).
The resulting mixture was then stirred for 1 h at 25.degree. C.,
then carefully quenched with aqueous sodium bicarbonate (250 mL).
The aqueous was extracted with ether (3.times.100 mL) and the
combined organics was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography with ether/petroleum ether (1:10-1:1) as the eluent
to obtain the title compound as a colorless oil (10.0 g, 16%).
##STR01326##
Compound 463.2.
Trimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane
[4073] Into a round-bottom flask, was placed a solution of compound
463.1, 2.00 g, 7.46 mmol, 1.00 equiv, 80%) in hexane (30 mL). The
system was purged with nitrogen. Quinoline (0.1 mL, 0.10 equiv) and
Lindlar reagent (poisoned by Pb) (0.2 g, 0.10 equiv, 5%) were added
to the mixture. The resulting mixture was hydrogenated overnight at
room temperature under atmosphere pressure of hydrogen. After
completion of the reaction, the system was purged with nitrogen and
the solids were removed by filtration. The filtrate was
concentrated in vacuo and the residue was purified by silica gel
chromatography with hexane/ether (20:1) as the eluent to obtain the
title compound as a colorless oil (1.50 g, 74%).
##STR01327##
Compound 463.3. 6-Methyl-3,6-dihydro-2H-pyran
[4074] Into around-bottom flask, was placed a mixture of
trimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane (compound
463.2, 1.50 g, 6.93 mmol, 1.00 equiv), acetaldehyde (900 mg, 20.4
mmol, 3.00 equiv), and indium(III) chloride (1.50 g, 1.00 equiv) in
dichloromethane (15 mL). The resulting mixture was stirred
overnight at 25.degree. C., then diluted with DCM (50 mL). The
organics was washed with brine (3.times.20 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to obtain
the title compound as a brown oil (0.600 g, 88%).
##STR01328##
Compound 463.4 and compound 463.5.
4-Bromo-2-methyldihydro-2H-pyran-3(4H)-one (Compound 463.4) and
3-bromo-2-methyldihydro-2H-pyran-4(3H)-one (Compound 463.5)
[4075] Into a round-bottom flask, was placed a solution of
o-iodoxybenzoic acid (IBX) (3.42 g, 6.11 mmol, 2.00 equiv) in DMSO
(12 mL). The mixture was stirred for 30 min at 25.degree. C. then a
solution of 6-methyl-3,6-dihydro-2H-pyran (compound 463.3, 600 mg,
4.28 mmol, 1.00 equiv, 70%) in dichloromethane (30 mL) was added
drop-wise. The mixture was cooled to 0-5.degree. C., then
N-bromosuccinimide (1.20 g, 6.74 mmol, 1.10 equiv) was added
portion-wise. The resulting mixture was stirred overnight at
25.degree. C., then the solids were removed by filtration. The
filtrate was diluted with dichloromethane (50 mL) and washed with
brine (3.times.20 mL). The mixture was dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue was purified by
silica gel chromatography with ethyl acetate/petroleum ether (1:20)
as the eluent to obtain a mixture of the title compounds as a brown
oil (600 mg, 73%).
##STR01329##
Compound 463.
4-(1-(2,4-Dimethyl-5-(4-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2--
yl)benzoyl)piperidin-4-yl)benzonitrile
[4076] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 461, except a mixture of
4-bromo-2-methyldihydro-2H-pyran-3(4H)-one (compound 463.4) and
3-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 463.5) was
used in place of 2-bromo-4-methoxycyclopentanone (compound 461.4).
m/z (ES+) 455 (M+H).sup.+.
##STR01330##
Compound 464.1. 4-(Allyloxy)pent-1-ene
[4077] A 500-mL four neck round-bottom flask was purged and
maintained with an inert atmosphere of nitrogen, then a suspension
of sodium hydride (14.0 g, 350 mmol, 2.01 equiv, 60%) in
N,N-dimethylformamide (100 mL) was added. The mixture was cooled to
0.degree. C., then a solution of pent-4-en-2-ol (15.0 g, 174 mmol,
1.00 equiv) in N,N-dimethylformamide (100 mL) was added drop-wise
and the mixture was stirred for 20 min at 0.degree. C. The mixture
was cooled to -20.degree. C. and a solution of 3-bromoprop-1-ene
(20.9 g, 172 mmol, 0.99 equiv) in N,N-dimethylformamide (100 mL)
was added. The resulting mixture was allowed to warm to room
temperature and stirred overnight, then carefully quenched with
H.sub.2O (500 mL). The aqueous was extracted with ethyl acetate
(4.times.100 mL) and the combined organics was washed with brine
(2.times.200 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to obtain the title compound as a yellow oil
(13.3 g, 61%).
##STR01331##
Compound 464.2. 2-Methyl-3,6-dihydro-2H-pyran
[4078] A 500-mL three neck round-bottom flask was purged and
maintained with an inert atmosphere of nitrogen, then a solution of
4-(allyloxy)pent-1-ene (compound 464.1, 3.00 g, 23.8 mmol, 1.00
equiv) in DCE (200 mL) was added. Grubbs catalyst was added (810
mg, 0.950 mmol, 0.04 equiv) and the mixture was stirred at
60.degree. C. for 4 h. The mixture was then concentrated in vacuo
at 20.degree. C. to obtain the title compound as a colorless oil
(2.00 g, 86%).
##STR01332##
Compound 464.3 and 464.4. 4-Bromo-6-methyltetrahydro-2H-pyran-3-ol
and 5-bromo-2-methyltetrahydro-2H-pyran-4-ol
[4079] Into a round-bottom flask, was placed a solution of
methyl-3,6-dihydro-2H-pyran (compound 464.2, 2.00 g, 20.4 mmol,
1.00 equiv) in a mixture of tetrahydrofuran and H.sub.2O (20/20
mL). N-Bromosuccinimide (3.60 g, 20.3 mmol, 1.00 equiv) was added
and the resulting mixture was stirred at room temperature
overnight. The mixture was extracted with dichloromethane
(2.times.20 mL) and the combined organics were washed with brine
(2.times.20 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to obtain a mixture of the title compounds as
a yellow oil (1.10 g, crude).
##STR01333##
Compound 464.5 and 464.6.
4-Bromo-6-methyldihydro-2H-pyran-3(4H)-one and
5-bromo-2-methyldihydro-2H-pyran-4(3H)-one
[4080] Into around-bottom flask, was placed a mixture of
4-bromo-6-methyltetrahydro-2H-pyran-3-ol (compound 464.3) and
5-bromo-2-methyltetrahydro-2H-pyran-4-ol (compound 464.4) (1.10 g,
5.64 mmol, 1.00 equiv) as a solution in dichloromethane (30 mL).
Dess-Martin periodinane (2.90 g, 6.84 mmol, 1.21 equiv) was added
and the resulting solution was stirred overnight at room
temperature, then quenched with water (20 mL). The aqueous was
extracted with dichloromethane (2.times.20 mL) and the combined
organics were washed with brine (2.times.50 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to obtain a
mixture of the title compounds as a yellow oil (0.7 g).
##STR01334##
Compound 464.7. Methyl
2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)ben-
zoate
[4081] Into around-bottom flask, was placed a mixture of
4-bromo-6-methyldihydro-2H-pyran-3(4H)-one (compound 464.5) and
5-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 464.6) (700
mg, 3.63 mmol) as a solution in acetonitrile (20 mL). Methyl
5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5,
750 mg) and potassium carbonate (1.00 g, 7.25 mmol) were added and
the mixture was stirred overnight at 75.degree. C. under nitrogen.
The mixture was cooled and the solids were removed by filtration.
The filtrate was concentrated in vacuo and the residue was purified
by silica gel chromatography with ethyl acetate/petroleum ether
(1:1) as the eluent to obtain the title compound as a yellow solid
(100 mg, 9%).
##STR01335##
Compound 464.8.
2,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)ben-
zoic Acid
[4082] Into around-bottom flask, was placed a solution of methyl
2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)ben-
zoate (compound 464.7, 100 mg, 0.330 mmol, 1.00 equiv) in methanol
(10 mL). A solution of lithium hydroxide (76 mg, 3.17 mmol, 10.0
equiv) in water (10 mL) was added and the resulting solution was
stirred for 4 h at room temperature. The mixture was concentrated
in vacuo and then aqueous HCl was added until the pH was 5-6. The
mixture was adjusted to pH 5-6 with aqueous HCl and then the
resulting mixture was concentrated in vacuo. MeOH (5 mL) was added
to the residue and the solids were removed by filtration. The
filtrate was concentrated in vacuo to obtain the title compound as
a yellow solid (60 mg, 63%).
##STR01336##
Compound 464.
4-(1-(2,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2--
yl)benzoyl)piperidin-4-yl)benzonitrile
[4083] Into around-bottom flask, was placed a solution of
2,4-dimethyl-5-[6-methyl-3H,4H,6H,7H-pyrano[3,4-d]imidazol-2-yl]benzoic
acid (50 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (10
mL). EDC-HCl (67 mg, 0.35 mmol, 2.00 equiv),
4-dimethylaminopyridine (64 mg, 0.52 mmol, 3.00 equiv), and
4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 39 mg,
0.18 mmol, 1.00 equiv) were added and the solution was stirred for
2 h at room temperature. The reaction was quenched with water (20
mL) and the aqueous was extracted with ethyl acetate (2.times.20
mL). The combined organics was dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo. The residue was purified by silica gel
chromatography with ethyl acetate/petroleum ether (1:1) as the
eluent. The crude product (20 mg) was purified by Prep-HPLC with
the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,
Xbridge Prep Phenyl, 5 um, 19*150 mm; mobile phase, water with
0.03% NH.sub.3H.sub.2O and CH.sub.3CN (30% CH.sub.3CN up to 60% in
9 min, up to 100% in 1 min, down to 30% in 1 min); Detector, Waters
2489 254 nm & 220 nm. The fractions containing pure product
were combined and lyophilized to obtain the title compound as a
white solid (8.0 mg, 10%). m/z (ES+) 455 (M+H).sup.+.
##STR01337##
Compound 465.
2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-1,4,5,6-
-tetrahydrocyclopenta[d]imidazole-5-carbonitrile
[4084] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 461, except cyclopent-3-enecarbonitrile
(Johnson, C. R. et al. J. Org. Chem, 1969, 34, 860-864) was used in
place of 4-methoxycyclopent-1-ene (compound 461.2). m/z (ES+) 450
(M+H).sup.+.
##STR01338##
Compound 466.1. Tetrahydrofuran-3,4-diyl dimethanesulfonate
[4085] Into a round-bottom flask, was placed a solution of
tetrahydrofuran-3,4-diol (500 mg, 4.80 mmol, 1.00 equiv) and
triethylamine (1.45 g, 14.3 mmol, 3.00 equiv) in dichloromethane (8
mL). The mixture was cooled to 0-5.degree. C. and a solution of
methanesulfonyl chloride (1.40 g, 12.2 mmol, 2.50 equiv) in
dichloromethane (2 mL) was added drop-wise. The solution was
stirred at room temperature for 2 h, and then diluted with
dichloromethane (100 mL). The solution was washed with aqueous
NH.sub.4Cl (2.times.30 mL) then brine (30 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuum to obtain
the title compound as a brown solid (1.00 g, 72%).
##STR01339##
Compound 466.2. 3,4-Diazidotetrahydrofuran
[4086] Into a round-bottom flask, was placed a mixture of
tetrahydrofuran-3,4-diyl dimethanesulfonate (compound 466.1, 2.00
g, 7.30 mmol, 1.00 equiv, 95%) and sodium azide (4.00 g, 61.5 mmol,
8.00 equiv) in N,N-dimethylformamide (20 mL). The resulting mixture
was stirred overnight at 100.degree. C. behind a blast shield, then
cooled and diluted with ether (100 mL). The mixture was washed with
brine (5.times.20 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to obtain the title compound as a colorless
oil (1.00 g, 80%).
##STR01340##
Compound 466.3. Tetrahydrofuran-3,4-diamine
[4087] Into around-bottom flask, was placed a solution of
3,4-diazidotetrahydrofuran (compound 466.2, 900 mg, 5.26 mmol, 1.00
equiv, 90%) in ethanol (10 mL). The system was purged with nitrogen
and palladium on carbon (10 wt % Pd) (900 mg) was added. After
further purging the system with nitrogen, the atmosphere was
changed to hydrogen and the resulting suspension was stirred
overnight at room temperature under an atmosphere of hydrogen.
After purging the system with nitrogen, the solids were removed by
filtration and the filtrate was concentrated in vacuo to obtain the
title compound as a colorless oil (600 mg, 98%).
##STR01341##
Compound 466.4. Methyl
5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride
[4088] Into a 50-mL three neck round-bottom flask, was placed a
solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 900
mg, 4.28 mmol, 1.00 equiv, 90%) in methanol (20 mL). Hydrogen
chloride gas was introduced by bubbling through the solution for
0.5 hr. The reaction mixture was then transferred into a 30-mL
sealed tube and stirred overnight at room temperature. The mixture
was concentrated under vacuum and the residue was diluted with
ethyl acetate (30 mL) and extracted with water (10 mL). The aqueous
was concentrated in vacuo to obtain the title compound as a white
solid (200 mg, 15%).
##STR01342##
Compound 466.5. Methyl
2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate
[4089] Into around-bottom flask, was placed a solution of
tetrahydrofuran-3,4-diamine (compound 466.3, 140 mg, 1.17 mmol,
1.00 equiv, 85%) in ethanol (6 mL). Methyl
5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride
(compound 466.4, 300 mg, 0.930 mmol, 1.00 equiv) and triethylamine
(140 mg, 1.38 mmol, 1.00 equiv) were added and the resulting
solution was stirred overnight at 80.degree. C., then concentrated
in vacuo. The residue was purified by silica gel chromatography
with dichloromethane/methanol (10:1) as the eluent to obtain the
title compound as a brown oil (120 mg, 34%).
##STR01343##
Compound 466.5.
2,4-Dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoic
Acid
[4090] Into around-bottom flask, was placed a solution of methyl
2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate
(compound 466.5, 100 mg, 0.330 mmol, 1.00 equiv, 90%) and sodium
hydroxide (73 mg, 1.82 mmol, 5.00 equiv) in methanol/H.sub.2O (3/3
mL). The resulting solution was stirred overnight at 70.degree. C.,
then concentrated in vacuum. The residue was diluted with H.sub.2O
(5 mL) and the pH of the solution was adjusted to 2-3 with hydrogen
chloride (12 N), then extracted with ethyl acetate (3.times.10 mL).
The combined organics was concentrated in vacuo to obtain the title
compound as a yellow solid (80.0 mg, 84%).
##STR01344##
Compound 466.
4-(1-(2,4-Dimethyl-5-(-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile
[4091] Into around-bottom flask, was placed a solution of
2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoic
acid (compound 466.5, 80.0 mg, 0.250 mmol, 1.00 equiv, 80%) in
N,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5, 82.0 mg, 0.350 mmol, 1.20 equiv),
4-dimethylaminopyridine (76.0 mg, 0.620 mmol, 2.00 equiv), and
EDC-HCl (116 mg, 0.610 mmol, 2.00 equiv) were added and the
resulting solution was stirred overnight at room temperature. The
mixture was diluted with ethyl acetate (30 mL) and washed with
brine (3.times.15 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The crude product (50 mg) was purified by
Prep-HPLC with the following conditions
(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150
mm; mobile phase, water with 0.05% TFA and CH.sub.3CN (15%
CH.sub.3CN up to 50% in 9 min, up to 100% in 1 min, down to 15% in
1 min); Detector, Waters 2489 254 nm & 220 nm. The fractions
containing pure product were combined and lyophilized to obtain the
title compound as a white solid (13 mg, 12%). m/z (ES+) 429
(M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.70 (d,
2H), 7.53-7.36 (m, 4H), 5.09 (s, 2H), 4.17 (d, J=10.8 Hz, 2H), 3.77
(d, J=10.5 Hz, 2H), 3.60-3.44 (m, 1H), .about.3.3 (m, partially
overlapped with water, 1H), 3.10-2.92 (m, 2H), 2.48 (s, 3H), 2.45
and 2.35 (2 singlets, amide rotamers, Ar--CH.sub.3, 3H), 2.10-1.97
(m, 1H), 1.92-1.52 (m, 3H).
##STR01345##
Compound 467.
4-(1-(4-Fluoro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)b-
enzoyl)piperidin-4-yl)benzonitrile
[4092] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 1 and compound 2, except
4-fluoro-2-methylbenzoic acid was used in place of 2,4
dimethylbenzoic acid. m/z (ES+) 445 (M+H).sup.+.
##STR01346##
Compound 468.
4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chl-
oro-2-methylbenzoyl)piperidin-4-yl)benzonitrile
[4093] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 2, except 4-chloro-2-methylbenzoic acid was
used in place of 2,4 dimethylbenzoic acid. m/z (ES+) 502
(M+H).sup.+.
##STR01347##
Compound 469.
1-(2-(2-Chloro-5-(4-(4-fluorophenyl)piperidine-1-carbonyl)-4-methylphenyl-
)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone
[4094] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 2 and compound 468. m/z (ES+) 495
(M+H).sup.+.
##STR01348##
Compound 470.1. Methyl 2-bromo-4-fluorobenzoate
[4095] Into a round-bottom flask, was placed a solution of
2-bromo-4-fluorobenzoic acid (21.8 g, 99.5 mmol, 1.00 equiv) in a
solvent mixture of sulfuric acid (20 mL) and methanol (20 mL). The
resulting solution was stirred for 5 h at 85.degree. C., then
cooled and cooled and concentrated in vacuo. The residue was
diluted with ethyl acetate (200 mL) and washed with brine (200 mL)
then aqueous NaHCO.sub.3 (100 mL. Note: gas evolution), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to obtain
the title compound as a light yellow oil (22.0 g, 95%).
##STR01349##
Compound 470.1. Methyl 2-ethyl-4-fluorobenzoate
[4096] The title compound (colorless oil, 14.5 g, 93%) was prepared
using a procedure similar to that used for the preparation of
compound 48.1 and using of methyl 2-bromo-4-fluorobenzoate
(compound 470.1, 20.0 g) in place of methyl
2-bromo-4-methylbenzoate.
##STR01350##
Compound 470.
4-(1-(2-Ethyl-4-fluoro-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)be-
nzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[4097] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 1 and compound 2, except methyl
2-ethyl-4-fluorobenzoate (compound 470.1) was used in place of
2,4-dimethylbenzoic acid, and
4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound
11.2) was used in place of 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5). m/z (ES+) 477 (M+H).sup.+.
##STR01351##
Compound 471.1. 4-Chloro-5-iodo-2-methylbenzoic Acid
[4098] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 2.1, except 4-chloro-2-methylbenzoic acid
was used in place of 2,4-dimethylbenzoic acid.
##STR01352##
Compound 471.2. 4-Chloro-5-formyl-2-methylbenzoic Acid
[4099] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 392.2, except
4-chloro-5-iodo-2-methylbenzoic acid (compound 471.1) was used in
place of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound
392.1).
##STR01353##
Compound 471.
4-(1-(4-Chloro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)b-
enzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[4100] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 400, except
4-chloro-5-formyl-2-methylbenzoic acid (compound 471.2) was used in
place of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4),
3-bromodihydro-2H-pyran-4(3H)-one was used in place of
3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2) and
4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound
11.2) was used in place of 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5). m/z (ES+) 479 (M+H).sup.+.
##STR01354##
Compound 472.1. Methyl 4-chloro-2-ethyl-5-iodobenzoate
[4101] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 211.2, except methyl
4-chloro-2-ethylbenzoate (compound 178.2) was used in place of
methyl 2-ethyl-4-methylbenzoate (compound 48.1).
##STR01355##
Compound 472.2. 4-Chloro-2-ethyl-5-iodobenzoic Acid
[4102] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 211.3, except methyl
4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) was used in place
of 2-ethyl-5-iodo-4-methylbenzoate (compound 211.2).
##STR01356##
Compound 472.
4-(1-(4-Chloro-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)be-
nzoyl)-4-fluoropiperidin-4-yl)benzonitrile
[4103] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 400, except 4-chloro-2-ethyl-5-iodobenzoic
acid (compound 472.2) was used in place of
2-ethyl-5-formyl-4-methylbenzoic acid (211.4),
3-bromodihydro-2H-pyran-4(3H)-one was used in place of
3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2) and
4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound
11.2) was used in place of 4-(piperidin-4-yl)benzonitrile
hydrochloride (compound 1.5). m/z (ES+) 493 (M+H).sup.+.
##STR01357##
Compound 473.
4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chl-
oro-2-ethylbenzoyl)piperidin-4-yl)benzonitrile
[4104] The title compound was prepared using standard chemical
manipulations and procedures similar to those used for the
preparation of compound 2, except methyl
4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) was used in place
of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2). m/z (ES+) 516
(M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 7.73-7.54
(m, 4H), 7.53-7.42 (m, 2H), 4.75 and 4.70 (2 singlets, acetyl amide
rotamers, CH.sub.2, 2H), 4.02-3.88 (m, 2H), 3.68-3.52 (m, 1H),
3.32-3.20 (m, 1H), 3.07-2.88 (m, 3H), 2.88-2.58 (m, 3H), 2.25 and
2.22 (2 singlets, acetyl amide rotamers, acetyl CH.sub.3, 3H),
2.11-1.98 (m, 1H), 1.93-1.53 (m, 3H), 1.39-1.22 (m, 3H).
[4105] Additional example compounds are found in Table 1.
Example 1--FASN Inhibition by Compounds of the Present
Disclosure
[4106] Determination of FASN biochemical activity: The FASN enzyme
was isolated from SKBr3 cells. SKBr3 is a human breast cancer
cell-line with high levels of FASN expression. It is estimated that
FASN comprises about 25% of the cytosolic proteins in this cell
line. SKBr3 cells were homogenized in a dounce homogenizer then
centrifuged for 15 minutes at 4.degree. C. to remove particulate
matter. The supernatant was then analyzed for protein content,
diluted to the appropriate concentration, and used to measure FASN
activity. The presence of FASN was confirmed by western blot
analysis. A similar method for isolation of FASN from SKBr3 cells
is described in Teresa, P. et al. (Clin. Cancer Res. 2009; 15(24),
7608-7615).
[4107] FASN activity of the SKBr3 cell extract was determined by
measuring either NADPH oxidation or the amount of thiol-containing
coenzyme A (CoA) released during the fatty acid synthase reaction.
The dye CPM
(7-diethylamino-3-(4'-maleimidyl-phenyl)-4-methylcoumarin) contains
a thiol reactive group that increases its fluorescence emission on
reaction with the sulfhydryl group of CoA. The biochemical
activities shown in Table 1 were determined using the fluorescence
measurement of CoA release via a procedure described in Chung C. C.
et al. (Assay and Drug Development Technologies, 2008, 6(3),
361-374).
Example 2--Antiviral Activity
[4108] The antiviral activity of Structure (I-Z) was assessed using
the HCV1b replicon system:
##STR01358##
[4109] The replicon was constructed using the ET (luc-ubi-neo/ET)
cell line, a Huh7 human hepatoma cell line harboring an HCV
replicon with a stable luciferase (Luc) reporter and three cell
culture-adaptive mutations (Pietschmann, et al (2002) J. Virol.
76:4008-4021). The HCV replicon antiviral evaluation assay examined
the effects of compounds at six half-log concentrations. Human
interferon alpha-2b was included in each run as a positive control
compound. Sub-confluent cultures of the ET line were plated out
into 96-well plates that are dedicated for the analysis of cell
numbers (cytotoxicity) or antiviral activity and the next day drugs
were added to the appropriate wells. Cells were processed 72 hr
later when the cells were still sub-confluent. EC.sub.50
(concentrations inhibiting the replicon by 50% and 90%,
respectively), IC.sub.50 (concentration decreasing cell viability
by 50%) and SI (selective index: IC.sub.50/EC.sub.50) values were
determined. HCV RNA replicon levels were assessed as either HCV RNA
replicon-derived Luc activity or as HCV RNA by TaqMan RT-PCR. Two
methods were used to estimate cell counts (cytotoxicity). When the
Luc assay system was employed, the colorimetric CytoTox-1 cell
proliferation assay (Promega) was used to estimate cell numbers,
while ribosomal RNA (rRNA) levels determined via TaqMan RT-PCR were
used as an indication of cell numbers in the RNA-based assay. A
summary of the results is listed below in Table 2.
TABLE-US-00009 TABLE 2 Replicon EC50 Method (.mu.M) Cell IC50
(.mu.M) Selectivity Index Luciferase activity 0.017 >32 >1882
TaqMan RT-PCR 0.105 >100 >952
Example 3--FASN Inhibition Correlates to HCV Inhibition
[4110] The antiviral activities of 15 compounds of the present
disclosure (numbers correlate to the compounds in Table 1) were
measured using the HCV replicon system. Replicon cell line 1b (HCV
1b/Luc-Neo replicon (1b Con1 with Firefly gene integrated)) was
established following published methods (Lohmann et al. (1999)
Science 285(5424): 110-113, Lohmann et al. (2001) J. Virol.
75(3):1437-1449 and Qi et al. (2009) Antiviral Res. 81(2):166-173)
using Huh7 by G418 selection. The replicon was assembled using
synthetic gene fragments. The GT1b line has PV-EKT and harbors 3
adaptive mutations E1202G(NS3), T1280I(NS3), K1846T(NS4B) and the
backbone is Con1. The culture medium was: [4111] a) DMEM supplement
with 10% FBS, G418 (250 .mu.g/ml), streptomycin (100
.mu.g/ml)/penicillin (100 U/ml), L-glutamine (100.times.), NEAA
(100.times.) [4112] b) Media prepared as follows: [4113] i) 500 ml
DMEM media (Gibco, Cat#11960-077) [4114] ii) 57 ml Fetal Bovine
Serum (Gibco, Cat#16140-071) [4115] iii) 5.7 ml
Penicillin-Streptomycin (Gibco, Cat#15140-122) [4116] iv) 5.7 ml
MEM non-essential amino acids (Gibco, Cat#111140-050) [4117] v) 5.7
ml L-glutamine (Gibco, Cat#125030-081) [4118] vi) 574.1 ml
media+2.87 ml 50 mg/ml G418 [final 0.25 mg/ml] (Gibco,
Cat#10131-027)
[4119] Compounds were dissolved in DMSO to provide a 10 mM stock or
used from stock DMSO solutions. Compounds were diluted to generate
10-point half log (3.16-fold) serial dilutions for assay in
384-well plates (Echo qualified 384-well PP (Labcyte Cat#P-05525))
plus DMSO in duplicate. This experiment was repeated three times on
three different days.
[4120] Cells were harvested when confluency reached 90%-100%. Cell
concentrations were adjusted to 8.times.10.sup.4 cells/ml and added
to 384-well white assay microplates (tissue-culture
treated--Greiner Cat#781080) to reach a final cell density of 2,000
cells/well. Plates were incubated at 5% CO.sub.2 and 37.degree. C.
for 72 hours.
[4121] After 72 hours of incubation Bright-Glo Luciferase reagent
(Promega, cat#E2650) and Cell Titer Flo (Promega, cat#G6080/1/2)
were prepared and stored in the dark while equilibrating to room
temperature. Treated cells were likewise equilibrated to room
temperature. 10 .mu.L of Cell Titer Flo was added to each well of
compound-treated cells and incubated in microtiter plates for
approx. 0.5 hours. Cell viability was measured using an Envision
reader (available from Perkin Elmer) to estimate cytotoxicity. 30
.mu.L of firefly luciferase substrate were added to each well and
chemiluminescence was measured as an indicator of the extent of HCV
replication.
[4122] The anti-replicon activity (% inhibition) is calculated
using the equation:
% Inhibition = ( 1 - Cmpd - Control DMSO - Control ) .times. 100.
##EQU00001## Cytotoxicity is calculated using the equation :
##EQU00001.2## % Cytotoxicity = ( 1 - Cmpd - Background DMSO -
Background ) .times. 100. ##EQU00001.3##
[4123] There was determined to be a correlation between potency of
FASN inhibition and antiviral activity as illustrated in Table 3
below and FIG. 1. It is noted that none of the compounds caused
significant cytotoxicity.
TABLE-US-00010 TABLE 3 Molecule Biochemical IC50 (.mu.M) Antiviral
EC50 (.mu.M) 1 0.230 0.425 2 0.065 0.192 12 0.370 1.003 14 0.263
0.260 20 0.022 0.011 27 0.107 0.153 43 0.110 0.154 55 0.035 0.034
58 0.025 0.078 67 0.090 0.270 68 0.100 0.301 70 0.037 0.099 73
0.040 0.117 152 0.052 0.072 343 0.600 0.624
Example 4--FASN Inhibitors Retain Activity Against HCV Mutants that
Confer Resistance to Direct-Acting Antiviral Agents
[4124] One of the major challenges in treating hepatitis C is the
rapid emergence of resistance in response to direct-acting
antiviral agents. Resistance typically results when the virus
generates a point mutant that supports essential viral functions
but prevents antiviral agents from binding. Three FASN inhibitors
(compounds 55, 20, and 70) were tested for their ability to inhibit
mutants of HCV that confer resistance to representative antiviral
agents. Each of these mutants was introduced into a GT1b construct
based on a Con1 backbone containing the PVIRES-Luciferase Ubi-Neo
gene and harboring 1 adaptive mutation (S22041). (Lohmann et al.
(1999) Science 285(5424):110-113, Lohmann et al. (2001) J. Virol.
75(3):1437-1449 and Qi et al. (2009) Antiviral Res. 81(2):166-173).
Antiviral activities were measured by the method described in
Example 3.
[4125] The studied mutations are shown in Table 4 below.
TABLE-US-00011 TABLE 4 Studied Mutations Mutant Reference NS3 A156T
Susser et al J. Clin. Virol. 52(4), 321-327 (2011) and references
therein NS3 R155K Susser et al J. Clin. Virol. 52(4), 321-327
(2011) and references therein NS4B H94R Rai et al. Antiviral Res.
90, 93-101 (2011) NS5AY393H Fridell et a.l Antimicrob. Agents
Chemother. 54(9), 3641-3650 (2010) NS5B M423I (non-nucleoside site)
Troke et al. Antimicrob. Agents Chemother. 56(3), 1331-1341 (2012)
NS5B S282T (nucleoside site) Dutartre et al. Antimicrob. Agents
Chemother. 50(12), 4161-4169 (2006)
[4126] A known NS4B allosteric inhibitor (Compound A), a known NS5A
inhibitor (Compound B), a known non-nucleoside NS5B inhibitor
(Compound C), a known NS3/NS4A protease inhibitor (Compound D) and
a known nucleoside NS5B inhibitor (Compound E) were tested in
parallel with the FASN inhibitors of the present disclosure to
confirm the performance of the resistance mutations.
[4127] Antiviral EC.sub.50's for the various compounds against the
panel of mutants, along with the relative shift in EC.sub.50
relative to the GT1b wild-type replicon are shown below. Normal
assay variation is +3-4 fold. EC.sub.50 shifts outside this range
imply resistance and are indicated in bold. The 3 FASN inhibitors
retain activity across the panel of mutants, whereas the
direct-acting antiviral agents display resistance against mutations
in their respective binding sites.
TABLE-US-00012 TABLE 5 Antiviral EC.sub.50's. EC.sub.50 (nM) 1b
Wild NS3 NS3 NS4B NS5A NS5B NS5B Compound Type A156T R155K H94R
Y93H M423I S282T 55 49.63 143.00 156.10 67.31 109.40 19.22 73.30 20
16.71 44.06 25.46 17.02 32.00 19.70 25.60 70 39.18 49.97 43.91
36.00 108.90 58.69 56.90 Compound A 261.00 232.20 209.60 2813.00
n.t. 126.60 n.t. Compound B 0.01 0.01 n.t. n.t. 0.28 0.01 0.01
Compound D 0.67 105.00 236.60 0.39 n.t. 1.54 n.t. Compound C 4.27
4.57 8.43 4.61 3.00 34.09 3.00 Compound E 583.70 890.90 n.t. n.t.
1069.0 159.30 15650.0
TABLE-US-00013 TABLE 6 Fold shift in EC50 relative to wild-type HCV
Fold shift in EC50 relative to wild-type Binding NS3 NS3 NS4B NS5A
NS5B NS5B Compound Site A156T R155K H94R Y93H M423I S282T 55 2.88
3.15 1.36 2.20 0.39 1.48 20 2.64 1.52 1.02 1.92 1.18 1.53 70 1.28
1.12 0.92 2.78 1.50 1.45 Compound A NS4B 0.89 0.80 10.78 n.t. 0.49
n.t. Compound B NS5A 1.00 n.t. n.t. 35.13 0.75 0.88 Compound D
NS3/4A 156.46 352.56 0.58 n.t. 2.29 n.t. Compound C NS5B 1.07 1.98
1.08 0.70 7.99 0.70 (non-nuc) Compound E NS5B 1.53 n.t. n.t. 1.83
0.27 26.81 (nuc)
Example 5--FASN Inhibitors Useful in Combination Therapies
[4128] This example describes the in vitro antiviral activity and
cytotoxicity of the compound of Structure (V-K) in combination with
IFN-.alpha., Ribavirin, Compounds B, C, D and E against an HCV GT1b
replicon cell line.
##STR01359##
Materials:
[4129] Virus:
[4130] The GT1b replicon plasmid was assembled using synthetic gene
fragments. The replicon genome contains PVIRES-Luciferase Ubi-Neo
gene segments and harbors 1 adaptive mutation (S22041), and the
backbone is Con1. The replicon GT1b cell line was established by
the following published methods.
[4131] Medium and Reagents:
[4132] Table 7 below provides details regarding the culture medium
reagents used in this example.
TABLE-US-00014 TABLE 7 List of culture medium regents Reagent
Vendor Catalogue Number Dimethyl sulfoxide (DMSO) Sigma Cat
#34869-100ML DMEM Invitrogen Cat #11960-044 Fetal Bovine Serum
(FBS) Gibco Cat #16140 Pen-Strep Invitrogen Cat #15140-122 MEM
non-essential amino acids Invitrogen Cat #11140-050 L-Glutamin
Invitrogen Cat #25030-081 G418 (geneticin) Gibco Cat #10131-027
Trypsin/EDTA Invitrogen Cat #25200-072 DPBS/Modified Hyclone
SH30028.01B 96-well cell plate Greiner Cat #655090 Cell titer
fluoro Promega Cat #G6082 Bright-Glo Promega Cat #E264B
[4133] Analytical Instruments:
[4134] The following analytical instruments were used to perform
the assays of this example: [4135] POD-810 [4136] Topcount (PE)
[4137] Envision (PE) [4138] Multidrop (Thermo)
Methods:
[4139] Preparation of Compound Plates for Single Compound
Testing:
[4140] Compounds were supplied as dry powders and were
reconstituted in DMSO to generate stock solutions. The POD-810
system was used to generate 10-point half log (3.16-fold) serial
dilutions for the assay in 96-well plates. The highest test
concentrations are detailed for each compound in Table 8.
[4141] Assay Protocol (Single Compounds):
[4142] Each compound was assayed with 3.16-fold (half log) serial
dilutions for 10 concentrations plus DMSO in duplicate. HCV
replicon GT1b cells were harvested and adjusted to a cell
concentration of 8E+04 cells/ml. A Multidrop was used to plate 100
.mu.L/well into 96 assay microplates to reach a final cell density
of 8,000 cells/well. Plates were incubated at 5% CO.sub.2,
37.degree. C. for 72 hours.
[4143] At the end of the 72 hour incubation, antiviral activity and
cytotoxicity were measured. Bright-Glo Luciferase reagent and Cell
Titer Flo were prepared and stored in dark while equilibrating to
room temperature. The cell plates were allowed to equilibrate to
room temperature as well. A Multidrop was used to add 20 .mu.L Cell
Titer Flo to each well of compound-treated and compound-free cells.
The plates are incubated for 1 hour, and cell viability is measured
on an Envision reader for cytoxicity calculation. Fifty microliters
of firefly luciferase substrate are added to each well, incubated
for 2 minutes, and chemiluminescence is measured for EC.sub.50
calculation.
[4144] The anti-replicon activity (% inhibition) was calculated
using the following equation:
%
Inhibition=[1-((Compound-background)/(DMSO-background)).times.100].
[4145] Test Compounds and Assay Setup for Two-Compound Combination
Studies:
[4146] The DMSO stocks of the compounds used in the single compound
testing were also used in this analysis. Combination dilution
matrixes were generated by POD-810 in 96-well assay microplates.
The POD-810 system was used to generate 7-point, 2-fold serial
dilutions in a matrix format. The maximum concentration tested for
each compound is detailed below.
TABLE-US-00015 TABLE 8 Expected activities and upper concentrations
of compounds tested in single-agent and combination studies Highest
Highest concentration concentration Expected for single- for
combination GT1b EC50 agent testing testing Compound (.mu.M)
(.mu.M) (.mu.M) (V-K) 0.060 10.0 0.100 Compound D 0.0014 0.032
0.0032 Compound C 0.018 10.0 0.032 Compound B 0.000009 0.001
0.000032 Compound E 4.030 100.0 10.0 IFN 64.94 IU/ml 1000 IU/ml
10.0 IU/ml Ribavirin 26.830 320.0 100.0
[4147] The compound of Structure (V-K) was tested alone and in
combination with compounds detailed in Table 9. Each compound was
also tested alone as a single agent.
TABLE-US-00016 TABLE 9 Combinations of compounds for in vitro
evaluation. Regimen Combination 1 (V-K) + Compound D 2 (V-K) +
Compound C 3 (V-K) + Compound B 5 (V-K) + Compound E 6 (V-K) +
IFN-.alpha. 7 (V-K) + RBV
[4148] Assay Setup (Two-Drug Combinations):
[4149] Each compound was assayed with 2-fold serial dilutions for 7
concentrations in matrix format plus each drug alone. HCV replicon
GT1b cells were harvested and adjusted to a cell concentration of
8E+04 cells/ml. A Multidrop was used to plate 100 .mu.L into 96
assay microplates to reach a final cell density of 8,000
cells/well. Plates were incubated at 5% CO.sub.2, 37.degree. C. for
72 hours.
[4150] At the end of the 72 hour incubation, antiviral activity and
cytotoxicity were measured. Bright-Glo Luciferase reagent and Cell
Titer Flo were prepared and store in dark while allowing to
equilibrate to room temperature. The cells plates were allowed to
equilibrate to room temperature as well. A Multidrop was used to
add 20 .mu.L Cell Titer Flo to each well of compound-treated and
compound-free cells. The plates were incubated for 1 hour, and cell
viability was measured on an Envision reader for cytotoxicity
calculation. The liquid was then removed from the plates, after
which 50 .mu.L PBS and 50 .mu.L firefly luciferase substrate
solution were added to each well, after a 2-minute incubation
period, chemiluminescence (for HCV replication calculation) was
measured. The data were analyzed using MacSynergy.TM. II.
[4151] Assay Results:
[4152] Activity and Cytotoxicity of the Compounds.
[4153] The EC.sub.50 and CC.sub.50 values are summarized below in
Table 10.
TABLE-US-00017 TABLE 10 EC.sub.50 and CC.sub.50 of Each Test
Compound GT1b Expected EC.sub.50 Compound EC.sub.50 (.mu.M) (.mu.M)
CC.sub.50 (.mu.M) (V-K) 0.04 0.06 >10 Compound D 0.0021 0.0014
>0.032 Compound C 0.006 0.018 >10 Compound B 0.000012
0.000009 >0.001 Compound E 2.41 4.03 >100 IFN-.alpha. (IU/mL)
1.34 1 >1000 RBV 32.75 26.83 239
[4154] Combination Effect.
[4155] The combination effect of the compound pairs was calculated
using MacSynergy.TM. II and those results are summarized in Table
11 below.
TABLE-US-00018 TABLE 11 Summary of the combination effects of the
compound pairs MacSynergy .TM. II Compd 1 Compd 2 SYNERGY PLOT
(95%) (top conc) (top conc) SYNERGY Log volume ANTAGONISM Log
volume (V-K) Compound D 16.7 1.51 -13.03 -1.18 Compound C 2.93 0.27
-9.2 -0.83 Compound B 6.75 0.61 -7.11 -0.64 Compound E 1.08 0.1
-7.81 -0.73 IFN-.alpha. 5.44 0.49 -24.88 -2.25 RBV 1.64 0.15 -3.52
-0.32 * None of the combinations cause cytotoxicity.
Conclusions
[4156] The Z factors of the compound pairs summarized in Table 12
indicate that the assay quality is better than the QC standard.
TABLE-US-00019 TABLE 12 Summary of the Z factor of compound pairs Z
factor Drug Pairs Plate-1 Plate-2 Plate-3 (V-K) + Compound D 0.68
0.86 0.83 (V-K) + Compound C 0.66 0.78 0.65 (V-K) + Compound B 0.70
0.83 0.84 (V-K) + Compound E 0.72 0.76 0.74 (V-K) + IFN-.alpha.
0.75 0.70 0.66 (V-K) + RBV 0.78 0.78 0.72
[4157] The EC.sub.50 values of the individual compounds in the
combination matrix (summarized in Table 13) are consistent with the
EC.sub.50 data in obtained for single-compound inhibition Table
10.
TABLE-US-00020 TABLE 13 Summary of EC.sub.50 of single dose in
compound combination GT1b EC.sub.50 (.mu.M) in EC.sub.50 (.mu.M) of
single dose ranging dose in drug Compound assay combination (V-K)
0.04 0.07 Compound D 0.0021 0.0017 Compound C 0.006 0.009 Compound
B 0.000012 0.000009 Compound E 2.41 1.79 IFN-.alpha.(IU/mL) 1.34
3.43 RBV 32.75 31.63
[4158] The compound of Structure (V-K) was demonstrated to have
additive antiviral activity without enhanced cytotoxicity in
combination with agents representing a variety of mechanisms. These
results are summarized in Table 14 below.
TABLE-US-00021 TABLE 14 Summary of antiviral mechanisms that are
additive with the compound of Structure (V-K). The term
"direct-acting antiviral" ("DAA") refers to a compound that binds
to and inhibits a viral protein, rather than a host protein.
Molecule Mechanism Class IFN-.alpha. Cellular defense Host RBV
Multiple Host Compound D HCV Protease DAA Compound B NS5A Inhibitor
DAA Compound C NS5B Inhibitor DAA Compound E NS5B Inhibitor DAA
[4159] IFN-.alpha. and RBV represent current standard-of-care for
treating Hepatitis C infection, and the HCV protease inhibitors
Telaprevir and Boceprivir have recently been approved. The additive
antiviral activity and lack of enhanced cytotoxicity in combination
with IFN-.alpha. and RBV further suggest that compounds of this
invention will not interfere with critical host processes such as
cellular defense (IFN-.alpha.) or guanidine nucleotide biosynthesis
(RBV). Compounds of this invention such as the compound of
Structure (V-K) should therefore be therapeutically useful if
administered in combination regimens with current standard of care.
Moreover, the additive antiviral activities observed with Compound
B, Compound C, and Compound E suggest that molecules of this
invention such as the compound of Structure (V-K) can be
productively combined with agents currently in development that
target newer mechanisms (e.g., NS5A and NS5B inhibitors).
Example 6--Anti-Tumor Activity--Multiplexed Cytotoxicity Assay
[4160] Cells were grown in RPMI1640, 10% FBS, 2 mM
L-alanyl-L-Glutamine, 1 mM Na pyruvate or a special medium in a
humidified atmosphere of 5% CO.sub.2 at 37.degree. C. Cells were
seeded into 384-well plates and incubated in a humidified
atmosphere of 5% CO.sub.2 at 37.degree. C. Compounds were added 24
hours post cell seeding. At the same time, a time zero untreated
cell plate was generated.
[4161] After a 72 hour incubation period, cells were fixed and
stained with fluorescently labeled antibodies and nuclear dye to
allow visualization of nuclei, apoptotic cells and mitotic cells.
Apoptotic cells were detected using an anti-active caspase-3
antibody. Mitotic cells were detected using an anti
phospho-histone-3 antibody.
[4162] Compounds were serially diluted in half-log (3.16-fold)
increments and assayed over 10 concentrations in a final assay
concentration of 0.1% DMSO from the highest test concentration
specified in the sample information chapter. Automated fluorescence
microscopy was carried out using a GE Healthcare 1N Cell Analyzer
1000, and images were collected with a 4.times. objective.
[4163] Twelve bit tiff images were acquired using the InCell
Analyzer 1000 3.2 and analyzed with Developer Toolbox 1.6 software.
EC.sub.50 and IC.sub.50 values were calculated using nonlinear
regression to fit data to a sigmoidal 4 point, 4 parameter One-Site
dose response model, where: y (fit)=A+[(B-A)/(1+((C/x){circumflex
over ( )}D))]. Curve-fitting, EC.sub.50/IC.sub.50 calculations and
report generation are performed using a custom data reduction
engine MathIQ based software (AIM).
[4164] The multiplexed cytotoxicity assay uses a cell image based
analysis technique where cells are fixed and stained with
fluorescently labeled antibodies and nuclear dye to visualize
nuclei, and apoptotic and mitotic cells. Apoptotic cells are
detected using an anti-active caspase-3 antibody. Mitotic cells are
detected using an anti phospho-histone-3 antibody.
[4165] Cell proliferation is measured by the signal intensity of
the incorporated nuclear dye. The cell proliferation assay output
is referred to as the relative cell count. To determine the cell
proliferation end point, the cell proliferation data output is
transformed to percent of control (POC) using the following
formula:
POC=relative cell count (compound wells)/relative cell count
(vehicle wells).times.100
[4166] Time zero non-treated plate is used to determine number of
doublings in 72 hour assay period: Number of doublings in 72
hours=LN [Cell number (72 hr end point)*Cell number (time
zero)]/LN(2). The output of each biomarker is fold increase over
vehicle background normalized to the relative cell count in each
well.
[4167] The activated caspase-3 marker labels cells from early to
late stage apoptosis. The output is shown as a fold increase of
apoptotic cells over vehicle background normalized to the relative
cell count in each well. Concentrations of test compound that cause
a 5-fold induction in the caspase-3 signal indicates significant
apoptosis induction. Wells with concentrations higher than the
relative cell count IC.sub.95 are eliminated from the caspase3
induction analysis.
[4168] The phospho-histone-3 marker labels mitotic cells. The
output is shown as a fold induction of mitotic cells over vehicle
background normalized to the relative cell count in each well. When
the fold induction of mitotic cell signal over background is
.about.1, there is "no effect" on the cell cycle. Two or more fold
increase in phospho-histone-3 signal over vehicle background
indicates significant test compound induction of mitotic block.
[4169] Two or more fold decrease in the phospho-histone-3 signal
may indicate G1/S block only when cytotoxicity levels are below the
measured relative cell count IC.sub.95. When 2 or more fold
decrease in the phospho-histone-3 signal are observed at
concentrations higher than the relative cell count IC.sub.95, the
decrease in mitotic cell counts are most likely due to a more
general cytotoxicity effect rather than a true G1/S phase block.
Wells with concentrations higher than the relative cell count
IC.sub.95 are eliminated from the phospho-histone-3 analysis.
[4170] Cell proliferation measured by relative cell counts were the
criteria for positive response.
[4171] Apoptosis: [4172] >5-fold increase in activated caspase-3
signal indicates an apoptotic response Mitosis: [4173] >2-fold
increase in phospho-histone-3 indicates mitotic block [4174]
<2-fold decrease in phospho-histone-3 indicates G1/S block
TABLE-US-00022 [4174] TABLE 15 Results Max G1/S cell Max G2/M
Apoptosis Biochemical cycle block cell cycle Fold Compound
IC.sub.50 (.mu.M) (.mu.M) block Induction 205 0.220 0.160 1.36 2.39
95 0.030 0.012 0.94 2.45 142 0.140 0.031 1.28 2.34 153 0.060 0.014
1.17 2.55 427 0.080 0.019 1.00 2.39 42 0.070 0.013 1.09 2.20 48
0.170 0.027 1.27 2.20 156 0.030 0.031 1.28 2.59 182 0.150 0.030
1.54 2.07 183 0.170 0.031 1.00 2.40
Example 7--Effects of FASN Inhibitors on Fatty Liver Disease in
Mice
[4175] The impact a FASN inhibitor of the present application on
steatosis was determined in C57BL/6 male mice on a high fat diet
(HFD).
[4176] This example describes the effects of Compound 364A.
##STR01360##
[4177] 2 groups of 5 male C57BL/6NCrSim mice were employed vehicle
and FASN inhibitor treated groups, which were 4-5 weeks old at the
start of dosing. Mice were allowed unrestricted access to a diet
high in fat (Research Diets cat. No. D09100301: 40% kcal partially
hydrogenated vegetable oil shortening and by weight 20% fructose
and 2% cholesterol). In addition, all animals received once-daily
oral doses of vehicle or 10 mg per kg of mouse body weight of a
FASN inhibitor of the application for 57 consecutive days. At
sacrifice, the right liver lobe was placed in a preservative (10%
neutral buffered formalin) followed by preparation of liver samples
for microscopic evaluation by a licensed pathologist. Liver samples
were either stained for fat using Oil Red O stain or collagen with
Masson's trichrome stain.
[4178] Slides were prepared from right liver lobes and stained with
Oil Red O for fat and Masson's Trichrome for collagen. For study 1,
the histopathologic findings for Oil Red O and Trichrome stains are
summarized in Table 16 and representative images for stains are
shown in FIG. 2. Animals receiving vehicle for 57 days while on a
HFD developed severe fat deposits inside the liver cells. The liver
cells were enlarged and filled with small vesicles of lipid as
indicated by the Oil Red O staining. There was no significant
inflammation or accumulation of collagen. Animals on HFD which
received Compound 364A at 10 mg/kg for 57 days had no evidence of
fat deposits inside the liver cells and appeared normal. These
results are illustrated by the representative images in FIG. 2,
where lipid deposition and liver cell enlargement present in the
vehicle controls are totally absent in the normal-appearing livers
from animals treated with Compound 364A at 10 mg/kg. These results
demonstrate that prophylactic, once daily dosing of 10 mg/kg
Compound 364A inhibited the development of steatosis in this model.
These results support the utility of FASN inhibitors in the
treatment of NAFLD, NASH and metabolic syndrome.
TABLE-US-00023 TABLE 16 Study 1 histopathologic evaluation of
stained sections of liver and ranked hepatic steatosis severity Oil
Red O for Trichrome for Intracellular General Histology Test
Article Animal Lipid and Fibrosis Vehicle 1 4 4 Vehicle 2 4 4
Vehicle 3 3 4 Vehicle 4 3 4 Vehicle 5 3 4 Compound 364A @ 6 0 0 10
mg/kg Compound 364A @ 7 0 0 10 mg/kg Compound 364A @ 8 0 0 10 mg/kg
Compound 364A @ 9 0 0 10 mg/kg Compound 364A @ 10 0 0 10 mg/kg
[4179] A second study employed 3 groups of 5 male C57BL/6J mice
(vehicle for 28 days, vehicle for 57 days and vehicle for 28 days
followed by treatment with a FASN inhibitor compound of the
application for 29 days) which were 4-5 weeks old at the start of
dosing. Mice were allowed unrestricted access to a diet high in fat
(Research Diets cat. No. D09100301: 40% kcal partially hydrogenated
vegetable oil shortening and by weight 20% fructose and 2%
cholesterol). At sacrifice, the right liver lobe was placed in a
preservative (10.sup.% neutral buffered formalin) followed by
preparation of liver samples for microscopic evaluation by a
licensed pathologist. Liver samples were either stained for fat
using Oil Red O stain or collagen with Masson's trichrome
stain.
[4180] The histopathologic findings for tissue staining are
summarized in Table 17 and representative H&E stained images
for Study 2 are shown in FIG. 3. Animals dosed with vehicle for 57
days while on a HFD developed severe fat deposits inside the liver
cells. Fewer and much smaller fat deposits were observed in the
livers from animals which were dosed with vehicle for 28 days
followed by Compound 364A for 29 days even though these animals had
received the HFD for a total of 57 days. These results demonstrate
that therapeutic, once daily dosing of 10 mg/kg Compound 364A
inhibited progression of hepatic steatosis in this model.
TABLE-US-00024 TABLE 17 Study 2 histopathologic evaluation of
stained sections of liver and ranked hepatic steatosis severity
Overall Hepatic Group Animal changes Histopathologic findings 1 1
moderate[3] Variable-sized vacuoles throughout Vehicle section 28 2
moderate[3] Variable-sized vacuoles throughout Days section 3
marked[4] Some enlargement/ballooning of hepatocytes numerous
variable- sized vacuoles 4 moderate[3] Variable-sized vacuoles
throughout section with few large vacuoles 5 moderate[3]
Variable-sized vacuoles throughout section 6 minimal[1] Few small
vacuoles identified 7 moderate[3] Variable-sized vacuoles
throughout section with few large/ballooning hepatocytes 8 mild[2]
Small single and multiple vacuoles within hepatocytes 9 marked[4]
Focus of cellular alteration (fatty change) enlargement/ballooning
of hepatocytes numerous large vacuoles 10 marked[4] Numerous large
vacuoles enlargement/ballooning of hepatocytes foci of necrosis 2
11 severe[5] Diffuse enlargement/ballooning of Vehicle hepatocytes
cytoplasmic rarefaction, 57 scattered large vacuoles Days 12
severe[5] Diffuse enlargement/ballooning of hepatocytes cytoplasmic
rarefaction, large vacuoles in subcapsular region 13 marked[4]
Numerous variable-sized vacuoles throughout section 14 marked[4]
Some enlargement of hepatocytes numerous variable-sized vacuoles
throughout section 15 severe[5] Diffuse enlargement/ballooning of
hepatocytes cytoplasmic rarefaction, large vacuoles in subcapsular
region 16 severe[5] Diffuse enlargement/ballooning of hepatocytes
cytoplasmic rarefaction, large vacuoles in subcapsular region 17
severe[5] Diffuse enlargement/ballooning of hepatocytes cytoplasmic
rarefaction, few vacuoles in subcapsular region 18 moderate[3]
Variable-sized vacuoles some enlargement of hepatocytes 19
severe[5] Diffuse enlargement/ballooning of hepatocytes cytoplasmic
rarefaction, large scattered vacuoles 20 marked[4] Some enlargement
of hepatocytes few vacuoles 3 21 marked[4] Multifocal
enlargement/ballooning of Vehicle hepatocytes, occasional large
vacuoles 28 Days; 22 marked[4] Multifocal enlargement/ballooning of
C hepatocytes; numerous variable-sized Com- vacuoles throughout
section pound 23 moderate[3] Numerous small vacuoles; some 364A 29
enlargement/ballooning of hepatocytes days 24 marked[4] Multifocal
enlargement of hepatocytes numerous variable-sized vacuoles
throughout 25 marked[4] Numerous variable-sized vacuoles throughout
section 26 severe[5] Diffuse enlargement/ballooning of hepatocytes
cytoplasmic rarefaction; numerous small and large vacuoles 27
marked[4] Multifocal enlargement/ballooning of hepatocytes;
numerous variable-sized vacuoles throughout section 28 moderate[3]
Scattered variable-sized vacuoles 29 moderate[3] Scattered
variable-sized vacuoles 30 moderate[3] Scattered variable-sized
vacuoles
[4181] Hepatic Steatosis Scoring System as described in Tables 1
and 2 above: 0=Norma --Tissue considered to be normal under the
conditions of the study and considering the age, sex and strain of
the animal concerned Alterations may be present which, under other
circumstances, would be considered deviations from normal.
1=Minimal--The amount of change barely exceeds that which is
considered to be within normal limits. 2=Mild--In general, the
lesion is easily identified but of limited severity. The lesion
probably does not produce any functional impairment.
3=Moderate--The lesion is prominent but there is significant
potential for increased severity. Limited tissue or organ
dysfunction is possible. 4=Severe--The degree is either as complete
as considered possible or great enough in intensity or extent to
expect significant tissue or organ dysfunction.
Example 8--Effects of FASN Inhibitors on IL-113 Levels In Vivo and
In Vitro
[4182] The impact of a FASN inhibitor of the present application on
IL-1.beta. levels was evaluated in vivo and in vitro. This example
describes the effects of Compound 364A, Compound 6B and Compound
242A.
##STR01361##
Fast-Fed Study in Rats
[4183] Female Sprague Dawley rats were fasted for 12 hours and then
two groups were dosed orally with a FASN inhibitor of the
application at 60 mg/kg of body weight or 100 mg/kg. A separate
control group was dosed with the formulation vehicle material. One
hour later, the animals were allowed to feed for 6 hours followed
by a 5 hour fast and then given an additional 10 hours of feeding.
Blood samples were collected at time points to determine the level
of IL-1.beta..
High Fat Study in Mice
[4184] Two groups of male C57BL/6J mice were dosed orally once
daily with a FASN inhibitor of the application at 3 mg/kg or 10
mg/kg. A separate control group was dosed with the formulation
vehicle material. Blood samples were collected at time points to
determine the level of IL-1f.
Human IL-1b Study
[4185] Blood from healthy donors was treated with an anti-coagulant
and peripheral blood mononuclear cells (PBMC) were isolated. The
adherent monocyte cells in the PBMC were selected by allowing cells
to attach to tissue culture dishes.
[4186] The FASN inhibitors of the application lowered the level of
IL-1.beta. beta in blood serum which resulted after food intake in
fasted rats or which occurred in mice fed a high fat diet. The
release of IL-1.beta. from freshly isolated human blood cells was
also reduced by treatment with a FASN inhibitor. These results
support the utility of FASN inhibitors in the treatment of
inflammatory conditions that occur in NAFLD, NASH, metabolic
syndrome and other inflammatory diseases.
[4187] In rats, which either were not treated or were given
vehicle, IL-1.beta. levels in the serum progressively increased as
a response to feeding after fasting between 2 hour and 22 hours
(FIG. 4). Treatment with Compound 6B prior to feeding reduced the
IL-1 beta response over this complete time course and by 22 hours
the reduction was over 5 fold (FIG. 5).
[4188] After 14 and 37 days on a high fat diet, the level of
IL-1.beta. was determined in blood serum of the mice. Mice treated
with Compound 364A had reduced levels of IL-1.beta. beta at both 14
and 37 days, both before reintroduction of food (FIGS. 6A and 6B)
and after feeding (1 hr data in FIGS. 6A and 6B), compared to mice
which received vehicle (FIGS. 6A and 6B).
[4189] Human PBMC and monocytes in cell cultures were stimulated
with lipopolysaccharide (LPS), a Toll 4 receptor agonist, or
lipoteichoic acid (LTA), a Toll 2 receptor agonist. As shown in
FIGS. 7A and 7B, without stimulation neither cell culture secreted
IL-1 beta into the cell culture supernatants. Stimulation with
either LPS or LTA plus DMSO, the solvent for Compound 242A,
resulted in secretion of IL-1 beta. Compound 242A treatment of
PBMC, which is a mixed population of mononuclear cells including
both lymphocytes and monocytes, reduced the level of IL-1 beta
resulting from either LPS or LTA stimulation. For monocytes,
Compound 242A treatment reduced the level of IL-1 beta resulting
from LTA stimulation whereas there was only a slight reduction
after LPS stimulation.
Example 9--Effects of FASN Inhibitors on T-Cell Differentiation
[4190] The impact of FASN inhibitors on the differentiation of
naive CD4+ T cells, isolated from mouse or human blood, into
pro-inflammatory Th.sub.17 cells and anti-inflammatory T.sub.reg
cells was examined. This example describes the effects of Compound
364A and Compound 152.
##STR01362##
Naive T-Cell Isolation Procedure
[4191] Naive CD4+ T cells were isolated ex vivo from whole blood
collected in sodium citrate tubes and enriched with Dynabeads.TM.
Untouched mouse (Cat#11415D) or human (Cat#11346D) CD4+ T Cells
Isolation Kits (Thermo Fisher). Naive mouse CD4+ T cells were
plated into 48-well tissue culture plates (Costar) with 1 .mu.g/mL
anti-CD3 and anti-CD28 antibody coated beads. Differentiation of
naive mouse CD4+ T cells to generate mouse Th.sub.17 cell cultures
used medium containing the following additives for 4 days:
anti-IL-2 (30 ng/mL) (R&D Systems); recombinant mouse IL-6
(Peprotech) (10 ng/mL); recombinant human TGFbeta (1 ng/mL)
(Peprotech); recombinant mouse IL-1beta (10 ng/mL) (Peprotech);
recombinant mouse IL-23 (10 ng/mL) (R&D Systems); anti-IL-4
antibody (20 ng/mL) (Biocell); and anti-IFNgamma antibody (50
ng/mL) (Biocell). Th.sub.17 cells were cultured in IMDM GlutaMAX
medium (Life Technologies) supplemented with 10% heat-inactivated
FCS (Biochrom), 500 U penicillin-streptomycin (Life
Technologies).
Differentiation Procedure--Human T-Cells
[4192] Naive human CD4+ T cells were plated into 48-well tissue
culture plates (Costar) with 1 .mu.g/mL anti-CD3 with anti-CD28
antibody coated beads. See Endo et al., 2015, Cell Reports 12:
1042-1055. Differentiation of naive human CD4+ T cells to generate
human Th.sub.17 cultures used medium containing the following
additives for 4 days: anti-IL-2 (30 ng/mL) (R&D Systems);
recombinant human IL-6 (10 ng/mL) (BD Biosciences); recombinant
human TGFbeta (1 ng/mL) (BD Biosciences); recombinant human
IL-1beta (10 ng/mL) (BD Biosciences); recombinant human IL-23 (10
ng/mL) (BD Biosciences); anti-IL-4 antibody (20 ng/mL) (R&D
Systems); and anti-IFNgamma antibody (50 ng/mL) (R&D Systems).
Th.sub.17 cells were cultured in IMDM GlutaMAX medium (Life
Technologies) supplemented with 10% heat-inactivated FCS
(Biochrom), 500 U penicillin-streptomycin (Life Technologies).
Flow Cytometry
[4193] For mouse cells, monoclonal antibodies specific to the
following antigens (and labeled with the indicated fluorescent
markers) were used: CD4 PerCP (GK1.5; 1:800),
(Affymetrix/eBioscience); Foxp3 Alexa488 (FJK-16s; 1:400),
(Affymetrix/eBioscience); and IL-17A PE and IL-17A PE (eBiol7B7;
1:400 and 1:200), (Affymetrix/eBioscience).
[4194] For human cells, monoclonal antibodies specific to the
following antigens (and labeled with the indicated fluorescent
markers) were used: Foxp3 FITC (236A/E7; 1:100)
(Affymetrix/eBioscience); IL-17A PE-Cy7 (eBio64DEC17; 1:100)
(Affymetrix/eBioscience); and CD4 PerCP (SK3; 1:200) (BD
Biosciences).
[4195] For analysis of surface markers, cells were stained in PBS
containing 0.25% BSA and 0.02% azide. Dead cells were excluded by
LIVE/DEAD Fixable Dead Cell Stain Kit (Life Technologies).
[4196] For intracellular cytokine staining, cells were treated with
Brefeldin A (5 mg/mL) for 2 h and stained using the
Fixation/Permeabilization Kit (BD Biosciences) according to the
manufacturer's instruction.
[4197] Quantitation of fluorescent cells and their intensity were
acquired on a FACSCalibur (BD Biosciences), and data were analyzed
with CELLQuest software.
[4198] FASN inhibition (50 nM Compound 364A) of mouse CD4+ naive T
cells with 4 days of Th.sub.17 differentiation conditions inhibits
Th.sub.17 cell differentiation and stimulates T.sub.reg
differentiation. IL-17+ Th.sub.17 cells fall from 41.2% of the CD4+
population to 3.9%, while FoxP3+ Treg cells increase from 0.04% to
23.8% of the CD4+ population with Compound 364A treatment (FIGS. 8A
and 8B).
[4199] FASN inhibition (50 nM Compound 364A) of human CD4+ naive T
cells from two different donors with 4 days of Th.sub.17
differentiation conditions inhibits TH.sub.17 cell differentiation
and stimulates T.sub.reg differentiation. IL-17+ TH.sub.17 cells
fall from 31% to 1.7% (donor 1) and from 37.2% to 1.6% (donor 2) of
the CD4+ population, while FoxP3+ Treg cells increase from 0.05% to
24.2% (donor 1) and from 1.1% to 30.2% (donor 2) of the CD4+
population with Compound 364A treatment (FIGS. 9A-9D).
[4200] FASN inhibition (100 nM Compound 152) of human CD4+ naive T
cells from two different donors with 4 days of Th.sub.17
differentiation conditions inhibits TH.sub.17 cell differentiation
and stimulates Treg differentiation. IL-17+ TH.sub.17 cells fall
from 30% to 10.3% (donor 1) and from 30.2% to 6.4% (donor 2) of the
CD4+ population, while FoxP3+ Treg cells increase from 0.06% to
26.1% (donor 1) and from 0.04% to 20.4% (donor 2) of the CD4+
population with Compound 364A treatment (FIGS. 10A-10D).
[4201] The data clearly indicates that when naive CD4+ T cells are
stimulated to differentiate under pro-inflammatory conditions to
generate Th.sub.17 inflammatory cells, FASN is required for this
process and inhibition of FASN with small molecule inhibitors such
as Compound 364A or Compound 152 prevents this pro-inflammatory
differentiation and steers differentiation to the production of
anti-inflammatory T.sub.reg cells instead. These results support
the utility of FASN inhibitors in the treatment of inflammatory
conditions that occur in NAFLD, NASH, metabolic syndrome and other
inflammatory diseases.
[4202] While preferred aspects of the present invention have been
shown and described herein, it will be obvious to those skilled in
the art that such aspects are provided by way of example only.
Numerous variations, changes, and substitutions will now occur to
those skilled in the art without departing from the invention. It
should be understood that various alternatives to the aspects of
the invention described herein can be employed in practicing the
invention. It is intended that the following claims define the
scope of the invention and that methods and structures within the
scope of these claims and their equivalents be covered thereby.
[4203] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference.
TABLE-US-00025 ID Structure FASN IC50 (.mu.M) 1 ##STR01363## 0.230
2 ##STR01364## 0.065 2.9 ##STR01365## 0.060 3 ##STR01366## 0.146 4
##STR01367## 0.200 5 ##STR01368## 0.055 6 ##STR01369## 0.360 7
##STR01370## 0.050 8 ##STR01371## 0.125 9 ##STR01372## 0.040 11
##STR01373## 0.170 12 ##STR01374## 0.370 13 ##STR01375## 0.260 14
##STR01376## 0.263 15 ##STR01377## 0.180 16 ##STR01378## 0.058 17
##STR01379## 0.073 18 ##STR01380## 0.990 19 ##STR01381## 0.870 20
##STR01382## 0.022 21 ##STR01383## 0.045 22 ##STR01384## 0.085 23
##STR01385## 0.070 24 ##STR01386## 0.070 25 ##STR01387## 0.150 26
##STR01388## 7.195 27 ##STR01389## 0.107 28 ##STR01390## 0.490 29
##STR01391## 0.980 30 ##STR01392## 0.320 31 ##STR01393## 0.060 32
##STR01394## 0.215 33 ##STR01395## 7.500 34 ##STR01396## 0.080 35
##STR01397## 25.083 36 ##STR01398## 0.130 37 ##STR01399## 0.675 38
##STR01400## 2.345 39 ##STR01401## 1.710 40 ##STR01402## 0.050 41
##STR01403## 0.035 42 ##STR01404## 0.067 43 ##STR01405## 0.110 44
##STR01406## 0.180 45 ##STR01407## 0.147 46 ##STR01408## 0.050 47
##STR01409## 0.230 48 ##STR01410## 0.170 49 ##STR01411## 0.040 50
##STR01412## 0.520 51 ##STR01413## 1.700 52 ##STR01414## 31.650 53
##STR01415## 1.970 54 ##STR01416## 0.310 55 ##STR01417## 0.035 56
##STR01418## 2.800 57 ##STR01419## 0.030 58 ##STR01420## 0.025 60
##STR01421## 0.045 61 ##STR01422## 0.230 62 ##STR01423## 0.093 63
##STR01424## 0.510 64 ##STR01425## 0.170 65 ##STR01426## 0.090 66
##STR01427## 0.230 67 ##STR01428## 0.090 68 ##STR01429## 0.100 69
##STR01430## 0.065 70 ##STR01431## 0.037 71 ##STR01432## 0.030 72
##STR01433## 0.200 73 ##STR01434## 0.040 74 ##STR01435## 0.120 75
##STR01436## 0.130 76 ##STR01437## 0.035 77 ##STR01438## 0.080 78
##STR01439## 0.035 79 ##STR01440## 0.045 80 ##STR01441## 0.400 81
##STR01442## 0.200 82 ##STR01443## 0.077 83 ##STR01444## 0.090 84
##STR01445## 5.320 85 ##STR01446## 1.450 86 ##STR01447## 5.420 87
##STR01448## 0.310 88 ##STR01449## 0.040 89 ##STR01450## 0.030 90
##STR01451## 0.380 91 ##STR01452## 2.210 92 ##STR01453## 0.940 93
##STR01454## 0.550 94 ##STR01455## 5.260 95 ##STR01456## 0.030 96
##STR01457## 0.030 97 ##STR01458## 0.025 98 ##STR01459## 0.900 99
##STR01460## 0.220 100 ##STR01461## >50 101 ##STR01462## >50
102 ##STR01463## 0.085 103 ##STR01464## 0.035 104 ##STR01465##
0.130 105 ##STR01466## 0.015 106 ##STR01467## 0.900 107
##STR01468## 1.490 108 ##STR01469## 1.050 109 ##STR01470## 0.250
110 ##STR01471## 0.280 111 ##STR01472## 0.135 112 ##STR01473##
1.295 113 ##STR01474## 0.130 114 ##STR01475## 0.245 115
##STR01476## 0.480 116 ##STR01477## 0.090 117 ##STR01478## 0.090
118 ##STR01479## 0.350 119 ##STR01480## 120 ##STR01481## 0.460 121
##STR01482## 2.300 122 ##STR01483## 0.890 123 ##STR01484## 0.690
124 ##STR01485## 32.880
125 ##STR01486## >50 126 ##STR01487## >50 127 ##STR01488##
0.730 128 ##STR01489## 2.260 129 ##STR01490## >50 130
##STR01491## 0.300 131 ##STR01492## 0.220 132 ##STR01493## 0.450
133 ##STR01494## 0.790 134 ##STR01495## 1.330 135 ##STR01496##
2.040 136 ##STR01497## 0.240 137 ##STR01498## 0.500 138
##STR01499## 0.640 139 ##STR01500## 1.210 140 ##STR01501## 0.380
141 ##STR01502## >50 142 ##STR01503## 0.140 143 ##STR01504##
0.175 144 ##STR01505## 0.320 145 ##STR01506## 0.820 146
##STR01507## 0.260 147 ##STR01508## 0.250 148 ##STR01509## 0.180
149 ##STR01510## 0.240 150 ##STR01511## 0.300 151 ##STR01512##
0.420 152 ##STR01513## 0.052 153 ##STR01514## 0.055 154
##STR01515## 0.105 155 ##STR01516## 0.20 156 ##STR01517## 0.030 157
##STR01518## 0.090 158 ##STR01519## 0.057 159 ##STR01520## 0.070
160 ##STR01521## 0.055 161 ##STR01522## 0.040 162 ##STR01523##
0.115 163 ##STR01524## 0.135 164 ##STR01525## >50 165
##STR01526## 1.000 166 ##STR01527## 0.160 167 ##STR01528## 0.125
168 ##STR01529## 0.060 169 ##STR01530## 0.090 170 ##STR01531##
0.090 171 ##STR01532## 0.070 172 ##STR01533## 0.140 173
##STR01534## 0.240 174 ##STR01535## 0.200 175 ##STR01536## 0.310
176 ##STR01537## 5.990 177 ##STR01538## 1.110 178 ##STR01539##
0.555 179 ##STR01540## 1.260 180 ##STR01541## 8.230 181
##STR01542## 0.115 182 ##STR01543## 0.145 183 ##STR01544## 0.170
184 ##STR01545## 0.085 185 ##STR01546## 0.080 186 ##STR01547##
0.055 187 ##STR01548## 0.065 188 ##STR01549## 0.070 189
##STR01550## 0.270 190 ##STR01551## 5.060 191 ##STR01552## 0.200
192 ##STR01553## 0.300 193 ##STR01554## 0.440 194 ##STR01555##
0.400 195 ##STR01556## >50 196 ##STR01557## >50 197
##STR01558## 11.105 198 ##STR01559## 0.705 199 ##STR01560## 1.060
200 ##STR01561## 13.520 201 ##STR01562## 23.140 202 ##STR01563##
0.055 203 ##STR01564## 0.045 204 ##STR01565## 0.195 205
##STR01566## 0.220 206 ##STR01567## 0.320 207 ##STR01568## 0.300
208 ##STR01569## 0.100 209 ##STR01570## 0.105 210 ##STR01571##
0.310 211 ##STR01572## 0.830 212 ##STR01573## 7.190 213
##STR01574## 0.790 214 ##STR01575## 28.760 215 ##STR01576## 0.080
216 ##STR01577## 0.090 217 ##STR01578## 0.100 218 ##STR01579##
0.170 219 ##STR01580## 0.085 220 ##STR01581## 0.055 221
##STR01582## 0.250 222 ##STR01583## 0.065 223 ##STR01584## 0.030
224 ##STR01585## 0.160 225 ##STR01586## 0.140 226 ##STR01587##
0.055 227 ##STR01588## 0.070 228 ##STR01589## 0.110 229
##STR01590## 0.090 230 ##STR01591## 30.990 231 ##STR01592## 0.300
232 ##STR01593## 0.650 233 ##STR01594## 1.630 234 ##STR01595##
>50 235 ##STR01596## 0.030 236 ##STR01597## 0.060 237
##STR01598## 0.080 238 ##STR01599## 0.100 239 ##STR01600## 0.050
240 ##STR01601## 0.050 241 ##STR01602## 0.120 242 ##STR01603##
0.050 243 ##STR01604## 0.120 244 ##STR01605## 0.220 245
##STR01606## 0.020 246 ##STR01607## 0.050 247 ##STR01608## 0.020
248 ##STR01609## 0.060 249 ##STR01610## 0.070 250 ##STR01611##
0.030
251 ##STR01612## 0.580 252 ##STR01613## 0.180 253 ##STR01614##
0.090 254 ##STR01615## 0.090 255 ##STR01616## 0.410 256
##STR01617## 0.090 257 ##STR01618## 0.580 258 ##STR01619## 0.150
259 ##STR01620## 1.330 260 ##STR01621## 3.500 261 ##STR01622##
21.750 262 ##STR01623## 5.343 263 ##STR01624## 0.250 264
##STR01625## >50 265 ##STR01626## >50 266 ##STR01627## >50
267 ##STR01628## 30.260 268 ##STR01629## 0.390 269 ##STR01630##
1.350 270 ##STR01631## 1.980 272 ##STR01632## 0.520 273
##STR01633## 0.060 274 ##STR01634## 2.345 275 ##STR01635## 2.245
276 ##STR01636## 9.060 277 ##STR01637## 11.680 278 ##STR01638##
1.750 279 ##STR01639## 0.330 280 ##STR01640## 0.700 281
##STR01641## 42.300 282 ##STR01642## 30.090 283 ##STR01643## 1.000
284 ##STR01644## 1.005 285 ##STR01645## >50 286 ##STR01646##
>50 287 ##STR01647## >40 288 ##STR01648## 289 ##STR01649##
32.733 290 ##STR01650## 0.470 291 ##STR01651## 0.370 292
##STR01652## 0.270 293 ##STR01653## 1.080 294 ##STR01654## 295
##STR01655## 3.820 296 ##STR01656## 3.250 297 ##STR01657## 0.025
298 ##STR01658## 299 ##STR01659## 300 ##STR01660## 301 ##STR01661##
302 ##STR01662## >50 303 ##STR01663## 304 ##STR01664## 0.680 305
##STR01665## >50 306 ##STR01666## 2.900 307 ##STR01667## 5.360
308 ##STR01668## 2.750 309 ##STR01669## 310 ##STR01670## 8.780 311
##STR01671## 312 ##STR01672## 0.025 313 ##STR01673## 1.630 314
##STR01674## 0.047 315 ##STR01675## 0.267 316 ##STR01676## 0.690
317 ##STR01677## 1.170 318 ##STR01678## 0.037 319 ##STR01679##
0.195 320 ##STR01680## 1.020 321 ##STR01681## 0.030 322
##STR01682## 0.180 323 ##STR01683## 0.360 324 ##STR01684## 1.175
325 ##STR01685## 0.340 326 ##STR01686## 2.750 327 ##STR01687##
0.610 328 ##STR01688## 0.220 329 ##STR01689## 8.870 330
##STR01690## 0.120 331 ##STR01691## 0.085 332 ##STR01692## 0.050
333 ##STR01693## 334 ##STR01694## 0.140 335 ##STR01695## 0.490 336
##STR01696## 0.420 337 ##STR01697## 0.165 338 ##STR01698## 0.035
339 ##STR01699## 0.093 340 ##STR01700## 0.080 341 ##STR01701##
0.085 342 ##STR01702## 0.090 343 ##STR01703## 0.600 344
##STR01704## 0.250 345 ##STR01705## 0.140 346 ##STR01706## 0.330
347 ##STR01707## 0.300 348 ##STR01708## 0.455 349 ##STR01709##
>50 350 ##STR01710## 32.600 351 ##STR01711## >50 352
##STR01712## 0.880 353 ##STR01713## 18.500 354 ##STR01714## 0.380
355 ##STR01715## 0.140 356 ##STR01716## >50 357 ##STR01717##
0.230 358 ##STR01718## 0.805 359 ##STR01719## 0.105 360
##STR01720## 0.280 361 ##STR01721## 0.360 362 ##STR01722## 0.247
363 ##STR01723## 0.050 364 ##STR01724## 37.000 365 ##STR01725##
0.310 366 ##STR01726## 1.100 367 ##STR01727## 368 ##STR01728##
0.310 369 ##STR01729## 7.150 370 ##STR01730## 371 ##STR01731## 372
##STR01732## 373 ##STR01733## >50 374 ##STR01734## 3.580 375
##STR01735## 6.360 376 ##STR01736## 6.070
377 ##STR01737## 2.550 378 ##STR01738## 379 ##STR01739## 0.705 380
##STR01740## 0.420 381 ##STR01741## >50 382 ##STR01742## >50
383 ##STR01743## >50 384 ##STR01744## >50 385 ##STR01745##
8.867 386 ##STR01746## 387 ##STR01747## >50 388 ##STR01748##
13.380 389 ##STR01749## 16.600 390 ##STR01750## >50 391
##STR01751## >50 392 ##STR01752## 0.025 393 ##STR01753## 0.065
394 ##STR01754## 0.135 395 ##STR01755## 0.260 396 ##STR01756##
0.050 397 ##STR01757## 0.040 398 ##STR01758## 0.035 399
##STR01759## 0.030 400 ##STR01760## 0.260 401 ##STR01761## 0.065
402 ##STR01762## 0.077 403 ##STR01763## 0.045 404 ##STR01764##
0.040 405 ##STR01765## 0.010 406 ##STR01766## 0.020 407
##STR01767## 0.040 408 ##STR01768## 0.145 409 ##STR01769## 0.020
410 ##STR01770## 0.010 411 ##STR01771## 0.035 412 ##STR01772##
0.035 413 ##STR01773## 0.033 414 ##STR01774## 0.033 415
##STR01775## 0.040 416 ##STR01776## 0.055 417 ##STR01777## 0.020
418 ##STR01778## 0.050 419 ##STR01779## 0.010 420 ##STR01780##
0.020 421 ##STR01781## 0.050 422 ##STR01782## 0.020 423
##STR01783## 0.175 424 ##STR01784## 0.165 425 ##STR01785## 0.075
426 ##STR01786## 0.060 427 ##STR01787## 0.080 428 ##STR01788##
0.040 429 ##STR01789## 0.060 430 ##STR01790## 0.035 431
##STR01791## 0.025 432 ##STR01792## 0.065 433 ##STR01793## 0.040
434 ##STR01794## 0.470 435 ##STR01795## 0.365 436 ##STR01796##
0.040 437 ##STR01797## 0.050 438 ##STR01798## 0.060 439
##STR01799## 0.110 440 ##STR01800## 0.050 441 ##STR01801## 0.140
442 ##STR01802## 12.480 443 ##STR01803## 0.060 444 ##STR01804##
0.040 445 ##STR01805## 0.490 446 ##STR01806## 0.390 447
##STR01807## 448 ##STR01808## 10.610 449 ##STR01809## 0.135 450
##STR01810## 0.105 451 ##STR01811## 0.070 452 ##STR01812## 0.130
453 ##STR01813## 0.070 454 ##STR01814## 0.077 455 ##STR01815##
0.130 456 ##STR01816## 0.135 457 ##STR01817## 0.080 458
##STR01818## 0.130 459 ##STR01819## 0.310 460 ##STR01820## 0.090
461 ##STR01821## 0.105 462 ##STR01822## 0.780 463 ##STR01823##
0.440 464 ##STR01824## 0.065 465 ##STR01825## 0.050 466
##STR01826## 34.670 467 ##STR01827## 1.810 468 ##STR01828## 0.170
469 ##STR01829## 2.100 470 ##STR01830## 1.130 471 ##STR01831##
0.450 472 ##STR01832## 0.230 473 ##STR01833## 0.110 474
##STR01834## 0.180 475 ##STR01835## 0.050 476 ##STR01836## >50
477 ##STR01837## 0.130 478 ##STR01838## 0.420 479 ##STR01839##
0.110 480 ##STR01840## 0.180 481 ##STR01841## 21.240 482
##STR01842## 0.240 483 ##STR01843## 0.100 484 ##STR01844## 0.070
485 ##STR01845## 0.130 486 ##STR01846## 0.540 487 ##STR01847##
0.380 488 ##STR01848## 0.030 489 ##STR01849## 0.180 490
##STR01850## 0.090 491 ##STR01851## 0.070 492 ##STR01852## 0.030
493 ##STR01853## 0.090 494 ##STR01854## >50
* * * * *
References