U.S. patent application number 16/225991 was filed with the patent office on 2019-05-02 for substituted chromanes and method of use.
The applicant listed for this patent is AbbVie S.a.r.l., Galapagos NV. Invention is credited to Robert J. Altenbach, Andrew Bogdan, Stephen N. Greszler, John R. Koenig, Philip R. Kym, Bo Liu, Xenia B. Searle, Eric Voight, Xueqing Wang, Ming C. Yeung.
Application Number | 20190127356 16/225991 |
Document ID | / |
Family ID | 55858309 |
Filed Date | 2019-05-02 |
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United States Patent
Application |
20190127356 |
Kind Code |
A1 |
Altenbach; Robert J. ; et
al. |
May 2, 2019 |
Substituted Chromanes and Method of Use
Abstract
The invention provides for compounds of formula (I) ##STR00001##
wherein R.sup.1, X, Y, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, m, and
R'' have any of the values defined in the specification, and
pharmaceutically acceptable salts thereof, that are useful as
agents in the treatment of diseases and conditions mediated and
modulated by CFTR, including cystic fibrosis, Sjogren's syndrome,
pancreatic insufficiency, chronic obstructive lung disease, and
chronic obstructive airway disease. Also provided are
pharmaceutical compositions comprised of one or more compounds of
formula (I).
Inventors: |
Altenbach; Robert J.;
(Chicago, IL) ; Bogdan; Andrew; (Evanston, IL)
; Greszler; Stephen N.; (Vernon Hills, IL) ;
Koenig; John R.; (Chicago, IL) ; Kym; Philip R.;
(Libertyville, IL) ; Liu; Bo; (Waukegan, IL)
; Searle; Xenia B.; (Grayslake, IL) ; Voight;
Eric; (Pleasant Prairie, WI) ; Wang; Xueqing;
(Sunnyvale, CA) ; Yeung; Ming C.; (Grayslake,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie S.a.r.l.
Galapagos NV |
Luxembourg
Mechelen |
|
LU
BE |
|
|
Family ID: |
55858309 |
Appl. No.: |
16/225991 |
Filed: |
December 19, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15467737 |
Mar 23, 2017 |
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16225991 |
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14925649 |
Oct 28, 2015 |
9642831 |
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15467737 |
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62073573 |
Oct 31, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61P 11/00 20180101; A61K 31/4025 20130101; A61K 31/435 20130101;
A61K 31/353 20130101; A61K 45/06 20130101; C07D 405/14 20130101;
A61K 31/397 20130101; A61P 43/00 20180101; A61K 31/436 20130101;
A61K 31/00 20130101; C07D 491/107 20130101; C07D 413/14 20130101;
A61P 1/00 20180101; A61K 31/453 20130101; A61K 31/4433 20130101;
C07D 407/12 20130101; C07D 491/052 20130101; A61K 31/353 20130101;
A61K 2300/00 20130101; A61K 31/397 20130101; A61K 2300/00 20130101;
A61K 31/4025 20130101; A61K 2300/00 20130101; A61K 31/435 20130101;
A61K 2300/00 20130101; A61K 31/436 20130101; A61K 2300/00 20130101;
A61K 31/4433 20130101; A61K 2300/00 20130101; A61K 31/453 20130101;
A61K 2300/00 20130101; A61K 31/5377 20130101; A61K 2300/00
20130101 |
International
Class: |
C07D 407/12 20060101
C07D407/12; C07D 491/107 20060101 C07D491/107; C07D 491/052
20060101 C07D491/052; A61K 31/5377 20060101 A61K031/5377; A61K
31/453 20060101 A61K031/453; A61K 31/4433 20060101 A61K031/4433;
A61K 31/435 20060101 A61K031/435; A61K 45/06 20060101 A61K045/06;
A61K 31/397 20060101 A61K031/397; A61K 31/353 20060101 A61K031/353;
A61K 31/00 20060101 A61K031/00; A61K 31/436 20060101 A61K031/436;
C07D 413/14 20060101 C07D413/14; C07D 405/14 20060101 C07D405/14;
A61K 31/4025 20060101 A61K031/4025 |
Claims
1. A compound having the formulae: ##STR00044## or a
pharmaceutically acceptable salt thereof; wherein one or more
hydrogen atoms of the compound are replaced by deuterium.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/467,737 filed on Mar. 23, 2017, which is a
continuation of U.S. patent application Ser. No. 14/925,649 filed
on Oct. 28, 2015, which claims priority to U.S. Provisional Patent
Application No. 62/073,573, filed Oct. 31, 2014, which is
incorporated herein by reference for all purposes.
BACKGROUND
[0002] The invention relates to substituted chromane compounds that
are modulators of the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) protein, useful in treating diseases and
conditions mediated and modulated by CFTR. Additionally, the
invention relates to compositions containing compounds of the
invention and processes for their preparation.
[0003] Cystic fibrosis (CF), one of the most common autosomal
recessive genetic diseases in the Caucasian population, is caused
by loss of function mutations in the Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR) gene, which is located on chromosome 7
(http://www.cff.org/AboutCF/; Rowe S. M et al. (2005); N Eng J Med.
(352), 1992-2001). Approximately 1:3500 and 1:3000 infants born in
the United States and in Europe, respectively, are affected by CF,
resulting in .about.75,000 cases worldwide, .about.30,000 of which
are in the United State. Approximately 1,000 new cases of CF are
diagnosed each year, with more than 75% of patients being diagnosed
by 2 years of age. Nearly half the CF population is currently 18
years of age and older. The CFTR protein (Gregory, R. J. et al.
(1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature
347:358-362; Riordan, J. R. et al. (1989) Science 245:1066-1073) is
a cAMP/ATP-mediated ion channel expressed in a variety of cell
types, including secretory and absorptive epithelial cells. CFTR
regulates chloride and bicarbonate anion flux across the cell
membrane, maintaining electro neutrality and osmolarity across the
epithelial membrane (Quinton, P. M. (1990), FASEB J. 4: 2709-2727).
CFTR is also responsible for regulating the activity of other ion
channels and proteins (Guggino, W. B. et al. (2006), Nat Revs
Molecular Cell Biology 7, 426-436).
[0004] Aberrations in CFTR function result in imbalance of the
airway surface liquid, leading to mucus dehydration, inflammation,
recurrent bacterial infection and irreversible lung damage, which
lead to premature death in affected patients. Besides respiratory
disease, CF patients suffer from gastrointestinal problems and
pancreatic insufficiency. The majority of males (95%) with cystic
fibrosis are infertile as a result of azoospermia caused by altered
vas deferens; which may be absent, atrophic, or fibrotic. Fertility
is also decreased among females with cystic fibrosis due to
abnormal cervical mucus.
[0005] The F508del mutation, the most common of the approximately
1900 identified polymorphisms in CFTR, results in defective
processing of CFTR in the endoplasmic reticulum (ER)
(http://www.cftr2.org/index.php). Approximately 90% of the CF
patients carry at least one copy of the F508del mutation (deletion
of a phenylalanine on position 508), and 50% 60% of the patients
are homozygous for this mutation. The defective processing of CFTR
results in early CFTR degradation, which leads to reduced
trafficking or absence of the protein on the membrane. As there
have been over 100 CF disease-causing mutations identified, they
have been classified according to their phenotypic consequences and
belong to synthesis, maturation, regulation, conductance, reduced
number due to quantity and reduced number due to stability
classifications.
[0006] Current CF drug discovery efforts focus upon developing two
classes of compounds to modulate CFTR. One class, called
Correctors, helps to overcome the folding defects of the mutated
CFTR protein to promote its maturation resulting in higher cell
surface expression. The other classes of compounds, called
Potentiators, help overcome the defective regulation and/or
conductance of the protein by increasing the probability of channel
opening on the membrane surface.
[0007] In addition, as the modulation of CFTR protein mutations to
promote proper protein folding is beneficial for CF, there are
other diseases mediated by CFTR. For example, Sjogren's Syndrome
(SS), an autoimmune disorder that results in symptoms of xerostomia
(dry mouth) and keratoconjunctivitis sicca (KCS, dry eyes) may
result from dysregulation of moisture producing glands throughout
the body. Chronic obstructive lung disease (COLD), or chronic
obstructive airway disease (COAD), which is a progressive and
irreversible airflow limitation in the airways is result of several
physiologic abnormalities, including mucus hyper secretion and
impaired mucociliary secretion. Increasing the anion secretion by
CFTR potentiators have been suggested to overcome these phenotypic
complexities with Sjogren's Syndrome by increasing the corneal
hydration and by overcoming the impaired mucociliary secretion in
COAD (Bhowmik A, et al. (2009) Vol. 103(4), 496-502; Sloane P, et
al. PLOS One (2012) Vol 7(6), 239809 (1-13)).
[0008] Accordingly, there is a need for novel compounds able to
modulate CFTR. In particular, the present invention discloses
compounds that may act as CFTR modulators for the treatment of
cystic fibrosis. The present invention also provides methods for
the preparation of these compounds, pharmaceutical compositions
comprising these compounds and methods for the treatment of cystic
fibrosis by administering the compounds of the invention.
SUMMARY
[0009] In one aspect the invention provides for compounds of
formula (I)
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein: [0010] X is
CR.sup.2 and Y is CR.sup.3; or [0011] X is N and Y is CR.sup.3; or
[0012] X is CR.sup.2 and Y is N; [0013] m is 0, 1, 2, or 3; [0014]
R'' are optional substituents on the cyclopropyl ring, and at each
occurrence, are each independently halogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; [0015] R.sup.1 and R.sup.2,
are each independently hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, --C(O)OR.sup.1B,
--NR.sup.1AR.sup.2A, or --C(O)NR.sup.1AR.sup.2A; [0016] R.sup.1A
and R.sup.2A, at each occurrence, are each independently hydrogen,
C.sub.1-C.sub.6 haloalkyl, G.sup.1A, or C.sub.1-C.sub.6 alkyl;
wherein the C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl
are each optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.ZA,
--SR.sup.ZA, --S(O).sub.2R.sup.ZA, --C(O)R.sup.ZA, --C(O)OR.sup.ZA,
--C(O)N(R.sup.ZA).sub.2, --N(R.sup.ZA).sub.2,
--N(R.sup.ZA)C(O)R.sup.ZB, --N(R.sup.ZA)S(O).sub.2R.sup.ZB,
--N(R.sup.ZA)C(O)OR.sup.ZB, --N(R.sup.ZA)C(O)N(R.sup.ZA).sub.2,
--CN, and G.sup.1A; or R.sup.1A and R.sup.2A together with the
nitrogen atom to which they are attached form a 4-6 membered
heterocycle wherein the 4-6 membered heterocycle is optionally
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.j, and N(R.sup.j).sub.2;
wherein [0017] R.sup.ZA, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
G.sup.1A, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1A; and [0018]
R.sup.ZB, at each occurrence, is independently C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, G.sup.1A, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1A; [0019] R.sup.1B is hydrogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; [0020] R.sup.3 and R.sup.14,
are each independently hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OH, or --O--(C.sub.1-C.sub.6
alkyl); [0021] R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0022] R.sup.5 is hydrogen, --C(O)R.sup.i,
--C(O)OH, --C(O)O(C.sub.1-C.sub.6 alkyl), --C(O)N(R.sup.h).sub.2,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or G.sup.2A;
wherein the C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl
are each optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.h,
--OC(O)N(R.sup.h).sub.2, --C(O)R.sup.h, --C(O)OR.sup.h,
--C(O)N(R.sup.h).sub.2, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, and
G.sup.2A; or [0023] R.sup.4 and R.sup.5, together with the carbon
atom to which they are attached, form a C.sub.3-C.sub.6 cycloalkyl
or a 4-6 membered heterocycle; wherein the C.sub.3-C.sub.6
cycloalkyl and the 4-6 membered heterocycle are each optionally
substituted with 1, 2, or 3 independently selected R.sup.p groups;
[0024] G.sup.2A, at each occurrence, is independently cycloalkyl,
cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is
independently unsubstituted or substituted with 1, 2, or 3
independently selected R.sup.q groups; [0025] R.sup.p and R.sup.q,
at each occurrence, are each independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 haloalkyl, --CN, oxo, NO.sub.2,
--OR.sup.h, --OC(O)R.sup.i, --OC(O)N(R.sup.h).sub.2, --SR.sup.h,
--S(O).sub.2R.sup.h, --S(O).sub.2N(R.sup.h).sub.2, --C(O)R.sup.h,
--C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2,
--C(O)N(R.sup.h)S(O).sub.2R.sup.h, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, or
G.sup.A, wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.h, --OC(O)R.sup.i, --OC(O)N(R.sup.h).sub.2, --SR.sup.h,
--S(O).sub.2R.sup.h, --S(O).sub.2N(R.sup.h).sub.2, --C(O)R.sup.h,
--C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2,
--C(O)N(R.sup.h)S(O).sub.2R.sup.h, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, --CN,
and G.sup.A; [0026] R.sup.h, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.A, wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.j, --OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[0027] R.sup.i, at each occurrence, is independently
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or G.sup.A,
wherein the C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl
are each optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.j,
--OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[0028] R.sup.6 is hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0029] R.sup.7 is hydrogen, halogen,
--OR.sup.j, --N(R.sup.j).sub.2, --N(R.sup.j)C(O)R.sup.k,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3A; [0030] R.sup.8
is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl;
[0031] R.sup.9, R.sup.10, and R.sup.13, are each independently
hydrogen, halogen, --OR.sup.j, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0032] R.sup.11 and R.sup.12 are each
independently hydrogen, C.sub.1-C.sub.3 alkyl, or halogen; [0033]
G.sup.1A, G.sup.3A, and G.sup.A, at each occurrence, are each
independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or
heteroaryl, each of which is independently unsubstituted or
substituted with 1, 2, or 3 independently selected R.sup.s groups;
wherein [0034] R.sup.s, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, oxo, NO.sub.2,
--OR.sup.j, --OC(O)R.sup.k, --OC(O)N(R.sup.j).sub.2, --SR.sup.j,
--S(O).sub.2R.sup.j, --S(O).sub.2N(R.sup.j).sub.2, --C(O)R.sup.j,
--C(O)OR.sup.j, --C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2,
--N(R.sup.j)C(O)R.sup.k, --N(R.sup.j)S(O).sub.2R.sup.k,
--N(R.sup.j)C(O)O(R.sup.k), --N(R.sup.j)C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.1, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.j, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.j,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)O(R.sup.k), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)N(R.sup.j).sub.2, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [0035] R.sup.j at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; and
[0036] R.sup.k, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.
[0037] Another aspect of the invention relates to pharmaceutical
compositions comprising compounds of the invention or
pharmaceutically acceptable salts thereof, and a pharmaceutical
carrier. Such compositions can be administered in accordance with a
method of the invention, typically as part of a therapeutic regimen
for treatment or prevention of conditions and disorders related to
Cystic Fibrosis Transmembrane Conductance Regulator activity. In a
particular aspect, the pharmaceutical compositions may additionally
comprise further one or more therapeutically active ingredients
suitable for use in combination with the compounds of the
invention. In a more particular aspect, the further therapeutically
active ingredient is an agent for the treatment of cystic
fibrosis.
[0038] Moreover, the compounds of the invention or pharmaceutically
acceptable salts thereof, useful in the pharmaceutical compositions
and treatment methods disclosed herein, are pharmaceutically
acceptable as prepared and used.
[0039] Yet another aspect of the invention relates to a method of
correcting the folding defects of the mutated CFTR protein(s) to
promote its maturation resulting in higher cell surface expression.
The method is useful for treating, or preventing conditions and
disorders related to Cystic Fibrosis Transmembrane Conductance
Regulator activity in mammals. More particularly, the method is
useful for treating or preventing conditions and disorders related
to cystic fibrosis, Sjogren's syndrome, pancreatic insufficiency,
chronic obstructive lung disease, or chronic obstructive airway
disease. Accordingly, the compounds and compositions of the
invention are useful as a medicament for treating or preventing
Cystic Fibrosis Transmembrane Conductance Regulator modulated
disease.
[0040] The compounds, compositions comprising the compounds or
pharmaceutically acceptable salts thereof, methods for making the
compounds, and methods for treating or preventing conditions and
disorders by administering the compounds are further described
herein.
[0041] In a particular aspect, the compounds of the invention or
pharmaceutically acceptable salts thereof are provided for use in
the treatment of cystic fibrosis. In a particular aspect, the
compounds of the invention or pharmaceutically acceptable salts
thereof are provided for use in the treatment of cystic fibrosis
caused by class I, II, III, IV, V, and/or VI mutations.
[0042] The present invention also provides pharmaceutical
compositions comprising a compound of the invention or
pharmaceutically acceptable salts thereof, and a suitable
pharmaceutical carrier for use in medicine. In a particular aspect,
the pharmaceutical composition is for use in the treatment of
cystic fibrosis.
[0043] In an alternative embodiment, certain compounds of the
invention have a corrector activity.
[0044] In another particular aspect, certain compounds of the
invention have improved potency, in addition to exhibiting low
effects on CYP3A4 expression, which suggest low drug-drug
interaction potential, and accordingly may be advantageous for
patients under multiple therapies.
[0045] These and other objects of the invention are described in
the following paragraphs. These objects should not be deemed to
narrow the scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0046] Described herein are compounds of formula (I)
##STR00003##
wherein R.sup.1, x, y, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, m, and
R'' are defined above in the Summary of the Invention and below in
the Detailed Description. Further, compositions comprising such
compounds and methods for treating conditions and disorders using
such compounds and compositions are also included.
[0047] Compounds included herein may contain one or more
variable(s) that occur more than one time in any substituent or in
the formulae herein. Definition of a variable on each occurrence is
independent of its definition at another occurrence. Further,
combinations of substituents are permissible only if such
combinations result in stable compounds. Stable compounds are
compounds, which can be isolated from a reaction mixture.
Definitions
[0048] It is noted that, as used in this specification and the
intended claims, the singular form "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes a single
compound as well as one or more of the same or different compounds,
reference to "optionally a pharmaceutically acceptable carrier"
refers to a single optional pharmaceutically acceptable carrier as
well as one or more pharmaceutically acceptable carriers, and the
like.
[0049] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0050] The term "alkenyl" as used herein, means a straight or
branched hydrocarbon chain containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond. The term
"C.sub.2-C.sub.6 alkenyl" means an alkenyl group containing 2-6
carbon atoms. Non-limiting examples of C.sub.2-C.sub.6 alkenyl
include buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl,
3-butenyl, 4-pentenyl, and 5-hexenyl.
[0051] The term "alkyl" as used herein, means a saturated, straight
or branched hydrocarbon chain radical. In some instances, the
number of carbon atoms in an alkyl moiety is indicated by the
prefix "C.sub.x-C.sub.y", wherein x is the minimum and y is the
maximum number of carbon atoms in the substituent. Thus, for
example, "C.sub.1-C.sub.6 alkyl" means an alkyl substituent
containing from 1 to 6 carbon atoms and "C.sub.1-C.sub.3 alkyl"
refers to an alkyl substituent containing from 1 to 3 carbon atoms.
Representative examples of C.sub.1-C.sub.6 alkyl include, but are
not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl,
and 1,2,2-trimethylpropyl.
[0052] The term "alkylene" or "alkylenyl" means a divalent radical
derived from a straight or branched, saturated hydrocarbon chain,
for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms
(C.sub.1-C.sub.6 alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3
carbon atoms (C.sub.1-C.sub.3 alkylenyl) or of 2 to 6 carbon atoms
(C.sub.2-C.sub.6 alkylenyl). Examples of C.sub.1-C.sub.6 alkylenyl
include, but are not limited to, --CH.sub.2--,
--CH.sub.2CH.sub.2--,
--C((CH.sub.3).sub.2)--CH.sub.2CH.sub.2CH.sub.2--,
--C((CH.sub.3).sub.2)--CH.sub.2CH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0053] The term "C.sub.2-C.sub.6 alkynyl" as used herein, means a
straight or branched chain hydrocarbon radical containing from 2 to
6 carbon atoms and containing at least one carbon-carbon triple
bond. Representative examples of C.sub.2-C.sub.6 alkynyl include,
but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,
3-butynyl, 2-pentynyl, and 1-butynyl.
[0054] The term "aryl" as used herein, means phenyl or a bicyclic
aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a
monocyclic cycloalkyl, or a phenyl fused to a monocyclic
cycloalkenyl. Non-limiting examples of the aryl groups include
dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and
tetrahydronaphthalenyl. The phenyl and the bicyclic aryls
(including exemplary rings) are optionally substituted unless
otherwise indicated. The phenyl and the bicyclic aryls are attached
to the parent molecular moiety through any carbon atom contained
within the bicyclic ring systems.
[0055] The term "cycloalkyl" as used herein, refers to a radical
that is a monocyclic cycloalkyl or a bicyclic cycloalkyl. The
monocyclic cycloalkyl is a carbocyclic ring system containing three
to eight carbon atoms, zero heteroatoms and zero double bonds.
Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic
cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic
cycloalkyl ring. The monocyclic and the bicyclic cycloalkyl groups
may further contain one or two alkylene bridges, each consisting of
one, two, three, or four carbon atoms in length, and each bridge
links two non-adjacent carbon atoms of the ring system.
Non-limiting examples of bridged ring systems include
bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,
bicyclo[1.1.1]pentyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl,
bicyclo[4.2.1]nonyl, tricyclo[3.3.1.0.sup.3,7]nonyl
(octahydro-2,5-methanopentalene or noradamantyl), and
tricyclo[3.3.1.1.sup.3,7]decane (adamantyl). The monocyclic and the
bicyclic cycloalkyls, including exemplary rings, are optionally
substituted unless otherwise indicated. The monocyclic cycloalkyl
and the bicyclic cycloalkyl are attached to the parent molecular
moiety through any substitutable carbon atom contained within the
ring systems.
[0056] The term "C.sub.3-C.sub.6 cycloalkyl" as used herein, means
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which
is optionally substituted unless otherwise indicated.
[0057] The term "cycloalkenyl" as used herein, refers to a
monocyclic or a bicyclic hydrocarbon ring radical. The monocyclic
cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms
and zero heteroatoms. The four-membered ring systems have one
double bond, the five- or six-membered ring systems have one or two
double bonds, and the seven- or eight-membered ring systems have
one, two, or three double bonds. Representative examples of
monocyclic cycloalkenyl groups include, but are not limited to,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and
cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic
cycloalkenyl fused to a monocyclic cycloalkyl group, or a
monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.
The monocyclic and bicyclic cycloalkenyl ring may contain one or
two alkylene bridges, each consisting of one, two, or three carbon
atoms, and each linking two non-adjacent carbon atoms of the ring
system. Representative examples of the bicyclic cycloalkenyl groups
include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene,
octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic
and the bicyclic cycloalkenyls, including exemplary rings, are
optionally substituted unless otherwise indicated. The monocyclic
cycloalkenyl and bicyclic cycloalkenyl are attached to the parent
molecular moiety through any substitutable atom contained within
the ring systems.
[0058] The term "halo" or "halogen" as used herein, means Cl, Br,
I, and F.
[0059] The term "haloalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five or six
hydrogen atoms are replaced by halogen. The term "C.sub.1-C.sub.6
haloalkyl" means a C.sub.1-C.sub.6 alkyl group, as defined herein,
in which one, two, three, four, five, or six hydrogen atoms are
replaced by halogen. The term "C.sub.1-C.sub.3 haloalkyl" means a
C.sub.1-C.sub.3 alkyl group, as defined herein, in which one, two,
three, four, or five hydrogen atoms are replaced by halogen.
Representative examples of C.sub.1-C.sub.6 haloalkyl include, but
are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl,
difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl,
trifluorobutyl, and trifluoropropyl.
[0060] The term "heterocycle" or "heterocyclic" as used herein,
means a radical of a monocyclic heterocycle and a bicyclic
heterocycle. A monocyclic heterocycle is a three-, four-, five-,
six-, seven-, or eight-membered carbocyclic ring wherein at least
one carbon atom is replaced by heteroatom independently selected
from the group consisting of O, N, and S. A three- or four-membered
ring contains zero or one double bond, and one heteroatom selected
from the group consisting of O, N, and S. A five-membered ring
contains zero or one double bond and one, two, or three heteroatoms
selected from the group consisting of O, N, and S. Examples of
five-membered heterocyclic rings include those containing in the
ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1
N; or 1 O and 2 N. Non limiting examples of 5-membered heterocyclic
groups include 1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl,
tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl,
imidazolinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl,
pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, and
thiazolidinyl. A six-membered ring contains zero, one, or two
double bonds and one, two, or three heteroatoms selected from the
group consisting of O, N, and S. Examples of six-membered
heterocyclic rings include those containing in the ring: 1 O; 2 O;
1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2
N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples
of 6-membered heterocyclic groups include tetrahydropyranyl,
dihydropyranyl, dioxanyl, 1,4-dithianyl, hexahydropyrimidine,
morpholinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl,
tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl.
Seven- and eight-membered rings contains zero, one, two, or three
double bonds and one, two, or three heteroatoms selected from the
group consisting of O, N, and S. Representative examples of
monocyclic heterocycles include, but are not limited to,
azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,
1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,
imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl,
oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl,
pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl,
tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,
thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. The
bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl
group, or a monocyclic heterocycle fused to a monocyclic
cycloalkyl, or a monocyclic heterocycle fused to a monocyclic
cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic
heterocycle. Representative examples of bicyclic heterocycles
include, but are not limited to, benzopyranyl, benzothiopyranyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl,
2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,
hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl. The monocyclic
heterocycle and the bicyclic heterocycle may further contain one or
two alkylene bridges, each consisting of no more than four carbon
atoms and each linking two non-adjacent atoms of the ring system.
Examples of such bridged heterocycle include, but are not limited
to, azabicyclo[2.2.1]heptyl (including
2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2.1]oct-8-yl,
octahydro-2,5-epoxypentalene,
hexahydro-2H-2,5-methanocyclopenta[b]furan,
hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane
(1-azatricyclo[3.3.1.1.sup.3,7]decane), and oxa-adamantane
(2-oxatricyclo[3.3.1.1.sup.3,7]decane). The monocyclic and the
bicyclic heterocycles, including exemplary rings, are optionally
substituted unless otherwise indicated. The monocyclic and the
bicyclic heterocycles are connected to the parent molecular moiety
through any carbon atom or any nitrogen atom contained within the
ring systems. The nitrogen and sulfur heteroatoms in the
heterocycle rings may optionally be oxidized (e.g.
1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl,
1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally
be quarternized.
[0061] The term "4-6 membered heterocycle" or "4-6 membered
heterocyclic" as used herein, means a 4, 5, or 6 membered
monocyclic heterocycle as defined herein above. Examples of 4-6
membered heterocycle include azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl,
thiomorpholinyl, and morpholinyl. The 4-6 membered heterocycles,
including exemplary rings, are optionally substituted unless
indicated otherwise.
[0062] The term "5-6 membered heterocycle" or "5-6 membered
heterocyclic" as used herein, means a 5 or 6 membered monocyclic
heterocycle as defined herein above. Examples of 5-6 membered
heterocycle include 1,3-dioxolanyl, pyrrolidinyl,
1,2-thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl,
piperazinyl, piperidinyl, thiomorpholinyl, and morpholinyl. The 5-6
membered heterocycles, including exemplary rings, are optionally
substituted unless indicated otherwise.
[0063] The term "heteroaryl" as used herein, means a monocyclic
heteroaryl and a bicyclic heteroaryl. The monocyclic heteroaryl is
a five- or six-membered ring. The five-membered ring contains two
double bonds. The five membered ring may contain one heteroatom
selected from O or S; or one, two, three, or four nitrogen atoms
and optionally one oxygen or one sulfur atom. The six-membered ring
contains three double bonds and one, two, three or four nitrogen
atoms. Representative examples of monocyclic heteroaryl include,
but are not limited to, furanyl, imidazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,
thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The
bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a
phenyl, or a monocyclic heteroaryl fused to a monocyclic
cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic
cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic
heteroaryl, or a monocyclic heteroaryl fused to a monocyclic
heterocycle. Representative examples of bicyclic heteroaryls
include, but are not limited to, benzofuranyl, benzothienyl,
benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl,
2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,
6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,
6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,
indolyl, isoindolyl, isoquinolinyl, naphthyridinyl,
pyridoimidazolyl, quinolinyl,
2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,
thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and
5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic
heteroaryls, including exemplary rings, are optionally substituted
unless otherwise indicated. The monocyclic and bicyclic heteroaryls
are connected to the parent molecular moiety through any
substitutable carbon atom or any substitutable nitrogen atom
contained within the ring systems. The nitrogen atom in the
heteroaryl rings may optionally be oxidized and may optionally be
quarternized.
[0064] The term "5-6 membered heteroaryl" as used herein, means a
5- or 6-membered monocyclic heteroaryl as described above. Examples
of 5-6 membered heteroaryl include furanyl, thienyl, pyrazolyl,
imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,3-thiazolyl,
pyridinyl, pyrimidinyl, and pyrazinyl. The 5-6 membered
heteroaryls, including exemplary rings, are optionally substituted
unless indicated otherwise.
[0065] The term "heteroatom" as used herein, means a nitrogen,
oxygen, and sulfur.
[0066] The term "oxo" as used herein, means a .dbd.O group.
[0067] The term "radiolabel" refers to a compound of the invention
in which at least one of the atoms is a radioactive atom or
radioactive isotope, wherein the radioactive atom or isotope
spontaneously emits gamma rays or energetic particles, for example
alpha particles or beta particles, or positrons. Examples of such
radioactive atoms include, but are not limited to, .sup.3H
(tritium), .sup.14C, .sup.11C, .sup.15O, .sup.18F, .sup.35S,
.sup.123I, and .sup.125I.
[0068] If a moiety is described as "substituted", a non-hydrogen
radical is in the place of hydrogen radical of any substitutable
atom of the moiety. Thus, for example, a substituted heterocycle
moiety is a heterocycle moiety in which at least one non-hydrogen
radical is in the place of a hydrogen radical on the heterocycle.
It should be recognized that if there are more than one
substitution on a moiety, each non-hydrogen radical may be
identical or different (unless otherwise stated).
[0069] If a moiety is described as being "optionally substituted,"
the moiety may be either (1) not substituted or (2) substituted. If
a moiety is described as being optionally substituted with up to a
particular number of non-hydrogen radicals, that moiety may be
either (1) not substituted; or (2) substituted by up to that
particular number of non-hydrogen radicals or by up to the maximum
number of substitutable positions on the moiety, whichever is less.
Thus, for example, if a moiety is described as a heteroaryl
optionally substituted with up to 3 non-hydrogen radicals, then any
heteroaryl with less than 3 substitutable positions would be
optionally substituted by up to only as many non-hydrogen radicals
as the heteroaryl has substitutable positions. To illustrate,
tetrazolyl (which has only one substitutable position) would be
optionally substituted with up to one non-hydrogen radical. To
illustrate further, if an amino nitrogen is described as being
optionally substituted with up to 2 non-hydrogen radicals, then a
primary amino nitrogen will be optionally substituted with up to 2
non-hydrogen radicals, whereas a secondary amino nitrogen will be
optionally substituted with up to only 1 non-hydrogen radical.
[0070] Unless otherwise indicated, the terms C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.6 haloalkyl, and
C.sub.1-C.sub.3 haloalkyl are not further substituted.
[0071] The terms "treat", "treating", and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms.
[0072] The terms "prevent", "preventing", and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring a disease.
[0073] The phrase "therapeutically effective amount" means an
amount of a compound, or a pharmaceutically acceptable salt
thereof, sufficient to prevent the development of or to alleviate
to some extent one or more of the symptoms of the condition or
disorder being treated when administered alone or in conjunction
with one or more additional therapeutic agents for treatment in a
particular subject or subject population. For example in a human or
other mammal, a therapeutically effective amount can be determined
experimentally in a laboratory or clinical setting, or may be the
amount required by the guidelines of the United States Food and
Drug Administration, or equivalent foreign agency, for the
particular disease and subject being treated.
[0074] The term "subject" is defined herein to refer to animals
such as mammals, including, but not limited to, primates (e.g.,
humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits,
rats, mice and the like. In preferred embodiments, the subject is a
human.
[0075] The term `one or more` refers to one to four. In one
embodiment it refers to one or three. In another embodiment it
refers to one to three. In a further embodiment it refers to one to
two. In yet other embodiment it refers to two. In yet other further
embodiment it refers to one.
[0076] As used herein, "Class I mutation(s)" refers to mutations
which interfere with protein synthesis. They result in the
introduction of a premature signal of termination of translation
(stop codon) in the mRNA. The truncated CFTR proteins are unstable
and rapidly degraded, so, the net effect is that there is no
protein at the apical membrane. In particular, Class I mutation(s)
refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T),
or c.579+1G>T (711+1G>T) mutation. More particularly, Class I
mutation(s) refers to G542X; or W1282X mutations.
[0077] As used herein, "Class II mutation(s)" refers to mutations
which affect protein maturation. These lead to the production of a
CFTR protein that cannot be correctly folded and/or trafficked to
its site of function on the apical membrane. In particular, Class
II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or
p.Asn1303Lys (N1303K) mutations. More particularly, Class II
mutation(s) refers to F508del or N1303K mutations.
[0078] As used herein, "Class III mutation(s)" refers to mutations
which alter the regulation of the CFTR channel. The mutated CFTR
protein is properly trafficked and localized to the plasma membrane
but cannot be activated, or it cannot function as a chloride
channel. In particular, Class III mutation(s) refers to p.Gly551Asp
(G551D), G551S, R553G; G1349D; S1251N, G178R, S549N mutations. More
particularly, Class III mutation(s) refers to G551D, R553G, G1349D,
S1251N, G178R, or S549N mutations.
[0079] As used herein, "Class IV mutation(s)" refers to mutations
which affect chloride conductance. The CFTR protein is correctly
trafficked to the cell membrane but generates reduced chloride flow
or a "gating defect" (most are missense mutations located within
the membrane-spanning domain). In particular, Class IV mutation(s)
refers to p.Arg117His (R117H), R347P, or p.Arg334Trp (R334W)
mutations.
[0080] As used herein, "Class V mutation(s)" refers to mutations
which reduce the level of normally functioning CFTR at the apical
membrane or result in a "conductance defect" (for example partially
aberrant splicing mutations or inefficient trafficking missense
mutations). In particular, Class V mutation(s) refers to
c.1210-12T[5] (5T allele), c.S3140-26A>G (3272-26A>G),
c.3850-2477C>T (3849+10kbC>T) mutations.
[0081] As used herein, "Class VI mutation(s)" refers to mutations
which decrease the stability of the CFTR which is present or which
affect the regulation of other channels, resulting in inherent
instability of the CFTR protein. In effect, although functional,
the CFTR protein is unstable at the cell surface and it is rapidly
removed and degraded by cell machinery. In particular, Class VI
mutation(s) refers to Rescued F508del, 120del23, N287Y, 4326del1TC,
or 4279insA mutations. More particularly, Class VI mutation(s)
refers to Rescued F508del mutations.
Compounds
[0082] Compounds of the invention have the general formula (I) as
described above.
[0083] Particular values of variable groups are as follows. Such
values may be used where appropriate with any of the other values,
definitions, claims or embodiments defined hereinbefore or
hereinafter.
[0084] In certain embodiments of formula (I), X is CR.sup.2 and Y
is CR.sup.3. Thus, included herein are compounds of formula (I-a)
or pharmaceutically acceptable salts thereof
##STR00004##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, m, and R'', are as defined in the Summary and embodiments
herein below.
[0085] In certain embodiments of formula (I), X is N and Y is
CR.sup.3. Thus, included herein are compounds of formula (I-b) or
pharmaceutically acceptable salts thereof
##STR00005##
wherein R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
m, and R'', are as defined in the Summary and embodiments herein
below.
[0086] In certain embodiments of formula (I), X is CR.sup.2 and Y
is N. Thus, included herein are compounds of formula (I-c) or
pharmaceutically acceptable salts thereof
##STR00006##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, m, and R'', are as defined in the Summary and embodiments
herein below.
[0087] In certain embodiments, m is 0, 1, 2, or 3.
[0088] In certain embodiments, m is 0.
[0089] In certain embodiments, m is 2.
[0090] In certain embodiments, R'', if present, is halogen. In some
such embodiments, R'' is F.
[0091] In certain embodiments, R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A,
--C(O)OR.sup.1B, --NR.sup.1AR.sup.2A, or
--C(O)NR.sup.1AR.sup.2A.
[0092] In certain embodiments, R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or
--C(O)OR.sup.1B. In some such embodiments, R.sup.1A is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl; and R.sup.1B is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0093] In certain embodiments, R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A.
In some such embodiments, R.sup.1A is C.sub.1-C.sub.3 alkyl.
[0094] In certain embodiments, R.sup.1 is hydrogen, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A. In some such embodiments, R.sup.1A is
C.sub.1-C.sub.3 alkyl.
[0095] In certain embodiments, R.sup.1 is hydrogen, CH.sub.3, or
--OCH.sub.3.
[0096] In certain embodiments, R.sup.1 is hydrogen.
[0097] In certain embodiments, R.sup.1 is halogen. In some such
embodiments, R.sup.1 is F or Cl. In some such embodiments,
R.sup.1-- is F.
[0098] In certain embodiments, R.sup.1 is --OR.sup.1A. In some such
embodiments, R.sup.1A is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl. In some such embodiments, R.sup.1A is
C.sub.1-C.sub.3 alkyl. In some such embodiments, R.sup.1A is
CH.sub.3.
[0099] In certain embodiments, R.sup.1-- is C.sub.1-C.sub.6 alkyl.
In some such embodiments, R.sup.1 is C.sub.1-C.sub.3 alkyl. In some
such embodiments, R.sup.1 is CH.sub.3.
[0100] In certain embodiments, R.sup.1 is --C(O)OR.sup.1B. In some
such embodiments, R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl. In
some such embodiments, R.sup.1B is hydrogen or CH.sub.3. In some
such embodiments, R.sup.1B is hydrogen. In some such embodiments,
R.sup.1B is CH.sub.3
[0101] In certain embodiments, R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or
--C(O)OR.sup.1B. In some such embodiments, R.sup.1A is hydrogen,
C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the
C.sub.1-C.sub.3 alkyl is optionally substituted with one
substituent selected from the group consisting of --OR.sup.ZA,
--C(O)OH, and G.sup.1A; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl. In some such embodiments, G.sup.1A is phenyl optionally
substituted with 1, 2, or 3 R.sup.s groups wherein each R.sup.s is
independently C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
halogen, or --OCH.sub.3. In some such embodiments, G.sup.1A is
unsubstituted phenyl. In some such embodiments, R.sup.ZA is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl.
[0102] In certain embodiments, R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A.
In some such embodiments, the halogen is Br, F or Cl. In some such
embodiments, R.sup.1A is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3 alkyl is
optionally substituted with one --OR.sup.ZA wherein R.sup.ZA is
C.sub.1-C.sub.3 alkyl.
[0103] In certain embodiments, R.sup.2 is hydrogen, halogen, or
--OR.sup.1A wherein R.sup.1A is C.sub.1-C.sub.3 alkyl or
C.sub.1-C.sub.3 haloalkyl. In some such embodiments, the halogen is
F or Cl.
[0104] In certain embodiments, R.sup.2 is hydrogen, F, CF.sub.3,
CH.sub.3, --OCH.sub.3, --OCHF.sub.2, --OCH.sub.2CH.sub.2F, or
--OCH.sub.2CH.sub.2OCH.sub.3.
[0105] In certain embodiments, R.sup.2 is hydrogen.
[0106] In certain embodiments, R.sup.2 is halogen. In some such
embodiments, the halogen is F, Cl, or Br. In some such embodiments,
the halogen is F or Cl.
[0107] In certain embodiments, R.sup.2 is C.sub.1-C.sub.6
haloalkyl. In certain embodiments, R.sup.2 is C.sub.1-C.sub.3
haloalkyl. In some such embodiments, R.sup.2 is CF.sub.3.
[0108] In certain embodiments, R.sup.2 is C.sub.1-C.sub.6 alkyl. In
some such embodiments, R.sup.2 is C.sub.1-C.sub.3 alkyl. In some
such embodiments, R.sup.2 is CH.sub.3.
[0109] In certain embodiments, R.sup.2 is --OR.sup.1A.
[0110] In certain embodiments, R.sup.2 is --OR.sup.1A wherein
R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl
wherein the C.sub.1-C.sub.3 alkyl is optionally substituted with
one substituent selected from the group consisting of --OR.sup.ZA,
--C(O)OH, and G.sup.1A. In some such embodiments, G.sup.1A is
phenyl optionally substituted with 1, 2, or 3 R.sup.s groups
wherein each R.sup.s is independently C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, halogen, or --OCH.sub.3. In some such
embodiments, G.sup.1A is unsubstituted phenyl. In some such
embodiments, R.sup.ZA is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl. In some such embodiments, R.sup.ZA is
C.sub.1-C.sub.3 alkyl.
[0111] In certain embodiments R.sup.2 is --OR.sup.1A wherein
R.sup.1A is --CHF.sub.2, --CH.sub.2CH.sub.2F, or C.sub.1-C.sub.3
alkyl wherein the C.sub.1-C.sub.3 alkyl is optionally substituted
with one --OCH.sub.3.
[0112] In certain embodiments, R.sup.3 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OH, or
--O--(C.sub.1-C.sub.6 alkyl).
[0113] In certain embodiments, R.sup.3 is hydrogen or halogen. In
some such embodiments, the halogen is F or Cl. In some such
embodiments, the halogen is F.
[0114] In certain embodiments, R.sup.3 is hydrogen.
[0115] In certain embodiments, R.sup.3 is halogen. In some such
embodiments, the halogen is F or Cl. In some such embodiments, the
halogen is F.
[0116] In certain embodiments, R.sup.4 is hydrogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; and R.sup.5 is hydrogen,
--C(O)R.sup.1, --C(O)OH, --C(O)O(C.sub.1-C.sub.6 alkyl),
--C(O)N(R.sup.h).sub.2, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkyl, or G.sup.2A.
[0117] In certain embodiments, R.sup.4 is hydrogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; and R.sup.5 is hydrogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or G.sup.2A. In
some such embodiments, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 4-6 membered heterocycle, or 5-6 membered heteroaryl.
In some such embodiments, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, azetidinyl, tetrahydrofuranyl or pyridinyl. In some
such embodiments, G.sup.2A is phenyl or cyclohexyl. In some such
embodiments, G.sup.2A is phenyl. In some such embodiments, G.sup.2A
is monocyclic cycloalkyl. In some such embodiments, G.sup.2A is
cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, or cyclohexyl. In
some such embodiments, G.sup.2A is C.sub.3-C.sub.6 cycloalkyl. In
some such embodiments, G.sup.2A is cyclopropyl or cyclohexyl. In
some such embodiments, G.sup.2A is cyclohexyl. In some such
embodiments, G.sup.2A is 5-6 membered heteroaryl. In some such
embodiments, G.sup.2A is thiazolyl or pyridinyl. In some such
embodiments, G.sup.2A is pyridinyl. In some such embodiments,
G.sup.2A is 4-6 membered heterocycle. In some such embodiments,
G.sup.2A is azetidinyl or tetrahydrofuranyl.
[0118] In certain embodiments, R.sup.4 is hydrogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; and R.sup.5 is hydrogen,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl.
[0119] In certain embodiments, R.sup.4 is hydrogen, CH.sub.2F,
CHF.sub.2, CF.sub.3, CH.sub.3, or CH.sub.2CH.sub.3; and R.sup.5 is
hydrogen, CH.sub.2F, CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3.
[0120] In certain embodiments, R.sup.4 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.5 is hydrogen or C.sub.1-C.sub.3
alkyl.
[0121] In certain embodiments, R.sup.4 is hydrogen; and R.sup.5 is
hydrogen.
[0122] In certain embodiments, R.sup.4 is hydrogen, C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl; and R.sup.5 is G.sup.2A.
[0123] In certain embodiments, R.sup.4 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.5 is G.sup.2A.
[0124] In certain embodiments, R.sup.4 is hydrogen and R.sup.5 is
G.sup.2A.
[0125] In certain embodiments, examples of G.sup.2A include phenyl,
monocyclic cycloalkyl (for example, cyclopropyl, cyclobutyl,
bicyclo[1.1.1]pentyl, or cyclohexyl), 4-6 membered heterocycle (for
example, azetidinyl or tetrahyrofuranyl), or 5-6 membered
heteroaryl (for example, thiazolyl or pyridinyl).
[0126] In certain embodiments, examples of G.sup.2A include phenyl,
C.sub.3-C.sub.6 cycloalkyl (for example, cyclopropyl, cyclohexyl),
4-6 membered heterocycle (for example, azetidinyl,
tetrahyrofuranyl), or 5-6 membered heteroaryl (for example,
pyridinyl).
[0127] In certain embodiments, G.sup.2A is phenyl, cyclopropyl,
cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentyl, azetidinyl,
tetrahyrofuranyl, thiazolyl, or pyridinyl.
[0128] In certain embodiments, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, azetidinyl, tetrahyrofuranyl, or pyridinyl.
[0129] In certain embodiments, G.sup.2A is phenyl.
[0130] In certain embodiments, G.sup.2A is monocyclic
cycloalkyl.
[0131] In certain embodiments, G.sup.2A is C.sub.3-C.sub.6
cycloalkyl.
[0132] In certain embodiments, G.sup.2A is 4-6 membered
heterocycle.
[0133] In certain embodiments, G.sup.2A is 5-6 membered
heteroaryl.
[0134] In certain embodiments, G.sup.2A is phenyl or
cyclohexyl.
[0135] In certain embodiments, G.sup.2A is cyclopropyl or
cyclohexyl.
[0136] In certain embodiments, G.sup.2A is cyclohexyl.
[0137] Each G.sup.2A, including specific examples, is optionally
substituted with 1, 2, or 3 independently selected R.sup.q
groups.
[0138] In certain embodiments, G.sup.2A, including specific
examples, is unsubstituted.
[0139] In certain embodiments, G.sup.2A, including specific
examples, is substituted with 1, 2, or 3 independently selected
R.sup.q groups.
[0140] In certain embodiments, G.sup.2A, including specific
examples, is substituted with one R.sup.q group.
[0141] In certain embodiments, R.sup.q, when present, is [0142]
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one --OH group; halogen, [0143]
C.sub.1-C.sub.6 haloalkyl; [0144] --OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0145] --C(O)R.sup.h wherein
R.sup.h is G.sup.A; and G.sup.A is optionally substituted 4-6
membered heterocycle; [0146] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl; [0147] --C(O)N(R.sup.h).sub.2;
wherein R.sup.h, at each occurrence, is independently hydrogen,
optionally substituted cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
substituents independently selected from the group consisting of
--OH and optionally substituted cycloalkyl; [0148]
--C(O)N(R.sup.h)S(O).sub.2R.sup.h wherein R.sup.h is hydrogen or
C.sub.1-C.sub.6 alkyl; or [0149] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0150] In certain embodiments, R.sup.q, when present, is [0151]
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one --OH group; halogen, [0152]
C.sub.1-C.sub.6 haloalkyl; [0153] --OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0154] --C(O)R.sup.h wherein
R.sup.h is G.sup.A; and G.sup.A is optionally substituted 4-6
membered heterocycle; [0155] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl; [0156] --C(O)N(R.sup.h).sub.2;
wherein R.sup.h, at each occurrence, is independently hydrogen,
optionally substituted cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0157] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0158] In certain embodiments, R.sup.q, when present, is --OR.sup.h
wherein R.sup.h is C.sub.1-C.sub.3 alkyl, or R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl.
[0159] In certain embodiments, one of R.sup.q is --C(O)OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.6 alkyl, or one of
R.sup.q is --C(O)N(H)(R.sup.h) wherein R.sup.h is cyclopentyl, or
R.sup.h is C.sub.1-C.sub.6 alkyl which is substituted with 1 or 2
--OH groups; and the other optional R.sup.q groups are
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, and C.sub.1-C.sub.3 haloalkyl.
[0160] In certain embodiments, R.sup.q is --C(O)OR.sup.h wherein
R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. In some such
embodiments, R.sup.h is hydrogen. In some such embodiments, R.sup.h
is C.sub.1-C.sub.3 alkyl.
[0161] In certain embodiments, G.sup.2A is
##STR00007##
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. In some such
embodiments, R.sup.h is hydrogen. In some such embodiments, R.sup.h
is C.sub.1-C.sub.3 alkyl.
[0162] In certain embodiments, G.sup.2A is
##STR00008##
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. In some such
embodiments, R.sup.h is hydrogen. In some such embodiments, R.sup.h
is C.sub.1-C.sub.3 alkyl.
[0163] In certain embodiments, G.sup.2A is
##STR00009##
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. In some such
embodiments, R.sup.h is hydrogen. In some such embodiments, R.sup.h
is C.sub.1-C.sub.3 alkyl.
[0164] In certain embodiments, G.sup.2A is
##STR00010##
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. In some such
embodiments, R.sup.h is hydrogen. In some such embodiments, R.sup.h
is C.sub.1-C.sub.3 alkyl.
[0165] In certain embodiments, R.sup.4 is hydrogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; and R.sup.5 is --C(O)OH,
--C(O)O(C.sub.1-C.sub.6 alkyl), --C(O)R.sup.i, or
--C(O)N(R.sup.h).sub.2. In some such embodiments, R.sup.i is
optionally substituted monocyclic heterocycle. In some such
embodiments, one of R.sup.h is hydrogen or C.sub.1-C.sub.6 alkyl
which is optionally substituted with one or two --OH, and the other
R.sup.h is optionally substituted monocyclic heterocycle,
optionally substituted aryl, or C.sub.1-C.sub.6 alkyl which is
optionally substituted with one or two substituents independently
selected from the group consisting of --OH and optionally
substituted phenyl.
[0166] In certain embodiments, R.sup.4 and R.sup.5, together with
the carbon atom to which they are attached, form a C.sub.3-C.sub.6
cycloalkyl or a 4-6 membered heterocycle.
[0167] In certain embodiments R.sup.4 and R.sup.5, together with
the carbon atom to which they are attached, form a 4-6 membered
heterocycle. In some such embodiments, the 4-6 membered heterocycle
is azetidinyl or piperidinyl.
[0168] In certain embodiments R.sup.4 and R.sup.5, together with
the carbon atom to which they are attached, form a C.sub.3-C.sub.6
cycloalkyl, optionally substituted with 1 or 2 R.sup.p groups.
[0169] In certain embodiments, the C.sub.3-C.sub.6 cycloalkyl is
unsubstituted cyclobutyl or unsubstituted cyclopentyl.
[0170] In certain embodiments, the 4-6 membered heterocycle formed
by R.sup.4 and R.sup.5, and the carbon atom to which they are
attached, is optionally substituted with 1 or 2 R.sup.p groups.
[0171] In certain embodiments, R.sup.p, when present, are each
independently C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with 1 or 2 --OH groups; [0172]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [0173]
C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl or
--CH.sub.2-phenyl; or [0174] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0175] In certain embodiments, R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.7 is hydrogen or C.sub.1-C.sub.3
alkyl.
[0176] In certain embodiments, R.sup.6 is hydrogen and R.sup.7 is
hydrogen.
[0177] In certain embodiments, R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.7 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3A. In some such embodiments, R.sup.7 is
--(CH.sub.2)-G.sup.3A.
[0178] In certain embodiments, G.sup.3A is phenyl which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.s groups. In some such embodiments, each R.sup.s is
independently C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3
haloalkyl, or --OR.sup.j wherein R.sup.j is hydrogen or
C.sub.1-C.sub.3 alkyl. In some such embodiments, each R.sup.s is
independently --OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3
alkyl.
[0179] In certain embodiments of, R.sup.8 is hydrogen,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl.
[0180] In certain embodiments, R.sup.8 is hydrogen.
[0181] In certain embodiments, R.sup.9, R.sup.10, and R.sup.13, are
each independently hydrogen, halogen, --OR.sup.j, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl.
[0182] In certain embodiments, R.sup.9, R.sup.10, and R.sup.13, are
each independently hydrogen or halogen.
[0183] In certain embodiments, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen.
[0184] In certain embodiments, R.sup.11 and R.sup.12, are each
independently hydrogen, C.sub.1-C.sub.3 alkyl, or halogen.
[0185] In certain embodiments, R.sup.11 and R.sup.12 are each
independently hydrogen or halogen. In some such embodiments, the
halogen is F.
[0186] In certain embodiments, R.sup.11 and R.sup.12 are hydrogen,
or R.sup.11 and R.sup.12 are halogen. In some such embodiments, the
halogen is F.
[0187] In certain embodiments, R.sup.11 and R.sup.12 are
hydrogen.
[0188] In certain embodiments, R.sup.11 and R.sup.12 are
halogen.
[0189] In certain embodiments, R.sup.11 and R.sup.12 are F.
[0190] In certain embodiments, R.sup.11 is hydrogen or halogen.
[0191] In certain embodiments, R.sup.11 is hydrogen.
[0192] Various embodiments of substituents R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, m, and R'' have
been discussed above. These substituents embodiments can be
combined to form various embodiments of the invention. All
embodiments of present compounds, formed by combining the
substituent embodiments discussed above are within the scope of
Applicant's invention, and some illustrative embodiments of present
compounds are provided below.
[0193] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein R.sup.8 is hydrogen; and
m is 0.
[0194] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein R.sup.8 is hydrogen; m
is 0, and R.sup.9, R.sup.10, and R.sup.13 are each independently
hydrogen or halogen.
[0195] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein R.sup.8 is hydrogen; m
is 0, and R.sup.9, R.sup.10, and R.sup.13 are hydrogen.
[0196] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein R.sup.8 is hydrogen; m
is 0, R.sup.9, R.sup.10, and R.sup.13 are each independently
hydrogen or halogen; and R.sup.11 and R.sup.12 are hydrogen, or
R.sup.11 and R.sup.12 are halogen. In some such embodiment, the
halogen is F.
[0197] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein R.sup.8 is hydrogen; m
is 0, R.sup.9, R.sup.10, and R.sup.13 are hydrogen, and R.sup.11
and R.sup.12 are halogen. In some such embodiment, R.sup.11 and
R.sup.12 are F.
[0198] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein R.sup.8 is hydrogen; m
is 0, R.sup.9, R.sup.10, and R.sup.13 are hydrogen, R.sup.11 and
R.sup.12 are halogen, and R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or
--C(O)OR.sup.1B; wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl. In some such embodiment, R.sup.11 and R.sup.12 are F.
[0199] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), or (I-c), wherein [0200] R.sup.8 is hydrogen;
[0201] m is 0, [0202] R.sup.9, R.sup.10, and R.sup.13 are hydrogen,
[0203] R.sup.11 and R.sup.12 are halogen, [0204] R.sup.1 is
hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkyl, --OR.sup.1A, or --C(O)OR.sup.1B; wherein R.sup.1A is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl; and R.sup.1B is
hydrogen or C.sub.1-C.sub.3 alkyl; and [0205] R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
--OR.sup.1A, or --C(O)OR.sup.1B; wherein R.sup.1A is hydrogen,
C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the
C.sub.1-C.sub.3 alkyl is optionally substituted with one
substituent selected from the group consisting of --OR.sup.ZA,
--C(O)OH, and G.sup.1A; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl.
[0206] In some such embodiment, G.sup.1A is phenyl optionally
substituted with 1, 2, or 3 R.sup.s groups wherein each R.sup.s is
independently C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
halogen, or --OCH.sub.3. In some such embodiment, G.sup.1A is
unsubstituted phenyl. In some such embodiment, R.sup.ZA is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl.
[0207] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), or (I-b), wherein [0208] R.sup.8 is hydrogen;
[0209] m is 0, [0210] R.sup.9, R.sup.10, and R.sup.13 are hydrogen,
[0211] R.sup.11 and R.sup.12 are halogen, [0212] R.sup.1 is
hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkyl, --OR.sup.1A, or --C(O)OR.sup.1B; wherein R.sup.1A is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl; and R.sup.1B is
hydrogen or C.sub.1-C.sub.3 alkyl; and [0213] R.sup.3 is hydrogen
or halogen.
[0214] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, and R.sup.14 is
hydrogen or halogen.
[0215] In one embodiment, the invention is directed to compounds of
formula (I), (Ia), (I-b), or (I-c) wherein
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, or G.sup.2A; R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.7 is hydrogen or C.sub.1-C.sub.3
alkyl.
[0216] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0217] In one embodiment, the invention is directed to compounds of
formula (I) or (Ia) wherein [0218] R.sup.4 and R.sup.5, together
with the carbon atom to which they are attached, form a
C.sub.3-C.sub.6 cycloalkyl or a 4-6 membered heterocycle; wherein
the C.sub.3-C.sub.6 cycloalkyl and the 4-6 membered heterocycle are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.p groups; [0219] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0220] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0221] In some such embodiment, R.sup.p, when present, are each
independently C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with 1 or 2 --OH groups; [0222]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [0223]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [0224] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0225] In one embodiment, the invention is directed to compounds of
formula (I) or (I-a) wherein
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen
or C.sub.1-C.sub.3 alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and R.sup.7 is --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3A.
[0226] In some such embodiment, R.sup.7 is --(CH.sub.2)-G.sup.3A.
In some such embodiment, G.sup.3A is phenyl optionally substituted
with 1, 2, or 3 independently selected R.sup.s groups. In some such
embodiment, G.sup.3A is phenyl optionally substituted with 1, 2, or
3 R.sup.s groups wherein each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, halogen, or
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[0227] In one embodiment, the invention is directed to compounds of
formula (I) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, R.sup.4 is hydrogen,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl; R.sup.5 is
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.2A; R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl; and R.sup.14 and R.sup.3 are
each independently hydrogen or halogen.
[0228] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0229] In one embodiment, the invention is directed to compounds of
formula (I) wherein [0230] R.sup.8 is hydrogen; [0231] m is 0,
[0232] R.sup.9, R.sup.10, and R.sup.13 are hydrogen, [0233]
R.sup.11 and R.sup.12 are halogen, [0234] R.sup.4 and R.sup.5,
together with the carbon atom to which they are attached, form a
C.sub.3-C.sub.6 cycloalkyl or a 4-6 membered heterocycle; wherein
the C.sub.3-C.sub.6 cycloalkyl and the 4-6 membered heterocycle are
each optionally substituted with 1, 2, or 3 independently selected
R' groups; [0235] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl;
[0236] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0237]
R.sup.14 and R.sup.3 are each independently hydrogen or halogen.
[0238] In some such embodiment, R.sup.p, when present, are each
independently C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with 1 or 2 --OH groups; [0239]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [0240]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [0241] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0242] In one embodiment, the invention is directed to compounds of
formula (I) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, R.sup.4 is hydrogen or
C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen or C.sub.1-C.sub.3
alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.7 is
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3A; and R.sup.14 and R.sup.3
are each independently hydrogen or halogen.
[0243] In some such embodiment, R.sup.7 is --(CH.sub.2)-G.sup.3A.
In some such embodiment, G.sup.3A is phenyl optionally substituted
with 1, 2, or 3 independently selected R.sup.s groups. In some such
embodiment, G.sup.3A is phenyl optionally substituted with 1, 2, or
3 R.sup.s groups wherein each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, halogen, or
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[0244] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein R.sup.8 is hydrogen; and m is 0.
[0245] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein R.sup.8 is hydrogen; m is 0, and R.sup.9,
R.sup.10, and R.sup.13 are each independently hydrogen or
halogen.
[0246] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein R.sup.8 is hydrogen; m is 0, and R.sup.9,
R.sup.10, and R.sup.13 are hydrogen.
[0247] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are each independently hydrogen or halogen;
and R.sup.11 and R.sup.12 are hydrogen, or R.sup.11 and R.sup.12
are halogen. In some such embodiment, the halogen is F.
[0248] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, and R.sup.11 and R.sup.12 are
halogen. In some such embodiment, R.sup.11 and R.sup.12 are F.
[0249] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, R.sup.11 and R.sup.12 are
halogen, and R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl. In some
such embodiment, R.sup.11 and R.sup.12 are F.
[0250] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein
[0251] R.sup.8 is hydrogen; [0252] m is 0, [0253] R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, [0254] R.sup.11 and R.sup.12
are halogen, [0255] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; and
[0256] R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1A; wherein
R.sup.1A is hydrogen, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3
alkyl wherein the C.sub.1-C.sub.3 alkyl is optionally substituted
with one substituent selected from the group consisting of
--OR.sup.ZA, --C(O)OH, and G.sup.1A; and R.sup.1B is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0257] In some such embodiment, G.sup.1A is phenyl optionally
substituted with 1, 2, or 3 R.sup.s groups wherein each R.sup.s is
independently C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
halogen, or --OCH.sub.3. In some such embodiments, G.sup.1A is
unsubstituted phenyl. In some such embodiments, R.sup.ZA is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl.
[0258] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein [0259] R.sup.8 is hydrogen; [0260] m is 0,
[0261] R.sup.9, R.sup.10, and R.sup.13 are hydrogen, [0262]
R.sup.11 and R.sup.12 are halogen, [0263] R.sup.1 is hydrogen,
halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
--OR.sup.1A, or --C(O)OR.sup.1B; wherein R.sup.1A is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl; and R.sup.1B is
hydrogen or C.sub.1-C.sub.3 alkyl; and [0264] R.sup.3 is hydrogen
or halogen.
[0265] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, and R.sup.14 is
hydrogen or halogen.
[0266] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, or G.sup.2A; R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.7 is hydrogen or C.sub.1-C.sub.3
alkyl.
[0267] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0268] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein [0269] R.sup.4 and R.sup.5, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.6
cycloalkyl or a 4-6 membered heterocycle; wherein the
C.sub.3-C.sub.6 cycloalkyl and the 4-6 membered heterocycle are
each optionally substituted with 1, 2, or 3 independently selected
R.sup.p groups; [0270] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0271] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0272] In some such embodiment, R.sup.p, when present, are each
independently C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with 1 or 2 --OH groups; [0273]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [0274]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [0275] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0276] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen
or C.sub.1-C.sub.3 alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and R.sup.7 is --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3A.
[0277] In some such embodiment, R.sup.7 is --(CH.sub.2)-G.sup.3A.
In some such embodiment, G.sup.3A is phenyl optionally substituted
with 1, 2, or 3 independently selected R.sup.s groups. In some such
embodiment, G.sup.3A is phenyl optionally substituted with 1, 2, or
3 R.sup.s groups wherein each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, halogen, or
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[0278] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, R.sup.4 is hydrogen,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl; R.sup.5 is
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.2A; R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl; and R.sup.14 and R.sup.3 are
each independently hydrogen or halogen.
[0279] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0280] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein
[0281] R.sup.8 is hydrogen; [0282] m is 0, [0283] R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, [0284] R.sup.11 and R.sup.12
are halogen, [0285] R.sup.4 and R.sup.5, together with the carbon
atom to which they are attached, form a C.sub.3-C.sub.6 cycloalkyl
or a 4-6 membered heterocycle; wherein the C.sub.3-C.sub.6
cycloalkyl and the 4-6 membered heterocycle are each optionally
substituted with 1, 2, or 3 independently selected R' groups;
[0286] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; [0287] R.sup.7
is hydrogen or C.sub.1-C.sub.3 alkyl; and [0288] R.sup.14 and
R.sup.3 are each independently hydrogen or halogen. [0289] In some
such embodiment, R.sup.p, when present, are each independently
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with 1 or 2 --OH groups; [0290]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [0291]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [0292] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0293] In one embodiment, the invention is directed to compounds of
formula (I-a) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, R.sup.4 is hydrogen or
C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen or C.sub.1-C.sub.3
alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.7 is
--(C.sub.1-C.sub.6 alkylenyl)-G.sup.3A; and R.sup.14 and R.sup.3
are each independently hydrogen or halogen.
[0294] In some such embodiment, R.sup.7 is --(CH.sub.2)-G.sup.3A.
In some such embodiment, G.sup.3A is phenyl optionally substituted
with 1, 2, or 3 independently selected R.sup.s groups. In some such
embodiment, G.sup.3A is phenyl optionally substituted with 1, 2, or
3 R.sup.s groups wherein each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, halogen, or
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[0295] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein R.sup.8 is hydrogen; and m is 0.
[0296] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein R.sup.8 is hydrogen; m is 0, and R.sup.9,
R.sup.10, and R.sup.13 are each independently hydrogen or
halogen.
[0297] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein R.sup.8 is hydrogen; m is 0, and R.sup.9,
R.sup.10, and R.sup.13 are hydrogen.
[0298] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are each independently hydrogen or halogen;
and R.sup.11 and R.sup.12 are hydrogen, or R.sup.11 and R.sup.12
are halogen. In some such embodiment, the halogen is F.
[0299] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, and R.sup.11 and R.sup.12 are
halogen. In some such embodiment, R.sup.11 and R.sup.12 are F.
[0300] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, R.sup.11 and R.sup.12 are
halogen, and R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl. In some
such embodiment, R.sup.11 and R.sup.12 are F.
[0301] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein
[0302] R.sup.8 is hydrogen; [0303] m is 0, [0304] R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, [0305] R.sup.11 and R.sup.12
are halogen, [0306] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; and
[0307] R.sup.3 is hydrogen or halogen.
[0308] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, and R.sup.14 is
hydrogen or halogen.
[0309] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, or G.sup.2A; R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.7 is hydrogen or C.sub.1-C.sub.3
alkyl.
[0310] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0311] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, R.sup.4 is hydrogen,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl; R.sup.5 is
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.2A; R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl; and R.sup.14 and R.sup.3 are
each independently hydrogen or halogen.
[0312] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0313] In one embodiment, the invention is directed to compounds of
formula (I-b) wherein [0314] R.sup.8 is hydrogen; [0315] m is 0,
[0316] R.sup.9, R.sup.10, and R.sup.13 are hydrogen, [0317]
R.sup.11 and R.sup.12 are halogen, [0318] R.sup.4 is hydrogen or
C.sub.1-C.sub.3 alkyl; [0319] R.sup.5 is G.sup.2A wherein G.sup.2A
is phenyl which is substituted with one R.sup.q; wherein R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.3
alkyl; [0320] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; [0321]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl; [0322] R.sup.14 and
R.sup.3 are each independently hydrogen or halogen; and [0323]
R.sup.1 is hydrogen.
[0324] In some such embodiment, R.sup.q is --C(O)OR.sup.h wherein
R.sup.h is hydrogen. In some such embodiment, R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is C.sub.1-C.sub.3 alkyl.
[0325] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein R.sup.8 is hydrogen; and m is 0.
[0326] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein R.sup.8 is hydrogen; m is 0, and R.sup.9,
R.sup.10, and R.sup.13 are each independently hydrogen or
halogen.
[0327] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein R.sup.8 is hydrogen; m is 0, and R.sup.9,
R.sup.10, and R.sup.13 are hydrogen.
[0328] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are each independently hydrogen or halogen;
and R.sup.11 and R.sup.12 are hydrogen, or R.sup.11 and R.sup.12
are halogen. In some such embodiment, the halogen is F.
[0329] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, and R.sup.11 and R.sup.12 are
halogen. In some such embodiment, R.sup.11 and R.sup.12 are F.
[0330] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein R.sup.8 is hydrogen; m is 0, R.sup.9,
R.sup.10, and R.sup.13 are hydrogen, R.sup.11 and R.sup.12 are
halogen, and R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl. In some
such embodiment, R.sup.11 and R.sup.12 are F.
[0331] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein [0332] R.sup.8 is hydrogen; [0333] m is 0,
[0334] R.sup.9, R.sup.10, and R.sup.13 are hydrogen, [0335]
R.sup.11 and R.sup.12 are halogen, [0336] R.sup.1 is hydrogen,
halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
--OR.sup.1A, or --C(O)OR.sup.1B; wherein R.sup.1A is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl; and R.sup.1B is
hydrogen or C.sub.1-C.sub.3 alkyl; and [0337] R.sup.2 is hydrogen,
halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
--OR.sup.1A, or --C(O)OR.sup.1B; wherein R.sup.1A is hydrogen,
C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the
C.sub.1-C.sub.3 alkyl is optionally substituted with one
substituent selected from the group consisting of --OR.sup.ZA,
--C(O)OH, and G.sup.1A; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl.
[0338] In some such embodiment, G.sup.1A is phenyl optionally
substituted with 1, 2, or 3 R.sup.s groups wherein each R.sup.s is
independently C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
halogen, or --OCH.sub.3. In some such embodiments, G.sup.1A is
unsubstituted phenyl. In some such embodiments, R.sup.ZA is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl.
[0339] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, and R.sup.14 is
hydrogen or halogen.
[0340] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, or G.sup.2A; R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.7 is hydrogen or C.sub.1-C.sub.3
alkyl.
[0341] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0342] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein
R.sup.8 is hydrogen; m is 0, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen, R.sup.11 and R.sup.12 are halogen, R.sup.4 is hydrogen,
C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl; R.sup.5 is
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.2A; R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl; and R.sup.14 is hydrogen or
halogen.
[0343] In some such embodiment, G.sup.2A is phenyl, C.sub.3-C.sub.6
cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocycle.
In some such embodiment, G.sup.2A is phenyl, cyclopropyl,
cyclohexyl, pyridinyl, tetrahydropyranyl, or azetidinyl. In some
such embodiment, G.sup.2A is phenyl or cyclohexyl. In some such
embodiment, G.sup.2A is phenyl. In some such embodiment, G.sup.2A
is cyclohexyl. Each G.sup.2A is optionally substituted with 1, 2,
or 3 independently selected R.sup.q groups.
[0344] In one embodiment, the invention is directed to compounds of
formula (I-c) wherein [0345] R.sup.8 is hydrogen; [0346] m is 0,
[0347] R.sup.9, R.sup.10, and R.sup.13 are hydrogen, [0348]
R.sup.11 and R.sup.12 are halogen, [0349] R.sup.4 is hydrogen or
C.sub.1-C.sub.3 alkyl; [0350] R.sup.5 is G.sup.2A wherein G.sup.2A
is phenyl which is substituted with one R.sup.q; wherein R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.3
alkyl; [0351] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; [0352]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl; [0353] R.sup.14 is
hydrogen or halogen; [0354] R.sup.1 is hydrogen; and [0355] R.sup.2
is hydrogen, halogen, or --OR.sup.1A wherein R.sup.1A is
C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl.
[0356] In some such embodiment, R.sup.q is --C(O)OR.sup.h wherein
R.sup.h is hydrogen. In some such embodiment, R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is C.sub.1-C.sub.3 alkyl.
[0357] One embodiment is directed to compounds of formula (I-d)
##STR00011##
wherein [0358] X is CR.sup.2 and Y is CR.sup.3; or [0359] X is N
and Y is CR.sup.3; or [0360] X is CR.sup.2 and Y is N; [0361]
R.sup.1 and R.sup.2, at each occurrence, are each independently
hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkyl, --OR.sup.1A, --C(O)OR.sup.1B, --NR.sup.1AR.sup.2A or
--C(O)NR.sup.1AR.sup.2A; [0362] R.sup.1A and R.sup.2A, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6
haloalkyl, G.sup.1A, or C.sub.1-C.sub.6 alkyl; wherein the
C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl are each
optionally substituted with one or two substituents independently
selected from the group consisting of --OR.sup.ZA, --SR.sup.ZA,
--S(O).sub.2R.sup.ZA, --C(O)R.sup.ZA, --C(O)OR.sup.ZA,
--C(O)N(R.sup.ZA).sub.2, --N(R.sup.ZA).sub.2,
--N(R.sup.ZA)C(O)R.sup.ZB, --N(R.sup.ZA)S(O).sub.2R.sup.ZB,
--N(R.sup.ZA)C(O)OR.sup.ZB, --N(R.sup.ZA)C(O)N(R.sup.ZA).sub.2,
--CN, and G.sup.1A; or R.sup.1A and R.sup.2A together with the
nitrogen atom to which they are attached form a 4-6 membered
heterocycle wherein the 4-6 membered heterocycle is optionally
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.j, and N(R.sup.j).sub.2;
wherein [0363] R.sup.ZA, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
G.sup.1A, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1A; and [0364]
R.sup.ZB, at each occurrence, is independently C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, G.sup.1A, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1A; [0365] R.sup.1B is hydrogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; [0366] R.sup.3 and R.sup.14
are each independently hydrogen or halogen; [0367] R.sup.4 is
hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl;
[0368] R.sup.5 is hydrogen, --C(O)R.sup.i, --C(O)OH,
--C(O)N(R.sup.h).sub.2, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkyl, or G.sup.2A; wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.h, --OC(O)N(R.sup.h).sub.2, --C(O)R.sup.h,
--C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, and
G.sup.2A; or [0369] R.sup.4 and R.sup.5, together with the carbon
atom to which they are attached, form a C.sub.3-C.sub.6 cycloalkyl
or a 4-6 membered heterocycle; wherein the C.sub.3-C.sub.6
cycloalkyl and the 4-6 membered heterocycle are each optionally
substituted with 1, 2, or 3 independently selected R' groups;
[0370] G.sup.2A, at each occurrence, is independently cycloalkyl,
cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is
independently unsubstituted or substituted with 1, 2, or 3
independently selected R.sup.q groups; [0371] R.sup.p and R.sup.q,
at each occurrence, are each independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 haloalkyl, --CN, oxo, NO.sub.2,
--OR.sup.h, --OC(O)R.sup.i, --OC(O)N(R.sup.h).sub.2, --SR.sup.h,
--S(O).sub.2R.sup.h, --S(O).sub.2N(R.sup.h).sub.2, --C(O)R.sup.h,
--C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, or
G.sup.A, wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.h, --OC(O)R.sup.i, --OC(O)N(R.sup.h).sub.2, --SR'',
--S(O).sub.2R.sup.h, --S(O).sub.2N(R.sup.h).sub.2, --C(O)R.sup.h,
--C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, --CN,
and G.sup.A; [0372] R.sup.h, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.A, wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.j, --OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[0373] R.sup.i, at each occurrence, is independently
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or G.sup.A,
wherein the C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl
are each optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.j,
--OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[0374] R.sup.6 is hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0375] R.sup.7 is hydrogen, halogen,
--OR.sup.j, --N(R.sup.j).sub.2, --N(R.sup.j)C(O)R.sup.k,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3A; [0376] R.sup.9,
R.sup.10, and R.sup.13, are each independently hydrogen or halogen;
[0377] G.sup.1A, G.sup.3A, and G.sup.A, at each occurrence, are
each independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or
heteroaryl, each of which is independently unsubstituted or
substituted with 1, 2, or 3 independently selected R.sup.s groups;
wherein [0378] R.sup.s, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, oxo, NO.sub.2,
--OR.sup.j, --OC(O)R.sup.k, --OC(O)N(R.sup.j).sub.2, --SR.sup.j,
--S(O).sub.2R.sup.j, --S(O).sub.2N(R.sup.j).sub.2, --C(O)R.sup.j,
--C(O)OR.sup.j, --C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2,
--N(R.sup.j)C(O)R.sup.k, --N(R.sup.j)S(O).sub.2R.sup.k,
--N(R.sup.j)C(O)O(R.sup.k), --N(R.sup.j)C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.j, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.j,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)O(R.sup.k), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)N(R.sup.j).sub.2, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [0379] R.sup.j, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; and
[0380] R.sup.k, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.
[0381] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein R.sup.9, R.sup.10, and R.sup.13 are
hydrogen.
[0382] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or
--C(O)OR.sup.1B; wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl.
[0383] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0384] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; and [0385] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl.
[0386] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0387] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0388] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0389]
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; [0390] R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0391] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0392] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0393] In some such embodiment, R.sup.4 is hydrogen, CH.sub.2F,
CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3; and R.sup.5 is hydrogen,
CH.sub.2F, CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3.
[0394] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0395] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0396] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0397]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0398] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl, C.sub.3-C.sub.6 cycloalkyl,
4-6 membered heterocycle, or 5-6 membered heteroaryl; each of which
is optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups; [0399] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0400] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0401] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0402] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0403] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0404]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0405] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 independently selected R.sup.q groups; [0406]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0407] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0408] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0409] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0410] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0411]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0412] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups;
[0413] wherein each R.sup.q is independently [0414] C.sub.1-C.sub.6
alkyl wherein the C.sub.1-C.sub.6 alkyl is optionally substituted
with one --OH; [0415] halogen; [0416] C.sub.1-C.sub.6 haloalkyl;
[0417] --OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.3
alkyl, [0418] --C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein
G.sup.A is 4-6 membered heterocycle; [0419] --C(O)OR.sup.h wherein
R.sup.h is hydrogen or C.sub.1-C.sub.6 alkyl, [0420]
--C(O)N(R.sup.h).sub.2, wherein R.sup.h at each occurrence, is
independently hydrogen, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
haloalkyl and C.sub.1-C.sub.6 alkyl are each optionally substituted
with 1 or 2 --OH groups; or [0421] --SO.sub.2R.sup.h wherein
R.sup.h is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl;
[0422] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0423]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0424] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0425] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0426] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0427]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0428] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups; wherein one of R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl, or one of R.sup.q is --C(O)N(H)(R.sup.h) wherein R.sup.h is
cyclopentyl, or R.sup.h is C.sub.1-C.sub.6 alkyl which is
substituted with 1 or 2 --OH groups; and the other optional R.sup.q
groups are independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, halogen, and C.sub.1-C.sub.3 haloalkyl;
[0429] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0430]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0431] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0432] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0433] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0434]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0435] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is substituted with one
R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl; [0436] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0437] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0438] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0439] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0440] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0441] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0442]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0443] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00012##
[0443] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0444]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0445] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0446] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0447] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0448] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0449] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0450]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0451] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00013##
[0451] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0452]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0453] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0454] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0455] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0456] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0457] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0458]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0459] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00014##
[0459] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0460]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0461] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0462] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0463] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0464] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0465] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0466]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0467] R.sup.5 is
G.sup.2A wherein G.sup.2A is C.sub.3-C.sub.6 cycloalkyl which is
optionally substituted with 1, 2, or 3 R.sup.q groups; wherein each
R.sup.q is independently [0468] C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one --OH;
[0469] halogen; [0470] C.sub.1-C.sub.6 haloalkyl; [0471] --OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl, [0472]
--C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein G.sup.A is 4-6
membered heterocycle; [0473] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl, [0474] --C(O)N(R.sup.h).sub.2,
wherein R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0475] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl; [0476] R.sup.6
is hydrogen or C.sub.1-C.sub.3 alkyl; and [0477] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0478] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0479] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0480] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0481]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0482] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclopropyl or cyclohexyl, each of
which is optionally substituted with one R.sup.q; wherein R.sup.q
is [0483] --OR.sup.h wherein R.sup.h is C.sub.1-C.sub.3 alkyl, or
[0484] --C(O)OR.sup.h wherein R.sup.h is hydrogen or
C.sub.1-C.sub.6 alkyl; [0485] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0486] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0487] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0488] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0489] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0490]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0491] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclohexyl which is substituted with
one R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0492] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0493] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0494] In some such embodiment, R.sup.q is --C(O)OR.sup.h wherein
R.sup.h is hydrogen. In some such embodiment, R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is C.sub.1-C.sub.3 alkyl.
[0495] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0496] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0497] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0498]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0499] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00015##
[0499] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. [0500]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0501] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0502] In some such embodiment, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0503] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0504] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0505] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0506]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0507] R.sup.5 is
G.sup.2A wherein G.sup.2A is 4-6 membered heterocycle which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups; [0508] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0509] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0510] In some such embodiment, G.sup.2A is tetrahydrofuranyl or
azetidinyl, each of which is optionally substituted with 1, 2, or 3
independently selected R.sup.q groups.
[0511] In some such embodiments, G.sup.2A tetrahydrofuranyl or
azetidinyl, each of which is optionally substituted with 1, 2, or 3
R.sup.q groups; wherein each R.sup.q is independently
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one --OH; [0512] halogen; [0513]
C.sub.1-C.sub.6 haloalkyl; [0514] --OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0515] --C(O)R.sup.h wherein
R.sup.h is G.sup.A; wherein G.sup.A is 4-6 membered heterocycle;
[0516] --C(O)OR.sup.h wherein R.sup.h is hydrogen or
C.sub.1-C.sub.6 alkyl, [0517] --C(O)N(R.sup.h).sub.2, wherein
R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0518] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0519] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0520] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0521] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0522]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0523] R.sup.5 is
G.sup.2A wherein G.sup.2A is 5-6 membered heteroaryl which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups; [0524] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0525] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0526] In some such embodiment, G.sup.2A is pyridinyl which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups.
[0527] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0528] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0529] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0530]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl or a 4-6 membered
heterocycle; wherein the C.sub.3-C.sub.6 cycloalkyl and the 4-6
membered heterocycle are each optionally substituted with 1, 2, or
3 independently selected R.sup.p groups; and [0531] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[0532] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0533] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0534] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0535]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl which is optionally
substituted with 1 or 2 R.sup.p groups; and [0536] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[0537] In some such embodiment, the C.sub.3-C.sub.6 cycloalkyl
formed is cyclobutyl or cyclopentyl, each of which is optionally
substituted with 1 or 2 R.sup.p groups. In some such embodiment,
the C.sub.3-C.sub.6 cycloalkyl formed is unsubstituted cyclobutyl
or unsubstituted cyclopentyl. [0538] In some such embodiments, each
R.sup.p is independently C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1 or 2 --OH
groups; [0539] --C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6
alkyl; [0540] --C(O)OR.sup.h wherein R.sup.h is hydrogen,
C.sub.1-C.sub.6 alkyl, or --CH.sub.2-phenyl; or [0541]
--SO.sub.2R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 haloalkyl or
C.sub.1-C.sub.6 alkyl.
[0542] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0543] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0544] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0545]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a 4-6 membered heterocycle which is optionally
substituted with 1 or 2 R.sup.p groups; and [0546] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[0547] In some such embodiment, the 4-6 membered heterocycle formed
is azetidinyl, piperidinyl, each of which is optionally substituted
with 1 or 2 independently selected R.sup.p groups. [0548] In some
such embodiments, each R.sup.p is independently C.sub.1-C.sub.6
alkyl wherein the C.sub.1-C.sub.6 alkyl is optionally substituted
with 1 or 2 --OH groups; [0549] --C(O)R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 alkyl; [0550] --C(O)OR.sup.h wherein R.sup.h is
hydrogen, C.sub.1-C.sub.6 alkyl, or --CH.sub.2-phenyl; or [0551]
--SO.sub.2R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 haloalkyl or
C.sub.1-C.sub.6 alkyl.
[0552] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0553] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0554] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0555]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [0556] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [0557] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0558] R.sup.7 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3A.
[0559] In one embodiment, the invention is directed to compounds of
formula (I-d), wherein [0560] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0561] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0562]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [0563] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [0564] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; [0565] R.sup.7 is --(CH.sub.2)-G.sup.3A
wherein G.sup.3A is phenyl which is optionally substituted with 1,
2, or 3 R.sup.s group; and each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--OR.sup.j wherein R.sup.j is hydrogen or C.sub.1-C.sub.3
alkyl.
[0566] In some such embodiments, each R.sup.s is independently
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[0567] In one embodiment, the invention is directed to compounds of
formula (I-e)
##STR00016##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.9, R.sup.10, R.sup.13, and R.sup.14 are as described
in formula (I-d).
[0568] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein R.sup.9, R.sup.10, and R.sup.13 are
hydrogen.
[0569] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or
--C(O)OR.sup.1B; wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl.
[0570] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0571] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; and [0572] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl.
[0573] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0574] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0575] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0576]
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; [0577] R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0578] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0579] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0580] In some such embodiment, R.sup.4 is hydrogen, CH.sub.2F,
CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3; and R.sup.5 is hydrogen,
CH.sub.2F, CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3.
[0581] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0582] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0583] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0584]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0585] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl, C.sub.3-C.sub.6 cycloalkyl,
4-6 membered heterocycle, or 5-6 membered heteroaryl; each G.sup.2A
is optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups. [0586] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0587] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0588] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0589] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0590] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0591]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0592] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl optionally substituted with 1,
2, or 3 independently selected R.sup.q groups; [0593] R.sup.6 is
hydrogen or C.sub.1-C.sub.3 alkyl; and [0594] R.sup.7 is hydrogen
or C.sub.1-C.sub.3 alkyl.
[0595] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0596] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0597] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0598]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0599] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups; wherein each R.sup.q is
independently [0600] C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one --OH;
[0601] halogen; [0602] C.sub.1-C.sub.6 haloalkyl; [0603] --OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl, [0604]
--C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein G.sup.A is 4-6
membered heterocycle; [0605] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl, [0606] --C(O)N(R.sup.h).sub.2,
wherein R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0607] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl; [0608] R.sup.6
is hydrogen or C.sub.1-C.sub.3 alkyl; and [0609] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0610] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0611] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0612] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0613]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0614] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups; wherein one of R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl, or one of R.sup.q is --C(O)N(H)(R.sup.h) wherein R.sup.h is
cyclopentyl, or R.sup.h is C.sub.1-C.sub.6 alkyl which is
substituted with 1 or 2 --OH groups; and the other optional R.sup.q
groups are independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, halogen, and C.sub.1-C.sub.3 haloalkyl;
[0615] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0616]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0617] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0618] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0619] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0620]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0621] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is substituted with one
R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl; [0622] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0623] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0624] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0625] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0626] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0627] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0628]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0629] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00017##
[0629] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0630]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0631] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0632] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0633] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0634] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0635] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0636]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0637] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00018##
[0637] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0638]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0639] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0640] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0641] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0642] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0643] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0644]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0645] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00019##
[0645] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0646]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0647] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0648] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0649] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0650] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0651] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0652]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0653] R.sup.5 is
G.sup.2A wherein G.sup.2A is C.sub.3-C.sub.6 cycloalkyl which is
optionally substituted with 1, 2, or 3 R.sup.q groups; wherein each
R.sup.q is independently [0654] C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one --OH;
[0655] halogen; [0656] C.sub.1-C.sub.6 haloalkyl; [0657] --OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl, [0658]
--C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein G.sup.A is 4-6
membered heterocycle; [0659] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl, [0660] --C(O)N(R.sup.h).sub.2,
wherein R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0661] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl; [0662] R.sup.6
is hydrogen or C.sub.1-C.sub.3 alkyl; and [0663] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0664] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0665] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0666] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0667]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0668] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclopropyl or cyclohexyl, each of
which is optionally substituted with one R.sup.q; wherein R.sup.q
is --OR.sup.h wherein R.sup.h is C.sub.1-C.sub.3 alkyl, or R.sup.q
is --C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl; [0669] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and
[0670] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0671] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0672] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0673] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0674]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0675] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclohexyl which is substituted with
one R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0676] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0677] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0678] In some such embodiment, R.sup.h is hydrogen. In some such
embodiment, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0679] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0680] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0681] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0682]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0683] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00020##
[0683] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. [0684]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0685] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0686] In some such embodiment, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0687] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0688] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0689] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0690]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0691] R.sup.5 is
G.sup.2A wherein G.sup.2A is 4-6 membered heterocycle optionally
substituted with 1, 2, or 3 independently selected R.sup.q groups;
[0692] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0693]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0694] In some such embodiment, G.sup.2A is tetrahydrofuranyl or
azetidinyl, each of which is optionally substituted with 1, 2, or 3
independently selected R.sup.q groups.
[0695] In some such embodiments, G.sup.2A tetrahydrofuranyl or
azetidinyl, each of which is optionally substituted with 1, 2, or 3
R.sup.q groups; wherein each R.sup.q is independently
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one --OH; [0696] halogen; [0697]
C.sub.1-C.sub.6 haloalkyl; [0698] --OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0699] --C(O)R.sup.h wherein
R.sup.h is G.sup.A; wherein G.sup.A is 4-6 membered heterocycle;
[0700] --C(O)OR.sup.h wherein R.sup.h is hydrogen or
C.sub.1-C.sub.6 alkyl, [0701] --C(O)N(R.sup.h).sub.2, wherein
R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0702] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0703] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0704] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0705] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0706]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0707] R.sup.5 is
G.sup.2A wherein G.sup.2A is 5-6 membered heteroaryl optionally
substituted with 1, 2, or 3 independently selected R.sup.q groups;
[0708] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0709]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0710] In some such embodiment, G.sup.2A is pyridinyl optionally
substituted with 1, 2, or 3 independently selected R.sup.q
groups.
[0711] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0712] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0713] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0714]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl or a 4-6 membered
heterocycle; wherein the C.sub.3-C.sub.6 cycloalkyl and the 4-6
membered heterocycle are each optionally substituted with 1, 2, or
3 independently selected R.sup.p groups; and [0715] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[0716] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0717] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0718] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0719]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl which is optionally
substituted with 1 or 2 R.sup.p groups; and [0720] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[0721] In some such embodiment, the C.sub.3-C.sub.6 cycloalkyl
formed is cyclobutyl or cyclopentyl, each of which is optionally
substituted with 1 or 2 R.sup.p groups. In some such embodiment,
the C.sub.3-C.sub.6 cycloalkyl formed is unsubstituted cyclobutyl
or unsubstituted cyclopentyl. [0722] In some such embodiment, each
R.sup.p is independently C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1 or 2 --OH
groups; [0723] --C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6
alkyl; [0724] --C(O)OR.sup.h wherein R.sup.h is hydrogen,
C.sub.1-C.sub.6 alkyl, or --CH.sub.2-phenyl; or [0725]
--SO.sub.2R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 haloalkyl or
C.sub.1-C.sub.6 alkyl.
[0726] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0727] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0728] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0729]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a 4-6 membered heterocycle which is optionally
substituted with 1 or 2 R' groups; and [0730] R.sup.6 and R.sup.7
are each independently hydrogen or C.sub.1-C.sub.3 alkyl.
[0731] In some such embodiment, the 4-6 membered heterocycle formed
is azetidinyl or piperidinyl, each of which is optionally
substituted with 1 or 2 R.sup.p groups. [0732] In some such
embodiments, each R.sup.p is independently C.sub.1-C.sub.6 alkyl
wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with 1
or 2 --OH groups; [0733] --C(O)R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 alkyl; [0734] --C(O)OR.sup.h wherein R.sup.h is
hydrogen, C.sub.1-C.sub.6 alkyl, or --CH.sub.2-phenyl; or [0735]
--SO.sub.2R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 haloalkyl or
C.sub.1-C.sub.6 alkyl.
[0736] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0737] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0738] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0739]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [0740] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [0741] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0742] R.sup.7 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3A.
[0743] In one embodiment, the invention is directed to compounds of
formula (I-e), wherein [0744] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0745] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0746]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [0747] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [0748] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0749] R.sup.7 is --(CH.sub.2)-G.sup.3A
wherein G.sup.3A is phenyl which is optionally substituted with 1,
2, or 3 R.sup.s group; and each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--OR.sup.j wherein R.sup.j is hydrogen or C.sub.1-C.sub.3
alkyl.
[0750] In some such embodiments, each R.sup.s is independently
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[0751] One embodiment is directed to compounds of formula (I-f)
##STR00021##
wherein R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.9, R.sup.10, R.sup.13 and R.sup.14 are as described in
formula (I-d).
[0752] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein R.sup.9, R.sup.10, and R.sup.13 are
hydrogen.
[0753] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or
--C(O)OR.sup.1B; wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl.
[0754] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0755] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; and [0756] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl.
[0757] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0758] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0759] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0760]
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; [0761] R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0762] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0763] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0764] In some such embodiment, R.sup.4 is hydrogen, CH.sub.2F,
CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3; and R.sup.5 is hydrogen,
CH.sub.2F, CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3.
[0765] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0766] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0767] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0768]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0769] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl, C.sub.3-C.sub.6 cycloalkyl,
4-6 membered heterocycle, or 5-6 membered heteroaryl; each of which
is optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups; [0770] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0771] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0772] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0773] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0774] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0775]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0776] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 independently selected R.sup.q groups; [0777]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0778] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0779] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0780] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0781] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0782]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0783] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups; [0784] wherein each R.sup.q is
independently [0785] C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one --OH;
[0786] halogen; [0787] C.sub.1-C.sub.6 haloalkyl; [0788] --OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl, [0789]
--C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein G.sup.A is 4-6
membered heterocycle; [0790] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl, [0791] --C(O)N(R.sup.h).sub.2,
wherein R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0792] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl; [0793] R.sup.6
is hydrogen or C.sub.1-C.sub.3 alkyl; and [0794] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0795] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0796] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0797] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0798]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0799] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups; wherein one of R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl, or one of R.sup.q is --C(O)N(H)(R.sup.h) wherein R.sup.h is
cyclopentyl, or R.sup.h is C.sub.1-C.sub.6 alkyl which is
substituted with 1 or 2 --OH groups; and the other optional R.sup.q
groups are independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, halogen, and C.sub.1-C.sub.3 haloalkyl;
[0800] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0801]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0802] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0803] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0804] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0805]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0806] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is substituted with one
R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl; [0807] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0808] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0809] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0810] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0811] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0812] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0813]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0814] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00022##
[0814] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0815]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0816] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0817] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0818] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0819] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0820] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0821]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0822] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00023##
[0822] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0823]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0824] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0825] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0826] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0827] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0828] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0829]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0830] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00024##
[0830] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [0831]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0832] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0833] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0834] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0835] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0836] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0837]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0838] R.sup.5 is
G.sup.2A wherein G.sup.2A is C.sub.3-C.sub.6 cycloalkyl which is
optionally substituted with 1, 2, or 3 R.sup.q groups; wherein each
R.sup.q is independently [0839] C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one --OH;
[0840] halogen; [0841] C.sub.1-C.sub.6 haloalkyl; [0842] --OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl, [0843]
--C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein G.sup.A is 4-6
membered heterocycle; [0844] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl, [0845] --C(O)N(R.sup.h).sub.2,
wherein R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0846] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl; [0847] R.sup.6
is hydrogen or C.sub.1-C.sub.3 alkyl; and [0848] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0849] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0850] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0851] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0852]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0853] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclopropyl or cyclohexyl, each of
which is optionally substituted with one R.sup.q; wherein R.sup.q
is OR.sup.h wherein R.sup.h is C.sub.1-C.sub.3 alkyl, or R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl; [0854] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and
[0855] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0856] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0857] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0858] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0859]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0860] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclohexyl which is substituted with
one R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0861] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0862] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0863] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0864] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0865] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0866]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0867] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00025##
[0867] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. [0868]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0869] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0870] In some such embodiment, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0871] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0872] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0873] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0874]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0875] R.sup.5 is
G.sup.2A wherein G.sup.2A is 4-6 membered heterocycle which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups; [0876] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0877] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0878] In some such embodiment, G.sup.2A is tetrahydrofuranyl or
azetidinyl; each of which is optionally substituted with 1, 2, or 3
independently selected R.sup.q groups.
[0879] In some such embodiments, G.sup.2A tetrahydrofuranyl or
azetidinyl, each of which is optionally substituted with 1, 2, or 3
R.sup.q groups; wherein each R.sup.q is independently [0880]
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one --OH; [0881] halogen; [0882]
C.sub.1-C.sub.6 haloalkyl; [0883] --OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [0884] --C(O)R.sup.h wherein
R.sup.h is G.sup.A; wherein G.sup.A is 4-6 membered heterocycle;
[0885] --C(O)OR.sup.h wherein R.sup.h is hydrogen or
C.sub.1-C.sub.6 alkyl, [0886] --C(O)N(R.sup.h).sub.2, wherein
R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0887] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0888] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0889] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0890] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0891]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0892] R.sup.5 is
G.sup.2A wherein G.sup.2A is 5-6 membered heteroaryl which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups; [0893] R.sup.6 is hydrogen or C.sub.1-C.sub.3
alkyl; and [0894] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0895] In some such embodiment, G.sup.2A is pyridinyl which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups.
[0896] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0897] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0898] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0899]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl or a 4-6 membered
heterocycle; wherein the C.sub.3-C.sub.6 cycloalkyl and the 4-6
membered heterocycle are each optionally substituted with 1, 2, or
3 independently selected R' groups; and [0900] R.sup.6 and R.sup.7
are each independently hydrogen or C.sub.1-C.sub.3 alkyl.
[0901] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0902] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0903] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0904]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl which is optionally
substituted with 1 or 2 R.sup.p groups; and [0905] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[0906] In some such embodiment, the C.sub.3-C.sub.6 cycloalkyl
formed is cyclobutyl or cyclopentyl, each of which is optionally
substituted with 1 or 2 R.sup.p groups. In some such embodiment,
the C.sub.3-C.sub.6 cycloalkyl formed is unsubstituted cyclobutyl
or unsubstituted cyclopentyl.
[0907] In some such embodiment, each R.sup.p is independently
[0908] C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with 1 or 2 --OH groups; [0909]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [0910]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [0911] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0912] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein
[0913] R.sup.9, R.sup.10, and R.sup.13 are hydrogen; [0914] R.sup.1
is hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkyl, --OR.sup.1A, or --C(O)OR.sup.1B; wherein R.sup.1A is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl; and R.sup.1B is
hydrogen or C.sub.1-C.sub.3 alkyl; [0915] R.sup.4 and R.sup.5,
together with the carbon atom to which they are attached, form a
4-6 membered heterocycle which is optionally substituted with 1 or
2 independently selected R.sup.p groups; and [0916] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[0917] In some such embodiment, the 4-6 membered heterocycle formed
is azetidinyl or piperidinyl, each of which is optionally
substituted with 1 or 2 R.sup.p groups.
[0918] In some such embodiments, each R.sup.p is independently
[0919] C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with 1 or 2 --OH groups; [0920]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [0921]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [0922] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[0923] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0924] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0925] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0926]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [0927] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [0928] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0929] R.sup.7 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3A.
[0930] In one embodiment, the invention is directed to compounds of
formula (I-f), wherein [0931] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0932] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0933]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [0934] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [0935] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; [0936] R.sup.7 is --(CH.sub.2)-G.sup.3A
wherein G.sup.3A is phenyl which is optionally substituted with 1,
2, or 3 R.sup.s group; and each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--OR.sup.j wherein R.sup.j is hydrogen or C.sub.1-C.sub.3
alkyl.
[0937] In some such embodiments, each R.sup.s is independently
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[0938] One embodiment is directed to compounds of formula (I-g)
##STR00026##
wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.9, R.sup.10, R.sup.13, and R.sup.14 are as described in
formula (I-d).
[0939] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein R.sup.9, R.sup.10, and R.sup.13 are
hydrogen.
[0940] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or
--C(O)OR.sup.1B; wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or
C.sub.1-C.sub.3 alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3
alkyl.
[0941] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0942] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; and [0943] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl.
[0944] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0945] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0946] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0947]
R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6
alkyl; [0948] R.sup.5 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [0949] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0950] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0951] In some such embodiment, R.sup.4 is hydrogen, CH.sub.2F,
CHF.sub.2, CH.sub.3, or CH.sub.2CH.sub.3; and R.sup.5 is hydrogen,
CH.sub.2F, CHF.sub.2, CH.sub.3, or --CH.sub.2CH.sub.3.
[0952] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0953] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0954] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0955]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0956] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl, C.sub.3-C.sub.6 cycloalkyl,
4-6 membered heterocycle, or 5-6 membered heteroaryl; each of which
is optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups [0957] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl;
and [0958] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0959] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0960] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0961] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0962]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0963] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 independently selected R.sup.q groups; [0964]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0965] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0966] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0967] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0968] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0969]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0970] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups; [0971] wherein each R.sup.q is
independently [0972] C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one --OH;
[0973] halogen; [0974] C.sub.1-C.sub.6 haloalkyl; [0975] --OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl, [0976]
--C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein G.sup.A is 4-6
membered heterocycle; [0977] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl, [0978] --C(O)N(R.sup.h).sub.2,
wherein R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [0979] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl; [0980] R.sup.6
is hydrogen or C.sub.1-C.sub.3 alkyl; and [0981] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[0982] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0983] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0984] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0985]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0986] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is optionally substituted
with 1, 2, or 3 R.sup.q groups wherein one of R.sup.q is
--C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl, or one of R.sup.q is --C(O)N(H)(R.sup.h) wherein R.sup.h is
cyclopentyl, or R.sup.h is C.sub.1-C.sub.6 alkyl which is
substituted with 1 or 2 --OH groups; and the other optional R.sup.q
groups are independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, halogen, and C.sub.1-C.sub.3 haloalkyl;
[0987] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0988]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[0989] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0990] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0991] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [0992]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [0993] R.sup.5 is
G.sup.2A wherein G.sup.2A is phenyl which is substituted with one
R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl; [0994] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [0995] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[0996] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[0997] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [0998] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [0999] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1000]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1001] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00027##
[1001] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [1002]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [1003] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[1004] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1005] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1006] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1007] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.4
is hydrogen or C.sub.1-C.sub.3 alkyl; [1008] R.sup.5 is G.sup.2A
wherein G.sup.2A is
##STR00028##
[1008] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [1009]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [1010] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[1011] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1012] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1013] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1014] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1015]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1016] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00029##
[1016] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl; [1017]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [1018] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[1019] In some such embodiments, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1020] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1021] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1022] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1023]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1024] R.sup.5 is
G.sup.2A wherein G.sup.2A is C.sub.3-C.sub.6 cycloalkyl which is
optionally substituted with 1, 2, or 3 R.sup.q groups; wherein each
R.sup.q is independently [1025] C.sub.1-C.sub.6 alkyl wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one --OH;
[1026] halogen; [1027] C.sub.1-C.sub.6 haloalkyl; [1028] --OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl, [1029]
--C(O)R.sup.h wherein R.sup.h is G.sup.A; wherein G.sup.A is 4-6
membered heterocycle; [1030] --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl, [1031] --C(O)N(R.sup.h).sub.2,
wherein R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [1032] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl; [1033] R.sup.6
is hydrogen or C.sub.1-C.sub.3 alkyl; and [1034] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[1035] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1036] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1037] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1038]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1039] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclopropyl or cyclohexyl, each of
which is optionally substituted with one R.sup.q; wherein R.sup.q
is --OR.sup.h wherein R.sup.h is C.sub.1-C.sub.3 alkyl, or R.sup.q
is --C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.6
alkyl; [1040] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and
[1041] R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[1042] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1043] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1044] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1045]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1046] R.sup.5 is
G.sup.2A wherein G.sup.2A is cyclohexyl which is substituted with
one R.sup.q; wherein R.sup.q is --C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [1047] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [1048] R.sup.7 is hydrogen or
C.sub.1-C.sub.3 alkyl.
[1049] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1050] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1051] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1052]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1053] R.sup.5 is
G.sup.2A wherein G.sup.2A is
##STR00030##
[1053] wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl. [1054]
R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [1055] R.sup.7 is
hydrogen or C.sub.1-C.sub.3 alkyl.
[1056] In some such embodiment, R.sup.h is hydrogen. In some such
embodiments, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1057] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1058] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1059] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1060]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1061] R.sup.5 is
G.sup.2A wherein G.sup.2A is 4-6 membered heterocycle optionally
substituted with 1, 2, or 3 independently selected R.sup.q groups;
[1062] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [1063]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[1064] In some such embodiment, G.sup.2A is tetrahydrofuranyl or
azetidinyl, each of which is optionally substituted with 1, 2, or 3
independently selected R.sup.q groups.
[1065] In some such embodiments, G.sup.2A tetrahydrofuranyl or
azetidinyl, each of which is optionally substituted with 1, 2, or 3
R.sup.q groups; wherein each R.sup.q is independently [1066]
C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one --OH; [1067] halogen; [1068]
C.sub.1-C.sub.6 haloalkyl; [1069] --OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl, [1070] --C(O)R.sup.h wherein
R.sup.h is G.sup.A; wherein G.sup.A is 4-6 membered heterocycle;
[1071] --C(O)OR.sup.h wherein R.sup.h is hydrogen or
C.sub.1-C.sub.6 alkyl, [1072] --C(O)N(R.sup.h).sub.2, wherein
R.sup.h at each occurrence, is independently hydrogen,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 haloalkyl and
C.sub.1-C.sub.6 alkyl are each optionally substituted with 1 or 2
--OH groups; or [1073] --SO.sub.2R.sup.h wherein R.sup.h is
C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[1074] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1075] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1076] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1077]
R.sup.4 is hydrogen or C.sub.1-C.sub.3 alkyl; [1078] R.sup.5 is
G.sup.2A wherein G.sup.2A is 5-6 membered heteroaryl optionally
substituted with 1, 2, or 3 independently selected R.sup.q groups;
[1079] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; and [1080]
R.sup.7 is hydrogen or C.sub.1-C.sub.3 alkyl.
[1081] In some such embodiment, G.sup.2A is pyridinyl optionally
substituted with 1, 2, or 3 independently selected R.sup.q
groups.
[1082] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1083] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1084] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1085]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl or a 4-6 membered
heterocycle; wherein the C.sub.3-C.sub.6 cycloalkyl and the 4-6
membered heterocycle are each optionally substituted with 1, 2, or
3 independently selected R.sup.p groups; and [1086] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[1087] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1088] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1089] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1090]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.6 cycloalkyl which is optionally
substituted with 1 or 2 R.sup.p groups; and [1091] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[1092] In some such embodiment, the C.sub.3-C.sub.6 cycloalkyl
formed is cyclobutyl or cyclopentyl, each of which is optionally
substituted with 1 or 2 R.sup.p groups. In some such embodiment,
the C.sub.3-C.sub.6 cycloalkyl formed is unsubstituted cyclobutyl
or unsubstituted cyclopentyl.
[1093] In some such embodiment, each R.sup.p is independently
[1094] C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with 1 or 2 --OH groups; [1095]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [1096]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [1097] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[1098] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1099] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1100] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1101]
R.sup.4 and R.sup.5, together with the carbon atom to which they
are attached, form a 4-6 membered heterocycle which is optionally
substituted with 1 or 2 R.sup.p groups; and [1102] R.sup.6 and
R.sup.7 are each independently hydrogen or C.sub.1-C.sub.3
alkyl.
[1103] In some such embodiment, the 4-6 membered heterocycle formed
is azetidinyl or piperidinyl, each of which is optionally
substituted with 1 or 2 R.sup.p groups.
[1104] In some such embodiments, each R.sup.p is independently
[1105] C.sub.1-C.sub.6 alkyl wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with 1 or 2 --OH groups; [1106]
--C(O)R.sup.h wherein R.sup.h is C.sub.1-C.sub.6 alkyl; [1107]
--C(O)OR.sup.h wherein R.sup.h is hydrogen, C.sub.1-C.sub.6 alkyl,
or --CH.sub.2-phenyl; or [1108] --SO.sub.2R.sup.h wherein R.sup.h
is C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkyl.
[1109] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1110] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1111] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1112]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [1113] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [1114] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [1115] R.sup.7 is --(C.sub.1-C.sub.6
alkylenyl)-G.sup.3A.
[1116] In one embodiment, the invention is directed to compounds of
formula (I-g), wherein [1117] R.sup.9, R.sup.10, and R.sup.13 are
hydrogen; [1118] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; and R.sup.1B is hydrogen or C.sub.1-C.sub.3 alkyl; [1119]
R.sup.4 hydrogen or C.sub.1-C.sub.3 alkyl; and [1120] R.sup.5 is
hydrogen or C.sub.1-C.sub.3 alkyl; [1121] R.sup.6 is hydrogen or
C.sub.1-C.sub.3 alkyl; and [1122] R.sup.7 is --(CH.sub.2)-G.sup.3A
wherein G.sup.3A is phenyl which is optionally substituted with 1,
2, or 3 R.sup.s group; wherein each R.sup.s is independently
C.sub.1-C.sub.3 alkyl, halogen, C.sub.1-C.sub.3 haloalkyl, or
--OR.sup.j wherein R.sup.j is hydrogen or C.sub.1-C.sub.3
alkyl.
[1123] In some such embodiments, each R.sup.s is independently
--OR.sup.j wherein R.sup.j is C.sub.1-C.sub.3 alkyl.
[1124] Compounds described herein may contain one or more
asymmetrically substituted atoms, and thus may exist as individual
stereoisomers (including enantiomers and diastereomers) or mixtures
thereof. For example, certain embodiments are directed to compounds
of formula (I-h)
##STR00031##
wherein [1125] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3
alkyl; [1126] R.sup.2 is hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OR.sup.1A, or --C(O)OR.sup.1B;
wherein R.sup.A is hydrogen, C.sub.1-C.sub.3 haloalkyl, or
C.sub.1-C.sub.3 alkyl; wherein the C.sub.1-C.sub.3 alkyl is
optionally substituted with one substituent selected from the group
consisting of --OR.sup.ZA, --C(O)OH, and G.sup.1A; wherein G.sup.1A
is phenyl which is optionally substituted with 1, 2, or 3 R.sup.s
groups wherein each R.sup.s is independently C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, halogen, or --OCH.sub.3; and R.sup.ZA is
C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkyl; [1127] R.sup.1B
is hydrogen or C.sub.1-C.sub.3 alkyl; [1128] R.sup.3 and R.sup.14
are each independently hydrogen or halogen; [1129] R.sup.4 is
hydrogen, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkyl;
[1130] R.sup.5 is G.sup.2A; [1131] G.sup.2A is C.sub.3-C.sub.6
cycloalkyl, 4-6 membered heterocycle, phenyl, or 5-6 membered
heteroaryl, each of which is independently unsubstituted or
substituted with 1, 2, or 3 independently selected R.sup.q groups;
[1132] R.sup.q, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN,
oxo, NO.sub.2, --OR.sup.h, --OC(O)R.sup.i, --OC(O)N(R.sup.h).sub.2,
--SR.sup.h, --S(O).sub.2R.sup.h, --S(O).sub.2N(R.sup.h).sub.2,
--C(O)R.sup.h, --C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2,
--N(R.sup.h).sub.2, --N(R.sup.h)C(O)R.sup.i,
--N(R.sup.h)S(O).sub.2R.sup.i, --N(R.sup.h)C(O)O(R.sup.i),
--N(R.sup.h)C(O)N(R.sup.h).sub.2, or G.sup.A, wherein the
C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl are each
optionally substituted with one or two substituents independently
selected from the group consisting of --OR.sup.h, --OC(O)R.sup.i,
--OC(O)N(R.sup.h).sub.2, --SR.sup.h, --S(O).sub.2R.sup.h,
--S(O).sub.2N(R.sup.h).sub.2, --C(O)R.sup.h, --C(O)OR.sup.h,
--C(O)N(R.sup.h).sub.2, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, --CN,
and G.sup.A; [1133] R.sup.h, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.A, wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.j, --OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[1134] R.sup.i, at each occurrence, is independently
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or G.sup.A,
wherein the C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl
are each optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.j,
--OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[1135] R.sup.6 is hydrogen or C.sub.1-C.sub.3 alkyl; [1136] R.sup.7
is hydrogen or C.sub.1-C.sub.3 alkyl; [1137] R.sup.9, R.sup.10, and
R.sup.13, are each independently hydrogen or halogen; [1138]
G.sup.A, at each occurrence, is independently cycloalkyl,
cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is
independently unsubstituted or substituted with 1, 2, or 3
independently selected R.sup.s groups; [1139] R.sup.s, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, oxo, NO.sub.2, --OR.sup.j, --OC(O)R.sup.k,
--OC(O)N(R.sup.j).sub.2, --SR.sup.j, --S(O).sub.2R.sup.j,
--S(O).sub.2N(R.sup.j).sub.2, --C(O)R.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2,
--N(R.sup.j)C(O)R.sup.k, --N(R.sup.j)S(O).sub.2R.sup.k,
--N(R.sup.j)C(O)O(R.sup.k), --N(R.sup.j)C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.j, --(C.sub.1-C.sub.6 alkylenyl)-C(O)OR.sup.j,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)O(R.sup.k), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)N(R.sup.j).sub.2, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [1140] R.sup.j, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; and
[1141] R.sup.k, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.
[1142] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein R.sup.3, R.sup.14, R.sup.9, R.sup.10, and
R.sup.13 are hydrogen.
[1143] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein G.sup.2A is phenyl, cyclopropyl, cyclohexyl,
pyridinyl, azetidinyl, or tetrahydrofuranyl; each of which is
optionally substituted with 1, 2, or 3 independently selected
R.sup.q groups.
[1144] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein
G.sup.2A is phenyl, pyridinyl, cyclopropyl, cyclohexyl, pyridinyl,
azetidinyl, or tetrahydrofuranyl; each of which is optionally
substituted with 1, 2, or 3 independently selected R.sup.q groups;
and R.sup.3, R.sup.14, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen.
[1145] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1146] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; and [1147] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl.
[1148] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1149] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1150] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; and [1151] R.sup.3, R.sup.14,
R.sup.9, R.sup.10, and R.sup.13 are hydrogen.
[1152] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1153] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1154] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1155] R.sup.4 is hydrogen;
[1156] R.sup.6 is hydrogen; and [1157] R.sup.7 is hydrogen.
[1158] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1159] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1160] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1161] R.sup.4 is hydrogen;
[1162] R.sup.6 is hydrogen; [1163] R.sup.7 is hydrogen; and [1164]
R.sup.3, R.sup.14, R.sup.9, R.sup.10, and R.sup.13 are
hydrogen.
[1165] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein
R.sup.1 is hydrogen, CH.sub.3, or --OCH.sub.3; R.sup.2 is hydrogen,
F, CF.sub.3, CH.sub.3, --OCHF.sub.2, --OCH.sub.2CH.sub.2F, or
--OCH.sub.2CH.sub.2OCH.sub.3; R.sup.4 is hydrogen; R.sup.6 is
hydrogen; R.sup.7 is hydrogen; and R.sup.3, R.sup.14, R.sup.9,
R.sup.10, and R.sup.13 are hydrogen.
[1166] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1167] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1168] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1169] R.sup.4 is hydrogen;
[1170] R.sup.6 is hydrogen; [1171] R.sup.7 is hydrogen; and [1172]
G.sup.2A is phenyl substituted with 1, 2, or 3 R.sup.q groups;
wherein one of R.sup.q groups is C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.6 alkyl; or one of R.sup.q groups is
--C(O)N(H)(R.sup.h), wherein R.sup.h is cyclopentyl, or R.sup.h is
C.sub.1-C.sub.6 alkyl substituted with 1 or 2 --OH groups; and the
other optional R.sup.q groups are independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, halogen, and
C.sub.1-C.sub.3 haloalkyl.
[1173] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1174] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1175] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1176] R.sup.4 is hydrogen;
[1177] R.sup.6 is hydrogen; [1178] R.sup.7 is hydrogen; [1179]
R.sup.3, R.sup.14, R.sup.9, R.sup.10, and R.sup.13 are hydrogen;
and [1180] G.sup.2A is phenyl substituted with 1, 2, or 3 R.sup.q
groups; wherein one of R.sup.q groups is C(O)OR.sup.h wherein
R.sup.h is hydrogen or C.sub.1-C.sub.6 alkyl; or one of R.sup.q
groups is --C(O)N(H)(R.sup.h), wherein R.sup.h is cyclopentyl, or
R.sup.h is C.sub.1-C.sub.6 alkyl substituted with 1 or 2 --OH
groups; and the other optional R.sup.q groups are independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, and C.sub.1-C.sub.3 haloalkyl.
[1181] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1182] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1183] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1184] R.sup.4 is hydrogen;
[1185] R.sup.6 is hydrogen; [1186] R.sup.7 is hydrogen; and [1187]
G.sup.2A is phenyl or cyclohexyl; each of which is substituted with
one C(O)OR.sup.h wherein R.sup.h is hydrogen or C.sub.1-C.sub.3
alkyl.
[1188] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1189] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1190] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1191] R.sup.4 is hydrogen;
[1192] R.sup.6 is hydrogen; [1193] R.sup.7 is hydrogen; [1194]
R.sup.3, R.sup.14, R.sup.9, R.sup.10, and R.sup.13 are hydrogen;
and [1195] G.sup.2A is phenyl or cyclohexyl; each of which is
substituted with one C(O)OR.sup.h wherein R.sup.h is hydrogen or
C.sub.1-C.sub.3 alkyl.
[1196] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1197] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1198] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1199] R.sup.4 is hydrogen;
[1200] R.sup.6 is hydrogen; [1201] R.sup.7 is hydrogen; and [1202]
G.sup.2A is phenyl substituted with one C(O)OR.sup.h wherein
R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl.
[1203] In some such embodiment, R.sup.h is hydrogen. In some such
embodiment, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1204] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1205] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1206] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR' wherein R.sup.ZA is
C.sub.1-C.sub.3 alkyl; [1207] R.sup.4 is hydrogen; [1208] R.sup.6
is hydrogen; [1209] R.sup.7 is hydrogen; [1210] R.sup.3, R.sup.14,
R.sup.9, R.sup.10, and R.sup.13 are hydrogen; and [1211] G.sup.2A
is phenyl substituted with one C(O)OR.sup.h wherein R.sup.h is
hydrogen or C.sub.1-C.sub.3 alkyl.
[1212] In some such embodiment, R.sup.h is hydrogen. In some such
embodiment, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1213] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1214] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1215] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1216] R.sup.4 is hydrogen;
[1217] R.sup.6 is hydrogen; [1218] R.sup.7 is hydrogen; and [1219]
G.sup.2A is cyclohexyl substituted with one C(O)OR.sup.h wherein
R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl.
[1220] In some such embodiment, R.sup.h is hydrogen. In some such
embodiment, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1221] In one embodiment, the invention is directed to compounds of
formula (I-h) wherein [1222] R.sup.1 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 alkyl; [1223] R.sup.2 is
hydrogen, halogen, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 alkyl wherein the C.sub.1-C.sub.3
alkyl is optionally substituted with one --OR.sup.ZA wherein
R.sup.ZA is C.sub.1-C.sub.3 alkyl; [1224] R.sup.4 is hydrogen;
[1225] R.sup.6 is hydrogen; [1226] R.sup.7 is hydrogen; [1227]
R.sup.3, R.sup.14, R.sup.9, R.sup.10, and R.sup.13 are hydrogen;
and [1228] G.sup.2A is cyclohexyl substituted with one C(O)OR.sup.h
wherein R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl.
[1229] In some such embodiment, R.sup.h is hydrogen. In some such
embodiment, R.sup.h is C.sub.1-C.sub.3 alkyl.
[1230] One embodiment is directed to compounds of formula (I-i)
##STR00032##
wherein [1231] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.3
haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A; wherein R.sup.1A
is C.sub.1-C.sub.3 alkyl; and [1232] R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3
alkyl wherein the C.sub.1-C.sub.3 alkyl is optionally substituted
with one --OR.sup.ZA, and R.sup.ZA is C.sub.1-C.sub.3 alkyl; and
[1233] R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl.
[1234] In one embodiment, the invention is directed to compounds of
formula (I-i) wherein [1235] R.sup.1 is hydrogen, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3 alkyl;
and [1236] R.sup.h is hydrogen.
[1237] One embodiment is directed to compounds of formula (I j)
##STR00033##
wherein [1238] R.sup.1 is hydrogen, halogen, C.sub.1-C.sub.3
haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A; wherein R.sup.1A
is C.sub.1-C.sub.3 alkyl; and [1239] R.sup.2 is hydrogen, halogen,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkyl, or --OR.sup.1A;
wherein R.sup.1A is C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3
alkyl wherein the C.sub.1-C.sub.3 alkyl is optionally substituted
with one --OR.sup.ZA, and R.sup.ZA is C.sub.1-C.sub.3 alkyl; and
[1240] R.sup.h is hydrogen or C.sub.1-C.sub.3 alkyl.
[1241] In one embodiment, the invention is directed to compounds of
formula (I j) wherein [1242] R.sup.1 is hydrogen, C.sub.1-C.sub.3
alkyl, or --OR.sup.1A; wherein R.sup.1A is C.sub.1-C.sub.3 alkyl;
and [1243] R.sup.h is hydrogen.
[1244] One embodiment is directed to compounds of formula (I)
wherein [1245] X is CR.sup.2 and Y is CR.sup.3; or [1246] X is N
and Y is CR.sup.3; or [1247] X is CR.sup.2 and Y is N; [1248] m is
0, 1, 2, or 3; [1249] R'' are optional substituents on the
cyclopropyl ring, and at each occurrence, are each independently
halogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl;
[1250] R.sup.1 and R.sup.2, are each independently hydrogen,
halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
--OR.sup.1A, --C(O)OR.sup.1B, --NR.sup.1AR.sup.2A or
--C(O)NR.sup.1AR.sup.2A; [1251] R.sup.1A and R.sup.2A, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6
haloalkyl, G.sup.1A, or C.sub.1-C.sub.6 alkyl; wherein the
C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl are each
optionally substituted with one or two substituents independently
selected from the group consisting of --OR.sup.ZA, --SR.sup.ZA,
--S(O).sub.2R.sup.ZA, --C(O)R.sup.ZA, --C(O)OR.sup.ZA,
--C(O)N(R.sup.ZA).sub.2, --N(R.sup.ZA).sub.2,
--N(R.sup.ZA)C(O)R.sup.ZB, --N(R.sup.ZA)S(O).sub.2R.sup.ZB,
--N(R.sup.ZA)C(O)OR.sup.ZB, --N(R.sup.ZA)C(O)N(R.sup.ZA).sub.2,
--CN, and G.sup.1A; or R.sup.1A and R.sup.2A together with the
nitrogen atom to which they are attached form a 4-6 membered
heterocycle wherein the 4-6 membered heterocycle is optionally
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --OR.sup.j, and N(R.sup.j).sub.2;
wherein [1252] R.sup.ZA, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
G.sup.1A, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.1A; and [1253]
R.sup.ZB, at each occurrence, is independently C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, G.sup.1A, or --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1A; [1254] R.sup.1B is hydrogen, C.sub.1-C.sub.6
haloalkyl, or C.sub.1-C.sub.6 alkyl; [1255] R.sup.3 and R.sup.14,
are each independently hydrogen, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkyl, --OH, or --O--(C.sub.1-C.sub.6
alkyl); [1256] R.sup.4 is hydrogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [1257] R.sup.5 is hydrogen, --C(O)R.sup.1,
--C(O)OH, --C(O)N(R.sup.h).sub.2, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, or G.sup.2A; wherein the C.sub.1-C.sub.6
haloalkyl and the C.sub.1-C.sub.6 alkyl are each optionally
substituted with one or two substituents independently selected
from the group consisting of --OR.sup.h, --OC(O)N(R.sup.h).sub.2,
--C(O)R.sup.h, --C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2,
--N(R.sup.h).sub.2, --N(R.sup.h)C(O)R.sup.i,
--N(R.sup.h)S(O).sub.2R.sup.i, --N(R.sup.h)C(O)O(R.sup.i),
--N(R.sup.h)C(O)N(R.sup.h).sub.2, and G.sup.2A; or [1258] R.sup.4
and R.sup.5, together with the carbon atom to which they are
attached, form a C.sub.3-C.sub.6 cycloalkyl or a 4-6 membered
heterocycle; wherein the C.sub.3-C.sub.6 cycloalkyl and the 4-6
membered heterocycle are each optionally substituted with 1, 2, or
3 independently selected R.sup.p groups; [1259] G.sup.2A, at each
occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle,
aryl, or heteroaryl, each of which is independently unsubstituted
or substituted with 1, 2, or 3 independently selected R.sup.q
groups; [1260] R.sup.p and R.sup.q, at each occurrence, are each
independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, oxo, NO.sub.2, --OR.sup.h, --OC(O)R.sup.i,
--OC(O)N(R.sup.h).sub.2, --SR.sup.h, --S(O).sub.2R.sup.h,
--S(O).sub.2N(R.sup.h).sub.2, --C(O)R.sup.h, --C(O)OR.sup.h,
--C(O)N(R.sup.h).sub.2, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, or
G.sup.A, wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.h, --OC(O)R.sup.i, --OC(O)N(R.sup.h).sub.2, --SR.sup.h,
--S(O).sub.2R.sup.h, --S(O).sub.2N(R.sup.h).sub.2, --C(O)R.sup.h,
--C(O)OR.sup.h, --C(O)N(R.sup.h).sub.2, --N(R.sup.h).sub.2,
--N(R.sup.h)C(O)R.sup.i, --N(R.sup.h)S(O).sub.2R.sup.i,
--N(R.sup.h)C(O)O(R.sup.i), --N(R.sup.h)C(O)N(R.sup.h).sub.2, --CN,
and G.sup.A; [1261] R.sup.h, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or
G.sup.A, wherein the C.sub.1-C.sub.6 haloalkyl and the
C.sub.1-C.sub.6 alkyl are each optionally substituted with one or
two substituents independently selected from the group consisting
of --OR.sup.j, --OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[1262] R.sup.i, at each occurrence, is independently
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, or G.sup.A,
wherein the C.sub.1-C.sub.6 haloalkyl and the C.sub.1-C.sub.6 alkyl
are each optionally substituted with one or two substituents
independently selected from the group consisting of --OR.sup.j,
--OC(O)N(R.sup.j).sub.2, --SR.sup.j, --C(O)OR.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2, --CN, and G.sup.A;
[1263] R.sup.6 is hydrogen, halogen, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [1264] R.sup.7 is hydrogen, halogen,
--OR.sup.j, --N(R.sup.j).sub.2, --N(R.sup.j)C(O)R.sup.k,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.3A; [1265] R.sup.8
is hydrogen, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkyl;
[1266] R.sup.9, R.sup.10, and R.sup.13, are each independently
hydrogen, halogen, --OR.sup.j, C.sub.1-C.sub.6 haloalkyl, or
C.sub.1-C.sub.6 alkyl; [1267] R.sup.11 and R.sup.12 are each
independently hydrogen, C.sub.1-C.sub.3 alkyl, or halogen; [1268]
G.sup.1A, G.sup.3A, and G.sup.A, at each occurrence, are each
independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or
heteroaryl, each of which is independently unsubstituted or
substituted with 1, 2, or 3 independently selected R.sup.s groups;
wherein [1269] R.sup.s, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, oxo, NO.sub.2,
--OR.sup.j, --OC(O)R.sup.k, --OC(O)N(R.sup.j).sub.2, --SR.sup.j,
--S(O).sub.2R.sup.j, --S(O).sub.2N(R.sup.j).sub.2, --C(O)R.sup.j,
--C(O)OR.sup.j, --C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2,
--N(R.sup.j)C(O)R.sup.k, --N(R.sup.j)S(O).sub.2R.sup.k,
--N(R.sup.j)C(O)O(R.sup.k), --N(R.sup.j)C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.j, (C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2R.sup.j,
(C.sub.1-C.sub.6 alkylenyl)-S(O).sub.2N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-C(O)R.sup.j, (C.sub.1-C.sub.6
alkylenyl)-C(O)OR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-C(O)N(R.sup.j).sub.2, (C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j).sub.2, (C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)S(O).sub.2R.sup.k, (C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)O(R.sup.k), (C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)N(R.sup.j).sub.2, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [1270] R.sup.j, at each occurrence, is independently
hydrogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; and
[1271] R.sup.k, at each occurrence, is independently
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.
[1272] Exemplary compounds of formula (I) include, but are not
limited to: [1273]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
[1274]
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1275]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3,4-dimethoxyphenyl)--
7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1276]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4S)-2-(3,4-dimethoxyphenyl)--
7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1277] methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;
[1278] methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate;
[1279] methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate; [1280] methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate; [1281]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1282]
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1283] methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate; [1284]
methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate; [1285]
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1286]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1287]
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1288]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1289]
methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate; [1290]
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate; [1291]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1292]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-hydroxy-2-(3-methoxyph-
enyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1293]
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate; [1294]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-7-methoxy-2-(pyridin-
-3-yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1295]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1296]
ethyl
rel-3-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate;
[1297] ethyl
rel-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate;
[1298]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexane-
carboxylic acid; [1299]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1300]
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benz-
oic acid; [1301]
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid; [1302] methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;
[1303]
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid; [1304]
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid; [1305] rac-methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate; [1306]
rac-methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate; [1307]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic
acid; [1308]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic
acid; [1309] methyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)--
7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate; [1310]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1311]
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoate; [1312]
rac-N-[(2R,4R)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,-
2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1313]
rac-N-[(2R,4S)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,-
2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1314]
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-
-dihydro-2H-chromene-7-carboxylic acid; [1315]
3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcy-
clopentanecarboxylic acid; [1316]
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}am-
ino)-2-(3-methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylic acid;
[1317] methyl
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}ami-
no)-3,4-dihydro-2H-chromene-7-carboxylate; [1318] methyl
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}am-
ino)-2-(3-methoxycyclohexyl)-3,4-dihydro-2H-chromene-6-carboxylate;
[1319] methyl
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-2-(3-methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylate;
[1320]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxy-
propyl]benzamide; [1321]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[(3R)-3-hydroxypyr-
rolidin-1-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopr-
opanecarboxamide; [1322]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-(3,3,3-trifluoro-2-hydroxy-
propyl)benzamide; [1323]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-(2-hydroxy-2-methylpropyl)-
benzamide; [1324]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[3-(hydroxymethyl)-
piperidin-1-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclo-
propanecarboxamide; [1325]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[2-(hydroxymethyl)-
morpholin-4-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclo-
propanecarboxamide; [1326]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(1-hydroxycyclobutyl)meth-
yl]benzamide; [1327]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[3-(hydroxymethyl)-
-3-methylazetidin-1-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4--
yl]cyclopropanecarboxamide; [1328]
N-(7-bromo-3,4-dihydro-2H-chromen-4-yl)-1-(2,2-difluoro-1,3-benzodioxol-5-
-yl)cyclopropanecarboxamide; [1329]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-methoxy-2-(pyridin-
-3-yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1330]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R)-2-[3-(hydroxymethyl)phenyl]-
-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide; [1331]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-methoxy-3,4-dihydro-2H-chromen-
-4-yl)cyclopropanecarboxamide; [1332]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-methoxy-2-phenyl-3,4-dihydro-2-
H-chromen-4-yl)cyclopropanecarboxamide; [1333]
N-[2-(3,4-dichlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-d-
ifluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1334]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-7-methox-
y-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1335]
N-[2-(4-chlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-diflu-
oro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1336]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{2-[4-(trifluoromethyl)phenyl]-3,-
4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide; [1337]
N-[2-(2-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-be-
nzodioxol-5-yl)cyclopropanecarboxamide; [1338]
N-[2-(3,4-dichlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,-
3-benzodioxol-5-yl)cyclopropanecarboxamide; [1339]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(2-phenyl-3,4-dihydro-2H-chromen--
4-yl)cyclopropanecarboxamide; [1340]
N-[2-(4-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-be-
nzodioxol-5-yl)cyclopropanecarboxamide; [1341]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-3,4-dihy-
dro-2H-chromen-4-yl]cyclopropanecarboxamide; [1342]
N-[2-(3-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-be-
nzodioxol-5-yl)cyclopropanecarboxamide; [1343]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-(4-fluorophenyl)-3,4-dihydro-2-
H-chromen-4-yl]cyclopropanecarboxamide; [1344]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-6-methox-
y-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1345]
N-(3-benzyl-3,4-dihydro-2H-chromen-4-yl)-1-(2,2-difluoro-1,3-benzodioxol--
5-yl)cyclopropanecarboxamide; [1346]
N-[(4R)-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-benz-
odioxol-5-yl)cyclopropanecarboxamide; [1347]
N-[(4R)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluor-
o-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1348]
N-[(4R)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluor-
o-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1349]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-8-fluoro-2,2-bis(fluorometh-
yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1350]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-3,4-dihydrospiro[chromene-2-
,1'-cyclopentan]-4-yl]cyclopropanecarboxamide; [1351]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-7-fluoro-2,2-bis(fluorometh-
yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1352]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4R)-2-(fluoromethyl)-2-methy-
l-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1353]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(difluoromethyl-
)-2-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1354]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4R)-2-(difluoromethyl)-2-met-
hyl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1355]
N-[(2S,4R)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4--
yl]-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;
[1356]
N-[(2R,4R)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4--
yl]-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;
[1357]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4R)-2-methyl-2-(trifluoromet-
hyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1358]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-7-fluoro-2,2-dimethyl-3,4-d-
ihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1359]
N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,-
2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1360]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4S)-6-fluoro-2,2-dimethyl-3,4-d-
ihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1361]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4S)-6-fluoro-3,4-dihydrospiro[c-
hromene-2,1'-cyclobutan]-4-yl]cyclopropanecarboxamide; [1362]
N-[(4R)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-1-(2,-
2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1363]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-7-methox-
y-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1364]
tert-butyl
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-f-
luoro-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxylate;
[1365]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-fluoro-3,4-dihydrospiro-
[chromene-2,4'-piperidin]-4-yl)cyclopropanecarboxamide; [1366]
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(2-methoxy ethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate;
[1367] methyl
3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl-
)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate;
[1368]
3-[(2R,4R)-7-(carboxymethoxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)c-
yclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1369]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-(2-methoxy
ethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1370]
3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclop-
ropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
[1371]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1'-[(2R)-2,3-dihydroxypropyl]-7--
fluoro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl}cyclopropanecarboxam-
ide; [1372] benzyl
4'-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7'-
-fluoro-3',4'-dihydro-1H-spiro[azetidine-3,2'-chromene]-1-carboxylate;
[1373]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7-fluoro-1'-(methylsulfon-
yl)-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide-
; [1374]
N-(1'-acetyl-7-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-
-yl)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;
[1375]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7'-fluoro-3',4'-dihydrospiro[aze-
tidine-3,2'-chromen]-4'-yl)cyclopropanecarboxamide; [1376]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7'-fluoro-1-(methylsulfonyl)-3',-
4'-dihydrospiro[azetidine-3,2'-chromen]-4'-yl]cyclopropanecarboxamide;
[1377]
N-(1-acetyl-7'-fluoro-3',4'-dihydrospiro[azetidine-3,2'-chromen]-4-
'-yl)-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide;
[1378]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid;
[1379]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1'-(3-hydroxy-2,2-dimethy-
lpropanoyl)-7-methoxy-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclo-
propanecarboxamide; [1380]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1381]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexane-
carboxylic acid; [1382] methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate; [1383]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1384]
methyl
rac-3-[(2R,4R)-7-chloro-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopr-
opyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;
[1385] methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;
[1386]
rac-3-[(2R,4R)-7-chloro-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)-
cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzo-
ic acid; [1387] tert-butyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)--
7-methoxy-3,4-dihydro-2H-chromen-2-yl]azetidine-1-carboxylate;
[1388]
N-[2-(azetidin-3-yl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluo-
ro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide; [1389]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{7-methoxy-2-[1-(methyl
sulfonyl)azetidin-3-yl]-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxami-
de; [1390] methyl
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate;
[1391]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
[1392] methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate; [1393]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1394]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1395] methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate;
[1396]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-hydroxy-2,2-dimethyl-3,4-dihyd-
ro-2H-chromen-4-yl)cyclopropanecarboxamide; [1397]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7-(difluoromethoxy)-2,2-dimethyl-
-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1398]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7-methoxy-2-(tetrahydrofuran-2-y-
l)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide; [1399]
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoate; [1400]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1401]
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-m-
ethoxy-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-3'-carboxylic
acid; [1402] ethyl
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate; [1403]
methyl
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate; [1404]
ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylate;
[1405]
2-[(4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylic
acid; [1406]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]-
carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylic
acid; [1407] ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylate;
[1408]
2-[(4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylic
acid; [1409] methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoate;
[1410] methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoate;
[1411]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoic
acid; [1412] ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate;
[1413] ethyl
rel-2-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate;
[1414] ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate;
[1415]
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylic
acid; [1416]
rel-2-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylic
acid; [1417]
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylic
acid; [1418]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoic
acid; [1419] methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]bicyclo[1.1.1]pentane-1--
carboxylate; [1420]
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]bicyclo[1.1.1]pentane-1--
carboxylic acid; [1421] ethyl
rac-6-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;
[1422] ethyl
rac-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;
[1423] ethyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)--
3,4-dihydro-2H-chromen-2-yl]cyclobutanecarboxylate; [1424]
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)--
3,4-dihydro-2H-chromen-2-yl]cyclobutanecarboxylic acid; [1425]
rac-6-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic acid;
[1426]
rac-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic acid;
[1427] ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-ca-
rboxylate; [1428]
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxyl-
ic acid; [1429] ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxyl-
ate; [1430]
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxyl-
ic acid; [1431] methyl
rel-6-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;
[1432] methyl
rel-6-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;
[1433] methyl
rel-6-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;
[1434] methyl
rel-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate;
[1435] ethyl
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate; [1436]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylic acid;
[1437]
rel-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic
acid; [1438]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxyethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-c-
arboxamide; [1439]
rac-(2R,4R)--N-benzyl-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2--
carboxamide; [1440]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxy-2-phenylethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chr-
omene-2-carboxamide; [1441]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-{[4-(2-hydroxyethy-
l)piperazin-1-yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cycloprop-
anecarboxamide; [1442]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(1-hydroxy-2-methylpropan-2-yl)-7-methoxy-3,4-dihydro-2H-chrome-
ne-2-carboxamide; [1443]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxy-1-phenylethyl)-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide; [1444]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3,4-dihydro-
-2H-chromene-2-carboxamide; [1445]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-7-methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chrom-
ene-2-carboxamide; [1446]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4R)-2-[(4,4-difluoropipe-
ridin-1-yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecar-
boxamide; [1447]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-methoxy-2-(1,4-oxa-
zepan-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1448]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]-
carbonyl}amino)-7-methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-
-2-carboxamide; [1449]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-methoxy-2-(morphol-
in-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1450]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]-
carbonyl}amino)-N-[2-hydroxy-1-(2-methoxyphenyl)ethyl]-7-methoxy-3,4-dihyd-
ro-2H-chromene-2-carboxamide; [1451]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-[2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2--
carboxamide; [1452]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(1,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2--
carboxamide; [1453]
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)-7-methoxy-3,4-dihydro-2H--
chromene-2-carboxamide; [1454]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxyphenyl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxami-
de; [1455]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-N-(2-hydroxy
ethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-carboxamide;
[1456]
rac-(2R,4S)--N-benzyl-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2--
carboxamide; [1457]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxy-2-phenylethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chr-
omene-2-carboxamide; [1458]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4S)-2-[(4-hydroxypiperid-
in-1-yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarbox-
amide; [1459]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-2-{[4-(2-hydroxy
ethyl)piperazin-1-yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cycl-
opropanecarboxamid; [1460]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxy-2-methylpropyl)-7-methoxy-3,4-dihydro-2H-chromene-2--
carboxamide; [1461]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(1-hydroxy-2-methylpropan-2-yl)-7-methoxy-3,4-dihydro-2H-chrome-
ne-2-carboxamid; [1462]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxy-1-phenylethyl)-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide; [1463]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3,4-dihydro-
-2H-chromene-2-carboxamide; [1464]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-7-methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chrom-
ene-2-carboxamide; [1465]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4S)-2-[(4,4-difluoropipe-
ridin-1-yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecar-
boxamide; [1466]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-7-methoxy-2-(1,4-oxa-
zepan-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1467]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]-
carbonyl}amino)-7-methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-
-2-carboxamide; [1468]
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-7-methoxy-2-(morphol-
in-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide;
[1469]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]-
carbonyl}amino)-N-[2-hydroxy-1-(2-methoxyphenyl)ethyl]-7-methoxy-3,4-dihyd-
ro-2H-chromene-2-carboxamide; [1470]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-[2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2--
carboxamide; [1471]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(1,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2--
carboxamide; [1472]
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbony-
l}amino)-N-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)-7-methoxy-3,4-dihydro-2H--
chromene-2-carboxamide; [1473]
rac-1-{[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]car-
bonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]carbonyl}pyrrolidine-3--
carboxylic acid; [1474]
4-[(2R,4R)-4-({[1-(6-bromo-2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]-
carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid;
[1475] methyl
44(2R,4R)-4-(1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-
carboxamido)-7-methoxychroman-2-yl)benzoate; and [1476]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]-N-(methylsulfonyl-
)benzamide.
[1477] Compound names are assigned by using Name 2012 naming
algorithm by Advanced Chemical Development or Struct=Name naming
algorithm as part of CHEMDRAW.RTM. ULTRA v. 12.0.2.1076.
[1478] Compounds of the invention may exist as stereoisomers
wherein asymmetric or chiral centers are present. These
stereoisomers are "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, in Pure
Appl. Chem., 1976, 45: 13-30. The invention contemplates various
stereoisomers and mixtures thereof and these are specifically
included within the scope of this invention. Stereoisomers include
enantiomers and diastereomers, and mixtures of enantiomers or
diastereomers. Individual stereoisomers of compounds of the
invention may be prepared synthetically from commercially available
starting materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by methods of 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
optional liberation of the optically pure product from the
auxiliary as described in Furniss, Hannaford, Smith, and Tatchell,
"Vogel's Textbook of Practical Organic Chemistry", 5th edition
(1989), Longman Scientific & Technical, Essex CM20 2JE,
England, or (2) direct separation of the mixture of optical
enantiomers on chiral chromatographic columns or (3) fractional
recrystallization methods.
[1479] Chiral centers, of which the relative but not the absolute
configuration is known, may be labelled arbitrarily, and the whole
name is prefixed by rel--(for relative). For example, ethyl
rel-3-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate
means
##STR00034##
[1480] Certain names are prefixed by rac--(for racemic), denoting a
racemic mixtures of two enantiomers in the ratio of about 1:1.
[1481] Compounds of the invention may exist as cis or trans
isomers, wherein sub stituents on a ring may attached in such a
manner that they are on the same side of the ring (cis) relative to
each other, or on opposite sides of the ring relative to each other
(trans). For example, cyclobutane may be present in the cis or
trans configuration, and may be present as a single isomer or a
mixture of the cis and trans isomers. Individual cis or trans
isomers of compounds of the invention may be prepared synthetically
from commercially available starting materials using selective
organic transformations, or prepared in single isomeric form by
purification of mixtures of the cis and trans isomers. Such methods
are well-known to those of ordinary skill in the art, and may
include separation of isomers by recrystallization or
chromatography.
[1482] It should be understood that the compounds of the invention
may possess tautomeric forms, as well as geometric isomers, and
that these also constitute an aspect of the invention.
[1483] The present disclosure includes all pharmaceutically
acceptable isotopically-labelled compounds of formula (I) wherein
one or more atoms are replaced by atoms having the same atomic
number, but an atomic mass or mass number different from the atomic
mass or mass number which predominates in nature. Examples of
isotopes suitable for inclusion in the compounds of the disclosure
include isotopes of hydrogen, such as .sup.2H and .sup.3H, carbon,
such as .sup.11C, .sup.13C and .sup.14C, chlorine, such as
.sup.36Cl, fluorine, such as .sup.18F, iodine, such as .sup.123I
and .sup.125I, nitrogen, such as .sup.13N and .sup.15N, oxygen,
such as .sup.15O, .sup.17O and .sup.18O phosphorus, such as
.sup.32P, and sulphur, such as .sup.35S. Certain
isotopically-labelled compounds of formula (I), for example, those
incorporating a radioactive isotope, are useful in drug and/or
substrate tissue distribution studies. The radioactive isotopes
tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection. Substitution with
heavier isotopes such as deuterium, i.e. .sup.2H, may afford
certain therapeutic advantages resulting from greater metabolic
stability, for example, increased in vivo half-life or reduced
dosage requirements, and hence may be preferred in some
circumstances. Substitution with positron emitting isotopes, such
as .sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of formula (I)
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples using an appropriate isotopically-labeled
reagents in place of the non-labeled reagent previously
employed.
[1484] Thus, the formula drawings within this specification can
represent only one of the possible tautomeric, geometric, or
stereoisomeric forms. It is to be understood that the invention
encompasses any tautomeric, geometric, or stereoisomeric form, and
mixtures thereof, and is not to be limited merely to any one
tautomeric, geometric, or stereoisomeric form utilized within the
formula drawings.
[1485] Compounds of formula (I) may be used in the form of
pharmaceutically acceptable salts. The phrase "pharmaceutically
acceptable salt" means those salts which are, within the scope of
sound medical judgement, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity,
irritation, allergic response and the like and are commensurate
with a reasonable benefit/risk ratio.
[1486] Pharmaceutically acceptable salts have been described in S.
M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.
[1487] Compounds of formula (I) may contain either a basic or an
acidic functionality, or both, and can be converted to a
pharmaceutically acceptable salt, when desired, by using a suitable
acid or base. The salts may be prepared in situ during the final
isolation and purification of the compounds of the invention.
[1488] Examples of acid addition salts include, but are not limited
to acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
malate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups can be quaternized with such agents as
lower alkyl halides such as, but not limited to, methyl, ethyl,
propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain
halides such as, but not limited to, decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides; arylalkyl halides like
benzyl and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained. Examples of acids which
may be employed to form pharmaceutically acceptable acid addition
salts include such inorganic acids as hydrochloric acid,
hydrobromic acid, sulfuric acid, and phosphoric acid and such
organic acids as acetic acid, fumaric acid, maleic acid,
4-methylbenzenesulfonic acid, succinic acid and citric acid.
[1489] Basic addition salts may be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as, but not limited to, the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to,
cations based on alkali metals or alkaline earth metals such as,
but not limited to, lithium, sodium, potassium, calcium, magnesium
and aluminum salts and the like and nontoxic quaternary ammonia and
amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine and the like. Other
examples of organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
[1490] The term "pharmaceutically acceptable prodrug" or "prodrug"
as used herein, represents those prodrugs of the compounds of the
invention which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use.
[1491] The invention contemplates compounds of formula (I) formed
by synthetic means or formed by in vivo biotransformation of a
prodrug.
[1492] Compounds described herein can exist in unsolvated as well
as solvated forms, including hydrated forms, such as hemi-hydrates.
In general, the solvated forms, with pharmaceutically acceptable
solvents such as water and ethanol among others are equivalent to
the unsolvated forms for the purposes of the invention.
General Synthesis
[1493] The compounds described herein in various embodiments,
including compounds of general formula (I) and specific examples
can be prepared by methodologies known in the art, for example,
through the reaction schemes depicted in schemes 1-9. The variables
R.sup.1, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, G.sup.2A, X, Y
and m used in the following schemes have the meanings as set forth
in the summary and detailed description sections, unless otherwise
noted.
[1494] Abbreviations used in the descriptions of the schemes and
the specific examples have the following meanings: n-BuLi for
n-butyllithium, DMF for N,N-dimethylformamide, DMSO for dimethyl
sulfoxide, dppf for 1,1'-bis(diphenylphosphino)ferrocene, HPLC for
High Performance Liquid chromatography, LC/MS for liquid
chromatography/mass spectrometry, Prep HPLC for Preparative High
Performance Liquid chromatography, MeOH for methanol, MTBE for
methyl tert-butyl ether, NMR is nuclear magnetic resonance, SFC for
Supercritical Fluid Chromatography, TFA for trifluoroacetic acid,
and THF for tetrahydrofuran.
[1495] Compounds of general formula (I) may be prepared utilizing
general procedure as described in Scheme 1. Acids of formula (1)
may be reacted with amines of formula (2) in the presence of
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate, and a base such as, but not limited to,
diisopropylethyl amine, in a solvent such as, but not limited to,
DMF, and at ambient temperature to provide amides of general
formula (I).
[1496] Alternatively, compounds of general formula (I) may be
prepared by (a) treatment of the acids (1) with oxalyl chloride in
the presence of catalytic amount of DMF, and in a solvent such as,
but not limited to, dichloromethane, at ambient temperature to
provide the corresponding acid chloride (3), and (b) reacting the
acid chloride (3) with the amines (2) in the presence of a base
such as, but not limited to, triethylamine, in a solvent such as,
but not limited to, dichloromethane, at ambient temperature.
##STR00035##
[1497] The requisite amines of formula (2) may be prepared by any
of several methods and synthetic intermediates selected by one of
ordinary skill in the art as illustrated in Schemes 2-5. Racemic
amines of general formula (2) may be prepared from the
corresponding chromanones as shown in Scheme 2. Chromanones (4) may
be treated with hydroxylamines or alkoxyamines such as methoxyamine
to provide oximes of formula (5). The oxime group of (5) may be
reduced using methodologies known by one skilled in the art, for
example, by hydrogenoloysis in the presence of hydrogen and a
catalyst such as, but not limited to, platinum on carbon, or
Raney-Nickel, or platinum (IV) oxide, to provide the amines of
general formula (2).
[1498] Alternatively, chromanones (4) may be treated with a
reducing agent such as, but not limited to, sodium borohydride, to
provide alcohols (6). Alcohols (6) may be converted to azides of
general formula (7) by activation with a sulfonylating agent such
as, but not limited to, methanesulfonic anhydride, followed by
displacement with a nucleophilic azide source such as, but not
limited to, tetrabutylammonium azide. Alternatively, alcohols (6)
may be treated with diphenylphosphoryl azide in the presence of a
base such as, but not limited to,
1,8-diazabicyclo[5.4.0]undec-7-ene, to provide azides (7). Amines
(2) may be prepared by reduction of azides (7) by treatment with a
phosphine agent such as, but not limited to triphenylphosphine with
an appropriate water miscible organic co-solvent such as, but not
limited to, THF.
##STR00036##
[1499] Chiral amines may be prepared using synthetic methods as
outlined in Schemes 3 and 4. Chiral amines of formula (8), (15),
and (16) may be converted to target compounds described herein
using synthetic methods as outlined in Scheme 1.
[1500] Chromanones (4) may be treated with chiral hydride sources
known to those skilled in the art (Corey, E. J. et al. J. Org.
Chem. 1988, 53, 2861; Kawanami, S. et al. Tetrahedron 2003, 59,
8411; Corey, E. J. et al. Tetrahedron Asymm. 2002, 13, 1347) to
provide chiral alcohols of general formula (9). Alcohols (9) may be
converted to azides of formula (10) and subsequently to amines (8),
by employing reagents and reaction conditions as described in
Scheme 2.
##STR00037##
[1501] Alternatively, the hydrochloride salts of the chiral amines
may be prepared according to the general procedure described by
Ellman and co-workers (Tanuwidjaja, J.; Ellman, J. A. et al. J.
Org. Chem. 2007, 72, 626) as illustrated in Scheme 4. Chromanones
(4) may be condensed with a chiral sulfinamide such as
tert-butanesulfinamide in the presence of a Lewis acid such as
titanium(IV) ethoxide to provide N-sulfinyl imine intermediates
(11) and (12). The diastereomeric mixture of (11) and (12) may be
separated via chromatography. The respective N-sulfinyl imine
intermediates (11) and (12) may undergo a subsequent reduction with
reagents such as sodium borohydride to provide sulfinamides of
general formula (13) and (14). Treatment of the sulfinamides (13)
and (14) with HCl or acetyl chloride and methanol provides the
hydrochloride salts of amines (15) and (16).
##STR00038##
[1502] Stereoselective hydrogenolysis of oximes of formula (17)
wherein R.sup.5 is G.sup.2A may be achieved in the presence of a
reducing agent such as platinum on carbon or platinum (IV)
oxide/acetic acid, as illustrated in Scheme 5. The reduction
provides selectively a single enantiomer of formula (18).
##STR00039##
[1503] Alcohols of general formula (6) and (9) wherein R.sup.4,
R.sup.6, and R.sup.7 are hydrogen, and R.sup.5 is alkyl or
G.sup.2A, may be prepared as shown in Scheme 6. Ethanones of
general formula (20) may be treated with lithium
bis(trimethylsilyl)amide in in a solvent such as THF at about
-78.degree. C., followed by treatment with aldehydes of formula
(19), to provide hydroxyketones of formula (21). Reduction of (21)
with a reducing agent such as, but not limited to, sodium
borohydride, optionally in presence of a complexing agent such as
diethylmethoxyborane, provides the diols of formula (22).
Cyclization of the diols (22) may be achieved in the presence of
DBU at elevated temperature (e.g. about 60.degree. C. to about
90.degree. C.). The cis and trans isomers may be obtained via
column chromatography of (23).
##STR00040##
[1504] Chromanones (4) wherein R.sup.4, R.sup.6, and R.sup.7 are
hydrogen, and R.sup.5 is alkyl or G.sup.2A, may be prepared as
shown in Scheme 7. Ethanones of general formula (20) may be reacted
with lithium bis(trimethylsilyl)amide in in a solvent such as THF
at about -78.degree. C., followed by treatment with acid chlorides
of formula (24), to provide intermediates of formula (25).
Cyclization of (25) in the presence of a base such as potassium
carbonate in a solvent such as, but not limited to, DMF, at
elevated temperature (e.g. about 90.degree. C. to about 120.degree.
C.) provides chromenones (26). Transformation of the chromenones
(26) to chromanones (26A) may be achieved by a) reduction of (26)
with a suitable reducing agent to provide the corresponding
chromanol (23), and b) oxidizing the chromanol with an oxidant such
as, but not limited to, Jones reagent.
##STR00041##
[1505] Chromanones (4) wherein R.sup.4, R.sup.6, and R.sup.7 are
hydrogen, and R.sup.5 is alkyl or G.sup.2A, may be prepared as
shown in Scheme 8. Hydroxyethanones (27) may be treated with
aldehydes (28) in the presence of a base such as sodium hydroxide
to provide intermediates (29). Cyclization of (29) to (26A) may be
achieved by treatment with concentrated HCl at elevated temperature
(e.g. about 100.degree. C.).
[1506] Alternatively, chromanones (26A) may be prepared from a)
treatment of hydroxyethanones (27) with lithium diisopropylamide
and aldehydes (28) to provide intermediate (30), and b) cyclization
of (30) in the presence of trifluoroacetic anhydride and DBU.
##STR00042##
[1507] Chiral chormanones (32) wherein R.sup.5 is aryl or
heteroaryl may be prepared as shown in Scheme 9. Hydroxyethanones
(27) may be treated with 1,1-dimethoxy-N,N-dimethylmethanamine at
elevated temperature (about 100.degree. C. to about 120.degree. C.)
or under microwave irradiation to provide chromenones (31).
Treatment of of (31) with aryl or heteroaryl boronic acid (or
esters thereof) in the presence of
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole, and a
catalyst such as bis(2,2,2-trifluroacetoxy)palladium provides the
chiral chromanones (32).
##STR00043##
[1508] Optimum reaction conditions and reaction times for each
individual step may vary depending on the particular reactants
employed and substituents present in the reactants used. Unless
otherwise specified, solvents, temperatures and other reaction
conditions may be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Reactions may be further processed in the conventional
manner, e.g. by eliminating the solvent from the residue and
further purified according to methodologies generally known in the
art such as, but not limited to, crystallization, distillation,
extraction, trituration and chromatography. Unless otherwise
described, the starting materials and reagents are either
commercially available or may be prepared by one skilled in the art
from commercially available materials using methods described in
the chemical literature.
[1509] Routine experimentations, including appropriate manipulation
of the reaction conditions, reagents and sequence of the synthetic
route, protection of any chemical functionality that can not be
compatible with the reaction conditions, and deprotection at a
suitable point in the reaction sequence of the method are included
in the scope of the invention. Suitable protecting groups and the
methods for protecting and deprotecting different substituents
using such suitable protecting groups are well known to those
skilled in the art; examples of which can be found in T. Greene and
P. Wuts, Protecting Groups in Organic Synthesis (3.sup.rd ed.),
John Wiley & Sons, NY (1999), which is incorporated herein by
reference in its entirety. Synthesis of the compounds of the
invention can be accomplished by methods analogous to those
described in the synthetic schemes described hereinabove and in
specific examples.
[1510] Starting materials, if not commercially available, can be
prepared by procedures selected from standard organic chemical
techniques, techniques that are analogous to the synthesis of
known, structurally similar compounds, or techniques that are
analogous to the above described schemes or the procedures
described in the synthetic examples section.
[1511] When an optically active form of a compound is required, it
can be obtained by carrying out one of the procedures described
herein using an optically active starting material (prepared, for
example, by asymmetric induction of a suitable reaction step), or
by resolution of a mixture of the stereoisomers of the compound or
intermediates using a standard procedure (such as chromatographic
separation, recrystallization or enzymatic resolution).
[1512] Similarly, when a pure geometric isomer of a compound is
required, it can be prepared by carrying out one of the above
procedures using a pure geometric isomer as a starting material, or
by resolution of a mixture of the geometric isomers of the compound
or intermediates using a standard procedure such as chromatographic
separation.
Pharmaceutical Compositions
[1513] This invention also provides for pharmaceutical compositions
comprising a therapeutically effective amount of a compound of
formula (I), or a pharmaceutically acceptable salt thereof together
with a pharmaceutically acceptable carrier, diluent, or excipient
thereof. The phrase "pharmaceutical composition" refers to a
composition suitable for administration in medical or veterinary
use.
[1514] The pharmaceutical compositions that comprise a compound of
formula (I), alone or in combination with one or more additional
therapeutic agents, may be administered to the subjects orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments or drops),
bucally or as an oral or nasal spray. The term "parenterally" as
used herein, refers to modes of administration which include
intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular injection and infusion.
[1515] The term "pharmaceutically acceptable carrier" as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which may serve as
pharmaceutically acceptable carriers are sugars such as, but not
limited to, lactose, glucose and sucrose; starches such as, but not
limited to, corn starch and potato starch; cellulose and its
derivatives such as, but not limited to, sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as, but not
limited to, cocoa butter and suppository waxes; oils such as, but
not limited to, peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; glycols; such a propylene
glycol; esters such as, but not limited to, ethyl oleate and ethyl
laurate; agar; buffering agents such as, but not limited to,
magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as, but not limited to, sodium lauryl
sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants may also be
present in the composition, according to the judgment of the
formulator.
[1516] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions as well as sterile
powders for reconstitution into sterile injectable solutions or
dispersions just prior to use. Examples of suitable aqueous and
nonaqueous carriers, diluents, solvents or vehicles include water,
ethanol, polyols (such as glycerol, propylene glycol, polyethylene
glycol and the like), vegetable oils (such as olive oil),
injectable organic esters (such as ethyl oleate), and suitable
mixtures thereof. Proper fluidity may be maintained, for example,
by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions and by the use of surfactants.
[1517] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption, such as aluminum
monostearate and gelatin.
[1518] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally-administered drug form may be
accomplished by dissolving or suspending the drug in an oil
vehicle.
[1519] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release may be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[1520] The injectable formulations may be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[1521] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In certain embodiments, solid
dosage forms may contain from 1% to 95% (w/w) of a compound of
formula (I). In certain embodiments, the compound of formula (I)
may be present in the solid dosage form in a range of from 5% to
70% (w/w). In such solid dosage forms, the active compound may be
mixed with at least one inert, pharmaceutically acceptable
excipient or carrier, such as sodium citrate or dicalcium phosphate
and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol and silicic acid; b) binders such as
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,
sucrose and acacia; c) humectants such as glycerol; d)
disintegrating agents such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates and sodium
carbonate; e) solution retarding agents such as paraffin; f)
absorption accelerators such as quaternary ammonium compounds; g)
wetting agents such as cetyl alcohol and glycerol monostearate; h)
absorbents such as kaolin and bentonite clay and i) lubricants such
as talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate and mixtures thereof. In the case of
capsules, tablets and pills, the dosage form may also comprise
buffering agents.
[1522] The pharmaceutical composition may be a unit dosage form. In
such form the preparation is subdivided into unit doses containing
appropriate quantities of the active component. The unit dosage
form can be a packaged preparation, the package containing discrete
quantities of preparation, such as packeted tablets, capsules, and
powders in vials or ampules. Also, the unit dosage form may be a
capsule, tablet, cachet, or lozenge itself, or it may be the
appropriate number of any of these in packaged form. The quantity
of active component in a unit dose preparation may be varied or
adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to
95% (w/w) of a unit dose, according to the particular application
and the potency of the active component. The composition may, if
desired, also contain other therapeutic agents.
[1523] The dose to be administered to a subject may be determined
by the efficacy of the particular compound employed and the
condition of the subject, as well as the body weight or surface
area of the subject to be treated. The size of the dose also will
be determined by the existence, nature, and extent of any adverse
side-effects that accompany the administration of a particular
compound in a particular subject. In determining the effective
amount of the compound to be administered in the treatment or
prophylaxis of the disorder being treated, the physician may
evaluate factors such as the circulating plasma levels of the
compound, compound toxicities, and/or the progression of the
disease, etc.
[1524] For administration, compounds may be administered at a rate
determined by factors that may include, but are not limited to, the
LD.sub.50 of the compound, the pharmacokinetic profile of the
compound, contraindicated drugs, and the side-effects of the
compound at various concentrations, as applied to the mass and
overall health of the subject. Administration may be accomplished
via single or divided doses.
[1525] The compounds utilized in the pharmaceutical method of the
invention may be administered at the initial dosage of about 0.001
mg/kg to about 100 mg/kg daily. In certain embodiments, the daily
dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages,
however, may be varied depending upon the requirements of the
subject, the severity of the condition being treated, and the
compound being employed. Determination of the proper dosage for a
particular situation is within the skill of the practitioner.
Treatment may be initiated with smaller dosages, which are less
than the optimum dose of the compound. Thereafter, the dosage is
increased by small increments until the optimum effect under
circumstances is reached. For convenience, the total daily dosage
may be divided and administered in portions during the day, if
desired.
[1526] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
carriers as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
[1527] The solid dosage forms of tablets, dragees, capsules, pills
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[1528] The active compounds may also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[1529] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols, and fatty acid esters of sorbitan and mixtures
thereof.
[1530] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[1531] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth and mixtures thereof.
[1532] Compositions for rectal or vaginal administration are
preferably suppositories which may be prepared by mixing the
compounds with suitable non-irritating carriers or carriers such as
cocoa butter, polyethylene glycol, or a suppository wax which are
solid at room temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity and release the
active compound.
[1533] Compounds may also be administered in the form of liposomes.
Liposomes generally may be derived from phospholipids or other
lipid substances. Liposomes are formed by mono- or multi-lamellar
hydrated liquid crystals which are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid
capable of forming liposomes may be used. The present compositions
in liposome form may contain, in addition to a compound of the
invention, stabilizers, preservatives, excipients, and the like.
Examples of lipids include, but are not limited to, natural and
synthetic phospholipids, and phosphatidyl cholines (lecithins),
used separately or together.
[1534] Methods to form liposomes have been described, see example,
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,
New York, N.Y. (1976), p. 33 et seq.
[1535] Dosage forms for topical administration of a compound
described herein include powders, sprays, ointments, and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
Methods of Use
[1536] The compounds and compositions using any amount and any
route of administration may be administered to a subject for the
treatment or prevention of cystic fibrosis, pancreatic
insufficiency, Sjogren's Syndrome (SS), chronic obstructive lung
disease (COLD), or chronic obstructive airway disease (COAD).
[1537] The term "administering" refers to the method of contacting
a compound with a subject. Thus, the compounds may be administered
by injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, parentally, or
intraperitoneally. Also, the compounds described herein may be
administered by inhalation, for example, intranasally.
Additionally, the compounds may be administered transdermally,
topically, and via implantation. In certain embodiments, the
compounds and compositions thereof may be delivered orally. The
compounds may also be delivered rectally, bucally, intravaginally,
ocularly, or by insufflation. CFTR-modulated disorders and
conditions may be treated prophylactically, acutely, and
chronically using compounds or pharmaceutically acceptable salts
thereof and compositions thereof, depending on the nature of the
disorder or condition. Typically, the host or subject in each of
these methods is human, although other mammals may also benefit
from the administration of compounds or pharmaceutically acceptable
salts thereof and compositions thereof as set forth
hereinabove.
[1538] Compounds of the invention are useful as modulators of CFTR.
Thus, the compounds and compositions are particularly useful for
treating or lessening the severity or progression of a disease,
disorder, or a condition where hyperactivity or inactivity of CFTR
is involved. Accordingly, the invention provides a method for
treating cystic fibrosis, pancreatic insufficiency, Sjogren's
Syndrome (SS), chronic obstructive lung disease (COLD), or chronic
obstructive airway disease (COAD) in a subject, wherein the method
comprises the step of administering to said subject a
therapeutically effective amount of a compound of formula (I),
(I-a), (I-b), (I-c), (I-d), (I-e), (I-g), (I-h), (I-i), or (I j) or
a pharmaceutically acceptable salt thereof, or a preferred
embodiment thereof as set forth above, with or without a
pharmaceutically acceptable carrier. Particularly, the method is
for the treatment or prevention of cystic fibrosis. In a more
particular embodiment, the cystic fibrosis is caused by a Class I,
II, III, IV, V, and/or VI mutation.
[1539] One embodiment is directed to a compound of the invention or
a pharmaceutically acceptable salt thereof, or pharmaceutical
compositions comprising a compound of the invention or a
pharmaceutically acceptable salt thereof for use in medicine.
[1540] One embodiment is directed to a compound according to
formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-g), (I-h),
(I-i), or (I j) or a pharmaceutically acceptable salt thereof, or
pharmaceutical compositions comprising a compound of the invention
or pharmaceutically acceptable salt thereof, for use in the
treatment of cystic fibrosis, pancreatic insufficiency, Sjogren's
Syndrome (SS), chronic obstructive lung disease (COLD) or chronic
obstructive airway disease (COAD). In a more particular embodiment,
the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or
VI mutation.
[1541] In one embodiment, the present invention provides
pharmaceutical compositions comprising a compound of the invention
or a pharmaceutically acceptable salt thereof, and one or more
additional therapeutic agents. In a particular embodiment, the
additional therapeutic agent is a cystic fibrosis treatment agent
other than a compound of the invention. In a more particular
embodiment, the cystic fibrosis is caused by a Class I, II, III,
IV, V, and/or VI mutation.
[1542] The present compounds or pharmaceutically acceptable salts
thereof may be administered as the sole active agent or it may be
co-administered with one or more additional therapeutic agents,
including other compounds that demonstrate the same or a similar
therapeutic activity and that are determined to be safe and
efficacious for such combined administration. The present compounds
may be co-administered to a subject. The term "co-administered"
means the administration of two or more different therapeutic
agents to a subject by combination in the same pharmaceutical
composition or in separate pharmaceutical compositions. Thus
co-administration involves administration at the same time of a
single pharmaceutical composition comprising two or more
therapeutic agents or administration of two or more different
compositions to the same subject at the same or different
times.
[1543] The compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with a
therapeutically effective amount of one or more additional
therapeutic agents to treat a CFTR mediated disease, where examples
of the therapeutic agents include, but are not limited to,
antibiotics (for example, aminoglycosides, colistin, aztreonam,
ciprofloxacin, and azithromycin), expectorants (for example,
hypertonic saline, acetylcysteine, dornase alfa, and denufosol),
pancreatic enzyme supplements (for example, pancreatin, and
pancrelipase), epithelial sodium channel blocker (ENaC) inhibitors,
CFTR modulators (for example, CFTR potentiators, CFTR correctors),
and CFTR amplifiers. In one embodiment, the CFTR mediated disease
is cystic fibrosis. In one embodiment, the compounds of the
invention or pharmaceutically acceptable salts thereof may be
co-administered with one or more additional therapeutic agents
selected from the group consisting of CFTR modulators and CFTR
amplifiers. In one embodiment, the compounds of the invention or
pharmaceutically acceptable salts thereof may be co-administered
with one or two CFTR modulators and one CFTR amplifier. In one
embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with one
potentiator, one or more correctors, and one CFTR amplifier. In one
embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with one or more
CFTR modulators. In one embodiment, the compounds of the invention
or pharmaceutically acceptable salts thereof may be co-administered
with one CFTR modulators. In one embodiment, the compounds of the
invention or pharmaceutically acceptable salts thereof may be
co-administered with two CFTR modulators. In one embodiment, the
compounds of the invention or pharmaceutically acceptable salts
thereof may be co-administered with three CFTR modulators. In one
embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with one
potentiator and one or more correctors. In one embodiment, the
compounds of the invention or pharmaceutically acceptable salts
thereof may be co-administered with one potentiator and two
correctors. In one embodiment, the compounds of the invention or
pharmaceutically acceptable salts thereof may be co-administered
with one potentiator. In one embodiment, the compounds of the
invention or pharmaceutically acceptable salts thereof may be
co-administered with one or more correctors. In one embodiment, the
compounds of the invention or pharmaceutically acceptable salts
thereof may be co-administered with one corrector. In one
embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with two
correctors.
[1544] Examples of potentiators include, but are not limited to,
Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, and
N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl-
)-1H-pyrazole-5-carboxamide. Examples of potentiators are also
disclosed in publications: WO2005120497, WO2008147952,
WO2009076593, WO2010048573, WO2006002421, WO2008147952,
WO2011072241, WO2011113894, WO2013038373, WO2013038378,
WO2013038381, WO2013038386, and WO2013038390; and U.S. application
Ser. Nos. 14/271,080 and 14/451,619.
[1545] In one embodiment, the potentiator can be selected from the
group consisting of [1546] Ivacaftor (VX-770,
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carbox-
amide); [1547] CTP-656; [1548] NVS-QBW251 [1549] FD1860293; [1550]
2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyr-
an-3-carboxamide; [1551]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl-
)-1H-pyrazole-5-carboxamide; [1552]
2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]py-
ran-3-carboxamide [1553]
2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-t-
hieno[2,3-c]pyran-3-carboxamide; [1554]
5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thien-
o[2,3-c]pyran-3-carboxamide; [1555]
2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thie-
no[2,3-c]pyran-3-carboxamide; [1556]
2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihy-
dro-4H-thieno[2,3-c]pyran-3-carboxamide; [1557]
2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H--
thieno[2,3-c]pyran-3-carboxamide; [1558]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-methyl-1H-pyrazole-3-carboxamide; [1559]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-cyclopropyl-1H-pyrazole-3-carboxamide; [1560]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-isopropyl-1H-pyrazole-3-carboxamide; [1561]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide; [1562]
5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-
-c]pyran-2-yl)-1H-pyrazole-3-carboxamide; [1563]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-ethyl-1H-pyrazole-3-carboxamide; [1564]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide; [1565]
2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]-
pyran-3-carboxamide; [1566]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-4-chloro-1H-pyrazole-3-carboxamide; [1567]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide; [1568]
4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]py-
ran-2-yl)-1H-pyrazole-3-carboxamide; [1569]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide; [1570]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-4-methyl-1H-pyrazole-3-carboxamide; [1571]
2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-t-
hieno[2,3-c]pyran-3-carboxamide; [1572]
2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-
-c]pyran-3-carboxamide; [1573]
5-(2-methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid
(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)--
amide; [1574]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-metho-
xypropyl)-1H-pyrazole-3-carboxamide; [1575]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethox-
yethyl)-1H-pyrazole-3-carboxamide; [1576]
2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-th-
ieno[2,3-c]pyran-3-carboxamide; [1577]
2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-th-
ieno[2,3-c]pyran-3-carboxamide; [1578]
2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thie-
no[2,3-c]pyran-3-carboxamide; [1579]
[5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl-
]pyrazol-1-yl]methyl dihydrogen phosphate; [1580]
[3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl-
]pyrazol-1-yl]methyl dihydrogen phosphate; [1581]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dio-
xan-2-yl)-1H-pyrazole-3-carboxamide; [1582]
5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl-
]amino]-4H-thieno[2,3-c]pyran-3-carboxamide; and [1583]
2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]py-
ran-3-carboxamide.
[1584] Non limiting examples of correctors include Lumacaftor
(VX-809),
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-f-
luoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxam-
ide (VX-661), VX-983, GLPG2665, VX-152, VX-440, FDL169, FDL304,
FD2052160, and FD2035659. Examples of correctors are also disclosed
in publications: US20140274933 and WO2014160478; and U.S.
Application 62/073,586.
[1585] In one embodiment, the corrector(s) can be selected from the
group consisting of [1586] Lumacaftor (VX-809); [1587]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-f-
luoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxam-
ide (VX-661); [1588] VX-983; [1589] GLPG2665; [1590] VX-152; [1591]
VX-440; [1592] FDL169 [1593] FDL304; [1594] FD2052160; [1595]
FD2035659; [1596]
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1597]
rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1598]
3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1599]
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1600]
rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;
[1601]
3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid; [1602]
3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid; and
[1603]
4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)tetrahydro-2H-pyran-2-yl]benzoic acid.
[1604] In one embodiment, the additional therapeutic agent is a
CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR
modulators, such as potentiators and correctors. An example of a
CFTR amplifier is PTI130. Examples of amplifiers are also disclosed
in publications: WO2015138909 and WO2015138934.
[1605] In one embodiment, the additional therapeutic agent is an
agent that reduces the activity of the epithelial sodium channel
blocker (ENaC) either directly by blocking the channel or
indirectly by modulation of proteases that lead to an increase in
ENaC activity (e.g., seine proteases, channel-activating
proteases). Exemplary of such agents include camostat (a
trypsin-like protease inhibitor), QAU145, 552-02, GS-9411,
INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that
reduce the activity of the epithelial sodium channel blocker (ENaC)
can be found, for example, in PCT Publication No. WO2009074575 and
U.S. Pat. No. 8,999,976.
[1606] In one embodiment, the ENaC inhibitor is VX-371.
[1607] This invention also is directed to kits that comprise one or
more compounds and/or salts of the invention, and, optionally, one
or more additional therapeutic agents.
[1608] This invention also is directed to methods of use of the
compounds, salts, compositions, and/or kits of the invention to,
with or without one or more additional therapeutic agents, for
example, modulate the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) protein, and treat a disease treatable by
modulating the Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR) protein (including cystic fibrosis, Sjogren's syndrome,
pancreatic insufficiency, chronic obstructive lung disease, and
chronic obstructive airway disease).
[1609] This invention also is directed to a use of one or more
compounds and/or salts of the invention in the preparation of a
medicament. The medicament optionally can comprise one or more
additional therapeutic agents. In some embodiments, the medicament
is useful for treating cystic fibrosis, Sjogren's syndrome,
pancreatic insufficiency, chronic obstructive lung disease, and
chronic obstructive airway disease. In a particular embodiment, the
medicament is for use in the treatment of cystic fibrosis. In a
more particular embodiment, the cystic fibrosis is caused by a
Class I, II, III, IV, V, and/or VI mutation.
[1610] This invention also is directed to a use of one or more
compounds and/or salts of the invention in the manufacture of a
medicament for the treatment of cystic fibrosis, Sjogren's
syndrome, pancreatic insufficiency, chronic obstructive lung
disease, and chronic obstructive airway disease. The medicament
optionally can comprise one or more additional therapeutic agents.
In a particular embodiment, the invention is directed to the use of
one or more compounds and/or salts of the invention in the
manufacture of a medicament for the treatment of cystic fibrosis.
In a more particular embodiment, the cystic fibrosis is caused by a
Class I, II, III, IV, V, and/or VI mutation.
[1611] Further benefits of Applicants' invention will be apparent
to one skilled in the art from reading this patent application.
[1612] The following Examples may be used for illustrative purposes
and should not be deemed to narrow the scope of the invention.
EXAMPLES
General Reverse Phase Purification Procedures:
Preparative LC/MS Method TFA1
[1613] Samples were purified by reverse phase preparative HPLC on a
Phenomenex Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 30
mL/min (0-0.5 min 5% A, 0.5-6.5 min linear gradient 5-100% A,
6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10
min 5% A). A sample volume of 1.0 mL was injected directly from the
flow reactor stream to the HPLC system. A custom purification
system was used, consisting of the following modules: Gilson 305
and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155
detector; Gilson 506C interface box; Gilson FC204 fraction
collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass
spectrometer. The system was controlled through a combination of
Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Preparative LC/MS Method TFA2
[1614] Samples were purified by preparative HPLC on a Phenomenex
Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (30 mm.times.75 mm). A
gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water
(B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5
min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min
linear gradient 95-5% A). Samples were injected in 1.5 mL DMSO:MeOH
(1:1). A custom purification system was used, consisting of the
following modules: Waters LC4000 preparative pump; Waters 996
diode-array detector; Waters 717+ autosampler; Waters SAT/IN
module, Alltech Varex III evaporative light-scattering detector;
Gilson 506C interface box; and two Gilson FC204 fraction
collectors. The system was controlled using Waters Millennium32
software, automated using an Abbott developed Visual Basic
application for fraction collector control and fraction tracking.
Fractions were collected based upon UV signal threshold and
selected fractions subsequently analyzed by flow injection analysis
mass spectrometry using positive APCI ionization on a Finnigan
Navigator using 70:30 MeOH:10 mM NH.sub.4OH(aqueous) at a flow rate
of 0.8 mL/min. Loop-injection mass spectra were acquired using a
Finnigan Navigator running Navigator 1.8 software and a Gilson 215
liquid handler for fraction injection controlled by an Abbott
developed Visual Basic application.
Preparative LC/MS Method TFA4
[1615] Samples were purified by reverse phase preparative HPLC on a
Phenomenex Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 30
mL/min (0-0.1 min 5% A, 0.1-0.5 min linear gradient 5-30% A,
0.5-6.5 min linear gradient 30-70% A, 6.5-7.0 min linear gradient
70-100% A, 7.0-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5%
A, 9.0-10 min 5% A). A sample volume of 1.0 mL was injected
directly from the flow reactor stream to the HPLC system. A custom
purification system was used, consisting of the following modules:
Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson
UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Preparative LC/MS Method TFA6
[1616] Samples were purified by reverse phase preparative HPLC on a
Phenomenex Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 30
mL/min (0-0.5 min 15% A, 0.5-8.0 min linear gradient 15-100% A,
8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient
100-15% A, 9.1-10 min 15% A). A sample volume of 1.0 mL was
injected directly from the flow reactor stream to the HPLC system.
A custom purification system was used, consisting of the following
modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module;
Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Preparative LC/MS Method TFA8
[1617] Samples were purified by reverse phase preparative HPLC on a
Phenomenex Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 30
mL/min (0-0.5 min 35% A, 0.5-8.0 min linear gradient 35-100% A,
8.0-9.0 min 100% A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient
100-35% A, 9.1-10 min 35% A). A sample volume of 1.0 mL was
injected directly from the flow reactor stream to the HPLC system.
A custom purification system was used, consisting of the following
modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module;
Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Preparative LC/MS Method AA2
[1618] Samples were purified by preparative HPLC on a Phenomenex
Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (30 mm.times.75 mm). A
gradient of acetonitrile (A) and 10 mM ammonium acetate in water
(B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5
min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min
linear gradient 95-5% A). Samples were injected in 1.5 mL DMSO:MeOH
(1:1). A custom purification system was used, consisting of the
following modules: Waters LC4000 preparative pump; Waters 996
diode-array detector; Waters 717+ autosampler; Waters SAT/IN
module, Alltech Varex III evaporative light-scattering detector;
Gilson 506C interface box; and two Gilson FC204 fraction
collectors. The system was controlled using Waters Millennium32
software, automated using an Abbott developed Visual Basic
application for fraction collector control and fraction tracking.
Fractions were collected based upon UV signal threshold and
selected fractions subsequently analyzed by flow injection analysis
mass spectrometry using positive APCI ionization on a Finnigan
Navigator using 70:30 MeOH:10 mM NH.sub.4OH(aq) at a flow rate of
0.8 mL/min. Loop-injection mass spectra were acquired using a
Finnigan Navigator running Navigator 1.8 software and a Gilson 215
liquid handler for fraction injection controlled by an Abbott
developed Visual Basic application.
Preparative LC/MS Method AA7
[1619] Samples were purified by reverse phase preparative HPLC on a
Phenomenex Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium
acetate in water (B) was used, at a flow rate of 30 mL/min (0-0.5
min 25% A, 0.5-8.0 min linear gradient 25-100% A, 8.0-9.0 min 100%
A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100-25% A,
9.1-10 min 25% A). A sample volume of 1.0 mL was injected directly
from the flow reactor stream to the HPLC system. A custom
purification system was used, consisting of the following modules:
Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson
UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Preparative LC/MS Method AA8
[1620] Samples were purified by reverse phase preparative HPLC on a
Phenomenex Luna C8(2) 5 .mu.m 100 .ANG. AXIA column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium
acetate in water (B) was used, at a flow rate of 30 mL/min (0-0.5
min 35% A, 0.5-8.0 min linear gradient 35-100% A, 8.0-9.0 min 100%
A, 7.0-8.9 min 100% A, 9.0-9.1 min linear gradient 100-35% A,
9.1-10 min 35% A). A sample volume of 1.0 mL was injected directly
from the flow reactor stream to the HPLC system. A custom
purification system was used, consisting of the following modules:
Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson
UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Example 1
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1621] To a solution of Example 6 (25 mg, 0.047 mmol) in
tetrahydrofuran (233 .mu.L) was added lithium hydroxide hydrate
(233 .mu.L of a 0.8 M solution in water). The resulting biphasic
mixture was stirred vigorously for 16 hours at room temperature,
followed by addition of more lithium hydroxide hydrate (233 .mu.L
of a 0.8 M solution). The reaction mixture was stirred for an
additional 5 hours at room temperature, acidified by the addition
of 6 M HCl (0.040 mL) and the resulting biphasic mixture loaded
directly onto a 4 g silica gel cartridge and eluted with 30% ethyl
acetate/heptanes over 15 minutes to give the title compound as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.20 (s,
1H), 8.06 (dd, J=7.9, 1.5 Hz, 1H), 7.71-7.61 (m, 1H), 7.48 (t,
J=7.7 Hz, 1H), 7.13 (dd, J=8.2, 1.7 Hz, 1H), 7.09 (d, J=1.7 Hz,
1H), 7.01 (d, J=8.2 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.52 (dd,
J=8.6, 2.5 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.49 (td, J=9.9, 6.0
Hz, 1H), 5.40 (d, J=8.9 Hz, 1H), 5.33-5.22 (m, 1H), 3.76 (s, 3H),
2.58 (ddd, J=13.3, 5.9, 2.0 Hz, 1H), 1.82-1.72 (m, 2H), 1.69-1.63
(m, 1H), 1.09 (q, J=2.8 Hz, 2H); MS (ESI-) m/z 522.1
(M-H).sup.-.
Example 2
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1622] To a solution of Example 5E (35 mg, 0.065 mmol) in
tetrahydrofuran (326 .mu.L) was added lithium hydroxide hydrate
(326 .mu.L of a 0.8 M solution). The resulting biphasic mixture was
stirred vigorously for 16 hours at room temperature, followed by
addition of more lithium hydroxide hydrate (326 .mu.L of a 0.8 M
solution). The reaction was stirred for an additional 5 hours at
room temperature, acidified by the addition of 6 M HCl (0.050 mL)
and the resulting biphasic mixture was loaded directly onto a 4 g
silica gel cartridge and eluted with 30% ethyl acetate/heptanes
over 15 minutes to give the title compound as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (t, J=1.8 Hz, 1H),
8.12-8.04 (m, 1H), 7.72-7.61 (m, 1H), 7.51 (t, J=7.7 Hz, 1H),
7.20-7.11 (m, 2H), 7.04 (dd, J=8.4, 4.1 Hz, 2H), 6.53 (dd, J=8.5,
2.6 Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 5.60 (d, J=6.6 Hz, 1H), 5.01
(dd, J=5.5, 2.8 Hz, 1H), 4.84 (dd, J=11.6, 2.2 Hz, 1H), 3.76 (s,
3H), 2.35 (dt, J=14.4, 2.5 Hz, 1H), 2.16 (ddd, J=14.4, 11.4, 4.5
Hz, 1H), 1.70 (q, J=3.7 Hz, 2H), 1.09 (q, J=3.7 Hz, 2H); MS (ESI-)
m/z 522.1 (M-H).sup.-.
Example 3
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3,4-dimethoxyphenyl)-7-
-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1623] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(CAS 68015-98-5) (120 mg, 0.496 mmol) in DMF (1239 .mu.L) was added
HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (245 mg, 0.644 mmol). The mixture was
stirred for 5 minutes at room temperature, and then
2-(3,4-dimethoxyphenyl)-7-methoxychroman-4-amine (156 mg, 0.496
mmol) was added, followed by dropwise addition of triethylamine
(276 .mu.L, 1.982 mmol). After 45 minutes, the mixture was quenched
with saturated aqueous sodium bicarbonate, and the aqueous layer
removed. The resulting oil was triturated with water and filtered
to give 283 mg of a white solid. The solid was dissolved in
dichloromethane and purified using a 24 g silica gel cartridge with
a gradient of 5-50% ethyl acetate/heptanes to give 189 mg of a
mixture of the two diastereomers. The mixture was subjected to
preparative supercritical fluid chromatography set to maintain a
backpressure at 100 bar using a CHIRALPAK IA.RTM., 21.times.250 mm,
5 micron, with the sample at a concentration of 20 mg/mL in
methanol using 16% methanol in CO.sub.2 at a flow rate of 70
mL/minute with a retention time of 7.2 minutes to give the title
compound (111 mg, 0.206 mmol, 41.5% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.39 (d, J=1.6 Hz, 1H),
7.32 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.3, 1.7 Hz, 1H), 7.13 (d,
J=9.1 Hz, 1H), 6.98-6.91 (m, 4H), 6.50 (dd, J=8.5, 2.6 Hz, 1H),
6.36 (d, J=2.5 Hz, 1H), 5.36-5.24 (m, 1H), 5.15 (dd, J=11.5, 1.9
Hz, 1H), 3.75 (d, J=1.4 Hz, 6H), 3.68 (s, 3H), 2.10 (q, J=11.8 Hz,
1H), 1.99 (ddd, J=12.9, 6.2, 2.1 Hz, 1H), 1.53-1.46 (m, 1H), 1.37
(ddd, J=8.4, 5.8, 2.8 Hz, 1H), 1.05 (dtdd, J=12.7, 9.6, 6.4, 3.3
Hz, 2H); MS (ESI+) m/z 402 (M+H).sup.+. Absolute stereochemistry
was assigned by X-ray diffraction analysis.
Example 4
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4S)-2-(3,4-dimethoxyphenyl)-7-
-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1624] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(120 mg, 0.496 mmol) in DMF (1239 .mu.L) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (245 mg, 0.644 mmol). The mixture was
stirred for 5 minutes at room temperature, and then
2-(3,4-dimethoxyphenyl)-7-methoxychroman-4-amine (156 mg, 0.496
mmol) was added, followed by dropwise addition of triethylamine
(276 .mu.L, 1.982 mmol). After 45 minutes, the mixture was quenched
with saturated aqueous sodium bicarbonate, the aqueous layer
removed, the resulting oil triturated with water and filtered to
give 283 mg of a white solid. The solid was dissolved in
dichloromethane and purified using a 24 g silica gel cartridge with
a gradient of 5-50% ethyl acetate/heptanes to give 189 mg of a
mixture of the two diastereomers. The mixture was subjected to
preparative supercritical fluid chromatography set to maintain a
backpressure at 100 bar using a CHIRALPAK.RTM. IA, 21.times.250 mm,
5 micron, with the sample at a concentration of 20 mg/mL in
methanol using 16% methanol in CO.sub.2 at a flow rate of 70
mL/minute with a retention time of 4.5 minutes to give the title
compound (106 mg, 0.196 mmol, 39.7% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.39 (d, J=1.6 Hz, 1H),
7.32 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.3, 1.7 Hz, 1H), 7.13 (d,
J=9.1 Hz, 1H), 6.98-6.91 (m, 4H), 6.50 (dd, J=8.5, 2.6 Hz, 1H),
6.36 (d, J=2.5 Hz, 1H), 5.36-5.24 (m, 1H), 5.15 (dd, J=11.5, 1.9
Hz, 1H), 3.75 (d, J=1.4 Hz, 6H), 3.68 (s, 3H), 2.10 (q, J=11.8 Hz,
1H), 1.99 (ddd, J=12.9, 6.2, 2.1 Hz, 1H), 1.53-1.46 (m, 1H), 1.37
(ddd, J=8.4, 5.8, 2.8 Hz, 1H), 1.05 (dtdd, J=12.7, 9.6, 6.4, 3.3
Hz, 2H); MS (ESI+) m/z 402 (M+H).sup.+.
Example 5
methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 5A
7-methoxy-4H-chromen-4-one
[1625] 1,1-Dimethoxy-N,N-dimethylmethanamine (1.0 mL, 7.53 mmol)
and 1-(2-hydroxy-4-methoxyphenyl)ethanone (1.251 g, 7.53 mmol) were
heated in the microwave at 115.degree. C. for 15 seconds to give a
red solution which solidified upon cooling. The solid was
triturated with heptane to give the enamine intermediate as red
crystals. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 14.96 (s,
1H), 7.82 (dd, J=10.6, 1.6 Hz, 2H), 6.37 (dd, J=8.8, 2.6 Hz, 1H),
6.32 (d, J=2.5 Hz, 1H), 5.84 (d, J=12.0 Hz, 1H), 3.75 (s, 3H), 3.17
(s, 3H), 2.95 (s, 3H). The enamine was dissolved in dichloromethane
(40 mL) and treated with HCl (4 mL) at reflux for one hour. The
aqueous layer was removed and extracted with 3.times.40 mL of
dichloromethane. The combined extracts were washed with saturated
aqueous sodium bicarbonate and dried over sodium sulfate, then
filtered and the solvent removed under reduced pressure to give
title compound (0.854 g, 4.85 mmol, 64.4% yield) as pale yellow
crystals. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.22 (d,
J=6.0 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.06
(dd, J=8.9, 2.4 Hz, 1H), 6.27 (d, J=6.0 Hz, 1H), 3.90 (s, 3H); MS
(ESI+) m/z 177 (M+H).sup.+.
Example 5B
(R)-methyl 3-(7-methoxy-4-oxochroman-2-yl)benzoate
[1626] A 4 mL vial was charged with
bis(2,2,2-trifluoroacetoxy)palladium (9.44 mg, 0.028 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (6.96 mg,
0.034 mmol), ammonium hexafluorophosphate(V) (27.8 mg, 0.170 mmol),
and 3-methoxycarbonylphenylboronic acid (204 mg, 1.135 mmol) were
stirred in dichloroethane (1.0 mL) for 5 minutes, and a pale yellow
color was observed. To this suspension was added Example 5A (100
mg, 0.568 mmol) and water (0.051 mL, 2.84 mmol) and the sides of
the vial washed with more dichloroethane (1.0 mL). The vial was
capped and the mixture stirred at 60.degree. C. overnight. The
mixture was filtered through a plug of silica gel and eluted with
dichloromethane and then ethyl acetate. The solvent was removed and
the crude material was chromatographed using a 12 g silica gel
cartridge with a gradient of 5-50% ethyl acetate/heptanes over 20
minutes to give the title compound (133 mg, 0.426 mmol, 75% yield)
as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.15
(t, J=1.8 Hz, 1H), 7.98 (dt, J=7.8, 1.4 Hz, 1H), 7.84 (dt, J=7.9,
1.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 6.69
(d, J=8.6 Hz, 2H), 5.77 (dd, J=12.9, 2.9 Hz, 1H), 3.88 (s, 3H),
3.83 (s, 3H), 3.17 (dd, J=16.8, 13.0 Hz, 1H), 2.80 (dd, J=16.8, 3.0
Hz, 1H); MS (ESI+) m/z 313 (M+H).sup.+.
Example 5C
(R)-methyl 3-(7-methoxy-4-(methoxyimino)chroman-2-yl)benzoate
[1627] Example 5B (100 mg, 0.320 mmol) and O-methylhydroxylamine
hydrochloride (29.4 mg, 0.352 mmol) were stirred in pyridine (640
.mu.L) at 60.degree. C. overnight. Added an additional 0.3
equivalent (7 mg) of amine and heated at 60.degree. C. for 12
hours. The mixture was concentrated and then diluted with ethyl
acetate, washed with saturated aqueous sodium bicarbonate and
saturated aqueous ammonium chloride sequentially. The solvent was
removed and the crude material purified using a 12 g silica gel
cartridge eluting with 5-20% ethyl acetate/heptanes over 20 minutes
to give the title compound (107 mg, 0.313 mmol) as a light pink
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (t, J=1.9 Hz,
1H), 8.03 (dt, J=7.7, 1.5 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H),
7.77-7.63 (m, 1H), 7.49 (t, J=7.7 Hz, 1H), 6.59 (dd, J=8.8, 2.6 Hz,
1H), 6.50 (d, J=2.5 Hz, 1H), 5.12 (dd, J=12.5, 3.1 Hz, 1H), 3.96
(s, 3H), 3.94 (s, 3H), 3.80 (s, 3H), 3.48 (dd, J=17.2, 3.1 Hz, 1H),
2.65 (dd, J=17.1, 12.5 Hz, 1H); MS (ESI+) m/z 342.0
(M+H).sup.+.
Example 5D
3-((2R)-4-amino-7-methoxy chroman-2-yl)benzoate
[1628] Example 5C (50 mg, 0.146 mmol) and methanol (10 mL) were
added to Ra--Ni 2800, water slurry (150 mg, 1.150 mmol) in a 50 mL
pressure bottle and stirred for 16 hours at 30 psi of hydrogen gas
and at ambient temperature. The reaction was filtered and the
solvent removed. The residue (44 mg) was dissolved in
methyl-tert-butyl ether. HCl (4.0 M in dioxane, 0.3 mL) was added
dropwise, and the resulting suspension was filtered to give the
hydrochloride salt of the title compound as a mixture of two
diastereomers. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.48 (s,
6H), 8.06 (dt, J=6.1, 1.8 Hz, 2H), 7.97 (ddd, J=9.2, 3.1, 1.4 Hz,
2H), 7.74 (dd, J=7.7, 1.7 Hz, 2H), 7.60 (t, J=7.7 Hz, 2H), 7.55 (d,
J=8.6 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 6.65 (ddd, J=8.7, 6.3, 2.6
Hz, 2H), 6.55 (d, J=2.6 Hz, 1H), 6.52 (d, J=2.6 Hz, 1H), 5.51 (dd,
J=11.9, 2.3 Hz, 1H), 5.33 (dd, J=11.8, 1.8 Hz, 1H), 4.75 (dd,
J=11.0, 6.4 Hz, 1H), 4.45 (dd, J=5.0, 2.4 Hz, 1H), 3.89 (s, 3H),
3.89 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 2.61 (ddd, J=13.1, 6.5,
1.9 Hz, 1H), 2.46 (t, J=2.4 Hz, 1H), 2.31 (ddd, J=15.0, 11.9, 5.0
Hz, 1H), 2.08 (dt, J=13.0, 11.4 Hz, 1H); MS (ESI-) m/z 297.1
(M-NH.sub.3).sup.-.
Example 5E
methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate
[1629] To a suspension of the product from Example 5D (90 mg, 0.257
mmol) in 1.3 mL of dichloromethane was added
N,N-diisopropylethylamine (135 .mu.L, 0.772 mmol). After a solution
was achieved, a solution of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl
chloride (prepared as described in Example 8D) (84 mg, 0.322 mmol)
in 1 mL of dichloromethane was added dropwise at ambient
temperature and the reaction was stirred for 1 hour. The reaction
mixture was diluted with 5 mL of methyl-tert-butyl ether and
quenched with saturated aqueous sodium bicarbonate. After stirring
for 10 minutes, the aqueous layer was removed and the organic layer
was washed twice more with saturated aqueous sodium bicarbonate.
The organics were dried over sodium sulfate then concentrated. The
residue was chromatographed using a 40 g silica gel cartridge with
10-20% methyl-tert-butyl ether/heptanes over 3 minutes then 20%
methyl-tert-butyl ether/heptanes for 17 minutes then a 20-30%
methyl-tert-butyl ether/heptanes gradient over 10 minutes to
provide the title compound as the first eluting isomer and Example
6 as the second eluting isomer. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.06 (t, J=1.8 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.59 (dt,
J=7.9, 1.4 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.15 (dd, J=8.2, 1.7
Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 7.07-6.99 (m, 2H), 6.52 (dd,
J=8.5, 2.6 Hz, 1H), 6.44 (d, J=2.5 Hz, 1H), 5.58 (d, J=6.6 Hz, 1H),
5.06-4.96 (m, 1H), 4.81 (dd, J=11.5, 2.1 Hz, 1H), 3.94 (s, 3H),
3.75 (s, 3H), 2.31 (dt, J=14.3, 2.5 Hz, 1H), 2.15 (ddd, J=14.4,
11.5, 4.6 Hz, 1H), 1.71-1.66 (m, 2H), 1.10-1.05 (m, 2H); MS (ESI-)
m/z 536.1 (M-H).sup.-. Relative stereochemistry confirmed by H NMR
NOE analysis.
Example 6
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate
[1630] The title compound was isolated as the second eluting isomer
from the column chromatography as described in Example 5E. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 8.08 (s, 1H), 8.00 (d, J=7.7 Hz,
1H), 7.58 (dt, J=7.8, 1.4 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.12
(dd, J=8.2, 1.7 Hz, 1H), 7.08 (d, J=1.7 Hz, 1H), 7.00 (d, J=8.2 Hz,
1H), 6.96 (dd, J=8.7, 1.0 Hz, 1H), 6.51 (dd, J=8.6, 2.6 Hz, 1H),
6.44 (d, J=2.6 Hz, 1H), 5.46-5.38 (m, 1H), 5.33 (d, J=8.8 Hz, 1H),
5.21 (dd, J=11.3, 1.9 Hz, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 2.51
(ddd, J=13.3, 6.0, 2.0 Hz, 1H), 1.86-1.62 (m, 3H), 1.11-1.03 (m,
2H); MS (ESI-) m/z 536.1 (M-H).sup.-.
Example 7
methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate
[1631] The title compound (36 mg, 0.067 mmol, 21.76% yield) was
collected as the first eluting isomer from the separation of the
two isomers as described in Example 8D. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.05 (d, J=2.1 Hz, 1H), 8.01 (dt, J=7.9, 1.6
Hz, 1H), 7.62-7.57 (m, 1H), 7.47 (dd, J=8.7, 6.8 Hz, 1H), 7.22 (td,
J=7.7, 1.8 Hz, 1H), 7.18-7.10 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.93
(t, J=7.5 Hz, 2H), 5.63 (d, J=6.8 Hz, 1H), 5.05 (dt, J=6.8, 3.4 Hz,
1H), 4.84 (dd, J=11.3, 2.4 Hz, 1H), 3.94 (s, 3H), 2.32 (dt, J=14.4,
2.7 Hz, 1H), 2.19 (ddd, J=14.4, 11.3, 4.6 Hz, 1H), 1.72-1.66 (m,
2H), 1.12-1.05 (m, 2H); MS (ESI+) m/z 508 (M+H).sup.+.
Example 8
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 8A
(R)-methyl 3-(4-oxochroman-2-yl)benzoate
[1632] A 20 mL vial was charged with
bis(2,2,2-trifluoroacetoxy)palladium (56.9 mg, 0.171 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (41.9 mg,
0.205 mmol), ammonium hexafluorophosphate(V) (167 mg, 1.026 mmol),
and 3-methoxycarbonylphenylboronic acid (1231 mg, 6.84 mmol). The
reaction was stirred in dichloroethane (5 mL) for 5 minutes, and a
pale yellow color was observed. To this suspension was added
4H-chromen-4-one (CAS 11013-97-1) (500 mg, 3.42 mmol) and water
(0.308 mL, 17.11 mmol) and the sides of the vial washed with more
dichloroethane (5 mL). The vial was capped and the mixture stirred
at 60.degree. C. for 16 hours. The mixture was filtered through a
plug of silica gel and celite and eluted with ethyl acetate to give
a red solution. The solvent was removed and the crude material was
chromatographed using a 40 g silica gel cartridge with a gradient
of 5-50% ethyl acetate/heptanes over 40 minutes to give the title
compound (329 mg, 1.165 mmol, 34.1% yield) as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16 (t, J=1.8 Hz, 1H),
7.98 (dt, J=7.7, 1.5 Hz, 1H), 7.84 (dt, J=7.9, 1.4 Hz, 1H), 7.81
(dd, J=7.8, 1.8 Hz, 1H), 7.65-7.58 (m, 2H), 7.17-7.10 (m, 2H), 5.80
(dd, J=13.1, 2.8 Hz, 1H), 3.88 (s, 3H), 3.28 (dd, J=16.8, 13.1 Hz,
1H), 2.88 (dd, J=16.8, 3.0 Hz, 1H); MS (ESI+) m/z 300
(M+NH.sub.4).sup.+.
Example 8B
(R)-methyl 3-(4-(hydroxyimino)chroman-2-yl)benzoate
[1633] Example 8A (200 mg, 0.708 mmol) was treated with
hydroxylamine hydrochloride (59.1 mg, 0.850 mmol) and sodium
acetate (69.7 mg, 0.850 mmol) in ethanol (3542 .mu.L). The reaction
was stirred at ambient temperature for 15 hours. The solvent was
removed under a stream of nitrogen. The crude material was washed
with water (2.times.2 mL) and dried under a stream of nitrogen to
provide the title compound (210 mg, 0.706 mmol, 100% yield) as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.35 (s,
1H), 8.11 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.8, 1.4 Hz, 1H), 7.82
(td, J=7.7, 7.2, 1.6 Hz, 2H), 7.59 (t, J=7.7 Hz, 1H), 7.31 (ddd,
J=8.6, 7.3, 1.7 Hz, 1H), 7.04-6.97 (m, 2H), 5.32 (dd, J=11.8, 3.2
Hz, 1H), 3.87 (s, 3H), 3.40 (dd, J=17.0, 3.3 Hz, 1H), 2.72 (dd,
J=17.0, 11.8 Hz, 1H); MS (ESI+) m/z 298 (M+H).sup.+.
Example 8C
methyl 3-((2R)-4-aminochroman-2-yl)benzoate
[1634] Example 8B (100 mg, 0.336 mmol) and methanol (10 ml) were
added to Ra--Ni 2800, water slurry (350 mg, 2.68 mmol) in a 50 mL
pressure bottle and shaken for 16 hours at 30 psi of H.sub.2 at
ambient temperature. The reaction was filtered and the solvent
removed under reduced pressure to provide the title compound (94
mg, 0.332 mmol, 99% yield) as a tan powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.06-8.01 (m, 1H), 7.91 (ddt, J=7.8, 2.7, 1.4
Hz, 1H), 7.71 (ddt, J=7.1, 3.4, 1.5 Hz, 1H), 7.59-7.53 (m, 1.5H),
7.33 (dd, J=7.7, 1.6 Hz, 0.5H), 7.12 (dtd, J=13.9, 7.4, 1.7 Hz,
1H), 6.95-6.83 (m, 1.5H), 6.78 (dd, J=8.2, 1.2 Hz, 0.5H), 5.41 (dd,
J=7.6, 5.7 Hz, 0.5H), 5.29 (dd, J=11.6, 2.1 Hz, 0.5H), 4.17 (dd,
J=11.2, 5.8 Hz, 0.5H), 3.95 (t, J=3.8 Hz, 0.5H), 3.87 (d, J=1.6 Hz,
3H), 2.36 (ddd, J=13.1, 5.7, 2.1 Hz, 1H), 2.09-2.05 (m, 1H),
1.93-1.84 (m, 2H)
Example 8D
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate
[1635] To a solution of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(75 mg, 0.310 mmol) in dichoromethane (774 .mu.L) was added one
quarter of a solution of oxalyl dichloride (108 .mu.L, 1.239 mmol)
in 200 .mu.L of dichloromethane followed by 1 drop of DMF. The
reaction bubbled vigorously. The remainder of the oxalyl chloride
solution was added dropwise. The reaction was stirred for 30
minutes, and the solvent removed under a stream of nitrogen. The
residue was chased with 2.times.0.5 mL of dichloromethane, drying
under a stream of nitrogen. This residue was taken up in
dichloromethane (774 .mu.L) and added to a mixture of the product
from Example 8C (88 mg, 0.310 mmol) and triethylamine (129 .mu.l,
0.929 mmol) in dichloromethane (774 .mu.L). After 15 minutes, the
mixture was quenched with saturated aqueous sodium bicarbonate,
concentrated, and the resulting oil purified on a 12 g silica gel
cartridge and eluted with a gradient of 5-100% ethyl
acetate/heptanes to give 137 mg of a mixture of the two
diastereomers. The mixture of diastereomers were chromatographed
again using 30% MTBE/heptanes to provide Example 7 as the first
eluting isomer and the title compound as the second eluting isomer
(36 mg, 0.066 mmol, 21.30% yield) as a clear foam. .sup.1H NMR (501
MHz, CDCl.sub.3) .delta. 8.08 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.7,
1.5 Hz, 1H), 7.59 (dt, J=7.8, 1.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H),
7.18 (td, J=7.9, 1.6 Hz, 1H), 7.13 (dd, J=8.2, 1.8 Hz, 1H),
7.10-7.06 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 6.93 (td, J=7.6, 1.2 Hz,
1H), 6.90 (dd, J=8.1, 1.2 Hz, 1H), 5.50 (td, J=10.6, 10.1, 6.2 Hz,
1H), 5.39 (d, J=8.9 Hz, 1H), 5.23 (dd, J=11.6, 1.9 Hz, 1H), 3.92
(s, 2H), 2.52 (ddd, J=13.2, 6.0, 2.0 Hz, 1H), 1.82 (dt, J=13.2,
11.3 Hz, 1H), 1.77-1.73 (m, 1H), 1.67-1.62 (m, 1H), 1.13-1.05 (m,
2H); MS (ESI+) m/z 508 (M+H).sup.+.
Example 9
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1636] To a suspension of Example 8D in tetrahydrofuran (164 .mu.L)
and water (82 .mu.L) was added lithium hydroxide (2.124 mg, 0.089
mmol). The reaction mixture was stirred at room temperature. After
2 hours, additional lithium hydroxide (2.209 mg, 0.092 mmol) was
added and the reaction mixture was stirred at ambient temperature
for 72 hours. The reaction was quenched with 10 drops of 1 M HCl
and this crude material was chromatographed directly using a 4 g
silica gel cartridge with a gradient of 5-100% ethyl
acetate/heptane to give the title compound (15 mg, 0.030 mmol,
61.7% yield) as white foam. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.19 (t, J=1.7 Hz, 1H), 8.06 (dt, J=7.7, 1.4 Hz, 1H), 7.67
(d, J=7.6 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.21-7.17 (m, 1H), 7.14
(dd, J=8.1, 1.8 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.08 (d, J=7.6 Hz,
1H), 7.02 (d, J=8.2 Hz, 1H), 6.96-6.89 (m, 2H), 5.56 (dd, J=16.7,
9.4 Hz, 1H), 5.45 (d, J=8.9 Hz, 1H), 5.29 (d, J=11.3 Hz, 1H), 2.59
(ddd, J=13.1, 5.9, 1.9 Hz, 1H), 1.85-1.76 (m, 2H), 1.71-1.64 (m,
2H), 1.12-1.08 (m, 2H); MS (ESI+) m/z 494 (M+H).sup.+.
Example 10
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1637] The title compound was prepared using the conditions similar
to that described in Example 1, substituting Example 7 for Example
6. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.12 (t, J=1.7 Hz,
1H), 8.08 (dt, J=7.8, 1.4 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.51 (t,
J=7.7 Hz, 1H), 7.22 (td, J=7.7, 1.6 Hz, 1H), 7.19-7.12 (m, 3H),
7.03 (d, J=8.2 Hz, 1H), 6.97-6.91 (m, 2H), 5.65 (d, J=6.8 Hz, 1H),
5.06 (t, J=6.8 Hz, 1H), 4.87 (dd, J=11.3, 2.2 Hz, 1H), 2.35 (dt,
J=14.3, 2.6 Hz, 1H), 2.20 (ddd, J=14.0, 11.2, 4.5 Hz, 1H), 1.71 (q,
J=3.6 Hz, 2H), 1.12-1.08 (m, 2H); MS (ESI+) m/z 494
(M+H).sup.+.
Example 11
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 11A
(R)-methyl 3-(6-methyl-4-oxochroman-2-yl)benzoate
[1638] The mixture of bis(2,2,2-trifluoroacetoxy)palladium (51.9
mg, 0.156 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (38.3 mg,
0.187 mmol), ammonium hexafluorophosphate(V) (153 mg, 0.937 mmol),
(3-(methoxycarbonyl) phenyl)boronic acid (1124 mg, 6.24 mmol) and
dichloroethane (10 mL) in a 20 mL vial were stirred for 5 minutes
at room temperature, followed by the addition of
6-methyl-4H-chromen-4-one (CAS 314041-54-8, MFCD00218598, 500 mg,
3.12 mmol) and water (0.26 mL, 14 mmol). The vial was capped and
the mixture was stirred at 60.degree. C. overnight. The reaction
mixture was filtered through a plug of celite and eluted with ethyl
acetate. The organics was washed with brine and dried over
MgSO.sub.4. The solvent was removed in vacuo and the crude material
was chromatographed using a 40 g silica gel cartridge, eluting with
a gradient of 5-40% ethyl acetate in heptane to provide the title
compound (410 mg, 44.3%). .sup.1H NMR (501 MHz, DMSO-d.sub.6)
.delta. 8.33 (t, J=1.7 Hz, 1H), 8.17 (dt, J=7.7, 1.5 Hz, 1H), 8.02
(dt, J=7.7, 1.5 Hz, 1H), 7.83-7.74 (m, 2H), 7.62 (dd, J=8.5, 2.4
Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 5.93 (dd, J=12.9, 2.9 Hz, 1H),
4.07 (s, 3H), 3.42 (dd, J=16.8, 13.0 Hz, 1H), 3.04 (dd, J=16.8, 3.0
Hz, 1H), 2.49 (s, 3H); MS (ESI+) m/z 297 (M+H).sup.+.
Example 11B
(R)-methyl 3-(4-(hydroxyimino)-6-methylchroman-2-yl)benzoate
[1639] The mixture of Example 11A (390 mg, 1.316 mmol),
hydroxylamine hydrochloride (183 mg, 2.63 mmol), sodium acetate
(216 mg, 2.63 mmol) in methanol (10 mL) was stirred at 60.degree.
C. for 4 hours. The solvent was evaporated under pressure and the
residue was dissolved in ethyl acetate, washed with brine, dried
over MgSO.sub.4, and filtered. The solvent was removed under
reduced pressure to provide the title compound (393 mg, 95% yield)
as white solid. .sup.1H NMR (501 MHz, DMSO-d.sub.6) .delta. 11.51
(s, 1H), 8.32 (t, J=1.7 Hz, 1H), 8.18 (dt, J=7.8, 1.5 Hz, 1H), 8.02
(dt, J=7.7, 1.3 Hz, 1H), 7.88-7.76 (m, 2H), 7.35 (dd, J=8.4, 2.2
Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 5.49 (dd, J=11.6, 3.1 Hz, 1H),
4.10 (s, 3H), 3.60 (dd, J=17.1, 3.3 Hz, 1H), 2.92 (dd, J=17.0, 11.6
Hz, 1H), 2.49 (s, 3H); MS (ESI+) m/z 312 (M+H).sup.+.
Example 11C
methyl 3-((2R)-4-amino-6-methylchroman-2-yl)benzoate
[1640] Example 11B (390 mg, 1.253 mmol) was added to Ra--Ni 2800,
water slurry (1.17 g) in a 100 mL pressure bottle. The mixture was
charged with 30 psi of hydrogen and stirred at ambient temperature
for 16 hours. LC/MS indicated that the reaction was completed. The
mixture was filtered and the solvent evaporated under reduced
pressure. The residue was dissolved in tert-butyl ethyl ether,
followed by the addition of 4 M HCl in dioxane (2 ml) drop wise.
The precipitated white solid was collected by filtration, washed
with tert-butyl methyl ether, and dried to yield the hydrochloride
salt of the title compound (355 mg, 1.063 mmol, 85% yield). LC/MS
m/z 281 (M-NH.sub.2).sup.+.
Example 11D
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate
[1641] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(332 mg, 1.372 mmol) in CH.sub.2Cl.sub.2 (6 mL) was added a few
drops of DMF, followed by the drop wise addition of oxalyl
dichloride (0.290 ml, 3.43 mmol). The mixture was stirred at room
temperature for 30 minutes. LC/MS with methanol as solvent showed a
completed methyl ester's peak. Solvent was removed in vacuo, excess
oxalyl chloride removed via azeotrope with dichloroethane, and the
crude material in CH.sub.2Cl.sub.2 (4 mL) was added to the product
from Example 11C (340 mg, 1.143 mmol) and pyridine (543 mg, 6.86
mmol) in CH.sub.2Cl.sub.2 (6 mL). The mixture was stirred at room
temperature for 2 hours and saturated NaHCO.sub.3 aqueous solution
and CH.sub.2Cl.sub.2 was added. The phases were separated and the
aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined
organics were dried over MgSO.sub.4, filtered, and concentrated
under reduced pressure. Purification of the residue by
chromatography using a 40 g silica gel cartridge, and eluting with
0-30% ethyl acetate in hexane provide Example 12 as the first
eluting isomer, and the title compound as the second eluting isomer
(133 mg, 0.255 mmol, 22.30% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.07 (t, J=1.7 Hz, 1H), 7.99 (dt, J=8.0, 1.4
Hz, 1H), 7.58 (dt, J=7.8, 1.4 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H),
7.18-7.06 (m, 2H), 7.05-6.92 (m, 2H), 6.88-6.72 (m, 2H), 5.53-5.29
(m, 2H), 5.19 (dd, J=11.5, 1.9 Hz, 1H), 3.92 (s, 3H), 2.53 (ddd,
J=13.4, 5.9, 2.0 Hz, 1H), 2.26 (s, 3H), 1.86-1.67 (m, 2H), 1.61 (d,
J=16.1 Hz, 1H), 1.17-1.00 (m, 2H); MS (ESI+) m/z 522
(M+H).sup.+.
Example 12
methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate
[1642] The title compound was isolated as the first eluting isomer
from the chromatography as described in Example 11D (97 mg, 16.27%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05 (t, J=1.7
Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.61-7.56 (m, 1H), 7.47 (t, J=7.7
Hz, 1H), 7.19-7.12 (m, 2H), 7.05-6.99 (m, 2H), 6.93 (d, J=2.2 Hz,
1H), 6.81 (d, J=8.3 Hz, 1H), 5.62 (d, J=6.9 Hz, 1H), 5.01 (ddd,
J=7.1, 4.6, 2.8 Hz, 1H), 4.80 (dd, J=11.2, 2.3 Hz, 1H), 3.94 (s,
3H), 2.34-2.23 (m, 4H), 2.17 (ddd, J=14.4, 11.1, 4.7 Hz, 1H),
1.74-1.64 (m, 2H), 1.13-1.04 (m, 2H); MS (ESI+) m/z 522
(M+H).sup.+.
Example 13
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1643] A mixture of Example 12 (96 mg, 0.184 mmol) and 2 M LiOH (2
mL) in methanol (6 mL) was stirred at 35.degree. C. for 4 hours.
Solvent was removed under reduced pressure and the residue
dissolved in water (2 mL), and the pH was adjusted with 2 M HCl to
pH 1.about.2. The precipitated white solid was collected by
filtration, washed with water, and dried to provide the title
compound (83 mg, 89% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.10 (t, J=1.7 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.64 (d,
J=7.7 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.20-7.13 (m, 2H), 7.06-6.99
(m, 2H), 6.93 (d, J=2.1 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 5.65 (d,
J=6.8 Hz, 1H), 5.01 (dt, J=7.0, 3.5 Hz, 1H), 4.83 (dd, J=11.2, 2.3
Hz, 1H), 2.31 (dt, J=14.4, 2.8 Hz, 1H), 2.26 (s, 3H), 2.18 (ddd,
J=14.7, 11.1, 4.7 Hz, 1H), 1.74-1.66 (m, 2H), 1.14-1.04 (m, 2H); MS
(ESI+) m/z 508(M+H).sup.+.
Example 14
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1644] The mixture of Example 11D (35 mg, 0.067 mmol) and 2 M LiOH
(1 mL) in methanol (4 mL) was stirred at 35.degree. C. for 4 hours.
Solvent was removed under reduced pressure and the residue
dissolved in water (2 mL), and the pH was adjusted with 2 M HCl to
pH 1.about.2. The white solid precipitated was collected by
filtration, washed with water, and dried to yield title compound
(30 mg, 88% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.18
(t, J=1.7 Hz, 1H), 8.05 (dt, J=7.9, 1.3 Hz, 1H), 7.65 (dt, J=7.6,
1.4 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.17-7.10 (m, 2H), 7.02 (d,
J=8.6 Hz, 1H), 6.98 (dd, J=8.3, 2.1 Hz, 1H), 6.84 (d, J=2.0 Hz,
1H), 6.80 (d, J=8.3 Hz, 1H), 5.49 (td, J=10.5, 9.8, 6.0 Hz, 1H),
5.42 (d, J=8.8 Hz, 1H), 5.25 (dd, J=11.6, 1.8 Hz, 1H), 2.59 (ddd,
J=13.3, 5.9, 1.9 Hz, 1H), 2.26 (s, 3H), 1.85-1.75 (m, 2H),
1.68-1.58 (m, 1H), 1.18-1.04 (m, 2H); MS (ESI+) m/z 508
(M+H).sup.+.
Example 15
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1645] The title compound was prepared using the conditions similar
to that described in Example 1, substituting Example 17 for Example
6. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.17-7.97 (m, 2H),
7.66-7.40 (m, 2H), 7.20-6.95 (m, 4H), 6.74 (t, J=3.4 Hz, 2H), 5.64
(d, J=6.8 Hz, 1H), 4.93 (ddd, J=70.0, 8.8, 3.0 Hz, 2H), 2.32 (dt,
J=14.4, 2.6 Hz, 1H), 2.28 (s, 3H), 2.17 (ddd, J=14.9, 11.1, 4.7 Hz,
1H), 1.70 (q, J=3.9 Hz, 2H), 1.08 (q, J=3.9 Hz, 2H); MS (ESI+) m/z
508 (M+H).sup.+.
Example 16
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1646] The mixture of 18E (130 mg, 0.249 mmol) and 2 M LiOH (1 ml)
in methanol (4 mL) was stirred at 35.degree. C. for 4 hours,
solvent was removed under pressure and the residue dissolved in
water (2 mL), and adjusted with 2 M HCl to pH 1-2. The precipitated
white solid was filtered, washed with water and dried to give title
compound (114 mg, 90% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.19 (s, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.6 Hz,
1H), 7.46 (t, J=7.7 Hz, 1H), 7.17-7.04 (m, 2H), 6.97 (dd, J=25.7,
7.9 Hz, 2H), 6.73 (d, J=9.0 Hz, 2H), 5.60-5.35 (m, 2H), 5.24 (d,
J=11.3 Hz, 1H), 2.58 (dd, J=12.9, 5.9 Hz, 1H), 2.27 (s, 3H),
1.86-1.70 (m, 2H), 1.66 (d, J=11.9 Hz, 1H), 1.09 (q, J=2.8 Hz, 2H);
MS (ESI+) m/z 508 (M+H).sup.+.
Example 17
methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate
[1647] The title compound (290 mg, 26.5% yield) was isolated as the
first eluting isomer from the separation of the isomers as
described in Example 18E. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.05 (t, J=1.8 Hz, 1H), 8.01 (dt, J=7.7, 1.5 Hz, 1H), 7.58 (dt,
J=7.5, 1.4 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.19-7.10 (m, 2H), 7.03
(dd, J=8.2, 1.7 Hz, 2H), 6.75 (dd, J=6.2, 1.9 Hz, 2H), 5.61 (d,
J=6.8 Hz, 1H), 5.01 (dt, J=7.1, 3.3 Hz, 1H), 4.81 (dd, J=11.3, 2.3
Hz, 1H), 3.94 (s, 3H), 2.34-2.29 (m, 1H), 2.29 (s, 3H), 2.16 (ddd,
J=14.2, 11.3, 4.6 Hz, 1H), 1.73-1.65 (m, 2H), 1.11-1.03 (m, 2H).);
MS (ESI+) m/z 522 (M+H).sup.+.
Example 18
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 18A
[1648] The mixture of 1-(2-hydroxy-4-methylphenyl)ethanone (2 ml,
14.12 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (2.063 ml,
15.53 mmol) was heated at 120.degree. C. for 2 hours, and then
cooled down. The precipitated orange solid was filtered, washed
with heptane, and dried to give intermediate
(E)-3-(dimethylamino)-1-(2-hydroxy-4-methylphenyl)prop-2-en-1-one,
which was dissolved in CH.sub.2Cl.sub.2 (120 mL) and treated with
concentrated HCl (15 mL). The mixture was refluxed for 2 hours, and
LC/MS indicated the reaction was complete. The water layer was
removed and extracted with CH.sub.2Cl.sub.2 (10 mL.times.2). The
combined organics was concentrated to give a crude orange color
solid. Purification by chromatography on 80 g silica gel cartridge,
eluting with ethyl acetate in heptane at 5-40% gradient gave title
compound as white solid (1.82 g, 80% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.09 (d, J=8.1 Hz, 1H), 7.81 (d, J=5.7 Hz, 1H),
7.24 (s, 1H), 7.23-7.19 (m, 1H), 6.30 (d, J=6.1 Hz, 1H), 2.48 (s,
3H); MS (ESI+) m/z 161 (M+H).sup.+.
Example 18B
(R)-methyl 3-(7-methyl-4-oxochroman-2-yl)benzoate
[1649] A 20 mL vial was charged with
bis(2,2,2-trifluoroacetoxy)palladium (0.353 g, 1.061 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.260 g,
1.274 mmol), ammonium hexafluorophosphate(V) (1.038 g, 6.37 mmol)
and (3-(methoxycarbonyl) phenyl) boronic acid (3.82 g, 21.23 mmol)
were stirred in dichloroethane (10 mL) at room temperature for 5
minutes. To this suspension was added Example 18A (1.70 g, 10.61
mmol) and water (0.256 mL, 14.19 mmol). The vial was capped and the
mixture was stirred at 60.degree. C. overnight. The mixture was
filtered through a plug of celite and eluted with ethyl acetate.
The solvent was removed under pressure and the crude material was
chromatographed using a 80 g silica gel cartridge, eluting with a
gradient of 5-50% ethyl acetate in heptane to provide the title
compound (2.6 g, 83% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.22-8.13 (m, 1H), 8.11-8.01 (m, 1H), 7.83 (d, J=8.3 Hz,
1H), 7.77-7.60 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 6.89 (d, J=6.8 Hz,
2H), 5.51 (dd, J=13.2, 2.9 Hz, 1H), 4.13 (s, OH), 3.95 (d, J=1.0
Hz, 3H), 3.76 (s, OH), 3.05 (ddd, J=16.8, 13.3, 1.0 Hz, 1H), 2.88
(ddd, J=16.8, 2.9, 0.9 Hz, 1H), 2.38 (s, 3H); MS (ESI+) m/z 297
(M+H).sup.+.
Example 18C
(R)-methyl 3-(4-(methoxyimino)-7-methylchroman-2-yl)benzoate
[1650] The mixture of Example 18B (1.2 g, 4.05 mmol), sodium
acetate (0.664 g, 8.10 mmol) and O-methylhydroxylamine,
hydrochloric acid (0.676 g, 8.10 mmol) in methanol (10 mL) was
stirred at 60.degree. C. overnight. The solvent was evaporated
under pressure and the residue washed with water, filtered, and
dried to provide the title compound (1.3 g, 4.00 mmol, 99% yield)
as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.14 (d,
J=1.9 Hz, 1H), 8.03 (dt, J=7.7, 1.5 Hz, 1H), 7.90-7.76 (m, 1H),
7.67 (dt, J=7.7, 1.5 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 6.81 (dd,
J=4.4, 2.6 Hz, 2H), 5.10 (dd, J=12.5, 3.1 Hz, 1H), 3.97 (s, 3H),
3.93 (s, 3H), 3.48 (dd, J=17.3, 3.1 Hz, 1H), 2.65 (dd, J=17.2, 12.5
Hz, 1H), 2.32 (s, 3H); MS (ESI+) m/z 326 (M+H).sup.+.
Example 18D
Methyl 3-((2R)-4-amino-7-methylchroman-2-yl)benzoate
[1651] Example 18C (820 mg, 2.52 mmol) was added to Ra--Ni 2800,
water slurry (2.5 g) in a 100 mL pressure bottle and charged with
30 psi of hydrogen. The mixture was stirred at ambient temperature
for 16 hours. The mixture was filtered and the solvent removed
under pressure. The residue was dissolved in tert-butyl ethyl
ether, followed by drop wise addition of 4 M HCl in dioxane (2 mL).
The precipitated white solid was collected by filtration, washed
with tert-butyl methyl ether, and dried to provide the
hydrochloride salt of the title compound with a cis-/trans-isomer
of about 1 to 1 (705 mg, 2.371 mmol, 94% yield). LC/MS m/z 281
(M-NH.sub.2).sup.+.
Example 18E
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoate
[1652] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(559 mg, 2.3 mmol) in DMF (5 ml) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate, 1196 mg, 3.15 mmol). The mixture was
stirred for 10 minutes at room temperature, followed by addition of
the product from Example 18D (700 mg, 2.1 mmol) and
N-ethyl-N-isopropylpropan-2-amine (1.461 ml, 8.39 mmol)
sequentially. The mixture was stirred at room temperature for 2
hours. LC/MS indicated the reaction was complete. Dichloromethane
(40 mL) was added and the solution was washed with brine (20
mL.times.2). The organic layer was dried over MgSO.sub.4 and
concentrated under reduced pressure. The resulting residue was
purified by chromatography on a 40 g silica gel cartridge, eluting
with a gradient of 0-25% ethyl acetate in heptane to provide
Example 17 as the first eluting isomer and the title compound as
the second eluting isomer (400 mg, 36.6% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.07 (d, J=1.9 Hz, 1H), 7.99 (dt, J=7.9,
1.4 Hz, 1H), 7.58 (dt, J=7.8, 1.5 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H),
7.15-7.05 (m, 2H), 6.97 (dd, J=21.0, 8.0 Hz, 2H), 6.74 (d, J=9.5
Hz, 2H), 5.49-5.39 (m, 1H), 5.36 (d, J=8.7 Hz, 1H), 5.20 (dd,
J=11.3, 1.9 Hz, 1H), 3.92 (s, 3H), 2.51 (ddd, J=13.2, 6.0, 2.0 Hz,
1H), 2.28 (s, 3H), 1.67-1.59 (m, 1H), 1.57 (d, J=1.1 Hz, 2H), 1.07
(td, J=3.6, 2.2 Hz, 2H); MS (ESI+) m/z 522(M+H).sup.+.
Example 19
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1653] A mixture of Example 21D (80 mg, 0.149 mmol) and aqueous
LiOH (2 M, 1 mL) in methanol (4 mL) was stirred at 35.degree. C.
for 4 hours; LC/MS indicated the reaction was complete. Solvent was
removed under reduced pressure and water (2 mL) was added. To the
mixture was added 2 M HCl to adjust pH to 1.about.2. The white
solid was collected by filtration, washed with water, and dried to
give the title compound (55 mg, 70.6% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.18 (s, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.65 (d,
J=7.6 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.17-7.11 (m, 2H), 7.02 (dd,
J=8.3, 3.7 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 6.75 (dd, J=8.8, 3.0
Hz, 1H), 6.59 (d, J=3.0 Hz, 1H), 5.49 (dt, J=18.5, 7.4 Hz, 2H),
5.22 (d, J=11.4 Hz, 1H), 3.74 (s, 3H), 2.66-2.49 (m, 1H), 1.79
(ddd, J=11.9, 6.8, 4.0 Hz, 2H), 1.69-1.63 (m, 1H), 1.11 (d, J=5.0
Hz, 2H); MS (ESI+) m/z 524 (M+H).sup.+.
Example 20
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-hydroxy-2-(3-methoxyphe-
nyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
Example 20A
(R)-7-hydroxy-2-(3-methoxyphenyl)chroman-4-one
[1654] A 250-mL round bottom flask was charged with
(3-methoxyphenyl)boronic acid (1.991 g, 13.11 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.094 g,
0.463 mmol), bis(2,2,2-trifluoroacetoxy)palladium (0.128 g, 0.385
mmol), and ammonium hexafluorophosphate (0.377 g, 2.313 mmol), and
dichloroethane (15.42 mL) was added. The reaction was stirred at
ambient temperature for 5 minutes, at which point a yellow color
was observed in the suspension. To the reaction mixture was added
7-hydroxy-4H-chromen-4-one (CAS 59887-89-7, MFCD00209371, 1.25 g,
7.71 mmol) and water (0.694 mL, 38.5 mmol) and an additional
dichloroethane (10.28 mL) was used to wash down the sides of the
flask. The reaction was stirred for 18 hours at 60.degree. C.,
cooled to ambient temperature, diluted with dichloromethane, and
filtered through a silica/celite filter, initially using 100%
dichloromethane but then 20% ethyl acetate/80% dichloromethane to
effectively remove the boronic acid. Combined filtrates was
concentrated and the crude material loaded onto a 40 g silica gel
column and eluted with 5-50% ethyl acetate/heptanes over 25 minutes
to provide the title compound as a white solid. LC/MS m/z 271
(M+H).sup.+.
Example 20B
(R)-7-hydroxy-2-(3-methoxyphenyl)chroman-4-one O-methyl oxime
[1655] Example 20A (1 g, 3.70 mmol) was dissolved in pyridine (3.70
mL) and O-methylhydroxylamine hydrochloride (0.927 g, 11.10 mmol)
was added. The resulting suspension was heated at 60.degree. C. for
2 hours, cooled to room temperature, and concentrated under reduced
pressure. The crude material was partitioned between saturated
aqueous ammonium chloride and methyl-tert-butyl ether. The crude
material obtained from the concentration of the organic layer was
purified using a 40 g silica gel cartridge, eluting with 5-20%
ethyl acetate/heptanes over 30 minutes to provide the title
compound (505 mg, 1.69 mmol) as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.80 (d, J=8.6 Hz, 1H), 7.31 (t, J=8.0 Hz,
1H), 7.13-6.96 (m, 2H), 6.98-6.82 (m, 1H), 6.48 (dd, J=8.7, 2.5 Hz,
1H), 6.43 (d, J=2.5 Hz, 1H), 5.91 (d, J=10.3 Hz, 1H), 5.03 (dd,
J=12.4, 3.1 Hz, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.43 (dd, J=17.3,
3.1 Hz, 1H), 2.66 (dd, J=17.3, 12.4 Hz, 1H); MS (ESI+) m/z 300.1
(M+H).sup.+.
Example 20C
(2R,4R)-4-amino-2-(3-methoxyphenyl)chroman-7-ol
[1656] Example 20B (430 mg, 1.437 mmol) was dissolved in acetic
acid (5 mL), and platinum (IV) oxide (48.9 mg, 0.215 mmol) was
added. The resulting suspension was stirred under an atmosphere of
hydrogen for 2 hours at room temperature. To the reaction mixture
was added 15% more catalyst and it was stirred for 2 more hours.
The solid was filtered and the filtrate concentrated. The residue
was dissolved in methyl-tert-butyl ether (4 mL). To the solution
was added HCl (4M solution in dioxane, 0.718 mL, 2.87 mmol). The
resulting solid was collected by filtration and dried to constant
weight to provide the hydrochloride salt of the title compound (407
mg, 1.32 mmol) as a solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.71 (s, 1H), 8.67 (d, J=5.3 Hz, 3H), 7.45 (d, J=8.5 Hz,
1H), 7.36 (t, J=7.8 Hz, 1H), 7.05-6.91 (m, 3H), 6.47 (dd, J=8.6,
2.4 Hz, 1H), 6.31 (d, J=2.3 Hz, 1H), 5.16 (d, J=11.6 Hz, 1H), 4.67
(dt, J=11.0, 5.8 Hz, 1H), 3.78 (s, 3H), 2.50-2.46 (m, 1H), 1.99 (q,
J=12.0 Hz, 1H); MS (ESI-) m/z 255.1 (M-NH.sub.2).
Example 20D
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-hydroxy-2-(3-methoxyphe-
nyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1657] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(40 mg, 0.165 mmol) in DMF (1 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (82 mg, 0.215 mmol). The mixture was
stirred for 5 minutes, and the product from Example 20C (50.8 mg,
0.165 mmol) was added, followed by addition of
N-ethyl-N-isopropylpropan-2-amine (0.115 mL, 0.661 mmol). The
mixture was stirred at ambient temperature for 2 hours, then
purified by chromatography on a 25 g silica gel, eluting with a
gradient of 5-50% ethyl acetatein heptanes to provide the title
compound (25 mg, 0.050 mmol, 30.5% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.30 (s, 1H), 7.38 (d, J=1.6 Hz, 1H),
7.32-7.27 (m, 2H), 7.19 (dd, J=8.3, 1.7 Hz, 1H), 7.07 (d, J=8.9 Hz,
1H), 6.98-6.92 (m, 2H), 6.88 (dd, J=8.1, 2.6 Hz, 1H), 6.85-6.80 (m,
1H), 6.34 (dd, J=8.3, 2.4 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 5.27
(td, J=9.9, 6.8 Hz, 1H), 5.16 (dd, J=10.8, 2.7 Hz, 1H), 3.75 (s,
3H), 2.09-1.95 (m, 2H), 1.49 (ddd, J=9.0, 5.4, 2.2 Hz, 1H),
1.41-1.30 (m, 1H), 1.10-0.98 (m, 2H); MS (ESI-) m/z 494
(M-H).sup.-.
Example 21
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 21A
(R)-methyl 3-(6-methoxy-4-oxochroman-2-yl)benzoate
[1658] A 20 mL vial was charged with
bis(2,2,2-trifluoroacetoxy)palladium (0.377 g, 1.135 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.278 g,
1.362 mmol), ammonium hexafluorophosphate(V) (1.110 g, 6.81 mmol)
and (3-(methoxycarbonyl)phenyl)boronic acid (3.06 g, 17.03 mmol).
The mixture was stirred in dichloroethane (5 mL) for 5 minutes at
room temperature, and a pale yellow color was observed. To this
suspension was added 6-methoxy-4H-chromen-4-one (CAS 117408-98-7,
2.0 g, 11.35 mmol) and water (0.256 mL, 14.19 mmol) and the sides
of the vial was washed with more dichloroethane (5 mL). The vial
was capped and the mixture stirred at 60.degree. C. overnight. The
reaction gradually turned black, with Pd plated out on the sides of
the vial. The mixture was filtered through a plug of silica gel and
celite and eluted with ethyl acetate to give a red solution. The
filtrate was concentrated under reduced pressure and the crude
material was chromatographed using a 40 g silica gel cartridge,
eluting with a gradient of 5-50% ethyl acetate/heptanes to provide
the title compound (1.85 g, 5.92 mmol, 52.2% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.18 (t, J=1.7 Hz, 1H), 8.06 (dt,
J=8.0, 1.4 Hz, 1H), 7.68 (dt, J=7.8, 1.5 Hz, 1H), 7.52 (t, J=7.8
Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.14 (dd, J=9.1, 3.1 Hz, 1H), 7.01
(d, J=9.0 Hz, 1H), 5.50 (dd, J=13.4, 3.0 Hz, 1H), 3.95 (s, 3H),
3.83 (s, 3H), 3.06 (dd, J=16.9, 13.4 Hz, 1H), 2.90 (dd, J=17.0, 3.0
Hz, 1H); MS (ESI+) m/z 329.9 (M+NH.sub.4).sup.+.
Example 21B
(R)-methyl 3-(6-methoxy-4-(methoxyimino)chroman-2-yl)benzoate
[1659] The mixture of 21A (1.85 g, 5.92 mmol), sodium acetate
(0.972 g, 11.85 mmol) and O-methylhydroxylamine, hydrochloric acid
(0.989 g, 11.85 mmol) in methanol (10 mL) was stirred at 60.degree.
C. overnight. The solvent was evaporated under reduced pressure.
The residue was dissolved in ethyl acetate, washed with water, and
partitioned. The organic layers was dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
chromatographed on a 80 g silica gel cartridge, eluting with a
gradient of 5-40% ethyl acetate/heptane to provided the title
compound (1.7 g, 4.98 mmol, 84% yield) as white solid. LC/MS: TFA
m/z 342 (M+H).sup.+.
Example 21C
methyl 3-((2R,4R)-4-amino-6-methoxy chroman-2-yl)benzoate
[1660] To Example 21B (1.5 g, 4.39 mmol) in acetic acid (10 mL) was
added 5% platinum (857 mg, 0.220 mmol) on carbon. The reaction
mixture was charged with 30 psi hydrogen and stirred at ambient
temperature for 24 hours, and then filtered. The solvent was
evaporated under reduced pressure and the residue dissolved in
t-butyl methyl ether (10 mL). HCl (4M in dioxane, 2.5 mL) was added
drop wise. The precipitated solid was collected by filtration and
dried to provide the hydrochloride salt of the title compound (842
mg, 54.8% yield). LC/MS: m/z 297 (M-NH.sub.2).sup.+.
Example 21D
methyl
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec-
arboxamido)-6-methoxychroman-2-yl)benzoate
[1661] The mixture of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(779 mg, 3.22 mmol) and HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (1427 mg, 3.75 mmol) in DMF (4 mL) was
stirred for 10 minutes at room temperature, and the product from
Example 21B (840 mg, 2.68 mmol) was added, followed by the addition
of N-ethyl-N-isopropylpropan-2-amine (1.868 mL, 10.72 mmol). The
mixture was stirred at ambient temperature for 2 hours. LC/MS
indicated the reaction was complete. Purification of the mixture by
chromatography on 80 g silica gel cartridge, eluting with a
gradient of 5-40% ethyl acetate in heptane provided the title
compound (835 mg, 57.9% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.07 (t, J=1.8 Hz, 1H), 7.99 (dt, J=7.9, 1.5 Hz, 1H), 7.59
(d, J=7.7 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.15-7.10 (m, 2H), 7.01
(d, J=8.0 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 6.75 (dd, J=8.9, 3.0 Hz,
1H), 6.59 (d, J=2.9 Hz, 1H), 5.49-5.33 (m, 2H), 5.20-5.13 (m, 1H),
3.92 (s, 3H), 3.74 (s, 3H), 2.52 (ddd, J=13.4, 5.9, 1.9 Hz, 1H),
1.84-1.72 (m, 2H), 1.66-1.61 (m, 1H), 1.11-1.06 (m, 2H); MS (ESI+)
m/z 537.9 (M+H).sup.+.
Example 22
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-7-methoxy-2-(pyridin--
3-yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
Example 22A
(E)-1-(2-hydroxy-4-methoxyphenyl)-3-(pyridin-3-yl)prop-2-en-1-one
[1662] To a solution of 1-(2-hydroxy-4-methoxyphenyl)ethanone (10
g, 60.2 mmol) in 1 M aqueous NaOH (600 mL) was added
nicotinaldehyde (16.95 mL, 181 mmol). The mixture was stirred for
16 hours at room temperature. The mixture was neutralized by
dropwise addition of 1 M HCl (about 600 mL). The resulting
precipitate was collected by filtration and dissolved in ethyl
acetate and methanol. The solvent was removed in vacuo and the
solid was then triturated with a small amount of methanol and
filtered to provide the title compound (4.6 g, 18.04 mmol, 30.07%
yield) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
13.21 (s, 1H), 8.80 (s, 1H), 8.57 (d, J=4.4 Hz, 1H), 7.73-7.89 (m,
3H), 7.57 (d, J=16 Hz, 1H), 7.30 (t, J=7.2 Hz, 1H), 6.42-6.45 (m,
2H), 3.80 (s, 3H); MS (ESI+) m/z 256 (M+H).sup.+.
Example 22B
7-methoxy-2-(pyridin-3-yl)chroman-4-one
[1663] To a solution of the product from Example 22A (2.0 g, 7.83
mmol) in 96% ethanol (100 mL) was added concentrated HCl (10 mL,
120 mmol) and water (6 mL). The mixture was heated (block at
100.degree. C.) at reflux for 72 hours, and cooled. The solvent was
removed in vacuo. The crude material was purified by silica gel
column chromatography, eluting with a gradient of 2-3%
methanol/dichloromethane to afford the title compound (1.5 g, 5.13
mmol, 65.5% yield). .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.06
(s, 1H), 8.79 (s, 1H), 8.42 (d, J=7.2 Hz, 1H), 7.97 (s, 1H),
7.88-7.90 (m, 1H), 8.69-8.72 (m, 1H), 6.56 (s, 1H), 5.73 (d, J=10.4
Hz, 1H), 3.89 (s, 3H), 2.98-3.00 (m, 2H); MS (ESI+) m/z 256
(M+H).sup.+.
Example 22C
7-methoxy-2-(pyridin-3-yl)chroman-4-one oxime
[1664] A solution of the product from Example 22B (1.1 g, 4.31
mmol) in methanol (50 mL) was treated with hydroxylamine
hydrochloride (0.359 g, 5.17 mmol) and sodium acetate (0.424 g,
5.17 mmol)). The mixture was stirred at 40.degree. C. for 16 hours.
The solvent was removed in vacuo. The crude material was washed
with water (2.times.20 mL) and dried under a stream of nitrogen to
provide the title compound (1.0 g, 3.31 mmol, 77% yield) as a brown
solid. MS (ESI+) m/z 271 (M+H).sup.+.
Example 22D
7-methoxy-2-(pyridin-3-yl)chroman-4-amine
[1665] A solution of Example 22C (500 mg, 1.850 mmol) in
ammonia-methanol solution (7 M, 50 mL) was treated with Raney
nickel (109 mg, 1.850 mmol). The mixture was stirred at room
temperature under 5 atmosphere of hydrogen for 5 hours. The mixture
was filtered and the filtrate was concenrated to dryness. To the
residue was added 1 M hydrogen chloride in ether. The precipitate
was collected to afford the hydrochlorid salt of the title compound
(235 mg, 0.917 mmol, 49.6% yield): .sup.1HNMR (400 MHz, CD.sub.3OD)
.delta. 8.72-8.95 (m, 2H), 8.40 (s, 1H), 7.87 (s, 1H), 7.39 (t,
J=8.8 Hz, 1H), 6.69-6.73 (m, 1H), 6.60-6.62 (m, 1H), 5.43-5.51 (m,
1H), 4.61 (s, 1H), 3.78 (d, J=2.4 Hz, 3H), 2.14-2.78 (m, 2H); MS
(ESI+): m/z 257 (M+H).sup.+.
Example 22E
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-7-methoxy-2-(pyridin--
3-yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1666] To a solution of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(45.5 mg, 0.188 mmol) in dichloromethane (1 mL) was added half of a
solution of oxalyl dichloride (0.060 mL, 0.683 mmol) in 1 mL of
dichloromethane followed by 1 drop of DMF. The reaction bubbled
vigorously, then the remainder of the oxalyl chloride solution was
added dropwise. The reaction was stirred for 30 minutes at room
temperature. The solvent was removed under a stream of nitrogen,
then chased with 2.times.1 mL of dichloromethane, drying under a
stream of nitrogen. This reagent was taken up in dichloromethane (1
mL) and added to a mixture of the product from Example 22D (50 mg,
0.171 mmol) and triethylamine (0.095 mL, 0.683 mmol) in
dichloromethane (1 mL). After 20 minutes of stirring at room
temperature, the mixture was quenched with saturated aqueous sodium
bicarbonate. The aqueous layer was removed and the organic phase
concentrated. The resulting oil was dissolved in dichloromethane
and purified on a 12 g silica gel cartridge, eluting with a
gradient of 5-100% ethyl acetate/heptanes in 16 minutes to provide
the crude product (71 mg) as an oil. The crude product was loaded
onto a 2.times.0.25 mm plates and eluted with 100% ethyl acetate.
The desired fractions were collected and concentrated to give
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(7-methoxy-2-(pyridin-3-yl)chr-
oman-4-yl)cyclopropanecarboxamide (45 mg, 0.094 mmol, 54.8% yield)
as a pale foam. This material was further purified via preparative
supercritical fluid chromatography set to maintain a back pressure
at 100 bar using a CHIRALPAK.RTM. OD-H, 21.times.250 mm, 5 micron,
with the sample at a concentration of 10 mg/mL in methanol using
16% methanol in CO.sub.2 at a flow rate of 70 mL/minute to provide
the title compound (retention time=3.8 minutes 18 mg, 0.037 mmol,
21.94% yield) and Example 57 (retention time=5.1 minutes). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.57 (d, J=2.2 Hz, 1H), 8.55
(dd, J=4.7, 1.5 Hz, 1H), 7.77 (dt, J=8.0, 1.9 Hz, 1H), 7.53 (d,
J=7.9 Hz, 1H), 7.43 (dd, J=5.5, 3.1 Hz, 2H), 7.32 (d, J=8.3 Hz,
1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.52
(dd, J=8.5, 2.5 Hz, 1H), 6.46 (d, J=2.5 Hz, 1H), 5.30 (dd, J=9.5,
2.7 Hz, 1H), 4.88 (dt, J=8.6, 4.7 Hz, 1H), 3.70 (s, 3H), 2.20 (ddd,
J=14.4, 9.7, 4.9 Hz, 1H), 2.10 (dt, J=14.1, 3.6 Hz, 1H), 1.40 (td,
J=12.8, 9.4 Hz, 2H), 1.04 (d, J=2.9 Hz, 2H); MS (ESI+) m/z 481
(M+H).sup.+.
Example 23
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid
Example 23A
7-hydroxy-4H-chromen-4-one
[1667] 1-(2,4-dihydroxyphenyl)ethanone (12.75 g, 84 mmol) was
dissolved in triethylorthoformate (80 mL, 480 mmol), and
concentrated perchloric acid (7 mL, 116 mmol) was added dropwise
over 5 minutes. During the addition of acid, the temperature rose
slowly but did not exceed 40.degree. C. A dark red color was
gradually formed. The reaction was stirred for 30 minutes and was
then diluted with diethyl ether (300 mL), which resulted in the
precipitation of a dark red solid. The solid was filtered and
washed with ether (50 mL) and used without additional purification
(a mixture of the perchlorate complex of the title compound and
unreacted starting material was present). To 14 g of the crude
intermediate mixture was added 150 mL of water, and the resulting
suspension was stirred for 30 minutes at room temperature, during
which point the red solid turned to a brownish color. The resulting
solid was collected by filtration and washed with water (50 mL).
The solid was dried to constant weight to provide the title
compound (5.31 g, 32.7 mmol, 39%) as a light purple solid. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 10.78 (s, 1H), 8.15 (d, J=6.0
Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 6.92 (dd, J=8.7, 2.3 Hz, 1H), 6.85
(d, J=2.3 Hz, 1H), 6.22 (d, J=6.0 Hz, 1H); MS (ESI+) m/z 163
(M+H).sup.+.
Example 23B
(R)-methyl 3-(7-hydroxy-4-oxochroman-2-yl)benzoate
[1668] A 250 mL round bottle flask was charged with
bis(2,2,2-trifluoroacetoxy) palladium (0.308 g, 0.925 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.227 g,
1.110 mmol), ammonium hexafluorophosphate(V) (0.905 g, 5.55 mmol),
and 3-methoxycarbonylphenylboronic acid (5.99 g, 33.3 mmol) were
stirred in dichloroethane (37 mL) for 5 minutes, and a pale yellow
color was observed. To this suspension was added Example 23A (3.0
g, 18.50 mmol) and water (1.667 mL, 93 mmol) and additional
dichloroethane (25 mL) was used to rinse the side of the flask. The
reaction mixture was heated at 60.degree. C. The reaction turned
progressively darker and precipitation of Pd black could be seen
along the sides of the flask. The reaction was allowed to stir
overnight at the same temperature for a total reaction time of 18
hour. The reaction seemed to stall at .about.50% conversion, so it
was cooled to room temperature, filtered through a silica/celite
plug using 100% dichloromethane to 90:10 dichloromethane:ethyl
acetate. The mixture was heated with methyl t-butyl ether to give
an off-white solid that was clean by LC-MS and used without
additional purification (2 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.63 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.97 (dt, J=7.5, 1.3
Hz, 1H), 7.82 (dd, J=8.1, 1.6 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.60
(t, J=7.7 Hz, 1H), 6.54 (dd, J=8.6, 2.2 Hz, 1H), 6.40 (d, J=2.2 Hz,
1H), 5.71 (dd, J=12.8, 2.9 Hz, 1H), 3.88 (s, 3H), 3.12 (dd, J=16.8,
12.9 Hz, 1H), 2.76 (dd, J=16.7, 3.0 Hz, 1H); MS (ESI+) m/z=299.0
(M+H).sup.+.
Example 23C
(R)-methyl 3-(7-hydroxy-4-(methoxyimino)chroman-2-yl)benzoate
[1669] Example 23B (2 g, 6.70 mmol) was dissolved in 13 mL of dry
pyridine. O-methylhydroxylamine hydrochloride (1.15 g, 13.77 mmol)
was added, and the resulting suspension was heated at 60.degree. C.
for 3 hours. Solvent was removed under reduced pressure and the
crude residue partitioned between ethyl acetate and and 1:1
saturated ammonium chloride solution in water. Combined organic
extracts were concentrated and purified on an 80 g silica gel
column, eluting with 20% ethyl acetate/heptanes to provide the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (d,
J=2.1 Hz, 1H), 8.03 (dd, J=7.9, 1.8 Hz, 1H), 7.81 (dd, J=8.5, 1.5
Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.50 (dd,
J=8.6, 2.6 Hz, 1H), 6.44 (d, J=2.5 Hz, 1H), 5.51 (d, J=9.5 Hz, 1H),
5.10 (dd, J=12.5, 3.1 Hz, 1H), 3.96 (s, 3H), 3.94 (d, J=1.4 Hz,
3H), 3.46 (dd, J=17.3, 3.2 Hz, 1H), 2.64 (dd, J=17.2, 12.4 Hz, 1H);
MS (ESI+) m/z=300.1 (M+H).sup.+.
Example 23D
methyl 3-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate
[1670] Example 23C (200 mg, 0.611 mmol) was dissolved in acetic
acid (2.5 mL), and platinum(IV) oxide (13.87 mg, 0.061 mmol) was
added. The resulting suspension was stirred under an atmosphere of
H.sub.2 for 18 hour at room temperature. The reaction mixture was
diluted with ethyl acetate and filtered through a syringe filter.
The filtrate was concentrated and suspended in methyl t-butyl ether
(6 mL), followed by addition of 2 equivalants of HCl in dioxane,
and was sonicated to ensure fine suspension, then stirred overnight
at room temperature. The mixture was concentrated to provide the
hydrochloride salt of the title compound (93 mg) as a light orange
solid, which was used without additional purification. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.74 (s, 1H), 8.66 (br. s, J=5.5
Hz, 3H), 8.04 (d, J=1.8 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.74 (d,
J=7.8 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 6.49
(dd, J=8.5, 2.4 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H), 5.32 (d, J=11.6
Hz, 1H), 4.69 (dt, J=11.2, 5.6 Hz, 1H), 3.88 (s, 3H), 2.57-2.52 (m,
1H), 2.03-1.95 (m, 1H); MS (ESI-) m/z=283.0 (M-NH.sub.3).sup.-.
Example 23E
Methyl
342R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecar-
boxamido)-7-hydroxychroman-2-yl)benzoate
[1671] The title compound was prepared using the conditions
described in Example 8D, substituting Example 23D for Example 8C,
to generate the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.06 (t, J=1.7 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.56 (d,
J=7.7 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.11 (dd, J=8.2, 1.6 Hz,
1H), 7.07 (d, J=1.6 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.92 (d, J=8.4
Hz, 1H), 6.43 (dd, J=8.5, 2.5 Hz, 1H), 6.38 (d, J=2.5 Hz, 1H), 5.40
(td, J=10.2, 9.8, 6.0 Hz, 1H), 5.32 (d, J=8.9 Hz, 1H), 5.22-5.16
(m, 1H), 5.04 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 2.49 (ddd, J=13.3,
5.9, 2.0 Hz, 1H), 1.87-1.69 (m, 2H), 1.07 (q, J=2.4 Hz, 2H); MS
(ESI-): m/z=522.2 (M-H).sup.-.
Example 23F
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1672] Lithium hydroxide hydrate (16.16 mg, 0.385 mmol) was
dissolved in 0.170 mL of water, and the resulting solution was
added to a solution of Example 23E (48 mg, 0.064 mmol) in
tetrahydrofuran (257 .mu.L). The reaction was stirred vigorously at
ambient temperature for 15 hours. The crude material was loaded
directedly onto a 12 g silica gel cartridge, eluting with 10-50%
ethyl acetate/heptanes over 20 minutes to provide the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (s, 1H),
8.04 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz,
1H), 7.14-7.06 (m, 2H), 7.01 (d, J=8.2 Hz, 1H), 6.91 (d, J=8.4 Hz,
1H), 6.49-6.37 (m, 2H), 5.43 (q, J=8.2, 7.0 Hz, 2H), 5.21 (d,
J=11.1 Hz, 1H), 2.56-2.51 (m, 1H), 1.79-1.64 (m, 3H), 1.09 (q,
J=2.2 Hz, 2H); MS (ESI-) m/z 507.9 (M-H).sup.-
Example 24
ethyl
rel-3-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate
Example 24A
methyl 3-(3-(3-chloropyridin-4-yl)-3-oxopropanoyl)benzoate
[1673] A solution of methyl 3-acetylbenzoate (2.278 g, 12.78 mmol)
in tetrahydrofuran (35 mL) at -78.degree. C. under N.sub.2 was
treated with 1 M lithium bis(trimethylsilyl)amide in
tetrahydrofuran (28.1 mL, 28.1 mmol) under N.sub.2. After stirring
at -78.degree. C. for 15 minutes, a solution of
3-chloroisonicotinoyl chloride (2.25 g, 12.78 mmol) in
tetrahydrofuran (25 mL) was added dropwise. After stirring at
-78.degree. C. for 15 minutes, the mixture was treated all at once
with 1 M HCl (50 mL) and allowed to warm to room temperature. The
mixture was diluted with water (200 mL) and stirred for 15 minutes.
The solid was collected by filtration, washed with water, and dried
under vacuum with heating (60.degree. C.) to provide the title
compound (3.1 g, 9.76 mmol, 76% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.84 (s, 1H), 8.73 (d, J=4.9 Hz, 1H),
8.57 (t, J=1.8 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.22 (d, J=7.8 Hz,
1H), 7.79 (d, J=4.9 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.11 (s, 1H),
3.91 (s, 3H).
Example 24B
methyl 3-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)benzoate
[1674] A mixture of the product from Example 24A (3.1 g, 9.76 mmol)
and K.sub.2CO.sub.3 (1.348 g, 9.76 mmol) in N,N-dimethylformamide
(30 mL) under N.sub.2 was heated to 95.degree. C. for 20 minutes,
heated to 110.degree. C. for 20 minutes, and heated to 120.degree.
C. for 20 minutes. The mixture was cooled to near 0.degree. C.,
treated all at once with 1 M HCl (15 mL), treated with water (150
mL) and stirred at room temperature for 15 minutes. The solid was
collected by filtration, washed with water and dried over night at
60.degree. C. under vacuum to provide the title compound (2.38 g,
8.46 mmol, 87% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 9.27 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 8.59 (s, 1H), 8.39 (d,
J=7.8 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 7.90 (d, J=5.1 Hz, 1H), 7.75
(t, J=7.7 Hz, 1H), 7.25 (s, 1H), 3.92 (s, 3H); MS (ESI) m/z 282
(M+H).sup.+.
Example 24C
methyl
3-(4-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl)benzoate
[1675] A solution of the product from Example 24B (1.2 g, 4.27
mmol) in methanol (7 mL) and CH.sub.2Cl.sub.2 (14 mL) was treated
with cobalt(II) phthalocyanine (0.122 g, 0.213 mmol), treated with
NaBH.sub.4 (0.646 g, 17.07 mmol), stirred at room temperature for
20 minutes, treated with more NaBH.sub.4 (about 0.3 g), stirred at
room temperature for 20 minutes, quenched with 1 M HCl (30 mL) and
basified to pH about 8 with solid NaHCO.sub.3. The mixture was
extracted with ethyl acetate (2 times, 1st extraction was filtered
through celite). The combined ethyl acetate layers were washed with
brine, dried (MgSO.sub.4), filtered, concentrated and
chromatographed on silica gel eluted with a gradient of 50%-100%
ethyl acetate in heptanes to provide the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.36-8.16 (m, 2H), 8.11 (s,
1H), 8.04 (d, J=7.7 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.54-7.46 (m,
2H), 5.27 (dd, J=11.9, 1.9 Hz, 1H), 5.11 (dd, J=10.9, 6.1 Hz, 1H),
3.94 (s, 3H), 2.57 (ddd, J=13.4, 6.2, 1.9 Hz, 1H), 2.16 (q, J=11.9
Hz, 1H); MS (ESI) m/z 286 (M+H).sup.+.
Example 24D
methyl
3-(4-oxo-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl)benzoate
[1676] A solution of the product from Example 24C (240 mg, 0.841
mmol) in acetone (10 mL) was treated dropwise with Jones reagent
until the starting material was consumed. The mixture was
concentrated to 2 mL volume on the rotovap with minimal heating.
The residue was partitioned between ethyl acetate and saturated
NaHCO.sub.3 solution. The layers were separated and the aqueous was
extracted with ethyl acetate. The combined ethyl acetate layers
were washed with brine, dried (MgSO.sub.4), filtered, concentrated
and chromatographed on silica gel eluted with a gradient of 15%-50%
ethyl acetate in heptanes to provide the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.63 (s, 1H), 8.41 (d, J=5.1
Hz, 1H), 8.18 (t, J=1.8 Hz, 1H), 8.12-8.07 (m, 1H), 7.71-7.67 (m,
2H), 7.55 (t, J=7.8 Hz, 1H), 5.60 (dd, J=13.2, 3.0 Hz, 1H), 3.95
(s, 3H), 3.16 (dd, J=17.1, 13.3 Hz, 1H), 3.01 (dd, J=17.0, 3.0 Hz,
1H); MS (ESI) m/z 284 (M+H).sup.+.
Example 24E
[1677] A solution of the product from Example 24D (67 mg, 0.237
mmol), (R)-(+)-2-methyl-2-propanesulfinamide (43.0 mg, 0.355 mmol)
and titanium(IV) ethoxide (298 .mu.L, 1.419 mmol) in
2-methyl-tetrahydrofuran (1.5 mL) was heated at 70.degree. C. over
night. The mixture was cooled and partitioned between water and
ethyl acetate. The layers were separated and the aqueous layer was
extracted with ethyl acetate. The combined ethyl acetate layers
were washed with brine, dried (MgSO.sub.4), filtered, concentrated,
and chromatographed on silica gel eluted with a gradient of 0%-100%
ethyl acetate in [9:1 CH.sub.2Cl.sub.2:ethyl acetate] to provide
Example 24E as the first eluting isomer and Example 24F as the
second eluting isomer. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 8.56-8.49 (m, 1H), 8.35-8.29 (m, 1H), 8.15 (s, 1H), 8.07 (d,
J=7.8 Hz, 1H), 7.78-7.72 (m, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.50 (t,
J=7.7 Hz, 1H), 5.32 (dd, J=12.8, 2.4 Hz, 1H), 4.40 (q, J=7.2 Hz,
2H), 3.97 (dd, J=17.7, 2.8 Hz, 1H), 3.37 (dd, J=17.7, 12.8 Hz, 1H),
1.41 (t, J=7.1 Hz, 3H), 1.34 (s, 9H); MS (ESI) m/z 399
(M-H).sup.-.
Example 24F
[1678] Example 24F was obtained as the second eluting isomer from
the chromatography of the crude material as described in Example
24E. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 8.56-8.49 (m,
1H), 8.35-8.28 (m, 1H), 8.15 (s, 1H), 8.07 (dt, J=7.8, 1.4 Hz, 1H),
7.78-7.74 (m, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H),
5.41 (dd, J=12.3, 2.8 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 4.26 (dd,
J=17.3, 2.9 Hz, 1H), 3.16 (dd, J=17.3, 12.2 Hz, 1H), 1.42 (t, J=7.2
Hz, 3H), 1.36 (s, 9H); MS (ESI) m/z 399 (M-H).sup.-.
Example 24G
[1679] A solution of the product from Example 24F (17 mg, 0.042
mmol) in ethanol (1 mL) was cooled to 0.degree. C., treated with
NaBH.sub.4 (4 mg), stirred at 0.degree. C. for 15 minutes and
partitioned between water and ethyl acetate. The layers were
separated and the aqueous layer was extracted with ethyl acetate.
The combined ethyl acetate layers were washed with brine, dried
(MgSO.sub.4), filtered, and concentrated to provide Example 24G.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.35-8.15 (m, 2H),
8.11 (s, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.71-7.67 (m, 1H), 7.65 (d,
J=7.8 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 5.29 (d, J=9.4 Hz, 1H),
4.89-4.81 (m, 1H), 4.41 (q, J=7.1 Hz, 2H), 3.58 (d, J=8.3 Hz, 1H),
2.53 (ddd, J=13.8, 6.2, 1.9 Hz, 1H), 2.20 (dt, J=13.6, 11.5 Hz,
1H), 1.41 (t, J=7.1 Hz, 3H), 1.25 (s, 9H); MS (ESI) m/z 403
(M+H).sup.+.
Example 24H
ethyl
rel-3-((2S,4S)-4-amino-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl)benz-
oate hydrochloride
[1680] A solution of the product from Example 24G (17 mg, 0.042
mmol) in ethanol (1 mL) was treated with 4 M HCl in dioxane (0.5
mL) and stirred at room temperature for 20 minutes. The mixture was
concentrated to dryness and dried under vacuum with heating at
60.degree. C. for 30 minutes to provide Example 24H. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 9.26-9.06 (m, 3H), 8.60-8.34
(m, 2H), 8.09-7.97 (m, 3H), 7.78 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.7
Hz, 1H), 5.60 (d, J=11.4 Hz, 1H), 5.04-4.92 (m, 1H), 4.35 (q, J=7.1
Hz, 2H), 2.71-2.64 (m, 1H), 2.20 (q, J=12.1 Hz, 1H), 1.34 (t, J=7.1
Hz, 3H); MS (ESI) m/z 299 (M+H).sup.+.
Example 24I
ethyl
rel-3-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate
[1681] A mixture of the product from Example 24H (14 mg, 0.042
mmol), difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylic acid
(10.13 mg, 0.042 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (17.49 mg, 0.046 mmol) in tetrahydrofuran (1
mL) was treated with triethylamine (17.49 .mu.L, 0.125 mmol). The
mixture was stirred at room temperature for 1 hour, diluted with
ethyl acetate (30 mL), washed with 1 M HCl (10 mL), washed with
saturated NaHCO.sub.3 solution (10 mL), washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel, eluting with a gradient of 50%-100%
[1:1 CH.sub.2Cl.sub.2:ethyl acetate] in heptanes to provide the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.25
(s, 1H), 8.17 (d, J=5.1 Hz, 1H), 8.06 (s, 1H), 8.03 (d, J=8.1 Hz,
1H), 7.59 (d, J=8.1 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.17-7.02 (m,
4H), 5.57-5.45 (m, 2H), 5.34-5.26 (m, 1H), 4.39 (q, J=7.1 Hz, 2H),
2.49 (ddd, J=13.5, 5.9, 1.9 Hz, 1H), 1.92 (q, J=11.8 Hz, 1H),
1.81-1.62 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.19-1.08 (m, 2H); MS
(ESI) m/z 523 (M+H).sup.+.
Example 25
ethyl
rel-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate
Example 25A
[1682] A solution of Example 24E (10.6 mg, 0.026 mmol) in ethanol
(1 mL) was cooled to 0.degree. C., treated with NaBH.sub.4 (4 mg),
stirred at 0.degree. C. for 15 minutes and partitioned between
water and ethyl acetate. The layers were separated and the aqueous
layer was extracted with ethyl acetate. The combined ethyl acetate
layers were washed with brine, dried (MgSO.sub.4), filtered, and
concentrated to provide Example 25A. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.32-8.29 (m, 1H), 8.21 (d, J=5.0 Hz, 1H),
8.11 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.49
(t, J=7.7 Hz, 1H), 7.36 (d, J=4.9 Hz, 1H), 5.28 (dd, J=11.5, 2.1
Hz, 1H), 4.79 (td, J=11.0, 6.0 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H),
3.35 (d, J=10.6 Hz, 1H), 2.95-2.85 (m, 1H), 2.16 (dt, J=13.7, 11.4
Hz, 1H), 1.41 (t, J=7.2 Hz, 3H), 1.32 (s, 9H); MS (ESI) m/z 403
(M+H).sup.+.
Example 25B
ethyl
rel-3-((2R,4R)-4-amino-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl)benz-
oate hydrochloride
[1683] A solution of the product from Example 25A (9.3 mg, 0.023
mmol) in ethanol (1 mL) was treated with 4 M HCl in dioxane (0.5
mL) and stirred at room temperature for 20 minutes. The mixture was
concentrated to dryness and dried under vacuum with heating at
60.degree. C. for 30 minutes to provide the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.11 (bs, 3H), 8.48 (s,
1H), 8.39 (d, J=5.2 Hz, 1H), 8.06 (s, 1H), 8.05-7.98 (m, 1H), 7.95
(d, J=5.4 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H),
5.57 (d, J=11.5 Hz, 1H), 5.01-4.90 (m, 1H), 4.35 (q, J=7.1 Hz, 2H),
2.70-2.63 (m, 1H), 2.18 (q, J=12.1 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H);
MS (ESI) m/z 299 (M+H).sup.+.
Example 25C
ethyl
rel-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate
[1684] A mixture of the product from Example 25B (7.7 mg, 0.023
mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (9.62 mg, 0.025 mmol) and
1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylic acid
(5.57 mg, 0.023 mmol) in tetrahydrofuran (1 mL) was treated with
triethylamine (9.62 .mu.L, 0.069 mmol). The mixture was stirred at
room temperature for 1 hour, diluted with ethyl acetate (30 mL),
washed with 1 M HCl (10 mL), washed with saturated NaHCO.sub.3
solution (10 mL), washed with brine, dried (MgSO.sub.4), filtered,
and concentrated. The crude product was chromatographed on silica
gel eluting with a gradient of 50%-100% [1:1 CH.sub.2Cl.sub.2:ethyl
acetate] in heptanes to provide the title compound. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 8.26 (s, 1H), 8.17 (d, J=5.0 Hz,
1H), 8.06 (s, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H),
7.47 (t, J=7.7 Hz, 1H), 7.15 (dd, J=8.2, 1.6 Hz, 1H), 7.10 (d,
J=1.5 Hz, 1H), 7.06-7.02 (m, 2H), 5.52 (td, J=10.8, 10.1, 6.0 Hz,
1H), 5.43 (d, J=8.9 Hz, 1H), 5.28 (dd, J=11.7, 1.9 Hz, 1H), 4.39
(q, J=7.1 Hz, 2H), 2.50 (ddd, J=13.5, 6.0, 2.0 Hz, 1H), 1.89 (dt,
J=13.3, 11.4 Hz, 1H), 1.80-1.63 (m, 2H), 1.40 (t, J=7.1 Hz, 3H),
1.17-1.08 (m, 2H); MS (ESI) m/z 523 (M+H).sup.+.
Example 26
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxyl-
ic acid
Example 26A
methyl
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec-
arboxamido)-7-(difluoromethoxy)chroman-2-yl)cyclohexanecarboxylate
[1685] The title compound (9.0 mg, 0.016 mmol, 9.04% yield) was
isolated as a second eluting compound from the purification of the
crude product as described in Example 27E. LC/MS m/z 580
(M+H).sup.+.
Example 26B
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxyl-
ic acid
[1686] The mixture of 26A (12 mg, 0.021 mmol) and 2 M LiOH (0.5 mL)
in methanol (2 mL) was stirred at 35.degree. C. for 4 hours. LC/MS
showed the reaction was complete. Solvent was removed and water (1
mL) was added. The pH of the mixture was adjusted with 2 M HCl to
pH 1.about.2. The precipitated white solid was collected by
filtration, washed with water, and dried to provide the title
compound (10 mg, 0.018 mmol, 85% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.21-7.10 (m, 2H), 7.07-6.92 (m, 2H), 6.64-6.58
(m, 1H), 6.54 (q, J=2.1 Hz, 1H), 6.47-6.22 (m, 1H), 5.29 (dt,
J=26.3, 8.2 Hz, 2H), 3.95 (t, J=12.4 Hz, 1H), 2.30 (d, J=58.5 Hz,
2H), 2.04 (d, J=12.1 Hz, 3H), 1.80-1.60 (m, 4H), 1.51-1.23 (m, 5H),
1.11 (d, J=3.5 Hz, 2H); MS (ESI-) m/z 564.2 (M-H).sup.-.
Example 27
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
Example 27A
7-(difluoromethoxy)-4H-chromen-4-one
[1687] To 7-hydroxy-4H-chromen-4-one (CAS 59887-89-7, MFCD00209371,
2.0 g, 12.33 mmol) and diethyl (bromodifluoromethyl)phosphonate
(4.38 mL, 24.67 mmol) in acetonitrile (40 mL) and water (20.00 mL)
was added 50% aqueous potassium hydroxide (8.30 g, 74.0 mmol) drop
wise via syringe while stirring vigorously. The temperature rose to
a maximum temperature of 38.degree. C. during the addition. After
the addition, LC/MS showed conversion done with a small by-product
peak. Additional water was added to the mixture. The mixture was
extracted with ethyl acetate (3.times.20 mL). The combined organics
were washed with 1 M HCl (10 mL), dried over MgSO.sub.4, filtered,
and concentrated. The crude mixture was purified on 80 g silica gel
cartridge, eluting with ethyl acetated in heptane (5-40%) to
provide the title compound (1.31 g, 6.17 mmol, 50.1% yield).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.22 (d, J=8.7 Hz, 1H),
7.84 (d, J=6.1 Hz, 1H), 7.21-7.10 (m, 2H), 6.64 (t, J=72.5 Hz, 1H),
6.34 (d, J=6.0 Hz, 1H); LC/MS m/z 213 (M+H).sup.+.
Example 27B
(R)-methyl 3-(7-(difluoromethoxy)-4-oxochroman-2-yl)benzoate
[1688] A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (901
mg, 5.01 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (49.1 mg,
0.240 mmol), bis(2,2,2-trifluoroacetoxy)-palladium (66.6 mg, 0.200
mmol), and ammonium exafluorophosphate (196 mg, 1.20 mmol) in (10
ml) dichloroethane was stirred at ambient temperature for 5
minutes, and to it was added Example 27A (850 mg, 4.0 mmol) and
water (0.36 mL, 20.0 mmol). The mixture was heated at 60.degree. C.
for overnight. The reaction mixture diluted with dichloroethane and
filtered through a plug of celite. The mixture washed with brine
and concentrated. The crude material loaded onto a 40 g silica gel
cartridge and eluted with 5-50% ethyl acetate/heptane to give the
title product as white solid. Analytic Chiral SFC showed 93% ee.
.sup.1H NMR (501 MHz, CDCl.sub.3) .delta. 8.17 (t, J=1.8 Hz, 1H),
8.08 (dt, J=7.8, 1.4 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.70-7.62 (m,
1H), 7.53 (t, J=7.7 Hz, 1H), 6.88-6.79 (m, 2H), 6.60 (t, J=72.8 Hz,
1H), 5.56 (dd, J=13.3, 2.9 Hz, 1H), 3.95 (s, 3H), 3.08 (dd, J=16.9,
13.4 Hz, 1H), 2.92 (dd, J=16.9, 2.9 Hz, 1H); MS (ESI+) m/z 349
(M+H).sup.+.
Example 27C
(R)-methyl
3-(7-(difluoromethoxy)-4-(methoxyimino)chroman-2-yl)benzoate
[1689] The mixture of Example 27B (410 mg, 1.177 mmol),
O-methylhydroxylamine hydrochloride (197 mg, 2.354 mmol) and sodium
acetate (193 mg, 2.354 mmol) in methanol (10 mL) was heated at
60.degree. C. for 4 hours. LC/MS indicated the reaction was
complete. The solvent was evaporated in vacuo, and ethyl acetate
(20 mL) was added. The mixture was washed with water, dried over
MgSO.sub.4, and concentrated in vacuo to provide the title
compounds as white solid (395 mg, 1.047 mmol, 89% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.14 (t, J=1.6 Hz, 1H), 8.04 (dt,
J=7.8, 1.3 Hz, 1H), 7.97-7.86 (m, 1H), 7.66 (dt, J=7.8, 1.4 Hz,
1H), 7.50 (t, J=7.7 Hz, 1H), 6.79-6.72 (m, 2H), 6.71 (s, 1H), 5.13
(dd, J=12.4, 3.0 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.50 (dd,
J=17.3, 3.1 Hz, 1H), 2.66 (dd, J=17.2, 12.5 Hz, 1H); MS (ESI+) m/z
378 (M+H).sup.+.
Example 27D
Methyl
3-((2R,4R)-4-amino-7-(difluoromethoxy)chroman-2-yl)benzoate
[1690] Platinum on carbon, 5% loading (199 mg, 0.051 mmol) was
added to a solution of Example 27C (385 mg, 1.02 mmol) in acetic
acid (5 mL) in a 50 mL round bottom flask. The flask was charged
with a hydrogen balloon and stirred for 48 hours at room
temperature. LC/MS indicated only about 60% conversion achieved.
The reaction was filtered, and the filtrate concentrated. The
resulting residue was purified on a 12 g silica gel cartridge,
eluting with (95% ethyl acetate/5% methanol/2% triethyl amine) in
heptane at 10-100% gradient to provide the title compound (63 mg,
34%), which contained about 15% over-reduced by product of methyl
3-((2R,4R)-4-amino-7-(difluoromethoxy)chroman-2-yl)cyclohexanecarboxylate-
. The resulting mixture was carried on without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19-8.07
(m, 1H), 8.03 (dt, J=7.8, 1.4 Hz, 1H), 7.69-7.58 (m, 1H), 7.56-7.44
(m, 2H), 6.75 (dd, J=8.6, 2.4 Hz, 1H), 6.68 (d, J=2.1 Hz, 1H),
6.50-6.26 (m, 1H), 5.23 (dd, J=11.8, 1.9 Hz, 1H), 4.26 (dd, J=11.3,
5.8 Hz, 1H), 3.94 (s, 3H), 3.73-3.66 (m, 1H), 2.43 (ddd, J=13.4,
5.8, 1.9 Hz, 1H); MS (ESI+) m/z 333 (M-NH.sub.2).sup.+.
Example 27E
methyl
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec-
arboxamido)-7-(difluoromethoxy)chroman-2-yl)benzoate
[1691] A mixture of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(41.6 mg, 0.172 mmol) and HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol
o[4,5-b]pyridinium 3-oxid hexafluorophosphate) (98 mg, 0.258 mmol)
in DMF (1 mL) was stirred for 5 minutes, and Example 27D (60 mg,
0.172 mmol) was added, followed by addition of
N-ethyl-N-isopropylpropan-2-amine (0.120 mL, 0.687 mmol). The
mixture was stirred at ambient temperature for 2 hours and LC/MS
showed the reaction was complete. The crude product was purified by
preparative LC method TFA2 to provide the title compound (43 mg,
43.7% yield) as the first eluting compound and Example 26A as the
second eluenting compound.
Example 27F
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxam-
ido)-7-(difluoromethoxy)chroman-2-yl)benzoic acid
[1692] A mixture of Example 27E (40 mg, 0.07 mmol) in methanol (2
mL) and 2 M aqueous LiOH was stirred at 35.degree. C. for 4 hours.
LC/MS showed the reaction was complete. Solvent was removed and
water (1 mL) added, and the pH of the mixture was adjusted pH to
1.about.2 with 2 M HCl. The precipitated white solid was collected
by filtration, washed with water, and dried to provide the title
compound (32 mg, 0.057 mmol, 82% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.99 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.53
(d, J=7.7 Hz, 1H), 7.48-6.99 (m, 7H), 6.74 (d, J=8.2 Hz, 1H), 6.65
(s, 1H), 5.38 (d, J=10.8 Hz, 2H), 2.23-2.01 (m, 2H), 1.45 (ddd,
J=44.1, 9.1, 3.1 Hz, 2H), 1.06 (d, J=3.7 Hz, 2H); MS (ESI-) m/z 558
(M-H).sup.-.
Example 28
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid
[1693] A solution of Example 30 (23 mg, 0.043 mmol) in
tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was treated with 1 M
NaOH (15 drops). The mixture was stirred at 50.degree. C. for 15
minutes, heated to 60.degree. C. for 30 minutes, cooled, diluted
with water (10 mL), treated with 1 M HCl (1 mL) and extracted with
ethyl acetate (30 mL). The ethyl acetate layer was washed with
brine, dried (MgSO.sub.4), filtered, and concentrated to provide
the title compound (22 mg, 0.042 mmol, 98% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.17 (t, J=1.7 Hz, 1H), 8.06 (d, J=7.8
Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.35 (d,
J=8.2 Hz, 1H), 7.11 (dd, J=8.2, 1.7 Hz, 1H), 7.07 (d, J=1.5 Hz,
1H), 7.02 (d, J=8.2 Hz, 1H), 6.41 (d, J=8.3 Hz, 1H), 5.48 (td,
J=9.8, 6.2 Hz, 1H), 5.39-5.29 (m, 2H), 3.89 (s, 3H), 2.58-2.51 (m,
1H), 1.85 (dt, J=13.3, 10.9 Hz, 1H), 1.78-1.62 (m, 2H), 1.13-1.05
(m, 2H); MS (ESI) m/z 523 (M+H).sup.+.
Example 29
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid
Example 29A
methyl
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzo-
ate
[1694] The product from Example 37G was chromatographed on silica
gel, eluting with a gradient of 50%-65% [9:1 CH.sub.2Cl.sub.2:ethyl
acetate] in heptanes to provide the title compound as the first
eluting isomer. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.06
(t, J=1.6 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.61 (dt, J=7.7, 1.5 Hz,
1H), 7.47 (t, J=7.7 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.15 (dd,
J=8.1, 1.7 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H),
6.41 (d, J=8.2 Hz, 1H), 5.50 (d, J=6.9 Hz, 1H), 5.00 (ddd, J=7.1,
4.4, 2.8 Hz, 1H), 4.96 (dd, J=11.5, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88
(s, 3H), 2.29 (dt, J=14.4, 2.7 Hz, 1H), 2.19 (ddd, J=14.4, 11.3,
4.5 Hz, 1H), 1.68 (q, J=3.4 Hz, 2H), 1.09 (q, J=3.3 Hz, 2H); MS
(ESI) m/z 537 (M-H).sup.-.
Example 29B
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid
[1695] The title compound was prepared using the procedure similar
to Example 28, substituting the product from Example 29A for the
product from Example 30. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 8.13 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H),
7.50 (t, J=7.7 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.16 (d, J=8.9 Hz,
1H), 7.13 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.41 (d, J=8.2 Hz, 1H),
5.53 (d, J=6.9 Hz, 1H), 5.05-4.95 (m, 2H), 3.89 (s, 3H), 2.32 (d,
J=14.6 Hz, 1H), 2.28-2.10 (m, 1H), 1.69 (q, J=3.2 Hz, 2H), 1.10 (q,
J=3.3 Hz, 2H); MS (ESI) m/z 523 (M-H).
Example 30
methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzo-
ate
[1696] The product from Example 37G was chromatographed on silica
gel, eluting with a gradient of 50%-65% [9:1 CH.sub.2Cl.sub.2:ethyl
acetate] in heptanes to provide the title compound as the second
eluting isomer. .sup.1H NMR (501 MHz, CDCl.sub.3) .delta. ppm 8.08
(t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.4 Hz, 1H), 7.62-7.59 (m, 1H),
7.44 (t, J=7.7 Hz, 1H), 7.34 (dd, J=8.3, 0.9 Hz, 1H), 7.09 (dd,
J=8.2, 1.7 Hz, 1H), 7.05 (d, J=1.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H),
6.40 (d, J=8.3 Hz, 1H), 5.46-5.39 (m, 1H), 5.32 (dd, J=11.2, 2.0
Hz, 1H), 5.26 (d, J=8.9 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 2.48
(ddd, J=13.5, 6.2, 2.1 Hz, 1H), 1.86 (dt, J=13.5, 10.9 Hz, 1H),
1.75-1.68 (m, 1H), 1.68-1.61 (m, 1H), 1.12-1.04 (m, 2H); MS (ESI)
m/z 537 (M-H).sup.-.
Example 31
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid
[1697] The title compound was prepared using the procedure similar
to that described in Example 28, substituting the product from
Example 33F for the product from Example 30. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.31 (s, 1H), 8.25 (d, J=4.3 Hz, 1H), 8.04
(d, J=7.7 Hz, 1H), 7.58-7.51 (m, 2H), 7.44 (t, J=7.7 Hz, 1H), 7.13
(dd, J=8.2, 1.5 Hz, 1H), 7.10 (d, J=1.3 Hz, 1H), 7.03-6.97 (m, 2H),
5.64-5.56 (m, 1H), 5.51 (d, J=9.1 Hz, 1H), 5.44 (d, J=11.2 Hz, 1H),
2.61 (ddd, J=13.5, 6.0, 2.0 Hz, 1H), 1.89-1.65 (m, 3H), 1.18-1.08
(m, 2H); MS (ESI) m/z 495 (M+H).sup.+.
Example 32
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid
[1698] The title compound was prepared using the procedure similar
to that described in Example 28, substituting the product from
Example 34 for the product from Example 30. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.28 (s, 2H), 8.05 (d, J=7.6 Hz, 1H), 7.60
(dd, J=7.5, 1.8 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz,
1H), 7.16 (dd, J=8.0, 1.7 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 7.03 (d,
J=8.2 Hz, 1H), 6.99 (dd, J=7.3, 5.0 Hz, 1H), 5.77 (d, J=6.8 Hz,
1H), 5.18-5.08 (m, 2H), 2.44 (dt, J=14.3, 2.6 Hz, 1H), 2.16 (ddd,
J=15.0, 11.4, 4.6 Hz, 1H), 1.72 (q, J=3.6 Hz, 2H), 1.12 (q, J=3.7
Hz, 2H); MS (ESI) m/z 495 (M+H).sup.+.
Example 33
rac-methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate
Example 33A
methyl 3-(3-(2-chloropyridin-3-yl)-3-oxopropanoyl)benzoate
[1699] A solution of methyl 3-acetylbenzoate (108 mg, 0.606 mmol)
in tetrahydrofuran (1 mL) was added to a -78.degree. C. solution of
1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.3 mL,
1.3 mmol) under N.sub.2. After stirring at -78 C for 15 minutes, a
solution of 2-chloronicotinoyl chloride (107 mg, 0.606 mmol) in
tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred
at room temperature for 15 minutes and quenched with 1 M HCl (about
2 mL). The mixture was allowed to warm to room temperature and then
extracted with ethyl acetate (about 30 mL). The ethyl acetate layer
was washed with brine, dried (MgSO.sub.4), filtered, and
concentrated. The crude product solidified on standing over night.
This residue was treated with 1:1 heptanes:ethyl acetate and the
mixture was diluted with heptanes. The solid was collected by
filtration, washed with 5:1 heptanes:ethyl acetate, and dried under
vacuum to provide the title compound (55.5 mg, 0.175 mmol, 28.8%
yield). MS (ESI) m/z 318 (M+H).sup.+.
Example 33B
methyl 3-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)benzoate
[1700] A mixture of the product from Example 33A (3.06 g, 9.63
mmol) and K.sub.2CO.sub.3 (1.331 g, 9.63 mmol) in
N,N-dimethylformamide (30 mL) was heated at 100.degree. C. for 30
minutes, cooled to near 0.degree. C., treated all at once with 1 M
HCl (15 mL) and then diluted with water (150 mL). The mixture was
stirred at room temperature for 15 minutes and the solid was
collected by filtration, washed with water, and dried under vacuum
with heating at 60.degree. C. for 2 hours to provide the title
compound (2.53 g, 9.00 mmol, 93% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.81 (dd, J=4.6, 2.0 Hz, 1H), 8.59 (t,
J=1.8 Hz, 1H), 8.51 (dd, J=7.7, 2.1 Hz, 1H), 8.37 (dd, J=8.3, 1.7
Hz, 1H), 8.17 (dt, J=7.8, 1.3 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.65
(dd, J=7.8, 4.7 Hz, 1H), 7.21 (s, 1H), 3.92 (s, 3H); MS (ESI) m/z
282 (M+H).sup.+.
Example 33C
methyl
3-(4-oxo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoate
[1701] A solution of the product from Example 33B (0.49 g, 1.742
mmol) in methanol (3 mL) and CH.sub.2Cl.sub.2 (6 mL) was treated
with cobalt(II) phthalocyanine (0.050 g, 0.087 mmol), treated with
NaBH.sub.4 (0.527 g, 13.94 mmol), stirred at room temperature for
10 minutes, and partitioned between ethyl acetate (30 mL) and 1 M
HCl (15 mL). The mixture was neutralized with saturated NaHCO.sub.3
solution. The layers were separated and the aqueous layer was
extracted with ethyl acetate (2.times.25 mL). The combined ethyl
acetate layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. This material was dissolved in
CH.sub.2Cl.sub.2 (about 10 mL), treated with pyridinium
chlorochromate (0.751 g, 3.48 mmol) and stirred for 20 minutes. The
residue was partitioned between saturated NaHCO.sub.3 solution and
CH.sub.2Cl.sub.2. This material was filtered through celite. The
layers were separated and the aqueous was extracted with
CH.sub.2Cl.sub.2 (2.times.). The combined CH.sub.2Cl.sub.2 layers
were dried (MgSO.sub.4), filtered, treated with silica gel (about 3
g), and concentrated to dryness. Chromatography of the residue on
silica gel and eluting with a gradient of 30%-100% ethyl acetate in
heptanes provided the title compound (115 mg, 0.406 mmol, 23.30%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.52 (dd,
J=4.9, 2.1 Hz, 1H), 8.29 (dd, J=7.6, 2.1 Hz, 1H), 8.20 (d, J=1.8
Hz, 1H), 8.07 (dt, J=7.8, 1.3 Hz, 1H), 7.73 (dt, J=7.8, 1.5 Hz,
1H), 7.52 (t, J=7.7 Hz, 1H), 7.14 (dd, J=7.6, 4.7 Hz, 1H), 5.69
(dd, J=12.9, 3.2 Hz, 1H), 3.94 (s, 3H), 3.13 (dd, J=16.9, 12.8 Hz,
1H), 3.00 (dd, J=16.9, 3.2 Hz, 1H); MS (ESI) m/z 284
(M+H).sup.+.
Example 33D
methyl
3-(4-(methoxyimino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoa-
te
[1702] A solution of the product from Example 33C (115 mg, 0.406
mmol) and O-methylhydroxylamine hydrochloride (102 mg, 1.218 mmol)
in pyridine (1 mL) was heated at 60.degree. C. for 2 hours. The
mixture was cooled, concentrated, and partitioned between
tert-butyl methyl ether and water. The tert-butyl methyl ether
layer was isolated and the water layer was extracted with
tert-butyl methyl ether. The combined tert-butyl methyl ether
layers were washed with brine, dried (MgSO.sub.4), filtered,
concentrated, and chromatographed on silica gel eluted with a
gradient of 25-100% ethyl acetate in heptanes to provide the title
compound (99 mg, 0.317 mmol, 78% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.31-8.26 (m, 2H), 8.17 (t, J=1.8 Hz, 1H),
8.03 (dt, J=7.8, 1.4 Hz, 1H), 7.73 (dt, J=7.8, 1.5 Hz, 1H), 7.49
(t, J=7.8 Hz, 1H), 7.01 (dd, J=7.4, 5.0 Hz, 1H), 5.30 (dd, J=12.1,
3.1 Hz, 1H), 4.01 (s, 3H), 3.93 (s, 3H), 3.53 (dd, J=17.2, 3.2 Hz,
1H), 2.71 (dd, J=17.2, 12.1 Hz, 1H); MS (ESI) m/z 313
(M+H).sup.+.
Example 33E
methyl
3-(4-amino-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoate
[1703] The product from Example 33D (99 mg, 0.317 mmol) and
methanol (10 mL) was added to Ra--Ni 2800, water slurry (0.5 g,
3.83 mmol) in a 50 mL pressure bottle and shaken in an atmosphere
of 30 psi H.sub.2 for 16 hours at room temperature. The mixture was
filtered, and the filtrate was concentrated to provide the title
compound.
Example 33F
rac-methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate
[1704] The title compound was isolated as the second eluting isomer
from the chromatography column while prepared and purified using
procedure similar to that described in Example 24I, substituting
the product from Example 33E for the product from Example 24H.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.15 (dd, J=5.2, 2.0
Hz, 1H), 8.09 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.4 Hz, 1H), 7.64
(dt, J=7.6, 1.5 Hz, 1H), 7.51-7.40 (m, 2H), 7.12 (dd, J=8.2, 1.7
Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.95 (dd,
J=7.5, 4.8 Hz, 1H), 5.54 (td, J=10.3, 6.2 Hz, 1H), 5.42-5.35 (m,
2H), 3.92 (s, 3H), 2.51 (ddd, J=13.4, 6.0, 2.0 Hz, 1H), 1.86 (dt,
J=13.4, 11.3 Hz, 1H), 1.80-1.62 (m, 2H), 1.17-1.04 (m, 2H); MS
(ESI) m/z 509 (M+H).sup.+.
Example 34
rac-methyl
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate
[1705] The title compound was isolated as the first eluting isomer
from the chromatography column while prepared and purified using
procedure similar to that described in Example 24I, substituting
the product from Example 33E for the product from Example 24H.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.19 (dd, J=4.8, 1.9
Hz, 1H), 8.05 (t, J=1.7 Hz, 1H), 8.01 (dt, J=7.9, 1.4 Hz, 1H), 7.61
(dt, J=7.9, 1.4 Hz, 1H), 7.54 (dd, J=7.5, 1.9 Hz, 1H), 7.46 (t,
J=7.7 Hz, 1H), 7.16 (dd, J=8.2, 1.7 Hz, 1H), 7.12 (d, J=1.6 Hz,
1H), 7.05 (d, J=8.2 Hz, 1H), 6.95 (dd, J=7.5, 4.8 Hz, 1H), 5.61 (d,
J=7.2 Hz, 1H), 5.13-5.03 (m, 2H), 3.93 (s, 3H), 2.32 (dt, J=14.5,
2.9 Hz, 1H), 2.19 (ddd, J=14.8, 10.9, 4.6 Hz, 1H), 1.70 (q, J=3.6
Hz, 2H), 1.11 (q, J=3.7 Hz, 2H); MS (ESI) m/z 509 (M+H).sup.+.
Example 35
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic
acid
Example 35A
methyl
3-((2R,4R)-4-amino-7-methoxychroman-2-yl)cyclohexanecarboxylate
[1706] The title compound was prepared using the conditions
described in Example 20C, substituting Example 5C for Example 20B.
The title compound was the by-product of over reduction of the
phenyl ring. Isolation of the title compound was achieved by
formation of its hydrochloride salt, prepared by the addition of
HCl (2.0 equivalents, 4M in dioxane) to a solution of the crude
amine (30 mg) in methyl tert-butyl ether (2 mL), which afforded the
hydrochloride salt of the title compound as colorless solid. The
solid was collected by filtration and dried to constant weight to
give the title compound (15 mg, 0.047 mmol, 53%).
Example 35B
methyl
34(2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropaneca-
rboxamido)-7-methoxychroman-2-yl)cyclohexanecarboxylate
[1707] The title compound was prepared using the procedures similar
to that described in Example 20D, substituting the product from
Example 35A for the product from Example 20C. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.18-7.11 (m, 2H), 7.02 (dd, J=8.2, 1.4 Hz,
1H), 6.87 (d, J=8.6 Hz, 1H), 6.43 (dd, J=8.6, 2.6 Hz, 1H), 6.31 (d,
J=2.4 Hz, 1H), 5.31 (d, J=8.8 Hz, 1H), 5.27-5.11 (m, 1H), 3.89 (dd,
J=11.4, 5.3 Hz, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 2.39-0.83 (m,
14H); MS (ESI-) m/z 542.2 (M-H).sup.-.
Example 35C
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic
acid
[1708] The title compound was prepared using the conditions similar
to that described in Example 1 substituting Example 35B for Example
6. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.20-7.07 (m, 2H),
7.02 (d, J=8.1 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.43 (dd, J=8.6,
2.5 Hz, 1H), 6.31 (t, J=1.9 Hz, 1H), 5.34 (d, J=8.7 Hz, 1H),
5.30-5.14 (m, 1H), 3.91 (td, J=11.5, 5.1 Hz, 1H), 3.73 (s, 3H),
2.41-1.03 (m, 16H); MS (ESI-) m/z 528.3 (M-H).sup.-.
Example 36
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic
acid
Example 36A
methyl
3-((2R,4R)-4-amino-7-fluorochroman-2-yl)cyclohexanecarboxylate
[1709] The title compound was isolated as the second eluting
compound from the purification of Example 39E (19 mg, 8.0% yield).
LC/MS m/z 532 (M+H).sup.+.
Example 36B
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic
acid
[1710] Example 36A (19 mg, 0.036 mmol) and 2 M NaOH aqueous
solution (0.5 mL) in methanol (2 mL) was stirred at 35 (.degree.
C.) for 2 hours. The solvent was removed and water (1 mL) was
added. The pH of the mixture was adjusted with 2 M HCl to
1.about.2. The precipitated white solid was collected by
filtration, washed with water, and dried to yield title compound
(14.5 mg, 83% yield). .sup.1H NMR (501 MHz, CDCl.sub.3) .delta.
7.16 (dt, J=8.2, 1.5 Hz, 1H), 7.12 (q, J=1.7 Hz, 1H), 7.03 (d,
J=8.0 Hz, 1H), 6.92 (t, J=7.5 Hz, 1H), 6.55 (td, J=8.3, 2.6 Hz,
1H), 6.46 (ddt, J=10.1, 4.8, 2.6 Hz, 1H), 5.37-5.30 (m, 1H),
5.29-5.19 (m, 1H), 3.92 (d, J=11.4 Hz, 1H), 2.35 (s, 1H), 2.23 (dd,
J=13.1, 6.2 Hz, 1H), 2.07-1.85 (m, 3H), 1.77-1.60 (m, 4H), 1.35
(dt, J=22.7, 14.4 Hz, 4H), 1.17-1.02 (m, 3H); MS (ESI+) m/z 517.9
(M+H).sup.+.
Example 37
methyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a-
mino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate
Example 37A
methyl 3-(3-(2,6-di chloropyridin-3-yl)-3-oxopropanoyl)benzoate
[1711] The title compound was prepared using the procedure similar
to that described in Example 24A, substituting
2,6-dichloronicotinoyl chloride for 3-chloroisonicotinoyl
chloride.
Example 37B
methyl 3-(7-chloro-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)benzoate
[1712] The title compound was prepared using the procedure similar
to that described in Example 33B, substituting the product from
Example 37A for the product from Example 33A.
Example 37C
methyl 3-(7-meth
oxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)benzoate
[1713] A solution of KOtBu (889 mg, 7.92 mmol) in methanol (25 mL)
was treated with the product from Example 37B (500 mg, 1.584 mmol)
and the resulting suspension was stirred for 10 minutes at
100.degree. C. The mixture was cooled in an ice bath and quenched
all at once with 1 M HCl (20 mL). The mixture was diluted with
water (80 mL) and the mixture was stirred for 5 minutes. The solid
was collected by filtration, washed with water, and dried under
vacuum at 60.degree. C. for 90 minutes to provide the title
compound (420 mg, 1.349 mmol, 85% yield).
Example 37D
methyl
3-(7-methoxy-4-oxo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzoat-
e
[1714] The title compound was prepared using the procedure similar
to that described in Example 33C, substituting the product from
Example 37C for the product from Example 33B. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.20 (t, J=1.8 Hz, 1H), 8.16 (d, J=8.5 Hz,
1H), 8.07 (dt, J=7.8, 1.5 Hz, 1H), 7.71 (dt, J=7.8, 1.6 Hz, 1H),
7.52 (t, J=7.8 Hz, 1H), 6.53 (d, J=8.5 Hz, 1H), 5.64 (dd, J=13.3,
3.1 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.09 (dd, J=17.0, 13.3 Hz,
1H), 2.87 (dd, J=16.9, 3.1 Hz, 1H); MS (ESI) m/z 314
(M+H).sup.+.
Example 37E
methyl
3-(7-methoxy-4-(methoxyimino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-
-yl)benzoate
[1715] The title compound was prepared using the procedure similar
to that described in Example 33D, substituting the product from
Example 37D for the product from Example 33C, provided the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.19-8.11
(m, 2H), 8.03 (dt, J=7.8, 1.4 Hz, 1H), 7.70 (dt, J=7.7, 1.4 Hz,
1H), 7.48 (t, J=7.7 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 5.26 (dd,
J=12.4, 3.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 3.47
(dd, J=17.2, 3.2 Hz, 1H), 2.69 (dd, J=17.1, 12.3 Hz, 1H); MS (ESI)
m/z 343 (M+H).sup.+.
Example 37F
methyl
3-(4-amino-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)benzo-
ate
[1716] The title compound was prepared using the procedure similar
to that described in Example 33E, substituting the product from
Example 37E for the product from Example 33D. MS (ESI) m/z 315
(M+H).sup.+.
Example 37G
methyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a-
mino)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoate
[1717] The title compound was prepared using the procedure similar
to that described in Example 24I, substituting the product from
Example 37F for the product from Example 24H. The crude product was
chromatographed on silica gel eluting with 30% ethyl acetate in
heptanes to provide the title compound as mixture of cis and trans
isomers. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10-8.05 (m,
1H), 8.04-7.97 (m, 1H), 7.64-7.58 (m, 1H), 7.50-7.38 (m, 1.5H),
7.37-7.32 (m, 0.5H), 7.17-6.97 (m, 3H), 6.43-6.38 (m, 1H), 5.50 (d,
J=6.8 Hz, 0.5H), 5.47-5.38 (m, 0.5H), 5.32 (d, J=10.7 Hz, 0.5H),
5.26 (d, J=8.8 Hz, 0.5H), 5.03-4.93 (m, 1H), 3.94 (s, 1.5H), 3.92
(s, 1.5H), 3.88 (s, 3H), 2.48 (dd, J=12.8, 5.4 Hz, 0.5H), 2.29 (d,
J=14.4 Hz, 0.5H), 2.19 (ddd, J=14.8, 11.6, 4.4 Hz, 0.5H), 1.93-1.79
(m, 0.5H), 1.77-1.57 (m, 2H), 1.13-1.05 (m, 2H).
Example 38
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1718] A mixture of Example 39E (90 mg, 0.171 mmol) and 2 M NaOH
aqueous solution (2 mL) in methanol (6 mL) was stirred at
35.degree. C. for 4 hours, solvent was removed and water (1 mL)
added. The mixture was adjusted with 2 M HCl to pH 1.about.2 and
the precipitated white solid was washed with water and dried to
provide the title compound (64 mg, 73.1% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.64
(d, J=7.9 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.18-7.07 (m, 2H), 7.02
(dt, J=8.5, 3.4 Hz, 2H), 6.71-6.52 (m, 2H), 5.61-5.44 (m, 1H), 5.40
(d, J=8.9 Hz, 1H), 5.35-5.22 (m, 1H), 2.58 (dd, J=13.2, 6.3 Hz,
1H), 1.79 (dd, J=12.6, 4.9 Hz, 2H), 1.71-1.61 (m, 1H), 1.10 (q,
J=2.2 Hz, 2H); MS (ESI+) m/z 511.9 (M+H).sup.+.
Example 39
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 39A
7-fluoro-4H-chromen-4-one
[1719] A mixture of 1-(4-fluoro-2-hydroxyphenyl)ethanone (1. g,
6.49 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.948 mL,
7.14 mmol) was heated at 120.degree. C. for 2 hours, and cooled
down. The precipitated orange solid was filtered, washed with
heptane, and dried to yield
(E)-3-(dimethylamino)-1-(4-fluoro-2-hydroxyphenyl)prop-2-en-1-one
which was dissolved in dichloromethane (120 mL) and treated with
concentrated HCl (15 mL). The mixture was refluxed for 2 hours.
Water layer was removed and organic layer was washed with brine (50
mL.times.2). The organics was concentrated and the residue was
purified by chromatography on 80 g silica gel cartridge, eluting
with 5-30% ethyl acetate in heptane to provide the title compound
(760 mg, 71.4% yield) as white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.23 (dd, J=9.6, 6.2 Hz, 1H), 7.83 (d, J=6.0
Hz, 1H), 7.19-7.08 (m, 2H), 6.33 (d, J=6.1 Hz, 1H); MS (ESI+) m/z
165 (M+H).sup.+.
Example 39B
(R)-methyl 3-(7-fluoro-4-oxochroman-2-yl)benzoate
[1720] A mixture of bis(2,2,2-trifluoroacetoxy)palladium (136 mg,
0.408 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole
(100 mg, 0.490 mmol), ammonium hexafluorophosphate(V) (399 mg,
2.449 mmol), (3-(methoxycarbonyl)phenyl)boronic acid (1102 mg, 6.12
mmol) and dichloroethane (10 mL) in a vial (20 mL) were stirred for
5 minutes, and then Example 39A (670 mg, 4.08 mmol) and water
(0.256 mL, 14.19 mmol) were added. The vial was capped and the
mixture stirred at 60.degree. C. overnight. The mixture was
filtered through a plug of celite and eluted with ethyl acetate.
The organic layers were removed in vacuo and the crude material was
chromatographed on a 80 g silica gel cartridge, eluting with ethyl
acetate in heptane at 5-40% gradient to provide the title compound
(767 mg, 62.6% yield). LC/MS m/z 300 (M+H).sup.+.
Example 39C
(R)-methyl 3-(7-fluoro-4-(methoxyimino)chroman-2-yl)benzoate
[1721] The mixture of Example 39B (760 mg, 2.53 mmol), sodium
acetate (415 mg, 5.06 mmol) and O-methylhydroxylamine, hydrochloric
acid (423 mg, 5.06 mmol) in methanol (10 mL) was stirred at
60.degree. C. overnight. Solvent was removed under pressure and the
residue dissolved in ethyl acetate and washed with water, the
organic layers dried over MgSO.sub.4, filtered, and concentrated
under pressure. The residue was purified by chromatography on a 80
g silica gel cartridge, eluting with ethyl acetate in heptane at
5-35% gradient to provide the title compound (752 mg, 90% yield) as
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (t,
J=1.8 Hz, 1H), 8.04 (dt, J=7.9, 1.5 Hz, 1H), 7.92 (dd, J=8.7, 6.5
Hz, 1H), 7.66 (dt, J=7.8, 1.5 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H),
6.77-6.62 (m, 2H), 5.13 (dd, J=12.4, 3.1 Hz, 1H), 3.98 (s, 3H),
3.94 (s, 3H), 3.49 (dd, J=17.2, 3.1 Hz, 1H), 2.66 (dd, J=17.2, 12.4
Hz, 1H); MS (ESI+) m/z 330 (M+H).sup.+.
Example 39D
methyl 3-((2R,4R)-4-amino-7-fluorochroman-2-yl)benzoate
[1722] To Example 39C (300 mg, 0.911 mmol) in acetic acid (10 mL)
was added 5% platinum on carbon (355 mg, 0.091 mmol). The mixture
was charged with a hydrogen balloon and stirred at ambient
temperature for 48 hours, LC/MS indicated 2/3 starting material
converted to product, but reduced benzoic acid ring was detected.
The mixture was purged with nitrogen, diluted with ethyl acetate
and filtered through a plug of celite. The filtrate was
concentrated under reduced pressure and the residue dissolved in
tert-butyl methyl ether, followed by drop wise addition of 4 M HCl
(1 mL). The precipitated white solid was collected by filtration
and dried to provide the title compound (153 mg, 49.6% yield),
which contained about 12% methyl
3-((2R,4R)-4-amino-7-fluorochroman-2-yl)cyclohexanecarboxylate.
Example 39E
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoate
[1723] A mixture of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(108 mg, 0.444 mmol) and HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol
o[4,5-b]pyridinium 3-oxid hexafluorophosphate) (220 mg, 0.577 mmol)
in DMF (3 mL) was stirred for 5 minutes, followed by addition of
Example 39D (150 mg, 0.48 mmol), followed by addition of
N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.78 mmol). The mixture
was stirred at ambient temperature for 2 hours; LC/MS indicated the
reaction was complete. Ethyl acetate (20 mL) and water (10 mL) were
added. The mixture was partitioned. The organic layer was washed
with saturated NaHCO.sub.3 aqueous solution and brine sequentially,
dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified by chromatography on a 40 g silica gel cartridge, eluting
with ethyl acetate in heptane at 0-30% gradient to provide the
title compound as the first eluting compound (140 mg, 60.0% yield)
and Example 36A as the second eluting compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.13-7.91 (m, 2H), 7.57 (dt, J=7.8, 1.5
Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.14-6.99 (m, 4H), 6.69-6.58 (m,
2H), 5.44 (td, J=10.1, 6.4 Hz, 1H), 5.33 (d, J=8.9 Hz, 1H), 5.23
(dd, J=11.5, 1.9 Hz, 1H), 3.93 (s, 3H), 3.48 (q, J=7.0 Hz, 1H),
2.50 (ddd, J=13.4, 6.0, 2.0 Hz, 1H), 1.77-1.60 (m, 2H), 1.10-1.06
(m, 2H); MS (ESI+) m/z 525.9 (M+H).sup.+; The .sup.1HNMR and
Analytical Chiral SFC (5-30% methanol:CO.sub.2, 10 minutes at 3
mL/minutes 150 bar, Column ChiralCel OJ-H) indicated the isolated
product was a cis-stereoeisomer with 94% ee purity.
Example 40
rac-N-[(2R,4R)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-
-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
Example 40A
3-cyclopropyl-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one
[1724] To a solution of 1 M NaOH (300 mL) was added
1-(2-hydroxy-4-methoxyphenyl)ethanone (5 g, 30.1 mmol), followed by
addition of cyclopropanecarbaldehyde (6.33 g, 90 mmol). The mixture
was stirred over 48 hours at ambient temperature. The mixture was
adjusted to pH 5 by 1 M HCl, extracted with ethyl acetate (100
mL.times.3), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography, eluted with a gradient of 15-50% petroleum
ether:ethyl acetate to provide the title compound (1.5 g, 22.84%)
as white oil. MS (ESI+) m/z 219 (M+H).sup.+.
Example 40B
2-cyclopropyl-7-methoxychroman-4-one
[1725] To a solution of Example 40A (2 g, 9.16 mmol) in 200 mL of
ethanol and 10 mL of water was added concentrated HCl (21 mL). The
reaction was refluxed for 16 hours. Ethanol was removed under
reduced pressure and 50 mL of water was added. The mixture was
extracted with ethyl acetate (50 mL.times.2). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography, eluted with a gradient of 10-15% petroleum
ether:ethyl acetate to provide the title compound (1.4 g, 70.0%) as
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.80 (s,
J=8.8 Hz, 1H), 6.56 (dd, J=9.2 Hz, 2.4 Hz, 1H), 6.45 (d, J=2.4 Hz,
1H), 3.83 (s, 3H), 3.69-3.75 (m, 1H), 2.70-2.83 (m, 2H), 1.20-1.26
(m, 1H), 0.71-0.74 (m, 2H), 0.66-0.69 (m, 1H), 0.62-0.64 (m, 1H);
MS (ESI+) m/z 219 (M+H).sup.+.
Example 40C
2-cyclopropyl-7-methoxychroman-4-one oxime
[1726] To a solution of Example 40B (940 mg, 4.31 mmol) in methanol
(20 mL) was added sodium acetate (424 mg, 5.17 mmol) and
hydroxylamine hydrochloride (359 mg, 5.17 mmol). The mixture was
stirred at 40.degree. C. for 16 hours. The solvent was removed
under reduced pressure. The resulting white solid was collected by
filtration, washed with water (30 mL), and dried under reduced
pressure to provide the title compound (980 mg, 86%) as white
solid. MS (ESI+) m/z 234 (M+H).sup.+.
Example 40D
2-cyclopropyl-7-methoxychroman-4-amine
[1727] A solution of Example 40C (500 mg, 2.144 mmol) in
ammonia-methanol solution (50 mL) was treated with nickel (126 mg,
2.144 mmol). The mixture was stirred at room temperature under
hydrogen for 5 hours. The mixture was filtered and concentrated to
dryness. To the residue was added 1 M hydrogen chloride in ether
and then the organics were concentrated to afford the hydrochloride
acid salt of the title compound (480 mg, 1.761 mmol, 82% yield).
.sup.1HNMR (400 MHz, CD.sub.3OD) .delta.: 7.25-7.29 (m, 1H),
6.43-6.46 (m, 1H), 4.48-4.63 (m, 1H), 3.76 (d, J=2.4 Hz, 3H),
3.42-3.53 (m, 1H), 1.88-2.56 (m, 2H), 1.10-1.16 (m, 1H), 0.38-0.71
(m, 4H); MS (ESI+) m/z 203 (M-NH.sub.2).sup.+.
Example 40E
rac-N-[(2R,4R)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-
-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1728] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(142 mg, 0.587 mmol) in dichloromethane (1.5 mL) was added half of
a solution of oxalyl dichloride (0.205 mL, 2.346 mmol) in
dichloromethane (1 mL), followed by 1 drop of DMF. The reaction
bubbled vigorously, then the remainder of the oxalyl chloride
solution was added dropwise. The reaction was stirred for 30
minutes at room temperature, then the solvent removed under a
stream of nitrogen, then chased with 2.times.1 mL of
dichloromethane, drying under a stream of nitrogen. The
intermediate was taken up in dichloromethane (1.5 mL) and added to
a mixture of the product from Example 40D (150 mg, 0.587 mmol) and
triethylamine (0.327 mL, 2.346 mmol) in dichloromethane (1.5 mL).
The mixture was stirred at room temperature for 20 minutes. The
mixture was quenched with saturated aqueous bicarbonate, and the
aqueous layer removed. The organic phase was concentrated and the
resulting oil dissolved in dichloromethane and purified on a 24 g
silica gel cartridge, eluting with a gradient of 5-60% ethyl
acetate/heptanes in 20 minutes to provide 110 mg of a mixture of
diastereomers. The mixture was further purified via preparative
supercritical fluid chromatography set to maintain a backpressure
at 100 bar using a Lux Cellulose.RTM. (21.times.250 mm, 5 micron),
with the sample at a concentration of 25 mg/mL in methanol using
16% methanol in CO.sub.2 at a flow rate of 70 mL/minute to provide
the title compound (retention time=4.4 minutes, 24 mg, 0.054 mmol,
9.23% yield) and Example 41 (retention time=3.7 minutes). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.38-7.32 (m, 2H), 7.29 (d,
J=8.4 Hz, 1H), 7.16 (dd, J=8.4, 1.7 Hz, 1H), 6.96 (d, J=8.5 Hz,
1H), 6.43 (dd, J=8.5, 2.5 Hz, 1H), 6.33 (d, J=2.5 Hz, 1H), 4.93
(dt, J=8.3, 4.4 Hz, 1H), 3.67 (s, 3H), 3.37 (td, J=9.2, 2.6 Hz,
1H), 1.89 (dt, J=14.0, 3.3 Hz, 1H), 1.81 (ddd, J=14.0, 9.6, 5.0 Hz,
1H), 1.41-1.31 (m, 2H), 1.08-0.97 (m, 3H), 0.60-0.46 (m, 2H),
0.36-0.28 (m, 1H), 0.14 (dt, J=9.5, 4.6 Hz, 1H); MS (ESI+) m/z 444
(M+H).sup.+.
Example 41
rac-N-[(2R,4S)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-
-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1729] The title compound (retention time=3.7 minutes, 21 mg, 0.047
mmol, 8.07% yield) was isolated from the preparative supercritical
fluid chromatography as described in Example 40E. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.38-7.32 (m, 2H), 7.29 (d, J=8.4 Hz,
1H), 7.16 (dd, J=8.4, 1.7 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.43
(dd, J=8.5, 2.5 Hz, 1H), 6.33 (d, J=2.5 Hz, 1H), 4.93 (dt, J=8.3,
4.4 Hz, 1H), 3.67 (s, 3H), 3.37 (td, J=9.2, 2.6 Hz, 1H), 1.89 (dt,
J=14.0, 3.3 Hz, 1H), 1.81 (ddd, J=14.0, 9.6, 5.0 Hz, 1H), 1.41-1.31
(m, 2H), 1.08-0.97 (m, 3H), 0.60-0.46 (m, 2H), 0.36-0.28 (m, 1H),
0.14 (dt, J=9.5, 4.6 Hz, 1H); MS (ESI+) m/z 444 (M+H).sup.+.
Example 42
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4--
dihydro-2H-chromene-7-carboxylic acid
[1730] To a suspension of the product from Example 45 (25 mg, 0.058
mmol) in tetrahydrofuran (193 .mu.L) and water (97 .mu.L) was added
lithium hydroxide (2.8 mg, 0.117 mmol). The reaction mixture was
stirred at room temperature overnight. The solvent was removed
under a stream of nitrogen and the reaction was quenched with 10
drops of 1N HCl. This crude material was chromatographed directly
on a 4 g silica gel cartridge, eluting with a gradient of 5-100%
ethyl acetate/heptane to provide the title compound (10 mg, 0.024
mmol, 41.3% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.45-7.37 (m, 3H), 7.31 (d, J=8.3 Hz, 1H),
7.23-7.18 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 5.11 (q, J=7.9 Hz, 1H),
4.24-4.10 (m, 2H), 2.02-1.85 (m, 2H), 1.48 (ddd, J=9.8, 6.0, 2.9
Hz, 1H), 1.37 (ddd, J=8.6, 5.9, 2.9 Hz, 1H), 1.05 (dtdd, J=12.6,
9.3, 6.2, 3.3 Hz, 2H). MS (ESI+) m/z 418 (M+H).sup.+.
Example 43
3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyc-
lopentanecarboxylic acid
Example 43A
ethyl
3-(3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropan-
ecarboxamido)-7-methylchroman-2-yl)benzamido)-1-methylcyclopentanecarboxyl-
ate
[1731] In a 4 mL vial, 300 .mu.L of a stock solution containing the
product from Example 16 (0.13 M, 0.039 mmol, 1.0 eq) and
diispropylethylamine (0.39 M, 0.12 mmol, 3.0 equivalents) in
dimethyl acetamide was added to a stock solution containing
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.15 M in dimethyl acetamide, 300 .mu.L,
0.046 mmol, 1.2 equivalents). A stock solution of ethyl
3-amino-1-methylcyclopentanecarboxylate (0.40 M in dimethyl
acetamide, 145 .mu.L, 0.058 mmol, 1.5 equivalents) was added and
the reaction was stirred at room temperature until complete as
determined by LC. The vial was loaded directly into a Gilson GX-271
autosampler and purified using preparative LC method TFA8 to
provide the title compound.
Example 43B
3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyc-
lopentanecarboxylic acid
[1732] Example 43A was dissolved in methanol (1 mL). A stock
solution of potassium hydroxide (4.0 M in water, 100 .mu.L) was
added and the reaction was heated at 50.degree. C. for 30 minutes,
after which the reaction was deemed complete by LC. Solvent was
removed under a stream of nitrogen and the residue was
reconstituted in acetonitrile (600 .mu.L) and 4 M HCl in dioxane
(400 .mu.L). The vial was loaded directly into a Gilson GX-271
autosampler and purified using preparative LC method TFA6 to
provide the title compound (15.7 mg, 66% yield). .sup.1H NMR (400
MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
7.88-7.79 (m, 1H), 7.76 (dt, J=7.7, 1.5 Hz, 1H), 7.55 (dt, J=7.6,
1.4 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H),
7.27-7.15 (m, 2H), 6.95-6.86 (m, 2H), 6.71 (dd, J=7.7, 1.7 Hz, 1H),
6.65-6.61 (m, 2H), 5.38-5.18 (m, 2H), 4.33 (p, J=7.7 Hz, 1H),
2.50-2.44 (m, 1H), 2.26-2.12 (m, 4H), 2.11-1.97 (m, 3H), 1.76-1.61
(m, 2H), 1.55-1.45 (m, 2H), 1.42-1.36 (m, 1H), 1.30 (s, 3H),
1.12-1.00 (m, 2H); MS (APCI+) m/z 633.5 (M+H).sup.+.
Example 44
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}ami-
no)-2-(3-methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylic
acid
[1733] The title compound was prepared using the conditions similar
to that described in Example 1, substituting Example 47E for
Example 6. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00-7.84 (m,
2H), 7.29 (t, J=7.9 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.14 (s, 1H),
7.03 (d, J=8.2 Hz, 1H), 6.98-6.81 (m, 4H), 5.50 (q, J=8.9 Hz, 1H),
5.40 (d, J=8.9 Hz, 1H), 5.26 (d, J=11.1 Hz, 1H), 3.81 (s, 3H),
2.61-2.46 (m, 1H), 1.92-1.74 (m, 2H), 1.63 (d, J=6.3 Hz, 1H),
1.16-1.07 (m, 2H), MS (ESI+) m/z 524 (M+H).sup.+.
Example 45
methyl
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amin-
o)-3,4-dihydro-2H-chromene-7-carboxylate
[1734] A 50 mL pressure bottle was charged with the product from
Example 56 (40 mg, 0.088 mmol), Pd-dppf (Heraeus) (1.294 mg, 1.769
.mu.mol), DMF (2 mL), methanol (2 mL), and triethylamine (0.025 mL,
0.177 mmol). The reaction was degassed with argon several times
followed by carbon monoxide. The mixture was heated at 100.degree.
C. for 16 hours at 70 psi carbon monoxide. To the reaction mixture
were added DMF (2 mL) and fresh catalyst, degassed with argon and
carbon monoxide was repeated, and the mixture was heated for 16
hours at 100.degree. C. at 70 psi carbon monoxide. Solvent was
removed under reduced pressure to give brown oil. The residue was
quenched with water to get a brown solid. The aqueous layer was
removed and the resulting solid dissolved in dichloromethane and
chromatographed on a 12 g silica gel cartridge, eluting with a
gradient of 5-100% ethyl acetate/heptanes over 20 minutes to
provide the title compound (32 mg, 0.074 mmol, 84% yield) as white
solid. .sup.1H NMR (501 MHz, DMSO-d.sub.6) .delta. 7.47-7.38 (m,
3H), 7.31 (d, J=8.3 Hz, 1H), 7.25-7.19 (m, 2H), 7.16 (dd, J=8.0,
1.0 Hz, 1H), 5.12 (td, J=8.6, 6.0 Hz, 1H), 4.22 (ddd, J=11.2, 5.1,
3.7 Hz, 1H), 4.16 (ddd, J=11.5, 9.5, 2.9 Hz, 1H), 3.80 (s, 3H),
2.03-1.86 (m, 2H), 1.48 (ddd, J=9.9, 6.1, 3.1 Hz, 1H), 1.37 (ddd,
J=9.2, 6.2, 3.2 Hz, 1H), 1.05 (dtdd, J=12.8, 9.4, 6.4, 3.4 Hz, 2H);
MS (ESI+) m/z 432 (M+H).sup.+.
Example 46
methyl
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-2-(3-methoxycyclohexyl)-3,4-dihydro-2H-chromene-6-carboxylate
Example 46A
(2R,4R)-methyl
4-amino-2-(3-methoxycyclohexyl)chroman-6-carboxylate
[1735] The title compound was obtained from Example 47D as a
by-product from the reduction.
Example 46B
methyl
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-2-(3-methoxycyclohexyl)-3,4-dihydro-2H-chromene-6-carboxylate
[1736] The title compound was obtained according to the preparation
of Example 47E, substituting Example 46A for Example 47D (17 mg,
0.031 mmol, 21.78% yield). .sup.1H NMR (501 MHz, CDCl.sub.3)
.delta. 7.79 (dd, J=8.4, 2.2 Hz, 1H), 7.73 (dd, J=2.1, 1.1 Hz, 1H),
7.22 (dt, J=8.3, 1.3 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.04 (d,
J=8.2 Hz, 1H), 6.78 (dd, J=8.6, 1.7 Hz, 1H), 5.35 (d, J=8.9 Hz,
1H), 5.28 (td, J=10.2, 9.0, 5.9 Hz, 1H), 4.03 (dddd, J=15.8, 11.7,
5.2, 1.6 Hz, 1H), 3.90 (s, 3H), 3.36 (d, J=3.6 Hz, 3H), 3.15 (tq,
J=11.0, 4.4 Hz, 1H), 2.30-2.26 (m, 1H), 2.11-2.05 (m, 1H), 1.83
(dddd, J=30.6, 10.1, 6.9, 3.5 Hz, 3H), 1.72-1.61 (m, 3H), 1.30-1.23
(m, 2H), 1.16-1.02 (m, 5H); MS (ESI+) m/z 544 (M+H).sup.+.
Example 47
methyl
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-2-(3-methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylate
Example 47A
(R)-6-bromo-2-(3-methoxyphenyl)chroman-4-one
[1737] A 20 mL vial was charged with
bis(2,2,2-trifluoroacetoxy)palladium (0.295 g, 0.889 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.218 g,
1.066 mmol), ammonium hexafluorophosphate(V) (0.869 g, 5.33 mmol)
and (3-methoxyphenyl)boronic acid (2.70 g, 17.77 mmol) were stirred
in dichloroethane (5 mL) for 5 minutes, and a pale yellow color was
observed. To this suspension was added 6-bromo-4H-chromen-4-one
(CAS 51483-92-2) (2.0 g, 8.89 mmol) and water (0.256 mL, 14.19
mmol) and the sides of the vial washed with more dichloroethane (5
mL). The vial was capped and the mixture stirred at 60.degree. C.
for 16 hours. The mixture was filtered through a plug of silica gel
and celite and eluted with ethyl acetate to give a light yellow
color solution. The solvent was removed under reduced pressure and
the crude material was chromatographed on a 40 g silica gel
cartridge, eluting with a gradient of 5-50% ethyl acetate/heptanes
to provide the title compound (2.10 g, 6.30 mmol, 70.9% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04 (d, J=2.6 Hz, 1H),
7.58 (dd, J=8.9, 2.6 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.08-6.87 (m,
4H), 5.45 (dd, J=13.1, 3.1 Hz, 1H), 3.84 (s, 3H), 3.07 (dd, J=17.0,
13.1 Hz, 1H), 2.91 (dd, J=17.0, 3.1 Hz, 1H).
Example 47B
(R)-methyl 2-(3-methoxyphenyl)-4-oxochroman-6-carboxylate
[1738] A 250 mL stainless steel pressure bottle was charged with
Example 47A (2.0 g, 6.00 mmol), Pd-dppf (Heraeus) (0.088 g, 0.120
mmol), methanol (20 mL) and triethylamine (1.673 mL, 12.01 mmol).
The reactor was degassed with argon several times followed by
carbon monoxide and the reaction heated to 100.degree. C. for 16
hours at 60 psi carbon monoxide. To the reaction mixture were added
DMF (2 mL) and fresh catalyst, degassed with argon and carbon
monoxide was repeated, and the mixture was heated for 16 hours at
100.degree. C. at 60 psi carbon monoxide. The reaction was filtered
and the solvent removed under reduced pressure. The crude product
was purified on a 40 g silica gel cartridge, eluting with 5-30%
heptane in ethyl acetate over 40 minutes to provide the title
compound (450 mg, 1.441 mmol, 24.00% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.63 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.7, 2.3
Hz, 1H), 7.36 (dd, J=8.7, 7.2 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H),
7.08-7.00 (m, 2H), 6.97-6.89 (m, 1H), 5.52 (dd, J=13.1, 3.0 Hz,
1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.11 (dd, J=16.9, 13.0 Hz, 1H),
2.95 (dd, J=17.0, 3.1 Hz, 1H); MS (ESI+) m/z 313 (M+H).sup.+.
Example 47C
(R)-methyl
4-(methoxyimino)-2-(3-methoxyphenyl)chroman-6-carboxylate
[1739] A mixture of Example 47B (450 mg, 1.441 mmol), sodium
acetate (236 mg, 2.88 mmol) and O-methylhydroxylamine hydrochloric
acid salt (120 mg, 1.441 mmol) in methanol (10 mL) was stirred at
60.degree. C. for 16 hours. The solvent was evaporated under
reduced pressure and the residue dissolved in ethyl acetate, and
washed with water. The organics were dried over magnesium sulfate,
filtered, and concentrated. The crude material was purified by
preparative LC method AA2 to provide the title compound (204 mg,
0.598 mmol, 41.5% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.63 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.6, 2.2 Hz, 1H), 7.33 (t,
J=7.9 Hz, 1H), 7.06-6.97 (m, 3H), 6.94-6.85 (m, 1H), 5.09 (dd,
J=12.3, 3.1 Hz, 1H), 4.01 (s, 3H), 3.91 (s, 3H), 3.83 (s, 3H),
3.54-3.46 (m, 1H), 2.70 (dd, J=17.2, 12.3 Hz, 1H); MS (ESI+) m/z
342 (M+H).sup.+.
Example 47D
(2R,4R)-methyl 4-amino-2-(3-methoxyphenyl)chroman-6-carboxylate
[1740] To the mixture of Example 47C (204 mg, 0.598 mmol) in acetic
acid (3 mL) was added platinum (IV) oxide (13.57 mg, 0.060 mmol).
The mixture was purged with hydrogen and stirred at ambient
temperature for 18 hours. The solvent was evaporated under reduced
pressure and the residue dissolved in ethyl acetate, and then
washed with water. The organics were dried over magnesium sulfate,
filtered, and concentrated. The crude material was purified by
preparative LC method AA2 to provide the title compound (105 mg,
0.335 mmol, 56.1% yield) as white solid, LC/MS m/z 297
(M-NH.sub.2).sup.+; and Example 46A (42 mg, 0.131 mmol, 22.00%
yield). LC/MS m/z 303 (M-NH.sub.2).sup.+.
Example 47E
methyl
(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-2-(3-methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylate
[1741] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(34.8 mg, 0.144 mmol) in DMF (3 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (82 mg, 0.215 mmol). The mixture was
stirred for 5 minutes, and then Example 47D (45 mg, 0.144 mmol) was
added, followed by addition of N-ethyl-N-isopropylpropan-2-amine
(0.100 mL, 0.574 mmol). The mixture was stirred at ambient
temperature for 2 hours. The reaction was purified on a 12 g silica
gel cartridge and eluted with a gradient of 5-100% ethyl
acetate/heptanes over 20 minutes to prodide the title compound (45
mg, 0.084 mmol, 58.3% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.91-7.75 (m, 2H), 7.29 (d, J=7.8 Hz, 1H), 7.18 (dd, J=8.1,
1.7 Hz, 1H), 7.13 (d, J=1.7 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H),
6.97-6.83 (m, 4H), 5.46 (td, J=10.1, 6.0 Hz, 1H), 5.36 (d, J=8.9
Hz, 1H), 5.23 (dd, J=11.5, 2.0 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H),
2.52 (ddd, J=13.3, 5.9, 2.1 Hz, 1H), 1.89-1.75 (m, 2H), 1.67-1.59
(m, 1H), 1.10 (dtd, J=9.5, 6.5, 3.2 Hz, 2H); MS (ESI+) m/z 537.9
(M+H).sup.+.
Example 48
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]b-
enzamide
Example 48A
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxam-
ido)-7-methylchroman-2-yl)-N--(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-
benzamide
[1742] In a 4 mL vial, 300 .mu.L of a stock solution containing the
product from Example 16 (0.13 M, 0.039 mmol, 1.0 equivalent) and
diispropylethylamine (0.39 M, 0.12 mmol, 3.0 equivalents) in
dimethyl acetamide was added to a stock solution containing
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.15 M in dimethyl acetamide, 300 .mu.L,
0.046 mmol, 1.2 equivalents). A stock solution of
(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.40 M in dimethyl
acetamide, 145 .mu.L, 0.058 mmol, 1.5 equivalents) was added and
the reaction was stirred at room temperature until complete as
determined by LC. The material was loaded directly into a Gilson
GX-271 autosampler and purified using preparative LC method TFA8 to
provide the title compound.
Example 48B
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]b-
enzamide
[1743] Example 48A was dissolved in acetonitrile (3 mL).
Trifluoroacetic acid (100 .mu.L) was added and the reaction
immediately deemed complete by LC. The material was loaded directly
into a Gilson GX-271 autosampler and purified using preparative LC
method TFA8 to yield the title compound (25.3 mg, 94% yield).
.sup.1H NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.87 (t, J=1.7 Hz, 1H), 7.78 (dt, J=7.7, 1.5 Hz,
1H), 7.61-7.52 (m, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.31 (d, J=1.6 Hz,
1H), 7.27-7.15 (m, 2H), 6.92 (d, J=7.7 Hz, 1H), 6.71 (dd, J=7.7,
1.7 Hz, 1H), 6.68-6.60 (m, 1H), 5.37-5.19 (m, 2H), 3.77-3.63 (m,
1H), 3.51-3.37 (m, 3H), 3.33-3.28 (m, 1H), 2.25-2.16 (m, 4H),
2.13-2.03 (m, 1H), 1.53-1.46 (m, 1H), 1.43-1.36 (m, 1H), 1.15-0.97
(m, 2H); MS (APCI+) m/z 581.5 (M+H).sup.+.
Example 49
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[(3R)-3-hydroxypyrr-
olidin-1-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclopro-
panecarboxamide
[1744] In a 4 mL vial, 300 .mu.L of a stock solution containing the
product from Example 16 (0.13 M, 0.039 mmol, 1.0 equivalent) and
diispropylethylamine (0.39 M, 0.12 mmol, 3.0 equivalents) in
dimethyl acetamide was added to a stock solution containing
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate (V) (0.15 M in dimethyl acetamide, 300 .mu.L,
0.046 mmol, 1.2 equivalents). A stock solution of
(R)-pyrrolidin-3-ol (0.40 M in dimethyl acetamide, 145 .mu.L, 0.058
mmol, 1.5 equivalents) was added and the reaction was stirred at
room temperature until complete as determined by LC. The material
was loaded directly into a Gilson GX-271 autosampler and purified
using preparative LC AA8 to yield the title compound (21.7 mg, 97%
yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.56-7.40 (m, 4H), 7.31
(d, J=1.6 Hz, 1H), 7.27-7.15 (m, 2H), 6.91 (d, J=8.0 Hz, 1H), 6.71
(dd, J=7.7, 1.7 Hz, 1H), 6.63 (d, J=1.6 Hz, 1H), 5.36-5.19 (m, 2H),
4.30 (s, 1H), 3.67-3.37 (m, 2H), 2.24-2.14 (m, 4H), 2.12-2.03 (m,
1H), 1.96 (dp, J=13.0, 5.3, 4.7 Hz, 1H), 1.83 (tt, J=9.2, 3.9 Hz,
1H), 1.54-1.46 (m, 1H), 1.43-1.36 (m, 1H), 1.11-0.98 (m, 2H); MS
(APCI+) m/z 577.4 (M+H).sup.+.
Example 50
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-(3,3,3-trifluoro-2-hydroxyp-
ropyl)benzamide
[1745] Example 50 was prepared according to the procedure for the
preparation of Example 49, substituting
3-amino-1,1,1-trifluoropropan-2-ol for (R)-pyrrolidin-3-ol (23.1
mg, 97% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.90 (t, J=1.8 Hz, 1H),
7.88-7.76 (m, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H),
7.34 (d, J=1.6 Hz, 1H), 7.30-7.18 (m, 2H), 6.94 (d, J=7.7 Hz, 1H),
6.79-6.71 (m, 1H), 6.66 (s, 1H), 5.39-5.22 (m, 2H), 4.25 (pd,
J=7.5, 4.6 Hz, 1H), 3.67 (dd, J=13.9, 4.7 Hz, 1H), 3.44 (dd,
J=14.0, 7.6 Hz, 1H), 2.25 (s, 4H), 2.15-2.05 (m, 1H), 1.57-1.49 (m,
1H), 1.45-1.37 (m, 1H), 1.17-1.00 (m, 2H); MS (APCI+) m/z 619.4
(M+H).sup.+.
Example 51
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-(2-hydroxy-2-methylpropyl)b-
enzamide
[1746] Example 51 was prepared according to the procedure for the
preparation of Example 49, substituting 1-amino-2-methylpropan-2-ol
for (R)-pyrrolidin-3-ol (19.1 mg, 86% yield). .sup.1H NMR (400 MHz,
90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.90 (t,
J=1.8 Hz, 1H), 7.81 (dt, J=7.6, 1.6 Hz, 1H), 7.62-7.56 (m, 1H),
7.50 (t, J=7.7 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.29-7.20 (m, 2H),
6.94 (d, J=7.8 Hz, 1H), 6.74 (dd, J=7.6, 1.7 Hz, 1H), 6.66 (d,
J=1.7 Hz, 1H), 5.39-5.22 (m, 2H), 3.32 (s, 2H), 2.29-2.19 (m, 4H),
2.16-2.05 (m, 1H), 1.56-1.49 (m, 1H), 1.46-1.38 (m, 1H), 1.17 (s,
6H), 1.12-1.01 (m, 2H); MS (APCI+) m/z 579.5 (M+H).sup.+.
Example 52
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[3-(hydroxymethyl)p-
iperidin-1-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclop-
ropanecarboxamide
[1747] Example 52 was prepared according to the procedure for the
preparation of Example 49, substituting piperidin-3-ylmethanol for
(R)-pyrrolidin-3-ol (23.0 mg, 99% yield). .sup.1H NMR (400 MHz,
90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.55-7.39
(m, 3H), 7.38-7.17 (m, 4H), 6.94 (d, J=7.9 Hz, 1H), 6.78-6.70 (m,
1H), 6.70-6.61 (m, 1H), 5.38-5.20 (m, 2H), 4.22-3.71 (m, 2H),
3.40-3.32 (m, 1H), 3.03-2.91 (m, 1H), 2.78 (dd, J=13.0, 10.1 Hz,
1H), 2.28-2.15 (m, 4H), 2.15-2.01 (m, 2H), 1.84-1.74 (m, 1H),
1.74-1.59 (m, 2H), 1.56-1.48 (m, 1H), 1.48-1.36 (m, 2H), 1.36-1.22
(m, 1H), 1.17-1.00 (m, 2H); MS (APCI+) m/z 605.5 (M+H).sup.+.
Example 53
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[2-(hydroxymethyl)m-
orpholin-4-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-yl]cyclop-
ropanecarboxamide
[1748] Example 53 was prepared according to the procedure for the
preparation of Example 49, substituting morpholin-2-ylmethanol for
(R)-pyrrolidin-3-ol (16.5 mg, 70% yield). .sup.1H NMR (400 MHz,
90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.55-7.44
(m, 4H), 7.38 (dt, J=7.1, 1.8 Hz, 1H), 7.34 (d, J=1.6 Hz, 1H),
7.29-7.20 (m, 2H), 6.94 (d, J=7.7 Hz, 1H), 6.76-6.70 (m, 1H), 6.66
(s, 1H), 5.36-5.23 (m, 2H), 4.11-3.92 (m, 1H), 3.92-3.75 (m, 2H),
3.58-3.35 (m, 4H), 3.19-3.05 (m, 1H), 2.94-2.84 (m, 1H), 2.27-2.16
(m, 4H), 2.13-2.05 (m, 1H), 1.56-1.49 (m, 1H), 1.46-1.39 (m, 1H),
1.15-1.02 (m, 2H); MS (APCI+) m/z 607.5 (M+H).sup.+.
Example 54
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(1-hydroxycyclobutyl)methy-
l]benzamide
[1749] Example 54 was prepared according to the procedure for the
preparation of Example 49, substituting 1-(aminomethyl)cyclobutanol
for (R)-pyrrolidin-3-ol (21.7 mg, 95% yield). .sup.1H NMR (400 MHz,
90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.90 (t,
J=1.7 Hz, 1H), 7.81 (dt, J=7.7, 1.5 Hz, 1H), 7.59 (dt, J=7.8, 1.5
Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.29-7.17
(m, 2H), 6.94 (d, J=7.9 Hz, 1H), 6.74 (dd, J=7.9, 1.8 Hz, 1H), 6.66
(d, J=1.6 Hz, 1H), 5.39-5.22 (m, 2H), 3.48 (s, 2H), 2.29-2.18 (m,
4H), 2.16-2.05 (m, 3H), 2.01-1.92 (m, 2H), 1.78-1.65 (m, 1H),
1.62-1.46 (m, 2H), 1.46-1.37 (m, 1H), 1.14-1.02 (m, 2H); MS (APCI+)
m/z 591.5 (M+H).sup.+.
Example 55
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3-{[3-(hydroxymethyl)--
3-methylazetidin-1-yl]carbonyl}phenyl)-7-methyl-3,4-dihydro-2H-chromen-4-y-
l]cyclopropanecarboxamide
[1750] Example 54 was prepared according to the procedure for the
preparation of Example 49, substituting
(3-methylazetidin-3-yl)methanol for (R)-pyrrolidin-3-ol, and
purified by preparative LC method AA7 (22.6 mg, 99% yield). .sup.1H
NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. 7.70-7.65 (m, 1H), 7.57 (ddt, J=11.8, 7.9, 1.6 Hz, 2H),
7.48 (t, J=7.6 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.28-7.19 (m, 2H),
6.94 (d, J=7.9 Hz, 1H), 6.73 (dd, J=7.9, 1.7 Hz, 1H), 6.68-6.64 (m,
1H), 5.36-5.24 (m, 2H), 4.08-3.93 (m, 2H), 3.85-3.66 (m, 2H), 3.43
(s, 2H), 2.29-2.16 (m, 4H), 2.16-2.05 (m, 1H), 1.56-1.48 (m, 1H),
1.46-1.38 (m, 1H), 1.24 (s, 3H), 1.16-1.00 (m, 2H); MS (APCI+) m/z
591.5 (M+H).sup.+.
Example 56
N-(7-bromo-3,4-dihydro-2H-chromen-4-yl)-1-(2,2-difluoro-1,3-benzodioxol-5--
yl)cyclopropanecarboxamide
Example 56A
7-bromochroman-4-one oxime
[1751] 7-bromochroman-4-one (CAS 18442-22-3, 0.523 g, 2.303 mmol)
was treated with hydroxylamine hydrochloride (0.192 g, 2.76 mmol)
and sodium acetate (0.227 g, 2.76 mmol) in ethanol (5 mL). The
reaction was stirred at 30.degree. C. for 16 hours, then at
100.degree. C. for 100 hours. The solvent was removed under a
stream of nitrogen and the crude material was triturated with
water, filtered, washed with water, and dried to provide the title
compound (0.429 g, 1.772 mmol, 77% yield) as a white solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.36 (s, 1H), 7.70 (d, J=8.1
Hz, 1H), 7.17-7.09 (m, 2H), 4.20 (t, J=6.2 Hz, 2H), 2.83 (t, J=6.2
Hz, 2H).
Example 56B
7-bromochroman-4-amine
[1752] A solution of the product from Example 56A (360 mg, 1.487
mmol) in tetrahydrofuran (20 mL) was added to Ra--Ni 2800, water
slurry (194 mg, 1.487 mmol) in a 50 mL pressure bottle. The mixture
was shaken for 32 hours at 30 psi hydrogen and at room temperature.
The reaction was filtered and the solvent removed to provide the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.33
(d, J=8.2 Hz, 1H), 7.03 (dd, J=8.3, 2.1 Hz, 1H), 6.93 (d, J=2.2 Hz,
1H), 4.25 (ddd, J=11.2, 8.3, 2.9 Hz, 1H), 4.16 (ddd, J=10.8, 6.8,
3.4 Hz, 1H), 3.89 (d, J=5.7 Hz, 1H), 2.00 (dq, J=9.1, 4.3 Hz, 1H),
1.75 (dtd, J=13.4, 6.4, 3.0 Hz, 1H).
Example 56C
N-(7-bromo-3,4-dihydro-2H-chromen-4-yl)-1-(2,2-difluoro-1,3-benzodioxol-5--
yl)cyclopropanecarboxamide
[1753] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(80 mg, 0.330 mmol) in DMF (826 .mu.L) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (163 mg, 0.429 mmol). The mixture was
stirred for 5 minutes, and then the product from Example 56B (75
mg, 0.330 mmol) was added, followed by dropwise addition of
triethylamine (184 .mu.L, 1.321 mmol). After 45 minutes the mixture
was quenched with water, the aqueous layer removed, the resulting
oil was dissolved in dichloromethane and purified on a 12 g silica
gel cartridge, eluting with a gradient of 5-100% ethyl
acetate/heptanes to provide the title compound (120 mg, 0.265 mmol,
80% yield) as a white solid. .sup.1H NMR (501 MHz, DMSO-d.sub.6)
.delta. 7.39 (d, J=1.7 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.31 (d,
J=8.3 Hz, 1H), 7.19 (dd, J=8.3, 1.8 Hz, 1H), 7.01 (dd, J=8.3, 2.0
Hz, 1H), 6.96 (dd, J=8.2, 0.9 Hz, 1H), 6.91 (d, J=1.9 Hz, 1H), 5.01
(td, J=8.2, 6.0 Hz, 1H), 4.20-4.09 (m, 2H), 1.97-1.84 (m, 2H),
1.48-1.42 (m, 1H), 1.36 (ddd, J=8.7, 5.9, 3.0 Hz, 1H), 1.04 (dtdd,
J=12.7, 9.4, 6.3, 3.2 Hz, 2H); MS (ESI-) m/z 450 (M-H).sup.-.
Example 57
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-methoxy-2-(pyridin--
3-yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1754] The title compound was isolated from the preparative
supercritical fluid chromatography with a retention time of 5.1
minutes as described in Example 22E. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.63 (d, J=2.3 Hz, 1H), 8.55 (dd, J=4.7, 1.6
Hz, 1H), 7.80 (dt, J=8.1, 1.9 Hz, 1H), 7.43 (dd, J=7.9, 4.8 Hz,
1H), 7.40 (d, J=1.7 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.21 (dd,
J=8.3, 1.8 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H),
6.53 (dd, J=8.6, 2.6 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 5.41-5.29 (m,
2H), 3.69 (s, 3H), 2.18-2.03 (m, 2H), 1.53-1.45 (m, 1H), 1.42-1.35
(m, 1H), 1.11-1.02 (m, 2H); MS (ESI+) m/z 481 (M+H).sup.+.
Example 58
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R)-2-[3-(hydroxymethyl)phenyl]--
3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide
[1755] To a solution of methyl
3-((2R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamid-
o)chroman-2-yl)benzoate (25 mg, 0.049 mmol) as a mixture of
disatereomers from Example 8D in tetrahydrofuran (164 .mu.L) and
methanol (82 .mu.L) was added sodium tetrahydroborate (1.864 mg,
0.049 mmol). The reaction was stirred at room temperature. After 30
minutes more sodium tetrahydroborate (1.864 mg, 0.049 mmol) was
added. After 2 hours, added more sodium borohydride about every 8
hours for 48 hours. The reaction was quenched with 2 mL of aqueous
ammonium acetate, then extracted with methyl-tert-butyl ether and
purified on a 12 g silica gel cartridge, eluting with a gradient of
5-100% ethyl acetate/heptanes to provide the title compound (20 mg,
0.042 mmol, 85% yield) as a 6:4 ratio of diastereomer mixture.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.42-7.36 (m, 2H),
7.36-7.29 (m, 2H), 7.23-7.05 (m, 5H), 7.01 (dd, J=8.2, 5.6 Hz, 1H),
6.95-6.87 (m, 2H), 5.63 (d, J=7.0 Hz, 0.6H), 5.52-5.45 (m, 0.4H),
5.39 (d, J=8.9 Hz, 0.4H), 5.19 (dd, J=11.4, 1.9 Hz, 0.4H), 5.05
(ddd, J=7.3, 4.4, 2.9 Hz, 0.6H), 4.81 (dd, J=11.0, 2.4 Hz, 0.6H),
4.75-4.69 (m, 2H), 2.50 (ddd, J=13.2, 6.0, 2.0 Hz, 0.4H), 2.30 (dt,
J=14.3, 2.8 Hz, 0.6H), 2.21 (ddd, J=14.2, 11.0, 4.7 Hz, 0.6H),
1.72-1.64 (m, 2.4H), 1.12-1.03 (m, 2H); MS (ESI+) m/z 480
(M+H).sup.+.
Example 59
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-methoxy-3,4-dihydro-2H-chromen--
4-yl)cyclopropanecarboxamide
[1756] To a solution of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(40 mg, 0.165 mmol) in DMF (413 .mu.L) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (82 mg, 0.215 mmol). The mixture was
stirred for 5 minutes, and then 7-methoxychroman-4-amine, sulfuric
acid salt (45.8 mg, 0.165 mmol) was added, followed by dropwise
addition of triethylamine (92 .mu.L, 0.661 mmol). After 45 minutes
the mixture was quenched with saturated aqueous bicarbonate, and
the aqueous layer removed. The resulting oil was triturated with
water to give a pink goo, which was dissolved in dichloromethane
and purified on a 12 g silica gel cartridge, eluted with a gradient
of 5-50% ethyl acetate/heptanes to provide the title compound (61
mg, 0.151 mmol, 92% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.39 (d, J=1.7 Hz, 1H), 7.31 (d, J=8.4 Hz,
1H), 7.26 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.3, 1.8 Hz, 1H), 6.92 (d,
J=8.5 Hz, 1H), 6.44 (dd, J=8.5, 2.6 Hz, 1H), 6.27 (d, J=2.5 Hz,
1H), 4.98 (q, J=7.2 Hz, 1H), 4.18-4.04 (m, 2H), 3.66 (s, 3H),
1.94-1.83 (m, 2H), 1.45 (ddd, J=9.6, 5.8, 2.7 Hz, 1H), 1.36 (ddd,
J=8.6, 5.6, 2.8 Hz, 1H), 1.11-0.97 (m, 2H); MS (ESI+) m/z 404
(M+H).sup.+.
Example 60
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-methoxy-2-phenyl-3,4-dihydro-2H-
-chromen-4-yl)cyclopropanecarboxamide
[1757] In a 4 mL vial, 300 .mu.L of a stock solution containing
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(0.25 M, 0.073 mmol, 1.0 equivalent) and diispropylethylamine (0.74
M, 0.22 mmol, 3.0 equivalents) in dimethyl acetamide was added to a
stock solution containing
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.30 M in dimethyl acetamide, 300 .mu.L,
0.089 mmol, 1.2 equivalents). A stock solution of
7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride (0.40 M in
dimethyl acetamide, 278 .mu.L, 0.111 mmol, 1.5 equivalents) was
added and the reaction was stirred at 50.degree. C. until complete
as determined by LC. The material was loaded directly into a Gilson
GX-271 autosampler and purified using preparative LC method TFA4 to
provide the title compound (27.1 mg, 76% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.44-7.25 (m, 7H),
7.25-7.12 (m, 2H), 6.95 (dd, J=8.6, 1.1 Hz, 1H), 6.52 (dd, J=8.5,
2.6 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 5.38-5.27 (m, 1H), 5.22 (dd,
J=11.3, 2.5 Hz, 1H), 3.69 (s, 3H), 2.19-1.93 (m, 2H), 1.50 (dt,
J=8.5, 3.0 Hz, 1H), 1.44-1.32 (m, 1H), 1.12-1.00 (m, 2H); MS
(APCI+) m/z 480.4 (M+H).sup.+.
Example 61
N-[2-(3,4-dichlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-di-
fluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1758] Example 61(33.7 mg, 83% yield) was prepared according to the
procedure similar to that as described in Example 60, substituting
2-(3,4-dichloro-phenyl)-7-methoxy-chroman-4-ylamine hydrochloride
for 7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.69-7.63 (m,
2H), 7.49-7.39 (m, 1H), 7.37 (d, J=1.7 Hz, 1H), 7.30 (d, J=8.4 Hz,
1H), 7.21 (dd, J=8.3, 1.7 Hz, 1H), 7.15 (d, J=8.9 Hz, 1H), 6.95
(dd, J=8.5, 1.0 Hz, 1H), 6.54 (dd, J=8.6, 2.6 Hz, 1H), 6.41 (d,
J=2.5 Hz, 1H), 5.38-5.17 (m, 2H), 3.69 (s, 3H), 2.16-1.95 (m, 2H),
1.50 (dt, J=8.8, 3.2 Hz, 1H), 1.42-1.33 (m, 1H), 1.15-0.99 (m, 2H);
MS (APCI+) m/z 548.3 (M+H).sup.+.
Example 62
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-7-methoxy-
-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1759] Example 62 hydrochloride (39.4 mg, 98% yield) was prepared
according to the procedure similar to that as described in Example
60, substituting
2-(3,4-dimethoxy-phenyl)-7-methoxy-chroman-4-ylamine for
7-methoxy-2-phenyl-chroman-4-ylamine. .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.38 (d, J=1.7 Hz, 1H),
7.30 (d, J=8.3 Hz, 1H), 7.22 (dd, J=8.4, 1.7 Hz, 1H), 7.15 (d,
J=8.9 Hz, 1H), 7.07-6.90 (m, 4H), 6.51 (dd, J=8.6, 2.6 Hz, 1H),
6.35 (d, J=2.5 Hz, 1H), 5.36-5.22 (m, 1H), 5.19-5.04 (m, 1H),
3.77-3.75 (m, 6H), 3.68 (s, 3H), 2.20-1.95 (m, 2H), 1.57-1.46 (m,
1H), 1.46-1.32 (m, 1H), 1.21-0.98 (m, 2H); MS (APCI+) m/z 540.4
(M+H).sup.+.
Example 63
N-[2-(4-chlorophenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluo-
ro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1760] Example 63 (26.5 mg, 69% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(4-chloro-phenyl)-7-methoxy-chroman-4-ylamine
hydrochloride for 7-methoxy-2-phenyl-chroman-4-ylamine
hydrochloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.56-7.39 (m, 4H), 7.37 (d, J=1.7 Hz, 1H), 7.30 (d,
J=8.3 Hz, 1H), 7.25-7.13 (m, 2H), 6.94 (dd, J=8.6, 1.0 Hz, 1H),
6.53 (dd, J=8.6, 2.6 Hz, 1H), 6.37 (d, J=2.5 Hz, 1H), 5.38-5.27 (m,
1H), 5.27-5.16 (m, 1H), 3.69 (s, 3H), 2.09-1.99 (m, 2H), 1.53-1.46
(m, 1H), 1.42-1.35 (m, 1H), 1.14-1.00 (m, 2H); MS (APCI+) m/z 514.2
(M+H).sup.+.
Example 64
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{2-[4-(trifluoromethyl)phenyl]-3,4-
-dihydro-2H-chromen-4-yl}cyclopropanecarboxamide
[1761] Example 64 (34.8 mg, 91% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(4-trifluoromethyl-phenyl)-chroman-4-ylamine
hydrochloride for 7-methoxy-2-phenyl-chroman-4-ylamine
hydrochloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.78 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.38
(d, J=1.6 Hz, 1H), 7.29 (dd, J=8.5, 1.9 Hz, 2H), 7.25-7.12 (m, 2H),
7.12-7.03 (m, 1H), 6.98-6.90 (m, 1H), 6.90-6.78 (m, 1H), 5.49-5.33
(m, 2H), 2.21-2.01 (m, 2H), 1.55-1.48 (m, 1H), 1.44-1.35 (m, 1H),
1.11-1.03 (m, 2H); MS (APCI+) m/z 518.4 (M+H).sup.+.
Example 65
N-[2-(2-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-ben-
zodioxol-5-yl)cyclopropanecarboxamide
[1762] Example 65 (35.8 mg, 99% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(2-chloro-phenyl)-chroman-4-ylamine hydrochloride
for 7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. The crude
material was purified using preparative LC method TFA1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.55 (dd, J=7.4,
1.9 Hz, 1H), 7.48-7.24 (m, 4H), 7.24-7.07 (m, 4H), 6.98-6.76 (m,
2H), 5.38 (dd, J=11.0, 2.2 Hz, 1H), 4.97 (t, J=3.8 Hz, 1H), 2.36
(d, J=14.0 Hz, 1H), 2.29-2.16 (m, 1H), 2.06-1.89 (m, 1H), 1.56-1.31
(m, 2H), 1.18-0.96 (m, 2H).
Example 66
N-[2-(3,4-dichlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-
-benzodioxol-5-yl)cyclopropanecarboxamide
[1763] Example 66 (15.2 mg, 39% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(3,4-dichloro-phenyl)-chroman-4-ylamine for
7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. The crude
material was purified using preparative LC method TFA1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.64-7.51 (m,
2H), 7.43-7.28 (m, 2H), 7.24-7.01 (m, 5H), 6.94-6.76 (m, 2H),
5.39-5.28 (m, 0.5H), 5.26-5.23 (m, 0.5H), 5.19 (dd, J=8.6, 4.0 Hz,
0.5H), 4.99-4.86 (m, 0.5H), 2.31-1.98 (m, 2H), 1.55-1.38 (m, 2H),
1.11-0.99 (m, 2H); MS (APCI+) m/z 468.3 (M+H).sup.+.
Example 67
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(2-phenyl-3,4-dihydro-2H-chromen-4-
-yl)cyclopropanecarboxamide
[1764] Example 67 (15.2 mg, 45% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-phenyl-chroman-4-ylamine hydrochloride for
7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. The crude
material was purified using preparative LC method TFA1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.56-7.00 (m,
11H), 6.98-6.77 (m, 2H), 5.46-5.32 (m, 0.7H), 5.30-5.19 (m, 1H),
4.90 (t, J=3.9 Hz, 0.3H), 2.25-2.00 (m, 2H), 1.56-1.33 (m, 2H),
1.12-1.02 (m, 2H); MS (APCI+) m/z 450.4 (M+H).sup.+.
Example 68
N-[2-(4-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-ben-
zodioxol-5-yl)cyclopropanecarboxamide
[1765] Example 68 (27.1 mg, 75% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(4-chloro-phenyl)-chroman-4-ylamine hydrochloride
for 7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. The crude
material was purified using preparative LC method TFA1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.59-7.40 (m,
4H), 7.38 (d, J=1.7 Hz, 1H), 7.34-7.25 (m, 2H), 7.22 (dd, J=8.3,
1.7 Hz, 1H), 7.19-7.10 (m, 1H), 7.10-7.00 (m, 1H), 6.93 (td, J=7.5,
1.2 Hz, 1H), 6.80 (dd, J=8.2, 1.2 Hz, 1H), 5.46-5.32 (m, 1H),
5.32-5.21 (m, 1H), 2.19-2.00 (m, 2H), 1.55-1.48 (m, 1H), 1.43-1.35
(m, 1H), 1.14-1.00 (m, 2H); MS (APCI+) m/z 484.3 (M+H).sup.+.
Example 69
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-(3,4-dimethoxyphenyl)-3,4-dihyd-
ro-2H-chromen-4-yl]cyclopropanecarboxamide
[1766] Example 69 (33.4 mg, 88% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(3,4-dimethoxy-phenyl)-chroman-4-ylamine for
7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. The crude
material was purified using preparative LC method TFA1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.31 (d, J=5.3
Hz, 1H), 7.29-7.07 (m, 3H), 7.07-6.91 (m, 3H), 6.91-6.72 (m, 3H),
5.37-5.27 (m, 0.5H), 5.14 (dd, J=11.1, 2.4 Hz, 0.5H), 5.06 (dd,
J=9.3, 3.3 Hz, 0.5H), 4.94 (t, J=4.7 Hz, 0.5H), 3.82-3.72 (m, 6H),
2.26-2.07 (m, 2H), 1.59-1.32 (m, 2H), 1.14-0.98 (m, 2H); MS (APCI+)
m/z 510.4 (M+H).sup.+.
Example 70
N-[2-(3-chlorophenyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-ben-
zodioxol-5-yl)cyclopropanecarboxamide
[1767] Example 70 (31.0 mg, 86% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(3-chloro-phenyl)-chroman-4-ylamine hydrochloride
for 7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. The crude
material was purified using preparative LC method TFA1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.47-7.24 (m,
5H), 7.24-7.00 (m, 4H), 6.95-6.71 (m, 2H), 5.30 (dd, J=10.9, 6.1
Hz, 0.4H), 5.23 (dd, J=11.3, 2.4 Hz, 0.4H), 5.16 (dd, J=8.0, 4.5
Hz, 0.6H), 4.90 (t, J=4.9 Hz, 0.6H), 2.27-1.95 (m, 2H), 1.55-1.32
(m, 2H), 1.10-0.96 (m, 2H); MS (APCI+) m/z 484.3 (M+H).sup.+.
Example 71
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-(4-fluorophenyl)-3,4-dihydro-2H-
-chromen-4-yl]cyclopropanecarboxamide
[1768] Example 71 (32.8 mg, 95% yield) was prepared according to
the procedure similar to that as described in Example 60,
substituting 2-(4-fluoro-phenyl)-chroman-4-ylamine for
7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride. The crude
material was purified using preparative LC method TFA1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.51-7.35 (m,
2H), 7.31 (d, J=5.8 Hz, 1H), 7.27-7.01 (m, 6H), 6.96-6.73 (m, 2H),
5.32 (dd, J=11.1, 6.2 Hz, 0.5H), 5.22 (dd, J=11.4, 2.3 Hz, 0.5H),
5.15 (t, J=6.3 Hz, 0.5H), 4.93 (t, J=4.8 Hz, 0.5H), 2.27-2.02 (m,
2H), 1.55-1.37 (m, 2H), 1.07 (dd, J=7.0, 2.9 Hz, 2H); MS (APCI+)
m/z 468.3 (M+H).sup.+.
Example 72
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-6-methoxy-
-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1769] A stock solution of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
and N,N-diisopropylethylamine (0.218 M and 0.654 M in
dimethylacetamide, respectively, 284 .mu.L, 0.061 mmol
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(1.0 equivalent) and 0.18 mmol N,N-diisopropylethylamine (3.0
equivalents)),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.26 M in dimethylacetamide, 284 .mu.L,
0.074 mmol, 1.2 equivalents), and
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine (Von P.
Pfeiffer et al., Justus Liebigs Annalen der Chemie (1949), 564,
208-19) (0.40 M in dimethylacetamide, 232 .mu.L, 0.093 mmol, 1.5
equivalents) were aspirated from their respective source vials,
mixed through a PFA (perfluoroalkoxy) mixing tube (0.2 mm inner
diameter), and loaded into an injection loop. The reaction segment
was injected into the flow reactor (Hastelloy coil, 0.75 mm inner
diameter, 1.8 mL internal volume) set at 100.degree. C., and passed
through the reactor at 180 .mu.L min.sup.-1 (10 minute residence
time). Upon exiting the reactor, the reaction was loaded directly
into an injection loop and purified using preparative LC method
TFA1 to yield the title compound (10.69 mg, 49% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.42 (d, J=8.9
Hz, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.20 (dd,
J=8.3, 1.8 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.77-6.61 (m, 4H), 6.50
(d, J=2.9 Hz, 1H), 4.91-4.79 (m, 1H), 4.02-3.93 (m, 1H), 3.75 (s,
6H), 3.64 (s, 3H), 3.46 (s, OH), 2.70-2.60 (m, 1H), 2.36-2.21 (m,
2H), 1.51-1.32 (m, 2H), 1.15-0.97 (m, 2H); MS (APCI+) m/z 554.1
(M+H).sup.+.
Example 73
N-(3-benzyl-3,4-dihydro-2H-chromen-4-yl)-1-(2,2-difluoro-1,3-benzodioxol-5-
-yl)cyclopropanecarboxamide
[1770] Example 73 (5.56 mg, 19% yield) was prepared according to
the procedure similar to that as described in Example 72,
substituting 3-benzyl-chroman-4-ylamine (Von P. Pfeiffer et al.,
Justus Liebigs Annalen der Chemie (1949), 564, 208-19) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.52-7.40 (m,
1H), 7.40-6.96 (m, 9H), 6.94-6.82 (m, 1H), 6.81-6.68 (m, 1H),
4.95-4.82 (m, 1H), 4.05-3.79 (m, 2H), 2.76-2.60 (m, 1H), 2.40-2.17
(m, 2H), 1.52-1.36 (m, 2H), 1.21-0.98 (m, 2H); MS (APCI+) m/z 464.2
(M+H).sup.+.
Example 74
N-[(4R)-2,2-diethyl-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-1,3-benzo-
dioxol-5-yl)cyclopropanecarboxamide
[1771] Example 74 (2.9 mg, 11% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(4R)-2,2-diethylchroman-4-amine (2S,3S)-2,3-dihydroxybutanedioic
acid (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.40 (d, J=1.6
Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.23 (dd, J=8.3, 1.8 Hz, 1H),
7.16-7.05 (m, 1H), 7.05-6.94 (m, 1H), 6.89-6.77 (m, 1H), 6.75-6.66
(m, 1H), 5.16-5.03 (m, 1H), 1.87-1.73 (m, 2H), 1.64-1.32 (m, 6H),
1.16-1.07 (m, 1H), 1.07-0.99 (m, 1H), 0.90-0.76 (m, 7H); MS (APCI+)
m/z 430.2 (M+H).sup.+.
Example 75
N-[(4R)-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-
-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1772] Example 75 (10.1 mg, 42% yield) was prepared according to
the procedure similar to that as described in Example 72,
substituting (4R)-2,2-bis(fluoromethyl)chroman-4-amine
(2S,3S)-2,3-dihydroxybutanedioic acid (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.6
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.24 (dd, J=8.3, 1.8 Hz, 1H),
7.20-7.10 (m, 1H), 7.08-6.98 (m, 1H), 6.93 (td, J=7.5, 1.2 Hz, 1H),
6.81 (dd, J=8.2, 1.1 Hz, 1H), 5.21-5.08 (m, 1H), 4.69-4.39 (m, 4H),
2.14-1.92 (m, 2H), 1.55-1.47 (m, 1H), 1.44-1.36 (m, 1H), 1.15-1.00
(m, 2H); MS (APCI+) m/z 438.2 (M+H).sup.+.
Example 76
N-[(4R)-7-chloro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluoro-
-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1773] Example 76 (3.3 mg, 12% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(4R)-7-chloro-2,2-dimethyl-chroman-4-amine
(2S,3S)-2,3-dihydroxybutanedioic acid (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.39 (d, J=1.7
Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.22 (dd, J=8.3, 1.8 Hz, 1H),
7.08-6.97 (m, 1H), 6.90 (dd, J=8.4, 2.2 Hz, 1H), 6.75 (d, J=2.1 Hz,
1H), 5.07 (t, J=9.1 Hz, 1H), 1.83 (d, J=9.1 Hz, 2H), 1.56-1.46 (m,
1H), 1.42-1.35 (m, 1H), 1.33 (s, 3H), 1.21 (s, 3H), 1.13-1.02 (m,
2H); MS (APCI+) m/z 436.1 (M+H).sup.+.
Example 77
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-8-fluoro-2,2-bis(fluoromethy-
l)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1774] Example 77 (1.4 mg, 5% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(4R)-8-fluoro-2,2-bis(fluoromethyl)chroman-4-amine
(2S,3S)-2,3-dihydroxybutanedioic acid (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.7
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.27-7.19 (m, 1H), 7.17-7.04 (m,
1H), 6.98-6.80 (m, 2H), 5.23-5.12 (m, 1H), 4.74-4.43 (m, 4H),
2.19-1.96 (m, 2H), 1.56-1.46 (m, 1H), 1.46-1.35 (m, 1H), 1.21-1.03
(m, 2H); MS (APCI+) m/z 456.1 (M+H).sup.+.
Example 78
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-3,4-dihydrospiro[chromene-2,-
1'-cyclopentan]-4-yl]cyclopropanecarboxamide
[1775] Example 78 (2.9 mg, 10% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(4R)-spiro[chromane-2,1'-cyclopentane]-4-amine
(2S,3S)-2,3-dihydroxybutanedioic acid (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.39 (d, J=1.6
Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.28-7.17 (m, 2H), 7.15-7.05 (m,
1H), 7.05-6.95 (m, 1H), 6.90-6.78 (m, 1H), 6.66 (dd, J=8.1, 1.2 Hz,
1H), 5.11 (dd, J=11.6, 6.2 Hz, 1H), 2.06 (t, J=12.2 Hz, 1H),
1.86-1.46 (m, 10H), 1.44-1.35 (m, 1H), 1.13-1.02 (m, 2H); MS
(APCI+) m/z 428.2 (M+H).sup.+.
Example 79
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-7-fluoro-2,2-bis(fluoromethy-
l)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1776] Example 79 (4.2 mg, 15% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(4R)-7-fluoro-2,2-bis(fluoromethyl)chroman-4-amine hydrochloride
(WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.6
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.24 (dd, J=8.4, 1.7 Hz, 1H),
7.12-6.99 (m, 1H), 6.78 (td, J=8.5, 2.6 Hz, 1H), 6.68 (dd, J=10.3,
2.6 Hz, 1H), 5.11 (dd, J=11.3, 6.4 Hz, 1H), 4.71-4.40 (m, 4H),
2.14-1.92 (m, 2H), 1.55-1.46 (m, 1H), 1.44-1.37 (m, 1H), 1.15-1.03
(m, 2H); MS (APCI+) m/z 456.1 (M+H).sup.+.
Example 80
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4R)-2-(fluoromethyl)-2-methyl-
-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1777] Example 80 (7.64 mg, 25% yield) was prepared according to
the procedure similar to that as described in Example 72,
substituting
(2S,4R)-2-(fluoromethyl)-2-methyl-7-(trifluoromethyl)chroman-4-amine
hydrochloride (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.6
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.28-7.16 (m, 3H), 7.10-7.01 (m,
1H), 5.15 (dd, J=11.8, 6.4 Hz, 1H), 4.61-4.46 (m, 1H), 4.46-4.32
(m, 1H), 2.11 (dd, J=13.7, 6.4 Hz, 1H), 2.02-1.93 (m, 1H),
1.55-1.47 (m, 1H), 1.44-1.37 (m, 1H), 1.33 (d, J=2.0 Hz, 3H),
1.15-1.01 (m, 2H); MS (APCI+) m/z 488.1 (M+H).sup.+.
Example 81
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(difluoromethyl)-2-meth-
yl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1778] Example 81 (10.7 mg, 40% yield) was prepared according to
the procedure similar to that as described in Example 72,
substituting (2R,4R)-2-difluoromethyl-2-methyl-chroman-4-ylamine
hydrochloride (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.7
Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.24 (dd,
J=8.3, 1.7 Hz, 1H), 7.20-7.10 (m, 1H), 7.10-6.98 (m, 1H), 6.98-6.87
(m, 1H), 6.78 (dd, J=8.2, 1.1 Hz, 1H), 6.02 (t, J=55.1 Hz, 1H),
5.26-5.12 (m, 1H), 2.11-1.96 (m, 1H), 1.82 (dd, J=12.9, 6.0 Hz,
1H), 1.56-1.48 (m, 1H), 1.46-1.37 (m, 1H), 1.31 (s, 3H), 1.17-1.00
(m, 2H); MS (APCI+) m/z 438.1 (M+H).sup.+.
Example 82
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4R)-2-(difluoromethyl)-2-meth-
yl-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1779] Example 82 (9.4 mg, 35% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(2S,4R)-2-difluoromethyl-2-methyl-chroman-4-ylamine hydrochloride
(WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.6
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.28-7.19 (m, 2H), 7.19-7.09 (m,
1H), 7.06-6.96 (m, 1H), 6.96-6.85 (m, 1H), 6.79 (dd, J=8.1, 1.1 Hz,
1H), 6.09 (t, J=54.8 Hz, 1H), 5.16 (dt, J=12.2, 6.5 Hz, 1H), 2.14
(dd, J=14.0, 6.2 Hz, 1H), 2.07-1.91 (m, 1H), 1.54-1.46 (m, 1H),
1.44-1.36 (m, 1H), 1.32 (s, 3H), 1.14-1.00 (m, 2H); MS (APCI+) m/z
438.1 (M+H).sup.+.
Example 83
N-[(2S,4R)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-y-
l]-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1780] Example 83 (9.7 mg, 33% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(2S,4R)-7-chloro-2-difluoromethyl-2-methyl-chroman-4-ylamine
hydrochloride (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.6
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.28-7.19 (m, 2H), 7.03 (dd,
J=8.3, 1.0 Hz, 1H), 6.97 (dd, J=8.3, 2.1 Hz, 1H), 6.88 (d, J=2.0
Hz, 1H), 6.12 (t, J=54.7 Hz, 1H), 5.17-5.04 (m, 1H), 2.16 (dd,
J=14.1, 6.3 Hz, 1H), 2.09-1.91 (m, 1H), 1.56-1.45 (m, 1H),
1.45-1.36 (m, 1H), 1.33 (s, 3H), 1.15-1.00 (m, 2H); MS (APCI+) m/z
472.1 (M+H).sup.+.
Example 84
N-[(2R,4R)-7-chloro-2-(difluoromethyl)-2-methyl-3,4-dihydro-2H-chromen-4-y-
l]-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1781] Example 84 (11.2 mg, 38% yield) was prepared according to
the procedure similar to that as described in Example 72,
substituting
(2R,4R)-7-chloro-2-difluoromethyl-2-methyl-chroman-4-ylamine
hydrochloride (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.6
Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.24 (dd,
J=8.3, 1.7 Hz, 1H), 7.12-7.02 (m, 1H), 6.99 (dd, J=8.3, 2.1 Hz,
1H), 6.87 (d, J=2.0 Hz, 1H), 6.04 (t, J=55.0 Hz, 1H), 5.15 (dt,
J=12.4, 6.4 Hz, 1H), 2.11-1.96 (m, 1H), 1.83 (dd, J=13.0, 6.1 Hz,
1H), 1.57-1.46 (m, 1H), 1.45-1.37 (m, 1H), 1.31 (s, 3H), 1.17-1.00
(m, 2H); MS (APCI+) m/z 472.1 (M+H).sup.+.
Example 85
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2S,4R)-2-methyl-2-(trifluorometh-
yl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1782] Example 85 (9.1 mg, 32% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(2S,4R)-2-methyl-2-trifluoromethyl-chroman-4-ylamine hydrochloride
(WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.43 (d, J=1.5
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.26 (dd, J=8.3, 1.7 Hz, 1H),
7.22-7.12 (m, 1H), 7.09-7.00 (m, 1H), 7.00-6.90 (m, 1H), 6.84 (dd,
J=8.2, 1.1 Hz, 1H), 5.13 (dd, J=12.0, 6.2 Hz, 1H), 2.28 (dd,
J=14.6, 6.1 Hz, 1H), 2.21-2.05 (m, 1H), 1.60-1.45 (m, 4H),
1.45-1.33 (m, 1H), 1.21-1.01 (m, 2H); MS (APCI+) m/z 456.1
(M+H).sup.+.
Example 86
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4R)-7-fluoro-2,2-dimethyl-3,4-di-
hydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1783] Example 86 (4.1 mg, 15% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(R)-7-fluoro-2,2-dimethylchroman-4-amine
(2S,3S)-2,3-dihydroxysuccinate (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.39 (d, J=1.7
Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.22 (dd, J=8.3, 1.7 Hz, 1H),
7.09-6.97 (m, 1H), 6.69 (td, J=8.6, 2.7 Hz, 1H), 6.52 (dd, J=10.6,
2.6 Hz, 1H), 5.07 (t, J=8.8 Hz, 1H), 1.83 (d, J=9.0 Hz, 2H),
1.56-1.45 (m, 1H), 1.44-1.35 (m, 1H), 1.33 (s, 3H), 1.21 (s, 3H),
1.19-0.99 (m, 2H); MS (APCI+) m/z 420.1 (M+H).sup.+.
Example 87
N-[(4R)-7-chloro-2,2-bis(fluoromethyl)-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-
-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1784] Example 87 (2.7 mg, 9% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(R)-7-chloro-2,2-bis-fluoromethyl-chroman-4-ylamine
(2S,3S)-2,3-dihydroxy-succinic acid (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.7
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.24 (dd, J=8.4, 1.7 Hz, 1H), 7.05
(d, J=8.3 Hz, 1H), 6.98 (dd, J=8.4, 2.1 Hz, 1H), 6.90 (d, J=2.0 Hz,
1H), 5.11 (dd, J=11.2, 6.4 Hz, 1H), 4.71-4.40 (m, 4H), 2.15-1.93
(m, 2H), 1.56-1.45 (m, 1H), 1.45-1.34 (m, 1H), 1.15-1.02 (m, 2H);
MS (APCI+) m/z 472.1 (M+H).sup.+.
Example 88
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4S)-6-fluoro-2,2-dimethyl-3,4-di-
hydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1785] Example 88 (1.8 mg, 7% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(S)-6-fluoro-2,2-dimethyl-chroman-4-ylamine with
(2R,3R)-2,3-dihydroxy-succinic acid (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.41 (d, J=1.7
Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.23 (dd, J=8.3, 1.7 Hz, 1H), 6.94
(td, J=8.6, 3.3 Hz, 1H), 6.78-6.66 (m, 2H), 5.14-5.01 (m, 1H),
1.87-1.73 (m, 2H), 1.56-1.44 (m, 1H), 1.43-1.36 (m, 1H), 1.32 (s,
3H), 1.20 (s, 3H), 1.14-1.03 (m, 2H); MS (APCI+) m/z 420.1
(M+H).sup.+.
Example 89
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(4S)-6-fluoro-3,4-dihydrospiro[ch-
romene-2,1'-cyclobutan]-4-yl]cyclopropanecarboxamide
[1786] Example 89 (2.0 mg, 8% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(S)-6-fluorospiro[chroman-2,1'-cyclobutan]-4-amine
(2R,3R)-2,3-dihydroxysuccinate (WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.43 (d, J=1.6
Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.25 (dd, J=8.3, 1.7 Hz, 1H), 6.94
(td, J=8.6, 3.2 Hz, 1H), 6.75 (dd, J=9.0, 4.8 Hz, 1H), 6.71-6.63
(m, 1H), 5.07 (dd, J=11.5, 5.9 Hz, 1H), 2.30-2.19 (m, 1H),
2.16-1.96 (m, 4H), 1.94-1.62 (m, 3H), 1.56-1.45 (m, 1H), 1.44-1.37
(m, 1H), 1.15-1.05 (m, 2H); MS (APCI+) m/z 432.1 (M+H).sup.+.
Example 90
N-[(4R)-8-chloro-7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-
-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1787] Example 90 (5.3 mg, 19% yield) was prepared according to the
procedure similar to that as described in Example 72, substituting
(R)-8-chloro-7-fluoro-2,2-dimethyl-chroman-4-ylamine
(WO2010045402A1) for
3-(3,4-dimethoxy-benzyl)-6-methoxy-chroman-4-ylamine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.39 (d, J=1.7
Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.22 (dd, J=8.3, 1.8 Hz, 1H),
7.08-6.96 (m, 1H), 6.90 (t, J=8.8 Hz, 1H), 5.10 (t, J=9.1 Hz, 1H),
1.93-1.80 (m, 2H), 1.56-1.44 (m, 1H), 1.44-1.35 (m, 4H), 1.24 (s,
3H), 1.20-1.00 (m, 2H); MS (APCI+) m/z 454.1 (M+H).sup.+.
Example 91
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-7-methoxy-
-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1788] A stock solution of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
and N,N-diisopropylethylamine (0.218 M and 0.654 M in
dimethylacetamide, respectively, 284 .mu.L, 0.061 mmol
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(1.0 equivalent) and 0.18 mmol N,N-diisopropylethylamine (3.0
equivalents)),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.26 M in dimethylacetamide, 284 .mu.L,
0.074 mmol, 1.2 equivalents), and
3-(3,4-dimethoxy-benzyl)-7-methoxy-chroman-4-ylamine (Von P.
Pfeiffer et al., Justus Liebigs Annalen der Chemie (1949), 564,
208-19) (0.40 M in dimethylacetamide, 232 .mu.L, 0.093 mmol, 1.5
equivalents) were mixed in a 4 mL vial at room temperature. The
reaction was deemed complete by LC and the reaction mixture was
loaded directly into an injection loop and purified using
preparative LC method TFA1 to provide the title compound (9.9 mg,
29% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. 7.38-7.24 (m, 3H), 7.19 (dd, J=8.3, 1.7 Hz, 1H), 6.90 (d,
J=8.7 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.65
(dd, J=8.1, 2.0 Hz, 1H), 6.48 (dd, J=8.6, 2.6 Hz, 1H), 6.27 (d,
J=2.5 Hz, 1H), 4.80 (t, J=8.5 Hz, 1H), 4.00 (dd, J=11.3, 2.7 Hz,
1H), 3.74 (s, 5H), 3.67 (s, 3H), 2.68-2.56 (m, 1H), 2.35-2.19 (m,
2H), 1.48-1.36 (m, 2H), 1.14-1.07 (m, 1H), 1.03-0.97 (m, 1H); MS
(APCI+) m/z 554.0 (M+H).sup.+.
Example 92
tert-butyl
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-fluoro-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxy-
late
Example 92A
tert-butyl
7-fluoro-4-hydroxyspiro[chroman-2,4'-piperidine]-1'-carboxylate
[1789] A solution of tert-butyl
7-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate
(CAS#936648-33-8, MFCD12912048) (500 mg, 1.491 mmol) in methanol (7
mL) was cooled to 0.degree. C., treated with NaBH.sub.4 (113 mg,
2.98 mmol) and stirred at room temperature for 10 minutes. The
mixture was concentrated to about 2 mL volume and quenched with 10%
acetic acid in water (10 mL). The mixture was extracted with ethyl
acetate (2 times). The combined ethyl acetate layers were washed
with saturated NaHCO.sub.3 solution, washed with brine, dried
(MgSO.sub.4), filtered, concentrated, and chromatographed on silica
gel eluted with a gradient of 20%-100% ethyl acetate in heptanes to
provide the title compound (0.5 g, 1.482 mmol, 99% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.38 (dd, J=8.6, 6.7 Hz, 1H),
6.65 (td, J=8.4, 2.5 Hz, 1H), 6.55 (dd, J=10.2, 2.5 Hz, 1H), 4.82
(t, J=6.7 Hz, 1H), 3.83 (bs, 2H), 3.19 (dt, J=29.3, 13.2 Hz, 2H),
2.29 (s, 1H), 2.11 (dd, J=13.7, 6.0 Hz, 1H), 1.97-1.91 (m, 1H),
1.88 (dd, J=13.8, 7.9 Hz, 1H), 1.77 (dq, J=13.7, 3.1 Hz, 1H), 1.65
(ddd, J=13.5, 11.8, 4.6 Hz, 1H), 1.56 (ddd, J=13.7, 11.9, 4.8 Hz,
1H), 1.46 (s, 9H).
Example 92B
tert-butyl
4-azido-7-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate\
[1790] A solution of the product from Example 92A (0.5 g, 1.482
mmol) in tetrahydrofuran (8 mL) was cooled to 0.degree. C. and
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.447 ml, 2.96
mmol) followed by diphenylphosphoryl azide (0.544 ml, 2.52 mmol).
The mixture was stirred at 0.degree. C. for 2 hours and then at
room temperature for 2 days. The mixture was partitioned between
tert-butyl methyl ether (30 mL) and 1 M NaOH (10 mL). The layers
were separated and the organic layer was washed with 1 M NaOH (10
mL), washed with 1% aqueous citric acid (2.times.20 mL), washed
with brine, dried (MgSO.sub.4), filtered, concentrated, and
chromatographed on silica gel eluted with a gradient of 10%-33%
ethyl acetate in heptanes to provide the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.39-7.18 (m, 2H), 6.69 (td,
J=8.4, 2.6 Hz, 1H), 6.60 (dd, J=10.1, 2.6 Hz, 1H), 4.59 (t, J=6.8
Hz, 1H), 3.89 (s, 3H), 3.19 (dt, J=22.9, 12.3 Hz, 2H), 2.13 (dd,
J=13.9, 6.0 Hz, 1H), 2.00 (dd, J=13.9, 7.6 Hz, 1H), 1.93 (dt,
J=14.1, 2.9 Hz, 1H), 1.77 (dq, J=13.9, 3.0 Hz, 1H), 1.72-1.52 (m,
2H), 1.47 (s, 9H).
Example 92C
tert-butyl
4-amino-7-fluorospiro[chroman-2,4'-piperidine]-1'-carboxylate
[1791] A solution of the product from Example 92B (0.23 g, 0.635
mmol) was dissolved in tetrahydrofuran (5 mL), treated with water
(0.5 mL), treated with triphenylphosphine (0.333 g, 1.269 mmol) and
heated at 65.degree. C. for 1 hour. The mixture was cooled and
concentrated. The residue was dissolved in tert-butyl methyl ether
(20 mL), washed with brine, dried (MgSO.sub.4), filtered,
concentrated, and chromatographed on silica gel eluted with a
gradient of 0%-100% [3:1 ethyl acetate:ethanol] in ethyl acetate,
then eluted with 75:25:2 ethyl acetate:ethanol:saturated NH.sub.4OH
solution to provide the title compound (0.15 g, 0.446 mmol, 70.3%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.41 (dd,
J=8.6, 6.7 Hz, 1H), 6.64 (td, J=8.4, 2.6 Hz, 1H), 6.54 (dd, J=10.2,
2.6 Hz, 1H), 4.01 (dd, J=10.9, 6.2 Hz, 1H), 3.94-3.77 (m, 2H), 3.31
(t, J=12.4 Hz, 1H), 3.07 (t, J=12.3 Hz, 1H), 2.07 (dd, J=13.4, 6.2
Hz, 1H), 1.85-1.61 (m, 6H), 1.54-1.41 (m, 10H).
Example 92D
tert-butyl
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-fluoro-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxy-
late
[1792] A mixture of the product from Example 92C (0.15 g, 0.446
mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.186 g, 0.490 mmol) and
1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylic acid
(0.108 g, 0.446 mmol) in tetrahydrofuran (2 mL) was treated with
triethylamine (0.124 ml, 0.892 mmol) and stirred at room
temperature for 3 hours. The mixture was diluted with ethyl acetate
(30 mL), washed with 5% aqueous citric acid (20 mL), washed with
saturated NaHCO.sub.3 solution (10 mL), washed with brine, dried
(MgSO.sub.4), filtered, concentrated, and chromatographed on silica
gel eluted with a gradient of 50%-100% [9:1 CH.sub.2Cl.sub.2:ethyl
acetate] in heptanes, then eluted with a gradient of 0%-100% ethyl
acetate in [9:1 CH.sub.2Cl.sub.2:ethyl acetate] to provide the
title compound (220 mg, 0.392 mmol, 88% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.15 (dd, J=8.2, 1.8 Hz, 1H), 7.11 (d,
J=1.7 Hz, 1H), 7.05-6.98 (m, 2H), 6.59 (td, J=8.3, 2.6 Hz, 1H),
6.52 (dd, J=10.1, 2.6 Hz, 1H), 5.33 (d, J=8.9 Hz, 1H), 5.27-5.15
(m, 1H), 3.84 (s, 2H), 3.26 (t, J=12.3 Hz, 1H), 3.12-2.98 (m, 1H),
2.11 (dd, J=13.4, 6.3 Hz, 1H), 1.82 (d, J=12.6 Hz, 1H), 1.77-1.48
(m, 6H), 1.46 (s, 9H), 1.16-1.04 (m, 2H); MS (ESI) m/z 559
(M-H).sup.-.
Example 93
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-fluoro-3,4-dihydrospiro[chromen-
e-2,4'-piperidin]-4-yl)cyclopropanecarboxamide
[1793] A solution of the product from Example 92D (210 mg, 0.375
mmol) in trifluoroacetic acid (2 mL) was heated at 60.degree. C.
for 2 minutes, concentrated, and partitioned between tert-butyl
methyl ether (30 mL) and 1 M NaOH (10 mL). The tert-butyl methyl
ether layer was washed with brine, dried (MgSO.sub.4), filtered,
and concentrated to provide the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.14 (dd, J=8.2, 1.7 Hz, 1H), 7.11 (d,
J=1.6 Hz, 1H), 7.04-6.98 (m, 2H), 6.58 (td, J=8.4, 2.6 Hz, 1H),
6.52 (dd, J=10.2, 2.6 Hz, 1H), 5.33 (d, J=8.8 Hz, 1H), 5.26-5.18
(m, 1H), 3.14-3.04 (m, 1H), 2.94-2.79 (m, 3H), 2.14 (dd, J=13.4,
6.3 Hz, 1H), 1.85-1.46 (m, 8H), 1.14-1.05 (m, 2H); MS (ESI) m/z 461
(M+H).sup.+.
Example 94
methyl
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate
[1794] To the product from Example 23E (60 mg, 0.115 mmol), and
2-methoxyethanol (13.08 mg, 0.172 mmol) in dichloromethane (2 mL)
was added triphenylphosphine (60.1 mg, 0.229 mmol), followed by
portion wise addition of di-t-butyl azodicarboxylate (52.8 mg,
0.229 mmol). The mixture was stirred at ambient temperature for 2
hours. Solvent was removed in vacuo and residue was purified on
silica gel cartridge eluted with a gradient of 5-50% ethyl acetate
in heptane to yield title compound (60 mg, 0.103 mmol, 90% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (t, J=1.7 Hz, 1H),
7.99 (dt, J=7.7, 1.4 Hz, 1H), 7.61-7.52 (m, 1H), 7.44 (t, J=7.7 Hz,
1H), 7.14-7.05 (m, 2H), 7.00 (d, J=8.2 Hz, 1H), 6.95 (d, J=8.6 Hz,
1H), 6.55 (dd, J=8.7, 2.5 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.41
(td, J=10.3, 9.8, 6.2 Hz, 1H), 5.31 (d, J=8.8 Hz, 1H), 5.20 (dd,
J=11.2, 1.9 Hz, 1H), 4.11-4.02 (m, 2H), 3.92 (s, 3H), 3.72 (dd,
J=5.6, 3.8 Hz, 2H), 3.43 (s, 3H), 2.50 (ddd, J=13.3, 6.1, 2.0 Hz,
1H), 1.85-1.70 (m, 2H), 1.65-1.59 (m, 1H), 1.06 (q, J=2.4 Hz, 2H);
MS (ESI-) m/z 580 (M-H).sup.-.
Example 95
methyl
3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)-
cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate
[1795] The title compound was prepared using the conditions similar
to that described in Example 94 substituting phenylmethanol for
2-methoxyethanol. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07
(t, J=1.7 Hz, 1H), 8.00 (dt, J=7.6, 1.4 Hz, 1H), 7.57 (dt, J=7.7,
1.5 Hz, 1H), 7.47-7.28 (m, 6H), 7.14-7.06 (m, 2H), 6.98 (dd,
J=15.3, 8.4 Hz, 2H), 6.58 (dd, J=8.6, 2.5 Hz, 1H), 6.52 (d, J=2.5
Hz, 1H), 5.42 (td, J=10.3, 9.8, 6.0 Hz, 1H), 5.33 (d, J=8.8 Hz,
1H), 5.24-5.16 (m, 1H), 5.01 (s, 2H), 3.92 (s, 3H), 2.50 (ddd,
J=13.4, 6.1, 2.0 Hz, 1H), 1.83-1.71 (m, 2H), 1.66-1.61 (m, 1H),
1.07 (td, J=3.6, 2.1 Hz, 2H); MS (ESI-) m/z 612 (M-H).sup.-.
Example 96
3-[(2R,4R)-7-(carboxymethoxy)-44
{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-di-
hydro-2H-chromen-2-yl]benzoic acid
Example 96A
methyl
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec-
arboxamido)-7-(2-methoxy-2-oxoethoxy)chroman-2-yl)benzoate
[1796] The title compound was prepared using conditions similar to
that described in Example 94, substituting methyl 2-hydroxyacetate
for 2-methoxyethanol. LC/MS m/z 596 (M+H).sup.+.
Example 96B
3-[(2R,4R)-7-(carboxymethoxy)-44
{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-di-
hydro-2H-chromen-2-yl]benzoic acid
[1797] Example 96A (60 mg, 0.10 mmol) and lithium hydroxide (24 mg,
1.0 mmol) in methanol (2 mL) and water (0.5 mL) were stirred at
ambient temperature for 1 hour and LC/MS indicated the reaction was
complete. Purification of the mixture by preparative LC method TFA2
provided the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.00 (s, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.65 (d, J=7.7 Hz,
1H), 7.52 (t, J=7.7 Hz, 1H), 7.39 (d, J=1.7 Hz, 1H), 7.31 (d, J=8.3
Hz, 1H), 7.24-7.11 (m, 2H), 6.96 (d, J=8.6 Hz, 1H), 6.51 (dd,
J=8.6, 2.6 Hz, 1H), 6.35 (d, J=2.5 Hz, 1H), 5.42-5.25 (m, 2H), 4.61
(s, 2H), 2.16-1.94 (m, 2H), 1.53-1.32 (m, 2H), 1.05 (d, J=3.2 Hz,
2H), MS (ESI-) m/z 566 (M-H).sup.-.
Example 97
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
[1798] The mixture of Example 94 (50 mg, 0.086 mmol) and lithium
hydroxide (12.35 mg, 0.516 mmol) in methanol (2 mL) and water (0.5
mL) was stirred at ambient temperature for 1 hour and LC/MS showed
the reaction was complete. Purification of the reaction mixture by
preparative LC method AA2 provided the title compound. .sup.1H NMR
(501 MHz, CDCl.sub.3) .delta. 8.17 (s, 1H), 8.04 (s, 1H), 7.61 (s,
1H), 7.44 (s, 1H), 7.16-7.04 (m, 2H), 7.00 (d, J=8.2 Hz, 1H), 6.94
(d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 6.44 (s, 1H), 5.46 (s,
1H), 5.39 (d, J=8.8 Hz, 1H), 5.23 (s, 1H), 4.13-3.97 (m, 2H), 3.71
(t, J=4.7 Hz, 2H), 3.43 (s, 3H), 2.54 (s, 1H), 1.76 (d, J=9.6 Hz,
2H), 1.08 (d, J=3.3 Hz, 2H); MS (ESI-) m/z 566 (M-H).sup.-.
Example 98
3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopr-
opyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1799] The mixture of Example 95 (60 mg, 0.098 mmol) and lithium
hydroxide (14.05 mg, 0.587 mmol) in methanol (2 ml) and water (0.5
ml) was stirred at ambient temperature for 2 hour and LC/MS showed
the reaction done. Purification of the reaction mixture by
preparative LC method AA2 provided the title compound (43 mg, 73.3%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15 (s, 1H),
8.01 (s, 1H), 7.55 (s, 1H), 7.45-7.30 (m, 6H), 7.09 (t, J=9.0 Hz,
2H), 7.02-6.84 (m, 2H), 6.51 (d, J=30.6 Hz, 2H), 5.41 (s, 2H), 5.16
(s, 1H), 4.97 (s, 2H), 2.52 (s, 1H), 1.75 (s, 2H), 1.26 (s, 1H),
1.07 (s, 2H); MS (ESI-) m/z 598 (M-H).sup.-.
Example 99
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1'-[(2R)-2,3-dihydroxypropyl]-7-f-
luoro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl}cyclopropanecarboxami-
de
[1800] A solution of the product from Example 93 (9.8 mg, 0.021
mmol) in methanol (0.3 mL) was treated with an excess of
(S)-glycidol (20 mg), stirred at room temperature for 30 minutes
and heated at 65.degree. C. for 45 minutes. The mixture was cooled,
diluted with ethyl acetate (2 mL), diluted with heptanes (2 mL),
and directly chromatographed on silica gel eluted with a gradient
of 0%-100% [3:1 ethyl acetate:methanol] in ethyl acetate to provide
the title compound (5.6 mg, 10.48 .mu.mol, 49.2% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.18-7.10 (m, 2H), 7.07-6.97
(m, 2H), 6.60 (td, J=8.4, 2.5 Hz, 1H), 6.52 (dd, J=10.2, 2.4 Hz,
1H), 5.37-5.29 (m, 1H), 5.21 (q, J=8.7 Hz, 1H), 3.89-3.82 (m, 1H),
3.79-3.74 (m, 1H), 3.52 (dd, J=11.4, 4.0 Hz, 1H), 2.90-2.78 (m,
1H), 2.74-2.53 (m, 3H), 2.46 (dt, J=12.8, 3.4 Hz, 1H), 2.42-1.97
(m, 5H), 1.89 (d, J=13.9 Hz, 1H), 1.81-1.65 (m, 4H), 1.55 (dd,
J=13.3, 10.5 Hz, 1H), 1.11 (dd, J=3.1, 1.6 Hz, 2H); MS (ESI) m/z
533 (M-H).sup.-.
Example 100
benzyl
4'-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}ami-
no)-7'-fluoro-3',4'-dihydro-1H-spiro[azetidine-3,2'-chromene]-1-carboxylat-
e
Example 100A
benzyl 3-(2-(4-fluoro-2-hydroxyphenyl)-2-oxoethyl)-3-hydroxy
azetidine-1-carboxylate
[1801] A solution of diisopropylamine (1.573 mL, 11.04 mmol) in
tetrahydrofuran (11 mL) was cooled to -10.degree. C., treated
dropwise with 2.5 M n-BuLi in hexanes (4.41 mL, 11.04 mmol),
stirred at -10.degree. C. for 5 minutes, treated dropwise with a
solution of 4'-fluoro-2'-hydroxyacetophenone (0.81 g, 5.26 mmol) in
tetrahydrofuran (5 mL), stirred between -10.degree. C. and
0.degree. C. for 1 hour, cooled to -60.degree. C., treated dropwise
with a solution of benzyl 3-oxoazetidine-1-carboxylate (1.402 g,
6.83 mmol) in tetrahydrofuran (5 mL) over 15 minutes, stirred
between -60.degree. C. and -50.degree. C. for 10 minutes, treated
with a 10% aqueous solution of KH.sub.2PO.sub.4 (50 mL) and allowed
to warm to room temperature. The mixture was extracted with ethyl
acetate (twice). The combined ethyl acetate layers were washed with
brine, dried (MgSO.sub.4), filtered, concentrated, and
chromatographed on silica gel eluted with a gradient of 20%-100%
ethyl acetate in heptanes to provide the title compound (1.35 g,
3.76 mmol, 71.5% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 12.08 (s, 1H), 7.72 (dd, J=8.8, 6.3 Hz, 1H), 7.40-7.26 (m, 5H),
6.71-6.63 (m, 2H), 5.10 (s, 2H), 4.11 (d, J=9.5 Hz, 2H), 3.95 (d,
J=9.4 Hz, 2H), 3.79 (s, 1H), 3.50 (s, 2H); MS (ESI) m/z 342
(M+H).sup.+.
Example 100B
benzyl
7'-fluoro-4'-oxospiro[azetidine-3,2'-chroman]-1-carboxylate
[1802] A solution of the product from Example 100A (1.25 g, 3.48
mmol) in pyridine (2.81 mL, 34.8 mmol) was cooled to 0.degree. C.,
treated dropwise with trifluoroacetic anhydride (0.737 mL, 5.22
mmol) over 20 minutes, stirred at 0.degree. C. for 30 minutes,
treated dropwise with more trifluoroacetic anhydride (0.5 mL),
stirred at 0.degree. C. for 30 minutes, treated with more
trifluoroacetic anhydride (0.7 mL), and stirred at room temperature
for 2 hours. The mixture was diluted with ethanol (10 mL), treated
with 1,8-diazabicyclo[5.4.0]undec-7-ene (6 mL), stirred at
50.degree. C. for 5 minutes, treated with more
1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL), stirred at 50.degree. C.
for 15 minutes, and stirred at room temperature over night. Mixture
was diluted with tert-butyl methyl ether (75 mL) and washed with
water (25 mL), washed with 1 M HCl (2.times.25 mL), washed with 1 M
NaOH (2.times.25 mL), washed with brine, dried (MgSO.sub.4),
filtered, concentrated, and chromatographed on silica gel eluted
with a gradient of 15%-50% ethyl acetate in heptanes to provide the
title compound (0.54 g, 1.582 mmol, 45.5% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.89 (dd, J=8.8, 6.5 Hz, 1H),
7.39-7.28 (m, 5H), 6.79 (td, J=8.4, 2.4 Hz, 1H), 6.74 (dd, J=9.6,
2.3 Hz, 1H), 5.11 (s, 2H), 4.16 (d, J=9.7 Hz, 2H), 4.04 (d, J=9.7
Hz, 2H), 3.02 (s, 2H); MS (ESI) m/z 342 (M+H).sup.+.
Example 100C
benzyl 7'-fluoro-4'-hydroxy
spiro[azetidine-3,2'-chroman]-1-carboxylate
[1803] The title compound was prepared using the procedure similar
to that as described in Example 92A, substituting the product from
Example 100B for tert-butyl
7-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.37-7.27 (m, 6H),
6.69 (td, J=8.3, 2.5 Hz, 1H), 6.62 (dd, J=10.0, 2.6 Hz, 1H), 5.12
(s, 2H), 4.87-4.83 (m, 1H), 4.38 (d, J=9.5 Hz, 1H), 4.19 (d, J=9.5
Hz, 1H), 4.07 (d, J=9.5 Hz, 2H), 2.38 (dd, J=14.0, 4.9 Hz, 1H),
2.26 (dd, J=14.0, 4.6 Hz, 1H), 1.77 (s, 1H); MS (ESI) m/z 344
(M+H).sup.+.
Example 100D
benzyl
4'-azido-7'-fluorospiro[azetidine-3,2'-chroman]-1-carboxylate
[1804] The title compound was prepared using the procedure similar
to that as described in Example 92B, substituting the product from
Example 100C for the product from Example 92A. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.39-7.29 (m, 5H), 7.21 (dd, J=8.6,
6.3 Hz, 1H), 6.72 (td, J=8.3, 2.6 Hz, 1H), 6.66 (dd, J=9.9, 2.5 Hz,
1H), 5.12 (s, 2H), 4.65 (t, J=4.8 Hz, 1H), 4.35 (d, J=9.6 Hz, 1H),
4.19 (d, J=9.6 Hz, 1H), 4.09-4.04 (m, 2H), 2.38 (dd, J=14.1, 4.6
Hz, 1H), 2.28 (dd, J=14.1, 4.9 Hz, 1H); MS (ESI) m/z 369
(M+H).sup.+.
Example 100E
benzyl
4'-amino-7'-fluorospiro[azetidine-3,2'-chroman]-1-carboxylate
[1805] The title compound was prepared using the procedure similar
to that as described in Example 92C, substituting the product from
Example 100D for the product from Example 92B. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.79 (bs, 1H), 7.56 (bs, 1H),
7.41-7.29 (m, 6H), 6.67 (td, J=8.4, 2.6 Hz, 1H), 6.57 (dd, J=10.0,
2.6 Hz, 1H), 5.12 (s, 2H), 4.24-4.14 (m, 2H), 4.08 (d, J=9.4 Hz,
1H), 4.04 (dd, J=8.9, 5.4 Hz, 1H), 3.99 (d, J=9.3 Hz, 1H), 2.36
(dd, J=13.4, 5.3 Hz, 1H), 1.99 (dd, J=13.3, 9.0 Hz, 1H).
Example 100F
benzyl
4'-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}ami-
no)-7'-fluoro-3',4'-dihydro-1H-spiro[azetidine-3,2'-chromene]-1-carboxylat-
e
[1806] A mixture of the product from Example 100E (86 mg, 0.251
mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (201 mg, 0.528 mmol) and
1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylic acid
(122 mg, 0.502 mmol) in tetrahydrofuran (2 mL) was treated with
triethylamine (140 .mu.L, 1.005 mmol), and stirred at room
temperature for 1 hour. The mixture was diluted with ethyl acetate
(30 mL), washed with 10% aqueous citric acid (10 mL), washed with
saturated NaHCO.sub.3 solution (10 mL), washed with brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel eluting with a gradient of 50%-100% [9:1 CH.sub.2Cl.sub.2:ethyl
acetate] in heptanes to provide the title compound (90 mg, 0.159
mmol, 63.2% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.40-7.29 (m, 5H), 7.16-7.07 (m, 2H), 6.97 (dd, J=8.6, 6.2 Hz, 2H),
6.63 (td, J=8.4, 2.6 Hz, 1H), 6.55 (dd, J=9.8, 2.6 Hz, 1H),
5.33-5.27 (m, 1H), 5.20-5.09 (m, 3H), 4.09-3.95 (m, 4H), 2.41 (dd,
J=13.5, 5.7 Hz, 1H), 1.97 (dd, J=13.5, 9.1 Hz, 1H), 1.76-1.65 (m,
2H), 1.15-1.06 (m, 2H); MS (ESI) m/z 565 (M-H).sup.-.
Example 101
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7-fluoro-1'-(methylsulfonyl)-3,4--
dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide
[1807] A solution of the product from Example 93 (11.1 mg, 0.024
mmol) in CH.sub.2Cl.sub.2 (0.3 mL) was treated with triethylamine
(0.03 mL), and methanesulfonyl chloride (2 drops). The mixture was
stirred at room temperature for 15 minutes and partitioned between
ethyl acetate (30 mL) and 1 M HCl (10 mL). The layers were
separated. The ethyl acetate layer was washed with saturated
NaHCO.sub.3 solution (10 mL), washed with brine, dried
(MgSO.sub.4), filtered, concentrated, and chromatographed on silica
gel eluted with a gradient of 25%-100% ethyl acetate in heptanes to
provide the title compound (11.6 mg, 0.022 mmol, 89% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.15 (dd, J=8.2, 1.7
Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.06-7.00 (m, 2H), 6.62 (td,
J=8.4, 2.6 Hz, 1H), 6.53 (dd, J=10.0, 2.6 Hz, 1H), 5.32 (d, J=8.7
Hz, 1H), 5.27-5.18 (m, 1H), 3.67-3.55 (m, 2H), 3.16 (dt, J=11.8,
7.4 Hz, 1H), 2.92 (td, J=12.0, 2.9 Hz, 1H), 2.81 (s, 3H), 2.12 (dd,
J=13.4, 6.3 Hz, 1H), 1.98 (d, J=14.0 Hz, 1H), 1.84-1.79 (m, 2H),
1.77-1.65 (m, 3H), 1.15-1.07 (m, 2H); MS (ESI) m/z 537
(M-H).sup.-.
Example 102
N-(1'-acetyl-7-fluoro-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl)-1-(2-
,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1808] A solution of the product from Example 93 (11.1 mg, 0.024
mmol) in pyridine (0.3 mL) was treated with acetic anhydride (2
drops) and stirred at room temperature for 30 minutes. The mixture
was partitioned between tert-butyl methyl ether (30 mL) and 1 M HCl
(15 mL). The layers were separated and the tert-butyl methyl ether
layer was washed with 1 M NaOH (10 mL), washed with brine, dried
(MgSO.sub.4), filtered, concentrated, and chromatographed on silica
gel eluted with a gradient of 25%-100% [3:1 ethyl acetate:ethanol]
in ethyl acetate to provide the title compound (10 mg, 0.020 mmol,
83% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.15 (dt,
J=8.1, 1.8 Hz, 1H), 7.11 (s, 1H), 7.02 (dd, J=16.6, 7.1 Hz, 2H),
6.61 (td, J=8.4, 2.6 Hz, 1H), 6.53 (ddd, J=10.1, 5.2, 2.6 Hz, 1H),
5.33 (t, J=7.9 Hz, 1H), 5.25-5.18 (m, 1H), 4.36 (dd, J=18.9, 14.3
Hz, 1H), 3.65-3.51 (m, 1.5H), 3.35 (ddd, J=13.9, 12.1, 3.0 Hz,
0.5H), 3.17-3.09 (m, 0.5H), 2.89 (td, J=12.8, 3.1 Hz, 0.5H),
2.14-2.06 (m, 4H), 1.89 (ddd, J=19.2, 14.1, 3.0 Hz, 1H), 1.79-1.47
(m, 6H), 1.14-1.06 (m, 2H); MS (ESI) m/z 501 (M-H).sup.-.
Example 103
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7'-fluoro-3',4'-dihydrospiro[azet-
idine-3,2'-chromen]-4'-yl)cyclopropanecarboxamide
[1809] A mixture of the product from Example 100F (81 mg, 0.143
mmol), 10% Pd on carbon (15 mg) and isopropyl alcohol (1 mL) was
stirred under an atmosphere of H.sub.2 using a balloon for 1 hour
at room temperature, heated at 60.degree. C. for 5 minutes, and
stirred again at room temperature for 15 minutes. The mixture was
filtered and the filtrate was concentrated to provide the title
compound (63.2 mg, 0.146 mmol, 102% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.15 (dd, J=8.2, 1.7 Hz, 1H), 7.12 (d,
J=1.6 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.97 (dd, J=8.5, 6.4 Hz,
1H), 6.60 (td, J=8.4, 2.6 Hz, 1H), 6.54 (dd, J=9.9, 2.5 Hz, 1H),
5.32 (d, J=8.4 Hz, 1H), 5.21-5.13 (m, 1H), 3.85-3.72 (m, 2H), 3.65
(d, J=8.0 Hz, 1H), 3.57 (d, J=8.2 Hz, 1H), 2.52 (dd, J=13.4, 5.7
Hz, 1H), 1.90 (dd, J=13.4, 9.4 Hz, 1H), 1.75-1.65 (m, 2H),
1.15-1.06 (m, 2H); MS (ESI) m/z 433 (M+H).sup.+.
Example 104
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7'-fluoro-1-(methylsulfonyl)-3',4-
'-dihydrospiro[azetidine-3,2'-chromen]-4'-yl]cyclopropanecarboxamide
[1810] The title compound was prepared using procedure similar to
that described in Example 101, substituting the product from
Example 103 for the product from Example 93. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.16 (dd, J=8.2, 1.7 Hz, 1H), 7.12 (d,
J=1.6 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.99 (dd, J=8.6, 6.3 Hz,
1H), 6.65 (td, J=8.3, 2.5 Hz, 1H), 6.56 (dd, J=9.7, 2.5 Hz, 1H),
5.31 (d, J=8.0 Hz, 1H), 5.21-5.13 (m, 1H), 4.02 (d, J=8.8 Hz, 1H),
3.99 (s, 2H), 3.91 (d, J=8.7 Hz, 1H), 2.91 (s, 3H), 2.50 (dd,
J=13.4, 5.7 Hz, 1H), 1.97 (dd, J=13.4, 9.5 Hz, 1H), 1.77-1.65 (m,
2H), 1.13 (s, 2H); MS (ESI) m/z 511 (M+H).sup.+.
Example 105
N-(1-acetyl-7'-fluoro-3',4'-dihydrospiro[azetidine-3,2'-chromen]-4'-yl)-1--
(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1811] The title compound was prepared using procedure similar to
that described in Example 102, substituting the product from
Example 103 for the product from Example 93, provided the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.18-7.11
(m, 2H), 7.01 (ddd, J=25.6, 8.4, 6.2 Hz, 2H), 6.65 (td, J=8.4, 2.4
Hz, 1H), 6.56 (dt, J=9.7, 2.9 Hz, 1H), 5.38-5.28 (m, 1H), 5.23-5.14
(m, 1H), 4.16-3.98 (m, 4H), 2.47-2.40 (m, 1H), 2.01-1.93 (m, 1H),
1.89 (s, 3H), 1.77-1.64 (m, 2H), 1.17-1.07 (m, 2H); MS (ESI) m/z
475 (M+H).sup.+.
Example 106
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
Example 106A
methyl
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec-
arboxamido)-7-(2-fluoroethoxy)chroman-2-yl)benzoate
[1812] To Example 23E (65 mg, 0.124 mmol) and 2-fluoroethanol
(11.93 mg, 0.186 mmol) in CH.sub.2Cl.sub.2 (2 ml) was added
triphenylphosphine (65.1 mg, 0.248 mmol), followed by addition of
di-tert-butyl azodicarboxylate (57.2 mg, 0.248 mmol) in portion.
The mixture was stirred at ambient temperature for 2 hours and
LC/MS indicated the reaction was complete. Solvent was removed and
residue purified by chromatography on a 1 2 g silica gel cartridge,
eluting with ethyl acetate in heptane at 5-40% gradient to provide
the title compound (63 mg, 90%). LC/MS m/z 570 (M+H).sup.+.
Example 106B
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
[1813] Example 106A (60 mg, 0.105 mmol) and 2 M lithium hydroxide
aqueous (0.5 mL) in methanol (2 mL) was stirred at ambient
temperature overnight. Solvent was removed and water (1 mL) added
to the mixture. The mixture was adjusted with 2 M HCl to pH
1.about.2. The precipitated white solid was collected by filtration
and dried to yield the title compound (43 mg, 74% yield). .sup.1H
NMR (501 MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 8.05 (s, 1H), 7.64
(s, 1H), 7.50 (s, 1H), 7.16-7.04 (m, 2H), 7.00 (d, J=8.2 Hz, 1H),
6.94 (d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 6.45 (s, 1H), 5.50
(s, 1H), 5.39 (d, J=8.8 Hz, 1H), 5.28 (s, 1H), 4.78 (d, 1H), 4.66
(d, 1H), 4.18 (s, 1H), 4.12 (s, 1H), 2.6-2.55 (m, 2H), 1.76 (m,
2H), 1.08 (m, 2H); MS (ESI-) m/z 554 (M-H).sup.-.
Example 107
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1'-(3-hydroxy-2,2-dimethylpropano-
yl)-7-methoxy-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanec-
arboxamide
Example 107A
1'-(3-hydroxy-2,2-dimethylpropanoyl)-7-methoxyspiro[chroman-2,4'-piperidin-
]-4-one
[1814] To 3-hydroxy-2,2-dimethylpropanoic acid (112 mg, 0.952 mmol)
in DMF (4 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (543 mg, 1.427 mmol). The mixture was
stirred for 5 minutes at room temperature, followed by the
sequential addition of
7-methoxyspiro[chroman-2,4'-piperidin]-4-one, hydrochloric acid
(CAS 1031416-37-1, MFCD11973587) (270 mg, 0.952 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.663 mL, 3.81 mmol). The
mixture was stirred at room temperature for 2 hours. Purification
by chromatography on silica gel, eluting with 5-50% ethyl acetate
in heptane provided the title compound (305 mg, 92% yield). LC/MS
m/z 348 (M+H).sup.+.
Example 107B
(E)-3-hydroxy-1-(7-methoxy-4-(methoxyimino)spiro[chroman-2,4'-piperidin]-1-
'-yl)-2,2-dimethylpropan-1-one
[1815] A mixture of Example 107A, O-methylhydroxylamine,
hydrochloric acid (144 mg, 1.727 mmol) and sodium acetate (142 mg,
1.727 mmol) in methanol (10 mL) was stirred at 60.degree. C. for
overnight. Solvent was removed and the residue was taken up in
ethyl acetate, and then washed with water. The organic layers was
dried over MgSO.sub.4, filtered, and concentrated. Purification by
preparative LC method AA2 provided the title compound (300 mg, 92%
yield). LC/MS m/z 377 (M+H).sup.+.
Example 107C
1-(4-amino-7-methoxyspiro[chroman-2,4'-piperidin]-1'-yl)-3-hydroxy-2,2-dim-
ethylpropan-1-one
[1816] Example 107B (300 mg, 0.797 mmol) and 5% platinum (155 mg,
0.040 mmol) in acetic acid (5 mL) was charged with 30 psi hydrogen
for 24 hours. The reaction mixture was filtered and solvent was
removed under reduced pressure. The residue was purified by
preparative LC method TFA2 to provide the trifluoroacetic acid salt
of the title compound (110 mg, 0.316 mmol, 39.6% yield). LC/MS m/z
350 (M+2H).sup.+.
Example 107D
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1'-(3-hydroxy-2,2-dimethylpropano-
yl)-7-methoxy-3,4-dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanec-
arboxamide
[1817] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(57.6 mg, 0.238 mmol) in DMF (4 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (123 mg, 0.324 mmol). The mixture was
stirred for 5 minutes at room temperature, followed by the
sequential addition of Example 107C (100 mg, 0.216 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.151 ml, 0.865 mmol). The
mixture was stirred at room temperature for 2 hours. LC/MS showed
the reaction was complete. Purification of the reaction mixture by
chromatography on 24 g silica gel cartridge, eluting with 5-50%
ethyl acetate in heptane provided the title compound (35 mg, 28.3%
yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.14 (dd, J=8.2,
1.7 Hz, 1H), 7.11 (d, J=1.7 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.94
(d, J=8.7 Hz, 1H), 6.49 (dd, J=8.6, 2.6 Hz, 1H), 6.36 (d, J=2.5 Hz,
1H), 5.35 (d, J=8.5 Hz, 1H), 5.23-5.11 (m, 1H), 4.15 (d, J=60.1 Hz,
2H), 3.75 (s, 3H), 3.50 (dd, J=9.9, 5.6 Hz, 2H), 3.27 (d, J=69.6
Hz, 2H), 2.56 (s, 1H), 2.12 (dd, J=13.4, 6.3 Hz, 1H), 1.93 (dq,
J=14.2, 2.6 Hz, 1H), 1.81-1.49 (m, 6H), 1.26 (d, J=1.9 Hz, 6H),
1.10 (td, J=3.3, 1.8 Hz, 2H); MS (ESI+) m/z 573 (M+H).sup.+.
Example 108
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
Example 108A
7-(trifluoromethyl)-4H-chromen-4-one
[1818] A mixture of 1-(2-hydroxy-4-(trifluoromethyl)phenyl)ethanone
(400 mg, 1.959 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine
(0.286 ml, 2.155 mmol) was heated at 120.degree. C. for 2 hours,
and cooled down. The precipitated orange solid was collected by
filration, washed with heptane, and dried to yield
(E)-3-(dimethylamino)-1-(4-trifluoromethyl-2-hydroxyphenyl)prop-2-en-1-on-
e which was dissolved in dichloromethane (120 mL) and treated with
concentrated HCl (15 mL). The mixture was refluxed for 2 hours. The
aqueous layer was removed and organic layer was washed with brine
(50 mL.times.2), and concentrated. The residue was purified by
chromatography on a 80 g silica gel cartridge, eluting with 5-30%
ethyl acetate in heptane to yield the title compound (310 mg, 73.9%
yield) as white solid.
Example 108B
(R)-methyl 3-(4-oxo-7-(trifluoromethyl)chroman-2-yl)benzoate
[1819] A mixture of bis(2,2,2-trifluoroacetoxy)palladium (46.6 mg,
0.140 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole
(34.3 mg, 0.168 mmol), ammonium hexafluorophosphate(V) (137 mg,
0.841 mmol), (3-(methoxycarbonyl)phenyl)boronic acid (504 mg, 2.80
mmol) and dichloroethane (5 mL) in a vial (20 mL) were stirred for
5 minutes at room temperature. Example 108A (300 mg, 1.41 mmol) and
water (0.256 mL, 14.19 mmol) were added to the mixture. The vial
was capped and the mixture stirred at 60.degree. C. overnight. The
mixture was filtered through a plug of celite and eluted with ethyl
acetate. The organic layers were removed in vacuo and the crude
material was chromatographed using a 80 g silica gel cartridge,
eluting with 5-40% ethyl acetate in heptane to provide the title
compound (230 mg, 46.9% yield).
Example 108 C
(R)-methyl
3-(4-(methoxyimino)-7-(trifluoromethyl)chroman-2-yl)benzoate
[1820] A mixture of Example 108B (230 mg, 2.53 mmol), sodium
acetate (108 mg, 1.31 mmol) and O-methylhydroxylamine, hydrochloric
acid (110 mg, 1.31 mmol) in methanol (10 mL) was stirred at
60.degree. C. overnight. The solvent was evaporated under reduced
pressure and the residue dissolved in ethyl acetate and washed with
water, dried over MgSO.sub.4, filtered, and concentrated. The title
compound (225 mg, 90% yield) was carried on to next step without
further purification. LC/MS m/z 380 (M+H).sup.+.
Example 108D
methyl
3-((2R,4R)-4-amino-7-(trifluoromethyl)chroman-2-yl)benzoate
[1821] To a mixture of Example 108C (270 mg, 0.712 mmol) and acetic
acid (30 mL) was added 5% platinum/carbon wet (90 mg, 0.190 mmol)
in a 50 mL pressure bottle and stirred for 32 hours at 30 psi of
hydrogen and at ambient temperature. The reaction mixture was
filtered, and the filtrate was concentrated under reduced pressure.
The resulting oil was purified by preparative LC method TFA2 to
provide the title compound and methyl
3-((2R,4R)-4-amino-7-(trifluoromethyl)chroman-2-yl)cyclohexanecarboxylate-
.
Example 108E
methyl
3-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec-
arboxamido)-7-(trifluoromethyl)chroman-2-yl)benzoate
[1822] A mixture of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(76 mg, 0.313 mmol) and HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (162 mg, 0.427 mmol) in DMF (4 mL) was
stirred for 5 minutes at room temperature, followed by the
sequential addition of Example 108D (150 mg, 0.48 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.198 mL, 1.14 mmol). The
mixture was stirred at ambient temperature for 2 hours. LC/MS
indicated the reaction was complete. Purification by chromatography
on 12 g silica gel cartridge, eluting with 5-40% ethyl acetate in
heptane to provide the title compound (45 mg, 27.5% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (t, J=1.9 Hz, 1H), 8.05-7.99
(m, 1H), 7.59 (dt, J=7.7, 1.6 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H),
7.21-7.15 (m, 3H), 7.14-7.08 (m, 2H), 7.03 (d, J=8.2 Hz, 1H),
5.60-5.48 (m, 1H), 5.40 (d, J=9.0 Hz, 1H), 5.28 (dd, J=11.5, 2.0
Hz, 1H), 3.94 (s, 3H), 3.69-3.63 (m, 1H), 2.53 (ddd, J=13.5, 6.2,
2.1 Hz, 1H), 1.89-1.79 (m, 2H), 1.12 (td, J=6.6, 3.2 Hz, 2H); MS
(ESI-) m/z 574 (M-H).sup.-
Example 108F
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
[1823] A mixture of Example 108E (40 mg, 0.07 mmol) and 2 M NaOH
(0.2 mL) in methanol (1 mL) was stirred at 35.degree. C. for 2
hours and the solvent was removed in vacuo. Water (0.5 mL) was
added to the residue and the pH was adjusted to 1.about.2. The
precipitated solid was collected by filtration, washed with water,
and dried to provide the title compound (33 mg, 85%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.18 (s, 1H), 8.12-8.03 (m, 1H), 7.65
(d, J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.20-7.06 (m, 6H),
5.71-5.52 (m, 1H), 5.45 (d, J=9.0 Hz, 1H), 5.32 (d, J=10.9 Hz, 1H),
2.58 (dd, J=13.3, 6.0 Hz, 1H), 1.84-1.77 (m, 1H), 1.73-1.60 (m,
2H), 1.15-1.07 (m, 2H); MS (ESI-) m/z 560 (M-H).sup.-.
Example 109
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxyl-
ic acid
Example 109A
methyl
34(2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropaneca-
rboxamido)-7-(trifluoromethyl)chroman-2-yl)cyclohexanecarboxylate
[1824] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(52.2 mg, 0.215 mmol) in DMF (1 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (112 mg, 0.294 mmol). The mixture was
stirred for 5 minutes at room temperature, followed by sequential
addition of methyl
34(2R,4R)-4-amino-7-(trifluoromethyl)chroman-2-yl)cyclohexanecarbo-
xylate (70 mg, 0.196 mmol) and N-ethyl-N-isopropylpropan-2-amine
(0.136 ml, 0.784 mmol). The mixture was stirred at ambient
temperature for 2 hours. LC/MS showed the reaction was complete.
Purification by chromatography on 12 g silica gel cartridge,
eluting with 5-40% ethyl acetate in heptane provided the title
compound (40 mg, 0.069 mmol, 35.1% yield). MS (ESI+) m/z 581.9
(M+H).sup.+.
Example 109B
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxyl-
ic acid
[1825] A mixture of Example 109A (36 mg, 0.062 mmol) and aqueous
NaOH aqueous (2 M, 0.2 mL) in methanol (1 mL) was stirred at
35.degree. C. for 2 hours. The solvent was removed, and water (0.5
mL) was added. The pH of the mixture was adjusted to 1.about.2. The
precipitated solid was collected by filtration, washed with water,
and dried to provide the title compound (28 mg, 80%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.21-6.97 (m, 6H), 5.49-5.24 (m, 2H),
3.98 (dt, J=11.4, 6.3 Hz, 1H), 2.38 (d, J=10.9 Hz, 1H), 2.25 (dd,
J=13.2, 5.3 Hz, 2H), 2.10-1.86 (m, 3H), 1.72 (ddd, J=27.0, 10.1,
3.8 Hz, 4H), 1.58-1.41 (m, 2H), 1.35 (q, J=12.8, 11.7 Hz, 2H), 1.12
(d, J=3.5 Hz, 2H),); MS (ESI+) m/z 567.9 (M+H).sup.+.
Example 110
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 110A
(R)-methyl 4-(7-methoxy-4-oxochroman-2-yl)benzoate
[1826] A 20 mL vial was charged with
bis(2,2,2-trifluoroacetoxy)palladium (0.264 g, 0.795 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.195 g,
0.954 mmol), ammonium hexafluorophosphate(V) (0.777 g, 4.77 mmol)
and (4-(methoxycarbonyl)phenyl)boronic acid (2.86 g, 15.89 mmol).
The reaction was stirred in dichloroethane (5 mL) for 5 minutes,
and a pale brown color suspension was observed. To this suspension
was added Example 5A (1.4 g, 7.95 mmol) and water (0.716 mL, 39.7
mmol) and the sides of the vial washed with more dichloroethane (5
mL). The vial was capped and the mixture stirred at 60.degree. C.
overnight. The mixture was filtered through a plug of silica gel
and celite and eluted with ethyl acetate to give a red solution.
The solvent was removed under reduced pressure and the crude
material was chromatographed using a 24 g silica gel cartridge with
a gradient of 5-60% ethyl acetate/heptanes over 20 minutes, a white
solid precipitated in the middle of fractions collection and
clogged up the line into the IR detection unit. The output line was
unclogged and the white solid was filtered, the filtrate was
concentrated and chromatographed again using a 12 g cartridge
eluting with 100% dichloromethane to give a white solid which was
combined to give the title compound (1.6 g, 5.12 mmol, 64.5%
yield)). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.02 (dd,
J=8.4, 2.1 Hz, 2H), 7.75-7.72 (m, 1H), 7.70 (d, J=8.4 Hz, 2H),
6.72-6.66 (m, 2H), 5.77 (dd, J=12.9, 3.1 Hz, 1H), 3.87 (s, 3H),
3.83 (d, J=2.0 Hz, 3H), 3.14 (dd, J=16.8, 12.9 Hz, 1H), 2.82 (dd,
J=16.7, 3.1 Hz, 1H); MS (EST+) m/z 313 (M+H).sup.+.
Example 110B
(R)-methyl 4-(7-methoxy-4-(methoxyimino)chroman-2-yl)benzoate
[1827] A solution of the product from Example 110A (0.6 g, 1.921
mmol), O-methylhydroxylamine hydrochloride (0.241 g, 2.88 mmol) in
pyridine (1.921 mL) in a 20 mL vial was stirred at ambient
temperature for 5 minutes and 65.degree. C. for 1 hour. The solvent
was removed under reduced pressure. The crude material was
dissolved in 10% methanol/dichloromethane and washed with water.
The organic layer was separated, and concentrated in vacuo. The
resulted white solid was rinsed with 10% dichloromethane/hexane and
collected by filtration to give title compounds as white solid
(0.581 g, 1.702 mmol, 89% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.03-7.96 (m, 2H), 7.71 (d, J=8.7 Hz, 1H),
7.69-7.63 (m, 2H), 6.62 (dd, J=8.8, 2.5 Hz, 1H), 6.59 (d, J=2.5 Hz,
1H), 5.32 (dd, J=11.8, 3.2 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H),
3.76 (s, 3H), 3.36 (d, J=3.4 Hz, 1H), 2.71 (dd, J=17.1, 11.9 Hz,
1H); MS (EST+) m/z 342 (M+H).sup.+.
Example 110C
methyl 4-((2R,4R)-4-amino-7-methoxychroman-2-yl)benzoate
[1828] To a mixture of Example 110B (580 mg, 1.69 mmol) and acetic
acid (20 mL) was added platinum (180 mg, 0.923 mmol) in a 50 mL
pressure bottle and stirred for 32 hours at 30 psi of hydrogen and
at ambient temperature. The reaction mixture was filtered, and the
filtrate was concentrated under reduced pressure. The resulting oil
was purified by flash chromatography on a 24 g cartridge, and
eluted with 5-70% ethyl acetate/heptane over 20 minutes to provide
the title compound (240 mg, 0.766 mmol, 45.1% yield) as white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.06-7.97 (m,
2H), 7.64-7.57 (m, 2H), 7.47 (d, J=8.5 Hz, 1H), 6.52 (dd, J=8.6,
2.6 Hz, 1H), 6.38 (d, J=2.5 Hz, 1H), 5.29 (dd, J=11.9, 1.7 Hz, 1H),
4.07 (dd, J=11.0, 5.7 Hz, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 2.28
(ddd, J=13.1, 5.7, 1.9 Hz, 1H), 1.72 (dt, J=13.0, 11.4 Hz, 1H); MS
(ESI+) m/z 314 (M+H).sup.+.
Example 110D
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate
[1829] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(83 mg, 0.345 mmol) in DMF (1 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (183 mg, 0.483 mmol). The solution was
stirred for 15 minutes at room temperature, followed by sequential
addition of Example 110C (108 mg, 0.345 mmol) and triethylamine
(0.144 mL, 1.034 mmol). The mixture was stirred at ambient
temperature for 5 hours and water (10 mL) was added. The resulted
white precipitate was filtered and purified by flash chromatography
on a 12 g cartridge, eluted with 5-60% ethyl acetate/heptane over
20 minutes to provide the title compound (126 mg, 0.234 mmol, 68.0%
yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.00-7.94 (m, 2H), 7.58-7.52 (m, 2H), 7.37 (d, J=1.7 Hz,
1H), 7.29 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 7.15 (d,
J=8.9 Hz, 1H), 6.93 (dd, J=8.5, 1.1 Hz, 1H), 6.51 (dd, J=8.6, 2.6
Hz, 1H), 6.39 (d, J=2.5 Hz, 1H), 5.33 (q, J=9.5, 8.4 Hz, 2H), 3.84
(s, 3H), 3.67 (s, 3H), 2.11-1.99 (m, 2H), 1.54-1.41 (m, 1H),
1.41-1.29 (m, 1H), 1.07-0.96 (m, 2H); MS (ESI-) m/z 536
(M-H).sup.-.
Example 111
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1830] To a solution of the product from Example 110D (81 mg, 0.151
mmol) in ethanol (1 mL) and tetrahydrofuran (0.4 mL) was added 3 N
sodium hydroxide (0.201 mL, 0.603 mmol). The reaction was stirred
at room temperature for 16 hours. The reaction was quenched with
HCl (1 N, 1 mL), and water (2 mL) was added. The organics were
removed under a stream of nitrogen to give an off-white
precipitate. The precipitate was collected by filtration, washed
with water, and then purified by flash chromatography on a 12 g
silica gel cartridge, and eluted with a gradient of 5-90% ethyl
acetate/heptanes over 20 minutes to provide the title compound (65
mg, 0.124 mmol, 82% yield) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.93 (s, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.51
(d, J=8.3 Hz, 2H), 7.37 (d, J=1.7 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H),
7.21-7.12 (m, 2H), 6.93 (d, J=8.5 Hz, 1H), 6.50 (dd, J=8.6, 2.6 Hz,
1H), 6.39 (d, J=2.5 Hz, 1H), 5.39-5.28 (m, 2H), 3.67 (s, 3H), 2.04
(td, J=7.9, 2.3 Hz, 2H), 1.51-1.43 (m, 1H), 1.41-1.33 (m, 1H), 1.03
(q, J=2.6 Hz, 2H); MS (ESI+) m/z 522 (M-H).sup.-.
Example 112
methyl
rac-3-[(2R,4R)-7-chloro-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)c-
yclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoa-
te
Example 112A
methyl
3-(3-(6-chloro-2-fluoropyridin-3-yl)-3-hydroxypropanoyl)benzoate
[1831] A solution of methyl 3-acetylbenzoate (1 g, 5.61 mmol) in
tetrahydrofuran (25 mL) was cooled to -78.degree. C., treated
dropwise with 1 M lithium bis(trimethylsilyl)amide in
tetrahydrofuran (7.30 ml, 7.30 mmol), stirred at -78.degree. C. for
15 minutes, treated dropwise with a solution of
6-chloro-2-fluoronicotinaldehyde (0.895 g, 5.61 mmol) in
tetrahydrofuran (10 mL), stirred at -78.degree. C. for 15 minutes,
treated with saturated NH.sub.4Cl solution (30 mL) and the mixture
was allowed to warm to near room temperature. The mixture was
extracted with ethyl acetate (30 mL) and the layers were separated.
The aqueous layer was extracted with ethyl acetate (20 mL). The
combined organic layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The residue was chromatographed on
silica gel and eluted with a gradient of 20%-100% ethyl acetate in
heptanes to provide the title compound (1.35 g, 4.00 mmol, 71.2%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.56 (t,
J=1.8 Hz, 1H), 8.28 (dt, J=7.7, 1.5 Hz, 1H), 8.15 (dt, J=7.9, 1.6
Hz, 1H), 8.10-8.05 (m, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.30 (dd,
J=7.8, 1.0 Hz, 1H), 5.53 (dt, J=9.4, 2.9 Hz, 1H), 3.96 (s, 3H),
3.89 (d, J=3.9 Hz, 1H), 3.55 (dd, J=18.0, 2.4 Hz, 1H), 3.29 (dd,
J=18.0, 9.3 Hz, 1H); MS (ESI) m/z 338 (M+H).sup.+.
Example 112B
[1832] A solution of the product from Example 112A (1.35 g, 4.00
mmol) in tetrahydrofuran (40 mL) under N.sub.2 was cooled to
-78.degree. C., treated with 1 M diethylmethoxyborane in
tetrahydrofuran (4.40 ml, 4.40 mmol), stirred at -78.degree. C. for
15 minutes, treated with NaBH.sub.4 (0.166 g, 4.40 mmol), stirred
at -78.degree. C. for 30 minutes, treated with acetic acid (4 mL)
and allowed to warm to room temperature. The mixture was
concentrated to near dryness. The residue was portioned between
tert-butyl methyl ether (about 30 mL) and 0.5 M NaOH (40 mL). The
layers were separated and the organic layer was washed with 1 M
NaOH (twice), washed with brine, dried (MgSO.sub.4), filtered, and
concentrated to provide the title compound (1.38 g, 4.06 mmol, 102%
yield) as a mixture of isomers. NMR of major isomer: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 8.05-7.96 (m, 2H), 7.96-7.92 (m,
1H), 7.59-7.54 (m, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.23 (d, J=7.7 Hz,
1H), 5.25 (t, J=6.2 Hz, 1H), 5.18-5.12 (m, 1H), 4.47 (s, 1H), 3.91
(s, 3H), 3.55 (s, 1H), 2.05-2.00 (m, 2H); MS (ESI) m/z 340
(M+H).sup.+.
Example 112C
methyl
rac-3-((2R,4R)-7-chloro-4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyrid-
in-2-yl)benzoate
[1833] A solution of the product from Example 112B (1.38 g, 4.06
mmol) in 2-methyl-tetrahydrofuran (40 mL) was treated with
1,8-diazabicyclo[5.4.0]undec-7-ene (about 3 mL) and heated at
75.degree. C. for 16 hours and then, heated at 80.degree. C. for 24
hours. The mixture was cooled, diluted with ethyl acetate and
washed with 10% citric acid solution. This acidic aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried (MgSO.sub.4), filtered, and concentrated.
The residue was chromatographed on silica gel and eluted with a
gradient of 25%-100% ethyl acetate in heptanes to provide the title
compound as the first eluting isomer. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.08 (s, 1H), 8.00 (dt, J=7.8, 1.5 Hz, 1H),
7.85 (dd, J=7.8, 1.1 Hz, 1H), 7.65 (d, J=6.7 Hz, 1H), 7.46 (t,
J=7.7 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 5.35 (dd, J=11.9, 1.9 Hz,
1H), 5.12 (dd, J=10.0, 5.8 Hz, 1H), 3.92 (s, 3H), 2.55 (ddd,
J=13.4, 6.0, 2.0 Hz, 1H), 2.11 (ddd, J=13.3, 12.0, 10.8 Hz,
1H).
Example 112D
methyl
rac-3-((2R,4S)-7-chloro-4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyrid-
in-2-yl)benzoate
[1834] The title compound was isolated as the second eluting isomer
from the column chromatography as described in Example 112C.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.07 (s, 1H), 7.98
(d, J=7.9 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H),
7.43 (t, J=7.7 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 5.53 (dd, J=11.9,
2.2 Hz, 1H), 4.87 (t, J=3.0 Hz, 1H), 3.90 (s, 3H), 3.25 (s, 1H),
2.32 (dt, J=14.7, 2.5 Hz, 1H), 2.12-2.03 (m, 1H).
Example 112E
methyl
rac-3-((2R,4R)-4-azido-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
-2-yl)benzoate
[1835] A solution of the product from Example 112D (122 mg, 0.382
mmol) in tetrahydrofuran (2 mL) under N.sub.2 was cooled to
0.degree. C., treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (115
.mu.L, 0.763 mmol) treated with diphenylphosphoryl azide (140
.mu.L, 0.649 mmol) and stirred over the weekend at room
temperature. The mixture was partitioned between ethyl acetate and
saturated NaHCO.sub.3 solution. The ethyl acetate layer was washed
with 10% citric acid solution, washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel and eluted with a gradient of
10%-100% ethyl acetate in heptanes to provide the title compound
(104.7 mg, 0.304 mmol, 80% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.12 (s, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.75
(d, J=7.9 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H),
7.06 (d, J=7.9 Hz, 1H), 5.40 (d, J=11.4 Hz, 1H), 4.85 (dd, J=11.3,
6.0 Hz, 1H), 3.94 (s, 3H), 2.65 (ddd, J=13.5, 6.0, 1.9 Hz, 1H),
2.33-2.17 (m, 1H); MS (ESI) m/z 345 (M+H).sup.+.
Example 112F
methyl
rac-3-((2R,4R)-4-amino-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
-2-yl)benzoate
[1836] A solution of the product from Example 112E (104.7 mg, 0.304
mmol) and triphenylphosphine (159 mg, 0.607 mmol) in
tetrahydrofuran (1 mL) and H.sub.2O 2O (219 .mu.L, 12.15 mmol) was
heated at 70.degree. C. for 2 hours. 2-methyl-tetrahydrofuran was
added and the reaction was heated at 90.degree. C. so that
tetrahydrofuran was removed from the reaction and the mixture was
heated at 90.degree. C. overnight. The mixture was cooled and
partitioned between tert-butyl methyl ether (20 mL) and 1 M HCl (5
mL). The layers were separated and the aqueous was washed with
tert-butyl methyl ether. The aqueous layer treated with ethyl
acetate (20 mL) was basified to pH>7 with 1 M NaOH and
extracted. The ethyl acetate layer was washed with brine, dried
(MgSO.sub.4), filtered, and concentrated to provide the title
compound (64 mg, 0.201 mmol, 66.1% yield). .sup.1H NMR (501 MHz,
CDCl.sub.3) .delta. ppm 8.11 (t, J=1.8 Hz, 1H), 8.02 (dt, J=7.8,
1.4 Hz, 1H), 7.91 (dd, J=7.9, 1.1 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H),
7.48 (t, J=7.7 Hz, 1H), 7.01 (d, J=7.9 Hz, 1H), 5.38 (dd, J=11.9,
2.0 Hz, 1H), 4.28 (dd, J=11.2, 5.6 Hz, 1H), 3.93 (s, 3H), 2.48
(ddd, J=13.5, 5.6, 2.0 Hz, 1H), 1.94 (dt, J=13.5, 11.6 Hz, 1H); MS
(ESI) m/z 319 (M+H).sup.+.
Example 112G
methyl
rac-3-[(2R,4R)-7-chloro-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)c-
yclopropyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoa-
te
[1837] The title compound was prepared using the procedure similar
to that described in Example 100F, substituting the product from
Example 112F for the product from Example 100E. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.06 (d, J=1.7 Hz, 1H), 8.00 (d, J=7.9
Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (dd,
J=8.3, 1.6 Hz, 1H), 7.08 (d, J=1.6 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H),
6.96 (d, J=7.9 Hz, 1H), 5.50 (td, J=10.5, 10.1, 6.1 Hz, 1H), 5.38
(d, J=3.9 Hz, 1H), 5.36 (s, 1H), 3.92 (s, 3H), 2.50 (ddd, J=13.6,
6.1, 2.0 Hz, 1H), 1.84 (dt, J=13.6, 11.4 Hz, 1H), 1.77-1.63 (m,
2H), 1.16-1.06 (m, 2H); MS (ESI) m/z 543 (M+H).sup.+.
Example 113
methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoa-
te
Example 113A
methyl
3-(3-(2,6-difluoropyridin-3-yl)-3-hydroxypropanoyl)benzoate
[1838] The title compound was prepared using procedure similar to
that described in Example 112A, substituting
2,6-difluoronicotinaldehyde (CAS#155601-65-3) for
6-chloro-2-fluoronicotinaldehyde. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.87 (t, J=1.8 Hz, 1H), 8.59 (dt, J=7.9, 1.5 Hz, 1H),
8.54-8.49 (m, 1H), 8.47 (dt, J=8.0, 1.5 Hz, 1H), 7.90 (t, J=7.8 Hz,
1H), 7.21 (dd, J=8.1, 2.8 Hz, 1H), 5.86 (dt, J=9.3, 2.8 Hz, 1H),
4.27 (s, 3H), 4.18 (d, J=3.7 Hz, 1H), 3.85 (dd, J=18.0, 2.5 Hz,
1H), 3.61 (dd, J=18.0, 9.3 Hz, 1H); MS (ESI) m/z 339
(M+NH.sub.4).sup.+.
Example 113B
methyl
3-(3-(2,6-difluoropyridin-3-yl)-1,3-dihydroxypropyl)benzoate
[1839] The title compound was prepared using procedure similar to
that described in Example 112B, substituting the product from
Example 113A for the product from Example 112A. MS (ESI) m/z 341
(M+NH.sub.4).sup.+.
Example 113C
methyl
rac-3-((2R,4R)-7-fluoro-4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyrid-
in-2-yl)benzoate
[1840] The title compound was isolated as the first eluting isomer
when prepared using procedure similar to that described in Example
112C, substituting the product from Example 113B for the product
from Example 112B. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
8.09 (s, 1H), 8.03-7.95 (m, 2H), 7.65 (d, J=7.7 Hz, 1H), 7.47 (t,
J=7.7 Hz, 1H), 6.59 (dd, J=8.1, 2.7 Hz, 1H), 5.36 (dd, J=11.9, 2.0
Hz, 1H), 5.17-5.08 (m, 1H), 3.92 (s, 3H), 2.60 (bs, 1H), 2.56 (ddd,
J=13.4, 6.1, 2.1 Hz, 1H), 2.12 (ddd, J=13.4, 12.0, 10.6 Hz, 1H); MS
(ESI) m/z 304 (M+H).sup.+.
Example 113D
methyl
rac-3-((2R,4S)-7-fluoro-4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyrid-
in-2-yl)benzoate
[1841] The title compound was isolated as the second eluting isomer
when prepared using procedure similar to that described in Example
112C, substituting the product from Example 113B for the product
from Example 112B. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
8.14 (t, J=1.8 Hz, 1H), 8.03 (dt, J=7.7, 1.3 Hz, 1H), 7.80 (t,
J=8.0 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.61
(dd, J=8.0, 2.8 Hz, 1H), 5.55 (dd, J=12.0, 2.2 Hz, 1H), 4.90 (q,
J=3.3 Hz, 1H), 3.93 (s, 3H), 2.34 (dt, J=14.5, 2.5 Hz, 1H), 2.23
(d, J=4.0 Hz, 1H), 2.14 (ddd, J=14.9, 11.9, 3.4 Hz, 1H); MS (ESI)
m/z 304 (M+H).sup.+.
Example 113E
methyl
rac-3-((2R,4R)-4-azido-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
-2-yl)benzoate
[1842] The title compound was prepared using procedure similar to
that described in Example 112E, substituting the product from
Example 113D for the product from Example 112D. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.13 (t, J=1.8 Hz, 1H), 8.06 (dt,
J=7.8, 1.5 Hz, 1H), 7.88 (td, J=8.0, 1.0 Hz, 1H), 7.70 (d, J=7.7
Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 6.66 (dd, J=8.2, 2.8 Hz, 1H), 5.41
(dd, J=11.8, 2.0 Hz, 1H), 4.84 (dd, J=11.1, 6.0 Hz, 1H), 3.94 (s,
3H), 2.66 (ddd, J=13.5, 6.0, 2.1 Hz, 1H), 2.26 (dt, J=13.4, 11.4
Hz, 1H); MS (ESI) m/z 329 (M+H).sup.+.
Example 113F
methyl
rac-3-((2R,4R)-4-amino-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
-2-yl)benzoate
[1843] The title compound was prepared using procedure similar to
that described in Example 112F, substituting the product from
Example 113E for the product from Example 112E. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.12 (s, 1H), 8.05-8.00 (m, 2H), 7.68
(d, J=7.6 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 6.60 (dd, J=8.1, 2.9 Hz,
1H), 5.39 (d, J=12.1 Hz, 1H), 4.33-4.23 (m, 1H), 3.93 (s, 3H), 2.49
(ddd, J=13.1, 5.3, 1.4 Hz, 1H), 1.94 (dt, J=13.7, 11.6 Hz, 1H).
Example 113G
methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoa-
te
[1844] A solution of the product from Example 113F (3.5 mg, 0.012
mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was treated with
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl
chloride (CAS#1004294-65-8) (3.92 mg, 0.015 mmol), and
triethylamine (4.84 .mu.L, 0.035 mmol). The mixture was stirred
overnight at room temperature. The mixture was partitioned between
tert-butyl methyl ether and 10% citric acid. The layers were
separated and the tert-butyl methyl ether layer was washed with
saturated NaHCO.sub.3 solution, washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel and eluted with a gradient of
50%-100% [9:1 CH.sub.2Cl.sub.2:ethyl acetate] in heptane to provide
the title compound (1.7 mg, 3.23 .mu.mol, 27.9% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 8.07 (s, 1H), 8.01 (d, J=7.8 Hz,
1H), 7.61 (d, J=7.7 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.45 (t, J=7.7
Hz, 1H), 7.11 (dd, J=8.2, 1.6 Hz, 1H), 7.07 (d, J=1.6 Hz, 1H), 7.02
(d, J=8.2 Hz, 1H), 6.57 (dd, J=8.1, 2.8 Hz, 1H), 5.54-5.46 (m, 1H),
5.42-5.30 (m, 2H), 3.92 (s, 3H), 2.52 (ddd, J=13.7, 6.1, 2.1 Hz,
1H), 1.86 (dt, J=13.2, 11.1 Hz, 1H), 1.78-1.63 (m, 2H), 1.11 (q,
J=2.5 Hz, 2H); MS (ESI) m/z 525 (M-H).sup.-.
Example 114
rac-3-[(2R,4R)-7-chloro-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopro-
pyl]carbonyl}amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoic
acid
[1845] The title compound was prepared using the procedure similar
to that described in Example 28, substituting the product from
Example 112G for the product from Example 30. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.16 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.68
(d, J=7.7 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.43 (dd, J=8.0, 1.1 Hz,
1H), 7.13 (dd, J=8.1, 1.7 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 7.03 (d,
J=8.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 5.57 (td, J=10.3, 6.0 Hz,
1H), 5.47-5.39 (m, 2H), 2.57 (ddd, J=13.5, 6.0, 2.0 Hz, 1H), 1.84
(dt, J=13.4, 11.3 Hz, 1H), 1.79-1.66 (m, 2H), 1.18-1.08 (m, 2H); MS
(ESI) m/z 527 (M-H).sup.-.
Example 115
tert-butyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbon-
yl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]azetidine-1-carboxylate
Example 115A
tert-butyl
3-(1-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-3-oxopropyl)azetidin-
e-1-carboxylate
[1846] The title compound was prepared using the procedure similar
to that described in Example 100A, substituting
1-(2-hydroxy-4-methoxyphenyl)ethanone for
4'-fluoro-2'-hydroxyacetophenone, and substituting tert-butyl
3-formylazetidine-1-carboxylate for benzyl
3-oxoazetidine-1-carboxylate. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 12.47 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.47-6.42 (m,
2H), 4.37-4.30 (m, 1H), 4.04-3.91 (m, 3H), 3.85 (s, 3H), 3.72 (dd,
J=8.6, 5.6 Hz, 1H), 3.27 (d, J=3.6 Hz, 1H), 3.03 (dd, J=17.2, 2.6
Hz, 1H), 2.93 (dd, J=17.1, 9.0 Hz, 1H), 2.70-2.60 (m, 1H), 1.44 (s,
9H); MS (ESI) m/z 350 (M-H).sup.-.
Example 115B
tert-butyl
3-(7-methoxy-4-oxochroman-2-yl)azetidine-1-carboxylate
[1847] The title compound was prepared using the procedure similar
to that described in Example 100B, substituting the product from
Example 115A for the product from Example 100A. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.82 (d, J=8.8 Hz, 1H), 6.60 (dd,
J=8.8, 2.3 Hz, 1H), 6.44 (d, J=2.3 Hz, 1H), 4.56 (q, J=7.7 Hz, 1H),
4.15-3.99 (m, 4H), 3.84 (s, 3H), 2.91-2.81 (m, 1H), 2.57 (d, J=7.8
Hz, 2H), 1.46 (s, 9H); MS (ESI) m/z 665 (2M-H).sup.-.
Example 115C
tert-butyl
3-(7-methoxy-4-(methoxyimino)chroman-2-yl)azetidine-1-carboxyla-
te
[1848] A solution of the product from Example 115B (54 mg, 0.162
mmol) and O-methylhydroxylamine hydrochloride (40.6 mg, 0.486 mmol)
in pyridine (1 mL) was heated at 60.degree. C. for 90 minutes and
then concentrated to remove the pyridine. The residue was
partitioned between ethyl acetate (.about.30 mL) and water
(.about.10 mL). The layers were separated and the ethyl acetate
layer was washed with brine, dried (MgSO.sub.4), filtered, and
concentrated to provide the title compound (57 mg, 0.157 mmol, 97%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.78 (d,
J=8.8 Hz, 1H), 6.54 (dd, J=8.8, 2.5 Hz, 1H), 6.41 (d, J=2.6 Hz,
1H), 4.15 (ddd, J=12.1, 7.4, 3.1 Hz, 1H), 4.08-3.95 (m, 3H), 3.94
(s, 3H), 3.85 (ddd, J=8.9, 6.1, 2.8 Hz, 1H), 3.79 (s, 3H), 3.15
(dd, J=17.0, 3.0 Hz, 1H), 2.80 (qt, J=8.0, 5.6 Hz, 1H), 2.22 (dd,
J=17.0, 12.0 Hz, 1H), 1.45 (s, 9H); MS (ESI) m/z 307
(M-tBu).sup.+.
Example 115D
tert-butyl
3-(4-amino-7-methoxychroman-2-yl)azetidine-1-carboxylate
[1849] The title compound (as 1:1 mixture of cis and trans isomers)
was prepared using the procedure similar to that described in
Example 33E, substituting the product from Example 115C for the
product from Example 33D. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 7.32 (d, J=8.5 Hz, 0.5H), 7.26 (s, 0.5H), 7.11 (d, J=8.4 Hz,
0.5H), 6.98 (s, 0.5H), 6.53 (dd, J=8.8, 2.6 Hz, 0.5H), 6.51 (dd,
J=8.6, 2.5 Hz, 0.5H), 6.40 (d, J=2.5 Hz, 0.5H), 6.36 (d, J=2.5 Hz,
0.5H), 4.34 (td, J=7.9, 4.6 Hz, 0.5H), 4.20 (dd, J=10.3, 7.6 Hz,
0.5H), 4.10-3.80 (m, 6H), 3.76 (s, 3H), 2.82-2.69 (m, 1H), 2.11
(ddd, J=13.1, 6.0, 1.7 Hz, 0.5H), 1.75-1.69 (m, 1H), 1.45 (s, 5H),
1.43 (s, 4H); MS (ESI) m/z 355 (M+H).sup.+.
Example 115E
tert-butyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbon-
yl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]azetidine-1-carboxylate
[1850] Using the procedure similar to that as described in Example
100F, substituting the product from Example 115D for the product
from Example 100E, and the crude product was chromatographed on
silica gel eluted with a gradient of 5%-100% ethyl acetate in
CH.sub.2Cl.sub.2, provide the title compound as a 1:1 mixture of
cis and trans isomers. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 7.15 (dd, J=8.1, 1.7 Hz, 0.5H), 7.13-7.09 (m, 1H), 7.07 (d,
J=1.7 Hz, 0.5H), 7.02 (d, J=8.2 Hz, 0.5H), 7.01-6.96 (m, 1H), 6.89
(d, J=8.6 Hz, 0.5H), 6.49-6.45 (m, 1H), 6.35-6.32 (m, 1H), 5.44 (d,
J=6.5 Hz, 0.5H), 5.33 (d, J=8.7 Hz, 0.5H), 5.28-5.20 (m, 0.5H),
4.92 (ddd, J=6.8, 4.6, 2.4 Hz, 0.5H), 4.19 (ddd, J=11.6, 6.9, 1.6
Hz, 0.5H), 4.06-3.95 (m, 2H), 3.93-3.88 (m, 1H), 3.86-3.75 (m,
1.5H), 3.74 (s, 1.5H), 3.73 (s, 1.5H), 2.78-2.64 (m, 1H), 2.22
(ddd, J=12.9, 6.0, 1.6 Hz, 0.5H), 2.01 (dt, J=14.2, 2.2 Hz, 0.5H),
1.76-1.61 (m, 2H), 1.46 (s, 4.5H), 1.44 (s, 4.5H), 1.07 (dq,
J=11.6, 2.4, 2.0 Hz, 2H); MS (ESI) m/z 557(M-H).sup.-.
Example 116
N-[2-(azetidin-3-yl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-1-(2,2-difluor-
o-1,3-benzodioxol-5-yl)cyclopropanecarboxamide
[1851] A solution of the product from Example 115E (65.6 mg, 0.117
mmol) in trifluoroacetic acid (1 mL) was heated to 55.degree. C.
for 2 minutes, and concentrated to dryness. The residue was
partitioned between 1 M NaOH (5 mL) and CH.sub.2Cl.sub.2 (25 mL).
The aqueous layer was extracted with CH.sub.2Cl.sub.2 (10 mL). The
combined CH.sub.2Cl.sub.2 layers were dried (MgSO.sub.4), filtered,
and concentrated to provide the title compound (40 mg, 0.087 mmol,
74.3% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.15
(dd, J=8.1, 1.6 Hz, 0.5H), 7.12-7.09 (m, 1H), 7.08 (d, J=1.7 Hz,
0.5H), 7.04-6.96 (m, 1.5H), 6.89 (dd, J=8.6, 1.0 Hz, 0.5H), 6.46
(ddd, J=8.6, 3.8, 2.6 Hz, 1H), 6.37 (d, J=2.6 Hz, 0.5H), 6.35 (d,
J=2.6 Hz, 0.5H), 5.45 (d, J=6.7 Hz, 0.5H), 5.33 (d, J=8.8 Hz,
0.5H), 5.24 (td, J=9.8, 8.7, 6.1 Hz, 0.5H), 4.91 (ddd, J=6.9, 4.7,
2.6 Hz, 0.5H), 4.23 (ddd, J=11.7, 7.0, 1.7 Hz, 0.5H), 3.90 (ddd,
J=11.5, 7.0, 2.0 Hz, 0.5H), 3.86-3.55 (m, 4H), 3.74 (s, 1.5H), 3.74
(s, 1.5H), 3.01-2.87 (m, 1H), 2.21 (ddd, J=12.9, 6.2, 1.6 Hz,
0.5H), 1.97 (dt, J=14.3, 2.3 Hz, 0.5H), 1.75-1.60 (m, 2H),
1.12-1.01 (m, 2H); MS (ESI) m/z 459 (M+H).sup.+.
Example 117
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{7-methoxy-2-[1-(methyl
sulfonyl)azetidin-3-yl]-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxami-
de
[1852] The title compound as a 1:1 mixture of cis and trans isomers
was prepared using procedure similar to that described in Example
101, substituting the product from Example 116 for the product from
Example 93, and the crude product was chromatographed on silica gel
eluted with a gradient of 5-100% ethyl acetate in CH.sub.2Cl.sub.2.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.16 (dd, J=8.1, 1.7
Hz, 0.5H), 7.13-7.10 (m, 1H), 7.07 (d, J=1.8 Hz, 0.5H), 7.05-6.97
(m, 1.5H), 6.90 (dd, J=8.6, 1.0 Hz, 0.5H), 6.51-6.47 (m, 1H), 6.32
(d, J=2.8 Hz, 0.5H), 6.31 (d, J=2.7 Hz, 0.5H), 5.44 (d, J=6.4 Hz,
0.5H), 5.34 (d, J=8.7 Hz, 0.5H), 5.28-5.21 (m, 0.5H), 4.92 (ddd,
J=6.6, 4.6, 2.3 Hz, 0.5H), 4.22 (ddd, J=11.8, 6.0, 1.6 Hz, 0.5H),
4.04-3.82 (m, 4.5H), 3.74 (s, 1.5H), 3.74 (s, 1.5H), 2.90 (s,
1.5H), 2.89 (s, 1.5H), 2.87-2.77 (m, 1H), 2.22 (ddd, J=13.0, 6.1,
1.6 Hz, 0.5H), 2.01 (dt, J=14.1, 2.2 Hz, 0.5H), 1.76-1.63 (m, 2H),
1.12-1.04 (m, 2H); MS (ESI) m/z 535 (M-H).sup.-.
Example 118
methyl
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoa-
te
Example 118A
methyl
rac-3-((2R,4S)-4-azido-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
-2-yl)benzoate
[1853] The title compound was prepared using the procedure similar
to that described in Example 112E, substituting the product from
Example 113C for the product from Example 112D. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.13 (s, 1H), 8.04 (d, J=7.7 Hz, 1H),
7.74 (t, J=7.9 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.8 Hz,
1H), 6.66 (dd, J=8.1, 2.8 Hz, 1H), 5.46 (dd, J=11.7, 2.3 Hz, 1H),
4.75 (t, J=3.1 Hz, 1H), 3.93 (s, 3H), 2.31 (dt, J=14.4, 2.5 Hz,
1H), 2.19 (ddd, J=14.7, 11.6, 3.9 Hz, 1H); MS (ESI) m/z 329
(M+H).sup.+.
Example 118B
methyl
rac-3-((2R,4S)-4-amino-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
-2-yl)benzoate
[1854] The title compound was prepared using the procedure similar
to that described in Example 112F, substituting the product from
Example 118A for the product from Example 112E. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.13 (s, 1H), 8.02 (d, J=7.9 Hz, 1H),
7.75 (t, J=8.0 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.48 (t, J=7.8 Hz,
1H), 6.59 (dd, J=8.0, 2.8 Hz, 1H), 5.57 (dd, J=10.5, 2.9 Hz, 1H),
4.15 (t, J=3.5 Hz, 1H), 3.93 (s, 3H), 2.21-2.07 (m, 2H); MS (ESI)
m/z 303 (M+H).sup.+.
Example 118C
methyl
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl]benzoa-
te
[1855] The title compound was prepared using the procedure similar
to that described in Example 100F, substituting the product from
Example 118B for the product from Example 100E. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.97 (d, J=7.6 Hz, 1H), 7.93 (s, OH),
7.58 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.39 (t, J=7.6 Hz,
1H), 7.18 (dd, J=8.1, 1.6 Hz, 1H), 7.15 (d, J=1.5 Hz, 1H), 7.06 (d,
J=8.2 Hz, 1H), 6.44 (dd, J=8.2, 2.6 Hz, 1H), 5.89 (d, J=7.0 Hz,
1H), 5.09-4.96 (m, 2H), 3.94 (s, 3H), 2.28 (dt, J=14.4, 2.7 Hz,
1H), 2.12-1.99 (m, 1H), 1.75-1.63 (m, 2H), 1.19-1.05 (m, 2H); MS
(ESI) m/z 525 (M-H).sup.-.
Example 119
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid
Example 119A
8-fluoro-4H-chromen-4-one
[1856] The title compound was prepared using the conditions similar
to that described in Example 39A, substituting
1-(3-fluoro-2-hydroxyphenyl)ethanone for
1-(4-fluoro-2-hydroxyphenyl)ethanone.
Example 119B
(R)-methyl 3-(8-fluoro-4-oxochroman-2-yl)benzoate
[1857] The title compound was prepared using the conditions similar
to that described in Example 39B, substituting Example 119A for
Example 39A.
Example 119C
(R)-methyl 3-(8-fluoro-4-(methoxyimino)chroman-2-yl)benzoate
[1858] The title compound was prepared using the conditions similar
to that described in Example 39C, substituting Example 119B for
Example 39B.
Example 119D
methyl 342R,4R)-4-amino-8-fluorochroman-2-yl)benzoate
[1859] The title compound was prepared using the conditions similar
to that described in Example 39D, substituting Example 119C for
Example 39C.
Example 119E
methyl
442R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecar-
boxamido)-8-fluorochroman-2-yl)benzoate
[1860] The title compound was prepared using the conditions similar
to that described in Example 39E, substituting Example 119D for
Example 39D.
Example 119F
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1861] The title compound was prepared using the conditions similar
to that described in Example 38, substituting Example 119E for
Example 39E. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.17 (s,
1H), 8.05 (s, 1H), 7.67 (s, 1H), 7.47 (s, 1H), 7.19-7.05 (m, 3H),
7.02 (d, J=8.1 Hz, 1H), 6.86-6.81 (m, 2H), 5.56 (s, 1H), 5.37 (dd,
J=46.4, 10.0 Hz, 2H), 2.58 (s, 1H), 1.82 (d, J=30.1 Hz, 2H), 1.66
(d, J=15.0 Hz, 1H), 1.10 (d, J=3.6 Hz, 2H); MS (ESI-) m/z=510
(M-H).sup.-.
Example 120
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 120A
(R)-methyl 4-(4-oxochroman-2-yl)benzoate
[1862] A mixture of bis(2,2,2-trifluoroacetoxy)palladium (0.341 g,
1.026 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole
(0.252 g, 1.232 mmol), ammonium hexafluorophosphate(V) (1.004 g,
6.16 mmol), methyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4.04 g,
15.40 mmol) and dichloroethane (8 mL) in a 20 ml vial was stirred
at room temperature for 5 minutes, followed by the addition of
4H-chromen-4-one (CAS 11013-97-1, 1.5 g, 10.26 mmol) and water
(0.256 mL, 14.19 mmol). The vial was capped and the mixture was
stirred at 60.degree. C. overnight. The reaction mixture gradually
turned to black with Pd plated out on the sides of the vial. The
mixture was filtered through a plug of celite and eluted with ethyl
acetate to give a red solution, which was washed with water and
dried over MgSO.sub.4. After filtration, the solvent was removed in
vacuo. The crude material was chromatographed using a 100 g silica
gel cartridge and eluted with a gradient of 5-40% ethyl acetate in
heptane to yield title compound (1.66 g, 57.3% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.16-8.06 (m, 2H), 7.94 (dd, J=8.0,
1.7 Hz, 1H), 7.62-7.47 (m, 3H), 7.14-7.02 (m, 2H), 5.56 (dd,
J=13.1, 3.1 Hz, 1H), 3.94 (s, 3H), 3.13-2.86 (m, 2H); LC/MS
(ESI+)=283 (M+1).sup.+.
Example 120B
(R)-Methyl 4-(4-(methoxyimino)chroman-2-yl)benzoate
[1863] A mixture of Example 120A (1.65 g, 5.85 mmol), sodium
acetate (0.959 g, 11.69 mmol) and O-methylhydroxylamine,
hydrochloric acid (0.976 g, 11.69 mmol) in methanol (20 mL) was
stirred at 60.degree. C. overnight. Solvent was removed under
reduced pressure and the residue dissolved in ethyl acetate and
washed with water. The organic layer was dried over MgSO.sub.4,
filtered, and concentrated. The residue was washed with ether to
provide the title compound (1.758 g, 97% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.16-8.04 (m, 2H), 7.93 (dd, J=8.2, 1.7
Hz, 1H), 7.62-7.47 (m, 2H), 7.32-7.26 (m, 1H), 7.01-6.95 (m, 2H),
5.13 (dd, J=12.4, 3.2 Hz, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.48
(dd, J=17.2, 3.2 Hz, 1H), 2.66 (dd, J=17.2, 12.3 Hz, 1H); MS(ESI+):
m/z=312 (M+H).sup.+.
Example 120C
Methyl 4-((2R,4R)-4-aminochroman-2-yl)benzoate
[1864] The product from Example 120B (1.75 g, 5.62 mmol) was
treated with 5% platinum (0.05 equivalent) on carbon in acetic acid
(10 mL). The reaction mixture was stirred for 24 hours at room
temperature under hydrogen (1 atmosphere). LC/MS showed the
conversion was over 95%, with a little over reduced by-product
detected. The reaction mixture was filtered through a celite pad
and the solvent removed under reduced pressure. Tert-butyl
methylether was added to the residue, followed by drop wise
addition of 4 M HCl in tetrahydrofuran solution (2 mL). The mixture
was stirred for 1 hour at room temperature. The precipitated white
solid was collected by filtration, washed with ether, and dried to
provide the hydrochloride salt of the title compound (1.2 g, 66.8%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d, J=7.9
Hz, 2H), 7.50 (dd, J=23.2, 7.8 Hz, 3H), 7.20 (t, J=7.8 Hz, 1H),
7.07-6.84 (m, 2H), 5.22 (d, J=11.4 Hz, 1H), 4.36 (dd, J=10.8, 5.8
Hz, 1H), 3.93 (s, 3H), 2.46 (dd, J=13.2, 5.8 Hz, 1H), 2.00-1.85 (m,
1H); MS(ESI+) m/z=267 (M-NH.sub.2).sup.+.
Example 120D
Methyl
44(2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropaneca-
rboxamido)chroman-2-yl)benzoate
[1865] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(300 mg, 1.239 mmol) in DMF (2 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate, 642 mg, 1.689 mmol). The mixture was
stirred for 5 minutes at room temperature, followed by the addition
of Example 120C (319 mg, 1.0 mmol), and
N-ethyl-N-isopropylpropan-2-amine (0.785 mL, 4.50 mmol). The
mixture was stirred at room temperature for 2 hours, LC/MS showed
the conversion was complete. The reaction mixture was directly
loaded on a 50 g silica gel cartridge, eluting with 5-50%, ethyl
acetate in heptane to provide the title compound (320 mg, 56.0%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07-8.02 (m,
2H), 7.50-7.44 (m, 2H), 7.21-7.15 (m, 1H), 7.14-7.05 (m, 3H), 7.00
(d, J=8.2 Hz, 1H), 6.96-6.87 (m, 2H), 5.53-5.44 (m, 1H), 5.38 (d,
J=8.8 Hz, 1H), 5.24 (dd, J=11.3, 1.9 Hz, 1H), 3.93 (s, 3H), 2.52
(ddd, J=13.3, 6.1, 2.1 Hz, 1H), 1.84-1.72 (m, 2H), 1.26 (s, 1H),
1.08 (td, J=3.5, 2.1 Hz, 2H); MS (ESI-) m/z=506.1 (M-H).sup.-.
Example 121
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1866] To Example 120D (300 mg, 0.591 mmol) in methanol (4 mL) and
water (1.0 mL) was added lithium hydroxide (85 mg, 3.55 mmol). The
mixture was stirred at 35.degree. C. for 4 hours. LC/MS showed
reaction was complete. Solvent was removed under reduced pressure.
Water (4 mL) added to the residue and the pH of the mixture was
adjusted to pH 1.about.2 with the addition of 2 M HCl. The
precipitated white solid was collected by filtration, and dried to
provide the title compound (252 mg, 0.511 mmol, 86% yield). .sup.1H
NMR (501 MHz, CDCl.sub.3) .delta. 8.11 (d, J=7.8 Hz, 2H), 7.47 (d,
J=7.9 Hz, 2H), 7.17 (t, J=7.6 Hz, 1H), 7.13-6.98 (m, 4H), 6.90 (dd,
J=13.1, 5.7 Hz, 2H), 5.49 (s, 1H), 5.42 (d, J=8.6 Hz, 1H), 5.23 (d,
J=11.1 Hz, 1H), 2.53 (s, 1H), 1.76 (d, J=10.9 Hz, 2H), 1.66 (d,
J=10.4 Hz, 1H), 1.08 (s, 2H); MS (ESI-) m/z=492 (M-H).sup.-.
Example 122
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
[1867] To Example 123E (130 mg, 0.227 mmol) in methanol (2 mL) and
water (0.5 mL) was added lithium hydroxide (32.6 mg, 1.360 mmol).
The mixture was stirred at 35.degree. C. for 4 hours, LC/MS showed
the conversion was complete. Solvent was removed under reduced
pressure and water (2 mL) was added. The pH of the mixture was
adjusted to pH 1.about.2 with the addition of 2 M HCl. The
precipitated white solid was collected by filtration, and dried to
provide the title compound (110 mg, 0.197 mmol, 87% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.17-8.03 (m, 2H), 7.49 (d, J=8.2
Hz, 2H), 7.16-6.99 (m, 4H), 6.73-6.67 (m, 2H), 6.38 (d, J=73.6 Hz,
1H), 5.48 (td, J=10.4, 6.1 Hz, 1H), 5.36 (d, J=8.8 Hz, 1H),
5.31-5.21 (m, 1H), 2.52 (ddd, J=13.3, 6.0, 2.2 Hz, 1H), 1.86-1.71
(m, 2H), 1.68-1.60 (m, 1H), 1.10 (q, J=3.7, 2.4 Hz, 2H); MS (ESI-)
m/z=558 (M-H).sup.-.
Example 123
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate
Example 123A
(R)-methyl 4-(7-hydroxy-4-oxochroman-2-yl)benzoate
[1868] A mixture of bis(2,2,2-trifluoroacetoxy)palladium (271 mg,
0.816 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole
(200 mg, 0.979 mmol), ammonium hexafluorophosphate(V) (798 mg, 4.90
mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2203 mg, 12.24
mmol) and dichloroethane (8 mL) in a 20 mL vial was stirred for 5
minutes at room temperature, followed by the addition of
7-hydroxy-4H-chromen-4-one (CAS 59887-89-7, MFCD00209371, 1323 mg,
8.16 mmol) and water (256 mg, 14.19 mmol). The vial was capped and
the mixture was stirred at 60.degree. C. overnight. The reaction
gradually turned black, with Pd plated out on the sides of the
vial. The mixture was filtered through a plug of celite and eluted
with ethyl acetate to give a red solution which was washed with
brine. The solvent was removed in vacuo and the crude material was
chromatographed using a 100 g silica gel cartridge and eluted with
a gradient of 5-40% ethyl acetate in heptane to provide the title
compound (1.62 g, 66.6% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.15-8.04 (m, 2H), 7.87 (d, J=8.7 Hz, 1H), 7.60-7.49 (m,
2H), 6.62-6.45 (m, 2H), 5.87 (s, 1H), 5.53 (dd, J=12.8, 3.2 Hz,
1H), 3.94 (s, 3H), 3.07-2.80 (m, 2H); MS (ESI+) m/z=299
(M+H).sup.+.
Example 123B
(R)-methyl 4-(7-hydroxy-4-(methoxyimino)chroman-2-yl)benzoate
[1869] The mixture of Example 123A (960 mg, 3.22 mmol), sodium
acetate (528 mg, 6.44 mmol) and O-methylhydroxylamine, hydrochloric
acid (538 mg, 6.44 mmol) in methanol (10 mL) was stirred at
60.degree. C. overnight. Solvent was removed under reduced
pressure. The residue was dissolved in ethyl acetate and washed
with water. The organic layers was dried over MgSO.sub.4, filtered,
and concentrated. The residue was washed with ether to provide the
title compound (810 mg, 2.475 mmol, 77% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.15-8.03 (m, 2H), 7.81 (d, J=8.7 Hz, 1H),
7.58-7.43 (m, 2H), 6.50 (dd, J=8.6, 2.5 Hz, 1H), 6.45 (d, J=2.5 Hz,
1H), 5.21 (d, J=3.0 Hz, 1H), 5.12 (dd, J=12.2, 3.2 Hz, 1H), 3.95
(s, 3H), 3.93 (s, 3H), 3.45 (dd, J=17.2, 3.2 Hz, 1H), 2.63 (dd,
J=17.2, 12.2 Hz, 1H); MS (ESI+) m/z 328 (M+H).sup.+.
Example 123C
Methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate
[1870] A mixture of Example 123B (570 mg, 1.741 mmol) was treated
with 5% platinum (0.05 equivalent) on carbon in acetic acid (5 mL).
The reaction was stirred at room temperature under hydrogen (1
atmosphere) for 24 hours, LC/MS showed conversion over 95%. The
mixture was filtered through a celite pad and solvent removed under
reduced pressure. The residue was purified by preparative LC method
TFA2 to provide the trifluroroacetic acid salt of the title
compound (300 mg, 44% yield). LC/MS m/z 283 (M-NH.sub.2).sup.+.
Example 123D
methyl
4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec-
arboxamido)-7-hydroxychroman-2-yl)benzoate
[1871] A mixture of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(162 mg, 0.668 mmol) and HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate, 380 mg, 1.0 mmol) in DMF (2 mL) was
stirred for 5 minutes at room temperature, followed by the addition
of Example 123C (200 mg, 0.334 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.466 ml, 2.67 mmol). The
mixture was stirred at room temperature for 2 hours, LC/MS showed
reaction complete. The mixture was loaded on to a 25 g silica gel
cartridge eluting with 5-50% ethyl acetate in heptane provide the
title compound (204 mg, 58.3% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.11-7.90 (m, 2H), 7.42 (d, J=8.0 Hz, 2H),
7.16-7.02 (m, 2H), 6.94 (dd, J=37.7, 8.3 Hz, 2H), 6.49-6.32 (m,
2H), 5.67 (s, 1H), 5.36 (dt, J=15.3, 8.7 Hz, 2H), 5.18 (d, J=10.7
Hz, 1H), 3.93 (s, 3H), 2.56-2.36 (m, 1H), 1.80-1.70 (m, 2H), 1.26
(d, J=2.2 Hz, 1H), 1.10-1.04 (m, 2H); MS (ESI-) m/z=521.9
(M-H).sup.-.
Example 123E
Methyl
442R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecar-
boxamido)-7-(difluoromethoxy)chroman-2-yl)benzoate
[1872] To Example 123D (190 mg, 0.363 mmol) and diethyl
(bromodifluoromethyl)phosphonate (0.129 ml, 0.726 mmol) in a
mixture of acetonitrile (2 mL) and water (1 mL) was added 50%
aqueous potassium hydroxide (244 mg, 2.178 mmol) drop wise via
syringe while stirring vigorously. After the addition was
completed, LC/MS showed conversion was complete with a small
by-product peak. Additional water was added to the mixture and the
mixture was extracted with ethyl acetate (3.times.20 mL). The
combined organic extracts were washed with 1 M HCl (5 mL) and
water, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by preparative LC method TFA2 to provide the
title compound (150 mg, 72% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.09-8.00 (m, 2H), 7.49-7.41 (m, 2H), 7.15-6.99
(m, 4H), 6.75-6.66 (m, 2H), 5.50-5.40 (m, 1H), 5.33 (d, J=8.9 Hz,
1H), 5.25 (dd, J=11.3, 2.0 Hz, 1H), 3.93 (s, 3H), 2.50 (ddd,
J=13.4, 6.1, 2.1 Hz, 1H), 1.84-1.71 (m, 2H), 1.65 (d, J=2.8 Hz,
1H), 1.11-1.06 (m, 2H); MS (ESI-) m/z=572 (M-H).sup.-.
Example 124
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-hydroxy-2,2-dimethyl-3,4-dihydr-
o-2H-chromen-4-yl)cyclopropanecarboxamide
Example 124A
7-hydroxy-2,2-dimethylchroman-4-one O-methyl oxime
[1873] The mixture of 7-hydroxy-2,2-dimethylchroman-4-one
(cas#17771-33-4) (680 mg, 3.54 mmol), sodium acetate (580 mg, 7.08
mmol) and O-methylhydroxylamine, hydrochloric acid (591 mg, 7.08
mmol) in methanol (10 mL) was stirred at 60.degree. C. overnight.
Solvent was evaporated under reduced pressure. The resulting
residue was dissolved in ethyl acetate, and washed with brine,
dried over MgSO.sub.4, and filtered. The solvent was removed under
reduced pressure to give the title compound (740 mg, 95%). LC/MS
(ESI+) m/z 222 (M+H).sup.+.
Example 124B
4-amino-2,2-dimethylchroman-7-ol hydrochloride
[1874] To Example 124A (740 mg, 3.34 mmol) and acetic acid (10 mL)
in a 50 mL pressure bottle was added 5% Pt/C wet (240 mg, 0.506
mmol). The mixture was stirred at 30 psi of hydrogen and at room
temperature for 40 hours. The reaction mixture was filtered, and
the solvent was removed. Diethyl ether (10 mL) was added to the
resulting residue, followed by drop wise addition of 4N HCl in
dioxane (1 mL). The white solid was collected by filtration and
dried to yield title compound (460 mg, 60%). LC/MS (ESI+) m/z=177
(M-NH.sub.2).sup.+.
Example 124C
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-(7-hydroxy-2,2-dimethyl-3,4-dihydr-
o-2H-chromen-4-yl)cyclopropanecarboxamide
[1875] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(CAS 68015-98-5) (485 mg, 2.0 mmol) in N,N-dimethylformamide (4 mL)
was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (1142 mg, 3.00 mmol). The mixture was
stirred at room temperature for 5 minutes, and Example 124B was
added, followed by addition of N-ethyl-N-isopropylpropan-2-amine
(1.395 mL, 8.01 mmol). The mixture was stirred at room temperature
for 2 hours. The mixture was purification by chromatography,
eluting with a gradient of 0-50% ethyl acetate in heptane, to yield
the title compound (505 mg, 1.210 mmol, 60.4% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.20-7.07 (m, 2H), 7.01 (d, J=8.2 Hz,
1H), 6.88 (dd, J=8.5, 1.0 Hz, 1H), 6.36 (dd, J=8.4, 2.5 Hz, 1H),
6.23 (d, J=2.6 Hz, 1H), 5.41-5.25 (m, 2H), 5.23-5.08 (m, 1H), 2.11
(dd, J=13.2, 6.2 Hz, 1H), 1.76-1.63 (m, 2H), 1.50 (dd, J=13.2, 10.5
Hz, 1H), 1.32 (s, 3H), 1.26 (s, 3H), 1.09 (td, J=3.2, 1.5 Hz, 2H);
MS (ESI.sup.+) m/z 417.7 (M+H).sup.+.
Example 125
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7-(difluoromethoxy)-2,2-dimethyl--
3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1876] The product of Example 124C (150 mg, 0.359 mmol) and diethyl
(bromodifluoromethyl)phosphonate (0.128 mL, 0.719 mmol) in a
mixture of acetonitrile (10 mL) and water (5 mL) were cooled to
<5.degree. C. in an ice-water bath. Potassium hydroxide (0.185
mL, 2.156 mmol, 50% water solution) was added drop wise via syringe
while stirring vigorously. The mixture was stirred at room
temperature for 30 minutes. The reaction mixture was diluted with
water (5 mL) and extracted with methyl tert-butyl ether (3.times.10
mL). The combined extracts were washed with 1M HCl (5 mL) and
purified by LC/MS method TFA1 to provide the title compound (85 mg,
50.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.15 (dd, J=8.1,
1.7 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.03 (dd, J=8.3, 1.2 Hz, 2H),
6.63-6.59 (m, 1H), 6.51 (d, J=2.4 Hz, 1H), 6.44, (1H), 5.35 (d,
J=8.8 Hz, 1H), 5.26-5.17 (m, 1H), 2.12 (dd, J=13.2, 6.2 Hz, 1H),
1.76-1.64 (m, 2H), 1.52 (dd, J=13.2, 10.9 Hz, 1H), 1.35 (s, 3H),
1.29 (s, 3H), 1.15-1.05 (m, 2H); MS(ESI+) m/z=468 (M+H).sup.+.
Example 126
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7-methoxy-2-(tetrahydrofuran-2-yl-
)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
Example 126A
2-acetyl-5-methoxyphenyl tetrahydrofuran-2-carboxylate
[1877] Oxalyl chloride (14.83 mL, 175 mmol) was added drop wise via
syringe to a mixture of tetrahydrofuran-2-carboxylic acid (18.5 g,
159 mmol) and N,N-dimethylformamide (0.116 g, 1.593 mmol) in
CH.sub.2Cl.sub.2 (100 mL) at 0.degree. C. under a nitrogen
atmosphere. The mixture was stirred for another 1 hour and then was
added dropwise via syringe to a mixture of
1-(2-hydroxy-4-methoxyphenyl)ethanone (CAS 552-41-0) (26.5 g, 159
mmol) and triethylamine (66.6 mL, 478 mmol) in CH.sub.2Cl.sub.2
(100 mL) at 0.degree. C. The resulting mixture was stirred at room
temperature for about 3 hours. The reaction mixture was diluted
with ethyl acetate, washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
chromatographed on silica gel eluting with 0-90% ethyl acetate in
hexanes to provide the title compound (36.5 g, 138 mmol, 87%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84 (d, J=8.8
Hz, 1H), 6.85 (dd, J=8.8, 2.5 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 4.78
(dd, J=8.5, 5.4 Hz, 1H), 4.18-4.09 (m, 1H), 4.06-3.98 (m, 1H), 3.88
(s, 3H), 2.54 (s, 1H), 2.58-2.45 (m, 3H), 2.47-2.33 (m, 1H),
2.23-2.08 (m, 1H), 2.10-1.95 (m, 1H); MS (ESI+) m/z 265
(M+H).sup.+.
Example 126B
1-(2-hydroxy-4-methoxyphenyl)-3-(tetrahydrofuran-2-yl)propane-1,3-dione
[1878] A solution of the product from Example 126A (18 g, 68.1
mmol) in tetrahydrofuran (200 mL) under an atmosphere of N.sub.2
was cooled to -70.degree. C. and treated with a 1 M solution of
lithium bis(trimethylsilyl)amide in tetrahydrofuran (170 mL, 170
mmol). The reaction mixture was stirred for 2 hours at room
temperature. The organic layer was washed with sat NH.sub.4Cl
(3.times.20 mL), dried with Na.sub.2SO.sub.4, filtered, and
concentrated to provide the titled compound (18 g, 54.5 mmol, 80%
yield). MS (ESI+) m/z 265 (M+H).sup.+.
Example 126C
7-methoxy-2-(tetrahydrofuran-2-yl)-4H-chromen-4-one
[1879] A solution of the product from Example 126B (10 g, 37.8
mmol) in CH.sub.2Cl.sub.2 (100 mL) was treated with iron(III)
chloride (18.41 g, 114 mmol). The resulting suspension was stirred
at room temperature overnight. The reaction was filtered and
concentrated to provide the title compound (9.32 g, 31.0 mmol, 82%
yield). MS (ESI+) m/z 247 (M+H).sup.+.
Example 126D
7-methoxy-2-(tetrahydrofuran-2-yl)chroman-4-one
[1880] The product from Example 126C (12 g, 48.7 mmol) was treated
with Pd/C (3.37 g) and triethyl amine (34.0 mL, 244 mmol) in ethyl
acetate (100 mL). The reaction was stirred at room temperature
overnight. The mixture was filtered and the solvent removed in
vacuo. The crude material was purified by chromatography on silica
gel, eluting with 0-90% ethyl acetate in petroleum ether to provide
the title compound (1.7 g, 6.85 mmol, 14.05% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.83 (d, J=8.8 Hz, 1H), 6.59 (dd,
J=8.8, 2.4 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 4.45-4.38 (m, 1H),
4.20-4.12 (m, 1H), 3.98-3.91 (m, 1H), 3.85 (s, 3H), 3.89-3.82 (m,
1H), 2.79 (dd, J=16.9, 12.2 Hz, 1H), 2.71 (dd, J=16.8, 3.8 Hz, 1H),
2.17-2.08 (m, 1H), 2.02-1.86 (m, 3H); MS (ESI+) m/z 249
(M+H).sup.+.
Example 126E
7-methoxy-2-(tetrahydrofuran-2-yl)chroman-4-one oxime
[1881] The product from Example 126D (700 mg, 2.82 mmol) was
treated with hydroxylamine hydrochloride (294 mg, 4.23 mmol) and
sodium acetate (347 mg, 4.23 mmol) in methanol (1 mL). The reaction
was stirred at ambient temperature for 3 hours. The mixture was
concentrated to dryness and the residue was purified by
chromatography on silica gel, eluting with 0-90% ethyl acetate in
petroleum ether to provide the title compound (742 mg, 2.82 mmol,
100% yield). MS (ESI+) m/z 264 (M+H).sup.+.
Example 126F
7-methoxy-2-(tetrahydrofuran-2-yl)chroman-4-amine hydrochloride
[1882] Methanol (10 mL) was treated for 1 minute with a stream of
NH.sub.3 gas. The product from Example 126E (0.742 g, 2.82 mmol)
was added followed by nickel (0.165 g, 2.82 mmol). The mixture was
stirred at room temperature under 5 atmospheres of H.sub.2 for 24
hours. The mixture was filtered and the filtrate was concentrated
to dryness. The residue was treated with HCl in diethyl ether, then
concentrated to provide the titled compound (0.762 g, 2.67 mmol,
95% yield). MS (ESI+) m/z 233 (M-NH.sub.3).sup.+.
Example 126G
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[7-methoxy-2-(tetrahydrofuran-2-yl-
)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1883] A mixture of the product from Example 126F (50.7 mg, 0.177
mmol),
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(55.9 mg, 0.231 mmol) and HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (101 mg, 0.266 mmol) in tetrahydrofuran
(2 mL) under N.sub.2 was treated with triethylamine (99 .mu.L,
0.710 mmol) and stirred overnight at room temperature. The mixture
was partitioned between methyl tert-butyl ether (30 mL) and 10%
citric acid (15 mL). The layers were separated and the methyl
tert-butyl ether layer was washed with saturated NaHCO.sub.3
solution (about 15 mL), washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The residue was purified by
chromatography on silica gel eluting with a gradient of 50-100%
[9:1 CH.sub.2Cl.sub.2:ethyl acetate] in heptane to provide the
title compound (67.9 mg, 0.143 mmol, 81% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.18-7.07 (m, 2H), 7.05-6.98 (m, 1.5H),
6.93 (d, J=8.7 Hz, 0.5H), 6.50-6.43 (m, 1.5H), 6.40 (d, J=2.4 Hz,
0.5H), 5.70 (d, J=8.9 Hz, 0.5H), 5.46 (d, J=6.8 Hz, 0.5H),
5.31-5.22 (m, 0.5H), 5.03-4.95 (m, 0.5H), 4.10-3.83 (m, 2H),
3.82-3.65 (m, 4H), 2.29 (ddd, J=13.2, 6.2, 2.3 Hz, 0.5H), 2.10-1.83
(m, 4.5H), 1.77-1.57 (m, 3H), 1.15-1.00 (m, 2H); MS (ESI-) m/z 472
(M-H).sup.-.
Example 127
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoate
[1884] The title compound was prepared as described in Example
123D.
Example 128
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-hydroxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid
[1885] To the product of Example 127 (33 mg, 0.063 mmol) in
methanol (2 mL) and water (0.5 mL) was added lithium hydroxide
(15.10 mg, 0.630 mmol). The mixture was stirred at 35.degree. C.
for 4 hours. Solvent was removed and water (1 mL) was added. The pH
of the reaction mixture was adjusted with 2M HCl to about
1.about.2. The white solid precipitated was collected by filtration
and dried to yield title compound (30 mg, 93% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.38 (s, 1H), 7.96 (d, J=8.0 Hz,
2H), 7.51 (d, J=8.1 Hz, 2H), 7.38 (s, 1H), 7.31 (d, J=8.4 Hz, 1H),
7.19 (d, J=7.9 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.84 (d, J=8.5 Hz,
1H), 6.37 (dd, J=8.5, 2.5 Hz, 1H), 6.21 (d, J=2.9 Hz, 1H), 5.30 (q,
J=8.8, 7.6 Hz, 2H), 2.08-1.97 (m, 2H), 1.49 (dt, J=8.8, 3.2 Hz,
1H), 1.40-1.33 (m, 1H), 1.06-1.00 (m, 2H); MS (ESI-)
m/z=508(M-H).sup.-.
Example 129
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-me-
thoxy-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-3'-carboxylic
acid
Example 129A
methyl
7-methoxy-4-oxospiro[chroman-2,1'-cyclobutane]-3'-carboxylate
[1886] To 1-(2-hydroxy-4-methoxyphenyl)ethanone (CAS 552-41-0) (500
mg, 3.01 mmol) in methanol (10 mL) was added methyl
3-oxocyclobutanecarboxylate (1157 mg, 9.03 mmol) and pyrrolidine
(0.754 mL, 9.03 mmol) at room temperature. The mixture was stirred
at room temperature overnight. The reaction mixture was extracted
with CH.sub.2Cl.sub.2 and the organic layer washed with water,
dried over NaSO.sub.4, filtered, and concentrated. Purification by
flash chromatography on silica gel, eluting with ethyl acetate in
heptane (0-30%) yielded title compound (200 mg, 24%).
Example 129B
[1887] methyl
7-methoxy-4-(methoxyimino)spiro[chroman-2,1'-cyclobutane]-3'-carboxylate
The mixture of Example 129A (196 mg, 0.709 mmol), sodium acetate
(116 mg, 1.419 mmol) and O-methylhydroxylamine, hydrochloric acid
(118 mg, 1.419 mmol) in methanol (10 mL) was stirred at 60.degree.
C. overnight. The solvent was evaporated under reduced pressure and
the residue was dissolved in ethyl acetate, and washed with brine.
The organic layers was dried over MgSO.sub.4, and filtered. The
solvent was removed under pressure to give crude product of title
compound (203 mg, 94%), which was used without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.75 (dd,
J=8.9, 5.8 Hz, 1H), 6.51 (ddt, J=8.4, 5.6, 2.5 Hz, 1H), 6.42 (td,
J=6.1, 2.8 Hz, 1H), 3.96 (t, J=4.4 Hz, 3H), 3.75 (dt, J=32.6, 2.8
Hz, 6H), 2.95 (d, J=7.2 Hz, 2H), 2.56-2.28 (m, 4H); MS (ESI+) m/z
306 (M+H).sup.+.
Example 129C
methyl
4-amino-7-methoxyspiro[chroman-2,1'-cyclobutane]-3'-carboxylate
[1888] To a solution of Example 129B (200 mg, 0.655 mmol) in
methanol (10 mL) was added Raney nickel (1 g, 17.04 mmol) in a 50
mL pressure bottle. The mixture was stirred at 30 psi of hydrogen
and at room temperature for 52 hours. The reaction mixture was
filtered and concentrated to dryness to provide the title compound
(150 mg, 83%). MS (ESI+) m/z 261 (M-NH.sub.2).sup.+.
Example 129D
methyl
4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-
-7-methoxy spiro[chroman-2,1'-cyclobutane]-3'-carboxylate
[1889] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(34.9 mg, 0.144 mmol) in N,N-dimethylformamide (4 mL) was added
HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (82 mg, 0.216 mmol). The mixture was
stirred for 5 minutes, and then Example 129C (40 mg, 0.144 mmol)
was added, following by addition of
N-ethyl-N-isopropylpropan-2-amine (0.100 mL, 0.577 mmol). The
mixture was stirred at room temperature for 2 hours. The mixture
was purified by chromatography, eluting with 0-50% ethyl acetate in
heptane to provide the title compound (60 mg, 83% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.18-7.07 (m, 2H), 7.00 (d, J=8.1
Hz, 1H), 6.94 (dd, J=8.6, 0.9 Hz, 1H), 6.46 (dd, J=8.6, 2.6 Hz,
1H), 6.34 (d, J=2.5 Hz, 1H), 5.32 (d, J=8.5 Hz, 1H), 5.17-5.05 (m,
1H), 3.73 (d, J=9.6 Hz, 6H), 3.29 (tt, J=9.3, 7.7 Hz, 1H),
2.47-2.32 (m, 4H), 2.26 (dd, J=13.3, 5.8 Hz, 1H), 1.79 (dd, J=13.4,
8.4 Hz, 1H), 1.69 (t, J=3.6 Hz, 2H), 1.12-1.05 (m, 2H); MS(ESI-)
m/z 500.2 (M-H).sup.-.
Example 129E
4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-me-
thoxy-3,4-dihydrospiro[chromene-2,1'-cyclobutane]-3'-carboxylic
acid
[1890] To a solution of Example 129D (58 mg, 0.116 mmol) in
methanol (4 mL) and water (1 mL) was added lithium hydroxide (27
mg, 1.16 mmol). The mixture was stirred at 35.degree. C. for 4
hours and solvent removed under reduced pressure, and then water (1
mL) was added. The mixture was adjusted with 2N HCl to pH
1.about.2. The white solid precipitated was collected and washed
with water and dried to yield title compound as solid (53 mg, 94%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.19-7.08 (m, 2H), 7.01
(t, J=7.9 Hz, 1H), 6.95-6.83 (m, 1H), 6.46 (ddd, J=8.6, 4.4, 2.5
Hz, 1H), 6.33 (dd, J=6.9, 2.5 Hz, 1H), 5.39 (dd, J=8.5, 5.6 Hz,
1H), 5.14 (dtd, J=17.2, 9.2, 8.6, 6.1 Hz, 1H), 3.73 (d, J=6.5 Hz,
3H), 3.31 (p, J=8.3 Hz, 1H), 2.91-2.58 (m, 1H), 2.52-2.28 (m, 4H),
1.84-1.64 (m, 3H), 1.14-1.05 (m, 2H); MS (ESI-) m/z=486.2
(M-H).sup.-.
Example 130
Ethyl
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate
Example 130A
ethyl 7-methoxy-4-oxo-4H-chromene-2-carboxylate
[1891] 1-(2-hydroxy-4-methoxyphenyl)ethanone (CAS 552-41-0) (10 g,
60.2 mmol) was dissolved in ethanol (175 mL). Diethyl oxalate (41.1
mL, 301 mmol) was added, followed by a 2.5 M solution of sodium
ethoxide in ethanol (94 mL, 241 mmol). The mixture was heated at
75.degree. C. for 1 hour, cooled to room temperature, acidified
with HCl (7.31 mL, 241 mmol), then concentrated in vacuo. This
intermediate was dissolved in CH.sub.2Cl.sub.2 (200 mL), treated
with concentrated HCl (20 mL) and stirred at room temperature for 3
hours. The organic layer was isolated and dried over sodium
sulfate, filtered, and concentrated. The residue was triturated
with methyl tert-butyl ether and the solid was collected by
filtration to provide the title compound as an off-white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.94 (d, J=8.9 Hz, 1H),
7.22 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.9, 2.4 Hz, 1H), 6.88 (s, 1H),
4.40 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 1.36 (t, J=7.1 Hz, 3H).
Example 130B
ethyl 7-methoxy-4-oxochroman-2-carboxylate
[1892] A mixture of the product from Example 130A (2.16 g, 8.70
mmol), ammonium formate (1.646 g, 26.1 mmol) and 10% Pd/C (0.695 g,
0.653 mmol) in ethanol (40 mL) was heated at 85.degree. C.
overnight under an N.sub.2 atmosphere (balloon). The mixture was
cooled, filtered to remove the solids, and concentrated. The
residue was purified by chromatography on silica gel eluting with a
gradient of 50-100% CH.sub.2Cl.sub.2 in heptane to provide the
title compound (0.8 g, 3.20 mmol, 36.7% yield). .sup.1H NMR (501
MHz, CDCl.sub.3) .delta. 7.81 (d, J=8.8 Hz, 1H), 6.61 (dd, J=8.8,
2.4 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.06 (dd, J=8.5, 5.9 Hz, 1H),
4.27 (q, J=7.1 Hz, 2H), 3.85 (s, 3H), 3.04-2.95 (m, 2H), 1.30 (t,
J=7.1 Hz, 3H); MS (ESI+) m/z 251 (M+H).sup.+.
Example 130C
ethyl 7-methoxy-4-(methoxyimino)chroman-2-carboxylate
[1893] A solution of the product from Example 130B (0.8 g, 3.20
mmol) and O-methylhydroxylamine hydrochloride (0.801 g, 9.59 mmol)
in pyridine (10 mL) was heated at 60.degree. C. for 75 minutes,
cooled, concentrated and partitioned between ethyl acetate and
water. The ethyl acetate layer was washed with brine, dried
(MgSO.sub.4), filtered, and concentrated to provide the title
compound (0.8 g, 2.86 mmol, 90% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.78 (d, J=8.7 Hz, 1H), 6.56 (dd, J=8.7, 2.5
Hz, 1H), 6.53 (d, J=2.3 Hz, 1H), 4.70 (dd, J=9.9, 4.3 Hz, 1H), 4.27
(q, J=7.1 Hz, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 3.33 (dd, J=17.2,
4.3 Hz, 1H), 2.91 (dd, J=17.2, 10.0 Hz, 1H), 1.30 (t, J=7.1 Hz,
3H); MS (ESI+) m/z 280 (M+H).sup.+.
Example 130D
methyl 4-amino-7-methoxychroman-2-carboxylate and ethyl
4-amino-7-methoxychroman-2-carboxylate
[1894] A solution of the product from Example 130C in methanol (20
mL) was added to Ra--Ni 2800, water slurry, (6 g, 46.0 mmol) in a
50 mL pressure bottle and shaken for 4 hours at 30 psi of hydrogen
and at room temperature. The mixture was filtered and concentrated
to provide the title compounds. MS (ESI+) m/z 220
(M-NH.sub.3).sup.+ for methyl ester and m/z 235 (M-NH.sub.3).sup.+
for ethyl ester.
Example 130E
ethyl
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate
[1895] A mixture of the product from Example 130D (650 mg, 2.59
mmol),
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(689 mg, 2.85 mmol) and HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol
o[4,5-b]pyridinium 3-oxid hexafluorophosphate) (1475 mg, 3.88 mmol)
in N,N-dimethylformamide (20 mL) under N.sub.2 was treated with
triethylamine (1082 .mu.L, 7.76 mmol) and stirred at room
temperature for 90 minutes. The mixture was partitioned between
methyl tert-butyl ether (30 mL) and 1 M HCl (15 mL). The layers
were separated and the ethyl acetate layer was washed sequentially
with saturated NaHCO.sub.3 solution (10 mL) and brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was purified
by chromatography on silica gel eluting with a gradient of 10 to
100% ethyl acetate in heptane to provide the title compound as the
first eluting product. This product was further purified by
chromatography on silica gel eluting with a gradient of 25-100%
[9:1 CH.sub.2Cl.sub.2:ethyl acetate] in heptanes. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.13 (dd, J=8.2, 1.7 Hz, 1H), 7.10 (d,
J=1.6 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.50
(dd, J=8.4, 2.5 Hz, 1H), 6.48 (d, J=2.5 Hz, 1H), 5.42 (d, J=6.9 Hz,
1H), 5.02-4.96 (m, 1H), 4.44 (dd, J=9.2, 3.5 Hz, 1H), 4.29 (q,
J=7.1 Hz, 2H), 3.75 (s, 3H), 2.31-2.18 (m, 2H), 1.74-1.65 (m, 2H),
1.33 (t, J=7.1 Hz, 3H), 1.12-1.04 (m, 2H); MS (ESI-) m/z 474
(M-H).sup.-.
Example 131
methyl
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate
[1896] The title compound was isolated as the second eluting isomer
from the first chromatography as described in Example 130E. This
product was further purified by chromatography on silica gel
eluting with a gradient of 25-100% [9:1 CH.sub.2Cl.sub.2:ethyl
acetate] in heptanes. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.15 (dd, J=8.2, 1.6 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 7.02 (d,
J=8.2 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.52 (dd, J=8.5, 2.5 Hz,
1H), 6.49 (d, J=2.5 Hz, 1H), 5.44 (d, J=6.8 Hz, 1H), 5.02-4.96 (m,
1H), 4.48 (dd, J=9.7, 3.1 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H),
2.36-2.29 (m, 1H), 2.22 (ddd, J=14.2, 9.7, 4.8 Hz, 1H), 1.71 (tq,
J=7.3, 4.2 Hz, 2H), 1.09 (p, J=6.1, 5.6 Hz, 2H); MS (ESI-) m/z 460
(M-H).sup.-.
Example 132
ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylate
Example 132A
(E)-methyl
2-(3-(tert-butoxy)-2-(2-hydroxybenzoyl)-3-oxoprop-1-en-1-yl)thi-
azole-5-carboxylate
[1897] A mixture of tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate
(0.704 g, 2.98 mmol, CAS#936182-86-4, Biddle, et al., Journal of
the American Chemical Society 2007, 129(13), p 3830-3831), methyl
2-formylthiazole-5-carboxylate (CAS#1408075-35-3, 0.51 g, 2.98
mmol), piperidine (0.015 mL, 0.149 mmol) and acetic acid (8.53
.mu.L, 0.149 mmol) in benzene was heated at reflux using
Dean-Starke trap overnight. The mixture was concentrated and
purified by chromatography on silica gel, and eluting with a
gradient of 15-100% ethyl acetate in heptane to provide the title
compound (0.26 g, 0.668 mmol, 22.41% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 11.66 (s, 1H), 8.33 (s, 1H), 7.85 (s, 1H),
7.53-7.46 (m, 2H), 7.09-7.06 (m, 1H), 6.87-6.82 (m, 1H), 3.90 (s,
3H), 1.45 (s, 9H); MS (ESI-) m/z 388 (M-H).sup.-.
Example 132B
methyl 2-(4-oxochroman-2-yl)thiazole-5-carboxylate
[1898] A solution of the product from Example 132A (0.25 g, 0.642
mmol) and
1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1R,2R)-(-)-2-(dimethylamino)cy-
clohexyl]thiourea (0.053 g, 0.128 mmol) in toluene (4 mL) was
stirred at room temperature for 2 days. The mixture was treated
with DL-10-camphorsulfonic acid (0.149 g, 0.642 mmol) and was
heated at 95.degree. C. for 3 hours. The mixture was cooled and
partitioned between ethyl acetate and saturated NaHCO.sub.3
solution. The ethyl acetate layer was washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The resulting residue was
purified by chromatography on silica gel, and eluting with a
gradient of 10 to 100% ethyl acetate in heptane to provide the
title compound (0.14 g, 0.484 mmol, 75% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.38 (s, 1H), 7.95 (dd, J=7.8, 1.6 Hz,
1H), 7.58 (ddd, J=8.8, 7.3, 1.7 Hz, 1H), 7.16-7.10 (m, 2H), 5.86
(dd, J=10.3, 4.3 Hz, 1H), 3.94 (s, 3H), 3.33 (dd, J=17.0, 4.3 Hz,
1H), 3.24 (dd, J=17.0, 10.3 Hz, 1H); MS (ESI.sup.+) m/z 290
(M+H).sup.+.
Example 132C
ethyl
rel-2-((S)-4-(((R)-tert-butylsulfinyl)imino)chroman-2-yl)thiazole-5--
carboxylate
[1899] A solution of product from Example 132B (70 mg, 0.242 mmol),
titanium(IV) ethoxide (331 mg, 1.452 mmol), and
(R)-(+)-2-methyl-2-propanesulfinamide (44.0 mg, 0.363 mmol) in
tetrahydrofuran (1 mL) was heated at 70.degree. C. overnight. The
mixture was cooled and partitioned between ethyl acetate (30 mL)
and water (15 mL). The solid present was removed by filtration
through diatomaceous earth. The ethyl acetate layer was isolated,
washed with brine, dried (MgSO.sub.4), filtered, and concentrated.
The resulting residue was purified by chromatography on silica gel,
eluting with a gradient of 50-100% [9:1 CH.sub.2Cl.sub.2:ethyl
acetate] in heptanes, then further eluted with a gradient of 0-50%
ethyl acetate in [9:1 CH.sub.2Cl.sub.2:ethyl acetate] to provide
the title compound (35.6 mg, 0.088 mmol, 36.2% yield) as the first
eluting isomer. The stereochemistry was arbitrarily assigned.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.36 (s, 1H), 8.02 (d,
J=8.1 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.07 (dd, J=7.8, 3.7 Hz,
2H), 5.59 (dd, J=11.3, 3.3 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.05
(dd, J=17.5, 3.4 Hz, 1H), 3.56 (dd, J=17.5, 11.4 Hz, 1H), 1.40 (t,
J=7.0 Hz, 3H), 1.33 (s, 9H); MS (ESI+) m/z 407 (M+H).sup.+.
Example 132D
ethyl rel-2-((2S,4S)-4-aminochroman-2-yl)thiazole-5-carboxylate
[1900] A solution of the product from Example 132C (35.6 mg, 0.088
mmol) in ethanol (2 mL) was cooled to 0.degree. C., treated with
NaBH.sub.4 (3.31 mg, 0.088 mmol), stirred at 0.degree. C. for 15
minutes, treated with more NaBH.sub.4 (5 mg), and stirred at
0.degree. C. for 75 minutes. The reaction was treated with 4 M HCl
in dioxane (219 .mu.L, 0.876 mmol) and stirred at room temperature
for 40 minutes. The mixture was partitioned between water (10 mL)
and methyl tert-butyl ether (30 mL). The aqueous layer was basified
with solid NaHCO.sub.3 and extracted with ethyl acetate (30 mL).
The ethyl acetate layer was washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to provide the title compound (26.2 mg,
0.086 mmol, 98% yield). The stereochemistry was arbitrarily
assigned. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.38 (s, 1H),
7.56 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.7 Hz, 1H), 7.05 (t, J=7.3 Hz,
1H), 6.98 (d, J=8.2 Hz, 1H), 5.53 (dd, J=11.0, 2.3 Hz, 1H), 4.41
(q, J=7.2 Hz, 2H), 4.35 (dd, J=10.6, 5.8 Hz, 1H), 2.83 (ddd,
J=13.1, 5.6, 2.2 Hz, 1H), 2.09-1.99 (m, 1H), 1.42 (t, J=7.1 Hz,
3H); MS (ESI+) m/z 305 (M+H).sup.+.
Example 132E
ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylate
[1901] The title compound was prepared using procedure similar to
that as described in Example 130E, substituting the product from
Example 132D for the product from Example 130D. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.24 (s, 1H), 7.21 (t, J=7.6 Hz, 1H),
7.15-7.10 (m, 3H), 7.01 (d, J=8.1 Hz, 1H), 6.99-6.96 (m, 1H), 6.94
(d, J=8.3 Hz, 1H), 5.56 (d, J=8.6 Hz, 1H), 5.53-5.45 (m, 2H), 4.38
(q, J=7.1 Hz, 2H), 2.87 (ddd, J=13.4, 6.1, 2.8 Hz, 1H), 2.05-1.94
(m, 1H), 1.78-1.66 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.09 (d, J=3.0
Hz, 2H); MS (ESI-) m/z 527 (M-H).sup.-.
Example 133
2-[(4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}ami-
no)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylic acid
[1902] A solution of product from Example 132E (36 mg, 0.068 mmol)
in tetrahydrofuran (1 mL) was diluted with methanol (1 mL) and then
treated with 1 M NaOH (0.5 mL). The mixture was stirred at room
temperature for 15 minutes and acidified by the addition of 1 M HCl
(2 mL). The mixture was extracted with ethyl acetate (30 mL). The
layers were separated and the ethyl acetate layer was washed with
brine, dried (MgSO.sub.4), filtered, and concentrated to provide
the title compound (31 mg, 0.062 mmol, 91% yield) as a 2:1 ratio of
cis:trans isomers. The stereochemistry of the chiral center bearing
the amino group was arbitrarily assigned as "S". .sup.1H NMR (501
MHz, CDCl.sub.3) .delta. 8.46 (s, 0.35H), 8.36 (s, 0.65H),
7.28-7.21 (m, 1H), 7.19 (dd, J=8.2, 1.7 Hz, 0.35H), 7.17-7.12 (m,
2.65H), 7.05-6.98 (m, 2.35H), 6.96 (dd, J=8.2, 1.0 Hz, 0.65H), 5.63
(d, J=7.0 Hz, 0.35H), 5.59-5.49 (m, 1.95H), 5.28 (dd, J=10.0, 2.8
Hz, 0.35H), 5.14-5.10 (m, 0.35H), 2.91 (ddd, J=13.4, 6.0, 2.7 Hz,
0.65H), 2.67-2.58 (m, 0.35H), 2.35 (ddd, J=14.5, 10.2, 5.0 Hz,
0.35H), 2.01 (dt, J=13.3, 9.9 Hz, 0.65H), 1.82-1.68 (m, 2H),
1.17-1.08 (m, 2H); MS (ESI-) m/z 499 (M-H).sup.-.
Example 134
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylic acid
[1903] A solution of product from Example 130E in tetrahydrofuran
(2 mL) was diluted with methanol (2 mL) and then treated with 1 M
NaOH (2 mL). The mixture was stirred at room temperature for 15
minutes and acidified by the addition of 1 M HCl. The mixture was
extracted with ethyl acetate (30 mL). The layers were separated and
the ethyl acetate layer was washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to provide the titled compound. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.16 (dd, J=8.2, 1.6 Hz, 1H),
7.13 (d, J=1.5 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.95 (d, J=8.5 Hz,
1H), 6.52 (dd, J=8.5, 2.5 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 5.52 (d,
J=7.1 Hz, 1H), 5.03 (q, J=5.5 Hz, 1H), 4.58 (dd, J=7.9, 3.7 Hz,
1H), 3.76 (s, 3H), 2.38-2.23 (m, 2H), 1.78-1.70 (m, 2H), 1.16-1.08
(m, 2H); MS (ESI-) m/z 446 (M-H).sup.-.
Example 135
ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylate
Example 135A
ethyl
rel-2-((R)-4-(((R)-tert-butylsulfinyl)imino)chroman-2-yl)thiazole-5--
carboxylate
[1904] The title compound was isolated as the second eluting isomer
from the chromatography purification described in Example 132C.
Stereochemistry was arbitrarily assigned. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.35 (s, 1H), 8.03 (dd, J=7.9, 1.5 Hz, 1H),
7.50-7.45 (m, 2H), 7.10-7.04 (m, 2H), 5.71 (dd, J=8.6, 4.2 Hz, 1H),
4.38 (q, J=7.1 Hz, 1H), 4.15 (dd, J=17.1, 4.2 Hz, 1H), 3.66 (dd,
J=17.1, 8.7 Hz, 1H), 1.40 (t, J=7.1 Hz, 3H), 1.36 (s, 9H); MS
(ESI+) m/z 407 (M+H).sup.+.
Example 135B
ethyl rel-2-((2R,4R)-4-aminochroman-2-yl)thiazole-5-carboxylate
[1905] The title compound was prepared using procedure similar to
that described in Example 132D, substituting the product from
Example 135A for the product from Example 132C. Stereochemistry was
arbitrarily assigned. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.37 (s, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.2 Hz, 1H), 7.03
(t, J=7.0 Hz, 1H), 6.96 (dd, J=8.2, 0.9 Hz, 1H), 5.51 (dd, J=11.1,
2.4 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.33 (dd, J=10.6, 5.7 Hz, 1H),
2.81 (ddd, J=13.3, 5.7, 2.4 Hz, 1H), 2.01 (dt, J=13.2, 10.9 Hz,
1H), 1.40 (t, J=7.1 Hz, 3H); MS (ESI+) m/z 305 (M+H).sup.+.
Example 135C
ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylate
[1906] The title compound was prepared using procedure similar to
that described in Example 130E, substituting the product from
Example 135B for the product from Example 130D. Stereochemistry was
arbitrarily assigned. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.24 (s, 1H), 7.21 (td, J=7.9, 7.5, 1.1 Hz, 1H), 7.16-7.10 (m, 3H),
7.01 (d, J=8.1 Hz, 1H), 6.98 (dd, J=7.5, 1.1 Hz, 1H), 6.93 (dd,
J=8.3, 1.0 Hz, 1H), 5.58-5.44 (m, 3H), 4.38 (q, J=7.1 Hz, 2H), 2.87
(ddd, J=13.4, 6.1, 2.8 Hz, 1H), 2.00 (dt, J=13.4, 9.8 Hz, 1H),
1.78-1.65 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.13-1.05 (m, 2H); MS
(ESI+) m/z 529 (M+H).sup.+.
Example 136
2-[(4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}ami-
no)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-5-carboxylic acid
[1907] The title compound was isolated as 2:1 ratio of cis:trans
isomers, using procedure similar to that as described in Example
133, substituting the product from Example 135C for the product
from Example 132E. The stereochemistry of the chiral center bearing
the amino group was arbitrarily assigned as "R". .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.44 (s, 0.35H), 8.34 (s, 0.65H),
7.26-7.10 (m, 3.5H), 7.04-6.93 (m, 3.5H), 5.60 (d, J=6.9 Hz,
0.35H), 5.57-5.46 (m, 1.95H), 5.25 (dd, J=9.7, 2.1 Hz, 0.35H),
5.14-5.08 (m, 0.35H), 2.92-2.85 (m, 0.65H), 2.64-2.58 (m, 0.35H),
2.37-2.29 (m, 0.35H), 1.99 (dt, J=12.9, 9.7 Hz, 0.65H), 1.80-1.66
(m, 2H), 1.15-1.07 (m, 2H); MS (ESI-) m/z 499 (M-H).sup.-.
Example 137
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoate
Example 137A
(R)-methyl 2-fluoro-4-(7-methoxy-4-oxochroman-2-yl)benzoate
[1908] In a 20 mL vial was charged with
bis(2,2,2-trifluoroacetoxy)palladium (84 mg, 0.253 mmol),
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (61.9 mg,
0.303 mmol), ammonium hexafluorophosphate(V) (247 mg, 1.515 mmol)
and (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (500 mg, 2.53
mmol). The mixture was stirred in dichloroethane (10 mL) for 5
minutes, and 7-methoxy-4H-chromen-4-one (CAS 5751-52-0) (534 mg,
3.03 mmol) and water (0.256 mL, 14.19 mmol) were added. The mixture
was stirred at 60.degree. C. overnight, filtered through a plug of
diatomaceous earth and eluted and washed with ethyl acetate to give
a red solution. The solvent was removed under vacuum and the crude
material chromatographed on 24 g silica gel cartridge, eluting with
ethyl acetate in heptane at a gradient of 0-40% to yield title
compound (235 mg, 0.711 mmol, 28.2%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.00 (t, J=7.7 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H),
7.35-7.27 (m, 2H), 6.65 (dd, J=8.9, 2.4 Hz, 1H), 6.53 (d, J=2.4 Hz,
1H), 5.51 (dd, J=12.3, 3.6 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H),
3.03-2.81 (m, 2H). MS(ESI+): m/z=331 (M+H)+
Example 137B
(R)-methyl
2-fluoro-4-(7-methoxy-4-(methoxyimino)chroman-2-yl)benzoate
[1909] The mixture of Example 137A (230 mg, 0.696 mmol), sodium
acetate (114 mg, 1.393 mmol) and O-methylhydroxylamine
hydrochloride (116 mg, 1.393 mmol) in methanol (10 mL) was stirred
at 60.degree. C. for 4 hours. Solvent was removed under reduced
pressure. The resulting residue was dissolved in ethyl acetate,
washed with water, dried over MgSO.sub.4, and filtered. The solvent
was removed under reduced pressure. The resulting white solid was
washed with diethyl ether to provide the title compound (228 mg,
0.634 mmol, 91% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.97 (dd, J=8.3, 7.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.32-7.29 (m,
1H), 7.27 (s, 1H), 6.59 (dd, J=8.8, 2.6 Hz, 1H), 6.50 (d, J=2.5 Hz,
1H), 5.11 (dd, J=12.2, 3.2 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H),
3.80 (s, 3H), 3.46 (dd, J=17.1, 3.2 Hz, 1H), 2.60 (dd, J=17.2, 12.1
Hz, 1H); MS(ESI+) m/z=360 (M+H).sup.+.
Example 137C
methyl 4-((2R,4R)-4-amino-7-methoxychroman-2-yl)-2-fluorobenzoate,
hydrochloric Acid
[1910] The mixture of Example 137B (220 mg, 0.612 mmol) and
platinum (119 mg, 0.031 mmol) on carbon in methanol (6 mL) was
charged with a hydrogen balloon and stirred at room temperature for
24 hours, LC/MS showed about 50% conversion. The balloon was
refilled. The reaction mixture was charged with more platinum
catalyst (0.05 equivalent) and stirred for another 24 hours, at
which time LC/MS showed 95% conversion. The reaction mixture was
filtered through a diatomaceous earth pad and solvent was removed
under reduced pressure. To the residue was added 4 M HCl in dioxane
drop wise. The precipitated white solid was filtered and dried to
yield title compound (110 mg, 48.9%). MS (ESI+) m/z=315
(M-NH.sub.2).sup.+.
Example 137D
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoate
[1911] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(87 mg, 0.359 mmol) in N,N-dimethylformamide (4 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (186 mg, 0.489 mmol). The mixture was
stirred for 5 minutes, and then Example 137C (120 mg, 0.326 mmol)
was added, followed by the addition of
N-ethyl-N-isopropylpropan-2-amine (0.227 mL, 1.305 mmol). The
mixture was stirred at room temperature for 2 hours. Purification
by chromatography on silica gel and eluting with a gradient of
5-40% ethyl acetate in heptane provided the title compound (120 mg,
66.2% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.94 (t,
J=7.7 Hz, 1H), 7.24-7.17 (m, 2H), 7.12-7.03 (m, 2H), 7.00 (d, J=8.2
Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 6.52 (dd, J=8.7, 2.5 Hz, 1H), 6.44
(d, J=2.5 Hz, 1H), 5.38 (td, J=10.0, 9.5, 5.8 Hz, 1H), 5.30 (d,
J=8.6 Hz, 1H), 5.19 (dd, J=11.1, 2.0 Hz, 1H), 3.94 (s, 3H), 3.76
(s, 3H), 2.51 (ddd, J=13.4, 6.1, 2.2 Hz, 1H), 1.79-1.70 (m, 2H),
1.29-1.23 (m, 1H), 1.07 (d, J=3.8 Hz, 2H); MS(ESI-) m/z 554
(M-H).sup.+.
Example 138
methyl
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoate
[1912] The title compound (115 mg, 66.2% yield) was prepared using
the procedures similar to that described in Examples 137A-137D,
substituting (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid for
(3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.83 (dd, J=8.1, 1.5 Hz, 1H), 7.72 (dd,
J=10.7, 1.6 Hz, 1H), 7.57 (t, J=7.5 Hz, 1H), 7.12-7.06 (m, 2H),
7.01-6.95 (m, 2H), 6.53 (dt, J=8.7, 3.2 Hz, 1H), 6.43 (d, J=2.6 Hz,
1H), 5.51-5.45 (m, 1H), 5.42 (dt, J=10.2, 4.9 Hz, 1H), 5.30 (d,
J=8.7 Hz, 1H), 3.94 (d, J=2.6 Hz, 3H), 3.76 (s, 3H), 2.53 (ddd,
J=13.4, 6.2, 2.1 Hz, 1H), 1.82-1.69 (m, 2H), 1.27 (d, J=3.6 Hz,
1H), 1.07 (q, J=2.4, 1.5 Hz, 2H); MS(ESI-) m/z=554 (M-H).sup.+.
Example 139
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoic
acid
[1913] To a solution of Example 137D (105 mg, 0.189 mmol) in
methanol (2 mL) was added 4N LiOH (0.5 mL). The mixture was stirred
at 35.degree. C. for 2 hours. The solvent was removed and water
(0.5 mL) was added to the resulting residue. The pH of the mixture
was adjusted with 2N HCl to pH 1.about.2. The resulting white solid
was collected by filtration and dried to yield the title compound
(97 mg, 95% yield). .sup.1H NMR (501 MHz, CDCl.sub.3) .delta. 8.00
(s, 1H), 7.23 (d, J=9.5 Hz, 2H), 7.14-7.06 (m, 2H), 7.01 (dd,
J=8.2, 4.6 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.51 (dd, J=8.6, 2.5
Hz, 1H), 6.44 (d, J=2.6 Hz, 1H), 5.46-5.30 (m, 2H), 5.20 (d, J=11.1
Hz, 1H), 3.76 (s, 3H), 2.54 (d, J=12.6 Hz, 1H), 1.67 (s, 1H), 1.09
(d, J=3.5 Hz, 2H); MS (ESI-) m/z 540 (M-H).sup.+.
Example 140
ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate
Example 140A
ethyl
2-(1-hydroxy-3-(2-hydroxyphenyl)-3-oxopropyl)thiazole-4-carboxylate
[1914] A solution of diisopropylamine (923 .mu.L, 6.48 mmol) in
tetrahydrofuran (10 mL) was cooled to -78.degree. C. under N.sub.2,
treated with 2.5 M n-butyllithium in hexanes (2.246 mL, 5.62 mmol),
stirred at 0.degree. C. for 15 minutes, treated with
2'-hydroxyacetophenone (286 .mu.L, 2.376 mmol), stirred for 1 hour
at 0.degree. C., cooled to -78.degree. C., treated with a solution
of ethyl 2-formylthiazole-4-carboxylate (CAS #73956-17-9) (400 mg,
2.160 mmol) in tetrahydrofuran (5 mL), stirred at -78.degree. C.
for 10 minutes, quenched with 10% aqueous solution of
KH.sub.2PO.sub.4 (50 mL) and allowed to warm to room temperature.
The mixture was extracted with ethyl acetate (twice). The combined
ethyl acetate layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The residue was purified by
chromatography on silica gel eluting with a gradient of 25-100%
ethyl acetate in heptane to provide the title compound (0.38 g,
1.183 mmol, 54.8% yield).
Example 140B
ethyl 2-(4-oxochroman-2-yl)thiazole-4-carboxylate
[1915] A solution of 40% w/w diethyl azodicarboxylate in toluene
(0.619 mL, 1.360 mmol) and triphenylphosphine (0.357 g, 1.360 mmol)
in tetrahydrofuran (10 mL) was stirred at room temperature for 15
minutes. A solution of the product from Example 140A (0.38 g, 1.183
mmol) in tetrahydrofuran (10 mL) was added drop wise over 10
minutes. The mixture was stirred at 0.degree. C. for 1 hour and
then at room temperature for 30 minutes. The reaction was not
proceeding. In a separate flask, a solution of triphenylphosphine
(0.357 g, 1.360 mmol) in tetrahydrofuran (10 mL) under N.sub.2 was
cooled to 0.degree. C. and treated with 40% w/w diethyl
azodicarboxylate in toluene (0.619 mL, 1.360 mmol) over 3 minutes,
stirred for 15 minutes and transferred to the original reaction
mixture drop wise over 15 minutes. The mixture was stirred at
0.degree. C. for 1 hour. The mixture was concentrated. The residue
was purified by chromatography on silica gel eluting with a
gradient of 10 to 100% ethyl acetate in heptane. The isolated
impure product was further purified by chromatography on silica gel
eluting with a gradient of [9:1 CH.sub.2Cl.sub.2:ethyl acetate] in
heptanes to provide the title compound (70 mg, 0.231 mmol, 19.52%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.24 (s, 1H),
7.96-7.92 (m, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.14-7.08 (m, 2H), 5.88
(dd, J=11.7, 3.7 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 3.34 (dd, J=17.0,
3.7 Hz, 1H), 3.19 (dd, J=17.0, 11.7 Hz, 1H), 1.42 (t, J=7.1 Hz,
3H); MS (ESI+) m/z 304 (M+H).sup.+, m/z 321 (M+NH.sub.4).sup.+.
Example 140C
ethyl
rel-2-((S)-4-(((R)-tert-butylsulfinyl)imino)chroman-2-yl)thiazole-4--
carboxylate
[1916] The title compound was isolated as the first eluting isomer
from the procedure similar to that described in Example 132C,
substituting the product from Example 140B for the product from
Example 132B. Stereochemistry was arbitrarily assigned. .sup.1H NMR
(501 MHz, CDCl.sub.3) .delta. 8.26 (s, 1H), 8.07 (dd, J=8.0, 1.7
Hz, 1H), 7.48 (ddd, J=8.5, 7.3, 1.6 Hz, 1H), 7.12-7.07 (m, 2H),
5.66 (dd, J=12.7, 3.0 Hz, 1H), 4.48 (qd, J=7.1, 2.7 Hz, 2H), 4.14
(dd, J=17.5, 3.1 Hz, 1H), 3.38 (dd, J=17.5, 12.7 Hz, 1H), 1.45 (t,
J=7.1 Hz, 3H), 1.35 (s, 9H); MS (ESI+) m/z 407 (M+H).sup.+.
Example 140D
ethyl rel-2-((2S,4S)-4-aminochroman-2-yl)thiazole-4-carboxylate
[1917] A solution of product from Example 140C (31 mg, 0.076 mmol)
in ethanol (2 mL) was cooled to 0.degree. C., treated with
NaBH.sub.4 (8.66 mg, 0.229 mmol), stirred at 0.degree. C. for 15
minutes, and stirred at room temperature for 1 hour. The mixture
was treated with 4 M HCl in dioxane (191 .mu.L, 0.763 mmol) and
stirred at room temperature for 40 minutes. The mixture was
partitioned between water (10 mL) and methyl tert-butyl ether (30
mL). The aqueous layer was basified with solid NaHCO.sub.3 and
extracted with ethyl acetate (twice, 2.times.30 mL). The combined
ethyl acetate layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to provide the title compound (20 mg,
0.066 mmol, 86% yield). Stereochemistry was arbitrarily assigned.
.sup.1H NMR (501 MHz, CDCl.sub.3) .delta. 8.23 (s, 1H), 7.57 (d,
J=7.5 Hz, 1H), 7.26-7.21 (m, 1H), 7.07-7.03 (m, 2H), 6.97 (dd,
J=8.2, 1.1 Hz, 1H), 5.60 (dd, J=11.4, 2.2 Hz, 1H), 4.47 (q, J=7.1
Hz, 2H), 4.36-4.30 (m, 1H), 2.88 (ddd, J=13.0, 5.6, 2.2 Hz, 1H),
1.45 (t, J=7.1 Hz, 3H); MS (ESI+) m/z 305 (M+H).sup.+.
Example 140E
ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate
[1918] The title compound was prepared using the procedure similar
to that described in Example 126G, substituting the product from
Example 140D for the product from Example 126F, and purification by
chromatography on silica gel eluting with a gradient of 0-50% ethyl
acetate in [9:1 CH.sub.2Cl.sub.2:ethyl acetate]. Stereochemistry
was arbitrarily assigned. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.21 (s, 1H), 7.27-7.20 (m, 1H), 7.17 (dd, J=8.2, 1.7 Hz, 1H),
7.16-7.10 (m, 2H), 7.04 (d, J=8.2 Hz, 1H), 7.00 (td, J=7.6, 1.1 Hz,
1H), 6.97 (dd, J=8.2, 1.0 Hz, 1H), 5.59 (dd, J=11.1, 2.4 Hz, 1H),
5.51 (td, J=10.0, 6.2 Hz, 1H), 5.39 (d, J=8.9 Hz, 1H), 4.48 (q,
J=7.1 Hz, 2H), 2.97 (ddd, J=13.2, 6.0, 2.4 Hz, 1H), 1.94 (dt,
J=13.2, 11.0 Hz, 1H), 1.81-1.77 (m, 1H), 1.72-1.68 (m, 1H), 1.46
(t, J=7.1 Hz, 3H), 1.15-1.09 (m, 2H); MS (ESI-) m/z 527
(M-H).sup.-.
Example 141
ethyl
rel-2-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate
Example 141A
ethyl rel-2-((R)-4-(((R)-tert-butyl
sulfinyl)imino)chroman-2-yl)thiazole-4-carboxylate
[1919] The title compound was isolated as the second eluting isomer
from the procedure similar to that described in Example 132C,
substituting the product from Example 140B for the product from
Example 132B. Stereochemistry was arbitrarily assigned. .sup.1H NMR
(501 MHz, CDCl.sub.3) .delta. 8.23 (s, 1H), 8.06 (dd, J=8.4, 1.6
Hz, 1H), 7.48 (ddd, J=8.9, 7.6, 1.7 Hz, 1H), 7.11-7.06 (m, 2H),
5.74 (dd, J=10.1, 3.8 Hz, 1H), 4.46 (qd, J=7.1, 1.0 Hz, 2H), 4.28
(dd, J=17.1, 3.8 Hz, 1H), 3.48 (dd, J=17.2, 10.1 Hz, 1H), 1.45 (t,
J=7.1 Hz, 3H), 1.35 (s, 9H); MS (ESI+) m/z 407 (M+H).sup.+.
Example 141B
ethyl rel-2-((2R,4R)-4-aminochroman-2-yl)thiazole-4-carboxylate
and
ethyl rel-2-((2R,4S)-4-aminochroman-2-yl)thiazole-4-carboxylate
[1920] Using the procedure similar to that described in Example
140D, substituting the product from Example 141A for the product
from Example 140C, provided the titled compound as a 4:1 mixture of
cis and trans isomers. Stereochemistry was arbitrarily assigned.
NMR of peaks of major cis isomer: .sup.1H NMR (501 MHz, CDCl.sub.3)
.delta. 8.23 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.26-7.21 (m, 1H),
7.05 (td, J=7.6, 1.1 Hz, 1H), 6.97 (dd, J=8.2, 1.1 Hz, 1H), 5.60
(dd, J=11.4, 2.2 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 4.36-4.29 (m,
1H), 2.88 (ddd, J=13.1, 5.7, 2.2 Hz, 1H), 2.03-1.95 (m, 1H), 1.45
(t, J=7.1 Hz, 3H); MS (ESI+) m/z 305 (M+H).sup.+.
Example 141C
ethyl
rel-2-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate
[1921] The title compound was prepared using the procedure similar
to that described in Example 126G, substituting the product from
Example 141B for the product from Example 126F. Purification by
chromatography on silica gel eluting with a gradient of 0-50% ethyl
acetate in [9:1 CH.sub.2Cl.sub.2:ethyl acetate] provided the title
compound as the first eluting isomer. Stereochemistry was
arbitrarily assigned. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.23 (s, 1H), 7.30-7.25 (m, 1H), 7.22 (dd, J=8.2, 1.7 Hz, 1H),
7.20-7.17 (m, 2H), 7.04 (d, J=8.2 Hz, 1H), 7.03-6.98 (m, 2H), 5.62
(d, J=6.7 Hz, 1H), 5.30 (dd, J=11.2, 2.6 Hz, 1H), 5.14-5.09 (m,
1H), 4.49 (q, J=7.1 Hz, 2H), 2.74 (dt, J=14.2, 2.8 Hz, 1H), 2.25
(ddd, J=14.3, 11.2, 4.9 Hz, 1H), 1.78 (ddd, J=10.0, 6.7, 3.4 Hz,
1H), 1.70 (ddd, J=9.9, 6.8, 3.6 Hz, 1H), 1.47 (t, J=7.1 Hz, 3H),
1.20 (ddd, J=10.3, 6.7, 3.6 Hz, 1H), 1.07 (ddd, J=9.7, 6.8, 3.3 Hz,
1H); MS (ESI+) m/z 529 (M+H).sup.+.
Example 142
ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylate
[1922] The title compound was isolated as the second eluting isomer
from the chromatography of the crude material as described in
Example 141C. Stereochemistry was arbitrarily assigned. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.20 (s, 1H), 7.25-7.20 (m, 1H), 7.16
(dd, J=8.2, 1.7 Hz, 1H), 7.14-7.10 (m, 2H), 7.02 (d, J=8.2 Hz, 1H),
7.01-6.94 (m, 2H), 5.58 (dd, J=11.1, 2.4 Hz, 1H), 5.54-5.46 (m,
1H), 5.38 (d, J=8.9 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.96 (ddd,
J=13.2, 6.0, 2.3 Hz, 1H), 1.93 (dt, J=13.1, 11.0 Hz, 1H), 1.78 (dd,
J=10.1, 3.7 Hz, 1H), 1.69 (dd, J=9.5, 3.5 Hz, 1H), 1.45 (t, J=7.1
Hz, 3H), 1.15-1.07 (m, 2H); MS (ESI-) m/z 527 (M-H).sup.-.
Example 143
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylic
acid
[1923] The title compound was prepared using procedure similar to
that described in Example 152, substituting the product from
Example 140E for the product from Example 151G. Stereochemistry was
arbitrarily assigned. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.33 (s, 1H), 7.27-7.23 (m, 1H), 7.18 (dd, J=8.2, 1.6 Hz, 1H),
7.15-7.12 (m, 2H), 7.05 (d, J=8.2 Hz, 1H), 7.03-6.99 (m, 1H), 6.98
(d, J=8.2 Hz, 1H), 5.58 (dd, J=11.1, 1.7 Hz, 1H), 5.56-5.51 (m,
1H), 5.44 (d, J=8.8 Hz, 1H), 2.99 (dd, J=12.3, 5.0 Hz, 1H),
2.00-1.90 (m, 1H), 1.81 (dd, J=9.8, 3.2 Hz, 1H), 1.72 (dd, J=9.8,
3.1 Hz, 1H), 1.19-1.11 (m, 2H); MS (ESI-) m/z 499 (M-H).sup.-.
Example 144
rel-2-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylic
acid
[1924] The title compound was prepared using procedure similar to
that described in Example 152, substituting the product from
Example 141C for the product from Example 151G. Stereochemistry was
arbitrarily assigned. .sup.1H NMR (501 MHz, CDCl.sub.3) .delta.
8.32 (s, 1H), 7.29-7.25 (m, 1H), 7.20 (dd, J=8.2, 1.7 Hz, 1H),
7.18-7.15 (m, 2H), 7.03 (d, J=8.2 Hz, 1H), 7.02-6.98 (m, 2H), 5.63
(d, J=6.8 Hz, 1H), 5.29 (dd, J=10.5, 2.6 Hz, 1H), 5.15-5.11 (m,
1H), 2.69 (dt, J=14.3, 3.0 Hz, 1H), 2.33 (ddd, J=14.6, 10.7, 3.9
Hz, 2H), 1.77 (ddd, J=9.7, 6.5, 3.1 Hz, 1H), 1.72 (ddd, J=9.6, 6.3,
3.1 Hz, 1H), 1.17 (ddd, J=9.9, 6.5, 3.5 Hz, 1H), 1.09 (ddd, J=9.2,
6.4, 3.0 Hz, 1H); MS (ESI+) m/z 501 (M+H).sup.+.
Example 145
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxylic
acid
[1925] The title compound was prepared using procedure similar to
that described in Example 152, substituting the product from
Example 142 for the product from Example 151G. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.33 (s, 1H), 7.27-7.23 (m, 1H), 7.18 (dd,
J=8.2, 1.7 Hz, 1H), 7.16-7.12 (m, 2H), 7.05 (d, J=8.2 Hz, 1H),
7.04-7.00 (m, 1H), 6.98 (d, J=8.2 Hz, 1H), 5.57 (dd, J=11.0, 1.8
Hz, 1H), 5.56-5.51 (m, 1H), 5.43 (d, J=8.7 Hz, 1H), 2.99 (ddd,
J=13.3, 5.8, 1.8 Hz, 1H), 2.00-1.90 (m, 1H), 1.83-1.78 (m, 1H),
1.75-1.70 (m, 1H), 1.18-1.11 (m, 2H); MS (ESI-) m/z 499
(M-H).sup.-.
Example 146
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-3-fluorobenzoic
acid
[1926] The mixture of Example 138 (100 mg, 0.180 mmol) and 2N
aqueous LiOH (0.5 mL) in methanol (2 mL) was stirred at 35.degree.
C. for 2 hours. Solvent was removed and water was added (0.5 mL).
The pH of the mixture was adjusted with 2N HCl to pH 1.about.2. The
precipitated white solid was collected by filtration and dried to
yield title compound (85 mg, 87% yield). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.92 (ddd, J=18.8, 8.0, 1.5 Hz, 1H), 7.79 (td,
J=10.2, 1.6 Hz, 1H), 7.64 (dt, J=20.9, 7.5 Hz, 1H), 7.19-7.07 (m,
2H), 7.04-6.95 (m, 2H), 6.54 (ddd, J=8.6, 4.5, 2.5 Hz, 1H), 6.45
(dd, J=6.3, 2.5 Hz, 1H), 5.50 (dd, J=11.3, 2.0 Hz, 1H), 5.44 (td,
J=9.7, 6.1 Hz, 1H), 5.34 (d, J=8.8 Hz, 1H), 3.76 (d, J=1.6 Hz, 3H),
2.55 (ddd, J=13.4, 6.2, 2.1 Hz, 1H), 1.82-1.70 (m, 2H), 1.66 (ddd,
J=9.7, 4.3, 2.0 Hz, 1H), 1.14-1.03 (m, 2H); MS (ESI-) m/z 540
(M-H).sup.+.
Example 147
methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]bicyclo[1.1.1]pent-
ane-1-carboxylate
Example 147A
methyl
3-(7-methoxy-4-oxochroman-2-yl)bicyclo[1.1.1]pentane-1-carboxylate
[1927] The title compound was prepared and purified using the
procedures similar to that described in Example 129A, substituting
methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate for methyl
3-oxocyclobutanecarboxylate.
Example 147B
methyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}a-
mino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]bicyclo[1.1.1]pentane-1-carbox-
ylate
[1928] The title compound was prepared and purified using the
procedures similar to that described in Example 129 B, substituting
Example 147A for Example 129A (73% yield). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.76 (d, J=8.8 Hz, 1H), 6.52 (dd, J=8.8, 2.5
Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 4.06 (dd, J=11.2, 3.5 Hz, 1H),
3.96 (s, 3H), 3.79 (s, 3H), 3.69 (s, 3H), 3.06 (dd, J=17.0, 3.5 Hz,
1H), 2.43-2.28 (m, 1H), 2.13-2.01 (m, 6H); MS (ESI+) m/z=332
(M+H).sup.+.
Example 147C
methyl rac-3-((2R,4R)-4-amino-7-methoxy
chroman-2-yl)bicyclo[1.1.1]pentane-1-carboxylate hydrochloride
[1929] Example 147B (150 mg, 0.453 mmol) in acetic acid was charged
with a hydrogen balloon and reduced to amine using 5% platinum (177
mg, 0.045 mmol) on carbon as catalyst and was stirred for 18 hours
at room temperature. The reaction mixture was filtered through a
diatomaceous earth pad and the solvent removed under pressure. To
the residue was added methyl tert-butyl ether (2 mL), followed by
slow addition of 4M HCl in dioxane (0.5 mL). The precipitated white
solid was collected by filtration and dried to provide title
compound (105 mg, 0.309 mmol, 68.3% yield). MS (ESI+) m/z=287
(M-NH.sub.2).sup.+.
Example 147D
methyl
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]bicyclo[1.1.1]pent-
ane-1-carboxylate
[1930] To
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(78 mg, 0.324 mmol) in N,N-dimethylformamide (2 mL) was added HATU
(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate) (168 mg, 0.441 mmol). The mixture was
stirred at room temperature for 5 minutes, followed by addition of
Example 147C (100 mg, 0.294 mmol) and
N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.177 mmol). The
mixture was stirred at room temperature for 2 hours. Purification
by chromatography, eluting with 0-40% ethyl acetate in heptane to
provide the title compound (68 mg, 43.8%). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.19-7.12 (m, 2H), 7.03 (d, J=8.2 Hz, 1H), 6.86
(dd, J=8.5, 1.0 Hz, 1H), 6.44 (dd, J=8.6, 2.6 Hz, 1H), 6.32 (d,
J=2.6 Hz, 1H), 5.32 (d, J=8.8 Hz, 1H), 5.26-5.17 (m, 1H), 4.07 (dd,
J=11.9, 1.6 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 2.21 (ddd, J=13.0,
6.2, 1.8 Hz, 1H), 2.08-1.99 (m, 6H), 1.97-1.84 (m, 1H), 1.74 (ddd,
J=9.0, 5.4, 2.2 Hz, 1H), 1.69-1.63 (m, 1H), 1.08 (tdd, J=9.6, 6.2,
3.0 Hz, 2H); MS(ESI-) m/z 526 (M-H).sup.+.
Example 148
rac-3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]bicyclo[1.1.1]pentane-1-c-
arboxylic acid
[1931] To Example 147D (23 mg, 0.044 mmol) in a 4 mL vial was added
methanol (1.5 mL), followed by addition of 4N LiOH solution in
water (0.5 mL). The mixture was stirred at 35.degree. C. for 2
hours. Solvent was removed and water was added (1 mL), followed by
addition of 2N HCl drop wise to adjust pH to 1.about.2. The white
solid precipitated was collected by filtration and dried to yield
the title compound (21.5 mg, 96%). 1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.17 (dd, J=8.2, 1.7 Hz, 1H), 7.15-7.05 (m, 2H), 7.03 (d,
J=8.1 Hz, 1H), 6.86 (dd, J=8.5, 1.0 Hz, 1H), 6.47-6.41 (m, 1H),
6.32 (d, J=2.5 Hz, 1H), 5.33 (d, J=8.8 Hz, 1H), 5.27-5.15 (m, 1H),
4.08 (dd, J=11.7, 1.6 Hz, 1H), 3.74 (d, J=1.5 Hz, 3H), 2.22 (ddd,
J=12.9, 6.2, 1.8 Hz, 1H), 2.11-2.02 (m, 6H), 1.74 (ddd, J=8.9, 5.4,
2.2 Hz, 1H), 1.65 (dpd, J=19.3, 7.6, 6.5, 3.1 Hz, 2H), 1.12-1.05
(m, 2H), MS(ESI-) m/z 512 (M-H)
Example 149
ethyl
rac-6-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate
Example 149A
tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate
[1932] To a solution of diisopropylamine (26.6 mL, 190 mmol) in
anhydrous tetrahydrofuran (100 mL) under nitrogen and at
-78.degree. C. was added 1.6 M n-butyl lithium in hexanes (110 mL,
176 mmol). After the resulting suspension had been stirred a while,
a solution of tert-butyl acetate (20.1 mL, 150 mmol) in
tetrahydrofuran (30 mL) was added over 15 minutes. Then, after the
solution had been stirred at -78.degree. C. about 100 minutes, a
solution of methyl salicylate (6.45 mL, 50.0 mmol) in
tetrahydrofuran (50 mL) was added to the reaction mixture over
nearly 20 minutes. The reaction mixture was permitted to warm to
room temperature overnight and the reaction mixture was then
quenched with 1 M aqueous citric acid (80 mL). The aqueous phase
was separated and extracted twice with ethyl acetate. The combined
organic phases were washed with brine, concentrated and
chromatographed on silica (30 to 50% CH.sub.2Cl.sub.2/heptane) to
give some purified material and additional fractions which were
still impure. The impure fractions were concentrated and
chromatographed on silica (eluted with 25 to 50%
CH.sub.2Cl.sub.2/heptane). The desired fractions from both columns
were combined and concentrated to give title compound (9.55 g).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.49 (s, 9H), 3.95
(s, 2H), 6.95 (ddd, J=8.0, 7.3, 1.1 Hz, 1H), 7.04 (dd, J=8.4, 1.1
Hz, 1H), 7.53 (ddd, J=8.4, 7.3, 1.7 Hz, 1H), 7.71 (dd, J=8.0, 1.7
Hz, 1H), 11.95 (s, 1H); MS (DCI) m/z 237 (M+H).sup.+, 254
(M+NH.sub.4).sup.+.
Example 149B
tert-Butyl 3-(5-bromopyridin-2-yl)-2-(2-hydroxybenzoyl)acrylate
[1933] The mixture of Example 149A (1.66 g, 7.0 mmol),
5-bromopicolinaldehyde (1.33 g, 7.15 mmol), piperidine (30 .mu.L,
0.30 mmol) and acetic acid (17.5 .mu.L, 0.31 mmol) was heated at
gentle reflux in anhydrous toluene (30 mL), within a round-bottomed
flask with a Dean-Stark apparatus attached, for 40 minutes. The
heat was increased to very slowly azeotrope water over. After an
hour, the heat was reduced back to gentle reflux, 3A molecular
sieves (3.5 grams) were added. After 30 minutes of refluxing the
reaction mixture was cooled to room temperature. The sieves were
filtered off with a thorough chloroform rinse, and the filtrate was
concentrated to a dark syrup which was chromatographed on silica
(20% methyl tert-butyl ether/heptane) to give an impure solid which
was slurried in heptane. The title compound was collected by
filtration, with a heptane rinse, as a yellow powder (1.105 g).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.41 (s, 9H),
6.74-6.79 (m, 1H), 7.00-7.04 (m, 1H), 7.28 (d, J=8.2 Hz, 1H),
7.40-7.45 (m, 2H), 7.68 (s, 1H), 7.76-7.80 (m, 1H), 8.40 (d, J=2.3
Hz, 1H), 11.73 (s, 1H); MS (ESI) m/z 406 (M+H).sup.+.
Example 149C
2-(5-bromopyridin-2-yl)chroman-4-one
[1934] A mixture of Example 149B (1.103 g, 2.72 mmol) and
1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl-
)thiourea (170 mg, 0.41 mmol) were stirred in anhydrous toluene (15
mL) for 3 hours at room temperature and then at 40.degree. C.
overnight. (rac)-Camphorsulfonic acid (316 mg, 1.36 mmol) was added
and the solution was heated at 90.degree. C. for two days and
cooled to room temperature. The reaction mixture was placed on a
silica column and chromatographed (20 to 35% methyl tert-butyl
ether/heptane) to give title compound (414 mg). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 3.11-3.15 (m, 2H), 5.57 (dd, J=7.7 Hz,
1H), 7.04-7.10 (m, 2H), 7.50-7.56 (m, 2H), 7.90 (dd, J=8.4, 2.4 Hz,
1H), 7.92-7.95 (m, 1H), 8.66-8.68 (m, 1H); MS (DCI) m/z 306
(M+H).sup.+.
Example 149D
ethyl 6-(4-oxochroman-2-yl)nicotinate
[1935] To Example 149C (410 mg, 1.35 mmol) and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (49 mg,
0.068 mmol) in a 50 mL pressure bottle were added ethanol (10 mL)
and triethylamine (0.377 mL, 2.70 mmol). The reactor was degassed
with argon several times, then filled with carbon monoxide and
heated at 100.degree. C. for 16 hours at 70 psi. The sample was
concentrated and filtered through silica (80%
CH.sub.2Cl.sub.2/heptane), and the filtrate was concentrated and
chromatographed on silica (60 to 100% CH.sub.2Cl.sub.2/heptane) to
give title compound as an orange solid (242 mg). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 1.42 (t, J=7.1 Hz, 3H), 3.12 (dd,
J=17.0, 11.6 Hz, 1H), 3.20 (dd, J=17.0, 4.0 Hz, 1H), 4.43 (q, J=7.1
Hz, 2H), 5.67 (dd, J=11.6, 4.0 Hz, 1H), 7.05-7.13 (m, 2H), 7.54
(ddd, J=8.6, 7.2, 1.8 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.94 (dd,
J=7.8, 1.8 Hz, 1H), 8.38 (dd, J=8.2, 2.2 Hz, 1H), 9.20 (d, J=2.2
Hz, 1H); MS (DCI) m/z 298 (M+H).sup.+.
Example 149E
ethyl 6-(4-(ethoxyimino)chroman-2-yl)nicotinate
[1936] A mixture of Example 149D (239 mg, 0.80 mmol),
O-ethylhydroxylamine hydrochloride (117 mg, 1.20 mmol) and
potassium acetate (118 mg, 1.20 mmol) were heated in ethanol (3 mL)
at 50.degree. C. for 90 minutes and then cooled to room
temperature, concentrated, and chromatographed on silica (30%
methyl tert-butyl ether/heptane) to give title compound as an
orange syrup (262 mg). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
ppm 1.31 (t, J=7.1 Hz, 3H), 1.42 (t, J=7.1 Hz, 3H), 2.75 (dd,
J=17.2, 11.8 Hz, 1H), 3.71 (dd, J=17.2, 3.5 Hz, 1H), 4.21-4.26 (m,
2H), 4.43 (q, J=7.1 Hz, 2H), 5.26 (dd, J=11.8, 3.5 Hz, 1H),
6.97-7.03 (m, 2H), 7.29 (ddd, J=8.2, 7.2, 1.7 Hz, 1H), 7.70-7.73
(m, 1H), 7.95 (dd, J=7.9, 1.7 Hz, 1H), 8.36 (dd, J=8.2, 2.1 Hz,
1H), 9.20 (dd, J=2.1, 0.8 Hz, 1H); MS (DCI) m/z 341
(M+H).sup.+.
Example 149F
ethyl 6-(4-aminochroman-2-yl)nicotinate
[1937] Example 149E (259 mg, 0.76 mmol) and ethanol (25 mL) were
added to Ra--Ni 2800 water slurry (2.6 g, 20 mmol) in a 50 mL
pressure bottle and stirred or shaken for 16 hours under hydrogen
at 30 psi and at room temperature. The reaction mixture was
filtered, concentrated, and chromatographed on silica (0 to 3%
concentrated aqueous NH.sub.4OH in acetonitrile) to give title
compound as a syrup (119 mg). MS (ESI) m/z 299 (M+H).sup.+.
Example 149G
ethyl
rac-6-((2R,4S)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropa-
necarboxamido)chroman-2-yl)nicotinate
[1938]
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(132 mg, 0.55 mmol), carbonyl diimidazole (89 mg, 0.55 mmol) and
1-hydroxy-7-azabenzotriazole (8 mg, 0.06 mmol) were stirred in
anhydrous acetonitrile (1.3 mL) for 100 minutes and then
transferred to a flask containing Example 149F (115 mg, 0.39 mmol)
with an acetonitrile (0.2 mL) rinse. After several minutes,
diisopropylethylamine (50 .mu.L, 0.29 mmol) was added and the
solution was stirred at room temperature for 3.5 hours. Then the
solution was concentrated and chromatographed on silica (5 to 20%
methyl tert-butyl ether in 1:1 CH.sub.2Cl.sub.2/heptane) to give
the title compound as the first eluting isomer (84 mg), and Example
150 (85 mg) as the second eluting isomer. .sup.1H NMR (501 MHz,
CDCl.sub.3) .delta. ppm 1.04-1.12 (m, 2H), 1.42 (t, J=7.1 Hz, 3H),
1.66-1.73 (m, 2H), 2.23 (ddd, J=14.1, 10.3, 4.9 Hz, 1H), 2.47 (ddd,
J=14.1, 4.1, 2.9 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 5.01-5.06 (m,
2H), 5.62 (d, J=7.4 Hz, 1H), 6.91-7.04 (m, 4H), 7.13-7.16 (m, 2H),
7.18 (dd, J=8.2, 1.7 Hz, 1H), 7.23 (ddd, J=8.6, 7.2, 1.7 Hz, 1H),
7.62 (d, J=8.2 Hz, 1H), 8.32 (dd, J=8.2, 2.1 Hz, 1H), 9.19-9.21 (m,
1H); MS (ESI) m/z 523 (M+H).sup.+.
Example 150
ethyl
rac-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylate
[1939] The title compound was obtained as the second eluting isomer
from the chromatography described in Example 149G. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. ppm 1.04-1.11 (m, 2H), 1.43 (t, J=7.1 Hz,
3H), 1.64-1.68 (m, 1H), 1.73-1.77 (m, 1H), 1.84 (ddd, J=13.3, 10.9,
10.8 Hz, 1H), 2.78 (ddd, J=13.3, 6.2, 2.3 Hz, 1H), 4.43 (q, J=7.1
Hz, 2H), 5.33 (dd, J=10.8, 2.3 Hz, 1H), 5.41 (d, J=8.9 Hz, 1H),
5.48-5.55 (m, 1H), 6.91-7.03 (m, 3H), 7.08-7.13 (m, 3H), 7.17-7.22
(m, 1H), 7.63 (d, J=8.2 Hz, 1H), 8.32 (dd, J=8.2, 2.1 Hz, 1H), 9.14
(dd, J=2.1, 0.8 Hz, 1H); MS (ESI) m/z 523 (M+H).sup.+.
Example 151
ethyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}am-
ino)-3,4-dihydro-2H-chromen-2-yl]cyclobutanecarboxylate
Example 151A
ethyl 3-methylenecyclobutanecarboxylate
[1940] A mixture of 3-methylenecyclobutanecarboxylic acid
(CAS#15760-36-8) (2.06 g, 18.37 mmol), ethyl iodide (1.782 mL,
22.05 mmol) and Cs.sub.2CO.sub.3 (13.17 g, 40.4 mmol) in
N,N-dimethylformamide (100 mL) under N.sub.2 was stirred at room
temperature overnight. The mixture was poured slowly into a stirred
0.degree. C. mixture of 0.2 M HCl (500 mL) and methyl tert-butyl
ether (1000 mL). The layers were separated and the methyl
tert-butyl ether layer was washed with water (500 mL.times.2),
washed with brine, dried (MgSO.sub.4), filtered, and concentrated
to provide the title compound (2.5 g, 17.83 mmol, 97% yield).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 4.83 (p, J=2.3 Hz, 2H),
4.19 (q, J=7.1 Hz, 2H), 3.18-3.11 (m, 1H), 3.07-3.00 (m, 2H),
2.97-2.89 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).
Example 151B
ethyl 3-(hydroxymethyl)cyclobutanecarboxylate
[1941] A solution of product from Example 151A (2.5 g, 17.83 mmol)
in tetrahydrofuran (20 mL) was treated with borane-methyl sulfide
complex (4.46 mL, 8.92 mmol) and the mixture was stirred at room
temperature for approximately 3 hours. A suspension of sodium
perborate (1.751 g, 21.40 mmol) in water (15 mL) was added (slowly
at first) followed by dioxane (15 mL). The mixture was heated to
65.degree. C. for 2 hours and allowed to slowly cool to room
temperature overnight. The mixture was partitioned between ethyl
acetate (100 mL) and water (50 mL). The layers were separated and
the aqueous was extracted with ethyl acetate (50 mL). The combined
ethyl acetate layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to provide the title compound (2.8 g,
17.70 mmol, 99% yield) as a 1:1 mixture of cis and trans isomers.
MS (DCI+) m/z 176 (M+NH.sub.4).sup.+.
Example 151C
ethyl 3-formylcyclobutanecarboxylate
[1942] Following a procedure described in Kasar, et al.
WO2012154204A1, 2012, a solution of oxalyl chloride (3.10 mL, 35.4
mmol) in CH.sub.2Cl.sub.2 (115 mL) was cooled to -78.degree. C.
under N.sub.2, treated dropwise with a solution of
dimethylsulfoxide (5.02 mL, 70.8 mmol) in CH.sub.2Cl.sub.2 (10 mL),
followed by the addition of a solution of the product from Example
151B (2.8 g, 17.70 mmol) in CH.sub.2Cl.sub.2 (40 mL). The mixture
was stirred at -78.degree. C. for 2 hours, treated with
triethylamine (24.67 mL, 177 mmol), stirred at -78.degree. C. for
20 minutes, quenched with saturated NH.sub.4C.sub.1 solution (100
mL), and allowed to warm to room temperature. The layers were
separated and the aqueous was extracted with CH.sub.2Cl.sub.2
(twice). The combined CH.sub.2Cl.sub.2 layers were dried
(MgSO.sub.4), filtered, and concentrated. The residue was purified
by chromatography on silica gel eluting with a gradient 0-90% of
ethyl acetate in heptanes to provide the titled compound.
Example 151D
ethyl 3-(4-oxochroman-2-yl)cyclobutanecarboxylate
[1943] A mixture of 2'-hydroxyacetophenone (212 mg, 1.560 mmol) and
the product from Example 151C (203 mg, 1.300 mmol) in ethanol (1
mL) was treated with pyrrolidine (107 .mu.L, 1.300 mmol) and
stirred at room temperature overnight. Mixture was partitioned
between ethyl acetate (30 mL) and 1 M HCl (10 mL). The ethyl
acetate layer was washed with brine, dried (MgSO.sub.4), filtered,
and concentrated. The residue was purified by chromatography on
silica gel eluting with a gradient of 10 to 30% ethyl acetate in
heptane to provide the titled compound (0.27 g, 0.984 mmol, 76%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.93-7.88 (m,
1H), 7.55-7.47 (m, 1H), 7.07-6.99 (m, 2H), 4.49-4.37 (m, 1H),
4.24-4.14 (m, 2H), 3.23-3.04 (m, 1H), 2.83-2.74 (m, 0.5H),
2.70-2.57 (m, 2.5H), 2.52-2.24 (m, 4H), 1.33-1.27 (m, 3H); MS
(ESI+) m/z 275 (M+H).sup.+.
Example 151E
ethyl 3-(4-(methoxyimino)chroman-2-yl)cyclobutanecarboxylate
[1944] A solution of the product from Example 151D (270 mg, 0.984
mmol) and O-methylhydroxylamine hydrochloride (247 mg, 2.95 mmol)
in pyridine (2 mL) was heated at 65.degree. C. for 1 hour. The
mixture was cooled, concentrated, and partitioned between ethyl
acetate (50 mL) and water (15 mL). The ethyl acetate layer was
washed with brine, dried (MgSO.sub.4), filtered, concentrated, and
dried under vacuum to provide the title compound (0.27 g, 0.890
mmol, 90% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.50
(td, J=6.5, 3.1 Hz, 0.1H), 7.90 (ddd, J=7.9, 6.5, 1.5 Hz, 0.9H),
7.36-7.22 (m, 1H), 6.98-6.89 (m, 2H), 4.18 (dq, J=14.2, 7.1 Hz,
2H), 4.08-3.95 (m, 4H), 3.22-2.99 (m, 1.5H), 2.78-2.65 (m, 0.5H),
2.62-2.21 (m, 5H), 1.34-1.25 (m, 3H); MS (ESI+) m/z 304
(M+H).sup.+.
Example 151F
ethyl 3-(4-aminochroman-2-yl)cyclobutanecarboxylate
[1945] A solution of the product from Example 151E (0.27 g, 0.890
mmol) in ethanol (20 mL) was added to Ra--Ni 2800, water slurry, (3
g, 23.00 mmol) in a 50 mL pressure bottle and stirred at room
temperature under an atmosphere of H.sub.2 for 16 hours at a
pressure of 30 pounds per square inch. The mixture was filtered to
remove the solids and the filtrate was concentrated to provide the
title compound (230 mg, 0.835 mmol, 94% yield) as a mixture of
isomers. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.44 (t, J=7.4
Hz, 0.5H), 7.23 (dt, J=7.6, 1.6 Hz, 0.5H), 7.20-7.11 (m, 1H),
6.96-6.79 (m, 2H), 4.23-3.98 (m, 4H), 3.21-2.98 (m, 1H), 2.65 (dt,
J=15.0, 7.4 Hz, 0.5H), 2.57-2.21 (m, 5H), 2.12 (dtd, J=12.8, 6.4,
1.7 Hz, 0.5H), 1.76 (ddd, J=7.6, 5.9, 3.1 Hz, 1H), 1.32-1.24 (m,
3H); MS (ESI+) m/z 259 (M-NH.sub.3).sup.+.
Example 151G
ethyl
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}am-
ino)-3,4-dihydro-2H-chromen-2-yl]cyclobutanecarboxylate
[1946] The title compound was prepared using the procedure similar
to that described in Example 126G, substituting the product from
Example 151F for the product from Example 126F. The crude material
was purified by chromatography on silica gel, eluting with a
gradient of 15-50% ethyl acetate in heptanes to provide the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.20-7.07 (m,
3.5H), 7.06-6.98 (m, 1.5H), 6.91-6.77 (m, 2H), 5.55-5.50 (m, 0.5H),
5.39 (dd, J=8.7, 5.4 Hz, 0.5H), 5.36-5.26 (m, 0.5H), 5.05-4.98 (m,
0.5H), 4.22-3.99 (m, 2.5H), 3.74-3.64 (m, 0.5H), 3.15-2.96 (m, 1H),
2.69-2.53 (m, 0.5H), 2.51-2.14 (m, 4H), 1.96 (ddt, J=12.7, 7.8, 2.3
Hz, 0.5H), 1.80-1.66 (m, 1H), 1.34-1.23 (m, 3H), 1.14-1.04 (m, 2H),
0.93-0.81 (m, 3H); MS (ESI+) m/z 500 (M+H).sup.+.
Example 152
3-[4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-
,4-dihydro-2H-chromen-2-yl]cyclobutanecarboxylic acid
[1947] A solution of the product from Example 151G (50 mg, 0.100
mmol) in tetrahydrofuran (1.5 mL) was diluted with methanol (1.5
mL), treated with 1 M NaOH (1 mL) and stirred at room temperature
for 15 minutes. The mixture was treated with 1 M HCl (5 mL) and
extracted with ethyl acetate (30 mL). The ethyl acetate layer was
washed with brine, dried (MgSO.sub.4), filtered, and concentrated
to provide the title compound (47 mg, 0.100 mmol, 100% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.21-7.08 (m, 3.5H),
7.06-6.98 (m, 1.5H), 6.91-6.78 (m, 2H), 5.54 (d, J=6.8 Hz, 0.5H),
5.42 (dd, J=8.8, 2.3 Hz, 0.5H), 5.31 (s, 0.5H), 5.05-4.98 (m,
0.5H), 4.10-4.00 (m, 0.5H), 3.75-3.63 (m, 0.5H), 3.22-3.03 (m, 1H),
2.74-2.57 (m, 0.5H), 2.55-2.17 (m, 5H), 2.00-1.92 (m, 0.5H),
1.81-1.64 (m, 3H), 1.15-1.03 (m, 2H); MS (ESI+) m/z 472
(M+H).sup.+.
Example 153
rac-6-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic
acid
[1948] The product from Example 149G (18 mg, 35 .mu.mol) was
dissolved in anhydrous tetrahydrofuran (140 .mu.L) and methanol (35
.mu.L), treated with two drops of 3 M aqueous NaOH (about 40 .mu.L)
and stirred at room temperature for two hours. The reaction mixture
was concentrated, acidified with a drop of concentrated aqueous HCl
and partitioned between brine and methyl tert-butyl ether. The
aqueous phase was separated and extracted with more methyl
tert-butyl ether. The combined organic phases were dried
(Na.sub.2SO.sub.4), filtered, and concentrated. When it was
discovered that the reaction was incomplete, the material was
resubjected to the reaction conditions, stirred overnight and
worked up as before to give the title compound (17 mg). .sup.1H NMR
(501 MHz, CDCl.sub.3) .delta. ppm 1.09-1.16 (m, 2H), 1.73-1.78 (m,
2H), 2.25-2.34 (m, 1H), 2.52-2.59 (m, 1H), 5.06-5.11 (m, 1H), 5.16
(bs, 1H), 5.20-5.26 (m, 1H), 5.75 (d, J=7.2 Hz, 1H), 6.96-7.05 (m,
3H), 7.15-7.29 (m, 4H), 7.75 (d, J=7.6 Hz, 1H), 8.45 (d, J=7.3 Hz,
1H), 9.23-9.28 (m, 1H); MS (ESI) m/z 493 (M-H).sup.-.
Example 154
rac-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic
acid
[1949] The product from Example 150 (18 mg, 35 .mu.mol) was
dissolved in anhydrous THF (170 .mu.L) and methanol (70 .mu.L),
treated with three drops of 3 M aqueous NaOH (about 70 .mu.L) and
stirred at room temperature overnight. The reaction mixture was
concentrated, acidified with a drop of concentrated aqueous HCl and
partitioned between brine and methyl tert-butyl ether. The aqueous
phase was separated and extracted with more methyl tert-butyl
ether. The combined organic phases were dried (Na.sub.2SO.sub.4),
and filtered with a methyl tert-butyl ether rinse. The filter disc
was then washed through with methanol, and the filtrate
concentrated to give the title compound (6 mg). MS (ESI) m/z=493
(M-H).sup.-.
Example 155
ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-car-
boxylate
Example 155A
ethyl
2-(1-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-3-oxopropyl)thiazole-4-ca-
rboxylate
[1950] Using the procedure similar to that described in Example
140A, substituting a solution of 2'-hydroxy-4'-methoxyacetophenone
(269 mg, 1.620 mmol) in tetrahydrofuran for 2'-hydroxyacetophenone,
and quenching with saturated NH.sub.4Cl solution in place of a 10%
aqueous solution of KH.sub.2PO.sub.4, provided the titled compound.
.sup.1H NMR (501 MHz, CDCl.sub.3) .delta. 12.33 (s, 1H), 8.19 (s,
1H), 7.68 (d, J=9.0 Hz, 1H), 6.48 (dd, J=8.9, 2.5 Hz, 1H), 6.45 (d,
J=2.5 Hz, 1H), 5.61 (ddd, J=8.7, 4.7, 2.7 Hz, 1H), 4.45 (q, J=7.1
Hz, 2H), 4.30 (d, J=4.7 Hz, 1H), 3.90 (dd, J=17.9, 2.8 Hz, 1H),
3.87 (s, 3H), 3.49 (dd, J=17.8, 8.8 Hz, 1H), 1.43 (t, J=7.1 Hz,
3H); MS (ESI+) m/z 352 (M+H).sup.+.
Example 155B
ethyl 2-(7-methoxy-4-oxochroman-2-yl)thiazole-4-carboxylate
[1951] A solution of the product from Example 155A (0.38 g, 1.081
mmol) and triphenylphosphine (0.567 g, 2.163 mmol) in
tetrahydrofuran (12 mL) was cooled to 0.degree. C., treated portion
wise with 40% w/w diethyl azodicarboxylate in toluene (0.739 mL,
1.622 mmol) over 20 minutes, stirred at room temperature for 1
hour, treated with silica gel (3 g) and concentrated to dryness.
This silica gel suspension was subjected to chromatography on
silica gel, eluting with a gradient of 15-50% ethyl acetate in
heptane to provide impure product. The impure product was further
purified by chromatography on silica gel eluting with a gradient of
50-100% [9:1 CH.sub.2Cl.sub.2:ethyl acetate] in heptanes to provide
the titled compound (0.15 g, 0.450 mmol, 41.6% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.26 (s, 1H), 7.90 (d, J=8.8 Hz, 1H),
6.68 (dd, J=8.8, 2.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 5.89 (dd,
J=11.5, 3.8 Hz, 1H), 4.46 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.28
(dd, J=17.0, 3.8 Hz, 1H), 3.14 (dd, J=17.0, 11.6 Hz, 1H), 1.44 (t,
J=7.1 Hz, 3H); MS (ESI+) m/z 334 (M+H).sup.+.
Example 155C
ethyl
rel-2-((R)-4-(((S)-tert-butylsulfinyl)imino)-7-methoxychroman-2-yl)t-
hiazole-4-carboxylate
[1952] The title compound was prepared using the procedure similar
to that described in Example 132C, substituting the product from
Example 155B for the product from Example 132B, and substituting
(S)-(-)-2-methyl-2-propanesulfinamide for
(R)-(+)-2-methyl-2-propanesulfinamide. Purification by
chromatography on silica gel eluting with a gradient of 0-100% [9:1
CH.sub.2Cl.sub.2:ethyl acetate] in [1:1 CH.sub.2Cl.sub.2:ethyl
acetate] provided the title compound as the first eluting isomer.
This compound contained some impurities and was further purified by
chromatography on silica gel eluting with a gradient of 20-100%
ethyl acetate in heptanes to provide the title compound. .sup.1H
NMR (501 MHz, CDCl.sub.3) .delta. 8.26 (s, 1H), 8.01 (d, J=8.9 Hz,
1H), 6.67 (dd, J=9.0, 2.5 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H), 5.66
(dd, J=12.6, 3.1 Hz, 1H), 4.48 (qd, J=7.1, 3.2 Hz, 2H), 4.06 (dd,
J=17.4, 3.1 Hz, 1H), 3.88 (s, 3H), 3.34 (dd, J=17.4, 12.6 Hz, 1H),
1.45 (t, J=7.1 Hz, 3H), 1.34 (s, 9H); MS (ESI+) m/z 437
(M+H).sup.+. Stereochemistry was arbitrarily assigned.
Example 155D
ethyl
rel-2-((2R,4R)-4-amino-7-methoxychroman-2-yl)thiazole-4-carboxylate
[1953] Using the procedure similar to that described in Example
140D, substituting the product from Example 155C for the product
from Example 140C, provided the title compound. MS (ESI+) m/z 318
(M-NH.sub.3).sup.+. Stereochemistry was arbitrarily assigned.
Example 155E
ethyl
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-car-
boxylate
[1954] Using the procedure similar to that described in Example
126G, substituting the product from Example 155D for the product
from Example 126F, and purification by chromatography on silica gel
eluting with a gradient of 0-50% ethyl acetate in [9:1
CH.sub.2Cl.sub.2:ethyl acetate], provided the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 7.17-6.97
(m, 4H), 6.57 (dd, J=8.6, 2.5 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 5.55
(dd, J=10.8, 2.2 Hz, 1H), 5.46-5.37 (m, 1H), 5.31 (d, J=8.9 Hz,
1H), 4.47 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 2.93 (ddd, J=13.3, 5.9,
2.2 Hz, 1H), 1.99-1.87 (m, 1H), 1.79-1.62 (m, 2H), 1.45 (t, J=7.1
Hz, 3H), 1.09 (m, 2H); MS (ESI-) m/z 557 (M-H).sup.-.
Example 156
rel-2-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxyli-
c acid
[1955] Using the procedure similar to that described in Example
152, substituting the product from Example 155E for the product
from Example 151G, provided the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.30 (s, 1H), 7.17-7.10 (m, 2H), 7.05-6.98
(m, 2H), 6.58 (dd, J=8.6, 2.2 Hz, 1H), 6.49 (d, J=2.2 Hz, 1H), 5.54
(d, J=10.9 Hz, 1H), 5.48-5.40 (m, 1H), 5.35 (d, J=8.5 Hz, 1H), 3.80
(s, 3H), 2.95 (dd, J=13.2, 5.8 Hz, 1H), 1.98-1.87 (m, 1H),
1.81-1.63 (m, 2H), 1.16-1.07 (m, 2H); MS (ESI-) m/z 529
(M-H).sup.-.
Example 157
ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-car-
boxylate
Example 157A
ethyl
rel-2-((S)-4-(((S)-tert-butylsulfinyl)imino)-7-methoxychroman-2-yl)t-
hiazole-4-carboxylate
[1956] The impure title compound was obtained as the second eluting
isomer from the first chromatography described in Example 155C.
This material was further purified by chromatography on silica gel
eluting with a gradient of 20-100% ethyl acetate in heptanes to
provide the title compound. .sup.1H NMR (501 MHz, CDCl.sub.3)
.delta. 8.23 (s, 1H), 8.02 (d, J=8.9 Hz, 1H), 6.65 (dd, J=8.9, 2.5
Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 5.73 (dd, J=10.1, 3.8 Hz, 1H),
4.52-4.40 (m, 2H), 4.20 (dd, J=17.1, 3.8 Hz, 1H), 3.88 (s, 3H),
3.41 (dd, J=17.1, 10.1 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.32 (s,
9H); MS (ESI+) m/z 437 (M+H).sup.+. Stereochemistry was arbitrarily
assigned.
Example 157B
ethyl
rel-2-((2S,4S)-4-amino-7-methoxychroman-2-yl)thiazole-4-carboxylate
[1957] Using the procedure similar to that described in Example
140D, substituting the product from Example 157A for the product
from Example 140C, provided the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.21 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 6.61
(dd, J=8.6, 2.5 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 5.56 (d, J=9.8 Hz,
1H), 4.45 (q, J=7.1 Hz, 2H), 4.29-4.21 (m, 1H), 3.81 (s, 3H),
2.86-2.79 (m, 1H), 2.00-1.89 (m, 1H), 1.43 (t, J=7.1 Hz, 3H); MS
(ESI+) m/z 318 (M-NH.sub.3).sup.+.
Example 157C
ethyl
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl-
]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-car-
boxylate
[1958] Using the procedure similar to that described in Example
126G, substituting the product from Example 157B for the product
from Example 126F, and purification by chromatography on silica gel
eluting with a gradient of 0-50% ethyl acetate in [9:1
CH.sub.2Cl.sub.2:ethyl acetate], provided the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 7.15-7.07
(m, 2H), 7.04-6.98 (m, 2H), 6.57 (dd, J=8.6, 2.6 Hz, 1H), 6.48 (d,
J=2.5 Hz, 1H), 5.55 (dd, J=10.8, 1.8 Hz, 1H), 5.45-5.38 (m, 1H),
5.31 (d, J=8.6 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 2.93
(ddd, J=13.3, 6.0, 2.3 Hz, 1H), 1.99-1.86 (m, 1H), 1.82-1.64 (m,
2H), 1.45 (t, J=7.1 Hz, 3H), 1.14-1.05 (m, 2H); MS (ESI-) m/z 557
(M-H).sup.-.
Example 158
rel-2-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]-1,3-thiazole-4-carboxyli-
c acid
[1959] Using the procedure similar to that described in Example
152, substituting the product from Example 157C for the product
from Example 151G, provided the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.29 (s, 1H), 7.17-6.97 (m, 4H), 6.57 (dd,
J=8.6, 2.5 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 5.53 (d, J=11.0 Hz,
1H), 5.48-5.39 (m, 1H), 5.34 (d, J=12.7 Hz, 1H), 3.80 (s, 3H), 2.94
(dd, J=12.1, 4.7 Hz, 1H), 2.00-1.87 (m, 1H), 1.81-1.66 (m, 2H),
1.15-1.06 (m, 2H); MS (ESI-) m/z 529 (M-H).sup.-.
Example 159
methyl
rel-6-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxy-
late
Example 159A
tert-butyl 3-(2-hydroxy-4-methoxyphenyl)-3-oxopropanoate
[1960] To a solution of diisopropylamine (36.3 mL, 259 mmol) in
anhydrous tetrahydrofuran (130 mL) under nitrogen and at
-78.degree. C. was added 1.6 M n-butyl lithium in hexanes (150 mL,
240 mmol). After the resulting suspension had been stirred 15
minutes, a solution of tert-butyl acetate (28.2 mL, 210 mmol) in
tetrahydrofuran (40 mL) was added over 15 minutes. Then, after the
solution had been stirred at -78.degree. C. for 100 minutes, a
solution of methyl 4-methoxysalicylate (12.75 g, 70.0 mmol) in THF
(70 mL) was added to the reaction mixture over 20 minutes. The
reaction mixture was permitted to warm to room temperature
overnight, the flask placed in a water bath and the reaction
mixture quenched with 1 M aqueous citric acid (110 mL). The aqueous
phase was separated and extracted twice with ethyl acetate. The
combined organic phases were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The resulting
residue was chromatographed on silica (25 to 60%
CH.sub.2Cl.sub.2/heptanes) to give the impure product which was
chromatographed on silica (25 to 70% CH.sub.2Cl.sub.2/heptane) to
give title compound as a light oil (4.88 g). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.48 (s, 9H), 3.85 (s, 2H), 3.87 (s, 3H),
6.44-6.51 (m, 2H), 7.60 (d, J=8.8 Hz, 1H), 12.42 (s, 1H); MS (DCI)
m/z 267 (M+H).sup.+, 284 (M+NH.sub.2).sup.+.
Example 159B
tert-butyl
2-(5-bromopyridin-2-yl)-7-methoxy-4-oxochroman-3-carboxylate
[1961] Example 159A (799 mg, 3.0 mmol), 5-bromopicolinaldehyde (558
mg, 3.0 mmol), piperidine (30 .mu.L, 0.30 mmol) and acetic acid (18
.mu.L, 0.31 mmol) were stirred at room temperature in anhydrous
acetonitrile (9.0 mL) and anhydrous methanol (3.0 mL) for 4.5 hours
and then concentrated. The residue was chromatographed twice on
silica (15% methyl tert-butyl ether/heptane) to give 836 mg of a
mixture of the (E/Z)-tert-butyl
3-(5-bromopyridin-2-yl)-2-(2-hydroxy-4-methoxybenzoyl)acrylates and
cyclized product. The mixture was stirred with piperidine (30
.mu.L, 0.30 mmol) in methanol (6 mL) and acetonitrile (3 mL), and
after one hour water (3 mL) was added. The white precipitate was
collected by filtration and washed with 1:1 methanol/water, and a
second crop was similarly isolated. Both crops were dried under
vacuum to give title compound (836 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.40 (s, 9H), 3.84 (s, 3H), 4.22 (d, J=10.2
Hz, 1H), 5.80 (d, J=10.2 Hz, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.62 (dd,
J=8.8, 2.4 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.83-7.89 (m, 2H),
8.67-8.68 (m, 1H); MS (DCI) m/z 434/436 (M+H).sup.+.
Example 159C
2-(5-bromopyridin-2-yl)-7-methoxy chroman-4-one
[1962] Example 159B (792 mg, 1.8 mmol) and (rac)-camphorsulfonic
acid (210 mg, 0.90 mmol) were heated under nitrogen in anhydrous
toluene (10 mL) at 85.degree. C. overnight and brought to room
temperature. The reaction mixture was diluted with heptane (2 mL)
and placed directly on silica for chromatography (20% methyl
tert-butyl ether in 1:1 CH.sub.2Cl.sub.2/heptane) to give title
compound as a white powder (350 mg). 1H NMR (501 MHz, CDCl.sub.3)
.delta. ppm 3.02-3.12 (m, 2H), 3.85 (s, 3H), 5.56 (dd, J=10.1, 5.4
Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 7.51
(d, J=8.3 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.3, 2.3 Hz,
1H), 8.67 (d, J=2.3 Hz, 1H); MS (DCI) m/z 334/336 (M+H).sup.+.
Example 159D
methyl 6-(7-methoxy-4-oxochroman-2-yl)nicotinate
[1963] To Example 159C (349 mg, 1.044 mmol) and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (15 mg,
0.021 mmol) in a 50 mL Hast C reactor were added methanol (10 mL)
and triethylamine (0.29 mL, 2.1 mmol). The reactor was degassed
with argon several times, then filled with carbon monoxide and
heated at 100.degree. C. for 11 hr at 60 psi. The sample was
concentrated and partitioned between water and methyl tert-butyl
ether. The aqueous phase was separated and extracted with methyl
tert-butyl ether and the combined organic phases were washed again
with water then with brine, dried (Na.sub.2SO.sub.4), filtered,
concentrated, and chromatographed (25 to 50% methyl tert-butyl
ether/heptane) to give impure title compound (79 mg). 1H NMR (500
MHz, CDCl.sub.3) .delta. ppm 3.07 (dd, J=17.0, 11.6 Hz, 1H), 3.12
(dd, J=17.0, 4.1 Hz, 1H), 3.86 (s, 3H), 3.97 (s, 3H), 5.65 (dd,
J=11.6, 4.1 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.64 (dd, J=8.8, 2.4
Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.38 (dd,
J=8.2, 2.1 Hz, 1H), 9.20-9.21 (m, 1H); MS (DCI) m/z 314
(M+H).sup.+.
Example 159E
methyl 6-(4-(ethoxyimino)-7-methoxychroman-2-yl)nicotinate
[1964] The impure methyl 6-(7-methoxy-4-oxochroman-2-yl)nicotinate
from Example 159D (77 mg, <0.25 mmol), O-ethylhydroxylamine
hydrochloride (22 mg, 0.23 mmol) and potassium acetate (36 mg, 0.37
mmol) were heated in ethanol (1 mL) at 50.degree. C. for 20
minutes. Additional O-ethylhydroxylamine hydrochloride (13 mg, 0.13
mmol) was added and the mixture was heated at 50.degree. C. for
another 3 hours. The suspension was brought to room temperature,
concentrated, and chromatographed on silica (30% methyl tert-butyl
ether/heptane) to give title compound as an impure solid (about 75
mg). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.30 (t, J=7.1
Hz, 3H), 2.72 (dd, J=17.2, 11.8 Hz, 1H), 3.68 (dd, J=17.2, 3.5 Hz,
1H), 3.81 (s, 3H), 3.97 (s, 3H), 4.20 (d, J=7.1 Hz, 2H), 5.26 (dd,
J=11.8, 3.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 6.59 (dd, J=8.8, 2.5
Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 8.36 (dd,
J=8.2, 2.1 Hz, 1H), 9.19-9.22 (m, 1H); MS (DCI) m/z 357
(M+H).sup.+.
Example 159F
methyl 6-(4-amino-7-methoxychroman-2-yl)nicotinate
[1965] The impure methyl
6-(4-(ethoxyimino)-7-methoxychroman-2-yl)nicotinate from Example
159E (72 mg, 0.2 mmol) and methanol (10 mL) were added to a Ra--Ni
2800 water slurry (700 mg, 5.4 mmol) in a 50 mL pressure bottle and
shaken for 36 hours under hydrogen at 30 psi and room temperature.
The sample was filtered, concentrated, and chromatographed on
silica (0 to 5% conc. aqueous NH.sub.4OH/acetonitrile) to give the
title compound as an amber syrup (38 mg); MS (DCI) m/z 315
(M+H).sup.+.
Example 159G
methyl
rel-6-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxy-
late
[1966] The mixture of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(40 mg, 0.16 mmol), carbonyl diimidazole (27 mg, 0.17 mmol) and
1-hydroxy-7-azabenzotriazole (2.4 mg, 18 .mu.mol) were stirred in
anhydrous acetonitrile (350 .mu.L) for 100 minutes and then
transferred to a flask containing Example 159F (about 37 mg, 0.12
mmol) with an acetonitrile (100 .mu.L) rinse. After several
minutes, diisopropylethylamine (16 .mu.L, 92 .mu.mol) was added and
the solution was stirred at room temperature for four hours before
being concentrated. The residue was chromatographed on silica (5 to
25% methyl tert-butyl ether in 1:1 CH.sub.2Cl.sub.2/heptane) to
give a mixture of diastereomers. The appropriate fractions were
combined, concentrated, and subjected to preparative supercritical
fluid chromatography set to maintain a maximum back pressure of 10
MPa using a Whelk-O S.S (21.times.250 mm) column, with the sample
at a concentration of 5 mg/mL in methanol, using a co-solvent of
15% methanol and 0.1% diethylamine in CO.sub.2 at a flow rate of 70
mL/minute to provide Example 159G (retention time=11.50 minutes).
The stereochemistry was arbitrarily assigned. .sup.1H NMR (400 MHz,
CD.sub.2Cl.sub.2) 6 ppm 1.04-1.09 (m, 2H), 1.60-1.64 (m, 2H), 2.16
(ddd, J=14.2, 10.4, 4.8 Hz, 1H), 2.44 (ddd, J=14.2, 3.8, 2.6 Hz,
1H), 3.75 (s, 3H), 3.93 (s, 3H), 4.92 (ddd, J=7.1, 4.8, 3.8 Hz,
1H), 5.01 (dd, J=10.4, 2.6 Hz, 1H), 5.56 (d, J=7.1 Hz, 1H), 6.46
(d, J=2.5 Hz, 1H), 6.51 (dd, J=8.5, 2.5 Hz, 1H), 7.00-7.07 (m, 2H),
7.15-7.22 (m, 2H), 7.62 (d, J=8.2 Hz, 1H), 8.30 (dd, J=8.2, 2.1 Hz,
1H), 9.14 (d, J=2.1 Hz, 1H); MS (ESI) m/z=537 (M-H)-.
Example 160
methyl
rel-6-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxy-
late
[1967] The title compound (retention time=14.20 minutes) was
isolated from the preparative supercritical fluid chromatography
described Example 159 G. The stereochemistry was arbitrarily
assigned. .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) 6 ppm 1.05-1.08
(m, 2H), 1.60-1.63 (m, 2H), 2.16 (ddd, J=14.1, 10.4, 4.8 Hz, 1H),
2.44 (ddd, J=14.1, 3.9, 2.7 Hz, 1H), 3.75 (s, 3H), 3.93 (s, 3H),
4.92 (ddd, J=7.1, 4.8, 3.9 Hz, 1H), 5.01 (dd, J=10.4, 2.7 Hz, 1H),
5.55 (d, J=7.1 Hz, 1H), 6.46 (d, J=2.6 Hz, 1H), 6.50 (dd, J=8.5,
2.6 Hz, 1H), 7.01-7.05 (m, 2H), 7.15-7.21 (m, 2H), 7.62 (d, J=8.2
Hz, 1H), 8.30 (dd, J=8.2, 2.2 Hz, 1H), 9.14-9.15 (m, 1H); MS (ESI)
m/z 537 (M-H).sup.-.
Example 161
methyl
rel-6-[(2S,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxy-
late
[1968] The title compound (retention time=16.19 minutes) was
isolated from the preparative supercritical fluid chromatography
described Example 159G. MS (ESI) m/z 537 (M-H).sup.-. The
stereochemistry was arbitrarily assigned.
Example 162
methyl
rel-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxy-
late
[1969] The title compound (retention time=19.80 minutes) was
isolated from the preparative supercritical fluid chromatography
described Example 159G. MS (ESI) m/z 537 (M-H).sup.-. The
stereochemistry was arbitrarily assigned.
Example 163
ethyl
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate
Example 163A
rac-(2R,4R)-ethyl 4-amino-7-methoxychroman-2-carboxylate
hydrochloride
[1970] A solution of the product from Example 130C (1.5 g, 5.37
mmol) in acetic acid (5 mL) was treated with platinum(IV) oxide
(0.244 g, 1.074 mmol). The flask was sparged with N.sub.2 then the
reaction was stirred under a balloon of H.sub.2 overnight at room
temperature. The solids were removed by filtration and the filtrate
was concentrated. The resulting colorless oil was dissolved in
methyl tert-butyl ether (10 mL) and acidified with 3 M HCl in
cyclopentyl methyl ether (0.326 mL, 10.74 mmol). The mixture was
concentrated and placed under vacuum overnight at 50.degree. C. to
provide the title compound as a 13:1 ratio of cis:trans. Only the
peaks of the major cis isomer only are reported in the NMR: .sup.1H
NMR (501 MHz, DMSO-d.sub.6) .delta. 7.44 (d, J=8.6 Hz, 1H), 6.56
(dd, J=8.6, 2.6 Hz, 1H), 6.43 (d, J=2.5 Hz, 1H), 4.87 (dd, J=10.6,
2.6 Hz, 1H), 4.30 (dd, J=9.8, 5.8 Hz, 1H), 4.20 (qd, J=7.1, 1.4 Hz,
2H), 3.72 (s, 3H), 2.46 (ddd, J=13.1, 5.7, 2.6 Hz, 1H), 1.94-1.85
(m, 1H), 1.24 (t, J=7.1 Hz, 3H).
Example 163B
ethyl
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca-
rbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylate
[1971] A solution of the product from Example 163A (2.1 g, 7.30
mmol) and triethylamine (3.05 mL, 21.89 mmol) in CH.sub.2Cl.sub.2
(29 mL) at 0.degree. C. was treated drop wise with a solution of
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl
chloride (prepared as described in Example 8D) in CH.sub.2Cl.sub.2
(5 mL) and then stirred at 30 minutes at 0.degree. C. The mixture
was partitioned between 1M HCl (10 mL) and CH.sub.2Cl.sub.2. The
layers were separated and the aqueous was extracted with
CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2 layers were
concentrated. The residue was purified by chromatography on silica
gel eluting with a gradient of 0-40% ethyl acetate in heptanes to
provide a product which was a 14:1 mixture of cis and trans
isomers. 1.5 g of this product was precipitated from ethyl
acetate/heptanes to provide the diastereomerically pure title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.10 (d, J=8.1
Hz, 1H), 7.08 (s, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.95 (d, J=8.5 Hz,
1H), 6.49 (dd, J=8.6, 2.5 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 5.56 (d,
J=8.3 Hz, 1H), 5.21 (q, J=7.3 Hz, 1H), 4.71 (dd, J=8.0, 3.6 Hz,
1H), 4.22-4.07 (m, 2H), 3.74 (s, 3H), 2.53 (ddd, J=13.8, 6.0, 3.7
Hz, 1H), 1.99 (dt, J=15.1, 7.8 Hz, 1H), 1.74-1.68 (m, 1H),
1.66-1.61 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.13-1.02 (m, 2H); MS
(ESI-) m/z 474 (M-H).sup.-.
Example 164
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxylic acid
[1972] Using the procedure similar to that described in Example
152, substituting the product from Example 163B for the product
from Example 151G, provided the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.14 (dd, J=8.1, 1.7 Hz, 1H), 7.12 (d,
J=1.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.51
(dd, J=8.6, 2.5 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 5.48 (d, J=7.9 Hz,
1H), 5.21 (q, J=7.7 Hz, 1H), 4.80 (dd, J=8.6, 3.5 Hz, 1H), 3.75 (s,
3H), 2.59 (ddd, J=13.6, 5.7, 3.5 Hz, 1H), 2.14-2.06 (m, 1H),
1.80-1.71 (m, 1H), 1.71-1.62 (m, 1H), 1.14-1.06 (m, 2H); MS (ESI-)
m/z 446 (M-H).sup.-.
Example 165
rel-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic
acid
Example 165A
(S)--N-(1-(2-hydroxy-4-methoxyphenyl)ethylidene)-2-methylpropane-2-sulfina-
mide
[1973] A solution of 2'-hydroxy-4'-methoxyacetophenone (1 g, 6.02
mmol) and (S)-(-)-2-methyl-2-propanesulfinamide (0.802 g, 6.62
mmol) in 2-methyl-tetrahydrofuran (10 mL) was treated with
titanium(IV) ethoxide (5.15 g, 22.57 mmol), heated at 90.degree. C.
under N.sub.2 for 2 hours, cooled and partitioned between ethyl
acetate and water. The mixture was filtered through diatomaceous
earth to remove the solids. The ethyl acetate layer was washed with
brine, dried (MgSO.sub.4), filtered, concentrated, and
chromatographed on silica gel, eluting with a gradient of 30% to
100% ethyl acetate in heptane provided the title compound (377 mg,
1.400 mmol, 23.26% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 13.62 (s, 1H), 7.55 (d, J=8.9 Hz, 1H), 6.48-6.43 (m, 2H),
3.84 (s, 3H), 2.76 (s, 3H), 1.32 (s, 9H); MS (ESI+) m/z 435
(M+H).sup.+; MS (ESI-) m/z 433 (M-H).sup.-.
Example 165B
methyl
rel-6-((S)-3-(((S)-tert-butylsulfinyl)imino)-1-hydroxy-3-(2-hydroxy-
-4-methoxyphenyl)propyl)nicotinate
[1974] A solution of diisopropylamine (163 .mu.L, 1.143 mmol) in
tetrahydrofuran (2 mL) under N.sub.2 at -20.degree. C. was treated
with 2.5 M n-butyl lithium in hexanes (437 .mu.L, 1.091 mmol) and
stirred for 15 minutes. In a separate flask, a solution of the
product from Example 165A (140 mg, 0.520 mmol) in tetrahydrofuran
(2 mL) under N.sub.2 at -20.degree. C. was treated over 1 minute
with the solution of lithium diisopropylamine. The resulting
mixture was stirred at -20.degree. C. for 1 hour, cooled to
-78.degree. C., treated with a solution of methyl
6-formylnicotinate (86 mg, 0.520 mmol) in tetrahydrofuran (1.5 mL),
warmed to 0.degree. C., cooled to -30.degree. C., treated with a
solution of 10% acetic acid in tetrahydrofuran (about 1.5 mL) and
allowed to warm to room temperature. The mixture was partitioned
between ethyl acetate and saturated NaHCO.sub.3 solution. The ethyl
acetate layer was washed with brine, dried (MgSO.sub.4), filtered,
concentrated, and chromatographed on silica gel (ethyl
acetate/heptanes) to provide the title compound (52 mg, 23% yield)
as the second eluting isomer. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 13.25 (s, 1H), 9.19 (d, J=1.9 Hz, 1H), 8.22 (dd, J=8.2, 2.1
Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.38 (d, J=9.1 Hz, 1H), 6.40 (d,
J=2.6 Hz, 1H), 6.28 (dd, J=9.1, 2.6 Hz, 1H), 5.34 (q, J=5.1 Hz,
1H), 4.92 (d, J=5.2 Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H), 3.82-3.71
(m, 2H), 1.39 (s, 9H); MS (ESI+) m/z 435 (M+H).sup.+.
Stereochemistry was arbitrarily assigned.
Example 165C
methyl
rel-6-((R)-4-(((S)-tert-butylsulfinyl)imino)-7-methoxychroman-2-yl)-
nicotinate
[1975] A solution of the product from Example 165B (52 mg, 0.120
mmol) and triphenylphosphine (31.4 mg, 0.120 mmol) in
CH.sub.2Cl.sub.2 (1 mL) at 0.degree. C. was treated drop wise with
a 40 weight % solution diethyl azodicarboxylate in toluene (54.5
.mu.L, 0.120 mmol) over 3 minutes, stirred at 0.degree. C. for 10
minutes, allowed to stir at ambient temperature for 1 hour,
concentrated and directly chromatographed on silica gel eluting
with ethyl acetate in heptanes to provide the titled compound (18
mg, 0.043 mmol, 36.1% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.20-9.18 (m, 1H), 8.37 (dd, J=8.2, 2.1 Hz, 1H), 7.98 (d,
J=8.9 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 6.62 (dd, J=8.9, 2.5 Hz,
1H), 6.53 (d, J=2.5 Hz, 1H), 5.40 (dd, J=12.5, 3.0 Hz, 1H), 3.97
(s, 3H), 3.92 (dd, J=17.5, 3.1 Hz, 1H), 3.85 (s, 3H), 3.28 (dd,
J=17.5, 12.5 Hz, 1H), 1.30 (s, 9H); MS (ESI+) m/z 417 (M+H).sup.+.
Stereochemistry was arbitrarily assigned.
Example 165D
methyl rel-6-((2R,4R)-4-amino-7-methoxychroman-2-yl)nicotinate
[1976] A solution of the product from Example 165C (17.4 mg, 0.042
mmol) in methanol (1 mL) was cooled to 0.degree. C., treated with
NaBH.sub.4 (4.74 mg, 0.125 mmol), stirred at 0.degree. C. for 30
minutes, treated with 4 M HCl in dioxane (209 .mu.L, 0.836 mmol),
stirred at 0.degree. C. for 5 minutes and then stirred at ambient
temperature for 30 minutes. The mixture was partitioned between
methyl tert-butyl ether (30 mL) and water (15 mL). The aqueous
layer was basified to pH 8 with solid NaHCO.sub.3 and extracted
with ethyl acetate. The ethyl acetate layer was washed with brine,
dried (MgSO.sub.4), filtered, and concentrated to provide the title
compound (12 mg, 0.038 mmol, 91% yield). .sup.1H NMR (501 MHz,
CDCl.sub.3) .delta. 9.18 (d, J=1.5 Hz, 1H), 8.36 (dd, J=8.2, 2.1
Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 6.59 (d,
J=8.5 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 5.32 (d, J=10.8 Hz, 1H),
4.29 (s, 1H), 3.97 (s, 3H), 3.80 (s, 3H), 2.68 (dd, J=12.5, 4.0 Hz,
1H), 1.83 (q, J=11.5 Hz, 1H). Stereochemistry was arbitrarily
assigned.
Example 165E
methyl
rel-64(2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropa-
necarboxamido)-7-methoxychroman-2-yl)nicotinate
[1977] Using the procedure similar to that described in Example
126G, substituting the product from Example 165D for the product
from Example 126F, and purification by chromatography on silica gel
eluting with a gradient of 30-100% ethyl acetate in heptane,
provided the titled compound. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.14 (d, J=1.9 Hz, 1H), 8.31 (dd, J=8.2, 2.1 Hz, 1H), 7.61
(d, J=8.2 Hz, 1H), 7.10 (dd, J=8.2, 1.6 Hz, 1H), 7.06 (d, J=1.6 Hz,
1H), 7.01 (d, J=4.6 Hz, 1H), 6.99 (d, J=4.3 Hz, 1H), 6.53 (dd,
J=8.6, 2.6 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 5.43 (dt, J=9.4, 4.3
Hz, 1H), 5.36-5.30 (m, 2H), 3.98 (s, 3H), 3.77 (s, 3H), 2.76 (ddd,
J=13.3, 6.1, 2.4 Hz, 1H), 1.85 (dt, J=13.3, 10.4 Hz, 1H), 1.77-1.62
(m, 2H), 0.92-0.80 (m, 2H); MS (ESI-) m/z 537 (M-H).sup.-.
Example 165F
rel-6-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]pyridine-3-carboxylic
acid
[1978] Using the procedure similar to that described in Example
152, substituting the product from Example 165E for the product
from Example 151G, provided the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.24 (s, 1H), 8.40 (d, J=8.2 Hz, 1H), 7.68
(d, J=8.2 Hz, 1H), 7.13 (dd, J=8.2, 1.5 Hz, 1H), 7.10 (d, J=1.5 Hz,
1H), 7.04-7.00 (m, 2H), 6.56 (dd, J=8.6, 2.5 Hz, 1H), 6.50 (d,
J=2.4 Hz, 1H), 5.52-5.32 (m, 3H), 3.80 (s, 3H), 2.82 (ddd, J=13.4,
6.0, 1.9 Hz, 1H), 1.91-1.67 (m, 3H), 1.15-1.06 (m, 2H); MS (ESI-)
m/z 523 (M-H).sup.-.
Example 166
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxyethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-ca-
rboxamide
[1979] A stock solution Example 164 and diisopropylethylamine
(0.089 M and 0.26 M in dimethylacetamide, respectively, 344 .mu.L,
0.031 mmol Example 164 (1.0 equivalent) and 0.092 mmol
diisopropylethylamine (3.0 equivalents)),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.11 M in dimethylacetamide, 344 .mu.L,
0.037 mmol, 1.2 equivalents), and 2-propylamino-ethanol (0.40 M in
dimethylacetamide, 117 .mu.L, 0.046 mmol, 1.5 equivalents) were
aspirated from their respective source vials, mixed through a PFA
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 75.degree. C., and passed through the reactor at 180 .mu.L
min.sup.-1 (10 minute residence time). Upon exiting the reactor,
the reaction was loaded directly into an injection loop and
purified using preparative LC method TFA1 to yield the title
compound (11.4 mg, 70% yield). .sup.1H NMR (400 MHz, 120.degree.
C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.27 (d, J=1.5 Hz,
1H), 7.25-7.12 (m, 2H), 6.95 (dd, J=8.5, 1.0 Hz, 1H), 6.46 (dd,
J=8.5, 2.6 Hz, 1H), 6.29 (d, J=2.6 Hz, 1H), 5.11 (t, J=7.3 Hz, 2H),
3.69 (s, 3H), 3.60-3.18 (m, 6H), 2.23-2.11 (m, 1H), 2.11-1.96 (m,
1H), 1.74-1.33 (m, 4H), 1.14-0.90 (m, 2H), 0.82 (t, J=7.5 Hz, 3H);
MS (APCI+) m/z 533.1 (M+H).sup.+.
Example 167
rac-(2R,4R)--N-benzyl-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide
[1980] Example 167 was prepared according to the procedure for the
preparation of Example 166, substituting 2-benzylamino-ethanol for
2-propylamino-ethanol and purified using preparative LC method TFA6
to provide the title compound (7.3 mg, 41% yield). .sup.1H NMR (400
MHz, 120.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
7.35-7.12 (m, 8H), 6.96 (d, J=8.5 Hz, 1H), 6.47 (dd, J=8.5, 2.6 Hz,
1H), 6.36-6.09 (m, 1H), 5.23-5.05 (m, 2H), 4.73-4.36 (m, 2H), 3.68
(s, 3H), 3.59-3.46 (m, 3H), 3.47-3.23 (m, 1H), 2.30-1.95 (m, 2H),
1.55-1.34 (m, 2H), 1.13-0.97 (m, 2H); MS (APCI+) m/z 581.0
(M+H).sup.+.
Example 168
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxy-2-phenyl
ethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chromene-2-carboxamide
[1981] Example 168 was prepared according to the procedure for the
preparation of Example 166, substituting
2-methylamino-1-phenyl-ethanol for 2-propylamino-ethanol and
purified using preparative LC method TFA6 to provide the title
compound (15.5 mg, 87% yield). .sup.1H NMR (400 MHz, 120.degree.
C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.42-7.12 (m, 8H),
6.94 (td, J=8.5, 0.9 Hz, 1H), 6.46 (dt, J=8.5, 2.2 Hz, 1H), 6.28
(dd, J=11.6, 2.5 Hz, 1H), 5.05 (s, 2H), 4.80 (dd, J=7.2, 5.3 Hz,
1H), 3.69 (d, J=3.4 Hz, 3H), 3.63-3.36 (m, 2H), 2.92 (s, 3H),
2.17-1.90 (m, 2H), 1.44 (tdd, J=12.2, 7.3, 3.3 Hz, 2H), 1.05 (tt,
J=5.2, 2.6 Hz, 2H); MS (APCI+) m/z 581.0 (M+H).sup.+.
Example 169
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-{[4-(2-hydroxy
ethyl)piperazin-1-yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cycl-
opropanecarboxamide
[1982] Example 169 was prepared according to the procedure for the
preparation of Example 166, substituting 2-piperazin-1-yl-ethanol
for 2-propylamino-ethanol and purified using preparative LC method
TFA6 to provide the title compound (15.2 mg, 73% yield). .sup.1H
NMR (400 MHz, 120.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. 7.27 (d, J=1.6 Hz, 1H), 7.24-7.14 (m, 2H), 6.94 (dd, J=8.6,
1.0 Hz, 1H), 6.48 (dd, J=8.6, 2.6 Hz, 1H), 6.31 (d, J=2.5 Hz, 1H),
5.20-5.07 (m, 2H), 3.91-3.72 (m, 6H), 3.68 (s, 3H), 3.29 (s, 4H),
3.25-3.19 (m, 2H), 2.24-2.11 (m, 1H), 2.11-1.95 (m, 1H), 1.55-1.34
(m, 2H), 1.15-0.99 (m, 2H); MS (APCI+) m/z 560.0 (M+H).sup.+.
Example 170
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(1-hydroxy-2-methylpropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromen-
e-2-carboxamide
[1983] Example 170 was prepared according to the procedure for the
preparation of Example 166, substituting
2-amino-2-methyl-propan-1-ol for 2-propylamino-ethanol and purified
using preparative LC method TFA6 to provide the title compound (5.6
mg, 35% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.31 (d, J=1.6 Hz, 1H),
7.28-7.15 (m, 2H), 6.93 (dd, J=8.5, 1.0 Hz, 1H), 6.49 (dd, J=8.6,
2.6 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 5.09 (dd, J=9.3, 6.5 Hz, 1H),
4.54 (dd, J=10.0, 2.9 Hz, 1H), 3.70 (s, 3H), 3.45-3.30 (m, 2H),
2.23 (ddd, J=13.5, 6.3, 2.9 Hz, 1H), 1.91 (dt, J=13.5, 9.8 Hz, 1H),
1.55-1.33 (m, 2H), 1.21 (s, 3H), 1.17 (s, 3H), 1.14-0.97 (m, 2H);
MS (APCI+) m/z 519.1 (M+H).sup.+.
Example 171
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxy-1-phenylethyl)-7-methoxy-3,4-dihydro-2H-chromene-2-ca-
rboxamide
[1984] Example 171 was prepared according to the procedure for the
preparation of Example 166, substituting 2-amino-2-phenyl-ethanol
for 2-propylamino-ethanol and purified using preparative LC method
TFA6 to provide the title compound (14.2 mg, 81% yield). .sup.1H
NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. 7.33 (d, J=4.4 Hz, 2H), 7.29-7.06 (m, 6H), 7.01-6.82 (m,
1H), 6.55-6.47 (m, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.10 (dd, J=9.1,
6.2 Hz, 1H), 4.85 (td, J=5.9, 2.7 Hz, 1H), 4.77-4.62 (m, 1H),
3.76-3.60 (m, 5H), 2.32-2.15 (m, 1H), 2.06-1.87 (m, 1H), 1.52-1.29
(m, 2H), 1.10-0.93 (m, 2H); MS (APCI+) m/z 567.0 (M+H).sup.+.
Example 172
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3,4-dihydro--
2H-chromene-2-carboxamide
[1985] Example 172 was prepared according to the procedure for the
preparation of Example 166, substituting 1,1-dioxothian-4-amine for
2-propylamino-ethanol and purified using preparative LC method TFA6
to provide the title compound (9.0 mg, 51% yield). .sup.1H NMR (400
MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.32
(d, J=1.7 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.20 (dd, J=8.3, 1.7 Hz,
1H), 6.93 (d, J=8.6 Hz, 1H), 6.48 (dd, J=8.5, 2.6 Hz, 1H), 6.43 (d,
J=2.5 Hz, 1H), 5.09 (dd, J=9.5, 6.2 Hz, 1H), 4.60 (dd, J=10.1, 3.0
Hz, 1H), 3.92 (p, J=7.3, 6.9 Hz, 1H), 3.70 (s, 3H), 3.24-2.96 (m,
4H), 2.29-2.17 (m, 1H), 2.14-1.86 (m, 5H), 1.53-1.36 (m, 2H),
1.13-0.99 (m, 2H).\; MS (APCI+) m/z 578.2 (M+H).sup.+.
Example 173
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chrome-
ne-2-carboxamide
[1986] Example 173 was prepared according to the procedure for the
preparation of Example 166, substituting
3-(trifluoromethyl)oxetan-3-amine for 2-propylamino-ethanol and
purified using preparative LC method TFA6 to provide the title
compound (2.3 mg, 13% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.32 (d, J=1.7 Hz, 1H),
7.28-7.14 (m, 2H), 6.94 (d, J=8.5 Hz, 1H), 6.51 (dd, J=8.5, 2.6 Hz,
1H), 6.46 (d, J=2.6 Hz, 1H), 5.12 (dd, J=9.6, 6.2 Hz, 1H),
4.82-4.60 (m, 5H), 3.71 (s, 3H), 2.30-2.18 (m, 1H), 2.07-1.87 (m,
1H), 1.54-1.34 (m, 2H), 1.15-0.97 (m, 2H); MS (APCI+) m/z 571.0
(M+H).sup.+.
Example 174
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4R)-2-[(4,4-difluoropiper-
idin-1-yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarb-
oxamide
[1987] Example 174 was prepared according to the procedure for the
preparation of Example 166, substituting 4,4-difluoropiperidine
hydrochloride for 2-propylamino-ethanol and purified using
preparative LC method TFA6 to provide the title compound (7.3 mg,
41% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.31 (d, J=1.8 Hz, 1H),
7.25 (d, J=8.3 Hz, 1H), 7.19 (dd, J=8.4, 1.8 Hz, 1H), 6.97 (d,
J=8.5 Hz, 1H), 6.49 (dd, J=8.6, 2.6 Hz, 1H), 6.32 (d, J=2.5 Hz,
1H), 5.21-5.06 (m, 2H), 3.69 (d, J=0.9 Hz, 3H), 3.61 (s, 4H),
2.26-1.83 (m, 6H), 1.54-1.35 (m, 2H), 1.15-0.97 (m, 2H); MS (APCI+)
m/z 551.0 (M+H).sup.+.
Example 175
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-methoxy-2-(1,4-oxaz-
epan-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1988] Example 175 was prepared according to the procedure for the
preparation of Example 166, substituting 1,4-oxazepane
hydrochloride for 2-propylamino-ethanol and purified using
preparative LC method TFA6 to provide the title compound (14.1 mg,
86% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.30 (d, J=1.7 Hz, 1H),
7.24 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.3, 1.7 Hz, 1H), 6.97 (d,
J=8.6 Hz, 1H), 6.48 (dd, J=8.6, 2.6 Hz, 1H), 6.30 (d, J=2.5 Hz,
1H), 5.12 (t, J=7.2 Hz, 2H), 3.85-3.40 (m, 11H), 2.21-1.98 (m, 2H),
1.98-1.68 (m, 2H), 1.53-1.32 (m, 2H), 1.14-0.96 (m, 2H); MS (APCI+)
m/z 531.0 (M+H).sup.+.
Example 176
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-2-carbo-
xamide
[1989] Example 176 was prepared according to the procedure for the
preparation of Example 166, substituting N-methyloxetan-3-amine for
2-propylamino-ethanol and purified using preparative LC method TFA6
to provide the title compound (16.2 mg, >99% yield). .sup.1H NMR
(400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
7.32 (d, J=1.7 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.21 (dd, J=8.3,
1.7 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.52 (dd, J=8.6, 2.6 Hz, 1H),
6.36 (d, J=2.5 Hz, 1H), 5.14 (dd, J=10.0, 6.0 Hz, 1H), 4.89 (dd,
J=10.7, 2.8 Hz, 1H), 4.51-4.20 (m, 2H), 3.81-3.61 (m, 5H), 3.44 (d,
J=6.5 Hz, 1H), 2.68 (s, 3H), 2.40-2.30 (m, 1H), 2.16-1.97 (m, 1H),
1.58-1.29 (m, 2H), 1.14-0.98 (m, 2H); MS (APCI+) m/z 517.1
(M+H).sup.+.
Example 177
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-7-methoxy-2-(morpholi-
n-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[1990] Example 177 was prepared according to the procedure for the
preparation of Example 166, substituting morpholine for
2-propylamino-ethanol and purified using preparative LC method TFA6
to provide the title compound (10.2 mg, 64% yield). .sup.1H NMR
(400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
7.30 (d, J=1.8 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.3,
1.7 Hz, 1H), 6.96 (dd, J=8.6, 1.0 Hz, 1H), 6.48 (dd, J=8.6, 2.6 Hz,
1H), 6.31 (d, J=2.6 Hz, 1H), 5.16-5.05 (m, 2H), 3.87 (s, OH), 3.69
(s, 3H), 3.65-3.55 (m, 4H), 3.49 (s, 4H), 2.22-2.09 (m, 1H),
2.09-1.96 (m, 1H), 1.54-1.35 (m, 2H), 1.15-0.96 (m, 2H); MS (APCI+)
m/z 517.1 (M+H).sup.+.
Example 178
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-[2-hydroxy-1-(2-methoxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-ch-
romene-2-carboxamide
[1991] Example 178 was prepared according to the procedure for the
preparation of Example 166, substituting
2-amino-2-(2-methoxy-phenyl)-ethanol for 2-propylamino-ethanol and
purified using preparative LC method TFA6 to provide the title
compound (5.5 mg, 30% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) spectrum contains diasteromer
peaks .delta. 7.35-7.07 (m, 4H), 7.07-6.80 (m, 4H), 6.56-6.48 (m,
1H), 6.48-6.38 (m, 1H), 5.21-5.03 (m, 2H), 4.69 (ddd, J=16.6, 10.0,
3.0 Hz, 1H), 3.89-3.78 (m, 3H), 3.76-3.68 (m, 3H), 3.68-3.47 (m,
2H), 2.31-2.17 (m, 1H), 2.06-1.84 (m, 1H), 1.53-1.31 (m, 2H),
1.10-0.95 (m, 2H); MS (APCI+) m/z 597.0 (M+H).sup.+.
Example 179
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-[2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide
[1992] Example 179 was prepared according to the procedure for the
preparation of Example 166, substituting 3-(2-aminoethyl)phenol
hydrochloride for 2-propylamino-ethanol and purified using
preparative LC method TFA6 to provide the title compound (11.8 mg,
68% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.30 (d, J=1.6 Hz, 1H),
7.27-7.13 (m, 2H), 7.06 (td, J=7.3, 1.4 Hz, 1H), 6.93 (dd, J=8.6,
1.0 Hz, 1H), 6.66-6.55 (m, 3H), 6.48 (dd, J=8.6, 2.6 Hz, 1H), 6.39
(d, J=2.6 Hz, 1H), 5.15-5.01 (m, 1H), 4.57 (dd, J=10.0, 3.1 Hz,
1H), 3.70 (s, 3H), 3.30 (t, J=7.3 Hz, 2H), 2.66 (t, J=7.3 Hz, 2H),
2.28-2.14 (m, 1H), 1.96-1.80 (m, 1H), 1.55-1.32 (m, 2H), 1.16-0.97;
MS (APCI+) m/z 567.0 (M+H).sup.+.
Example 180
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(1,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide
[1993] Example 180 was prepared according to the procedure for the
preparation of Example 166, substituting 2-amino-propane-1,3-diol
for 2-propylamino-ethanol and purified using preparative LC method
TFA6 to provide the title compound (11.3 mg, 71% yield). .sup.1H
NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. 7.32 (d, J=1.7 Hz, 1H), 7.28-7.15 (m, 2H), 6.92 (dd, J=8.6,
1.0 Hz, 1H), 6.49 (dd, J=8.6, 2.6 Hz, 1H), 6.41 (d, J=2.6 Hz, 1H),
5.10 (dd, J=9.8, 6.3 Hz, 1H), 4.62 (dd, J=10.5, 2.9 Hz, 1H), 3.77
(p, J=5.5 Hz, 1H), 3.70 (s, 3H), 3.60-3.37 (m, 4H), 2.32-2.18 (m,
1H), 2.01-1.84 (m, 1H), 1.55-1.34 (m, 2H), 1.15-0.97 (m, 2H); MS
(APCI+) m/z 521.0 (M+H).sup.+.
Example 181
rac-(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)-7-methoxy-3,4-dihydro-2H-c-
hromene-2-carboxamide
[1994] Example 181 was prepared according to the procedure for the
preparation of Example 166, substituting 1-amino-indan-2-ol for
2-propylamino-ethanol and purified using preparative LC method TFA6
to provide the title compound (11.3 mg, 70% yield). .sup.1H NMR
(400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) spectrum
contains diasteromer peaks .delta. 7.34-6.77 (m, 8H), 6.57-6.44 (m,
1H), 6.41-6.31 (m, 1H), 5.20-5.06 (m, 2H), 4.86-4.73 (m, 1H),
4.52-4.36 (m, 1H), 3.72-3.62 (m, 3H), 3.15-3.01 (m, 1H), 2.92-2.79
(m, 1H), 2.44-2.26 (m, 1H), 2.15-1.96 (m, 1H), 1.56-1.36 (m, 2H),
1.15-0.96 (m, 2H); MS (APCI+) m/z 579.0 (M+H).sup.+.
Example 182
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxyphenyl)-7-methoxy-3,4-dihydro-2H-chromene-2-carboxamid-
e
[1995] A stock solution Example 134 and diisopropylethylamine
(0.089 M and 0.26 M in dimethylacetamide, respectively, 344 .mu.L,
0.031 mmol Example 134 (1.0 equivalent) and 0.092 mmol
diisopropylethylamine (3.0 equivalents)),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (0.11 M in dimethylacetamide, 344 .mu.L,
0.037 mmol, 1.2 equivalents), and 2-aminophenol (0.40 M in
dimethylacetamide, 117 .mu.L, 0.046 mmol, 1.5 equivalents) were
aspirated from their respective source vials, mixed through a PFA
mixing tube (0.2 mm inner diameter), and loaded into an injection
loop. The reaction segment was injected into the flow reactor
(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume)
set at 75.degree. C., and passed through the reactor at 180 .mu.L
min.sup.-1 (10 minute residence time). Upon exiting the reactor,
the reaction was loaded directly into an injection loop and
purified using preparative LC method TFA6 to yield the title
compound (5.7 mg, 34% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.93 (dd, J=8.1, 1.6 Hz,
1H), 7.32 (d, J=1.8 Hz, 1H), 7.28-7.13 (m, 2H), 7.05-6.91 (m, 2H),
6.88 (dd, J=8.1, 1.5 Hz, 1H), 6.79 (td, J=7.7, 1.5 Hz, 1H), 6.54
(dd, J=8.5, 2.6 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 4.96-4.90 (m, 1H),
4.81 (dd, J=8.4, 3.7 Hz, 1H), 3.73 (s, 3H), 2.31-2.07 (m, 2H),
1.53-1.33 (m, 2H), 1.15-0.97 (m, 2H); MS (APCI+) m/z 539.0
(M+H).sup.+.
Example 183
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxyethyl)-7-methoxy-N-propyl-3,4-dihydro-2H-chromene-2-ca-
rboxamide
[1996] Example 183 was prepared according to the procedure for the
preparation of Example 182, substituting 2-propylamino-ethanol for
2-aminophenol to provide the title compound (9.6 mg, 59% yield).
.sup.1H NMR (400 MHz, 120.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.25 (d, J=1.6 Hz, 1H), 7.22-7.12 (m, 2H), 6.95 (dd,
J=8.4, 0.8 Hz, 1H), 6.45 (dd, J=8.5, 2.6 Hz, 1H), 6.30 (d, J=2.6
Hz, 1H), 5.05-4.86 (m, 2H), 3.68 (s, 3H), 3.63-3.20 (m, 6H),
2.15-1.91 (m, 2H), 1.70-1.45 (m, 2H), 1.45-1.31 (m, 2H), 1.13-0.89
(m, 2H), 0.82 (t, J=7.4 Hz, 3H); MS (APCI+) m/z 533.1
(M+H).sup.+.
Example 184
rac-(2R,4S)--N-benzyl-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropy-
l]carbonyl}amino)-N-(2-hydroxyethyl)-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide
[1997] Example 184 was prepared according to the procedure for the
preparation of Example 182, substituting 2-benzylamino-ethanol for
2-aminophenol to provide the title compound (7.4 mg, 41% yield).
.sup.1H NMR (400 MHz, 120.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.39-7.11 (m, 8H), 6.96 (d, J=8.5 Hz, 1H), 6.47 (dd,
J=8.5, 2.6 Hz, 1H), 6.31-6.20 (m, 1H), 5.15-5.07 (m, 1H), 4.99 (t,
J=4.9 Hz, 1H), 4.64 (s, 2H), 3.68 (s, 3H), 3.56 (t, J=5.9 Hz, 2H),
3.49-3.31 (m, 2H), 2.20-1.97 (m, 2H), 1.41 (td, J=11.4, 10.5, 8.1
Hz, 2H), 1.11-0.95 (m, 2H); MS (APCI+) m/z 581.0 (M+H).sup.+.
Example 185
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxy-2-phenyl
ethyl)-7-methoxy-N-methyl-3,4-dihydro-2H-chromene-2-carboxamide
[1998] Example 185 was prepared according to the procedure for the
preparation of Example 182, substituting
2-methylamino-1-phenyl-ethanol for 2-aminophenol to provide the
title compound (11.2 mg, 63% yield). .sup.1H NMR (400 MHz,
90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.44-7.06
(m, 8H), 6.96 (t, J=7.8 Hz, 1H), 6.48 (dd, J=8.5, 2.5 Hz, 1H),
6.37-6.24 (m, 1H), 5.10-4.86 (m, 2H), 4.81 (t, J=6.4 Hz, 1H), 3.69
(s, 3H), 3.60-3.34 (m, 2H), 2.91 (d, J=23.4 Hz, 3H), 2.07-1.89 (m,
2H), 1.56-1.13 (m, 2H), 1.07-0.99 (m, 2H); MS (APCI+) m/z 581.0
(M+H).sup.+.
Example 186
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4S)-2-[(4-hydroxypiperidi-
n-1-yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarboxa-
mide
[1999] Example 186 was prepared according to the procedure for the
preparation of Example 182, substituting piperidin-4-ol for
2-aminophenol to provide the title compound (6.8 mg, 42% yield).
.sup.1H NMR (400 MHz, 120.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.26 (d, J=1.7 Hz, 1H), 7.22-7.12 (m, 2H), 6.94 (d,
J=8.5 Hz, 1H), 6.45 (dd, J=8.5, 2.6 Hz, 1H), 6.30 (d, J=2.5 Hz,
1H), 5.05-4.91 (m, 2H), 3.86-3.73 (m, 3H), 3.68 (s, 3H), 3.26-3.11
(m, 2H), 2.14-1.91 (m, 2H), 1.83-1.66 (m, 2H), 1.39 (dt, J=11.7,
9.5 Hz, 4H), 1.11-0.97 (m, 2H); MS (APCI+) m/z 531.0
(M+H).sup.+.
Example 187
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-2-{[4-(2-hydroxy
ethyl)piperazin-1-yl]carbonyl}-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cycl-
opropanecarboxamide
[2000] Example 187 was prepared according to the procedure for the
preparation of Example 182, substituting 2-piperazin-1-yl-ethanol
for 2-aminophenol to provide the title compound (15.9 mg, 77%
yield). .sup.1H NMR (400 MHz, 120.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.27 (d, J=1.7 Hz, 1H),
7.22-7.13 (m, 2H), 7.03-6.92 (m, 1H), 6.48 (dd, J=8.5, 2.6 Hz, 1H),
6.34 (d, J=2.5 Hz, 1H), 5.03 (dd, J=8.1, 3.7 Hz, 1H), 4.97 (t,
J=5.5 Hz, 1H), 3.93-3.74 (m, 6H), 3.69 (s, 3H), 3.31 (t, J=5.3 Hz,
4H), 3.27-3.20 (m, 2H), 2.21-1.92 (m, 2H), 1.54-1.31 (m, 2H),
1.13-0.97 (m, 2H); MS (APCI+) m/z 560.0 (M+H).sup.+.
Example 188
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxy-2-methylpropyl)-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide
[2001] Example 188 was prepared according to the procedure for the
preparation of Example 182, substituting
1-amino-2-methyl-propan-2-ol for 2-aminophenol to provide the title
compound (9.0 mg, 56% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.31 (d, J=1.8 Hz, 1H),
7.28-7.13 (m, 2H), 6.97 (d, J=8.5 Hz, 1H), 6.50 (dd, J=8.5, 2.6 Hz,
1H), 6.45 (d, J=2.5 Hz, 1H), 4.89 (t, J=5.4 Hz, 1H), 4.61 (dd,
J=8.6, 3.5 Hz, 1H), 3.71 (s, 3H), 3.19-3.00 (m, 2H), 2.22-1.95 (m,
2H), 1.51-1.32 (m, 2H), 1.13-0.97 (m, 8H); MS (APCI+) m/z 519.1
(M+H).sup.+.
Example 189
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(1-hydroxy-2-methylpropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromen-
e-2-carboxamide
[2002] Example 189 was prepared according to the procedure for the
preparation of Example 182, substituting
2-amino-2-methyl-propan-1-ol for 2-aminophenol to provide the title
compound (8.8 mg, 55% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.30 (d, J=1.7 Hz, 1H),
7.27-7.13 (m, 2H), 6.96 (d, J=8.6 Hz, 1H), 6.50 (dd, J=8.5, 2.6 Hz,
1H), 6.43 (d, J=2.5 Hz, 1H), 4.87 (t, J=5.3 Hz, 1H), 4.47 (dd,
J=8.8, 3.4 Hz, 1H), 3.71 (s, 3H), 3.45-3.33 (m, 2H), 2.18-1.90 (m,
2H), 1.51-1.32 (m, 2H), 1.25 (s, 3H), 1.22 (s, 3H), 1.19-0.95 (m,
2H); MS (APCI+) m/z 519.1 (M+H).sup.+.
Example 190
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxy-1-phenylethyl)-7-methoxy-3,4-dihydro-2H-chromene-2-ca-
rboxamide
[2003] Example 190 was prepared according to the procedure for the
preparation of Example 182, substituting 2-amino-2-phenyl-ethanol
for 2-aminophenol to provide the title compound (11.4 mg, 65%
yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) spectrum contains diasteromer
peaks .delta. 7.37-6.91 (m, 9H), 6.57-6.43 (m, 2H), 4.95-4.80 (m,
2H), 4.74-4.53 (m, 1H), 3.76-3.59 (m, 5H), 2.21-1.93 (m, 2H),
1.51-1.31 (m, 2H), 1.12-0.94 (m, 2H); MS (APCI+) m/z 567.0
(M+H).sup.+.
Example 191
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-7-methoxy-3,4-dihydro--
2H-chromene-2-carboxamide
[2004] Example 191 was prepared according to the procedure for the
preparation of Example 182, substituting 1,1-dioxothian-4-amine for
2-aminophenol to provide the title compound (9.8 mg, 55% yield).
.sup.1H NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.30 (d, J=1.7 Hz, 1H), 7.28-7.13 (m, 2H), 6.96 (d,
J=8.6 Hz, 1H), 6.55-6.39 (m, 2H), 4.88 (t, J=5.4 Hz, 1H), 4.54 (dd,
J=8.8, 3.5 Hz, 1H), 3.99 (p, J=7.2 Hz, 1H), 3.71 (s, 3H), 3.24-3.10
(m, 2H), 3.10-2.92 (m, 2H), 2.19-1.90 (m, 6H), 1.52-1.32 (m, 2H),
1.14-0.96 (m, 2H); MS (APCI+) m/z 579.0 (M+H).sup.+.
Example 192
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-N-[3-(trifluoromethyl)oxetan-3-yl]-3,4-dihydro-2H-chrome-
ne-2-carboxamide
[2005] Example 192 was prepared according to the procedure for the
preparation of Example 182, substituting
3-(trifluoromethyl)oxetan-3-amine for 2-aminophenol to provide the
title compound (3.3 mg, 19% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.30 (d, J=1.7 Hz, 1H),
7.28-7.13 (m, 2H), 6.98 (d, J=8.6 Hz, 1H), 6.51 (dd, J=8.4, 2.6 Hz,
1H), 6.49-6.42 (m, 1H), 4.90 (t, J=5.2 Hz, 1H), 4.80 (d, J=7.9 Hz,
2H), 4.69 (d, J=8.6 Hz, 2H), 4.63 (dd, J=9.1, 3.4 Hz, 1H), 3.71 (s,
3H), 2.22-1.93 (m, 2H), 1.52-1.32 (m, 2H), 1.13-0.96 (m, 2H); MS
(APCI+) m/z 571.0 (M+H).sup.+.
Example 193
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{(2R,4S)-2-[(4,4-difluoropiper-
idin-1-yl)carbonyl]-7-methoxy-3,4-dihydro-2H-chromen-4-yl}cyclopropanecarb-
oxamide
[2006] Example 193 was prepared according to the procedure for the
preparation of Example 182, substituting 4,4-difluoropiperidine
hydrochloride for 2-aminophenol to provide the title compound (9.8
mg, 58% yield). .sup.1H NMR (400 120.degree. C., MHz,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.33-7.26 (m, 1H),
7.26-7.13 (m, 2H), 6.97 (d, J=8.5 Hz, 1H), 6.49 (dd, J=8.5, 2.6 Hz,
1H), 6.35 (d, J=2.5 Hz, 1H), 5.03 (dd, J=8.7, 3.4 Hz, 1H), 4.98 (t,
J=5.1 Hz, 1H), 3.70 (s, 3H), 3.68-3.60 (m, 4H), 2.22-1.93 (m, 6H),
1.53-1.31 (m, 2H), 1.12-0.97 (m, 2H); MS (APCI+) m/z 551.0
(M+H).sup.+.
Example 194
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-7-methoxy-2-(1,4-oxaz-
epan-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[2007] Example 194 was prepared according to the procedure for the
preparation of Example 182, substituting 1,4-oxazepane
hydrochloride for 2-aminophenol to provide the title compound (8.7
mg, 53% yield). .sup.1H NMR (400 MHz, 120.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.28 (d, J=1.5 Hz, 1H),
7.25-7.12 (m, 2H), 6.98 (d, J=8.5 Hz, 1H), 6.48 (dd, J=8.5, 2.6 Hz,
1H), 6.33 (d, J=2.6 Hz, 1H), 5.04-4.93 (m, 2H), 3.70 (s, 7H),
3.64-3.55 (m, 4H), 2.17-1.93 (m, 2H), 1.93-1.73 (m, 2H), 1.49-1.33
(m, 2H), 1.12-0.96 (m, 2H); MS (APCI+) m/z 531.0 (M+H).sup.+.
Example 195
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-N-methyl-N-(oxetan-3-yl)-3,4-dihydro-2H-chromene-2-carbo-
xamide
[2008] Example 195 was prepared according to the procedure for the
preparation of Example 182, substituting N-methyloxetan-3-amine for
2-aminophenol to provide the title compound (13.7 mg, 86% yield).
.sup.1H NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.31 (d, J=1.7 Hz, 1H), 7.29-7.14 (m, 2H), 6.94 (d,
J=8.6 Hz, 1H), 6.51 (dd, J=8.6, 2.6 Hz, 1H), 6.37 (d, J=2.6 Hz,
1H), 4.99-4.83 (m, 2H), 4.47-4.27 (m, 2H), 3.80-3.55 (m, 5H),
3.55-3.34 (m, 1H), 2.72-2.60 (m, 3H), 2.21 (d, J=5.8 Hz, 2H),
1.53-1.32 (m, 2H), 1.21-0.98 (m, 2H); MS (APCI+) m/z 517.1
(M+H).sup.+.
Example 196
rac-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4S)-7-methoxy-2-(morpholi-
n-4-ylcarbonyl)-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide
[2009] Example 196 was prepared according to the procedure for the
preparation of Example 182, substituting morpholine for
2-aminophenol to provide the title compound (9.5 mg, 60% yield).
.sup.1H NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. 7.31 (d, J=1.7 Hz, 1H), 7.27-7.14 (m, 2H), 6.97 (d,
J=8.4 Hz, 1H), 6.49 (dd, J=8.5, 2.6 Hz, 1H), 6.34 (d, J=2.6 Hz,
1H), 5.07-4.93 (m, 2H), 3.70 (s, 3H), 3.60 (td, J=4.8, 1.6 Hz, 4H),
3.51 (t, J=4.9 Hz, 4H), 2.14-1.92 (m, 2H), 1.52-1.32 (m, 2H),
1.13-0.97 (m, 2H); MS (APCI+) m/z 517.1 (M+H).sup.+.
Example 197
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-[2-hydroxy-1-(2-methoxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-ch-
romene-2-carboxamide
[2010] Example 197 was prepared according to the procedure for the
preparation of Example 182, substituting
2-amino-2-(2-methoxy-phenyl)-ethanol for 2-aminophenol to provide
the title compound (11.3 mg, 70% yield). .sup.1H NMR (400 MHz,
90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) spectrum contains
diasteromer peaks .delta. 7.33-7.12 (m, 5H), 7.04-6.85 (m, 3H),
6.56-6.41 (m, 2H), 5.22-5.10 (m, 1H), 4.94-4.76 (m, 1H), 4.70-4.51
(m, 1H), 3.80 (d, J=17.0 Hz, 3H), 3.75-3.68 (m, 3H), 3.68-3.49 (m,
2H), 2.23-1.92 (m, 2H), 1.51-1.32 (m, 2H), 1.13-0.97 (m, 2H); MS
(APCI+) m/z 597.0 (M+H).sup.+.
Example 198
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-[2-(3-hydroxyphenyl)ethyl]-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide
[2011] Example 198 was prepared according to the procedure for the
preparation of Example 182, substituting 3-(2-aminoethyl)phenol
hydrochloride for 2-aminophenol to provide the title compound (12.7
mg, 73% yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.30 (d, J=1.7 Hz, 1H),
7.27-7.13 (m, 2H), 7.05 (t, J=7.7 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H),
6.65-6.55 (m, 3H), 6.49 (dd, J=8.5, 2.6 Hz, 1H), 6.42 (d, J=2.6 Hz,
1H), 4.86 (t, J=5.1 Hz, 1H), 4.51 (dd, J=9.2, 3.4 Hz, 1H), 3.71 (s,
3H), 3.35 (t, J=7.3 Hz, 2H), 2.68 (t, J=7.3 Hz, 2H), 2.12 (dt,
J=14.0, 4.1 Hz, 1H), 2.05-1.87 (m, 1H), 1.51-1.32 (m, 2H),
1.21-0.95 (m, 2H); MS (APCI+) m/z 567.0 (M+H).sup.+.
Example 199
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(1,3-dihydroxypropan-2-yl)-7-methoxy-3,4-dihydro-2H-chromene-2-c-
arboxamide
[2012] Example 199 was prepared according to the procedure for the
preparation of Example 182, substituting 2-amino-propane-1,3-diol
for 2-aminophenol to provide the title compound (10.7 mg, 67%
yield). .sup.1H NMR (400 MHz, 90.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. 7.30 (d, J=1.7 Hz, 1H),
7.28-7.13 (m, 2H), 6.98 (d, J=8.5 Hz, 1H), 6.50 (dd, J=8.5, 2.6 Hz,
1H), 6.44 (d, J=2.5 Hz, 1H), 4.88 (t, J=4.9 Hz, 1H), 4.55 (dd,
J=9.3, 3.3 Hz, 1H), 3.80 (h, J=5.3 Hz, 1H), 3.71 (d, J=1.0 Hz, 3H),
3.59-3.36 (m, 4H), 2.15 (dt, J=14.0, 4.2 Hz, 1H), 2.07-1.90 (m,
1H), 1.51-1.32 (m, 2H), 1.21-0.95 (m, 2H); MS (APCI+) m/z 521.0
(M+H).sup.+.
Example 200
rac-(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-N-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)-7-methoxy-3,4-dihydro-2H-c-
hromene-2-carboxamide
[2013] Example 200 was prepared according to the procedure for the
preparation of Example 182, substituting 1-amino-indan-2-ol for
2-aminophenol to provide the title compound (11.3 mg, 70% yield).
.sup.1H NMR (400 MHz, 90.degree. C., DMSO-d.sub.6:D.sub.2O=9:1
(v/v)) spectrum contains diasteromer peaks .delta. 7.37-6.90 (m,
8H), 6.57-6.45 (m, 1H), 6.39 (dd, J=6.5, 2.6 Hz, 1H), 5.23 (d,
J=5.3 Hz, 1H), 5.04-4.89 (m, 1H), 4.83-4.67 (m, 1H), 4.54-4.40 (m,
1H), 3.69 (d, 3H), 3.10 (dd, J=16.4, 5.2 Hz, 1H), 2.92-2.78 (m,
1H), 2.32-1.98 (m, 2H), 1.55-1.34 (m, 2H), 1.22-0.97 (m, 2H); MS
(APCI+) m/z 579.0 (M+H).sup.+.
Example 201
rac-1-{[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]carbonyl}pyrrolidine-3-c-
arboxylic acid
[2014] A stock solution Example 134 and diisopropylethylamine
(0.044 M and 0.13 M in dimethylacetamide, respectively, 1.0 mL,
0.044 mmol Example 134 (1.0 equivalent) and 0.13 mmol
diisopropylethylamine (3.0 equivalents)) and
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroni-
um hexafluorophosphate(V) (0.054 M in dimethylacetamide, 1.0 mL,
0.054 mmol, 1.2 equivalents) were combined and stirred at room
temperature for 10 minutes. Pyrrolidine-3-carboxylic acid (0.40 M
in dimethylacetamide, 167 .mu.L, 0.067 mmol, 1.5 equivalents) was
added and the reaction was stirred at 75.degree. C. for 30 minutes.
The reaction was loaded directly into an injection loop and
purified using preparative LC method TFA6 to yield the title
compound (5.7 mg, 34% yield). .sup.1H NMR (400 MHz, 120.degree. C.,
DMSO-d.sub.6:D.sub.2O=9:1 (v/v)) spectrum contains diasteromer
peaks .delta. 7.26 (s, 1H), 7.20-7.14 (m, 2H), 6.95 (d, J=8.5 Hz,
1H), 6.46 (dd, J=8.5, 2.6 Hz, 1H), 6.32 (t, J=2.5 Hz, 1H), 4.94 (s,
1H), 4.80 (dd, J=7.9, 4.2 Hz, 1H), 3.68 (s, 3H), 3.62-3.34 (m, 4H),
2.07 (d, J=39.1 Hz, 5H), 1.43-1.37 (m, 2H), 1.04-0.99 (m, 2H); MS
(APCI+) m/z 545.4 (M+H).sup.+.
Example 202
4-[(2R,4R)-4-({[1-(6-bromo-2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid
Example 202A
(R)-methyl
4-(4-((benzyloxy)imino)-7-methoxychroman-2-yl)benzoate
[2015] Example 110A (29.52 g, 95 mmol) was dissolved in 190 mL of
dry pyridine. O-benzylhydroxylamine hydrochloride (15.84 g, 99
mmol) was added, and the solution was heated at 50.degree. C. for
16 hours. The reaction flask was cooled to room temperature,
concentrated in vacuo, and partitioned between ethyl acetate (300
mL) and saturated aqueous ammonium chloride (150 mL). The organic
layer was washed with 1M HCl (3.times.100 mL) and brine (100 mL)
then concentrated and triturated with heptanes to give a solid
mass, which was filtered then crushed with a mortar/pestle and
dried to constant weight to give 35 g of the title compound, which
was used without additional purification. Analytical data for the
major isomer are show here. .sup.1H NMR (501 MHz, CDCl.sub.3)
.delta. 8.06 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.54-7.46
(m, 2H), 7.40-7.28 (m, 5H), 6.57 (dd, J=8.8, 2.5 Hz, 1H), 6.48 (d,
J=2.5 Hz, 1H), 5.19 (d, J=2.0 Hz, 2H), 5.11 (dd, J=12.3, 3.2 Hz,
1H), 3.92 (s, 3H), 3.78 (s, 3H), 3.48 (dd, J=17.2, 3.2 Hz, 1H),
2.67 (dd, J=17.2, 12.2 Hz, 1H); MS (ESI+) m/z 418.1
(M+H).sup.+.
Example 202B
methyl 4-((2R,4R)-4-amino-7-methoxychroman-2-yl)benzoate
hydrochloride
[2016] Example 202A (20 g 47.9 mmol) was dissolved in 300 mL of
acetic acid and 5% Pt/C wet (1.5 g wet weight, 58.9% water, 0.884 g
or 4.42% dry basis) in a 300-mL stainless steel reactor. The
headspace was inerted with argon and then pressurized to 30 psi
with hydrogen. The mixture was shaken at room temperature under 30
psi of hydrogen for 18 hours. The reaction was monitored by HPLC
for disappearance of the starting material. Once about 95%
conversion was achieved (18 hours, monitored by LC-MS), the reactor
was vented and the reaction mixture was filtered through 0.45 .mu.m
GHP Acrodisc membrane. The solvent was removed in vacuo to give 60
g of crude material. The crude material was heated at 70.degree. C.
in 250 mL of 4:1 methyl tert-butyl ether:heptanes until a clear
solution resulted. HCl (3M in cyclopropyl methyl ether, 47.9 mL,
144 mmol) was added drop wise at the same temperature, and a white
solid precipitated from the reaction mixture. The flask was allowed
to cool to room temperature over 1 hour, and the resulting
off-white solid was removed via filtration using a fritted funnel.
The solid was washed with methyl tert-butyl ether (2.times.100 mL)
and dried in the funnel. The resulting white solid was further
heated at 70.degree. C. in toluene (20 mL) for 30 minutes to remove
additional impurities. After cooling to room temperature, the
resulting solid was filtered using a fritted funnel and washed with
75 mL of toluene and 100 mL of heptanes then dried to constant
weight to give 19.8 g of the title compound (79% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.67 (s, 3H), 8.08-7.95 (m,
2H), 7.58 (dd, J=8.4, 6.1 Hz, 3H), 6.62 (dd, J=8.7, 2.6 Hz, 1H),
6.50 (d, J=2.5 Hz, 1H), 5.33 (dd, J=11.8, 1.6 Hz, 1H), 4.70 (dd,
J=11.1, 6.2 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 2.60-2.50 (m, 1H),
1.96 (q, J=11.8 Hz, 1H); MS (ESI+) m/z 297.1
(M-NH.sub.3).sup.+.
Example 202C
methyl
1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxy-
late
[2017]
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
(2 g, 8.26 mmol) was suspended in acetonitrile (16.52 mL) and
N-bromosuccinimide (1.911 g, 10.74 mmol) was added, followed by
iron (III) chloride (0.670 g, 4.13 mmol). The reaction was stirred
at room temperature for 16 hours. The reaction mixture was diluted
with ethyl acetate and washed with water, saturated sodium
thiosulfate, and brine then dried over sodium sulfate then
concentrated to give a dark crude oil. The crude material was
dissolved in a 2:1 mixture of tetrahydrofuran and methanol (20 mL
total) and TMS-diazomethane (2M in diethyl ether, 5.37 mL, 10.74
mmol) was added drop wise. After the addition was complete, TLC
indicated that complete conversion to the methyl ester had
occurred. The solvent was removed in vacuo and the resulting crude
residue was purified by flash column chromatography, eluting with
0-10% ethyl acetate/heptanes over 20 minutes on a 40 g silica gel
column to give 1.56 g of the title compound as a colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.29 (s, 1H), 7.04 (s,
1H), 3.64 (s, 3H), 1.78 (m, 2H), 1.21-1.09 (m, 2H).
Example 202D
1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic
acid
[2018] Example 202C (1.354 g, 4.04 mmol) was dissolved in
tetrahydrofuran (10.10 mL) and potassium trimethylsilanolate (0.778
g, 6.06 mmol) was added. The resulting light yellow solution was
heated at 40.degree. C. for 2 hours. The flask was cooled to room
temperature and stirred with 1M HCl (10 mL) for 5 minutes and
partitioned between ethyl acetate and water. The organic extracts
were dried over sodium sulfate, filtered, and concentrated to give
1.25 g of the title compound as a white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.29 (s, 1H), 7.04 (s, 1H), 1.97-1.73 (m,
2H), 1.27 (br s, 2H); MS (ESI+) m/z 338.3 (M+H.sub.2O).sup.+.
Example 202E
1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl
chloride
[2019] Example 202D (1 g, 3.11 mmol) was dissolved in
dichloromethane (7.79 mL). The resulting solution was treated with
oxalyl dichloride (0.791 mL, 9.34 mmol) and N,N-dimethylformamide
(4.55 mg, 0.062 mmol). The solution was stirred for 1 hour at room
temperature, and concentrated. The resulting crude oil was
dissolved in 10 mL of dichloromethane and concentrated in vacuo.
The obtained acid chloride was used immediately in the amide
coupling reaction after preparation of the compound as a solution
in 5 mL of dry dichloromethane.
Example 202F
methyl
44(2R,4R)-4-(1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclop-
ropanecarboxamido)-7-methoxychroman-2-yl)benzoate
[2020] A solution of Example 202B (1.092 g, 3.12 mmol) in
dichloromethane (15.61 mL) in a 100-mL round-bottomed flask was
cooled to <5.degree. C. in an ice-water bath, and triethylamine
(1.305 mL, 9.37 mmol) was added. A freshly prepared solution of
Example 202E (1.06 g, 3.12 mmol) in 2 mL of dichloromethane was
added drop wise via syringe, and the reaction was stirred for 15
minutes at the same temperature. The reaction mixture was diluted
with methyl tert-butyl ether (30 mL) and was stirred with 1M HCl
(10 mL) for 5 minutes at room temperature. After standard aqueous
workup, the resulting crude solid was slurried with hot ethyl
acetate/heptanes mixture (1:4, 10 mL) at 75.degree. C. for 30
minutes and was then cooled to room temperature. The resulting
white solid was collected via filtration using a fritted funnel and
was dried to constant weight to give 1.25 g of the title compound.
.sup.1H NMR (501 MHz, CDCl.sub.3) .delta. 8.07 (d, J=8.4 Hz, 2H),
7.60-7.43 (m, 2H), 7.33 (s, 1H), 7.12 (d, J=24.1 Hz, 2H), 6.55 (dd,
J=8.6, 2.6 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 5.47 (td, J=9.7, 6.2
Hz, 1H), 5.32-5.16 (m, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 2.56 (ddd,
J=13.3, 6.1, 2.1 Hz, 1H), 1.93 (br s, 1H), 1.83 (dt, J=13.4, 11.0
Hz, 2H), 1.12 (br s, 2H); MS(ESI+) m/z 297.1 (M-Amide+H).sup.+.
Example 202G
methyl
44(2R,4R)-4-(1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclop-
ropanecarboxamido)-7-hydroxychroman-2-yl)benzoate
[2021] Example 202F (1 g, 1.622 mmol) and tetrabutylammonium iodide
(1.798 g, 4.87 mmol) were dissolved in 10 mL of dry dichloromethane
and the solution was cooled to <-20.degree. C. in an acetone-dry
ice bath. Boron trichloride (1M in dichloromethane, 4.87 mL, 4.87
mmol) solution was added drop wise over 5 minutes, and the reaction
was kept at the same temperature for 1 hour. The resulting solution
was poured into ice water and extracted with dichloromethane
(3.times.20 mL). The combined extracts were concentrated in vacuo
to approximately 5 mL and were then diluted with 20 mL of methyl
tert-butyl ether. The volatiles were removed in vacuo and the
resulting crude material was slurried with 15 mL of methyl
tert-butyl ether and concentrated partially in vacuo then followed
by addition of methyl tert-butyl ether, concentrated again and
slurried with methyl tert-butyl ether. The slurry was washed with
water (2.times.20 mL) and the organic layer was then concentrated
in vacuo and filtered through a 1-inch pad of silica, eluting with
methyl tert-butyl ether. The solvent was removed in vacuo to give a
crude white solid, which was used without additional purification.
.sup.1H NMR (501 MHz, CDCl.sub.3) .delta. 8.05 (d, J=8.4 Hz, 2H),
7.45 (d, J=8.1 Hz, 2H), 7.32 (s, 1H), 7.09 (br s, 2H), 6.49 (d,
J=0.7 Hz, 1H), 6.43 (s, 1H), 6.00-5.78 (br s, 1H), 5.44 (q, J=8.8
Hz, 1H), 5.29 (d, J=8.7 Hz, 1H), 5.20 (dd, J=11.3, 2.0 Hz, 1H),
3.95 (s, 3H), 2.53 (ddd, J=13.3, 6.0, 2.0 Hz, 1H), 1.93 (br s, 1H),
1.81 (dt, J=13.1, 10.8 Hz, 2H), 1.11 (br s, 2H); MS (ESI+) m/z
283.1 (M-Amide+H).sup.+.
Example 202H
4-((2R,4R)-4-(1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-
carboxamido)-7-(difluoromethoxy)chroman-2-yl)benzoic acid
[2022] Example 202G (0.980 g, 1.627 mmol) was suspended in
acetonitrile (8.13 mL). The suspension was cooled to
<-25.degree. C. in an acetone-dry ice bath and diethyl
(bromodifluoromethyl)phosphonate (0.434 mL, 2.440 mmol) was added,
followed by drop wise addition of aqueous potassium hydroxide (4 M,
8.13 mL, 32.5 mmol) at such a rate that the temperature was
maintained below -15.degree. C. After the addition was complete (2
minutes), the reaction was stirred for an additional 15 minutes, at
which point it was warmed to room temperature. Methanol (5 mL) was
added, and the reaction was heated at 40.degree. C. for 15 minutes.
The flask was cooled to room temperature, diluted with 10 mL of
isopropyl acetate and washed with KOH (2 M, 3.times.10 mL), 20 mL
of 1M HCl, and brine then dried over sodium sulfate, filtered, and
concentrated. The residue was purified via flash column
chromatography, eluting with 0-100% ethyl acetate/heptanes over 20
minutes on a 40 g silica gel column to afford 275 mg of the title
compound as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6;
90.degree. C.) .delta. 7.96 (d, J=8.2 Hz, 2H), 7.65 (s, 1H), 7.52
(d, J=8.1 Hz, 2H), 7.44 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.05 (t,
J=72 Hz 1H; CF.sub.2H) 7.01 (d, J=8.7 Hz, 1H), 6.72 (dd, J=8.5, 2.6
Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 5.46-5.30 (m, 2H), 2.22-1.95 (m,
2H), 1.68 (dt, J=9.7, 3.0 Hz, 1H), 1.57 (dt, J=8.7, 2.9 Hz, 1H),
1.08 (s, 2H); MS (ESI+) m/z=636.0 (M-H).sup.-.
Example 203
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}-
amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]-N-(methyl
sulfonyl)benzamide
[2023] A mixture of the product from Example 122 (0.100 g, 0.178
mmol), TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate) (0.086 g, 0.268 mmol), and triethylamine (0.080
mL, 0.572 mmol) in tetrahydrofuran (2 mL) was stirred at room
temperature for 90 minutes, at which time a cloudy white mixture
was seen. The mixture was then treated with lithium chloride (2.5
mg, 0.059 mmol) and methanesulfonamide (22 mg, 0.228 mmol), and the
reaction stirred overnight at room temperature. After this time,
the reaction mixture was concentrated in vacuo, and the residue was
purified by reverse-phase preparative HPLC on a Phenomenex.RTM.
Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.75
mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid
in water (B) was used, at a flow rate of 50 mL/minute (0-0.5
minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0
minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A),
yielding the title compound as a white solid (45 mg, 40% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.15 (s, 1H), 7.97 (d,
J=8.3 Hz, 2H), 7.61-7.17 (m, 6H), 7.09-7.01 (m, 2H), 6.77-6.68 (m,
2H), 5.50-5.32 (m, 2H), 3.38 (s, 3H), 2.13-2.02 (m, 2H), 1.52-1.34
(m, 2H). 1.06 (m, 2H); MS (ESI.sup.+) m/z 636.9 (M+H).sup.+.
Determination of Biological Activity
Cellular Assays
[2024] Cell Surface Expression-Horse Radish Peroxidase (CSE-HRP)
Assay:
[2025] A cellular assay for measuring the F508delCFTR cell surface
expression after correction with test compounds was developed in
human lung derived epithelial cell line (CFBE41o-) (Veit G et al,
(2012) Mol Biol Cell. 23(21): 4188-4202). This was achieved by
expressing the F508delCFTR mutation along with a horseradish
peroxidase (HRP) in the fourth exofacial loop and then measuring
the HRP activity using luminescence readout from these cells,
CFBE41o-F508delCFTR-HRP, that were incubated overnight with the
test corrector compounds. Briefly, for this primary assay, the
CFBE41o-F508delCFTR-HRP cells were plated in 384-well plates
(Greiner Bio-one; Cat 781080) at 4,000 cells/well along with 0.5
.mu.g/mL doxycycline to induce the F508delCFTR-HRP expression and
further incubated at 37.degree. C., 5% CO.sub.2 for 72 hours. The
test compounds were then added at the required concentrations and
further incubated for 18-24 hours at 33.degree. C. The highest
concentration tested was 20 .mu.M with an 8-point concentration
response curve using a 3-fold dilution. Three replicate plates were
run to determine one EC.sub.50. All plates contained negative
controls (dimethyl sulfoxide, DMSO) and positive controls (3 .mu.M
of
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) as well
as on-plate concentration response of the positive control. Post
incubation, the plates were washed 5.times. times with Dulbecco's
phosphate buffered saline (DPBS), followed by the addition of the
HRP substrate, luminol (50 .mu.L), and measuring the HRP activity
using luminescence readout on EnVision.RTM. Multilabel Plate Reader
(Perkin Elmer; product number 2104-0010). The raw counts from the
experiment are analyzed using Accelrys.RTM. Assay Explorer
v3.3.
[2026] Z' greater than 0.5 was used as passing quality control
criteria for the plates.
[2027] The Z' is defined as:
1-[3*SD.sub.Positive Control+3*SD.sub.Negative
Control/Absolute(Mean.sub.Postivie Control-Mean.sub.Negative
Control)]
wherein "SD" is standard deviation.
[2028] The % activity measured at each of the 8 test concentrations
of the test compound was normalized to the on-plate positive
control using the following formula:
% activity=[(test compound response-DMSO response)/(positive
control response-DMSO response)]*100
[2029] The maximum % activity achieved for the test compound at any
tested concentration is presented in Table 1 along with the
EC.sub.50 calculated using the following general sigmoidal curve
with variable Hill slope equation (described as Model 42 in the
Accelrys.RTM. Assay Explorer v3.3 software):
y=(a-d)/(1+(x/c) b)+d
[2030] General sigmoidal curve with concentration, response, top,
bottom, EC.sub.50 and Hill slope.
[2031] This model describes a sigmoidal curve with an adjustable
baseline, a. The equation can be used to fit curves where response
is either increasing or decreasing with respect to the independent
variable, "x".
"x" is a concentration of drug under test. "y" is the response. "a"
is the maximum response, and "d" is the minimum response "c" is the
inflection point (EC.sub.50) for the curve. That is, "y" is halfway
between the lower and upper asymptotes when x=c. "b" is the
slope-factor or Hill coefficient. The sign of b is positive when
the response increases with increasing dose and is negative when
the response decreases with increasing dose (inhibition).
TABLE-US-00001 TABLE 1 CSE-HRP data Example EC.sub.50 (.mu.M)
Maximum % activity (%) 1 0.28 102 2 2.71 122 3 0.39 135 4 1.19 73 5
2.45 92 6 0.38 120 7 5.84 58 8 1.75 98 9 0.42 84 10 4.1 112 11 0.91
102 12 5.47 58 13 4.57 118 14 0.85 78 15 2.47 101 16 0.37 108 17
2.64 78 18 0.35 113 19 0.63 103 20 4.62 30 21 0.80 142 22 1.77 109
23 20 12 24 8.37 63 25 3.91 41 26 0.34 93 27 0.12 113 28 3.24 98 29
5.71 106 30 1.88 78 31 10.7 21 32 20 16 33 7.65 38 34 20 15 35 1.16
82 36 1.82 78 37 3.05 88 38 0.61 93 39 1.72 82 40 2.68 107 41 2.58
73 42 20 5 43 0.85 78 44 20 14 45 1.33 89 46 5.14 27 47 4 43 48 1
104 49 0.97 105 50 0.86 101 51 0.97 83 52 1.01 93 53 1.76 90 54
0.86 92 55 2.11 101 56 3.12 124 57 1.69 112 58 2.54 101 59 3.66 101
60 0.7 131 61 2.04 132 62 0.69 135 63 0.63 106 64 1.61 78 65 10.1
45 66 6.1 89 67 5.89 128 68 0.87 89 69 2.12 109 70 6.84 94 71 2.84
91 72 2.5 71 73 7.63 57 74 5.53 98 75 3.28 75 76 2.99 105 78 5.28
95 79 7.25 117 80 1.55 114 81 4.5 98 82 2.72 97 83 2.72 106 84 2.24
91 85 6.81 108 86 3.5 101 87 4.63 146 90 3.44 42 91 2.71 82 92 2.57
71 93 2.8 26 94 0.94 119 95 0.92 98 96 20 15 97 0.38 90 98 0.57 102
99 3.89 56 100 3.08 40 101 6.65 60 102 4.86 89 103 8.53 28 104 6.58
49 105 7.46 34 106 0.31 88 107 1.13 99 108 0.34 115 109 0.45 94 110
0.28 115 111 0.044 113 112 20 5 113 3.55 49 114 4.76 61 115 1.94 77
116 7.64 59 117 6.01 82 118 8.15 25 119 0.88 71 120 0.50 110 121
0.13 102 122 0.026 122 123 0.050 115 124 6.76 26 125 2.14 115 126
1.38 79 127 2.81 65 128 4.57 66 129 6.20 44 130 2.56 79 131 3.60 70
132 3.44 86 133 7.02 25 134 >20 4 135 1.51 97 136 3.36 90 137
0.14 131 138 0.05 119 139 0.10 115 140 2.28 53 141 3.05 54 142 1.18
87 143 8.50 27 144 >20 11 145 2.45 96 146 0.03 129 147 2.04 78
148 2.12 77 149 1.53 85 150 0.42 106 151 6.12 64 152 6.35 59 153
1.90 84 154 0.67 106 155 0.37 108 156 1.23 112 157 1.52 77 158 6.65
101 159 1.36 92 160 0.60 104 161 2.26 82 162 0.17 105 163 3.59 42
164 >20 2 165 0.09 123 166 2.00 65 167 1.08 66 168 1.16 67 169
4.90 38 170 1.55 65 171 2.29 40 172 4.08 66 173 2.15 27 174 1.73 55
175 3.20 54 176 9.63 30 177 2.91 56 178 0.74 64 179 0.80 69 180
5.93 59 181 1.59 57 182 0.80 46 183 0.86 67 184 0.58 73 185 0.64 77
186 1.36 66 187 1.95 76 188 4.65 43 189 3.83 58 190 2.79 39 191
4.10 51 192 4.40 29 193 0.47 68 194 0.88 68 195 7.53 37 196 1.24 67
197 2.10 73 198 1.71 67 199 6.89 27 200 2.35 61 201 7.92 35 202
0.01 142 202F 0.04 131 203 0.69 157
[2032] Transepithelial Clamp Circuit on Human Bronchial Epithelial
Cells Conductance Assay:
[2033] A cell based assay using the primary human bronchial
epithelial cells (hBE) was used as a secondary assay to test novel
F508delCFTR correctors for their activity on primary hBE cells with
F508del/F508del CFTR mutation. The assay used a TECC-24
(Transepithelial Clamp Circuit for 24 wells) instrument that
measures the functionality of the mutated channel by measuring the
equivalent short circuit current (Ieq) generated by the polarized
epithelial cells. The instrument works by measuring the
transepithelial potential difference (Vt) and transepithelial
resistance (Rt) in an open circuit format, and the Ieq is
calculated by using Ohms law (Ieq=Vt/Rt). The assay was run in a
24-well format and all 24-wells were measured at the same time
point giving a higher throughput for this assay.
[2034] Primary human bronchial epithelial (hBE) cells from
F508del/F508delCFTR patients were expanded from 1.times.10.sup.6 to
250.times.10.sup.6 cells (Neuberger T, Burton B, Clark H and
VanGoor F; Cystic Fibrosis, Methods in Mole Biol 741; eds. Amaral
MD and Kunzelmann K, 2011). For this purpose, cells isolated from
CF patients with the homozygous mutation were seeded onto 24 well
Corning (Cat #3378) filter plates that were coated with 3T3
conditioned media and grown at an air-liquid interface for 35 days
using an Ultroser.RTM. G supplemented differentiation media. Apical
surface mucus was removed 72 hours before the experiment using 3 mM
dithiothreitol (DTT) in phosphate buffered saline (PBS). The apical
surface was washed again 24 hours before the experiment using PBS.
The cells were incubated with the desired dose response of the
corrector compounds 18-24 hours at 37.degree. C., 5% CO.sub.2. The
corrector compounds are only added on the basolateral side of the
epithelial cells.
[2035] On the day of measuring the corrector activity on the TECC,
the cells were switched into a bicarbonate and serum free F-12
Coon's medium and allowed to equilibrate for 90 minutes in a
CO.sub.2 free incubator. At the time of measurement, the apical and
basolateral sides of the filter were bathed with the F-12 Coon's
modification media (with 20 mM
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4
(using 1 M tris(hydroxymethyl)aminomethane (Tris)), and the
measurements were made at 36.5.degree. C. Transepithelial voltage
(Vt) and transepithelial resistance (Rt) were measured using a 24
channel transepithelial current clamp (TECC-24). Current responses
to the sequential addition of benzamil (apical 6 .mu.M addition;
for inhibiting epithelial ENaC channel), forskolin (apical and
basolateral 10 .mu.M addition; for activating the CFTR channel),
control potentiator
(N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-y-
l)-1H-pyrazole-5-carboxamide; apical and basolateral 1 .mu.M
addition; for potentiating the CFTR channel) and bumetanide
(basolateral 20 .mu.M addition; for inhibiting the Na:2Cl:K
co-transporter, an indirect measure of inhibiting the Cl--secretion
driven by CFTR channel) were measured.
[2036] All plates contained negative controls (dimethyl sulfoxide,
DMSO) which coupled with the control potentiator
(N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-y-
l)-1H-pyrazole-5-carboxamide) sets the null response and positive
controls (3 .mu.M of
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) coupled
with the control potentiator sets the 100% response to measure the
correction of the mutated CFTR channel. The maximum percent
activity is reported relative to the positive control value.
[2037] The % activity measured at each of the 6 test concentrations
of the test compound was normalized to the on-plate positive
control using the following formula:
% activity=[(test compound response-DMSO response)/(positive
control response-DMSO response)]*100
[2038] The following log(agonist) vs response using a four
parameters variable slope was used to calculate EC.sub.50 (4 PL in
Prism v 5 software):
F(x)=D+(A-D)/(1+(x/C) B)
Where:
[2039] "x" is a concentration of drug under test. "F(x)" is the
response. "A" is the maximum response, and "D" is the minimum
response "C" is the inflection point (EC.sub.50) for the curve.
That is, "F(x)" is halfway between the lower and upper asymptotes
when x=C. "B" is the slope-factor or Hill coefficient. The sign of
B is positive when the response increases with increasing dose and
is negative when the response decreases with increasing dose
(inhibition).
[2040] The maximum percent activity and EC.sub.50 values for tested
corrector compounds are presented in Table 2.
TABLE-US-00002 TABLE 2 hBE-TECC data Example EC.sub.50 (.mu.M)
Maximum % activity (%) 1 0.29 95 9 0.16 92 19 0.21 111 26 0.11 88
27 0.075 117 28 3.4 51 38 0.61 106 108 0.086 96 109 0.055 70 111
0.005 90 119 0.45 80 121 0.038 87 122 0.004 87 139 0.0313 100 146
0.004 98 148 1.1 44
CYP3A4 Induction:
[2041] Cryopreserved primary human hepatocytes were thawed and
cultured overnight prior to treatment. Cultured hepatocytes were
treated with either test compounds (10 .mu.M), vehicle control
(0.1% v/v DMSO), or prototypical inducer of CYP3A4 (rifampin 10
.mu.M) for 48 hours, with culture medium being refreshed every 24
hours. Following the 48 hour treatment, hepatocytes were harvested
for RNA isolation and reverse transcription, followed by CYP3A4
mRNA quantitation using RT-PCR (real time reverse transcript
polymerase chain reaction).
[2042] CYP3A4 mRNA level was used as a measure of CYP3A4 expression
in hepatocytes, which was not expected to change in hepatocytes
treated with vehicle control (0.1% v/v DMSO), but was expected to
be significantly increased in hepatocytes treated with prototypical
inducer (Rifampin). CYP3A4 mRNA levels measured in compound treated
hepatocytes were expressed as a percentage of the response of
positive control (Rifampin 10 .mu.M).
Fold Induction=Fold of Treated/Fold of Vehicle Control
% positive control=(Fold Induction of Treated-1)/(Fold Induction of
Prototypical Inducer-1)
[2043] In test compound treated hepatocytes, CYP3A4 mRNA level
increase by less than 20% of the response of positive control
(Rifampin) is considered low risk for CYP3A4 induction.
TABLE-US-00003 TABLE 3 CYP3A4 Hepatocytes mRNA Examples % of
positive control 1 14 3 49.3 9 16.1 14 3.54 19 9.38 28 9.41 38 40.2
108 39.6 109 42.2 111 -0.105 122 10.6 146 11.6 Rifampin (positive
control) 100
[2044] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the embodiments will be
apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations, or methods, or any combination of such
changes and modifications of use of the invention, may be made
without departing from the spirit and scope thereof.
* * * * *
References