U.S. patent application number 14/451709 was filed with the patent office on 2015-03-05 for modulators of atp-binding cassette transporters.
The applicant listed for this patent is Vertex Pharmaceuticals Incorporated. Invention is credited to Brian Bear, Peter D.J. Grootenhuis, Sara S. Hadida Ruah, Jason McCartney, Mark T. Miller.
Application Number | 20150065497 14/451709 |
Document ID | / |
Family ID | 38309711 |
Filed Date | 2015-03-05 |
United States Patent
Application |
20150065497 |
Kind Code |
A1 |
Hadida Ruah; Sara S. ; et
al. |
March 5, 2015 |
MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
Abstract
Compounds of the present invention and pharmaceutically
acceptable compositions thereof, are useful as modulators of
ATP-Binding Cassette ("ABC") transporters or fragments thereof,
including Cystic Fibrosis Transmembrane Conductance Regulator
("CFTR"). The present invention also relates to methods of treating
ABC transporter mediated diseases using compounds of the present
invention.
Inventors: |
Hadida Ruah; Sara S.; (La
Jolla, CA) ; Miller; Mark T.; (San Diego, CA)
; Bear; Brian; (Carlsbad, CA) ; McCartney;
Jason; (Cardiff by the Sea, CA) ; Grootenhuis; Peter
D.J.; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vertex Pharmaceuticals Incorporated |
Boston |
MA |
US |
|
|
Family ID: |
38309711 |
Appl. No.: |
14/451709 |
Filed: |
August 5, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13928719 |
Jun 27, 2013 |
8846753 |
|
|
14451709 |
|
|
|
|
12704605 |
Feb 12, 2010 |
8524767 |
|
|
13928719 |
|
|
|
|
11647092 |
Dec 28, 2006 |
7691902 |
|
|
12704605 |
|
|
|
|
60802580 |
May 22, 2006 |
|
|
|
60754558 |
Dec 28, 2005 |
|
|
|
Current U.S.
Class: |
514/230.5 ;
435/375; 514/259.1; 514/300; 514/302; 514/338; 514/424; 514/444;
514/616; 544/105; 544/281; 546/115; 546/121; 546/283.7; 548/542;
549/60; 564/158 |
Current CPC
Class: |
A61P 19/04 20180101;
C07D 317/68 20130101; A61P 3/00 20180101; A61P 5/16 20180101; A61P
25/16 20180101; A61P 35/00 20180101; C07D 207/48 20130101; C07D
471/04 20130101; A61P 13/12 20180101; A61K 31/40 20130101; A61P
9/00 20180101; A61K 45/06 20130101; A61P 7/04 20180101; A61P 13/04
20180101; A61P 21/02 20180101; C07D 409/12 20130101; A61K 31/381
20130101; A61P 25/00 20180101; A61P 5/00 20180101; A61P 11/00
20180101; A61K 31/357 20130101; A61P 3/06 20180101; A61P 7/10
20180101; C07D 413/12 20130101; C07D 487/04 20130101; A61P 3/12
20180101; A61P 5/14 20180101; A61K 31/519 20130101; C07D 317/54
20130101; A61K 31/167 20130101; C07D 317/60 20130101; A61P 7/02
20180101; A61P 19/08 20180101; C07D 405/12 20130101; A61K 31/443
20130101; A61P 13/00 20180101; A61P 21/00 20180101; A61K 31/538
20130101; C07D 498/04 20130101; A61P 7/12 20180101; A61P 25/14
20180101; C07C 235/16 20130101; A61K 31/437 20130101; A61P 5/18
20180101; A61P 25/28 20180101; A61P 21/04 20180101; A61P 5/50
20180101; A61P 7/00 20180101; A61P 27/02 20180101; A61P 43/00
20180101; A61P 27/04 20180101; A61P 3/10 20180101 |
Class at
Publication: |
514/230.5 ;
564/158; 514/616; 546/115; 514/302; 549/60; 514/444; 546/283.7;
514/338; 544/105; 548/542; 514/424; 544/281; 514/259.1; 546/121;
514/300; 435/375 |
International
Class: |
C07D 498/04 20060101
C07D498/04; A61K 31/167 20060101 A61K031/167; A61K 45/06 20060101
A61K045/06; A61K 31/437 20060101 A61K031/437; C07D 409/12 20060101
C07D409/12; A61K 31/381 20060101 A61K031/381; C07D 405/12 20060101
C07D405/12; A61K 31/443 20060101 A61K031/443; C07D 413/12 20060101
C07D413/12; A61K 31/538 20060101 A61K031/538; C07D 207/48 20060101
C07D207/48; A61K 31/40 20060101 A61K031/40; C07D 487/04 20060101
C07D487/04; A61K 31/519 20060101 A61K031/519; C07D 471/04 20060101
C07D471/04; C07C 235/16 20060101 C07C235/16 |
Claims
1. A compound of formula (I): ##STR01299## or a pharmaceutically
acceptable salt thereof, wherein: Each R.sub.1 is independently an
optionally substituted C.sub.1-6 aliphatic, an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted C.sub.3-10 membered cycloaliphatic or an
optionally substituted 4 to 10 membered heterocycloaliphatic,
carboxy, amido, amino, halo, or hydroxy, provided that at least one
R.sub.1 is an optionally substituted aryl attached to the
3-position of the phenyl ring; R.sub.2 is hydrogen, an optionally
substituted C.sub.1-6 aliphatic, an optionally substituted
C.sub.3-6 cycloaliphatic, an optionally substituted phenyl, or an
optionally substituted heteroaryl; Ring A is an optionally
substituted cycloaliphatic; Each R.sub.4 is an optionally
substituted aryl or an optionally substituted heteroaryl, provided
that R.sub.4 is not a benzo[d][1,3]dioxolyl ring; and n is 1, 2, 3,
4, or 5.
2. The compound of claim Error! Reference source not found. 1,
wherein the one R.sub.1 attached to the 3-position of the phenyl
ring is an aryl optionally substituted with 1, 2, or 3 of R.sup.A,
wherein R.sup.A is --Z.sup.AR.sub.5; in which each Z.sup.A is
independently a bond or an optionally substituted branched or
straight C.sub.1-6 aliphatic chain wherein up to two carbon units
of Z.sup.A are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--,
--OCO--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--; each R.sub.5
is independently R.sup.B, halo, --B(OH).sub.2, --OH, --NH.sub.2,
--NO.sub.2, --CN, or --OCF.sub.3; and each R.sup.B is independently
hydrogen, an optionally substituted C.sub.1-8 aliphatic group, an
optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
3. The compound of claim 2, wherein the one R.sub.1 attached to the
3-position of the phenyl ring is a phenyl optionally substituted
with 1, 2, or 3 of R.sup.A.
4. The compound of claim 3, wherein the one R.sub.1 attached to the
3-position of the phenyl ring is a phenyl substituted with one of
R.sup.A, wherein R.sup.A is --Z.sup.AR.sub.5; each Z.sup.A is
independently a bond or an optionally substituted branched or
straight C.sub.1-6 aliphatic chain wherein up to two carbon units
of Z.sup.A are optionally and independently replaced by --O--,
--NHC(O)--, --C(O)NR.sup.B--, --SO.sub.2--, --NHSO.sub.2--,
--NHC(O)--, --SO--, --NR.sup.BSO.sub.2--, --SO.sub.2NH--,
--SO.sub.2NR.sup.B--, --NH--, or --C(O)O--.
5. The compound of claim 4, wherein one carbon unit of Z.sup.A is
replaced by --O--, --NHC(O)--, --C(O)NR.sup.B--, --SO.sub.2--,
--NHSO.sub.2--, --NHC(O)--, --SO--, --NR.sup.BSO.sub.2--,
--SO.sub.2NH--, --SO.sub.2NR.sup.B--, --NH--, or --C(O)O--.
6. The compound of claim 2, wherein R.sub.5 is independently an
optionally substituted aliphatic, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, an optionally substituted heteroaryl,
or halo.
7.-10. (canceled)
11. The compound of claim 2, wherein R.sub.1 is: ##STR01300##
wherein W.sub.1 is --C(O)--, --SO.sub.2--, --NHC(O)--, or
--CH.sub.2--; and D is H, hydroxy, or an optionally substituted
aliphatic, an optionally substituted cycloaliphatic, an optionally
substituted alkoxy, and amino.
12. The compound of claim 11, wherein D is OH, an optionally
substituted C.sub.1-6 aliphatic, an optionally substituted
C.sub.3-C.sub.8 cycloaliphatic, an optionally substituted alkoxy,
or an optionally substituted amino.
13. The compound of claim Error! Reference source not found. 12,
wherein D is an optionally substituted amino of the formula
##STR01301## wherein each of A and B is independently H, an
optionally substituted C.sub.1-6 aliphatic, an optionally
substituted C.sub.3-C.sub.8 cycloaliphatic, an optionally
substituted 3-8 membered heterocycloaliphatic, acyl, sulfonyl, or A
and B, taken together, form an optionally substituted 3-7 membered
heterocycloaliphatic ring.
14. The compound of claim 11, wherein R.sub.1 is: ##STR01302##
wherein: W.sub.1 is --C(O)--, --SO.sub.2--, --NHC(O)--, or
--CH.sub.2--; Each of A and B is independently H or an optionally
substituted C.sub.1-6 aliphatic; or A and B, taken together, form
an optionally substituted 4-7 membered heterocycloaliphatic
ring.
15. The compound of claim 13, wherein A is H and B is C.sub.1-6
aliphatic optionally substituted with 1, 2, or 3 of halo, oxo, CN,
hydroxy, an optionally substituted alkyl, an optionally substituted
alkenyl, an optionally substituted hydroxyalkyl, an optionally
substituted alkoxy, an optionally substituted alkoxyalkyl, an
optionally substituted cycloaliphatic, amino, an optionally
substituted heterocycloaliphatic, an optionally substituted aryl,
or an optionally substituted heteroaryl.
16. The compound of claim 13, wherein A and B, taken together with
the nitrogen atom, form an optionally substituted 3-7 membered
heterocycloaliphatic ring.
17. The compound of claim 15, wherein A and B, taken together with
the nitrogen atom, form an optionally substituted pyrrolidinyl,
piperidinyl, morpholinyl, piperazinyl, oxazolidin-3-yl, and
1,4-diazepan-1-yl.
18. The compound of claim 15, wherein the heterocycloaliphatic ring
is optionally substituted with 1, 2, or 3 of halo, oxo, alkyl,
aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,
amino, amido, or carboxy.
19. The compound of claim Error! Reference source not found. 1,
wherein R.sub.2 is hydrogen or methyl.
20. The compound of claim 1, wherein ring A is an unsubstituted
C.sub.3-7 cycloaliphatic.
21. The compound of claim 20, wherein ring A is an unsubstituted
cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted
cyclohexyl.
22. The compound of claim 21, wherein ring A is an unsubstituted
cyclopropyl.
23. The compound of claim 1, wherein R.sub.4 is an aryl or
heteroaryl optionally substituted with 1, 2, or 3 of
--Z.sup.CR.sub.8, wherein each Z.sup.C is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.C are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.C--,
--CONR.sup.CNR.sup.C--, --CO.sub.2--, --OCO--,
--NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--,
--OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.C--, --SO.sub.2NR.sup.C--,
--NR.sup.CSO.sub.2--, or --NR.sup.CSO.sub.2NR.sup.C--; each R.sub.8
is independently R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN,
or --OCF.sub.3; and each R.sup.C is independently hydrogen, an
optionally substituted C.sub.1-8 aliphatic group, an optionally
substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
24. The compound of claim 23, wherein R.sub.4 is an aryl optionally
substituted with 1, 2, or 3 of --Z.sup.CR.sub.8.
25. The compound of claim 24, wherein R.sub.4 is phenyl optionally
substituted with 1, 2, or 3 of --Z.sup.CR.sub.8.
26. The compound of claim 23, wherein R.sub.4 is a heteroaryl
optionally substituted with 1, 2, or 3 of --Z.sup.CR.sub.8.
27. The compound of claim 23, wherein R.sub.4 is one selected from
##STR01303## ##STR01304##
28.-66. (canceled)
67. A compound having a structure selected from: ##STR01305##
##STR01306## ##STR01307## ##STR01308## ##STR01309## ##STR01310##
##STR01311## ##STR01312## ##STR01313## ##STR01314## ##STR01315##
##STR01316## ##STR01317## ##STR01318## ##STR01319## ##STR01320##
##STR01321## ##STR01322## ##STR01323## ##STR01324## ##STR01325##
##STR01326## ##STR01327## ##STR01328## ##STR01329## ##STR01330##
##STR01331## ##STR01332## ##STR01333## ##STR01334## ##STR01335##
##STR01336## ##STR01337## ##STR01338## ##STR01339## ##STR01340##
##STR01341## ##STR01342## ##STR01343## ##STR01344## ##STR01345##
##STR01346## ##STR01347## ##STR01348## ##STR01349## ##STR01350##
##STR01351## ##STR01352## ##STR01353## ##STR01354## ##STR01355##
##STR01356##
68. A pharmaceutical composition comprising: (i) a compound
according to claim 1; and (ii) a pharmaceutically acceptable
carrier.
69. The composition of claim 68, optionally further comprising a
mucolytic agent, a bronchodialator, an anti-biotic, an
anti-infective agent, an anti-inflammatory agent, a CFTR modulator,
or a nutritional agent.
70. A method of modulating ABC transporter activity comprising the
step of contacting said ABC transporter with a compound of claim
1.
71. The method of claim 70 wherein the ABC transporter is CFTR.
72. A method for treating or lessening the severity of a disease in
a patient need thereof, wherein said disease is selected from
cystic fibrosis, hereditary emphysema, hereditary hemochromatosis,
coagulation-fibrinolysis deficiencies, such as protein C
deficiency, Type 1 hereditary angioedema, lipid processing
deficiencies, such as familial hypercholesterolemia, Type 1
chylomicronemia, abetalipoproteinemia, lysosomal storage diseases,
such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses,
Sandhof/Tay-Sachs, Crigler-Najjar type II,
polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron
dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism,
melanoma, glycanosis CDG type 1, congenital hyperthyroidism,
osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT
deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic
DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease, amyotrophic lateral sclerosis, progressive supranuclear
plasy, Pick's disease, several polyglutamine neurological disorders
asuch as Huntington, spinocerebullar ataxia type I, spinal and
bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic
dystrophy, as well as spongiform encephalopathies, such as
hereditary Creutzfeldt-Jakob disease (due to prion protein
processing defect), Fabry disease, Straussler-Scheinker syndrome,
COPD, dry-eye disease, or Sjogren's disease; provided that R.sub.4
is not a benzo[d][1,3]dioxolyl ring when the disease is cystic
fibrosis
73. A kit for use in measuring the activity of an ABC transporter
or a fragment thereof in a biological sample in vitro or in vivo,
comprising: (i) a composition comprising a compound of formula (I)
according to claim 1; and (ii) instructions for: a) contacting the
composition with the biological sample; and b) measuring activity
of said ABC transporter or a fragment thereof.
74. The kit of claim 73, further comprising instructions for a)
contacting an additional composition with the biological sample; b)
measuring the activity of said ABC transporter or a fragment
thereof in the presence of said additional composition; and c)
comparing the activity of the ABC transporter in the presence of
the additional composition with the density of the ABC transporter
in the presence of a composition comprising a compound of formula
(I).
75. The kit of claim 73 or claim 74, wherein the kit is used to
measure the activity of CFTR.
Description
CROSS-REFERENCE
[0001] This application claims priority to U.S. Ser. Nos.
60/754,558, filed on Dec. 28, 2005, and 60/802,580, filed on May
22, 2006, both of which are hereby incorporated herein by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to modulators of ATP-Binding
Cassette ("ABC") transporters or fragments thereof, including
Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"),
compositions thereof and methods therewith. The present invention
also relates to methods of treating ABC transporter mediated
diseases using such modulators.
BACKGROUND OF THE INVENTION
[0003] ABC transporters are a family of membrane transporter
proteins that regulate the transport of a wide variety of
pharmacological agents, potentially toxic drugs, and xenobiotics,
as well as anions. ABC transporters are homologous membrane
proteins that bind and use cellular adenosine triphosphate (ATP)
for their specific activities. Some of these transporters were
discovered as multidrug resistance proteins (like the MDR1-P
glycoprotein, or the multidrug resistance protein, MRP1), defending
malignant cancer cells against chemotherapeutic agents. To date, 48
ABC Transporters have been identified and grouped into 7 families
based on their sequence identity and function.
[0004] ABC transporters regulate a variety of important
physiological roles within the body and provide defense against
harmful environmental compounds. Because of this, they represent
important potential drug targets for the treatment of diseases
associated with defects in the transporter, prevention of drug
transport out of the target cell, and intervention in other
diseases in which modulation of ABC transporter activity may be
beneficial.
[0005] One member of the ABC transporter family commonly associated
with disease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is
expressed in a variety of cells types, including absorptive and
secretory epithelia cells, where it regulates anion flux across the
membrane, as well as the activity of other ion channels and
proteins. In epithelia cells, normal functioning of CFTR is
critical for the maintenance of electrolyte transport throughout
the body, including respiratory and digestive tissue. CFTR is
composed of approximately 1480 amino acids that encode a protein
made up of a tandem repeat of transmembrane domains, each
containing six transmembrane helices and a nucleotide binding
domain. The two transmembrane domains are linked by a large, polar,
regulatory (R)-domain with multiple phosphorylation sites that
regulate channel activity and cellular trafficking.
[0006] The gene encoding CFTR has been identified and sequenced
(See 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). A defect in this gene causes mutations in
CFTR resulting in Cystic Fibrosis ("CF"), the most common fatal
genetic disease in humans. Cystic Fibrosis affects approximately
one in every 2,500 infants in the United States. Within the general
United States population, up to 10 million people carry a single
copy of the defective gene without apparent ill effects. In
contrast, individuals with two copies of the CF associated gene
suffer from the debilitating and fatal effects of CF, including
chronic lung disease.
[0007] In patients with cystic fibrosis, mutations in CFTR
endogenously expressed in respiratory epithelia leads to reduced
apical anion secretion causing an imbalance in ion and fluid
transport. The resulting decrease in anion transport contributes to
enhanced mucus accumulation in the lung and the accompanying
microbial infections that ultimately cause death in CF patients. In
addition to respiratory disease, CF patients typically suffer from
gastrointestinal problems and pancreatic insufficiency that, if
left untreated, results in death. In addition, the majority of
males with cystic fibrosis are infertile and fertility is decreased
among females with cystic fibrosis. In contrast to the severe
effects of two copies of the CF associated gene, individuals with a
single copy of the CF associated gene exhibit increased resistance
to cholera and to dehydration resulting from diarrhea--perhaps
explaining the relatively high frequency of the CF gene within the
population.
[0008] Sequence analysis of the CFTR gene of CF chromosomes has
revealed a variety of disease causing mutations (Cutting, G. R. et
al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell
61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080;
Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451).
To date, >1000 disease causing mutations in the CF gene have
been identified (http://www.genet.sickkids.on.ca/cftr/). The most
prevalent mutation is a deletion of phenylalanine at position 508
of the CFTR amino acid sequence, and is commonly referred to as
.DELTA.F508-CFTR. This mutation occurs in approximately 70% of the
cases of cystic fibrosis and is associated with a severe
disease.
[0009] The deletion of residue 508 in .DELTA.F508-CFTR prevents the
nascent protein from folding correctly. This results in the
inability of the mutant protein to exit the ER, and traffic to the
plasma membrane. As a result, the number of channels present in the
membrane is far less than observed in cells expressing wild-type
CFTR. In addition to impaired trafficking, the mutation results in
defective channel gating. Together, the reduced number of channels
in the membrane and the defective gating lead to reduced anion
transport across epithelia leading to defective ion and fluid
transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies
have shown, however, that the reduced numbers of .DELTA.F508-CFTR
in the membrane are functional, albeit less than wild-type CFTR.
(Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al.,
supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50).
In addition to .DELTA.F508-CFTR, other disease causing mutations in
CFTR that result in defective trafficking, synthesis, and/or
channel gating could be up- or down-regulated to alter anion
secretion and modify disease progression and/or severity.
[0010] Although CFTR transports a variety of molecules in addition
to anions, it is clear that this role (the transport of anions)
represents one element in an important mechanism of transporting
ions and water across the epithelium. The other elements include
the epithelial Na.sup.+ channel, ENaC, Na.sup.+/2Cl.sup.-/K.sup.+
co-transporter, Na.sup.+--K.sup.+-ATPase pump and the basolateral
membrane K.sup.+ channels, that are responsible for the uptake of
chloride into the cell.
[0011] These elements work together to achieve directional
transport across the epithelium via their selective expression and
localization within the cell. Chloride absorption takes place by
the coordinated activity of ENaC and CFTR present on the apical
membrane and the Na.sup.+--K.sup.+-ATPase pump and Cl-- channels
expressed on the basolateral surface of the cell. Secondary active
transport of chloride from the luminal side leads to the
accumulation of intracellular chloride, which can then passively
leave the cell via Cl.sup.- channels, resulting in a vectorial
transport. Arrangement of Na.sup.+/2Cl.sup.-/K.sup.+
co-transporter, Na.sup.+--K.sup.+-ATPase pump and the basolateral
membrane K.sup.+ channels on the basolateral surface and CFTR on
the luminal side coordinate the secretion of chloride via CFTR on
the luminal side. Because water is probably never actively
transported itself, its flow across epithelia depends on tiny
transepithelial osmotic gradients generated by the bulk flow of
sodium and chloride.
[0012] In addition to Cystic Fibrosis, modulation of CFTR activity
may be beneficial for other diseases not directly caused by
mutations in CFTR, such as secretory diseases and other protein
folding diseases mediated by CFTR. These include, but are not
limited to, chronic obstructive pulmonary disease (COPD), dry eye
disease, and Sjogren's Syndrome.
[0013] COPD is characterized by airflow limitation that is
progressive and not fully reversible. The airflow limitation is due
to mucus hypersecretion, emphysema, and bronchiolitis. Activators
of mutant or wild-type CFTR offer a potential treatment of mucus
hypersecretion and impaired mucociliary clearance that is common in
COPD. Specifically, increasing anion secretion across CFTR may
facilitate fluid transport into the airway surface liquid to
hydrate the mucus and optimized periciliary fluid viscosity. This
would lead to enhanced mucociliary clearance and a reduction in the
symptoms associated with COPD. Dry eye disease is characterized by
a decrease in tear aqueous production and abnormal tear film lipid,
protein and mucin profiles. There are many causes of dry eye, some
of which include age, Lasik eye surgery, arthritis, medications,
chemical/thermal burns, allergies, and diseases, such as Cystic
Fibrosis and Sjogrens's syndrome. Increasing anion secretion via
CFTR would enhance fluid transport from the corneal endothelial
cells and secretory glands surrounding the eye to increase corneal
hydration. This would help to alleviate the symptoms associated
with dry eye disease. Sjogrens's syndrome is an autoimmune disease
in which the immune system attacks moisture-producing glands
throughout the body, including the eye, mouth, skin, respiratory
tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth,
and vagina, as well as lung disease. The disease is also associated
with rheumatoid arthritis, systemic lupus, systemic sclerosis, and
polymypositis/dermatomyositis. Defective protein trafficking is
believed to cause the disease, for which treatment options are
limited. Modulators of CFTR activity may hydrate the various organs
afflicted by the disease and help to elevate the associated
symptoms.
[0014] As discussed above, it is believed that the deletion of
residue 508 in .DELTA.F508-CFTR prevents the nascent protein from
folding correctly, resulting in the inability of this mutant
protein to exit the ER, and traffic to the plasma membrane. As a
result, insufficient amounts of the mature protein are present at
the plasma membrane and chloride transport within epithelial
tissues is significantly reduced. In fact, this cellular phenomenon
of defective ER processing of ABC transporters by the ER machinery
has been shown to be the underlying basis not only for CF disease,
but for a wide range of other isolated and inherited diseases. The
two ways that the ER machinery can malfunction is either by loss of
coupling to ER export of the proteins leading to degradation, or by
the ER accumulation of these defective/misfolded proteins [Aridor
M, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et
al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J.,
et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, J P et
al., TIPS, 21, pp. 466-469 (2000); Bross P., et al., Human Mut.,
14, pp. 186-198 (1999)]. The diseases associated with the first
class of ER malfunction are Cystic fibrosis (due to misfolded
.DELTA.F508-CFTR as discussed above), Hereditary emphysema (due to
al-antitrypsin; non Piz variants), Hereditary hemochromatosis,
Coagulation-Fibrinolysis deficiencies, such as Protein C
deficiency, Type 1 hereditary angioedema, Lipid processing
deficiencies, such as Familial hypercholesterolemia, Type 1
chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases,
such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses (due to
Lysosomal processing enzymes), Sandhof/Tay-Sachs (due to
.beta.-Hexosaminidase), Crigler-Najjar type II (due to
UDP-glucuronyl-sialyc-transferase),
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus (due to
Insulin receptor), Laron dwarfism (due to Growth hormone receptor),
Myleoperoxidase deficiency, Primary hypoparathyroidism (due to
Preproparathyroid hormone), Melanoma (due to Tyrosinase). The
diseases associated with the latter class of ER malfunction are
Glycanosis CDG type 1, Hereditary emphysema (due to
.alpha.1-Antitrypsin (PiZ variant), Congenital hyperthyroidism,
Osteogenesis imperfecta (due to Type I, II, IV procollagen),
Hereditary hypofibrinogenemia (due to Fibrinogen), ACT deficiency
(due to .alpha.1-Antichymotrypsin), Diabetes insipidus (DI),
Neurophyseal DI (due to Vasopvessin hormone/V2-receptor),
Neprogenic DI (due to Aquaporin II), Charcot-Marie Tooth syndrome
(due to Peripheral myelin protein 22), Perlizaeus-Merzbacher
disease, neurodegenerative diseases such as Alzheimer's disease
(due to .beta.APP and presenilins), Parkinson's disease,
Amyotrophic lateral sclerosis, Progressive supranuclear plasy,
Pick's disease, several polyglutamine neurological disorders asuch
as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar
muscular atrophy, Dentatorubal pallidoluysian, and Myotonic
dystrophy, as well as Spongiform encephalopathies, such as
Hereditary Creutzfeldt-Jakob disease (due to Prion protein
processing defect), Fabry disease (due to lysosomal
.alpha.-galactosidase A) and Straussler-Scheinker syndrome (due to
Prp processing defect).
[0015] In addition to up-regulation of CFTR activity, reducing
anion secretion by CFTR modulators may be beneficial for the
treatment of secretory diarrheas, in which epithelial water
transport is dramatically increased as a result of secretagogue
activated chloride transport. The mechanism involves elevation of
cAMP and stimulation of CFTR.
[0016] Although there are numerous causes of diarrhea, the major
consequences of diarrheal diseases, resulting from excessive
chloride transport are common to all, and include dehydration,
acidosis, impaired growth and death.
[0017] Acute and chronic diarrheas represent a major medical
problem in many areas of the world. Diarrhea is both a significant
factor in malnutrition and the leading cause of death (5,000,000
deaths/year) in children less than five years old.
[0018] Secretory diarrheas are also a dangerous condition in
patients of acquired immunodeficiency syndrome (AIDS) and chronic
inflammatory bowel disease (IBD). 16 million travelers to
developing countries from industrialized nations every year develop
diarrhea, with the severity and number of cases of diarrhea varying
depending on the country and area of travel.
[0019] Diarrhea in barn animals and pets such as cows, pigs and
horses, sheep, goats, cats and dogs, also known as scours, is a
major cause of death in these animals. Diarrhea can result from any
major transition, such as weaning or physical movement, as well as
in response to a variety of bacterial or viral infections and
generally occurs within the first few hours of the animal's
life.
[0020] The most common diarrhea causing bacteria is enterotoxogenic
E-coli (ETEC) having the K99 pilus antigen. Common viral causes of
diarrhea include rotavirus and coronavirus. Other infectious agents
include cryptosporidium, giardia lamblia, and salmonella, among
others.
[0021] Symptoms of rotaviral infection include excretion of watery
feces, dehydration and weakness. Coronavirus causes a more severe
illness in the newborn animals, and has a higher mortality rate
than rotaviral infection. Often, however, a young animal may be
infected with more than one virus or with a combination of viral
and bacterial microorganisms at one time. This dramatically
increases the severity of the disease.
[0022] Accordingly, there is a need for modulators of an ABC
transporter activity, and compositions thereof, that can be used to
modulate the activity of the ABC transporter in the cell membrane
of a mammal.
[0023] There is a need for methods of treating ABC transporter
mediated diseases using such modulators of ABC transporter
activity.
[0024] There is a need for methods of modulating an ABC transporter
activity in an ex vivo cell membrane of a mammal.
[0025] There is a need for modulators of CFTR activity that can be
used to modulate the activity of CFTR in the cell membrane of a
mammal.
[0026] There is a need for methods of treating CFTR-mediated
diseases using such modulators of CFTR activity.
[0027] There is a need for methods of modulating CFTR activity in
an ex vivo cell membrane of a mammal.
SUMMARY OF THE INVENTION
[0028] It has now been found that compounds of this invention, and
pharmaceutically acceptable compositions thereof, are useful as
modulators of ABC transporter activity. These compounds have the
general formula I:
##STR00001## [0029] or a pharmaceutically acceptable salt thereof,
wherein R.sub.1, R.sub.2, R.sub.4, ring A, and n are described
herein.
[0030] These compounds and pharmaceutically acceptable compositions
are useful for treating or lessening the severity of a variety of
diseases, disorders, or conditions, including, but not limited to,
Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis,
Coagulation-Fibrinolysis deficiencies, such as Protein C
deficiency, Type 1 hereditary angioedema, Lipid processing
deficiencies, such as Familial hypercholesterolemia, Type 1
chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases,
such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,
Sandhof/Tay-Sachs, Crigler-Najjar type II,
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism,
Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital
hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, Amyotrophic lateral
sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders such as Huntington,
Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,
Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob
disease, Fabry disease, Straussler-Scheinker syndrome, COPD,
dry-eye disease, and Sjogren's disease.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0031] As used herein, the following definitions shall apply unless
otherwise indicated.
[0032] The term "ABC-transporter" as used herein means an
ABC-transporter protein or a fragment thereof comprising at least
one binding domain, wherein said protein or fragment thereof is
present in vivo or in vitro. The term "binding domain" as used
herein means a domain on the ABC-transporter that can bind to a
modulator. See, e.g., Hwang, T. C. et al., J. Gen. Physiol. (1998):
111(3), 477-90.
[0033] The term "CFTR" as used herein means cystic fibrosis
transmembrane conductance regulator or a mutation thereof capable
of regulator activity, including, but not limited to, .DELTA.F508
CFTR and G551D CFTR (see, e.g.,
http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).
[0034] The term "modulating" as used herein means increasing or
decreasing, e.g. activity, by a measurable amount. Compounds that
modulate ABC Transporter activity, such as CFTR activity, by
increasing the activity of the ABC Transporter, e.g., a CFTR anion
channel, are called agonists. Compounds that modulate ABC
Transporter activity, such as CFTR activity, by decreasing the
activity of the ABC Transporter, e.g., CFTR anion channel, are
called antagonists. An agonist interacts with an ABC Transporter,
such as CFTR anion channel, to increase the ability of the receptor
to transduce an intracellular signal in response to endogenous
ligand binding. An antagonist interacts with an ABC Transporter,
such as CFTR, and competes with the endogenous ligand(s) or
substrate(s) for binding site(s) on the receptor to decrease the
ability of the receptor to transduce an intracellular signal in
response to endogenous ligand binding.
[0035] The phrase "treating or reducing the severity of an ABC
Transporter mediated disease" refers both to treatments for
diseases that are directly caused by ABC Transporter and/or CFTR
activities and alleviation of symptoms of diseases not directly
caused by ABC Transporter and/or CFTR anion channel activities.
Examples of diseases whose symptoms may be affected by ABC
Transporter and/or CFTR activity include, but are not limited to,
Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis,
Coagulation-Fibrinolysis deficiencies, such as Protein C
deficiency, Type 1 hereditary angioedema, Lipid processing
deficiencies, such as Familial hypercholesterolemia, Type 1
chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases,
such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,
Sandhof/Tay-Sachs, Crigler-Najjar type II,
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism,
Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital
hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, Amyotrophic lateral
sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders such as Huntington,
Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,
Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob
disease, Fabry disease, Straussler-Scheinker syndrome, COPD,
dry-eye disease, and Sjogren's disease.
[0036] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75th Ed.
Additionally, general principles of organic chemistry are described
in "Organic Chemistry", Thomas Sorrell, University Science Books,
Sausolito: 1999, and "March's Advanced Organic Chemistry", 5th Ed.,
Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York:
2001, the entire contents of which are hereby incorporated by
reference.
[0037] As used herein the term "aliphatic` encompasses the terms
alkyl, alkenyl, alkynyl, each of which being optionally substituted
as set forth below.
[0038] As used herein, an "alkyl" group refers to a saturated
aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4)
carbon atoms. An alkyl group can be straight or branched. Examples
of alkyl groups include, but are not limited to, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be
substituted (i.e., optionally substituted) with one or more
substituents such as halo, cycloaliphatic [e.g., cycloalkyl or
cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or
heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl,
acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or
(heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g.,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino], amino [e.g., aliphaticamino,
cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g.,
aliphaticsulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea,
sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,
heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.
Without limitation, some examples of substituted alkyls include
carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and
alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl,
acylalkyl, hydroxyalkyl, aralkyl, (alkoxyaryl)alkyl,
(sulfonylamino)alkyl (such as (alkylsulfonylamino)alkyl),
aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, cyanoalkyl, or
haloalkyl.
[0039] As used herein, an "alkenyl" group refers to an aliphatic
carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and
at least one double bond. Like an alkyl group, an alkenyl group can
be straight or branched. Examples of an alkenyl group include, but
are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An
alkenyl group can be optionally substituted with one or more
substituents such as halo, cycloaliphatic, heterocycloaliphatic,
aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,
(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl],
nitro, cyano, acyl [e.g., aliphaticcarbonyl,
cycloaliphaticcarbonyl, arylcarbonyl, heterocycloaliphaticcarbonyl
or heteroarylcarbonyl], amido [e.g.,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino alkylaminocarbonyl,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,
aliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g.,
alkylsulfonyl, cycloaliphaticsulfonyl, or arylsulfonyl], sulfinyl,
sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy,
aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy,
alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.
[0040] As used herein, an "alkynyl" group refers to an aliphatic
carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and
has at least one triple bond. An alkynyl group can be straight or
branched. Examples of an alkynyl group include, but are not limited
to, propargyl and butynyl. An alkynyl group can be optionally
substituted with one or more substituents such as aroyl,
heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,
heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy,
sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or
cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or
cycloaliphaticsulfinyl], sulfonyl [e.g., aliphaticsulfonyl,
aliphaticaminosulfonyl, or cycloaliphaticsulfonyl], amido [e.g.,
aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,
heteroarylcarbonylamino or heteroarylaminocarbonyl], urea,
thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy,
cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,
(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino
[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,
(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or
(heteroaryl)alkoxy.
[0041] As used herein, an "amido" encompasses both "aminocarbonyl"
and "carbonylamino". These terms when used alone or in connection
with another group refers to an amido group such as
N(R.sup.X).sub.2--C(O)-- or R.sup.YC(O)--N(R.sup.X)-- when used
terminally and --C(O)--N(R.sup.X)-- or --N(R.sup.X)--C(O)--when
used internally, wherein R.sup.X and R.sup.Y are defined below.
Examples of amido groups include alkylamido (such as
alkylcarbonylamino or alkylcarbonylamino),
(heterocycloaliphatic)amido, (heteroaralkyl)amido,
(heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido,
aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
[0042] As used herein, an "amino" group refers to --NR.sup.XR.sup.Y
wherein each of R.sup.X and R.sup.Y is independently hydrogen,
alkyl, cycloaliphatic, (cycloaliphatic)aliphatic, aryl,
araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic,
heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl,
(aliphatic)carbonyl, (cycloaliphatic)carbonyl,
((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,
(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or
(heteroaraliphatic)carbonyl, each of which being defined herein and
being optionally substituted. Examples of amino groups include
alkylamino, dialkylamino, or arylamino. When the term "amino" is
not a terminal group (e.g., alkylcarbonylamino), it is represented
by --NR.sup.X--. R.sup.X has the same meaning as defined above.
[0043] As used herein, an "aryl" group used alone or as part of a
larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers
to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl,
naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic
(e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl,
anthracenyl) ring systems in which the monocyclic ring system is
aromatic or at least one of the rings in a bicyclic or tricyclic
ring system is aromatic. The bicyclic and tricyclic groups include
benzofused 2-3 membered carbocyclic rings. For example, a
benzofused group includes phenyl fused with two or more C.sub.4-8
carbocyclic moieties. An aryl is optionally substituted with one or
more substituents including aliphatic [e.g., alkyl, alkenyl, or
alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;
heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl;
heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy;
aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy;
aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring
of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido;
acyl [e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl;
((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or
aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl or
cycloaliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; cyano;
halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl;
sulfamide; or carbamoyl. Alternatively, an aryl can be
unsubstituted.
[0044] Non-limiting examples of substituted aryls include haloaryl
[e.g., mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl];
(carboxy)aryl [e.g., (alkoxycarbonyl)aryl,
((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl
[e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl,
(alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and
(((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,
((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];
(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,
(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,
((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl;
(nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl;
((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl;
(cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl;
alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl;
p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or
(m-(heterocycloaliphatic)-o-(alkyl))aryl.
[0045] As used herein, an "araliphatic" such as an "aralkyl" group
refers to an aliphatic group (e.g., a C.sub.1-4 alkyl group) that
is substituted with an aryl group. "Aliphatic," "alkyl," and "aryl"
are defined herein. An example of an araliphatic such as an aralkyl
group is benzyl.
[0046] As used herein, an "aralkyl" group refers to an alkyl group
(e.g., a C.sub.1-4 alkyl group) that is substituted with an aryl
group. Both "alkyl" and "aryl" have been defined above. An example
of an aralkyl group is benzyl. An aralkyl is optionally substituted
with one or more substituents such as aliphatic [e.g., alkyl,
alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or
haloalkyl such as trifluoromethyl], cycloaliphatic [e.g.,
cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or
heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0047] As used herein, a "bicyclic ring system" includes 8-12
(e.g., 9, 10, or 11) membered structures that form two rings,
wherein the two rings have at least one atom in common (e.g., 2
atoms in common). Bicyclic ring systems include bicycloaliphatics
(e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics,
bicyclic aryls, and bicyclic heteroaryls.
[0048] As used herein, a "cycloaliphatic" group encompasses a
"cycloalkyl" group and a "cycloalkenyl" group, each of which being
optionally substituted as set forth below.
[0049] As used herein, a "cycloalkyl" group refers to a saturated
carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10
(e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl,
bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,
bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl,
azacycloalkyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl. A
"cycloalkenyl" group, as used herein, refers to a non-aromatic
carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or
more double bonds. Examples of cycloalkenyl groups include
cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl,
hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl,
bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl. A cycloalkyl or
cycloalkenyl group can be optionally substituted with one or more
substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl],
cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic,
(heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy,
(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,
heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,
(cycloaliphatic)carbonylamino,
((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino,
(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,
((heterocycloaliphatic)aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino],
nitro, carboxy [e.g., HOOC--, alkoxycarbonyl, or alkylcarbonyloxy],
acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)
aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or
(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto,
sulfonyl [e.g., alkylsulfonyl and arylsulfonyl], sulfinyl [e.g.,
alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea,
thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0050] As used herein, "cyclic moiety" includes cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, each of which has been
defined previously.
[0051] As used herein, the term "heterocyclic" encompasses a
heterocycloaliphatic group and a heteroaryl group.
[0052] As used herein, the term "heterocycloaliphatic" encompasses
a heterocycloalkyl group and a heterocycloalkenyl group, each of
which being optionally substituted as set forth below.
[0053] As used herein, a "heterocycloalkyl" group refers to a 3-10
membered mono- or bicylic (fused or bridged) (e.g., 5- to
10-membered mono- or bicyclic) saturated ring structure, in which
one or more of the ring atoms is a heteroatom (e.g., N, O, S, or
combinations thereof). Examples of a heterocycloalkyl group include
piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl,
1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl,
isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl,
octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl,
octahydropyrindinyl, decahydroquinolinyl,
octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,
1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, anad
2,6-dioxa-tricyclo[3.3.1.0.sup.3,7]nonyl. A monocyclic
heterocycloalkyl group can be fused with a phenyl moiety such as
tetrahydroisoquinoline. A "heterocycloalkenyl" group, as used
herein, refers to a mono- or bicylic (e.g., 5- to 10-membered mono-
or bicyclic) non-aromatic ring structure having one or more double
bonds, and wherein one or more of the ring atoms is a heteroatom
(e.g., N, O, or S). Monocyclic and bicycloheteroaliphatics are
numbered according to standard chemical nomenclature.
[0054] A heterocycloalkyl or heterocycloalkenyl group can be
optionally substituted with one or more substituents such as
aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic,
(cycloaliphatic)aliphatic, heterocycloaliphatic,
(heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy,
(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,
heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,
(cycloaliphatic)carbonylamino, ((cycloaliphatic)
aliphatic)carbonylamino, (aryl)carbonylamino,
(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,
((heterocycloaliphatic) aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino],
nitro, carboxy [e.g., HOOC--, alkoxycarbonyl, or alkylcarbonyloxy],
acyl [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)
aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or
(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy,
mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl
[e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy,
urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0055] A "heteroaryl" group, as used herein, refers to a
monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring
atoms wherein one or more of the ring atoms is a heteroatom (e.g.,
N, O, S, or combinations thereof) and in which the monocyclic ring
system is aromatic or at least one of the rings in the bicyclic or
tricyclic ring systems is aromatic. A heteroaryl group includes a
benzofused ring system having 2 to 3 rings. For example, a
benzofused group includes benzo fused with one or two 3-8 membered
heterocycloaliphatic moieties (e.g., indolizyl, indolyl,
isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of
heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,
thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,
isoquinolinyl, benzthiazolyl, xanthene, thioxanthene,
phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl,
puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl,
quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl,
benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.
[0056] Without limitation, monocyclic heteroaryls include furyl,
thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl,
2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl,
pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered
according to standard chemical nomenclature.
[0057] Without limitation, bicyclic heteroaryls include indolizyl,
indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl,
isoindolyl, indolyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl,
benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl,
isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl,
1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered
according to standard chemical nomenclature.
[0058] A heteroaryl is optionally substituted with one or more
substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl];
cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic;
(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;
heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;
heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or
heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy;
amido; acyl [e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl;
((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or
amino sulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl
[e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto;
sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl.
Alternatively, a heteroaryl can be unsubstituted.
[0059] Non-limiting examples of substituted heteroaryls include
(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];
(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl];
cyanoheteroaryl; aminoheteroaryl [e.g.,
((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl];
(amido)heteroaryl [e.g., aminocarbonylheteroaryl,
((alkylcarbonyl)amino)heteroaryl,
((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,
(((heteroaryl)amino)carbonyl)heteroaryl,
((heterocycloaliphatic)carbonyl)heteroaryl, and
((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;
(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,
(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,
(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;
(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;
((carboxy)alkyl)heteroaryl; [((dialkyl)amino)alkyl]heteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;
(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;
((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;
(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl];
(alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g.,
trihaloalkylheteroaryl].
[0060] A "heteroaraliphatic" (such as a heteroaralkyl group) as
used herein, refers to an aliphatic group (e.g., a C.sub.1-4 alkyl
group) that is substituted with a heteroaryl group. "Aliphatic,"
"alkyl," and "heteroaryl" have been defined above.
[0061] A "heteroaralkyl" group, as used herein, refers to an alkyl
group (e.g., a C.sub.1-4 alkyl group) that is substituted with a
heteroaryl group. Both "alkyl" and "heteroaryl" have been defined
above. A heteroaralkyl is optionally substituted with one or more
substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,
and haloalkyl such as trifluoromethyl), alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0062] As used herein, "cyclic moiety" includes cycloalkyl,
heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or
heteroaryl, each of which has been defined previously.
[0063] As used herein, an "acyl" group refers to a formyl group or
R.sup.X--C(O)-- (such as -alkyl-C(O)--, also referred to as
"alkylcarbonyl") where R.sup.X and "alkyl" have been defined
previously. Acetyl and pivaloyl are examples of acyl groups.
[0064] As used herein, an "aroyl" or "heteroaroyl" refers to an
aryl-C(O)-- or a heteroaryl-C(O)--. The aryl and heteroaryl portion
of the aroyl or heteroaroyl is optionally substituted as previously
defined.
[0065] As used herein, an "alkoxy" group refers to an alkyl-O--
group where "alkyl" has been defined previously.
[0066] As used herein, a "carbamoyl" group refers to a group having
the structure --O--CO--NR.sup.XR.sup.Y or
--NR.sup.X--CO--O--R.sup.Z wherein R.sup.X and R.sup.Y have been
defined above and R.sup.Z can be aliphatic, aryl, araliphatic,
heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
[0067] As used herein, a "carboxy" group refers to --COOH,
--COOR.sup.X, --OC(O)H, --OC(O)R.sup.X when used as a terminal
group; or --OC(O)-- or --C(O)O-- when used as an internal
group.
[0068] As used herein, a "haloaliphatic" group refers to an
aliphatic group substituted with 1, 2, or 3 halogen atoms. For
instance, the term haloalkyl includes the group --CF.sub.3.
[0069] As used herein, a "mercapto" group refers to --SH.
[0070] As used herein, a "sulfo" group refers to --SO.sub.3H or
--SO.sub.3R.sup.X when used terminally or --S(O).sub.3-- when used
internally.
[0071] As used herein, a "sulfamide" group refers to the structure
--NR.sup.X--S(O).sub.2--NR.sup.YR.sup.Z when used terminally and
--NR.sup.X--S(O).sub.2--NR.sup.Y-- when used internally, wherein
R.sup.X, R.sup.Y, and R.sup.Z have been defined above.
[0072] As used herein, a "sulfamoyl" group refers to the structure
--S(O).sub.2--NR.sup.XR.sup.Y or --NR.sup.X--S(O).sub.2--R.sup.Z
when used terminally; or --S(O).sub.2--NR.sup.X-- or
--NR.sup.X--S(O).sub.2-- when used internally, wherein R.sup.X,
R.sup.Y, and R.sup.Z are defined above.
[0073] As used herein a "sulfanyl" group refers to --S--R.sup.X
when used terminally and --S-- when used internally, wherein
R.sup.X has been defined above. Examples of sulfanyls include
alkylsulfanyl.
[0074] As used herein a "sulfinyl" group refers to --S(O)--R.sup.X
when used terminally and --S(O)--when used internally, wherein
R.sup.X has been defined above.
[0075] As used herein, a "sulfonyl" group refers to
--S(O).sub.2--R.sup.X when used terminally and --S(O).sub.2-when
used internally, wherein R.sup.X has been defined above.
[0076] As used herein, a "sulfoxy" group refers to --O--SO--R.sup.X
or --SO--O--R.sup.X, when used terminally and --O--S(O)-- or
--S(O)--O-- when used internally, where R.sup.X has been defined
above.
[0077] As used herein, a "halogen" or "halo" group refers to
fluorine, chlorine, bromine or iodine.
[0078] As used herein, an "alkoxycarbonyl," which is encompassed by
the term carboxy, used alone or in connection with another group
refers to a group such as alkyl-O--C(O)--.
[0079] As used herein, an "alkoxyalkyl" refers to an alkyl group
such as alkyl-O-alkyl-, wherein alkyl has been defined above.
[0080] As used herein, a "carbonyl" refer to --C(O)--.
[0081] As used herein, an "oxo" refers to .dbd.O.
[0082] As used herein, an "aminoalkyl" refers to the structure
R.sup.XR.sup.YN-alkyl-.
[0083] As used herein, a "cyanoalkyl" refers to the structure
(NC)-alkyl-.
[0084] As used herein, a "urea" group refers to the structure
--NR.sup.X--CO--NR.sup.YR.sup.Z and a "thiourea" group refers to
the structure --NR.sup.X--CS--NR.sup.YR.sup.Z when used terminally
and --NR.sup.X--CO--NR.sup.Y-- or --NR.sup.X--CS--NR.sup.Y-- when
used internally, wherein R.sup.X, R.sup.Y, and R.sup.Z have been
defined above.
[0085] As used herein, a "guanidino" group refers to the structure
--N.dbd.C(N(R.sup.XR.sup.Y))N(R.sup.XR.sup.Y) wherein R.sup.X and
R.sup.Y have been defined above.
[0086] As used herein, the term "amidino" group refers to the
structure --C.dbd.(NR.sup.X)N(R.sup.XR.sup.Y) wherein R.sup.X and
R.sup.Y have been defined above.
[0087] In general, the term "vicinal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to adjacent carbon atoms.
[0088] In general, the term "geminal" refers to the placement of
substituents on a group that includes two or more carbon atoms,
wherein the substituents are attached to the same carbon atom.
[0089] The terms "terminally" and "internally" refer to the
location of a group within a substituent. A group is terminal when
the group is present at the end of the substituent not further
bonded to the rest of the chemical structure. Carboxyalkyl, i.e.,
R.sup.XO(O)C-alkyl is an example of a carboxy group used
terminally. A group is internal when the group is present in the
middle of a substituent to at the end of the substituent bound to
the rest of the chemical structure. Alkylcarboxy (e.g.,
alkyl-C(O)O-- or alkyl-OC(O)--) and alkylcarboxyaryl (e.g.,
alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy
groups used internally.
[0090] As used herein, "cyclic group" includes mono-, bi-, and
tri-cyclic ring systems including cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, each of which has been
previously defined.
[0091] As used herein, a "bridged bicyclic ring system" refers to a
bicyclic heterocyclicalipahtic ring system or bicyclic
cycloaliphatic ring system in which the rings are bridged. Examples
of bridged bicyclic ring systems include, but are not limited to,
adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,
bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl,
2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl,
3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
A bridged bicyclic ring system can be optionally substituted with
one or more substituents such as alkyl (including carboxyalkyl,
hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl,
alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,
alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0092] As used herein, an "aliphatic chain" refers to a branched or
straight aliphatic group (e.g., alkyl groups, alkenyl groups, or
alkynyl groups). A straight aliphatic chain has the structure
--[CH.sub.2].sub.v--, where v is 1-6. A branched aliphatic chain is
a straight aliphatic chain that is substituted with one or more
aliphatic groups. A branched aliphatic chain has the structure
--[CHQ].sub.v- where Q is hydrogen or an aliphatic group; however,
Q shall be an aliphatic group in at least one instance. The term
aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl
chains, where alkyl, alkenyl, and alkynyl are defined above.
[0093] The phrase "optionally substituted" is used interchangeably
with the phrase "substituted or unsubstituted." As described
herein, compounds of the invention can optionally be substituted
with one or more substituents, such as are illustrated generally
above, or as exemplified by particular classes, subclasses, and
species of the invention. As described herein, the variables
R.sub.1, R.sub.2, R.sub.3, and R.sub.4, and other variables
contained therein formulae I encompass specific groups, such as
alkyl and aryl. Unless otherwise noted, each of the specific groups
for the variables R.sub.1, R.sub.2, R.sub.3, and R.sub.4, and other
variables contained therein can be optionally substituted with one
or more substituents described herein. Each substituent of a
specific group is further optionally substituted with one to three
of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl,
and alkyl. For instance, an alkyl group can be substituted with
alkylsulfanyl and the alkylsulfanyl can be optionally substituted
with one to three of halo, cyano, oxoalkoxy, hydroxy, amino, nitro,
aryl, haloalkyl, and alkyl. As an additional example, the
cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally
substituted with one to three of halo, cyano, alkoxy, hydroxy,
nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to
the same atom or adjacent atoms, the two alkxoy groups can form a
ring together with the atom(s) to which they are bound.
[0094] In general, the term "substituted," whether preceded by the
term "optionally" or not, refers to the replacement of hydrogen
radicals in a given structure with the radical of a specified
substituent. Specific substituents are described above in the
definitions and below in the description of compounds and examples
thereof. Unless otherwise indicated, an optionally substituted
group can have a substituent at each substitutable position of the
group, and when more than one position in any given structure can
be substituted with more than one substituent independently
selected from a specified group, the substituent can be either the
same or different at every position. A ring substituent, such as a
heterocycloalkyl, can be bound to another ring, such as a
cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings
share one common atom. As one of ordinary skill in the art will
recognize, combinations of substituents envisioned by this
invention are those combinations that result in the formation of
stable or chemically feasible compounds.
[0095] The phrase "up to" as used herein, refers to zero or any
integer number that is equal or less than the number following the
phrase. For example, "up to 3" means any one of 0, 1, 2, and 3.
[0096] The phrase "stable or chemically feasible," as used herein,
refers to compounds that are not substantially altered when
subjected to conditions to allow for their production, detection,
and preferably their recovery, purification, and use for one or
more of the purposes disclosed herein. In some embodiments, a
stable compound or chemically feasible compound is one that is not
substantially altered when kept at a temperature of 40.degree. C.
or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0097] As used herein, an effective amount is defined as the amount
required to confer a therapeutic effect on the treated patient, and
is typically determined based on age, surface area, weight, and
condition of the patient. The interrelationship of dosages for
animals and humans (based on milligrams per meter squared of body
surface) is described by Freireich et al., Cancer Chemother. Rep.,
50: 219 (1966). Body surface area may be approximately determined
from height and weight of the patient. See, e.g., Scientific
Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As
used herein, "patient" refers to a mammal, including a human.
[0098] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
[0099] Compounds
[0100] Compounds of the present invention are useful modulators of
ABC transporters and are useful in the treatment of ABC transporter
mediated diseases.
A. Generic Compounds
[0101] The present invention includes a compound of formula I,
##STR00002## [0102] or a pharmaceutically acceptable salt
thereof.
[0103] A method of modulating the number of functional ABC
transporters in a membrane of a cell comprising the step of
contacting said cell with a compound of formula I:
##STR00003## [0104] or a pharmaceutically acceptable salt thereof,
wherein:
[0105] Each R.sub.1 is an optionally substituted C.sub.1-6
aliphatic, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted C.sub.3-10
cycloaliphatic, or an optionally substituted 4 to 10 membered
heterocycloaliphatic, carboxy [e.g., hydroxycarbonyl or
alkoxycarbonyl], alkoxy, amido [e.g., aminocarbonyl], amino, halo,
cyano, alkylsulfanyl, or hydroxy;
[0106] provided that at least one R.sub.1 is an optionally
substituted aryl or an optionally substituted heteroaryl and said
R.sub.1 is attached to the 3- or 4-position of the phenyl ring;
[0107] Each R.sub.2 is hydrogen, an optionally substituted
C.sub.1-6 aliphatic, an optionally substituted C.sub.3-6
cycloaliphatic, an optionally substituted phenyl, or an optionally
substituted heteroaryl;
[0108] Each R.sub.4 is an optionally substituted aryl or an
optionally substituted heteroaryl;
[0109] Each n is 1, 2, 3, 4 or 5; and
[0110] Ring A is an optionally substituted cycloaliphatic or an
optionally substituted heterocycloaliphatic where the atoms of ring
A adjacent to C* are carbon atoms, and each of which is optionally
substituted with 1, 2, or 3 substituents.
B. Specific Embodiments
1. Substituent R.sub.1
[0111] Each R.sub.1 is an optionally substituted C.sub.1-6
aliphatic, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted C.sub.3-10
cycloaliphatic, an optionally substituted 4 to 10 membered
heterocycloaliphatic, carboxy [e.g., hydroxycarbonyl or
alkoxycarbonyl], amido [e.g., aminocarbonyl], amino, halo, alkoxy,
or hydroxy.
[0112] In some embodiments, one R.sub.1 is an optionally
substituted C.sub.1-6 aliphatic. In several examples, one R.sub.1
is an optionally substituted C.sub.1-6 alkyl, an optionally
substituted C.sub.2-6 alkenyl, or an optionally substituted
C.sub.2-6 alkynyl. In several examples, one R.sub.1 is C.sub.1-6
alkyl, C.sub.2-6 alkenyl, or C.sub.2-6 alkynyl.
[0113] In several embodiments, one R.sub.1 is an aryl or heteroaryl
with 1, 2, or 3 substituents. In several examples, one R.sub.1 is a
monocyclic aryl or heteroaryl. In several embodiments, R.sub.1 is
an aryl or heteroaryl with 1, 2, or 3 substituents. In several
examples, R.sub.1 is a monocyclic aryl or heteroaryl.
[0114] In several embodiments, at least one R.sub.1 is an
optionally substituted aryl or an optionally substituted heteroaryl
and R.sub.1 is bonded to the core structure at the 4-position on
the phenyl ring.
[0115] In several embodiments, at least one R.sub.1 is an
optionally substituted aryl or an optionally substituted heteroaryl
and R.sub.1 is bonded to the core structure at the 3-position on
the phenyl ring.
[0116] In several embodiments, one R.sub.1 is phenyl with up to 3
substituents. In several embodiments, R.sub.1 is phenyl with up to
2 substituents.
[0117] In several embodiments, one R.sub.1 is a heteroaryl ring
with up to 3 substituents. In certain embodiments, one R.sub.1 is a
monocyclic heteroaryl ring with up to 3 substituents. In other
embodiments, one R.sub.1 is a bicyclic heteroaryl ring with up to 3
substituents. In several embodiments, R.sub.1 is a heteroaryl ring
with up to 3 substituents.
[0118] In some embodiments, one R.sub.1 is an optionally
substituted C.sub.3-10 cycloaliphatic or an optionally substituted
3-8 membered heterocycloaliphatic. In several examples, one R.sub.1
is a monocyclic cycloaliphatic substituted with up to 3
substituents. In several examples, one R.sub.1 is a monocyclic
heterocycloaliphatic substituted with up to 3 substituents. In one
embodiment, one R.sub.1 is a 4 membered heterocycloaliphatic having
one ring member selected from oxygen, nitrogen (including NH and
NR.sup.X), or sulfur (including S, SO, and SO.sub.2); wherein said
heterocycloaliphatic is substituted with up to 3 substitutents. In
one example, one R.sub.1 is 3-methyloxetan-3-yl.
[0119] In several embodiments, one R.sub.1 is carboxy [e.g.,
hydroxycarbonyl or alkoxycarbonyl]. Or, one R.sub.1 is amido [e.g.,
aminocarbonyl]. Or, one R.sub.1 is amino. Or, is halo. Or, is
cyano. Or, hydroxy.
[0120] In some embodiments, R.sub.1 is hydrogen, methyl, ethyl,
iso-propyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, allyl, F, Cl, methoxy, ethoxy, iso-propoxy,
tert-butoxy, CF.sub.3, OCF.sub.3, SCH.sub.3, SCH.sub.2CH.sub.3, CN,
hydroxy, or amino. In several examples, R.sub.1 is hydrogen,
methyl, ethyl, iso-propyl, tert-butyl, methoxy, ethoxy, SCH.sub.3,
SCH.sub.2CH.sub.3, F, Cl, CF.sub.3, or OCF.sub.3. In several
examples, R.sub.1 can be hydrogen. Or, R.sub.1 can be methyl. Or,
R.sub.1 can be ethyl. Or, R.sub.1 can be iso-propyl. Or, R.sub.1
can be tert-butyl. Or, R.sub.1 can be F. Or, R.sub.1 can be Cl. Or,
R.sub.1 can be OH. Or, R.sub.1 can be OCF.sub.3. Or, R.sub.1 can be
CF.sub.3. Or, R.sub.1 can be methoxy. Or, R.sub.1 can be ethoxy.
Or, R.sub.1 can be SCH.sub.3.
[0121] In several embodiments, R.sub.1 is substituted with no more
than three substituents independently selected from halo, oxo, or
optionally substituted aliphatic, cycloaliphatic,
heterocycloaliphatic, amino [e.g., (aliphatic)amino], amido [e.g.,
aminocarbonyl, ((aliphatic)amino)carbonyl, and
((aliphatic).sub.2-amino)carbonyl], carboxy [e.g., alkoxycarbonyl
and hydroxycarbonyl], sulfamoyl [e.g., aminosulfonyl,
((aliphatic).sub.2-amino)sulfonyl,
((cycloaliphatic)aliphatic)aminosulfonyl, and
((cycloaliphatic)amino)sulfonyl], cyano, alkoxy, aryl, heteroaryl
[e.g., monocyclic heteroaryl and bicycloheteroaryl], sulfonyl
[e.g., aliphaticsulfonyl or (heterocycloaliphatic)sulfonyl],
sulfinyl [e.g., aliphaticsulfinyl], aroyl, heteroaroyl, or
heterocycloaliphaticcarbonyl.
[0122] In several embodiments, R.sub.1 is substituted with halo.
Examples of R.sub.1 substituents include F, Cl, and Br. In several
examples, R.sub.1 is substituted with F.
[0123] In several embodiments, R.sub.1 is substituted with an
optionally substituted aliphatic. Examples of R.sub.1 substituents
include optionally substituted alkoxyaliphatic,
heterocycloaliphatic, aminoalkyl, hydroxyalkyl,
(heterocycloalkyl)aliphatic, alkylsulfonylaliphatic,
alkylsulfonylaminoaliphatic, alkylcarbonylaminoaliphatic,
alkylaminoaliphatic, or alkylcarbonylaliphatic.
[0124] In several embodiments, R.sub.1 is substituted with an
optionally substituted amino. Examples of R.sub.1 substituents
include aliphaticcarbonylamino, aliphaticamino, arylamino, or
aliphaticsulfonylamino.
[0125] In several embodiments, R.sub.1 is substituted with a
sulfonyl. Examples of R.sub.1 include heterocycloaliphatic
sulfonyl, aliphatic sulfonyl, aliphaticaminosulfonyl,
aminosulfonyl, aliphaticcarbonylaminosulfonyl,
alkoxyalkylheterocycloalkylsulfonyl, alkylheterocycloalkylsulfonyl,
alkylaminosulfonyl, cycloalkylaminosulfonyl,
(heterocycloalkyl)alkylaminosulfonyl, and
heterocycloalkylsulfonyl.
[0126] In several embodiments, R.sub.1 is substituted with carboxy.
Examples of R.sub.1 substituents include alkoxycarbonyl and
hydroxycarbonyl.
[0127] In several embodiments R.sub.1 is substituted with amido.
Examples of R.sub.1 substituents include alkylaminocarbonyl,
aminocarbonyl, ((aliphatic).sub.2-amino)carbonyl, and
[((aliphatic)aminoaliphatic)amino]carbonyl.
[0128] In several embodiments, R.sub.1 is substituted with
carbonyl. Examples of R.sub.1 substituents include arylcarbonyl,
cycloaliphaticcarbonyl, heterocycloaliphaticcarbonyl, and
heteroarylcarbonyl.
[0129] In several embodiments, each R.sub.1 is a hydroxycarbonyl,
hydroxy, or halo.
[0130] In some embodiments, R.sub.1 is hydrogen. In some
embodiments, R.sub.1 is --Z.sup.ER.sub.9, wherein each Z.sup.E is
independently a bond or an optionally substituted branched or
straight C.sub.1-6 aliphatic chain wherein up to two carbon units
of Z.sup.E are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.E--, --CONR.sup.ENR.sup.E--, --CO.sub.2--,
--OCO--, --NR.sup.ECO.sub.2--, --O--, --NR.sup.ECONR.sup.E--,
--OCONR.sup.E--, --NR.sup.ENR.sup.E--, --NR.sup.ECO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.E--, --SO.sub.2NR.sup.E--,
--NR.sup.ESO.sub.2--, or --NR.sup.ESO.sub.2NR.sup.E--. Each R.sub.9
is hydrogen, R.sup.E, halo, --OH, --NH.sub.2, --NO.sub.2, --CN,
--CF.sub.3, or --OCF.sub.3. Each R.sup.E is independently a
C.sub.1-8 aliphatic group, a cycloaliphatic, a
heterocycloaliphatic, an aryl, or a heteroaryl, each of which is
optionally substituted with 1, 2, or 3 of R.sup.A. Each R.sup.A is
--Z.sup.AR.sub.5, wherein each Z.sup.A is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.A are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.B--,
--CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--. Each R.sub.5
is independently R.sup.B, halo, --B(OH).sub.2, --OH, --NH.sub.2,
--NO.sub.2, --CN, --CF.sub.3, or --OCF.sub.3. Each R.sup.B is
independently hydrogen, an optionally substituted C.sub.1-8
aliphatic group, an optionally substituted cycloaliphatic, an
optionally substituted heterocycloaliphatic, an optionally
substituted aryl, or an optionally substituted heteroaryl.
[0131] In several embodiments, R.sub.1 is --Z.sup.ER.sub.9, wherein
each Z.sup.E is independently a bond or an optionally substituted
branched or straight C.sub.1-6 aliphatic chain wherein up to two
carbon units of Z.sup.E are optionally and independently replaced
by --CO--, --CONR.sup.E--, --CO.sub.2--, --O--, --S--, --SO--,
--SO.sub.2--, --NR.sup.E--, or --SO.sub.2NR.sup.E--. Each R.sub.9
is hydrogen, R.sup.E, halo, --OH, --NH.sub.2, --CN, --CF.sub.3, or
--OCF.sub.3. Each R.sup.E is independently an optionally
substituted group selected from C.sub.1-8 aliphatic group,
cycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl. In one
embodiment, Z.sup.E is a bond. In one embodiment, Z.sup.E is a
straight C.sub.1-6 aliphatic chain, wherein one carbon unit of
Z.sub.E is optionally replaced by --CO--, --CONR.sup.E--,
--CO.sub.2--, --O--, or --NR.sup.E--. In one embodiment, Z.sup.E is
a C.sub.1-6 alkyl chain. In one embodiment, Z.sup.E is
--CH.sub.2--. In one embodiment, Z.sup.E is --CO--. In one
embodiment, Z.sup.E is --CO.sub.2--. In one embodiment, Z.sup.E is
--CONR.sup.E--.
[0132] In some embodiments, R.sub.9 is H, --NH.sub.2, hydroxy,
--CN, or an optionally substituted group selected from C.sub.1-8
aliphatic, C.sub.3-8 cycloaliphatic, 3-8 membered
heterocycloaliphatic, C.sub.6-10 aryl, and 5-10 membered
heteroaryl. In one embodiment, R.sub.9 is H. In one embodiment,
R.sub.9 is hydroxy. Or, R.sub.9 is --NH.sub.2. Or, R.sub.9 is --CN.
In some embodiments, R.sub.9 is an optionally substituted 3-8
membered heterocycloaliphatic, having 1, 2, or 3 ring members
independently selected from nitrogen (including NH and NR.sup.X),
oxygen, and sulfur (including S, SO, and SO.sub.2). In one
embodiment, R.sub.9 is an optionally substituted five membered
heterocycloaliphatic with one nitrogen (including NH and NR.sup.X)
ring member. In one embodiment, R.sub.9 is an optionally
substituted pyrrolidin-1-yl. Examples of said optionally
substituted pyrrolidin-1-yl include pyrrolidin-1-yl and
3-hydroxy-pyrrolidin-1-yl. In one embodiment, R.sub.9 is an
optionally substituted six membered heterocycloaliphatic with two
heteroatoms independently selected from nitrogen (including NH and
NR.sup.X) and oxygen. In one embodiment, R.sub.9 is morpholin-4-yl.
In some embodiments, R.sub.9 is an optionally substituted 5-10
membered heteroaryl. In one embodiment, R.sub.9 is an optionally
substituted 5 membered heteroaryl, having 1, 2, 3, or 4 ring
members independently selected from nitrogen (including NH and
NR.sup.X), oxygen, and sulfur (including S, SO, and SO.sub.2). In
one embodiment, R.sub.9 is 1H-tetrazol-5-yl.
[0133] In one embodiment, one R.sub.1 is Z.sup.ER.sub.9; wherein
Z.sup.E is CH.sub.2 and R.sub.9 is 1H-tetrazol-5-yl. In one
embodiment, one R.sub.1 is Z.sup.ER.sub.9; wherein Z.sup.E is
CH.sub.2 and R.sub.9 is morpholin-4-yl. In one embodiment, one
R.sub.1 is Z.sup.ER.sub.9; wherein Z.sup.E is CH.sub.2 and R.sub.9
is pyrrolidin-1-yl. In one embodiment, one R.sub.1 is
Z.sup.ER.sub.9; wherein Z.sup.E is CH.sub.2 and R.sub.9 is
3-hydroxy-pyrrolidin-1-yl. In one embodiment, one R.sub.1 is
Z.sup.ER.sub.9; wherein Z.sup.E is CO and R.sub.9 is
3-hydroxy-pyrrolidin-1-yl.
[0134] In some embodiments, R.sub.1 is selected from CH.sub.2OH,
COOH, CH.sub.2OCH.sub.3, COOCH.sub.3, CH.sub.2NH.sub.2,
CH.sub.2NHCH.sub.3, CH.sub.2CN, CONHCH.sub.3, CH.sub.2CONH.sub.2,
CH.sub.2OCH.sub.2CH.sub.3, CH.sub.2N(CH.sub.3).sub.2,
CON(CH.sub.3).sub.2, CH.sub.2NHCH.sub.2CH.sub.2OH,
CH.sub.2NHCH.sub.2CH.sub.2COOH, CH.sub.2OCH(CH.sub.3).sub.2,
CONHCH(CH.sub.3)CH.sub.2OH, or CONHCH(tert-butyl)CH.sub.2OH.
[0135] In several embodiments, R.sub.1 is halo, or R.sub.1 is
C.sub.1-6 aliphatic, aryl, heteroaryl, alkoxy, cycloaliphatic,
heterocycloaliphatic, each of which is optionally substituted with
1, 2, or 3 of R.sup.A; or R.sub.1 is halo; wherein each R.sup.A is
--Z.sup.AR.sub.5, each Z.sup.A is independently a bond or an
optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.A are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.B--,
--CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--; each R.sub.5
is independently R.sup.B, halo, --B(OH).sub.2, --OH, --NH.sub.2,
--NO.sub.2, --CN, --CF.sub.3, or --OCF.sub.3; and each R.sup.B is
hydrogen, optionally substituted C.sub.1-4 aliphatic, optionally
substituted C.sub.3-6 cycloaliphatic, optionally substituted
heterocycloaliphatic, optionally substituted phenyl, or optionally
substituted heteroaryl.
[0136] In some embodiments, Z.sup.A is independently a bond or an
optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.A are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.B--,
--CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--. In one
embodiment, Z.sup.A is a bond. In some embodiments, Z.sup.A is an
optionally substituted straight or branched C.sub.1-6 aliphatic
chain wherein up to two carbonunites of Z.sup.A are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.B--,
--CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--. In one
embodiment, Z.sup.A is an optionally substituted straight or
branched C.sub.1-6 alkyl chain wherein up to two carbon units of
Z.sup.A is optionally replaced by --O--, --NHC(O)--,
--C(O)NR.sup.B--, --SO.sub.2--, --NHSO.sub.2--, --NHC(O)--, --SO--,
--NR.sup.BSO.sub.2--, --SO.sub.2NH--, --SO.sub.2NR.sup.B--, --NH--,
or --C(O)O--. In one embodiment, Z.sup.A is an optionally
substituted straight or branched C.sub.1-6 alkyl chain wherein one
carbon unit of Z.sup.A is optionally replaced by --O--, --NHC(O)--,
--C(O)NR.sup.B--, --SO.sub.2--, --NHSO.sub.2--, --NHC(O)--, --SO--,
--NR.sup.BSO.sub.2--, --SO.sub.2NH--, --SO.sub.2NR.sup.B--, --NH--,
or --C(O)O--. In one embodiment, Z.sup.A is an optionally
substituted straight or branched C.sub.1-6 alkyl chain wherein one
carbon unit of Z.sup.A is optionally replaced by --CO--,
--CONR.sup.B--, --CO.sub.2--, --O--, --NR.sup.BCO--, --SO.sub.2--,
--NR.sup.B--, --SO.sub.2NR.sup.B--, or --NR.sup.BSO.sub.2--. In one
embodiment, Z.sup.A is an optionally substituted straight or
branched C.sub.1-6 alkyl chain wherein one carbon unit of Z.sup.A
is optionally replaced by --SO.sub.2--, --CONR.sup.B--, or
--SO.sub.2NR.sup.B--. In one embodiment, Z.sup.A is --CH.sub.2-- or
--CH.sub.2CH.sub.2--. In one embodiment, Z.sup.A is an optionally
substituted straight or branched C.sub.1-6 alkyl chain wherein one
carbon unit of Z.sup.A is optionally replaced by --CO--,
--CONR.sup.B--, --CO.sub.2--, --O--, --NHCO--, --SO--,
--SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--, or
--NR.sup.BSO.sub.2--. In some embodiments, Z.sup.A is --CO.sub.2--,
--CH.sub.2CO.sub.2--, --CH.sub.2CH.sub.2CO.sub.2--,
--CH(NH.sub.2)CH.sub.2CO.sub.2--, or
--CH(CH.sub.3)CH.sub.2CO.sub.2--. In some embodiments, Z.sup.A is
--CONH--, --NHCO--, or --CON(CH.sub.3)--. In some embodiments,
Z.sup.A is --O--. Or, Z.sup.A is --SO--, --SO.sub.2--,
--SO.sub.2NH--, or --SO.sub.2N(CH.sub.3). In one embodiment,
Z.sup.A is an optionally substituted branched or straight C.sub.1-6
aliphatic chain wherein one carbon unit of Z.sup.A is optionally
replaced by --SO.sub.2--.
[0137] In some embodiments, R.sub.5 is H, F, Cl, --B(OH).sub.2,
--OH, --NH.sub.2, --CF.sub.3, --OCF.sub.3, or --CN. In one
embodiment, R.sub.5 is H. Or, R.sub.5 is F. Or, R.sub.5 is Cl. Or,
R.sub.5 is --B(OH).sub.2. Or, R.sub.5 is --OH. Or, R.sub.5 is
--NH.sub.2. Or, R.sub.5 is --CF.sub.3. Or, R.sub.5 is --OCF.sub.3.
Or, R.sub.5 is --CN.
[0138] In some embodiments, R.sub.5 is an optionally substituted
C.sub.1-4 aliphatic. In one embodiment, R.sub.5 is an optionally
substituted C.sub.1-4 alkyl. In one embodiment, R.sub.5 is methyl,
ethyl, iso-propyl, or tert-butyl. In one embodiment, R.sub.5 is an
optionally substituted aryl. In one embodiment, R.sub.5 is an
optionally substituted phenyl. In some embodiments, R.sub.5 is an
optionally substituted heteroaryl or an optionally substituted
heterocycloaliphatic. In some embodiments, R.sub.5 is an optionally
substituted heteroaryl. In one embodiment, R.sub.5 is an optionally
substituted monocylic heteroaryl, having 1, 2, 3, or 4 ring members
optionally and independently replaced with nitrogen (including NH
and NR.sup.X), oxygen or sulfur (including S, SO, and SO.sub.2). In
one embodiment, R.sub.5 is an optionally substituted 5 membered
heteroaryl. In one embodiment, R.sub.5 is 1H-tetrazol-5-yl. In one
embodiment, R.sub.5 is an optionally substituted bicylic
heteroaryl. In one embodiment, R.sub.5 is a
1,3-dioxoisoindolin-2-yl. In some embodiments, R.sub.5 is an
optionally substituted heterocycloaliphatic having 1 or 2 nitrogen
(including NH and NR.sup.X) atoms and R.sub.5 attaches directly to
--SO.sub.2-- via one ring nitrogen.
[0139] In some embodiments, two occurrences of R.sup.A, taken
together with carbon atoms to which they are attached, form an
optionally substituted 3-8 membered saturated, partially
unsaturated, or aromatic ring, having up to 4 ring members
optionally and independently replaced with nitrogen (including NH
and NR.sup.X), oxygen, or sulfur (including S, SO, and SO.sub.2).
In some embodiments, two occurrences of R.sup.A, taken together
with carbon atoms to which they are attached, form C.sub.4-8
cycloaliphatic ring optionally substituted with 1, 2, or 3
substituents independently selected from oxo, .dbd.NR.sup.B,
.dbd.N--N(R.sup.B).sub.2, halo, CN, CO.sub.2, CF.sub.3, OCF.sub.3,
OH, SR.sup.B, S(O)R.sup.B, SO.sub.2R.sup.B, NH.sub.2, NHR.sup.B,
N(R.sup.B).sub.2, COOH, COOR.sup.B, OR.sup.B, or R.sup.B. In one
embodiment, said cycloaliphatic ring is substituted with oxo. In
one embodiment, said cycloaliphatic ring is
##STR00004##
[0140] In some embodiments, two occurrences of R.sup.A, taken
together with carbon atoms to which they are attached, form an
optionally substituted 5-8 membered heterocycloaliphatic ring,
having up to 4 ring members optionally and independently replaced
with nitrogen (including NH and NR.sup.X), oxygen, or sulfur
(including S, SO, and SO.sub.2). In some embodiments, two
occurrences of R.sup.A, taken together with carbon atoms to which
they are attached, form a 5 or 6 membered heterocycloaliphatic
ring, optionally substituted with 1, 2, or 3 substituents
independently selected from oxo, .dbd.NR.sup.B,
.dbd.N--N(R.sup.B).sub.2, halo, CN, CO.sub.2, CF.sub.3, OCF.sub.3,
OH, SR.sup.B, S(O)R.sup.B, SO.sub.2R.sup.B, NH.sub.2, NHR.sup.B,
N(R.sup.B).sub.2, COOH, COOR.sup.B, OR.sup.B, or R.sup.B. In some
embodiments, said heterocycloaliphatic ring is selected from:
##STR00005##
[0141] In some embodiments, two occurrences of R.sup.A, taken
together with carbon atoms to which they are attached, form an
optionally substituted C.sub.6-10 aryl. In some embodiments, two
occurrences of R.sup.A, taken together with carbon atoms to which
they are attached, form a 6 membered aryl, optionally substituted
with 1, 2, or 3 substituents independently selected from halo, CN,
CO.sub.2, CF.sub.3, OCF.sub.3, OH, SR.sup.B, S(O)R.sup.B,
SO.sub.2R.sup.B, NH.sub.2, NHR.sup.B, N(R.sup.B).sub.2, COOH,
COOR.sup.B, OR.sup.B, or R.sup.B. In some embodiments, said aryl
is
##STR00006##
[0142] In some embodiments, two occurrences of R.sup.A, taken
together with carbon atoms to which they are attached, form an
optionally substituted 5-8 membered heteroaryl, having up to 4 ring
members optionally and independently replaced with nitrogen
(including NH and NR.sup.X), oxygen, or sulfur (including S, SO,
and SO.sub.2). In some embodiments, two occurrences of R.sup.A,
taken together with carbon atoms to which they are attached, form a
5 or 6 membered heteroaryl, optionally substituted with 1, 2, or 3
substituents independently selected from halo, CN, CO.sub.2,
CF.sub.3, OCF.sub.3, OH, SR.sup.B, S(O)R.sup.B, SO.sub.2R.sup.B,
NH.sub.2, NHR.sup.B, N(R.sup.B).sub.2, COOH, COOR.sup.B, OR.sup.B,
or R.sup.B. In some embodiments, said heteroaryl is selected
from:
##STR00007##
[0143] In some embodiments, one R.sub.1 is aryl or heteroaryl, each
optionally substituted with 1, 2, or 3 of R.sup.A, wherein R.sup.A
is defined above.
[0144] In several embodiments, one R.sub.1 is carboxy [e.g.,
hydroxycarbonyl or alkoxycarbonyl], amido [e.g., aminocarbonyl],
amino, halo, cyano, or hydroxy.
[0145] In several embodiments, R.sub.1 is:
##STR00008## [0146] wherein [0147] W.sub.1 is --C(O)--,
--SO.sub.2--, --NHC(O)--, or --CH.sub.2--; [0148] D is H, hydroxy,
or an optionally substituted group selected from aliphatic,
cycloaliphatic, alkoxy, and amino; and [0149] R.sup.A is defined
above.
[0150] In several embodiments, W.sub.1 is --C(O)--. Or, W.sub.1 is
--SO.sub.2--. Or, W.sub.1 is --NHC(O)--. Or, W.sub.1 is
--CH.sub.2--.
[0151] In several embodiments, D is OH. Or, D is an optionally
substituted C.sub.1-6 aliphatic or an optionally substituted
C.sub.3-C.sub.8 cycloaliphatic. Or, D is an optionally substituted
alkoxy. Or, D is an optionally substituted amino.
[0152] In several examples, D is
##STR00009## [0153] wherein each of A and B is independently H, an
optionally substituted C.sub.1-6 aliphatic, an optionally
substituted C.sub.3-C.sub.8 cycloaliphatic, an optionally
substituted 3-8 membered heterocycloaliphatic, acyl, sulfonyl,
alkoxy or [0154] A and B, taken together, form an optionally
substituted 3-7 membered heterocycloaliphatic ring.
[0155] In some embodiments, A is H. In some embodiments, A is an
optionally substituted C.sub.1-6 aliphatic. In several examples, A
is an optionally substituted C.sub.1-6 alkyl. In one example, A is
methyl. Or, A is ethyl. Or, A is n-propyl. Or, A is iso-propyl. Or,
A is 2-hydroxyethyl. Or, A is 2-methoxyethyl.
[0156] In several embodiments, B is C.sub.1-6 straight or branched
alkyl, optionally substituted with 1, 2, or 3 substituents each
independently selected from halo, oxo, CN, hydroxy, or an
optionally substituted group selected from alkyl, alkenyl,
hydroxyalkyl, alkoxy, alkoxyalkyl, cycloaliphatic, amino,
heterocycloaliphatic, aryl, and heteroaryl. In several embodiments,
B is substituted with 1, 2, or 3 substituents each independently
selected from halo, oxo, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
hydroxy, hydroxy-(C.sub.1-6)alkyl, (C.sub.1-6)alkoxy,
(C.sub.1-6)alkoxy(C.sub.1-6)alkyl, NH.sub.2, NH(C.sub.1-6 alkyl),
N(C.sub.1-6 alkyl).sub.2, C.sub.3-8 cycloaliphatic, NH(C.sub.3-8
cycloaliphatic), N(C.sub.1-6 alkyl)(C.sub.3-8 cycloaliphatic),
N(C.sub.3-8 cycloaliphatic).sub.2, 3-8 membered
heterocycloaliphatic, phenyl, and 5-10 membered heteroaryl. In one
example, said substituent is oxo. Or, said substituent is
optionally substituted (C.sub.1-6) alkoxy. Or, is hydroxy. Or, is
NH.sub.2. Or, is NHCH.sub.3. Or, is NH(cyclopropyl). Or, is
NH(cyclobutyl). Or, is N(CH.sub.3).sub.2. Or, is CN. In one
example, said substituent is optionally substituted phenyl. In some
embodiments, B is substituted with 1, 2, or 3 substituents each
independently selected from an optionally substituted C.sub.3-8
cycloaliphatic or 3-8 membered heterocycloaliphatic. In one
example, said substituent is an optionally substituted group
selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclohexenyl, morpholin-4-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, 1,3-dioxolan-2-yl, and tetrahydrofuran-2-yl. In
some embodiments, B is substituted with 1, 2, or 3 substituents
each independently selected from an optionally substituted 5-8
membered heteroaryl. In one example, said substituent is an
optionally substituted group selected from pyridyl, pyrazyl,
1H-imidazol-1-yl, and 1H-imidazol-5-yl.
[0157] In some embodiments, B is C.sub.3-C.sub.8 cycloaliphatic
optionally substituted with 1, 2, or 3 substituents independently
selected from halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl, dialkyamino, or an optionally substituted group
selected from cycloaliphatic, heterocycloaliphatic, aryl, and
heteroaryl. In several examples, B is an optionally substituted
C.sub.3-C.sub.8 cycloalkyl. In one embodiment, B is cyclopropyl.
Or, B is cyclobutyl. Or, B is cyclopentyl. Or, B is cyclohexyl. Or,
B is cycloheptyl.
[0158] In some embodiments, B is 3-8 membered heterocycloaliphatic
optionally substituted with 1, 2, or 3 substituents independently
selected from oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy,
alkoxyalkyl, dialkyamino, or an optionally substituted group
selected from cycloaliphatic, heterocycloaliphatic, aryl, and
heteroaryl. In one example, B is 3-oxo-isoxazolid-4-yl.
[0159] In several embodiments, A is H and B is an optionally
substituted C.sub.1-6 aliphatic. In several embodiments, B is
substituted with 1, 2, or 3 substituents. Or, both, A and B, are H.
Exemplary substituents on B include halo, oxo, alkyl, hydroxy,
hydroxyalkyl, alkoxy, alkoxyalkyl, dialkyamino, or an optionally
substituted group selected from cycloaliphatic,
heterocycloaliphatic, aryl, and heteroaryl.
[0160] In several embodiments, A is H and B is an optionally
substituted C.sub.1-6 aliphatic. Exemplary substituents include
oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, and an
optionally substituted heterocycloaliphatic.
[0161] In several embodiments, A and B, taken together, form an
optionally substituted 3-7 membered heterocycloaliphatic ring. In
several examples, the heterocycloaliphatic ring is optionally
substituted with 1, 2, or 3 substituents. Exemplary such rings
include pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,
oxazolidin-3-yl, and 1,4-diazepan-1-yl. Exemplary said substituents
on such rings include halo, oxo, alkyl, aryl, heteroaryl, hydroxy,
hydroxyalkyl, alkoxy, alkoxyalkyl, acyl (e.g., alkylcarbonyl),
amino, amido, and carboxy. In some embodiments, each of said
substituents is independently halo, oxo, alkyl, aryl, heteroaryl,
hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or
carboxy. In one embodiment, the substituent is oxo, F, Cl, methyl,
ethyl, iso-propyl, 2-methoxyethyl, hydroxymethyl, methoxymethyl,
aminocarbonyl, --COOH, hydroxy, acetyl, or pyridyl.
[0162] In several embodiments, R.sub.1 is:
##STR00010##
wherein: [0163] W.sub.1 is --C(O)--, --SO.sub.2--, --NHC(O)--, or
--CH.sub.2--; [0164] Each of A and B is independently H, an
optionally substituted C.sub.1-6 aliphatic, an optionally
substituted C.sub.3-C.sub.8 cycloaliphatic; or [0165] A and B,
taken together, form an optionally substituted 4-7 membered
heterocycloaliphatic ring.
[0166] In several examples, R.sub.1 is selected from any one of the
exemplary compounds in Table 1.
2. Substituent R.sub.2
[0167] Each R.sub.2 is hydrogen, or optionally substituted
C.sub.1-6 aliphatic, C.sub.3-6 cycloaliphatic, phenyl, or
heteroaryl.
[0168] In several embodiments, R.sub.2 is a C.sub.1-6 aliphatic
that is optionally substituted with 1, 2, or 3 halo, C.sub.1-2
aliphatic, or alkoxy. In several examples, R.sub.2 is substituted
or unsubstituted methyl, ethyl, propyl, or butyl.
[0169] In several embodiments, R.sub.2 is hydrogen.
3. Ring A
[0170] Ring A is an optionally substituted cycloaliphatic or an
optionally substituted heterocycloaliphatic where the atoms of ring
A adjacent to C* are carbon atoms. In several embodiments, ring A
is C.sub.3-7 cycloaliphatic or 3-8 membered heterocycloaliphatic,
each of which is optionally substituted with 1, 2, or 3
substituents.
[0171] In several embodiments, ring A is optionally substituted
with 1, 2, or 3 of --Z.sup.BR.sub.7, wherein each Z.sup.B is
independently a bond, or an optionally substituted branched or
straight C.sub.1-4 aliphatic chain wherein up to two carbon units
of Z.sup.B are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--,
--OCO--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--; each R.sub.7
is independently R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN,
or --OCF.sub.3; and each R.sup.B is independently hydrogen, an
optionally substituted C.sub.1-8 aliphatic group, an optionally
substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0172] In several embodiments, ring A is a C.sub.3-7 cycloaliphatic
or a 3-8 membered heterocycloaliphatic, each of which is optionally
substituted with 1, 2, or 3 substituents.
[0173] In several embodiments, ring A is a 3, 4, 5, or 6 membered
cycloaliphatic that is optionally substituted with 1, 2, or 3
substituents. In several examples, ring A is an optionally
substituted cyclopropyl group. In several alternative examples,
ring A is an optionally substituted cyclobutyl group. In several
other examples, ring A is an optionally substituted cyclopentyl
group. In other examples, ring A is an optionally substituted
cyclohexyl group. In more examples, ring A is an unsubstituted
cyclopropyl.
[0174] In several embodiments, ring A is a 5, 6, or 7 membered
optionally substitute heterocycloaliphatic. For example, ring A is
an optionally substituted tetrahydropyranyl group.
4. Substituent R.sub.4
[0175] Each R.sub.4 is independently an optionally substituted aryl
or heteroaryl.
[0176] In several embodiments, R.sub.4 is an aryl having 6 to 10
members (e.g., 7 to 10 members) optionally substituted with 1, 2,
or 3 substituents. Examples of R.sub.4 are optionally substituted
benzene, naphthalene, or indene. Or, examples of R.sub.4 can be
optionally substituted phenyl, optionally substituted naphthyl, or
optionally substituted indenyl.
[0177] In several embodiments, R.sub.4 is an optionally substituted
heteroaryl. Examples of R.sub.4 include monocyclic and bicyclic
heteroaryl, such a benzofused ring system in which the phenyl is
fused with one or two C.sub.4-8 heterocycloaliphatic groups.
[0178] In some embodiments, R.sub.4 is an aryl or heteroaryl, each
optionally substituted with 1, 2, or 3 of --Z.sup.CR.sub.8. Each
Z.sup.C is independently a bond or an optionally substituted
branched or straight C.sub.1-6 aliphatic chain wherein up to two
carbon units of Z.sup.C are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--,
--CO.sub.2--, --OCO--, --NR.sup.CCO.sub.2--, --O--,
--NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--,
--NR.sup.CCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.C--,
--SO.sub.2NR.sup.C--, --NR.sup.CSO.sub.2--, or
--NR.sup.CSO.sub.2NR.sup.C--. Each R.sub.8 is independently
R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3.
Each R.sup.C is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl. In one embodiment, R.sub.4 is an aryl optionally
substituted with 1, 2, or 3 of Z.sup.CR.sub.8. In one embodiment,
R.sub.4 is an optionally substituted phenyl.
[0179] In several embodiments, R.sub.4 is a heteroaryl optionally
substituted with 1, 2, or 3 substituents. Examples of R.sub.4
include optionally substituted benzo[d][1,3]dioxole or
2,2-difluoro-benzo[d][1,3]dioxole.
[0180] In some embodiments, two occurrences of --Z.sup.CR.sub.8,
taken together with carbons to which they are attached, form a 4-8
membered saturated, partially saturated, or aromatic ring with up
to 3 ring atoms independently selected from the group consisting of
O, NH, NR.sup.C, and S (including S, SO, and SO.sub.2); wherein
R.sup.C is defined herein.
[0181] In several embodiments, R.sub.4 is one selected from
##STR00011## ##STR00012##
C. Sub-Generic Compounds
[0182] Another aspect of the present invention includes compounds
of formula Ia:
##STR00013## [0183] or a pharmaceutically acceptable salt thereof,
wherein R.sub.2, R.sub.4, and n have been defined in formula I.
[0184] Each R.sub.1 is independently aryl, monocyclic heteroaryl or
indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl,
benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzthiazolyl,
purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, imidazo[1,2-a]pyridinyl, or benzo[d]oxazolyl, each of
which is optionally substituted with 1, 2, or 3 of R.sup.A; or
R.sub.1 is independently methyl, trifluoromethyl, or halo. In one
embodiment, R.sub.1 is an optionally substituted
imidazo[1,2-a]pyridine-2-yl. In one embodiment, R.sub.1 is an
optionally substituted oxazolo[4,5-b]pyridine-2-yl. In one
embodiment, R.sub.1 is an optionally substituted
1H-pyrrolo[2,3-b]pyrid-6-yl. In one embodiment, R.sub.1 is an
optionally substituted benzo[d]oxazol-2-yl. In one embodiment,
R.sub.1 is an optionally substituted benzo[d]thiazol-2-yl.
[0185] In some embodiments, R.sub.1 is a monocyclic aryl or a
monocyclic heteroaryl, each is optionally substituted with 1, 2, or
3 of R.sup.A. In some embodiments, R.sub.1 is substituted or
unsubstituted phenyl. In one embodiment, R.sub.1 is substituted or
unsubstituted pyrid-2-yl. In some embodiments, R.sub.1 is
pyrid-3-yl, pyrid-4-yl, thiophen-2-yl, thiophen-3-yl,
1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-imidazol-5-yl, 1H-pyrazol-4-yl,
1H-pyrazol-3-yl, thiazol-4-yl, furan-3-yl, furan-2-yl, or
pyrimidin-5-yl, each of which is optionally substituted. In some
embodiments, R.sub.1 is phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl,
1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, thiazol-4-yl,
furan-3-yl, furan-2-yl, or pyrimidin-5-yl, each of which is
optionally substituted with 1, 2, or 3 substituents independently
selected from CN, or a group chosen from C.sub.1-6 alkyl, carboxy,
alkoxy, halo, amido, acetoamino, and aryl, each of which is further
optionally substituted.
[0186] Each R.sup.A is --Z.sup.AR.sub.5, wherein each Z.sup.A is
independently a bond or an optionally substituted branched or
straight C.sub.1-6 aliphatic chain wherein up to two carbon units
of Z.sup.A are optionally and independently replaced by --CS--,
--CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--,
--NR.sup.BCO.sub.2--, --NR.sup.BCONR.sup.B--, --NR.sup.BNR.sup.B--,
--NR.sup.BCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.B--,
--SO.sub.2NR.sup.B--, --NR.sup.BSO.sub.2--, or
--NR.sup.BSO.sub.2NR.sup.B--.
[0187] Each R.sub.5 is independently R.sup.B, halo, --OH,
--NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3.
[0188] Each R.sup.B is hydrogen, an optionally substituted
C.sub.1-4 aliphatic, an optionally substituted C.sub.3-6
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted phenyl, or an optionally substituted
heteroaryl.
[0189] Ring A is an optionally substituted cycloaliphatic, an
optionally substituted 5 membered heterocycloaliphatic having 1, 2,
or 3 heteroatoms independently selected from nitrogen (including NH
and NR.sup.X), oxygen, or sulfur (including S, SO, and SO.sub.2);
an optionally substituted 6 membered heterocycloaliphatic having 1
heteroatom selected from O and S (including S, SO, and SO.sub.2); a
piperidinyl optionally substituted with halo, aliphatic,
aminocarbonyl, aminocarbonylaliphatic, aliphatic carbonyl,
aliphaticsulfonyl, aryl, or combinations thereof; or an optionally
substituted 7-8 membered heterocycloaliphatic having 1, 2, or 3
heteroatoms independently selected from nitrogen (including NH and
NR.sup.X), oxygen, or sulfur (including S, SO, and SO.sub.2).
[0190] In some embodiments, one R.sub.1 attached to the 3- or
4-position of the phenyl ring is an aryl or heteroaryl optionally
substituted with 1, 2, or 3 of R.sup.A, wherein R.sup.A is
--Z.sup.AR.sub.5; in which each Z.sup.A is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.A are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.B--,
--CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--; each R.sub.5
is independently R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN,
or --OCF.sub.3; and each R.sup.B is independently hydrogen, an
optionally substituted C.sub.1-8 aliphatic group, an optionally
substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0191] In some embodiments, one R.sub.1 attached to the 3- or
4-position of the phenyl ring is a phenyl optionally substituted
with 1, 2, or 3 of R.sup.A.
[0192] In some embodiments, one R.sub.1 attached to the 3- or
4-position of the phenyl ring is a phenyl substituted with one of
R.sup.A, wherein R.sup.A is --Z.sup.AR.sub.5; each Z.sup.A is
independently a bond or an optionally substituted branched or
straight C.sub.1-6 aliphatic chain wherein up to two carbon units
of Z.sup.A are optionally and independently replaced by --O--,
--NHC(O)--, --C(O)NR.sup.B--, --SO.sub.2--, --NHSO.sub.2--,
--NHC(O)--, --SO--, --NR.sup.BSO.sub.2--, --SO.sub.2NH--,
--SO.sub.2NR.sup.B--, --NH--, or --C(O)O--. In one embodiment, one
carbon unit of Z.sup.A is replaced by --O--, --NHC(O)--,
--C(O)NR.sup.B--, --SO.sub.2--, --NHSO.sub.2--, --NHC(O)--, --SO--,
--NR.sup.BSO.sub.2--, --SO.sub.2NH--, --SO.sub.2NR.sup.B--, --NH--,
or --C(O)O--. In some embodiments, R.sub.5 is independently an
optionally substituted aliphatic, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, an optionally substituted heteroaryl,
hydrogen, or halo.
[0193] In some embodiments, one R.sub.1 attached to the 3- or
4-position of the phenyl ring is heteroaryl optionally substituted
with 1, 2, or 3 of R.sup.A. In several examples, one R.sub.1
attached to the 3- or 4-position of the phenyl ring is a 5 or 6
membered heteroaryl having 1, 2, or 3 heteroatoms independently
selected from nitrogen (including NH and NR.sup.X), oxygen or
sulfur (including S, SO, and SO.sub.2), wherein the heteroaryl is
substituted with one of R.sup.A, wherein R.sup.A is
--Z.sup.AR.sub.5; wherein each Z.sup.A is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.A are optionally and
independently replaced by --O--, --NHC(O)--, --C(O)NR.sup.B--,
--SO.sub.2--, --NHSO.sub.2--, --NHC(O)--, --SO--,
--NR.sup.BSO.sub.2--, --SO.sub.2NH--, --SO.sub.2NR.sup.B--, --NH--,
or --C(O)O--. In one embodiment, one carbon unit of Z.sup.A is
replaced by --O--, --NHC(O)--, --C(O)NR.sup.B--, --SO.sub.2--,
--NHSO.sub.2--, --NHC(O)--, --SO--, --NR.sup.BSO.sub.2--,
--SO.sub.2NH--, --SO.sub.2NR.sup.B--, --NH--, or --C(O)O--. In one
embodiment, R.sub.5 is independently an optionally substituted
aliphatic, an optionally substituted cycloaliphatic, an optionally
substituted heterocycloaliphatic, an optionally substituted aryl,
an optionally substituted heteroaryl, hydrogen, or halo.
[0194] Another aspect of the present invention includes compounds
of formula Ib:
##STR00014## [0195] or a pharmaceutically acceptable salt thereof,
wherein R.sub.2, R.sub.4 and ring A are defined in formula I.
[0196] The R.sub.1 attached at the para position relative to the
amide is an aryl or a heteroaryl optionally substituted with 1, 2,
or 3 of R.sup.A; wherein each R.sup.A is --Z.sup.AR.sub.5, each
Z.sup.A is independently a bond or an optionally substituted
branched or straight C.sub.1-6 aliphatic chain wherein up to two
carbon units of Z.sup.A are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--,
--CO.sub.2--, --OCO--, --NR.sup.BCO.sub.2--, --O--,
--NR.sup.BCONR.sup.B--, --OCONR.sup.B--, --NR.sup.BNR.sup.B--,
--NR.sup.BCO--, S--, --SO--, --SO.sub.2--, --NR.sup.B--,
--SO.sub.2NR.sup.B--, --NR.sup.BSO.sub.2--, or
--NR.sup.BSO.sub.2NR.sup.B--; each R.sub.5 is independently
R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3;
each R.sup.B is hydrogen, an optionally substituted C.sub.1-4
aliphatic, an optionally substituted C.sub.3-6 cycloaliphatic, an
optionally substituted heterocycloaliphatic, an optionally
substituted phenyl, or optionally substituted heteroaryl.
[0197] The other R.sub.1 are each independently hydrogen, halo,
optionally substituted C.sub.1-4 aliphatic, or optionally
substituted C.sub.1-4 alkoxy.
[0198] In several embodiments, the R.sub.1 attached at the para
position relative to the amide is a phenyl optionally substituted
with 1, 2, or 3 of R.sup.A and the other R.sub.1's are each
hydrogen. For example, the R.sub.1 attached at the para position
relative to the amide is phenyl optionally substituted with
aliphatic, alkoxy, (amino)aliphatic, hydroxyaliphatic,
aminosulfonyl, aminocarbonyl, alcoxycarbonyl,
(aliphatic)aminocarbonyl, COOH, (aliphatic)aminosulfonyl, or
combinations thereof, each of which is optionally substituted. In
other embodiments, the R.sub.1 attached at the para position
relative to the amide is phenyl optionally substituted with halo.
In several examples, the R.sub.1 attached at the para position
relative to the amide is phenyl optionally substituted with alkyl,
alkoxy, (amino)alkyl, hydroxyalkyl, aminosulfonyl,
(alkyl)aminocarbonyl, (alkyl)aminosulfonyl, or combinations
thereof, each of which is optionally substituted; or the R.sub.1
attached at the para position relative to the amide is phenyl
optionally substituted with halo.
[0199] In several embodiments, the R.sub.1 attached at the para
position relative to the amide is an optionally substituted
heteroaryl. In other embodiments, the R.sub.1 attached at the para
position relative to the amide is an optionally substituted
monocyclic or optionally substituted bicyclic heteroaryl. For
example, the R.sub.1 attached at the para position relative to the
amide is a benzo[d]oxazolyl, thiazolyl, benzo[d]thiazolyl, indolyl,
or imidazo[1,2-a]pyridinyl, each of which is optionally
substituted. In other examples, the R.sub.1 attached at the para
position relative to the amide is a benzo[d]oxazolyl, thiazolyl,
benzo[d]thiazolyl, or imidazo[1,2-a]pyridinyl, each of which is
optionally substituted with 1, 2, or 3 of halo, hydroxy, aliphatic,
alkoxy, or combinations thereof, each of which is optionally
substituted.
[0200] In several embodiments, each R.sub.1 not attached at the
para position relative to the amide is hydrogen. In some examples,
each R.sub.1 not attached at the para position relative to the
amide is methyl, ethyl, propyl, isopropyl, or tert-butyl, each of
which is optionally substituted with 1, 2, or 3 of halo, hydroxy,
cyano, or nitro. In other examples, each R.sub.1 not attached at
the para position relative to the amide is halo or optionally
substituted methoxy, ethoxy, or propoxy. In several embodiments,
each R.sub.1 not attached at the para position relative to the
amide is hydrogen, halo, --CH.sub.3, --OCH.sub.3, or
--CF.sub.3.
[0201] In several embodiments, compounds of formula Ib include
compounds of formulae Ib1, Ib2, Ib3, or Ib4:
##STR00015## [0202] where R.sup.A, R.sub.1, R.sub.2, R.sub.4, and
ring A are defined above.
[0203] In formula Ib4, ring B is monocyclic or bicyclic heteroaryl
that is substituted with 1, 2, or 3R.sup.A; and "n-1" is equal to
0, 1, or 2.
[0204] In several embodiments, the R.sub.1 attached at the para
position relative to the amide in formula Ib is an optionally
substituted aryl. In several embodiments, the R.sub.1 attached at
the para position relative to the amide is a phenyl optionally
substituted with 1, 2, or 3 of R.sup.A. For example, the R.sub.1
attached at the para position relative to the amide is phenyl
optionally substituted with 1, 2, or 3 aliphatic, alkoxy, COOH,
(amino)aliphatic, hydroxyaliphatic, aminosulfonyl,
(aliphatic)aminocarbonyl, (aliphatic)aminosulfonyl,
(((aliphatic)sulfonyl)amino)aliphatic,
(heterocycloaliphatic)sulfonyl, heteroaryl, aliphaticsulfanyl, or
combinations thereof, each of which is optionally substituted; or
R.sub.1 is optionally substituted with 1-3 of halo.
[0205] In several embodiments, the R.sub.1 attached at the para
position relative to the amide in formula Ib is an optionally
substituted heteroaryl. In other embodiments R.sub.1 is an
optionally substituted monocyclic or an optionally substituted
bicyclic heteroaryl. For example, R.sub.1 is a pyridinyl,
thiazolyl, benzo[d]oxazolyl, or oxazolo[4,5-b]pyridinyl, each of
which is optionally substituted with 1, 2, or 3 of halo, aliphatic,
alkoxy, or combinations thereof.
[0206] In several embodiments, one R.sub.1 not attached at the para
position relative to the amide is halo, optionally substituted
C.sub.1-4 aliphatic, C.sub.1-4 alkoxyC.sub.1-4 aliphatic, or
optionally substituted C.sub.1-4 alkoxy, such as For example, one
R.sub.1 not attached at the para position relative to the amide is
halo, --CH.sub.3, ethyl, propyl, isopropyl, tert-butyl, or
--OCF.sub.3.
[0207] In several embodiments, compounds of the invention include
compounds of formulae Ic1, Ic2, Ic3, Ic4, Ic5, Ic6, Ic7, or
Ic8:
##STR00016## ##STR00017## [0208] or pharmaceutically acceptable
salts, wherein R.sup.A, R.sub.2, R.sub.1, R.sub.4, and ring A are
defined above.
[0209] In formula Ic8, ring B is monocyclic or bicyclic heteroaryl
that is substituted with 1, 2, or 3R.sup.A; and "n-1" is equal to
0, 1, or 2.
[0210] Another aspect of the present invention provides compounds
of formula Id:
##STR00018##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, R.sub.4, and n are defined in formula I.
[0211] Ring A is an optionally substituted cycloaliphatic.
[0212] In several embodiments, ring A is a cyclopropyl,
cyclopentyl, or cyclohexyl, each of which is optionally
substituted.
[0213] Another aspect of the present invention provides compounds
of formula Ie:
##STR00019##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, and n are defined in formula I.
[0214] R.sub.4 is an optionally substituted phenyl or an optionally
substituted benzo[d][1,3]dioxolyl. In several embodiments, R.sub.4
is optionally substituted with 1, 2, or 3 of hydrogen, halo,
optionally substituted aliphatic, optionally substituted alkoxy, or
combinations thereof. In several embodiments, R.sub.4 is phenyl
that is substituted at position 2, 3, 4, or combinations thereof
with hydrogen, halo, optionally substituted aliphatic, optionally
substituted alkoxy, or combinations thereof. For example, R.sub.4
is phenyl that is optionally substituted at the 3 position with
optionally substituted alkoxy. In another example, R.sub.4 is
phenyl that is optionally substituted at the 3 position with
--OCH.sub.3. In another example, R.sub.4 is phenyl that is
optionally substituted at the 4 position with halo or substituted
alkoxy. A more specific example includes an R.sub.4 that is phenyl
optionally substituted with chloro, fluoro, --OCH.sub.3, or
--OCF.sub.3. In other examples, R.sub.4 is a phenyl that is
substituted at the 2 position with an optionally substituted
alkoxy. In more specific examples, R.sub.4 is a phenyl optionally
substituted at the 2 position with --OCH.sub.3. In other examples,
R.sub.4 is an unsubstituted phenyl.
[0215] In several embodiments, R.sub.4 is optionally substituted
benzo[d][1,3]dioxolyl. In several examples, R.sub.4 is
benzo[d][1,3]dioxolyl that is optionally mono-, di-, or
tri-substituted with 1, 2, or 3 halo. In more specific examples,
R.sub.4 is benzo[d][1,3]dioxolyl that is optionally di-substituted
with halo.
[0216] Another aspect of the present invention provides compounds
of formula If:
##STR00020##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, R.sub.4, and n are defined in formula I.
[0217] Another aspect of the present invention provides compounds
of formula Ig:
##STR00021##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, R.sub.4, and n are defined in formula I.
[0218] Another aspect of the present invention provides compounds
of formula Ih:
##STR00022##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, R.sub.4, and n are defined in formula I.
[0219] Ring A is an optionally substituted
heterocycloaliphatic.
[0220] In several embodiments, compounds of formula Ih include
compounds of formulae Ih1:
##STR00023##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, R.sub.4, and n are defined in formula I.
[0221] Another aspect of the present invention provides compounds
of formula II:
##STR00024## [0222] or a pharmaceutically acceptable salt thereof,
wherein [0223] R.sub.1, R.sub.2, ring A, and R.sub.4 are defined in
formula I; [0224] n is 1, 2, 3, or 4; and
[0225] Each R.sup.A is independently --Z.sup.AR.sub.5, wherein each
Z.sup.A is independently a bond or an optionally substituted
branched or straight C.sub.1-6 aliphatic chain wherein up to two
carbon units of Z.sup.A are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--,
--CO.sub.2--, --OCO--, --NR.sup.BCO.sub.2--, --O--,
--NR.sup.BCONR.sup.B--, --OCONR.sup.B--, --NR.sup.BNR.sup.B--,
--NR.sup.BCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.B--,
--SO.sub.2NR.sup.B--, --NR.sup.BSO.sub.2--, or
--NR.sup.BSO.sub.2NR.sup.B--. Each R.sub.5 is independently
R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3.
Each R.sup.B is independently hydrogen, an optionally substituted
C.sub.1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl.
[0226] In some embodiments, each R.sub.1 is an optionally
substituted C.sub.1-6 aliphatic, an optionally substituted aryl, an
optionally substituted heteroaryl, an optionally substituted 3 to
10 membered cycloaliphatic, or an optionally substituted 3 to 10
membered heterocycloaliphatic, each of which is optionally
substituted with 1, 2, or 3 of R.sup.A; wherein each R.sup.A is
--Z.sup.AR.sub.5, wherein each Z.sup.A is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.A are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.B--,
--CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--; and R.sub.5
is independently R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN,
or --OCF.sub.3; wherein each R.sup.B is independently hydrogen, an
optionally substituted C.sub.1-8 aliphatic group, an optionally
substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0227] In some embodiments, R.sub.2 is C.sub.1-4 aliphatic,
C.sub.3-6 cycloaliphatic, phenyl, or heteroaryl, each of which is
optionally substituted, or R.sub.2 is hydrogen.
[0228] In some embodiments, ring A is an optionally substituted
C.sub.3-7 cycloaliphatic or an optionally substituted C.sub.3-7
heterocycloaliphatic where the atoms of ring A adjacent to C* are
carbon atoms, and said ring A is optionally substituted with 1, 2,
or 3 of --Z.sup.BR.sub.7, wherein each Z.sup.B is independently a
bond, or an optionally substituted branched or straight C.sub.1-4
aliphatic chain wherein up to two carbon units of Z.sup.B are
optionally and independently replaced by --CO--, --CS--,
--CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--,
--NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--; Each R.sub.7
is independently R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN,
or --OCF.sub.3.
[0229] In some embodiments, each R.sub.4 is an aryl or heteroaryl,
each of which is optionally substituted with 1, 2, or 3 of
--Z.sup.CR.sub.8, wherein each Z.sup.C is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.C are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.C--,
--CONR.sup.CNR.sup.C--, --CO.sub.2--, --OCO--,
--NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--,
--OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.C--, --SO.sub.2NR.sup.C--,
--NR.sup.CSO.sub.2--, or --NR.sup.CSO.sub.2NR.sup.C--; wherein each
R.sub.8 is independently R.sup.C, halo, --OH, --NH.sub.2,
--NO.sub.2, --CN, or --OCF.sub.3; wherein each R.sup.C is
independently an optionally substituted C.sub.1-8 aliphatic group,
an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl.
[0230] Another aspect of the present invention provides compounds
of formula IIa:
##STR00025##
or pharmaceutically acceptable salts thereof, wherein R.sub.2, ring
A and R.sub.4 are defined in formula I, and R.sup.A is defined
above.
[0231] Another aspect of the present invention provides compounds
of formula IIb:
##STR00026##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1,
R.sub.2, R.sub.4, and n are defined in formula I and R.sup.A is
defined in formula II.
[0232] Another aspect of the present invention provides compounds
of formula IIc:
##STR00027##
or a pharmaceutically acceptable salt thereof, wherein:
[0233] T is an optionally substituted C.sub.1-2 aliphatic chain,
wherein each of the carbon units is optionally and independently
replaced by --CO--, --CS--, --COCO--, --SO.sub.2--, --B(OH)--, or
--B(O(C.sub.1-6 alkyl))-;
[0234] Each of R.sub.1 is independently an optionally substituted
C.sub.1-6 aliphatic, an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted 3 to 10 membered
cycloaliphatic, an optionally substituted 3 to 10 membered
heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy;
[0235] Each R.sup.A is independently --Z.sup.AR.sub.5, wherein each
Z.sup.A is independently a bond or an optionally substituted
branched or straight C.sub.1-6 aliphatic chain wherein up to two
carbon units of Z.sup.A are optionally and independently replaced
by --CO--, --CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--,
--CO.sub.2--, --OCO--, --NR.sup.BCO.sub.2--, --O--,
--NR.sup.BCONR.sup.B--, --OCONR.sup.B--, --NR.sup.BNR.sup.B--,
--NR.sup.BCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.B--,
--SO.sub.2NR.sup.B--, --NR.sup.BSO.sub.2--, or
--NR.sup.BSO.sub.2NR.sup.B--;
[0236] Each R.sub.5 is independently R.sup.B, halo, --OH,
--NH.sub.2, --NO.sub.2, --CN, --CF.sub.3, or --OCF.sub.3; [0237] or
two R.sup.A, taken together with atoms to which they are attached,
form a 3-8 membered saturated, partially unsaturated, or aromatic
ring with up to 3 ring members independently selected from the
group consisting of O, NH, NR.sup.B, and S, provided that one
R.sup.A is attached to carbon 3'' or 4''; [0238] Each R.sup.B is
independently hydrogen, an optionally substituted C.sub.1-8
aliphatic group, an optionally substituted cycloaliphatic, an
optionally substituted heterocycloaliphatic, an optionally
substituted aryl, or an optionally substituted heteroaryl; and
[0239] n is 2 or 3 provided that when n is 3, a first R.sub.1 is
attached ortho relative to the phenyl ring substituted with R.sup.A
and that a second one R.sub.1 is attached para relative to the
phenyl ring substituted with R.sup.A.
[0240] In some embodiments, T is an optionally substituted
--CH.sub.2--. In some other embodiments, T is an optionally
substituted --CH2CH.sub.2--.
[0241] In some embodiments, T is optionally substituted by
--Z.sup.FR.sub.10; wherein each Z.sup.F is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.F are optionally and
independently replaced by --CO--, --CS--, --CONR.sup.F--,
--CONR.sup.FNR.sup.F--, --CO.sub.2--, --OCO--,
--NR.sup.FCO.sub.2--, --O--, --NR.sup.FCONR.sup.F--,
--OCONR.sup.F--, --NR.sup.FNR.sup.F--, --NR.sup.FCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.F--, --SO.sub.2NR.sup.F--,
--NR.sup.FSO.sub.2--, or --NR.sup.FSO.sub.2NR.sup.F--; R.sub.10 is
independently R.sup.F, halo, --OH, --NH.sub.2, --NO.sub.2, --CN,
--CF.sub.3, or --OCF.sub.3; each R.sup.F is independently hydrogen,
an optionally substituted C.sub.1-8 aliphatic group, an optionally
substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an
optionally substituted heteroaryl. In one example, Z.sup.F is
--O--.
[0242] In some embodiments, R.sub.10 is an optionally substituted
C.sub.1-6 alkyl, an optionally substituted C.sub.2-6 alkenyl, an
optionally substituted C.sub.3-7 cycloaliphatic, or an optionally
substituted C.sub.6-10 aryl. In one embodiment, R.sub.10 is methyl,
ethyl, iso-propyl, or tert-butyl.
[0243] In some embodiments, up to two carbon units of T are
independently and optionally replaced with --CO--, --CS--,
--B(OH)--, or --B(O(C.sub.1-6 alkyl)-.
[0244] In some embodiments, T is selected from the group consisting
of --CH.sub.2--, --CH.sub.2CH.sub.2--, --CF.sub.2--,
--C(CH.sub.3).sub.2--, --C(O)--,
##STR00028##
--C(Phenyl).sub.2-, --B(OH)--, and --CH(OEt)-. In some embodiments,
T is --CH.sub.2--, --CF.sub.2--, --C(CH.sub.3).sub.2--,
##STR00029##
or --C(Phenyl).sub.2-. In other embodiments, T is
--CH.sub.2H.sub.2--, --C(O)--, --B(OH)--, and --CH(OEt)-. In
several embodiments, T is --CH.sub.2--, --CF.sub.2--,
--C(CH.sub.3).sub.2--,
##STR00030##
More preferably, T is --CH.sub.2--, --CF.sub.2--, or
--C(CH.sub.3).sub.2--. In several embodiments, T is --CH.sub.2--.
Or, T is --CF.sub.2--. Or, T is --C(CH.sub.3).sub.2--. Or, T is
##STR00031##
[0245] In some embodiments, each R.sub.1 is hydrogen. In some
embodiments, each of R.sub.1 is independently --Z.sup.ER.sub.9,
wherein each Z.sup.E is independently a bond or an optionally
substituted branched or straight C.sub.1-6 aliphatic chain wherein
up to two carbon units of Z.sup.E are optionally and independently
replaced by --CO--, --CS--, --CONR.sup.E--, --CONR.sup.ENR.sup.E--,
--CO.sub.2--, --OCO--, --NR.sup.ECO.sub.2--, --O--,
--NR.sup.ECONR.sup.E--, --OCONR.sup.E--, --NR.sup.ENR.sup.E--,
--NR.sup.ECO--, --S--, --SO--, --SO.sub.2--, --NR.sup.E--,
--SO.sub.2NR.sup.E--, --NR.sup.ESO.sub.2--, or
--NR.sup.ESO.sub.2NR.sup.E--. Each R.sub.9 is independently H,
R.sup.E, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, --CF.sub.3, or
--OCF.sub.3. Each R.sup.E is independently an optionally
substituted group selected from C.sub.1-8 aliphatic group,
cycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl.
[0246] In several embodiments, a first R.sub.1 is attached ortho
relative to the phenyl ring substituted with R.sup.A is H, F, Cl,
CF.sub.3, OCH.sub.3, --OCF.sub.3, methyl, ethyl, iso-propyl, or
tert-butyl.
[0247] In several embodiments, a first R.sub.1 is attached ortho
relative to the phenyl ring substituted with R.sup.A is
--Z.sup.ER.sub.9, wherein each Z.sup.E is independently a bond or
an optionally substituted branched or straight C.sub.1-6 aliphatic
chain wherein up to two carbon units of Z.sup.E are optionally and
independently replaced by --CO--, --CONR.sup.E--, --CO.sub.2--,
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.E--, or
--SO.sub.2NR.sup.E--. Each R.sub.9 is hydrogen, R.sup.E, halo,
--OH, --NH.sub.2, --CN, --CF.sub.3, or --OCF.sub.3. Each R.sup.E is
independently an optionally substituted group selected from the
group including C.sub.1-8 aliphatic group, a cycloaliphatic, a
heterocycloaliphatic, an aryl, and a heteroaryl. In one embodiment,
Z.sup.E is a bond. In one embodiment, Z.sup.E is a straight
C.sub.1-6 aliphatic chain, wherein one carbon unit of Z.sub.E is
optionally replaced by --CO--, --CONR.sup.E--, --CO.sub.2--, --O--,
or --NR.sup.E--. In one embodiment, Z.sup.E is a C.sub.1-6 alkyl
chain. In one embodiment, Z.sup.E is --CH.sub.2--. In one
embodiment, Z.sup.E is --CO--. In one embodiment, Z.sup.E is
--CO.sub.2--. In one embodiment, Z.sup.E is --CONR.sup.E--. In one
embodiment, Z.sup.E is --CO--.
[0248] In some embodiments, R.sub.9 is H, --NH.sub.2, hydroxy,
--CN, or an optionally substituted group selected from the group of
C.sub.1-8 aliphatic, C.sub.3-8 cycloaliphatic, 3-8 membered
heterocycloaliphatic, C.sub.6-10 aryl, and 5-10 membered
heteroaryl. In one embodiment, R.sub.9 is H. In one embodiment,
R.sub.9 is hydroxy. Or, R.sub.9 is --NH.sub.2. Or, R.sub.9 is --CN.
In some embodiments, R.sub.9 is an optionally substituted 3-8
membered heterocycloaliphatic, having 1, 2, or 3 ring members
independently selected from nitrogen (including NH and NR.sup.X),
oxygen, and sulfur (including S, SO, and SO.sub.2). In one
embodiment, R.sub.9 is an optionally substituted five membered
heterocycloaliphatic with one nitrogen (including NH and NR.sup.X)
ring member. In one embodiment, R.sub.9 is an optionally
substituted pyrrolidin-1-yl. Examples of said optionally
substituted pyrrolidin-1-yl include pyrrolidin-1-yl and
3-hydroxy-pyrrolidin-1-yl. In one embodiment, R.sub.9 is an
optionally substituted six membered heterocycloaliphatic with two
heteroatoms independently selected from nitrogen (including NH and
NR.sup.X) and oxygen. In one embodiment, R.sub.9 is morpholin-4-yl.
In some embodiments, R.sub.9 is an optionally substituted 5-10
membered heteroaryl. In one embodiment, R.sub.9 is an optionally
substituted 5 membered heteroaryl, having 1, 2, 3, or 4 ring
members independently selected from nitrogen (including NH and
NR.sup.X), oxygen, and sulfur (including S, SO, and SO.sub.2). In
one embodiment, R.sub.9 is 1H-tetrazol-5-yl.
[0249] In one embodiment, a first R.sub.1 is attached ortho
relative to the phenyl ring substituted with R.sup.A is
Z.sup.ER.sub.9; wherein Z.sup.E is CH.sub.2 and R.sub.9 is
1H-tetrazol-5-yl. In one embodiment, one R.sub.1' is
Z.sup.ER.sub.9; wherein Z.sup.E is CH.sub.2 and R.sub.9 is
morpholin-4-yl. In one embodiment, one R.sub.1' is Z.sup.ER.sub.9;
wherein Z.sup.E is CH.sub.2 and R.sub.9 is pyrrolidin-1-yl. In one
embodiment, one R.sub.1' is Z.sup.ER.sub.9; wherein Z.sup.E is
CH.sub.2 and R.sub.9 is 3-hydroxy-pyrrolidin-1-yl. In one
embodiment, one R.sub.1' is Z.sup.ER.sub.9; wherein Z.sup.E is CO
and R.sub.9 is 3-hydroxy-pyrrolidin-1-yl.
[0250] In some embodiments, a first R.sub.1 is attached ortho
relative to the phenyl ring substituted with R.sup.A is selected
from CH.sub.2OH, COOH, CH.sub.2OCH.sub.3, COOCH.sub.3,
CH.sub.2NH.sub.2, CH.sub.2NHCH.sub.3, CH.sub.2CN, CONHCH.sub.3,
CH.sub.2CONH.sub.2, CH.sub.2OCH.sub.2CH.sub.3,
CH.sub.2N(CH.sub.3).sub.2, CON(CH.sub.3).sub.2,
CH.sub.2NHCH.sub.2CH.sub.2OH, CH.sub.2NHCH.sub.2CH.sub.2COOH,
CH.sub.2OCH(CH.sub.3).sub.2, CONHCH(CH.sub.3)CH.sub.2OH, or
CONHCH(tert-butyl)CH.sub.2OH.
[0251] In some embodiments, a first R.sub.1 is attached ortho
relative to the phenyl ring substituted with R.sup.A is an
optionally substituted C.sub.3-10 cycloaliphatic or an optionally
substituted 4-10 membered heterocycloaliphatic. In one embodiment,
R.sub.1' is an optionally substituted 4, 5, or 6 membered
heterocycloalkyl containing one oxygen atom. In one embodiment,
R.sub.1' is 3-methyloxetan-3-yl.
[0252] In some embodiments, a second one R.sub.1 is attached para
relative to the phenyl ring substituted with R.sup.A is selected
from the group consisting of H, halo, optionally substituted
C.sub.1-6 aliphatic, and optionally substituted --O(C.sub.1-6
aliphatic). In some embodiments, a second one R.sub.1 is attached
para relative to the phenyl ring substituted with R.sup.A is
selected from the group consisting of H, methyl, ethyl, iso-propyl,
tert-butyl, F, Cl, CF.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--O-(iso-propyl), --O-(tert-butyl), and --OCF.sub.3. In one
embodiment, a second one R.sub.1 is attached para relative to the
phenyl ring substituted with R.sup.A is H. In one embodiment, a
second one R.sub.1 is attached para relative to the phenyl ring
substituted with R.sup.A is methyl. In one embodiment, a second one
R.sub.1 is attached para relative to the phenyl ring substituted
with R.sup.A is F. In one embodiment, a second one R.sub.1 is
attached para relative to the phenyl ring substituted with R.sup.A
is --OCF.sub.3. In one embodiment, a second one R.sub.1 is attached
para relative to the phenyl ring substituted with R.sup.A is
--OCH.sub.3.
[0253] In some embodiments, one R.sup.A is attached to carbon 3''
or 4'' and is --Z.sup.AR.sub.5, wherein each Z.sup.A is
independently a bond or an optionally substituted branched or
straight C.sub.1-6 aliphatic chain wherein up to two carbon units
of Z.sup.A are optionally and independently replaced by --CO--,
--CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--,
--OCO--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--,
--OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--,
--SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--,
--NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--. In yet some
embodiments, Z.sup.A is independently a bond or an optionally
substituted branched or straight C.sub.1-6 aliphatic chain wherein
one carbon unit of Z.sup.A is optionally replaced by --CO--,
--SO--, --SO.sub.2--, --COO--, --OCO--, --CONR.sup.B--,
--NR.sup.BCO--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BSO.sub.2--,
or --SO.sub.2NR.sup.B--. In some embodiments, one carbon unit of
Z.sup.A is optionally replaced by --CO--. Or, by --SO--. Or, by
--SO.sub.2--. Or, by --COO--. Or, by --OCO--. Or, by
--CONR.sup.B--. Or, by --NR.sup.BCO--. Or, by --NR.sup.BCO.sub.2--.
Or, by --O--. Or, by --NR.sup.BSO.sub.2--. Or, by
--SO.sub.2NR.sup.B--.
[0254] In several embodiments, R.sub.5 is hydrogen, halo, --OH,
--NH.sub.2, --CN, --CF.sub.3, --OCF.sub.3, or an optionally
substituted group selected from the group consisting of C.sub.1-6
aliphatic, C.sub.3-8 cycloaliphatic, 3-8 membered
heterocycloaliphatic, C.sub.6-10 aryl, and 5-10 membered
heteroaryl. In several examples, R.sub.5 is hydrogen, F, Cl, --OH,
--CN, --CF.sub.3, or --OCF.sub.3. In some embodiments, R.sub.5 is
C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic, 3-8 membered
heterocycloaliphatic, C.sub.6-10 aryl, and 5-10 membered
heteroaryl, each of which is optionally substituted with 1 or 2
substituents independently selected from the group consisting of
R.sup.B, oxo, halo, --OH, --NR.sup.BR.sup.B, --OR.sup.B,
--COOR.sup.B, and --CONR.sup.BR.sup.B. In several examples, R.sub.5
is optionally substituted by 1 or 2 substituents independently
selected from the group consisting of oxo, F, Cl, methyl, ethyl,
iso-propyl, tert-butyl, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--C(O)OH, --C(O)NH.sub.2, --CH.sub.2O(C.sub.1-6 alkyl),
--CH.sub.2CH.sub.2O(C.sub.1-6 alkyl), and --C(O)(C.sub.1-6
alkyl).
[0255] In one embodiment, R.sub.5 is hydrogen. In some embodiments,
R.sub.5 is selected from the group consisting of straight or
branched C.sub.1-6 alkyl or straight or branched C.sub.2-6 alkenyl;
wherein said alkyl or alkenyl is optionally substituted with 1 or 2
substituents independently selected from the group consisting of
R.sup.B, oxo, halo, --OH, --NR.sup.BR.sup.B, --OR.sup.B,
--COOR.sup.B, and --CONR.sup.BR.sup.B.
[0256] In other embodiments, R.sub.5 is C.sub.3-8 cycloaliphatic
optionally substituted with 1 or 2 substituents independently
selected from the group consisting of R.sup.B, oxo, halo, --OH,
--NR.sup.BR.sup.B, --OR.sup.B, --COOR.sup.B, and
--CONR.sup.BR.sup.B. Examples of cycloaliphatic include but are not
limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0257] In yet other embodiments, R.sub.5 is a 3-8 membered
heterocyclic with 1 or 2 heteroatoms independently selected from
the group consisting of nitrogen (including NH and NR.sup.X),
oxygen, and sulfur (including S, SO, and SO.sub.2); wherein said
heterocyclic is optionally substituted with 1 or 2 substituents
independently selected from the group R.sup.B, oxo, halo, --OH,
--NR.sup.BR.sup.B, --OR.sup.B, --COOR.sup.B, and
--CONR.sup.BR.sup.B. Examples of 3-8 membered heterocyclic include
but are not limited to
##STR00032##
[0258] In yet some other embodiments, R.sub.5 is an optionally
substituted 5-8 membered heteroaryl with one or two ring atom
independently selected from the group consisting of nitrogen
(including NH and NR.sup.X), oxygen, and sulfur (including S, SO,
and SO.sub.2). Examples of 5-8 membered heteroaryl include but are
not limited to
##STR00033##
[0259] In some embodiments, two R.sup.As, taken together with
carbons to which they are attached, form an optionally substituted
4-8 membered saturated, partially unsaturated, or aromatic ring
with 0-2 ring atoms independently selected from the group
consisting of nitrogen (including NH and NR.sup.X), oxygen, and
sulfur (including S, SO, and SO.sub.2). Examples of two R.sup.As,
taken together with phenyl containing carbon atoms to which they
are attached, include but are not limited to
##STR00034##
[0260] In some embodiments, one R.sup.A not attached top the carbon
3'' or 4'' is selected from the group consisting of H, R.sup.B,
halo, --OH, --(CH.sub.2).sub.rNR.sup.BR.sup.B,
--(CH.sub.2).sub.r--OR.sup.B, --SO.sub.2--R.sup.B,
--NR.sup.B--SO.sub.2--R.sup.B, --SO.sub.2NR.sup.BR.sup.B,
--C(O)R.sup.B, --C(O)OR.sup.B, --OC(O)OR.sup.B,
--NR.sup.BC(O)OR.sup.B, and --C(O)NR.sup.BR.sup.B; wherein r is 0,
1, or 2; and each R.sup.B is independently hydrogen, an optionally
substituted C.sub.1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl. In other embodiments, one R.sup.A not attached top the
carbon 3'' or 4'' is selected from the group consisting of H,
C.sub.1-6 aliphatic, halo, --CN, --NH.sub.2, --NH(C.sub.1-6
aliphatic), --N(C.sub.1-6 aliphatic).sub.2, --CH.sub.2--N(C.sub.1-6
aliphatic).sub.2, --CH.sub.2--NH(C.sub.1-6 aliphatic),
--CH.sub.2NH.sub.2, --OH, --O(C.sub.1-6 aliphatic), --CH.sub.2OH,
--CH.sub.2--O(C.sub.1-6 aliphatic), --SO.sub.2(C.sub.1-6
aliphatic), --N(C.sub.1-6 aliphatic), --SO.sub.2(C.sub.1-6
aliphatic), --NH--SO.sub.2(C.sub.1-6 aliphatic),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-6 aliphatic),
--SO.sub.2N(C.sub.1-6 aliphatic).sub.2, --C(O)(C.sub.1-6
aliphatic), --C(O)O(C.sub.1-6 aliphatic), --C(O)OH,
--OC(O)O(C.sub.1-6 aliphatic), --NHC(O)(C.sub.1-6 aliphatic),
--NHC(O)O(C.sub.1-6 aliphatic), --N(C.sub.1-6
aliphatic)C(O)O(C.sub.1-6 aliphatic), --C(O)NH.sub.2, and
--C(O)N(C.sub.1-6 aliphatic).sub.2. In several examples, R.sup.A2
is selected from the group consisting of H, C.sub.1-6 aliphatic,
halo, --CN, --NH.sub.2, --CH.sub.2NH.sub.2, --OH, --O(C.sub.1-6
aliphatic), --CH.sub.2OH, --SO.sub.2(C.sub.1-6 aliphatic),
--NH--SO.sub.2(C.sub.1-6 aliphatic), --C(O)O(C.sub.1-6 aliphatic),
--C(O)OH, --NHC(O)(C.sub.1-6 aliphatic), --C(O)NH.sub.2,
--C(O)NH(C.sub.1-6 aliphatic), and --C(O)N(C.sub.1-6
aliphatic).sub.2. For examples, one R.sup.A not attached top the
carbon 3'' or 4'' is selected from the group consisting of H,
methyl, ethyl, n-propyl, iso-propyl, tert-butyl, F, Cl, CN,
--NH.sub.2, --CH.sub.2NH.sub.2, --OH, --OCH.sub.3, --O-ethyl,
--O-(iso-propyl), --O-(n-propyl), --CH.sub.2OH, --SO.sub.2CH.sub.3,
--NH--SO.sub.2CH.sub.3, --C(O)OCH.sub.3, --C(O)OCH.sub.2CH.sub.3,
--C(O)OH, --NHC(O)CH.sub.3, --C(O)NH.sub.2, and
--C(O)N(CH.sub.3).sub.2. In one embodiment, all R.sup.As not
attached top the carbon 3'' or 4'' are hydrogen. In another
embodiment, one R.sup.A not attached top the carbon 3'' or 4'' is
methyl. Or, one R.sup.A not attached top the carbon 3'' or 4'' is
ethyl. Or, one R.sup.A not attached top the carbon 3'' or 4'' is F.
Or, one R.sup.A not attached top the carbon 3'' or 4'' is Cl. Or,
one R.sup.A not attached top the carbon 3'' or 4'' is
--OCH.sub.3.
[0261] In one embodiment, the present invention provides compounds
of formula IId or formula IIe:
##STR00035## [0262] wherein T, each R.sup.A, and R.sub.1 are as
defined above.
[0263] In one embodiment, T is --CH.sub.2--, --CF.sub.2--,
--C(CH.sub.3).sub.2--, or
##STR00036##
In one embodiment, T is --CH.sub.2--. In one embodiment, T is
--CF.sub.2--. In one embodiment, T is --C(CH.sub.3).sub.2--. In one
embodiment, T is
##STR00037##
[0264] In one embodiment, R.sub.1 is selected from the group
consisting of H, halo, CF.sub.3, or an optionally substituted group
selected from C.sub.1-6 aliphatic, --O(C.sub.1-6 aliphatic),
C.sub.3-5 cycloalkyl, 3-6 membered heterocycloalkyl containing one
oxygen atom, carboxy, and aminocarbonyl. Said C.sub.1-6 aliphatic,
--O(C.sub.1-6 aliphatic), C.sub.3-5 cycloalkyl, 3-6 membered
heterocycloalkyl containing one oxygen atom, carboxy, or
aminocarbonyl is optionally substituted with halo, CN, hydroxy, or
a group selected from amino, branched or straight C.sub.1-6
aliphatic, branched or straight alkoxy, aminocarbonyl, C.sub.3-8
cycloaliphatic, 3-10 membered heterocyclicaliphatic having 1, 2, or
3 ring membered independently selected from nitrogen (including NH
and NR.sup.X), oxygen, or sulfur (including S, SO, and SO.sub.2),
C.sub.6-10 aryl, and 5-10 membered heteroaryl, each of which is
further optionally substituted with halo or hydroxy. Exemplary
embodiments include H, methyl, ethyl, iso-propyl, tert-butyl, F,
Cl, CF.sub.3, CHF.sub.2, --OCF.sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --O-(iso-propyl), --O-(tert-butyl), --COOH,
--COOCH.sub.3, --CONHCH(tert-butyl)CH.sub.2OH,
--CONHCH(CH.sub.3)CH.sub.2OH, --CON(CH.sub.3).sub.2,
--CONHCH.sub.3, --CH.sub.2CONH.sub.2, pyrrolid-1-yl-methyl,
3-hydroxy-pyrrolid-1-yl-methyl, morpholin-4-yl-methyl,
3-hydroxy-pyrrolid-1-yl-formyl, tetrazol-5-yl-methyl, cyclopropyl,
hydroxymethyl, methoxymethyl, ethoxymethyl, methylaminomethyl,
dimethylaminomethyl, cyanomethyl, 2-hydroxyethylaminomethyl,
iso-propoxymethyl, or 3-methyloxetan-3-yl. IN still other
embodiments, R.sub.1 is H. Or, R.sub.1 is methyl. Or, R.sub.1 is
ethyl. Or, R.sub.1 is CF.sub.3. Or, R.sub.1 is oxetanyl.
[0265] In some embodiments, R.sup.A attached at the carbon carbon
3'' or 4'' is H, halo, OH, CF.sub.3, OCF.sub.3, CN, SCH.sub.3, or
an optionally substituted group selected from C.sub.1-6 aliphatic,
amino, alkoxy, or 3-8 membered heterocycloaliphatic having 1, 2, or
3 ring members each independently chosen from nitrogen (including
NH and NR.sup.X), oxygen, or sulfur (including S, SO, and
SO.sub.2). In some embodiments, R.sup.A attached at the carbon
carbon 3'' or 4'' is H, F, Cl, OH, CF.sub.3, OCF.sub.3, CN, or
SCH.sub.3. In some embodiments, R.sup.A attached at the carbon
carbon 3'' or 4'' is C.sub.1-6 alkyl, amino, alkoxy, or 3-8
membered heterocycloalkyl having 1, 2, or 3 ring members each
independently chosen from nitrogen (including NH and NR.sup.X),
oxygen, or sulfur (including S, SO, and SO.sub.2); wherein said
alkyl, amino, alkoxy, or heterocycloalkyl each is optionally
substituted with 1, 2, or 3 groups independently selected from oxo,
halo, hydroxy, or an optionally substituted group selected from
C.sub.1-6 aliphatic, cycloaliphatic, heterocycloaliphatic, aryl,
heteroaryl, carbonyl, amino, and carboxy. In one embodiment,
R.sup.A attached at the carbon carbon 3'' or 4'' is H, F, Cl, OH,
CF.sub.3, OCF.sub.3, CN, SCH.sub.3, methyl, ethyl, iso-propyl,
tert-butyl, 2-methylpropyl, cyanomethyl, aminomethyl,
hydroxymethyl, 1-hydroxyethyl, methoxymethyl, methylaminomethyl,
(2'-methylpropylamino)-methyl, 1-methyl-1-cyanoethyl,
n-propylaminomethyl, dimethylaminomethyl, 2-(methylsulfonyl)-ethyl,
CH.sub.2COOH, CH(OH)COOH, diethylamino, piperid-1-yl,
3-methyloxetan-3-yl, 2,5-dioxopyrrolid-1-yl, morpholin-4-yl,
2-oxopyrrolid-1-yl, tetrazol-5-yl, methoxy, ethoxy, OCH.sub.2COOH,
amino, dimethylamino, NHCH.sub.2COOH, or acetyl.
[0266] In one embodiment, R.sup.A attached at the carbon carbon 3''
or 4'' is Z.sup.AR.sub.5, wherein Z.sup.A is selected from CONH,
CON(C.sub.1-6 alkyl), NHCO, SO.sub.2NH, SO.sub.2N(C.sub.1-6 alkyl),
NHSO.sub.2, CH.sub.2NHSO.sub.2, CH.sub.2N(CH.sub.3)SO.sub.2,
CH.sub.2NHCO, CH.sub.2N(CH.sub.3)CO, COO, SO.sub.2, SO, or CO. In
one embodiment, R.sup.A attached at the carbon carbon 3'' or 4'' is
Z.sup.AR.sub.5, wherein Z.sup.A is selected from CONH, SO.sub.2NH,
SO.sub.2N(C.sub.1-6 alkyl), CH.sub.2NHSO.sub.2,
CH.sub.2N(CH.sub.3)SO.sub.2, CH.sub.2NHCO, COO, SO.sub.2, or
CO.
[0267] In one embodiment, Z.sup.A is COO and R.sub.5 is H. In one
embodiment, Z.sup.A is COO and R.sub.5 is an optionally substituted
straight or branched C.sub.1-6 aliphatic. In one embodiment,
Z.sup.A is COO and R.sub.5 is an optionally substituted straight or
branched C.sub.1-6 alkyl. In one embodiment, Z.sup.A is COO and
R.sub.5 is C.sub.1-6 alkyl. In one embodiment, Z.sup.A is COO and
R.sub.5 is methyl.
[0268] In one embodiment, Z.sup.A is CONH and R.sub.5 is H. In one
embodiment, Z.sup.A is CONH and R.sub.5 is an optionally
substituted straight or branched C.sub.1-6 aliphatic. In one
embodiment, Z.sup.A is CONH and R.sub.5 is C.sub.1-6 straight or
branched alkyl optionally substituted with one or more groups
independently selected from --OH, halo, CN, optionally substituted
C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloaliphatic,
optionally substituted 3-8 membered heterocycloaliphatic,
optionally substituted C.sub.6-10 aryl, optionally substituted 5-8
membered heteroaryl, optionally substituted alkoxy, optionally
substituted amino, and optionally substituted aminocarbonyl. In one
embodiment, Z.sup.A is CONH and R.sub.5 is 2-(dimethylamino)ethyl,
cyclopropylmethyl, cyclohexylmethyl, 2-(cyclohexen-1-yl)ethyl,
3-(morpholin-4-yl)propyl, 2-(morpholin-4-yl)ethyl,
2-(1H-imidazol-4-yl)ethyl, tetrahydrofuran-2-yl-methyl,
2-(pyrid-2-yl)ethyl, (1-ethyl-pyrrolidin-2-yl)methyl,
1-hydroxymethylpropyl, 1-hydroxymethylbutyl, 1-hydroxymethylpentyl,
1-hydroxymethyl-2-hydroxyethyl, 1-hydroxymethyl-2-methylpropyl,
1-hydroxymethyl-3-methylbutyl, 2,2-dimethyl-1-hydroxymethyl-propyl,
1,1-di(hydroxymethyl)ethyl, 1,1-di(hydroxymethyl)propyl,
3-ethoxypropyl, 2-acetoaminoethyl, 2-(2'-hydroxyethoxy)ethyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl,
2,3-dihydroxypropyl, 2-hydroxy-1-methylethyl, 2-methoxyethyl,
3-methoxypropyl, 2-cyanoethyl, or aminoformylmethyl. In one
embodiment, Z.sup.A is CONH and R.sub.5 is straight or branched
C.sub.1-6 alkyl. In one embodiment, Z.sup.A is CONH and R.sub.5 is
methyl, ethyl, n-propyl, iso-propyl, 3-methylbutyl,
3,3-dimethylbutyl, 2-methylpropyl, or tert-butyl.
[0269] In one embodiment, Z.sup.A is CONH and R.sub.5 is an
optionally substituted C.sub.3-10 cycloaliphatic. In one
embodiment, Z.sup.A is CONH and R.sub.5 is an optionally
substituted C.sub.3-10 cycloalkyl. In one embodiment, Z.sup.A is
CONH and R.sub.5 is cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl.
[0270] In some embodiment, Z.sup.A is CONH and R.sub.5 is an
optionally substituted 3-8 membered heterocycloaliphatic. In
several examples, Z.sup.A is CONH and R.sub.5 is an optionally
substituted 3-8 membered heterocycloalkyl, having 1, 2, or 3 ring
members independently selected from nitrogen (including NH and
NR.sup.X), oxygen, or sulfur (including S, SO, and SO.sub.2). In
several examples, Z.sup.A is CONH and R.sub.5 is 3-8 membered
heterocycloalkyl optionally substituted with 1, 2, or 3 groups
independently selected from oxo, halo, hydroxy, or an optionally
substituted group selected from C.sub.1-6 aliphatic,
cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, carbonyl,
amino, and carboxy. In one embodiment, Z.sup.A is CONH and R.sub.5
is 3-oxo-isoxazolidin-4-yl.
[0271] In some embodiments, Z.sup.A is CON(C.sub.1-6 aliphatic) and
R.sub.5 is an optionally substituted C.sub.1-6 aliphatic or an
optionally substituted C.sub.3-8 cycloaliphatic. In some
embodiments, Z.sup.A is CON(branched or straight C.sub.1-6 alkyl)
and R.sub.5 is branched or straight C.sub.1-6 alkyl or C.sub.3-8
cycloaliphatic, each optionally substituted with 1, 2, or 3 groups
independently selected from CN, OH, and an optionally substituted
group chosen from amino, branched or straight C.sub.1-6 aliphatic,
C.sub.3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic,
C.sub.6-10 aryl, and 5-10 membered heteroaryl. In one embodiment,
Z.sup.A is CON(CH.sub.3) and R.sub.5 is methyl, ethyl, n-propyl,
butyl, 2-pyrid-2-ylethyl, dimethylaminomethyl,
2-dimethylaminoethyl, 1,3-dioxolan-2-ylmethyl, 2-cyanoethyl,
cyanomethyl, or 2-hydroxyethyl. In one embodiment, Z.sup.A is
CON(CH.sub.2CH.sub.3) and R.sub.5 is ethyl, propyl, iso-propyl,
n-butyl, tert-butyl, cyclohexyl, 2-dimethylaminoethyl, or
2-hydroxyethyl. In one embodiment, Z.sup.A is
CON(CH.sub.2CH.sub.2CH.sub.3) and R.sub.5 is cyclopropylmethyl or
2-hydroxyethyl. In one embodiment, Z.sup.A is CON(iso-propyl) and
R.sub.5 is iso-propyl.
[0272] In some embodiments, Z.sup.A is CH.sub.2NHCO and R.sub.5 is
an optionally substituted straight or branched C.sub.1-6 aliphatic,
an optionally substituted C.sub.3-8 cycloaliphatic, an optionally
substituted alkoxy, or an optionally substituted heteroaryl. In
some embodiments, Z.sup.A is CH.sub.2NHCO and R.sub.5 is straight
or branched C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, or alkoxy, each
of which is optionally substituted with 1, 2, or 3 groups
independently selected from halo, oxo, hydroxy, or an optionally
substituted group selected from C.sub.1-6 aliphatic, C.sub.3-8
cycloaliphatic, 3-8 membered heterocycloaliphatic, C.sub.6-10 aryl,
5-10 membered heteroaryl, alkoxy, amino, carboxyl, and carbonyl. In
one embodiment, Z.sup.A is CH.sub.2NHCO and R.sub.5 is methyl,
ethyl, 1-ethylpropyl, 2-methylpropyl, 1-methylpropyl,
2,2-dimethylpropyl, n-propyl, iso-propyl, n-butyl, tert-butyl,
cyclopentyl, dimethylaminomethyl, methoxymethyl,
(2'-methoxyethoxy)methyl, (2'-methoxy)ethoxy, methoxy, ethoxy,
iso-propoxy, or tert-butoxy. In one embodiment, Z.sup.A is
CH.sub.2NHCO and R.sub.5 is an optionally substituted heteroaryl.
In one embodiment, Z.sup.A is CH.sub.2NHCO and R.sub.5 is
pyrazinyl.
[0273] In some embodiments, Z.sup.A is CH.sub.2N(CH.sub.3)CO and
R.sub.5 is an optionally substituted straight or branched C.sub.1-6
aliphatic, C.sub.3-8 cycloaliphatic, or an optionally substituted
heteroaryl. In some embodiments, Z.sup.A is CH.sub.2N(CH.sub.3)CO
and R.sub.5 is straight or branched C.sub.1-6 alkyl, or 5 or 6
membered heteroaryl, each of which is optionally substituted with
1, 2, or 3 groups independently selected from halo, oxo, hydroxy,
or an optionally substituted group selected from C.sub.1-6
aliphatic, C.sub.3-8 cycloaliphatic, 3-8 membered
heterocycloaliphatic, C.sub.6-10 aryl, 5-10 membered heteroaryl,
alkoxy, amino, carboxyl, and carbonyl. In one embodiment, Z.sup.A
is CH.sub.2N(CH.sub.3)CO and R.sub.5 is methoxymethyl,
(2'-methoxyethoxy)methyl, dimethylaminomethyl, or pyrazinyl. In
some embodiments, Z.sup.A is CH.sub.2N(CH.sub.3)CO and R.sub.5 is
branched or straight C.sub.1-6 alkyl or C.sub.3-8 cycloalkyl. In
one embodiment, Z.sup.A is CH.sub.2N(CH.sub.3)CO and R.sub.5 is
methyl, ethyl, iso-propyl, n-propyl, n-butyl, tert-butyl,
1-ethylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or
cyclopentyl.
[0274] In one embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is H.
In some embodiments, Z.sup.A is SO.sub.2NH and R.sub.5 is an
optionally substituted straight or branched C.sub.1-6 aliphatic. In
some embodiments, Z.sup.A is SO.sub.2NH and R.sub.5 is straight or
branched C.sub.1-6 alkyl optionally substituted with halo, oxo,
hydroxy, or an optionally substituted group selected from C.sub.1-6
aliphatic, C.sub.3-8 cycloaliphatic, 3-8 membered
heterocycloaliphatic, C.sub.6-10 aryl, 5-10 membered heteroaryl,
alkoxy, amino, amido, carboxyl, or carbonyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is methyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is ethyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is n-propyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is iso-propyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is tert-butyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is 3,3-dimethylbutyl. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
CH.sub.2CH.sub.2OH. In one embodiment, Z.sup.A is SO.sub.2NH and
R.sub.5 is CH.sub.2CH.sub.2OCH.sub.3. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is CH(CH.sub.3)CH.sub.2OH. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
CH.sub.2CH(CH.sub.3)OH. In one embodiment, Z.sup.A is SO.sub.2NH
and R.sub.5 is CH(CH.sub.2OH).sub.2. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is CH.sub.2CH(OH)CH.sub.2OH. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
CH.sub.2CH(OH)CH.sub.2CH.sub.3. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is C(CH.sub.3).sub.2CH.sub.2OH. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
CH(CH.sub.2CH.sub.3)CH.sub.2OH. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is CH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH. In
one embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
C(CH.sub.3)(CH.sub.2OH).sub.2. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is CH(CH.sub.3)C(O)OH. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is CH(CH.sub.2OH)C(O)OH. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is CH.sub.2C(O)OH. In
one embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
CH.sub.2CH.sub.2C(O)OH. In one embodiment, Z.sup.A is SO.sub.2NH
and R.sub.5 is CH.sub.2CH(OH)CH.sub.2C(O)OH. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is
CH.sub.2CH.sub.2N(CH.sub.3).sub.2. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is CH.sub.2CH.sub.2NHC(O)CH.sub.3. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
CH(CH(CH.sub.3).sub.2)CH.sub.2OH. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is CH(CH.sub.2CH.sub.2CH.sub.3)CH.sub.2OH.
In one embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
tetrahydrofuran-2-ylmethyl. In one embodiment, Z.sup.A is
SO.sub.2NH and R.sub.5 is furylmethyl. In one embodiment, Z.sup.A
is SO.sub.2NH and R.sub.5 is (5-methylfuryl)-methyl. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
2-pyrrolidinylethyl. In one embodiment, Z.sup.A is SO.sub.2NH and
R.sub.5 is 2-(1-methylpyrrolidinyl)-ethyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is 2-(morpholin-4-yl)-ethyl. In
one embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
3-(morpholin-4-yl)-propyl. In one embodiment, Z.sup.A is SO.sub.2NH
and R.sub.5 is C(CH.sub.2CH.sub.3)(CH.sub.2OH).sub.2. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is
2-(1H-imidazol-4-yl)ethyl. In one embodiment, Z.sup.A is SO.sub.2NH
and R.sub.5 is 3-(1H-imidazol-1-yl)-propyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is 2-(pyridin-2-yl)-ethyl.
[0275] In some embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is an
optionally substituted C.sub.3-8 cycloaliphatic. In several
examples, Z.sup.A is SO.sub.2NH and R.sub.5 is an optionally
substituted C.sub.3-8 cycloalkyl. In several examples, Z.sup.A is
SO.sub.2NH and R.sub.5 is C.sub.3-8 cycloalkyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is cyclobutyl. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is cyclopentyl. In one
embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is cyclohexyl.
[0276] In some embodiment, Z.sup.A is SO.sub.2NH and R.sub.5 is an
optionally substituted 3-8 membered heterocycloaliphatic. In
several examples, Z.sup.A is SO.sub.2NH and R.sub.5 is an
optionally substituted 3-8 membered heterocycloalkyl, having 1, 2,
or 3 ring members independently selected from nitrogen (including
NH and NR.sup.X), oxygen, or sulfur (including S, SO, and
SO.sub.2). In several examples, Z.sup.A is SO.sub.2NH and R.sub.5
is 3-8 membered heterocycloalkyl optionally substituted with 1, 2,
or 3 groups independently selected from oxo, halo, hydroxy, or an
optionally substituted group selected from C.sub.1-6 aliphatic,
aryl, heteroaryl, carbonyl, amino, and carboxy. In one embodiment,
Z.sup.A is SO.sub.2NH and R.sub.5 is 3-oxo-isoxazolidin-4-yl.
[0277] In some embodiments, Z.sup.A is SO.sub.2N(C.sub.1-6 alkyl)
and R.sub.5 is an optionally substituted straight or branched
C.sub.1-6 aliphatic or an optionally substituted cycloaliphatic. In
some embodiments, Z.sup.A is SO.sub.2N(C.sub.1-6 alkyl) and R.sub.5
is an optionally substituted straight or branched C.sub.1-6
aliphatic. In some embodiments, Z.sup.A is SO.sub.2N(C.sub.1-6
alkyl) and R.sub.5 is an optionally substituted straight or
branched C.sub.1-6 alkyl or an optionally substituted straight or
branched C.sub.2-6 alkenyl. In one embodiments, Z.sup.A is
SO.sub.2N(CH.sub.3) and R.sub.5 is methyl. In one embodiments,
Z.sup.A is SO.sub.2N(CH.sub.3) and R.sub.5 is n-propyl. In one
embodiments, Z.sup.A is SO.sub.2N(CH.sub.3) and R.sub.5 is n-butyl.
In one embodiments, Z.sup.A is SO.sub.2N(CH.sub.3) and R.sub.5 is
cyclohexyl. In one embodiments, Z.sup.A is SO.sub.2N(CH.sub.3) and
R.sub.5 is allyl. In one embodiments, Z.sup.A is
SO.sub.2N(CH.sub.3) and R.sub.5 is CH.sub.2CH.sub.2OH. In one
embodiments, Z.sup.A is SO.sub.2N(CH.sub.3) and R.sub.5 is
CH.sub.2CH(OH)CH.sub.2OH. In one embodiments, Z.sup.A is
SO.sub.2N(ethyl) and R.sub.5 is ethyl. In one embodiment, Z.sup.A
is SO.sub.2N(CH.sub.2CH.sub.3) and R.sub.5 is CH.sub.2CH.sub.3OH.
In one embodiments, Z.sup.A is SO.sub.2N(CH.sub.2CH.sub.2CH.sub.3)
and R.sub.5 is cyclopropylmethyl. In one embodiments, Z.sup.A is
SO.sub.2N(n-propyl) and R.sub.5 is n-propyl. In one embodiments,
Z.sup.A is SO.sub.2N(iso-propyl) and R.sub.5 is iso-prpopyl.
[0278] In some embodiments, Z.sup.A is CH.sub.2NHSO.sub.2 and
R.sub.5 is an optionally substituted C.sub.1-6 aliphatic. In some
embodiments, Z.sup.A is CH.sub.2NHSO.sub.2 and R.sub.5 is an
optionally substituted straight or branched C.sub.1-6 alkyl. In one
embodiment, Z.sup.A is CH.sub.2NHSO.sub.2 and R.sub.5 is methyl,
ethyl, n-propyl, iso-propyl, or n-butyl. In some embodiments,
Z.sup.A is CH.sub.2N(C.sub.1-6 aliphatic)SO.sub.2 and R.sub.5 is an
optionally substituted C.sub.1-6 aliphatic. In some embodiments,
Z.sup.A is CH.sub.2N(C.sub.1-6 aliphatic)SO.sub.2 and R.sub.5 is an
optionally substituted straight or branched C.sub.1-6 alkyl. In one
embodiment, Z.sup.A is CH.sub.2N(CH.sub.3)SO.sub.2 and R.sub.5 is
methyl, ethyl, n-propyl, iso-propyl, or n-butyl.
[0279] In one embodiment, Z.sup.A is SO and R.sub.5 is methyl. In
one embodiment, Z.sup.A is SO.sub.2 and R.sub.5 is OH. In some
embodiments, Z.sup.A is SO.sub.2 and R.sub.5 is an optionally
substituted straight or branched C.sub.1-6 aliphatic or an
optionally substituted 3-8 membered heterocyclic, having 1, 2, or 3
ring members independently selected from the group consisting of
nitrogen (including NH and NR.sup.X), oxygen, or sulfur (including
S, SO, and SO.sub.2). In some embodiments, Z.sup.A is SO.sub.2 and
R.sub.5 is straight or branched C.sub.1-6 alkyl or 3-8 membered
heterocycloaliphatic; each of which is optionally substituted with
1, 2, or 3 of oxo, halo, hydroxy, or an optionally substituted
group selected from C.sub.1-6 aliphatic, aryl, heteroaryl,
carbonyl, amino, and carboxy. In one embodiment, Z.sup.A is
SO.sub.2 and R.sub.5 is methyl, ethyl, or iso-propyl. In some
embodiments, Z.sup.A is SO.sub.2 and examples of R.sub.5 include
but are not limited to:
##STR00038##
[0280] In one embodiment, Z.sup.A is CO and R.sub.5 is an
optionally substituted amino, an optionally substituted C.sub.1-6
straight or branched aliphatic, or an optionally substituted 3-8
membered heterocyclic, having 1, 2, or 3 ring members independently
selected from the group consisting of nitrogen (including NH and
NR.sup.X), oxygen, or sulfur (including S, SO, and SO.sub.2). In
one embodiment, Z.sup.A is CO and R.sub.5 is
di-(2-methoxyethyl)amino or di-(2-hydroxyethyl)amino. In some
embodiments, Z.sup.A is CO and R.sub.5 is straight or branched
C.sub.1-6 alkyl or 3-8 membered heterocycloaliphatic each of which
is optionally substituted with 1, 2, or 3 of oxo, halo, hydroxy, or
an optionally substituted group selected from C.sub.1-6 aliphatic,
aryl, heteroaryl, carbonyl, amino, and carboxy. In one embodiment,
Z.sup.A is CO and R.sub.5 is
##STR00039## ##STR00040##
[0281] In some embodiments, Z.sup.A is NHCO and R.sub.5 is an
optionally substituted group selected from C.sub.1-6 aliphatic,
C.sub.1-6 alkoxy, amino, and heterocycloaliphatic. In one
embodiment, Z.sup.A is NHCO and R.sub.5 is C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, amino, or 3-8 membered heterocycloalkyl having 1,
2, or 3 ring member independently selected from nitrogen (including
NH and NR.sup.X), oxygen, or sulfur (including S, SO, and
SO.sub.2); wherein said alkyl, alkoxy, amino or heterocycloalkyl
each is optionally substituted with 1, 2, or 3 groups independently
selected from oxo, halo, hydroxy, or an optionally substituted
group selected from C.sub.1-6 aliphatic, 3-8 membered
heterocycloaliphatic, alkoxy, carbonyl, amino, and carboxy. In one
embodiment, Z.sup.A is NHCO and R.sub.5 is methyl, methoxymethyl,
hydroxymethyl, (morpholin-4-yl)-methyl, CH.sub.2COOH, ethoxy,
dimethylamino, or morpholin-4-yl.
[0282] In some embodiments, one R.sup.A not attached at the carbon
carbon 3'' or 4'' is selected from the group consisting of H,
R.sup.B, halo, --OH, --(CH.sub.2).sub.rNR.sup.BR.sup.B,
--(CH.sub.2).sub.rOR.sup.B, --SO.sub.2--R.sup.B,
--NR.sup.B--SO.sub.2--R.sup.B, --SO.sub.2NR.sup.BR.sup.B,
--C(O)R.sup.B, --C(O)OR.sup.B, --OC(O)OR.sup.B,
--NR.sup.BC(O)OR.sup.B, and --C(O)NR.sup.BR.sup.B; wherein r is 0,
1, or 2; and each R.sup.B is independently hydrogen, an optionally
substituted C.sub.1-8 aliphatic group, an optionally substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted
heteroaryl. In other embodiments, one R.sup.A not attached at the
carbon carbon 3'' or 4'' is selected from the group consisting of
H, C.sub.1-6 aliphatic, C.sub.3-8 cycloaliphatic, 3-8 membered
heterocycloaliphatic, C.sub.6-10 aryl, 5-8 membered heteroaryl,
halo, --CN, --NH.sub.2, --NH(C.sub.1-6 aliphatic), --N(C.sub.1-6
aliphatic).sub.2, --CH.sub.2--N(C.sub.1-6 aliphatic).sub.2,
--CH.sub.2--(heteroaryl), --CH.sub.2--NH(C.sub.1-6 aliphatic),
--CH.sub.2NH.sub.2, --OH, --O(C.sub.1-6 aliphatic), --CH.sub.2OH,
--CH.sub.2--O(C.sub.1-6 aliphatic), --SO.sub.2(C.sub.1-6
aliphatic), --N(C.sub.1-6 aliphatic), --SO.sub.2(C.sub.1-6
aliphatic), --NH--SO.sub.2(C.sub.1-6 aliphatic),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-6 aliphatic),
--SO.sub.2N(C.sub.1-6 aliphatic).sub.2, --C(O)(C.sub.1-6
aliphatic), --C(O)O(C.sub.1-6 aliphatic), --C(O)OH,
--OC(O)O(C.sub.1-6 aliphatic), --NHC(O)(C.sub.1-6 aliphatic),
--NHC(O)O(C.sub.1-6 aliphatic), --N(C.sub.1-6
aliphatic)C(O)O(C.sub.1-6 aliphatic), --C(O)NH.sub.2, and
--C(O)N(C.sub.1-6 aliphatic).sub.2. In several examples, R.sup.A2
is selected from the group consisting of H, C.sub.1-6 aliphatic,
5-8 membered heteroaryl, halo, --CN, --NH.sub.2,
--CH.sub.2NH.sub.2, --OH, --O(C.sub.1-6 aliphatic), --CH.sub.2OH,
--CH.sub.2-(5-8 membered heteroaryl), --SO.sub.2(C.sub.1-6
aliphatic), --NH--SO.sub.2(C.sub.1-6 aliphatic), --C(O)O(C.sub.1-6
aliphatic), --C(O)OH, --NHC(O)(C.sub.1-6 aliphatic),
--C(O)NH.sub.2, --C(O)NH(C.sub.1-6 aliphatic), and
--C(O)N(C.sub.1-6 aliphatic).sub.2. For examples, one R.sup.A not
attached at the carbon carbon 3'' or 4'' is selected from the group
consisting of H, methyl, ethyl, n-propyl, iso-propyl, tert-butyl,
tetrazol-5-yl, F, Cl, CN, --NH.sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2CN, --CH.sub.2COOH, --CH.sub.2CH.sub.2COOH,
1,3-dioxo-isoindolin-2-ylmethyl, --OH, --OCH.sub.3, --OCF.sub.3,
ethoxy, iso-propoxy, n-propoxy, --CH.sub.2OH, --CH.sub.2CH.sub.2OH,
--SO.sub.2CH.sub.3, --NH--SO.sub.2CH.sub.3, --C(O)OCH.sub.3,
--C(O)OCH.sub.2CH.sub.3, --C(O)OH, --NHC(O)CH.sub.3,
--C(O)NH.sub.2, and --C(O)N(CH.sub.3).sub.2. In one embodiment, one
R.sup.A not attached at the carbon carbon 3'' or 4'' is hydrogen.
In another embodiment, one R.sup.A not attached at the carbon
carbon 3'' or 4'' is methyl, ethyl, F, Cl, or --OCH.sub.3.
[0283] In some embodiments, one R.sup.A not attached at the carbon
carbon 3'' or 4'' is H, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.3-6 cycloalkyl, or NH.sub.2. In several examples,
R.sup.A2 is H, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy. Examples
of one R.sup.A not attached at the carbon carbon 3'' or 4'' include
H, F, Cl, methyl, ethyl, and methoxy.
5. Exemplary Compounds
[0284] Exemplary compounds of the present invention include, but
are not limited to, those illustrated in Table 1 below.
TABLE-US-00001 TABLE 1 Examples of compounds of the present
invention. ##STR00041## 1 ##STR00042## 2 ##STR00043## 3
##STR00044## 4 ##STR00045## 5 ##STR00046## 6 ##STR00047## 7
##STR00048## 8 ##STR00049## 9 ##STR00050## 10 ##STR00051## 11
##STR00052## 12 ##STR00053## 13 ##STR00054## 14 ##STR00055## 15
##STR00056## 16 ##STR00057## 17 ##STR00058## 18 ##STR00059## 19
##STR00060## 20 ##STR00061## 21 ##STR00062## 22 ##STR00063## 23
##STR00064## 24 ##STR00065## 25 ##STR00066## 26 ##STR00067## 27
##STR00068## 28 ##STR00069## 29 ##STR00070## 30 ##STR00071## 31
##STR00072## 32 ##STR00073## 33 ##STR00074## 34 ##STR00075## 35
##STR00076## 36 ##STR00077## 37 ##STR00078## 38 ##STR00079## 39
##STR00080## 40 ##STR00081## 41 ##STR00082## 42 ##STR00083## 43
##STR00084## 44 ##STR00085## 45 ##STR00086## 46 ##STR00087## 47
##STR00088## 48 ##STR00089## 49 ##STR00090## 50 ##STR00091## 51
##STR00092## 52 ##STR00093## 53 ##STR00094## 54 ##STR00095## 55
##STR00096## 56 ##STR00097## 57 ##STR00098## 58 ##STR00099## 59
##STR00100## 60 ##STR00101## 61 ##STR00102## 62 ##STR00103## 63
##STR00104## 64 ##STR00105## 65 ##STR00106## 66 ##STR00107## 67
##STR00108## 68 ##STR00109## 69 ##STR00110## 70 ##STR00111## 71
##STR00112## 72 ##STR00113## 73 ##STR00114## 74 ##STR00115## 75
##STR00116## 76 ##STR00117## 77 ##STR00118## 78 ##STR00119## 79
##STR00120## 80 ##STR00121## 81 ##STR00122## 82 ##STR00123## 83
##STR00124## 84 ##STR00125## 85 ##STR00126## 86 ##STR00127## 87
##STR00128## 88 ##STR00129## 89 ##STR00130## 90 ##STR00131## 91
##STR00132## 92 ##STR00133## 93 ##STR00134## 94 ##STR00135## 95
##STR00136## 96 ##STR00137## 97 ##STR00138## 98 ##STR00139## 99
##STR00140## 100 ##STR00141## 101 ##STR00142## 102 ##STR00143## 103
##STR00144## 104 ##STR00145## 105 ##STR00146## 106 ##STR00147## 107
##STR00148## 108 ##STR00149## 109 ##STR00150## 110 ##STR00151## 111
##STR00152## 112 ##STR00153## 113 ##STR00154## 114 ##STR00155## 115
##STR00156## 116 ##STR00157## 117 ##STR00158## 118 ##STR00159## 119
##STR00160## 120 ##STR00161## 121 ##STR00162## 122 ##STR00163##
123
##STR00164## 124 ##STR00165## 125 ##STR00166## 126 ##STR00167## 127
##STR00168## 128 ##STR00169## 129 ##STR00170## 130 ##STR00171## 131
##STR00172## 132 ##STR00173## 133 ##STR00174## 134 ##STR00175## 135
##STR00176## 136 ##STR00177## 137 ##STR00178## 138 ##STR00179## 139
##STR00180## 140 ##STR00181## 141 ##STR00182## 142 ##STR00183## 143
##STR00184## 144 ##STR00185## 145 ##STR00186## 146 ##STR00187## 147
##STR00188## 148 ##STR00189## 149 ##STR00190## 150 ##STR00191## 151
##STR00192## 152 ##STR00193## 153 ##STR00194## 154 ##STR00195## 155
##STR00196## 156 ##STR00197## 157 ##STR00198## 158 ##STR00199## 159
##STR00200## 160 ##STR00201## 161 ##STR00202## 162 ##STR00203## 163
##STR00204## 164 ##STR00205## 165 ##STR00206## 166 ##STR00207## 167
##STR00208## 168 ##STR00209## 169 ##STR00210## 170 ##STR00211## 171
##STR00212## 172 ##STR00213## 173 ##STR00214## 174 ##STR00215## 175
##STR00216## 176 ##STR00217## 177 ##STR00218## 178 ##STR00219## 179
##STR00220## 180 ##STR00221## 181 ##STR00222## 182 ##STR00223## 183
##STR00224## 184 ##STR00225## 185 ##STR00226## 186 ##STR00227## 187
##STR00228## 188 ##STR00229## 189 ##STR00230## 190 ##STR00231## 191
##STR00232## 192 ##STR00233## 193 ##STR00234## 194 ##STR00235## 195
##STR00236## 196 ##STR00237## 197 ##STR00238## 198 ##STR00239## 199
##STR00240## 200 ##STR00241## 201 ##STR00242## 202 ##STR00243## 203
##STR00244## 204 ##STR00245## 205 ##STR00246## 206 ##STR00247## 207
##STR00248## 208 ##STR00249## 209 ##STR00250## 210 ##STR00251## 211
##STR00252## 212 ##STR00253## 213 ##STR00254## 214 ##STR00255## 215
##STR00256## 216 ##STR00257## 217 ##STR00258## 218 ##STR00259## 219
##STR00260## 220 ##STR00261## 221 ##STR00262## 222 ##STR00263## 223
##STR00264## 224 ##STR00265## 225 ##STR00266## 226 ##STR00267## 227
##STR00268## 228 ##STR00269## 229 ##STR00270## 230 ##STR00271## 231
##STR00272## 232 ##STR00273## 233 ##STR00274## 234 ##STR00275## 235
##STR00276## 236 ##STR00277## 237 ##STR00278## 238 ##STR00279## 239
##STR00280## 240 ##STR00281## 241 ##STR00282## 242 ##STR00283## 243
##STR00284## 244 ##STR00285## 245 ##STR00286## 246 ##STR00287## 247
##STR00288## 248
##STR00289## 249 ##STR00290## 250 ##STR00291## 251 ##STR00292## 252
##STR00293## 253 ##STR00294## 254 ##STR00295## 255 ##STR00296## 256
##STR00297## 257 ##STR00298## 258 ##STR00299## 259 ##STR00300## 260
##STR00301## 261 ##STR00302## 262 ##STR00303## 263 ##STR00304## 264
##STR00305## 265 ##STR00306## 266 ##STR00307## 267 ##STR00308## 268
##STR00309## 269 ##STR00310## 270 ##STR00311## 271 ##STR00312## 272
##STR00313## 273 ##STR00314## 274 ##STR00315## 275 ##STR00316## 276
##STR00317## 277 ##STR00318## 278 ##STR00319## 279 ##STR00320## 280
##STR00321## 281 ##STR00322## 282 ##STR00323## 283 ##STR00324## 284
##STR00325## 285 ##STR00326## 286 ##STR00327## 287 ##STR00328## 288
##STR00329## 289 ##STR00330## 290 ##STR00331## 291 ##STR00332## 292
##STR00333## 293 ##STR00334## 294 ##STR00335## 295 ##STR00336## 296
##STR00337## 297 ##STR00338## 298 ##STR00339## 299 ##STR00340## 300
##STR00341## 301 ##STR00342## 302 ##STR00343## 303 ##STR00344## 304
##STR00345## 305 ##STR00346## 306 ##STR00347## 307 ##STR00348## 308
##STR00349## 309 ##STR00350## 310 ##STR00351## 311 ##STR00352## 312
##STR00353## 313 ##STR00354## 314 ##STR00355## 315 ##STR00356## 316
##STR00357## 317 ##STR00358## 318 ##STR00359## 319 ##STR00360## 320
##STR00361## 321 ##STR00362## 322 ##STR00363## 323 ##STR00364## 324
##STR00365## 325 ##STR00366## 326 ##STR00367## 327 ##STR00368## 328
##STR00369## 329 ##STR00370## 330 ##STR00371## 331 ##STR00372## 332
##STR00373## 333 ##STR00374## 334 ##STR00375## 335 ##STR00376## 336
##STR00377## 337 ##STR00378## 338 ##STR00379## 339 ##STR00380## 340
##STR00381## 341 ##STR00382## 342 ##STR00383## 343 ##STR00384## 344
##STR00385## 345 ##STR00386## 346 ##STR00387## 347 ##STR00388## 348
##STR00389## 349 ##STR00390## 350 ##STR00391## 351 ##STR00392## 352
##STR00393## 353 ##STR00394## 354 ##STR00395## 355 ##STR00396## 356
##STR00397## 357 ##STR00398## 358 ##STR00399## 359 ##STR00400## 360
##STR00401## 361 ##STR00402## 362 ##STR00403## 363 ##STR00404## 364
##STR00405## 365 ##STR00406## 366 ##STR00407## 367 ##STR00408## 368
##STR00409## 369 ##STR00410## 370 ##STR00411## 371 ##STR00412## 372
##STR00413## 373 ##STR00414## 374
##STR00415## 375 ##STR00416## 376 ##STR00417## 377 ##STR00418## 378
##STR00419## 379 ##STR00420## 380 ##STR00421## 381 ##STR00422## 382
##STR00423## 383 ##STR00424## 384 ##STR00425## 385 ##STR00426## 386
##STR00427## 387 ##STR00428## 388 ##STR00429## 389 ##STR00430## 390
##STR00431## 391 ##STR00432## 392 ##STR00433## 393 ##STR00434## 394
##STR00435## 395 ##STR00436## 396 ##STR00437## 397 ##STR00438## 398
##STR00439## 399 ##STR00440## 400 ##STR00441## 401 ##STR00442## 402
##STR00443## 403 ##STR00444## 404 ##STR00445## 405 ##STR00446## 406
##STR00447## 407 ##STR00448## 408 ##STR00449## 409 ##STR00450## 410
##STR00451## 411 ##STR00452## 412 ##STR00453## 413 ##STR00454## 414
##STR00455## 415 ##STR00456## 416 ##STR00457## 417 ##STR00458## 418
##STR00459## 419 ##STR00460## 420 ##STR00461## 421 ##STR00462## 422
##STR00463## 423 ##STR00464## 424 ##STR00465## 425 ##STR00466## 426
##STR00467## 427 ##STR00468## 428 ##STR00469## 429 ##STR00470## 430
##STR00471## 431 ##STR00472## 432 ##STR00473## 433 ##STR00474## 434
##STR00475## 435 ##STR00476## 436 ##STR00477## 437 ##STR00478## 438
##STR00479## 439 ##STR00480## 440 ##STR00481## 441 ##STR00482## 442
##STR00483## 443 ##STR00484## 444 ##STR00485## 445 ##STR00486## 446
##STR00487## 447 ##STR00488## 448 ##STR00489## 449 ##STR00490## 450
##STR00491## 451 ##STR00492## 452 ##STR00493## 453 ##STR00494## 454
##STR00495## 455 ##STR00496## 456 ##STR00497## 457 ##STR00498## 458
##STR00499## 459 ##STR00500## 460 ##STR00501## 461 ##STR00502## 462
##STR00503## 463 ##STR00504## 464 ##STR00505## 465 ##STR00506## 466
##STR00507## 467 ##STR00508## 468 ##STR00509## 469 ##STR00510## 470
##STR00511## 471 ##STR00512## 472 ##STR00513## 473 ##STR00514## 474
##STR00515## 475 ##STR00516## 476 ##STR00517## 477 ##STR00518## 478
##STR00519## 479 ##STR00520## 480 ##STR00521## 481 ##STR00522## 482
##STR00523## 483 ##STR00524## 484 ##STR00525## 485 ##STR00526## 486
##STR00527## 487 ##STR00528## 488 ##STR00529## 489 ##STR00530## 490
##STR00531## 491 ##STR00532## 492 ##STR00533## 493 ##STR00534## 494
##STR00535## 495 ##STR00536## 496 ##STR00537## 497 ##STR00538## 498
##STR00539## 499
##STR00540## 500 ##STR00541## 501 ##STR00542## 502 ##STR00543## 503
##STR00544## 504 ##STR00545## 505 ##STR00546## 506 ##STR00547## 507
##STR00548## 508 ##STR00549## 509 ##STR00550## 510 ##STR00551## 511
##STR00552## 512 ##STR00553## 513 ##STR00554## 514 ##STR00555## 515
##STR00556## 516 ##STR00557## 517 ##STR00558## 518 ##STR00559## 519
##STR00560## 520 ##STR00561## 521 ##STR00562## 522 ##STR00563## 523
##STR00564## 524 ##STR00565## 525 ##STR00566## 526 ##STR00567## 527
##STR00568## 528 ##STR00569## 529 ##STR00570## 530 ##STR00571## 531
##STR00572## 532 ##STR00573## 533 ##STR00574## 534 ##STR00575## 535
##STR00576## 536 ##STR00577## 537 ##STR00578## 538 ##STR00579## 539
##STR00580## 540 ##STR00581## 541 ##STR00582## 542 ##STR00583## 543
##STR00584## 544 ##STR00585## 545 ##STR00586## 546 ##STR00587## 547
##STR00588## 548 ##STR00589## 549 ##STR00590## 550 ##STR00591## 551
##STR00592## 552 ##STR00593## 553 ##STR00594## 554 ##STR00595## 555
##STR00596## 556 ##STR00597## 557 ##STR00598## 558 ##STR00599## 559
##STR00600## 560 ##STR00601## 561 ##STR00602## 562 ##STR00603## 563
##STR00604## 564 ##STR00605## 565 ##STR00606## 566 ##STR00607## 567
##STR00608## 568 ##STR00609## 569 ##STR00610## 570 ##STR00611## 571
##STR00612## 572 ##STR00613## 573 ##STR00614## 574 ##STR00615## 575
##STR00616## 576 ##STR00617## 577 ##STR00618## 578 ##STR00619## 579
##STR00620## 580 ##STR00621## 581 ##STR00622## 582 ##STR00623## 583
##STR00624## 584 ##STR00625## 585 ##STR00626## 586 ##STR00627## 587
##STR00628## 588 ##STR00629## 589 ##STR00630## 590 ##STR00631## 591
##STR00632## 592 ##STR00633## 593 ##STR00634## 594 ##STR00635## 595
##STR00636## 596 ##STR00637## 597 ##STR00638## 598 ##STR00639## 599
##STR00640## 600 ##STR00641## 601 ##STR00642## 602 ##STR00643## 603
##STR00644## 604 ##STR00645## 605 ##STR00646## 606 ##STR00647## 607
##STR00648## 608 ##STR00649## 609 ##STR00650## 610 ##STR00651## 611
##STR00652## 612 ##STR00653## 613 ##STR00654## 614 ##STR00655## 615
##STR00656## 616 ##STR00657## 617 ##STR00658## 618 ##STR00659## 619
##STR00660## 620 ##STR00661## 621 ##STR00662## 622 ##STR00663## 623
##STR00664## 624 ##STR00665## 625
##STR00666## 626 ##STR00667## 627 ##STR00668## 628 ##STR00669## 629
##STR00670## 630 ##STR00671## 631 ##STR00672## 632 ##STR00673## 633
##STR00674## 634 ##STR00675## 635 ##STR00676## 636 ##STR00677## 637
##STR00678## 638 ##STR00679## 639 ##STR00680## 640 ##STR00681## 641
##STR00682## 642 ##STR00683## 643 ##STR00684## 644 ##STR00685## 645
##STR00686## 646 ##STR00687## 647 ##STR00688## 648 ##STR00689## 649
##STR00690## 650 ##STR00691## 651 ##STR00692## 652 ##STR00693## 653
##STR00694## 654 ##STR00695## 655 ##STR00696## 656 ##STR00697## 657
##STR00698## 658 ##STR00699## 659 ##STR00700## 660 ##STR00701## 661
##STR00702## 662 ##STR00703## 663 ##STR00704## 654 ##STR00705## 665
##STR00706## 666 ##STR00707## 667 ##STR00708## 668 ##STR00709## 669
##STR00710## 670 ##STR00711## 671 ##STR00712## 672 ##STR00713## 673
##STR00714## 674 ##STR00715## 675 ##STR00716## 676 ##STR00717## 677
##STR00718## 678 ##STR00719## 679 ##STR00720## 680 ##STR00721## 681
##STR00722## 682 ##STR00723## 683 ##STR00724## 684 ##STR00725## 685
##STR00726## 686 ##STR00727## 687 ##STR00728## 688 ##STR00729## 689
##STR00730## 690 ##STR00731## 691 ##STR00732## 692 ##STR00733## 693
##STR00734## 694 ##STR00735## 695 ##STR00736## 696 ##STR00737## 697
##STR00738## 698 ##STR00739## 699 ##STR00740## 700 ##STR00741## 701
##STR00742## 702 ##STR00743## 703 ##STR00744## 704 ##STR00745## 705
##STR00746## 706 ##STR00747## 707 ##STR00748## 708 ##STR00749## 709
##STR00750## 710 ##STR00751## 711 ##STR00752## 712 ##STR00753## 713
##STR00754## 714 ##STR00755## 715 ##STR00756## 716 ##STR00757## 717
##STR00758## 718 ##STR00759## 719 ##STR00760## 720 ##STR00761## 721
##STR00762## 722 ##STR00763## 723 ##STR00764## 724 ##STR00765## 725
##STR00766## 726 ##STR00767## 727 ##STR00768## 728 ##STR00769## 729
##STR00770## 730 ##STR00771## 731 ##STR00772## 732 ##STR00773## 733
##STR00774## 734 ##STR00775## 735 ##STR00776## 736 ##STR00777## 737
##STR00778## 738 ##STR00779## 739 ##STR00780## 740 ##STR00781## 741
##STR00782## 742 ##STR00783## 743 ##STR00784## 744 ##STR00785## 745
##STR00786## 746 ##STR00787## 747 ##STR00788## 748 ##STR00789## 749
##STR00790## 750
##STR00791## 751 ##STR00792## 752 ##STR00793## 753 ##STR00794## 754
##STR00795## 755 ##STR00796## 756 ##STR00797## 757 ##STR00798## 758
##STR00799## 759 ##STR00800## 760 ##STR00801## 761 ##STR00802## 762
##STR00803## 763 ##STR00804## 764 ##STR00805## 765 ##STR00806## 766
##STR00807## 767 ##STR00808## 768 ##STR00809## 769 ##STR00810## 770
##STR00811## 771 ##STR00812## 772 ##STR00813## 773 ##STR00814## 774
##STR00815## 775 ##STR00816## 776 ##STR00817## 777 ##STR00818## 778
##STR00819## 779 ##STR00820## 780 ##STR00821## 781 ##STR00822## 782
##STR00823## 783 ##STR00824## 784 ##STR00825## 785 ##STR00826## 786
##STR00827## 787 ##STR00828## 788 ##STR00829## 789 ##STR00830## 790
##STR00831## 791 ##STR00832## 792 ##STR00833## 793 ##STR00834## 794
##STR00835## 795 ##STR00836## 796 ##STR00837## 797 ##STR00838## 798
##STR00839## 799 ##STR00840## 800 ##STR00841## 801 ##STR00842## 802
##STR00843## 803 ##STR00844## 804 ##STR00845## 805 ##STR00846## 806
##STR00847## 807 ##STR00848## 808 ##STR00849## 809 ##STR00850## 810
##STR00851## 811 ##STR00852## 812 ##STR00853## 813 ##STR00854## 814
##STR00855## 815 ##STR00856## 816 ##STR00857## 817 ##STR00858## 818
##STR00859## 819 ##STR00860## 820 ##STR00861## 821 ##STR00862## 822
##STR00863## 823 ##STR00864## 824 ##STR00865## 825 ##STR00866## 826
##STR00867## 827 ##STR00868## 828 ##STR00869## 829 ##STR00870## 830
##STR00871## 831 ##STR00872## 832 ##STR00873## 833 ##STR00874## 834
##STR00875## 835 ##STR00876## 836 ##STR00877## 837 ##STR00878## 838
##STR00879## 839 ##STR00880## 840 ##STR00881## 841 ##STR00882## 842
##STR00883## 843 ##STR00884## 844 ##STR00885## 845 ##STR00886## 846
##STR00887## 847 ##STR00888## 848 ##STR00889## 849 ##STR00890## 850
##STR00891## 851 ##STR00892## 852 ##STR00893## 853 ##STR00894## 854
##STR00895## 855 ##STR00896## 856 ##STR00897## 857 ##STR00898## 858
##STR00899## 859 ##STR00900## 860 ##STR00901## 861 ##STR00902## 862
##STR00903## 863 ##STR00904## 864 ##STR00905## 865 ##STR00906## 866
##STR00907## 867 ##STR00908## 868 ##STR00909## 869 ##STR00910## 870
##STR00911## 871 ##STR00912## 872 ##STR00913## 873 ##STR00914## 874
##STR00915## 875 ##STR00916## 876
##STR00917## 877 ##STR00918## 878 ##STR00919## 879 ##STR00920## 880
##STR00921## 881 ##STR00922## 882 ##STR00923## 883 ##STR00924## 884
##STR00925## 885 ##STR00926## 886 ##STR00927## 887 ##STR00928## 888
##STR00929## 889 ##STR00930## 890 ##STR00931## 891 ##STR00932## 892
##STR00933## 893 ##STR00934## 894 ##STR00935## 895 ##STR00936## 896
##STR00937## 897 ##STR00938## 898 ##STR00939## 899 ##STR00940## 900
##STR00941## 901 ##STR00942## 902 ##STR00943## 903 ##STR00944## 904
##STR00945## 905 ##STR00946## 906 ##STR00947## 907 ##STR00948## 908
##STR00949## 909 ##STR00950## 910 ##STR00951## 911 ##STR00952## 912
##STR00953## 913 ##STR00954## 914 ##STR00955## 915 ##STR00956## 916
##STR00957## 917 ##STR00958## 918 ##STR00959## 919 ##STR00960## 920
##STR00961## 921 ##STR00962## 922 ##STR00963## 923 ##STR00964## 924
##STR00965## 925 ##STR00966## 926 ##STR00967## 927 ##STR00968## 928
##STR00969## 929 ##STR00970## 930 ##STR00971## 931 ##STR00972## 932
##STR00973## 933 ##STR00974## 934 ##STR00975## 935 ##STR00976## 936
##STR00977## 937 ##STR00978## 938 ##STR00979## 939 ##STR00980## 940
##STR00981## 941 ##STR00982## 942 ##STR00983## 943 ##STR00984## 944
##STR00985## 945 ##STR00986## 946 ##STR00987## 947 ##STR00988## 948
##STR00989## 949 ##STR00990## 950 ##STR00991## 951 ##STR00992## 952
##STR00993## 953 ##STR00994## 954 ##STR00995## 955 ##STR00996## 956
##STR00997## 957 ##STR00998## 958 ##STR00999## 960 ##STR01000## 961
##STR01001## 962 ##STR01002## 963 ##STR01003## 964 ##STR01004## 965
##STR01005## 966 ##STR01006## 967 ##STR01007## 968 ##STR01008## 969
##STR01009## 970 ##STR01010## 971 ##STR01011## 972 ##STR01012## 973
##STR01013## 974 ##STR01014## 975 ##STR01015## 976 ##STR01016## 977
##STR01017## 978 ##STR01018## 979 ##STR01019## 980 ##STR01020## 981
##STR01021## 982 ##STR01022## 983 ##STR01023## 984 ##STR01024## 985
##STR01025## 986 ##STR01026## 987 ##STR01027## 988 ##STR01028## 989
##STR01029## 990 ##STR01030## 991 ##STR01031## 992 ##STR01032## 993
##STR01033## 994 ##STR01034## 995 ##STR01035## 996 ##STR01036## 997
##STR01037## 998 ##STR01038## 999 ##STR01039## 1000 ##STR01040##
1001 ##STR01041## 1002
##STR01042## 1003 ##STR01043## 1004 ##STR01044## 1005 ##STR01045##
1006 ##STR01046## 1007 ##STR01047## 1008 ##STR01048## 1009
##STR01049## 1010 ##STR01050## 1011 ##STR01051## 1012 ##STR01052##
1013 ##STR01053## 1014 ##STR01054## 1015 ##STR01055## 1016
##STR01056## 1017 ##STR01057## 1018 ##STR01058## 1019 ##STR01059##
1020 ##STR01060## 1021 ##STR01061## 1022 ##STR01062## 1023
##STR01063## 1024 ##STR01064## 1025 ##STR01065## 1026 ##STR01066##
1027 ##STR01067## 1028 ##STR01068## 1029 ##STR01069## 1030
##STR01070## 1031 ##STR01071## 1032 ##STR01072## 1033 ##STR01073##
1034 ##STR01074## 1035 ##STR01075## 1036 ##STR01076## 1037
##STR01077## 1038 ##STR01078## 1039 ##STR01079## 1040 ##STR01080##
1041 ##STR01081## 1042 ##STR01082## 1043 ##STR01083## 1044
##STR01084## 1045 ##STR01085## 1046 ##STR01086## 1047 ##STR01087##
1048 ##STR01088## 1049 ##STR01089## 1050 ##STR01090## 1051
##STR01091## 1052 ##STR01092## 1053 ##STR01093## 1054 ##STR01094##
1055 ##STR01095## 1056 ##STR01096## 1057 ##STR01097## 1058
##STR01098## 1059 ##STR01099## 1060 ##STR01100## 1061 ##STR01101##
1062 ##STR01102## 1063 ##STR01103## 1064 ##STR01104## 1065
##STR01105## 1066 ##STR01106## 1067 ##STR01107## 1068 ##STR01108##
1069 ##STR01109## 1070 ##STR01110## 1071 ##STR01111## 1072
##STR01112## 1073 ##STR01113## 1074 ##STR01114## 1075 ##STR01115##
1076 ##STR01116## 1077 ##STR01117## 1078 ##STR01118## 1079
##STR01119## 1080 ##STR01120## 1081 ##STR01121## 1082 ##STR01122##
1083 ##STR01123## 1084 ##STR01124## 1085 ##STR01125## 1086
##STR01126## 1087 ##STR01127## 1088 ##STR01128## 1089 ##STR01129##
1090 ##STR01130## 1091 ##STR01131## 1092 ##STR01132## 1093
##STR01133## 1094 ##STR01134## 1095 ##STR01135## 1096 ##STR01136##
1097 ##STR01137## 1098 ##STR01138## 1099 ##STR01139## 1100
##STR01140## 1101 ##STR01141## 1102 ##STR01142## 1103 ##STR01143##
1104 ##STR01144## 1105 ##STR01145## 1106 ##STR01146## 1107
##STR01147## 1108 ##STR01148## 1109 ##STR01149## 1110 ##STR01150##
1111 ##STR01151## 1112 ##STR01152## 1113 ##STR01153## 1114
##STR01154## 1115 ##STR01155## 1116 ##STR01156## 1117 ##STR01157##
1118 ##STR01158## 1119 ##STR01159## 1120 ##STR01160## 1121
##STR01161## 1122 ##STR01162## 1123 ##STR01163## 1124 ##STR01164##
1125 ##STR01165## 1126 ##STR01166## 1127 ##STR01167## 1128
##STR01168## 1129 ##STR01169## 1130 ##STR01170## 1131 ##STR01171##
1132 ##STR01172## 1133 ##STR01173## 1134 ##STR01174## 1135
##STR01175## 1136 ##STR01176## 1137 ##STR01177## 1138 ##STR01178##
1139 ##STR01179## 1140 ##STR01180## 1141 ##STR01181## 1142
##STR01182## 1143 ##STR01183## 1144 ##STR01184## 1145 ##STR01185##
1146 ##STR01186## 1147 ##STR01187## 1148 ##STR01188## 1149
##STR01189## 1150 ##STR01190## 1151 ##STR01191## 1152 ##STR01192##
1153 ##STR01193## 1154 ##STR01194## 1155 ##STR01195## 1156
##STR01196## 1157 ##STR01197## 1158 ##STR01198## 1159 ##STR01199##
1160 ##STR01200## 1161 ##STR01201## 1162 ##STR01202## 1163
##STR01203## 1164 ##STR01204## 1165 ##STR01205## 1166 ##STR01206##
1167 ##STR01207## 1168 ##STR01208## 1169 ##STR01209## 1170
##STR01210## 1171 ##STR01211## 1172 ##STR01212## 1173 ##STR01213##
1174 ##STR01214## 1175 ##STR01215## 1176 ##STR01216## 1177
##STR01217## 1178 ##STR01218## 1179 ##STR01219## 1180 ##STR01220##
1181 ##STR01221## 1182 ##STR01222## 1183 ##STR01223## 1184
##STR01224## 1185 ##STR01225## 1186 ##STR01226## 1187 ##STR01227##
1188 ##STR01228## 1189 ##STR01229## 1190 ##STR01230## 1192
##STR01231## 1193 ##STR01232## 1194 ##STR01233## 1195 ##STR01234##
1196 ##STR01235## 1197 ##STR01236## 1198 ##STR01237## 1199
##STR01238## 1200 ##STR01239## 1201 ##STR01240## 1202 ##STR01241##
1203 ##STR01242## 1204 ##STR01243## 1205 ##STR01244## 1191
##STR01245## 959
SYNTHETIC SCHEMES
[0285] Compounds of the invention may be prepared by well-known
methods in the art. Exemplary methods are illustrated below in
Scheme I and Scheme II.
##STR01246##
[0286] Referring to Scheme I, a nitrile of formula i is alkylated
(step a) with a dihalo-aliphatic in the presence of a base such as,
for example, 50% sodium hydroxide and, optionally, a phase transfer
reagent such as, for example, benzyltriethylammonium chloride
(BTEAC), to produce the corresponding alkylated nitrile (not shown)
which on hydrolysis in situ produces the acid ii. Compounds of
formula II may be converted to the acid chloride iii (step b) with
a suitable reagent such as, for example, thionyl chloride/DMF.
Reaction of the acid chloride iii with an aniline of formula iv
under known conditions, (step c) produces the amide compounds of
the invention formula I. Alternatively, the acid ii may be reacted
directly with the aniline iv (step d) in the presence of a coupling
reagent such as, for example, HATU, under known conditions to give
the amides I.
[0287] In some instances, when one of R.sub.1 is a halogen,
compounds of formula I may be further modified as shown below in
Scheme II.
##STR01247##
[0288] Referring to Scheme II, reaction of the amide v, wherein X
is halogen, with a boronic acid derivative vi (step e) wherein Z
and Z' are independently H, alkyl or Z and Z' together with the
atoms to which they are bound form a five or six membered
optionally substituted cycloaliphatic ring, in the presence of a
catalyst such as, for example, palladium acetate or
dichloro-[1,1-bis(diphenylphosphino) ferrocene]palladium(II)
(Pd(dppf)Cl.sub.2), provides compounds of the invention wherein one
of R.sub.1 is aryl or heteroaryl.
[0289] The phenylacetonitriles of formula i are commercially
available or may be prepared as shown in Scheme III.
##STR01248##
[0290] Referring to Scheme III, wherein R represents substituents
as described for R.sub.4, the aryl bromide vii is converted to the
ester viii with carbon monoxide and methanol in the presence of
tetrakis(triphenylphosphine)palladium (0). The ester viii is
reduced to the alcohol ix with a reducing reagent such as lithium
aluminum hydride. The benzyl alcohol ix is converted to the
corresponding benzylchloride with, for example, thionyl chloride.
Reaction of the benzylchloride x with a cyanide, for example sodium
cyanide, provides the starting nitriles i. Or the aldehyde xiv can
also be converted into the corresponding nitrile i by reaction with
TosMIC reagent.
[0291] The aryl bromides vii are commercially available or may be
prepared by known methods.
[0292] In some instances, the anilines iv (Scheme I) wherein one of
R.sub.1 is aryl or heteroaryl may be prepared as shown in Scheme
IV.
##STR01249##
[0293] Referring to Scheme IV, an aryl boronic acid xi is coupled
with an aniline xii protected as, for example, a
tert-butoxycarbonyl derivative (BOC), in the presence of a
palladium reagent as previously described for Scheme II to give
xiii. Removal of the protecting group under known conditions such
as aqueous HCl provides the desired substituted aniline.
[0294] Boronic acids are commercially available or may be prepared
by known methods.
[0295] In some instances, R.sub.1 and R.sub.4 may contain
functionality such as, for example, a carboxylate, a nitrile or an
amine, which may be further modified using known methods. For
example, carboxylates may be converted to amides or carbamates;
amines may be converted to amides, sulfonamides or carbamates;
nitriles may be reduced to amino methyl compounds which in turn may
be further converted to amine derivatives.
Formulations, Administrations, and Uses
Pharmaceutically Acceptable Compositions
[0296] Accordingly, in another aspect of the present invention,
pharmaceutically acceptable compositions are provided, wherein
these compositions comprise any of the compounds as described
herein, and optionally comprise a pharmaceutically acceptable
carrier, adjuvant or vehicle. In certain embodiments, these
compositions optionally further comprise one or more additional
therapeutic agents.
[0297] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative or a
prodrug thereof. According to the present invention, a
pharmaceutically acceptable derivative or a prodrug includes, but
is not limited to, pharmaceutically acceptable salts, esters, salts
of such esters, or any other adduct or derivative which upon
administration to a patient in need is capable of providing,
directly or indirectly, a compound as otherwise described herein,
or a metabolite or residue thereof.
[0298] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, 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. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof.
[0299] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge, et al. describes pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+ (C.sub.1-4alkyl).sub.4 salts.
This invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0300] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as 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 sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
Uses of Compounds and Pharmaceutically Acceptable Compositions
[0301] In yet another aspect, the present invention provides a
method of treating a condition, disease, or disorder implicated by
ABC transporter activity. In certain embodiments, the present
invention provides a method of treating a condition, disease, or
disorder implicated by a deficiency of ABC transporter activity,
the method comprising administering a composition comprising a
compound of formula (I) to a subject, preferably a mammal, in need
thereof.
[0302] In certain preferred embodiments, the present invention
provides a method of treating Cystic fibrosis, Hereditary
emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis
deficiencies, such as Protein C deficiency, Type 1 hereditary
angioedema, Lipid processing deficiencies, such as Familial
hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia,
Lysosomal storage diseases, such as I-cell disease/Pseudo-Hurler,
Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism,
Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital
hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, Amyotrophic lateral
sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders asuch as Huntington,
Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,
Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob
disease (due to Prion protein processing defect), Fabry disease,
Straussler-Scheinker disease, secretory diarrhea, polycystic kidney
disease, chronic obstructive pulmonary disease (COPD), dry eye
disease, and Sjogren's Syndrome, comprising the step of
administering to said mammal an effective amount of a composition
comprising a compound of formula (I), or a preferred embodiment
thereof as set forth above.
[0303] According to an alternative preferred embodiment, the
present invention provides a method of treating cystic fibrosis
comprising the step of administering to said mammal a composition
comprising the step of administering to said mammal an effective
amount of a composition comprising a compound of formula (I), or a
preferred embodiment thereof as set forth above.
[0304] According to the invention an "effective amount" of the
compound or pharmaceutically acceptable composition is that amount
effective for treating or lessening the severity of one or more of
Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis,
Coagulation-Fibrinolysis deficiencies, such as Protein C
deficiency, Type 1 hereditary angioedema, Lipid processing
deficiencies, such as Familial hypercholesterolemia, Type 1
chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases,
such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,
Sandhof/Tay-Sachs, Crigler-Najjar type II,
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism,
Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital
hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, Amyotrophic lateral
sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders asuch as Huntington,
Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,
Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob
disease, Fabry disease, Straussler-Scheinker disease, secretory
diarrhea, polycystic kidney disease, chronic obstructive pulmonary
disease (COPD), dry eye disease, and Sjogren's Syndrome.
[0305] The compounds and compositions, according to the method of
the present invention, may be administered using any amount and any
route of administration effective for treating or lessening the
severity of one or more of Cystic fibrosis, Hereditary emphysema,
Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies,
such as Protein C deficiency, Type 1 hereditary angioedema, Lipid
processing deficiencies, such as Familial hypercholesterolemia,
Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal storage
diseases, such as I-cell disease/Pseudo-Hurler,
Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism,
Melanoma, Glycanosis CDG type 1, Hereditary emphysema, Congenital
hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease, Amyotrophic lateral
sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine neurological disorders asuch as Huntington,
Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,
Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob
disease, Fabry disease, Straussler-Scheinker disease, secretory
diarrhea, polycystic kidney disease, chronic obstructive pulmonary
disease (COPD), dry eye disease, and Sjogren's Syndrome.
[0306] The exact amount required will vary from subject to subject,
depending on the species, age, and general condition of the
subject, the severity of the infection, the particular agent, its
mode of administration, and the like. The compounds of the
invention are preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed, and like
factors well known in the medical arts. The term "patient", as used
herein, means an animal, preferably a mammal, and most preferably a
human.
[0307] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0308] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, 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, dimethylformamide, 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.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0309] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0310] The injectable formulations can 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 prior to use.
[0311] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound 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 compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0312] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0313] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is 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, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, 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, for example, 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.
[0314] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. 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 can also be of a
composition 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
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0315] The active compounds can also be in microencapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition 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 that can be used include polymeric
substances and waxes.
[0316] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, eardrops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
are prepared by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0317] As described generally above, the compounds of the invention
are useful as modulators of ABC transporters. Thus, without wishing
to be bound by any particular theory, the compounds and
compositions are particularly useful for treating or lessening the
severity of a disease, condition, or disorder where hyperactivity
or inactivity of ABC transporters is implicated in the disease,
condition, or disorder. When hyperactivity or inactivity of an ABC
transporter is implicated in a particular disease, condition, or
disorder, the disease, condition, or disorder may also be referred
to as a "ABC transporter-mediated disease, condition or disorder".
Accordingly, in another aspect, the present invention provides a
method for treating or lessening the severity of a disease,
condition, or disorder where hyperactivity or inactivity of an ABC
transporter is implicated in the disease state.
[0318] The activity of a compound utilized in this invention as a
modulator of an ABC transporter may be assayed according to methods
described generally in the art and in the Examples herein.
[0319] It will also be appreciated that the compounds and
pharmaceutically acceptable compositions of the present invention
can be employed in combination therapies, that is, the compounds
and pharmaceutically acceptable compositions can be administered
concurrently with, prior to, or subsequent to, one or more other
desired therapeutics or medical procedures. The particular
combination of therapies (therapeutics or procedures) to employ in
a combination regimen will take into account compatibility of the
desired therapeutics and/or procedures and the desired therapeutic
effect to be achieved. It will also be appreciated that the
therapies employed may achieve a desired effect for the same
disorder (for example, an inventive compound may be administered
concurrently with another agent used to treat the same disorder),
or they may achieve different effects (e.g., control of any adverse
effects). As used herein, additional therapeutic agents that are
normally administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated".
[0320] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0321] The compounds of this invention or pharmaceutically
acceptable compositions thereof may also be incorporated into
compositions for coating an implantable medical device, such as
prostheses, artificial valves, vascular grafts, stents and
catheters. Accordingly, the present invention, in another aspect,
includes a composition for coating an implantable device comprising
a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for
coating said implantable device. In still another aspect, the
present invention includes an implantable device coated with a
composition comprising a compound of the present invention as
described generally above, and in classes and subclasses herein,
and a carrier suitable for coating said implantable device.
Suitable coatings and the general preparation of coated implantable
devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and
5,304,121. The coatings are typically biocompatible polymeric
materials such as a hydrogel polymer, polymethyldisiloxane,
polycaprolactone, polyethylene glycol, polylactic acid, ethylene
vinyl acetate, and mixtures thereof. The coatings may optionally be
further covered by a suitable topcoat of fluorosilicone,
polysaccarides, polyethylene glycol, phospholipids or combinations
thereof to impart controlled release characteristics in the
composition.
[0322] Another aspect of the invention relates to modulating ABC
transporter activity in a biological sample or a patient (e.g., in
vitro or in vivo), which method comprises administering to the
patient, or contacting said biological sample with a compound of
formula I or a composition comprising said compound. The term
"biological sample", as used herein, includes, without limitation,
cell cultures or extracts thereof; biopsied material obtained from
a mammal or extracts thereof; and blood, saliva, urine, feces,
semen, tears, or other body fluids or extracts thereof.
[0323] Modulation of ABC transporter activity in a biological
sample is useful for a variety of purposes that are known to one of
skill in the art. Examples of such purposes include, but are not
limited to, the study of ABC transporters in biological and
pathological phenomena; and the comparative evaluation of new
modulators of ABC transporters.
[0324] In yet another embodiment, a method of modulating activity
of an anion channel in vitro or in vivo, is provided comprising the
step of contacting said channel with a compound of formula (I). In
preferred embodiments, the anion channel is a chloride channel or a
bicarbonate channel. In other preferred embodiments, the anion
channel is a chloride channel.
[0325] According to an alternative embodiment, the present
invention provides a method of increasing the number of functional
ABC transporters in a membrane of a cell, comprising the step of
contacting said cell with a compound of formula (I). The term
"functional ABC transporter" as used herein means an ABC
transporter that is capable of transport activity. In preferred
embodiments, said functional ABC transporter is CFTR.
[0326] According to another preferred embodiment, the activity of
the ABC transporter is measured by measuring the transmembrane
voltage potential. Means for measuring the voltage potential across
a membrane in the biological sample may employ any of the known
methods in the art, such as optical membrane potential assay or
other electrophysiological methods.
[0327] The optical membrane potential assay utilizes
voltage-sensitive FRET sensors described by Gonzalez and Tsien (See
Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by
fluorescence resonance energy transfer in single cells" Biophys J
69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997)
"Improved indicators of cell membrane potential that use
fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in
combination with instrumentation for measuring fluorescence changes
such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E.,
K. Oades, et al. (1999) "Cell-based assays and instrumentation for
screening ion-channel targets" Drug Discov Today 4(9):
431-439).
[0328] These voltage sensitive assays are based on the change in
fluorescence resonant energy transfer (FRET) between the
membrane-soluble, voltage-sensitive dye, DiSBAC.sub.2(3), and a
fluorescent phospholipid, CC2-DMPE, which is attached to the outer
leaflet of the plasma membrane and acts as a FRET donor. Changes in
membrane potential (V.sub.m) cause the negatively charged
DiSBAC.sub.2(3) to redistribute across the plasma membrane and the
amount of energy transfer from CC2-DMPE changes accordingly. The
changes in fluorescence emission can be monitored using VIPR.TM.
II, which is an integrated liquid handler and fluorescent detector
designed to conduct cell-based screens in 96- or 384-well
microtiter plates.
[0329] In another aspect the present invention provides a kit for
use in measuring the activity of a ABC transporter or a fragment
thereof in a biological sample in vitro or in vivo comprising (i) a
composition comprising a compound of formula (I) or any of the
above embodiments; and (ii) instructions for a.) contacting the
composition with the biological sample and b.) measuring activity
of said ABC transporter or a fragment thereof. In one embodiment,
the kit further comprises instructions for a.) contacting an
additional composition with the biological sample; b.) measuring
the activity of said ABC transporter or a fragment thereof in the
presence of said additional compound, and c.) comparing the
activity of the ABC transporter in the presence of the additional
compound with the density of the ABC transporter in the presence of
a composition of formula (I). In preferred embodiments, the kit is
used to measure the density of CFTR.
PREPARATIONS AND EXAMPLES
General Procedure 1
##STR01250##
[0330] Preparation 1
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (A-8)
##STR01251##
[0332] A mixture of benzo[1,3]dioxole-5-acetonitrile (5.10 g 31.7
mmol), 1-bromo-2-chloroethane (9.00 mL 109 mmol), and
benzyltriethylammonium chloride (0.181 g, 0.795 mmol) was heated at
70.degree. C. and then 50% (wt./wt.) aqueous sodium hydroxide (26
mL) was slowly added to the mixture. The reaction was stirred at
70.degree. C. for 24 hours and was then heated at 130.degree. C.
for 48 hours. The dark brown reaction mixture was diluted with
water (400 mL) and extracted once with an equal volume of ethyl
acetate and once with an equal volume of dichloromethane. The basic
aqueous solution was acidified with concentrated hydrochloric acid
to pH less than one and the precipitate was filtered and washed
with 1 M hydrochloric acid. The solid material was dissolved in
dichloromethane (400 mL) and extracted twice with equal volumes of
1 M hydrochloric acid and once with a saturated aqueous solution of
sodium chloride. The organic solution was dried over sodium sulfate
and evaporated to dryness to give a white to slightly off-white
solid (5.23 g, 80%) ESI-MS m/z calc. 206.1. found 207.1
(M+1).sup.+. Retention time 2.37 minutes. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98
(s, 2H), 6.79 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).
Preparation 2
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid
(A-9)
##STR01252##
[0333] Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid
methyl ester
[0334] A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8
g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (0)
[Pd(PPh.sub.3).sub.4, 5.78 g, 5.00 mmol] in methanol (20 mL)
containing acetonitrile (30 mL) and triethylamine (10 mL) was
stirred under a carbon monoxide atmosphere (55 PSI) at 75.degree.
C. (oil bath temperature) for 15 hours. The cooled reaction mixture
was filtered and the filtrate was evaporated to dryness. The
residue was purified by silica gel column chromatography to give
crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester
(11.5 g), which was used directly in the next step.
Step b: (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-methanol
[0335] Crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid
methyl ester (11.5 g) dissolved in 20 mL of anhydrous
tetrahydrofuran (THF) was slowly added to a suspension of lithium
aluminum hydride (4.10 g, 106 mmol) in anhydrous THF (100 mL) at
0.degree. C. The mixture was then warmed to room temperature. After
being stirred at room temperature for 1 hour, the reaction mixture
was cooled to 0.degree. C. and treated with water (4.1 g), followed
by sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting
slurry was filtered and washed with THF. The combined filtrate was
evaporated to dryness and the residue was purified by silica gel
column chromatography to give
(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 76% over two
steps) as a colorless oil.
Step c: 5-Chloromethyl-2,2-difluoro-benzo[1,3]dioxole
[0336] Thionyl chloride (45 g, 38 mmol) was slowly added to a
solution of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g,
38 mmol) in dichloromethane (200 mL) at 0.degree. C. The resulting
mixture was stirred overnight at room temperature and then
evaporated to dryness. The residue was partitioned between an
aqueous solution of saturated sodium bicarbonate (100 mL) and
dichloromethane (100 mL). The separated aqueous layer was extracted
with dichloromethane (150 mL) and the organic layer was dried over
sodium sulfate, filtrated, and evaporated to dryness to give crude
5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) which was
used directly in the next step.
Step d: (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile
[0337] A mixture of crude
5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) and sodium
cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) was
stirred at room temperature overnight. The reaction mixture was
poured into ice and extracted with ethyl acetate (300 mL). The
organic layer was dried over sodium sulfate and evaporated to
dryness to give crude
(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (3.3 g) which was
used directly in the next step.
Step e:
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile
[0338] Sodium hydroxide (50% aqueous solution, 10 mL) was slowly
added to a mixture of crude
(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile,
benzyltriethylammonium chloride (3.00 g, 15.3 mmol), and
1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70.degree. C. The
mixture was stirred overnight at 70.degree. C. before the reaction
mixture was diluted with water (30 mL) and extracted with ethyl
acetate. The combined organic layers were dried over sodium sulfate
and evaporated to dryness to give crude
1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile,
which was used directly in the next step.
Step f:
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid
(A-9)
[0339] To
1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile
(crude from the last step) was added 10% aqueous sodium hydroxide
(50 mL) and the mixture was heated at reflux for 2.5 hours. The
cooled reaction mixture was washed with ether (100 mL) and the
aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The
precipitated solid was filtered to give
1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid
as a white solid (0.15 g, 2% over four steps). ESI-MS m/z calc.
242.2. found 243.3; .sup.1H NMR (CDCl.sub.3) .delta. 7.14-7.04 (m,
2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).
Preparation 3
2-(4-(Benzyloxy)-3-chlorophenyl)acetonitrile
##STR01253##
[0340] Step a: 4-Benzyloxy-3-chloro-benzaldehyde
[0341] To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32
mmol) and BnBr (6.6 g, 38 mmol) in CH.sub.3CN (100 mL) was added
K.sub.2CO.sub.3 (8.8 g, 64 mmol). The mixture was heated at reflux
for 2 hours. The resulting mixture was poured into water (100 mL),
and extracted with EtOAc (100 mL.times.3). The combined organic
layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under vacuum to give crude product,
which was purified by column (petroleum ether/EtOAc 15:1) to give
4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1H),
7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.47-7.34 (m, 5H), 7.08 (d, J=8.8 Hz,
1H), 4.26 (s, 2H).
Step b: 2-(4-(Benzyloxy)-3-chlorophenyl)acetonitrile
[0342] To a suspension of t-BuOK (11.7 g, 96 mmol) in THF (200 mL)
was added a solution of TosMIC (9.4 g, 48 mmol) in THF (100 mL) at
-78.degree. C. The mixture was stirred for 15 minutes, treated with
a solution of 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 30 mmol) in
THF (50 mL) dropwise, and continued to stir for 1.5 hours at
-78.degree. C. To the cooled reaction mixture was added methanol
(30 mL). The mixture was heated at reflux for 30 minutes. Solvent
of the reaction mixture was removed to give a crude product, which
was dissolved in water (300 mL). The aqueous phase was extracted
with EtOAc (3.times.100 mL). The combined organic layers were dried
and evaporated under reduced pressure to give crude product, which
was purified by column chromatography (petroleum ether/EtOAc 10:1)
to afford 2-(4-(benzyloxy)-3-chlorophenyl)acetonitrile (2.7 g,
34%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.52-7.32 (m, 6H),
7.15 (dd, J=2.4, 8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.26 (s, 2H),
3.73 (s, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 154.0,
136.1, 129.9, 128.7, 128.7, 128.1, 127.2, 127.1, 127.1, 124.0,
123.0, 117.5, 114.4, 70.9, 22.5.
Preparation 4
1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane-carboxylic
acid (A-19)
##STR01254##
[0343] Step a: 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid
methyl ester
[0344] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic
acid (50.0 g, 0.26 mol) in MeOH (500 mL) was added
toluene-4-sulfonic acid monohydrate (2.5 g, 13.1 mmol) at room
temperature. The reaction mixture was heated at reflux for 20
hours. MeOH was removed by evaporation under vacuum and EtOAc (200
mL) was added. The organic layer was washed with sat. aq.
NaHCO.sub.3 (100 mL) and brine, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under vacuum to give
1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53.5
g, 99%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.25-7.27 (m,
2H), 6.85 (d, J=8.8 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 3H), 1.58 (q,
J=3.6 Hz, 2H), 1.15 (q, J=3.6 Hz, 2H).
Step b: 1-(4-Methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid
methyl ester
[0345] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic
acid methyl ester (30.0 g, 146 mmol) in Ac.sub.2O (300 mL) was
added a solution of HNO.sub.3 (14.1 g, 146 mmol, 65%) in AcOH (75
mL) at 0.degree. C. The reaction mixture was stirred at
0.about.5.degree. C. for 3 h before aq. HCl (20%) was added
dropwise at 0.degree. C. The resulting mixture was extracted with
EtOAc (200 mL.times.3). The organic layer was washed with sat. aq.
NaHCO.sub.3 then brine, dried over anhydrous Na.sub.2SO.sub.4 and
evaporated under vacuum to give
1-(4-methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl
ester (36.0 g, 98%), which was directly used in the next step.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.84 (d, J=2.1 Hz, 1H),
7.54 (dd, J=2.1, 8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.97 (s, 3H),
3.65 (s, 3H), 1.68-1.64 (m, 2H), 1.22-1.18 (m, 2H).
Step c: 1-(4-Hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid
methyl ester
[0346] To a solution of
1-(4-methoxy-3-nitro-phenyl)-cyclopropane-carboxylic acid methyl
ester (10.0 g, 39.8 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added
BBr.sub.3 (12.0 g, 47.8 mmol) at -70.degree. C. The mixture was
stirred at -70.degree. C. for 1 hour, then allowed to warm to
-30.degree. C. and stirred at this temperature for 3 hours. Water
(50 mL) was added dropwise at -20.degree. C., and the resulting
mixture was allowed to warm room temperature before it was
extracted with EtOAc (200 mL.times.3). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under
vacuum to give the crude product, which was purified by column
chromatography on silica gel (petroleum ether/EtOAc 15:1) to afford
1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl
ester (8.3 g, 78%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.5
(s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.59 (dd, J=2.0, 8.8 Hz, 1H), 7.11
(d, J=8.4 Hz, 1H), 3.64 (s, 3H), 1.68-1.64 (m, 2H), 1.20-1.15 (m,
2H).
Step d: 1-(3-Amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid
methyl ester
[0347] To a solution of
1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl
ester (8.3 g, 35.0 mmol) in MeOH (100 mL) was added Raney Ni (0.8
g) under nitrogen atmosphere. The mixture was stirred under
hydrogen atmosphere (1 atm) at 35.degree. C. for 8 hours. The
catalyst was filtered off through a Celite pad and the filtrate was
evaporated under vacuum to give crude product, which was purified
by column chromatography on silica gel (P.E./EtOAc 1:1) to give
1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl
ester (5.3 g, 74%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 6.77
(s, 1H), 6.64 (d, J=2.0 Hz, 2H), 3.64 (s, 3H), 1.55-1.52 (m, 2H),
1.15-1.12 (m, 2H).
Step e:
1-(2-Oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid
methyl ester
[0348] To a solution of
1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl
ester (2.0 g, 9.6 mmol) in THF (40 mL) was added triphosgene (4.2
g, 14 mmol) at room temperature. The mixture was stirred for 20
minutes at this temperature before water (20 mL) was added dropwise
at 0.degree. C. The resulting mixture was extracted with EtOAc (100
mL.times.3). The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under vacuum to give
1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid
methyl ester (2.0 g, 91%), which was directly used in the next
step. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.66 (s, 1H),
7.13-7.12 (m, 2H), 7.07 (s, 1H), 3.66 (s, 3H), 1.68-1.65 (m, 2H),
1.24-1.20 (m, 2H).
Step f:
1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic
acid
[0349] To a solution of
1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid
methyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) was
added LiOH.H.sub.2O (1.7 g, 41 mmol) in portions at room
temperature. The reaction mixture was stirred for 20 hours at
50.degree. C. MeOH was removed by evaporation under vacuum before
water (100 mL) and EtOAc (50 mL) were added. The aqueous layer was
separated, acidified with HCl (3 mol/L) and extracted with EtOAc
(100 mL.times.3). The combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum to give
1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid
(1.5 g, 84%). .sup.1H NMR (DMSO, 400 MHz) .delta. 12.32 (brs, 1H),
11.59 (brs, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H),
1.44-1.41 (m, 2H), 1.13-1.10 (m, 2H). MS (ESI) m/e (M+H.sup.+)
218.1.
Preparation 5
1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (A-20)
##STR01255##
[0350] Step a: 1-Benzooxazol-5-yl-cyclopropanecarboxylic acid
methyl ester
[0351] To a solution of
1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl
ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate
(5.30 g, 14.5 mmol) and a catalytic amount of p-tolueneslufonic
acid monohydrate (0.3 g) at room temperature. The mixture was
stirred for 3 hours at room temperature. The mixture was diluted
with water and extracted with EtOAc (100 mL.times.3). The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4 and
evaporated under vacuum to give crude
1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1
g), which was directly used in the next step. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1H),
7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m,
2H), 1.27-1.24 (m, 2H).
Step b: 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid
[0352] To a solution of crude
1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g)
in EtSH (30 mL) was added AlCl.sub.3 (5.3 g, 40.1 mmol) in portions
at 0.degree. C. The reaction mixture was stirred for 18 hours at
room temperature. Water (20 mL) was added dropwise at 0.degree. C.
The resulting mixture was extracted with EtOAc (100 mL.times.3).
The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under vacuum to give the crude
product, which was purified by column chromatography on silica gel
(petroleum ether/EtOAc 1:2) to give
1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, two
steps: 11%). .sup.1H NMR (DMSO, 400 MHz) .delta. 12.25 (brs, 1H),
8.71 (s, 1H), 7.70-7.64 (m, 2H), 7.40 (dd, J=1.6, 8.4 Hz, 1H),
1.49-1.46 (m, 2H), 1.21-1.18 (m, 2H). MS (ESI) m/e (M+H.sup.+)
204.4.
Preparation 6
2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile
##STR01256##
[0353] Step a: 3-Chloro-4,5-dihydroxybenzaldehyde
[0354] To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde
(10 g, 54 mmol) in dichloromethane (300 mL) was added BBr.sub.3
(26.7 g, 107 mmol) dropwise at -40.degree. C. under N.sub.2. After
addition, the mixture was stirred at this temperature for 5 h and
then was poured into ice water. The precipitated solid was filtered
and washed with petroleum ether. The filtrate was evaporated under
reduced pressure to afford 3-chloro-4,5-dihydroxybenzaldehyde (9.8
g, 89%), which was directly used in the next step.
Step b: 7-Chlorobenzo[d][1,3]dioxole-5-carbaldehyde
[0355] To a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g,
46 mmol) and BrClCH.sub.2 (23.9 g, 185 mmol) in dry DMF (100 mL)
was added Cs.sub.2CO.sub.3 (25 g, 190 mmol). The mixture was
stirred at 60.degree. C. overnight and was then poured into water.
The resulting mixture was extracted with EtOAc (50 mL.times.3). The
combined extracts were washed with brine (100 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 70%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 9.74 (s, 1H), 7.42 (d, J=0.4 Hz,
1H), 7.26 (d, J=3.6 Hz, 1H), 6.15 (s, 2H)
Step c: (7-Chlorobenzo[d][1,3]dioxol-5-yl)methanol
[0356] To a solution of 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde
(6.0 g, 33 mmol) in THF (50 mL) was added NaBH.sub.4 (2.5 g, 64
mmol)) in portion at 0.degree. C. The mixture was stirred at this
temperature for 30 min and then poured into aqueous NH.sub.4Cl
solution. The organic layer was separated, and the aqueous phase
was extracted with EtOAc (50 mL.times.3). The combined extracts
were dried over Na.sub.2SO.sub.4 and evaporated under reduced
pressure to afford (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol,
which was directly used in the next step.
Step d: 4-Chloro-6-(chloromethyl)benzo[d][1,3]dioxole
[0357] A mixture of (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol (5.5
g, 30 mmol) and SOCl.sub.2 (5.0 mL, 67 mmol) in dichloromethane (20
mL) was stirred at room temperature for 1 h and was then poured
into ice water. The organic layer was separated and the aqueous
phase was extracted with dichloromethane (50 mL.times.3). The
combined extracts were washed with water and aqueous NaHCO.sub.3
solution, dried over Na.sub.2SO.sub.4 and evaporated under reduced
pressure to afford 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole,
which was directly used in the next step.
Step e: 2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile
[0358] A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole
(6.0 g, 29 mmol) and NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was
stirred at 40.degree. C. for 1 h and was then poured into water.
The mixture was extracted with EtOAc (30 mL.times.3). The combined
organic layers were washed with water and brine, dried over
Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford
2-(7-chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile (3.4 g, 58%).
.sup.1H NMR .delta. 6.81 (s, 1H), 6.71 (s, 1H), 6.07 (s, 2H), 3.64
(s, 2H). .sup.13C-NMR .delta.149.2, 144.3, 124.4, 122.0, 117.4,
114.3, 107.0, 102.3, 23.1.
Preparation 7
2-(7-Fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile
##STR01257##
[0359] Step a: 3-Fluoro-4,5-dihydroxy-benzaldehyde
[0360] To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde
(1.35 g, 7.94 mmol) in dichloromethane (100 mL) was added BBr.sub.3
(1.5 mL, 16 mmol) dropwise at -78.degree. C. under N.sub.2. After
addition, the mixture was warmed to -30.degree. C. and it was
stirred at this temperature for 5 h. The reaction mixture was
poured into ice water. The precipitated solid was collected by
filtration and washed with dichloromethane to afford
3-fluoro-4,5-dihydroxy-benzaldehyde (1.1 g, 89%), which was
directly used in the next step.
Step b: 7-Fluoro-benzo[1,3]dioxole-5-carbaldehyde
[0361] To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g,
9.6 mmol) and BrClCH.sub.2 (4.9 g, 38.5 mmol) in dry DMF (50 mL)
was added Cs.sub.2CO.sub.3 (12.6 g, 39 mmol). The mixture was
stirred at 60.degree. C. overnight and was then poured into water.
The resulting mixture was extracted with EtOAc (50 mL.times.3). The
combined organic layers were washed with brine (100 mL), dried over
Na.sub.2SO.sub.4 and evaporated under reduced pressure to give the
crude product, which was purified by column chromatography on
silica gel (petroleum ether/E.A.=10/1) to afford
7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 49%). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 9.78 (d, J=0.9 Hz, 1H), 7.26 (dd,
J=1.5, 9.3 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 6.16 (s, 2H).
Step c: (7-Fluoro-benzo[1,3]dioxol-5-yl)-methanol
[0362] To a solution of 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde
(0.80 g, 4.7 mmol) in MeOH (50 mL) was added NaBH.sub.4 (0.36 g,
9.4 mmol) in portions at 0.degree. C. The mixture was stirred at
this temperature for 30 min and was then concentrated to dryness.
The residue was dissolved in EtOAc. The EtOAc layer was washed with
water, dried over Na.sub.2SO.sub.4 and concentrated to dryness to
afford (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 98%),
which was directly used in the next step.
Step d: 6-Chloromethyl-4-fluoro-benzo[1,3]dioxole
[0363] To SOCl.sub.2 (20 mL) was added
(7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 4.7 mmol) in
portions at 0.degree. C. The mixture was warmed to room temperature
over 1 h and then was heated at reflux for 1 h. The excess
SOCl.sub.2 was evaporated under reduced pressure to give the crude
product, which was basified with saturated aqueous NaHCO.sub.3 to
pH.about.7. The aqueous phase was extracted with EtOAc (50
mL.times.3). The combined organic layers were dried over
Na.sub.2SO.sub.4 and evaporated under reduced pressure to give
6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 92%), which was
directly used in the next step.
Step e: 2-(7-Fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile
[0364] A mixture of 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80
g, 4.3 mmol) and NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was
stirred at 30.degree. C. for 1 h and was then poured into water.
The mixture was extracted with EtOAc (50 mL.times.3). The combined
organic layers were washed with water (50 mL) and brine (50 mL),
dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure
to give the crude product, which was purified by column
chromatography on silica gel (petroleum ether/E.A.=10/1) to afford
2-(7-fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (530 mg, 70%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.68-6.64 (m, 2H), 6.05
(s, 2H), 3.65 (s, 2H). .sup.13C-NMR .delta.151.1, 146.2, 134.1,
124.2, 117.5, 110.4, 104.8, 102.8, 23.3.
[0365] Additional acids given in Table 2 were either commercially
available or synthesized using appropriate starting materials and
the procedures of preparations 1-7.
TABLE-US-00002 TABLE 2 Carboxylic Acids. Acids Name A-1
1-Phenylcyclopropanecarboxylic acid A-2
1-(2-Methoxyphenyl)cyclopropanecarboxylic acid A-3
1-(3-Methoxyphenyl)cyclopropanecarboxylic acid A-4
1-(4-Methoxyphenyl)cyclopropanecarboxylic acid A-5
1-(4-(Trifluoromethoxy)phenyl)cyclopropanecarboxylic acid A-6
1-(4-Chlorophenyl)cyclopropanecarboxylic acid A-7
1-(3,4-Dimethoxyphenyl)cyclopropanecarboxylic acid A-8
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid A-9
1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)- cyclopropanecarboxylic acid
A-10 1-Phenylcyclopentanecarboxylic acid A-11
1-(4-Chlorophenyl)cyclopentanecarboxylic acid A-12
1-(4-Methoxyphenyl)cyclopentanecarboxylic acid A-13
1-(Benzo[d][1,3]dioxol-5-yl)cyclopentanecarboxylic acid A-14
1-Phenylcyclohexanecarboxylic acid A-15
1-(4-Chlorophenyl)cyclohexanecarboxylic acid A-16
1-(4-Methoxyphenyl)cyclohexanecarboxylic acid A-17
4-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid A-18
1-(3-Chloro-4-hydroxyphenyl)cyclopropanecarboxylic acid A-19
1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5- yl)cyclopropanecarboxylic
acid A-20 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid A-21
1-(7-Chlorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxylic acid
A-22 1-(7-Fluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic
acid A-23 1-(3,4-Difluorophenyl)cyclopropanecarboxylic acid A-24
1-(1H-Indol-5-yl)cyclopropanecarboxylic acid A-25
1-(2,3-Dihydrobenzo[b][1,4]dioxin-6- yl)cyclopropanecarboxylic acid
A-26 1-(2,3-Dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid A-27
1-(3,4-Dichlorophenyl)cyclopropanecarboxylic acid A-28
1-(2-Methyl-1H-benzo[d]imidazol-5- yl)cyclopropanecarboxylic acid
A-29 1-(4-Hydroxy-4-methoxychroman-6- yl)cyclopropanecarboxylic
acid A-30 1-(Benzofuran-6-yl)cyclopropanecarboxylic acid A-31
1-(1-Methyl-1H-benzo[d][1,2,3]triazol-5- yl)cyclopropanecarboxylic
acid A-32 1-(2,3-Dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid
A-33 1-(3-Methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid
A-34 1-(4-Oxochroman-6-yl)cyclopropanecarboxylic acid A-35
1-(Spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-
yl)cyclopropanecarboxylic acid A-36
1-(1,3-Dihydroisobenzofuran-5-yl)cyclopropanecarboxylic acid A-37
1-(6-Fluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
A-38 1-(Chroman-6-yl)cyclopropanecarboxylic acid
Preparation 8
3-Bromo-4-methoxybenzenamine
##STR01258##
[0367] 2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol),
SnCl.sub.2.2H.sub.2O (12.2 g, 53.9 mmol), and MeOH (30 mL) were
combined and allowed to stir for 3 h at ambient temperature. To the
mixture was added H.sub.2O (100 mL) and EtOAc (100 mL) resulting in
the formation of a thick emulsion. To this was added sat. aq.
NaHCO.sub.3 (30 mL). The layers were separated and the aqueous
layer was extracted with EtOAc (3.times.30 mL). The organics were
combined and dried over MgSO.sub.4 before being filtered.
Concentration of the filtrate in vacuo gave 2.02 g of an off-white
solid. This material was used without further purification.
[0368] In addition to bromo-anilines prepared according to
preparation 8, non-limiting examples of commercially available
bromo anilines and bromo nitrobenzenes are given in Table 3.
TABLE-US-00003 TABLE 3 Non-limiting examples of commercially
available anilines. Name 4-Bromoaniline 4-Bromo-3-methylaniline
4-Bromo-3-(trifluoromethyl)aniline 3-Bromoaniline
5-Bromo-2-methylaniline 5-Bromo-2-fluoroaniline
5-Bromo-2-(trifluoromethoxy)aniline 3-Bromo-4-methylaniline
3-Bromo-4-fluoroaniline 2-Bromo-1-methoxy-4-nitrobenzene
2-Bromo-1-chloro-4-nitrobenzene 4-Bromo-3-methylaniline
3-Bromo-4-methylaniline 3-Bromo-4-(trifluoromethoxy)aniline
3-Bromo-5-(trifluoromethyl)aniline 3-Bromo-2-methylaniline
Preparation 9
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)cyclopropane-carbo-
xamide (B-10)
##STR01259##
[0369] Step a: 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl
chloride
[0370] To an oven-dried round bottom flask containing
1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-8) (618
mg, 3.0 mmol) and CH.sub.2Cl.sub.2 (3 mL) was added thionyl
chloride (1.07 g, 9.0 mmol) and N,N-dimethylformamide (0.1 mL). The
reaction mixture was stirred at ambient temperature under an Ar
atmosphere until the gas evolution ceased (2-3 h). The excess
thionyl chloride was removed under vacuum and the resulting residue
dissolved in CH.sub.2Cl.sub.2 (3 mL). The mixture was used without
further manipulation.
Step b:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)-cycloprop-
ane-carboxamide (B-10)
[0371] To a solution of the crude
1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride (3.0 mmol) in
CH.sub.2Cl.sub.2 (30 mL) at ambient temperature was added a
solution of 3-bromo-4-methoxybenzenamine (3.3 mmol), Et.sub.3N (15
mmol), and CH.sub.2Cl.sub.2 (90 mL) dropwise. The mixture was
allowed to stir for 16 h before it was diluted with
CH.sub.2Cl.sub.2 (500 mL). The solution was washed with 1N HCl
(2.times.250 mL), sat. aq. NaHCO.sub.3 (2.times.250 mL), then brine
(250 mL). The organics were dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo to provide
1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)cyclopropanecarbo-
xamide (B-10) with suitable purity to be used without further
purification.
[0372] Table 4 lists additional N-bromophenyl amides prepared
according to preparation 9 and using appropriate starting
materials.
TABLE-US-00004 TABLE 4 N-bromophenyl amides prepared according to
preparation 9 and using appropriate starting materials. Aryl
bromides Name Anilines B-1 1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-
4-Bromoaniline bromophenyl)cyclopropanecarboxamide B-2
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromo-3- 4-Bromo-3-methylaniline
methylphenyl)cyclopropanecarboxamide B-3
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromo-3- 4-Bromo-3-
(trifluoromethyl)phenyl)cyclopropanecarboxamide
(trifluoromethyl)aniline B-4 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-
3-Bromoaniline bromophenyl)cyclopropanecarboxamide B-5
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-methylaniline
methylphenyl)cyclopropanecarboxamide B-6
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-fluoroaniline
fluorophenyl)cyclopropanecarboxamide B-7
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-
(trifluoromethoxy)phenyl)cyclopropanecarboxamide
(trifluoromethoxy)aniline B-8
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-methylaniline
methylphenyl)cyclopropanecarboxamide B-9
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-fluoroaniline
fluorophenyl)cyclopropanecarboxamide B-10
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-
methoxyphenyl)cyclopropanecarboxamide methoxybenzenamine B-11
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-chloroaniline
chlorophenyl)cyclopropanecarboxamide B-13
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-
isopropylphenyl)cyclopropanecarboxamide isopropylaniline B-14
N-(4-Bromo-3-methylphenyl)-1-(2,2- 4-Bromo-3-methylaniline
difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamide B-15
N-(3-Bromo-4-methylphenyl)-1-(2,2- 3-Bromo-4-methylaniline
difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamide B-16
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-tert-
tert-butylphenyl)cyclopropanecarboxamide butylaniline B-18
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-ethylaniline
ethylphenyl)cyclopropanecarboxamide B-19
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-
(trifluoromethoxy)phenyl)cyclopropanecarboxamide
(trifluoromethoxy)aniline B-20
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-fluoro-4-
fluoro-4- methylaniline methylphenyl)cyclopropanecarboxamide B-21
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-5- 3-Bromo-5-
(trifluoromethyl)phenyl)cyclopropanecarboxamide
(trifluromethyl)aniline B-22
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-2- 3-Bromo-2-methylaniline
methylphenyl)cyclopropanecarboxamide B-23
N-(3-Bromo-4-(3-methyloxetan-3-yl)phenyl)- 3-Bromo-4-(3-
1-(2,2-difluorobenzo[d][1,3]dioxol-5- methyloxetan-3-yl)aniline
yl)cyclopropanecarboxamide B-24 N-(3-Bromo-4-methylphenyl)-1-(4-
3-Bromo-4-methylaniline methoxyphenyl)cyclopropanecarboxamide
Preparation 10
((3'-Aminobiphenyl-4-yl)methyl)-methanesulfonamide (C-1)
##STR01260##
[0373] Step a: (4'-Cyano-biphenyl-3-yl)-carbamic acid tert-butyl
ester
[0374] A mixture of 4-cyanobenzeneboronic acid (14.7 g, 0.10 mol),
3-bromo-phenyl-carbamic acid tert-butyl ester (27.2 g, 0.10 mol),
Pd(Ph.sub.3P).sub.4 (11.6 g, 0.01 mol) and K.sub.2CO.sub.3 (21 g,
0.15 mol) in DMF/H.sub.2O (1:1, 350 mL) was stirred under argon at
80.degree. C. overnight. The DMF was evaporated under reduced
pressure, and the residue was dissolved in EtOAc (200 mL). The
mixture was washed with water and brine, dried over
Na.sub.2SO.sub.4, and concentrated to dryness. The residue was
purified by column chromatography (petroleum ether/EtOAc 50:1) on
silica gel to give (4'-cyano-biphenyl-3-yl)-carbamic acid
tert-butyl ester (17 g, 59%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 9.48 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.85 (s, 1H), 7.76
(d, J=8.4 Hz, 2H), 7.32-7.48 (m, 3H), 1.47 (s, 9H).
Step b: (4'-Aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl
ester
[0375] A suspension of (4'-cyano-biphenyl-3-yl)-carbamic acid
tert-butyl ester (7.6 g, 26 mmol) and Raney Ni (1 g) in EtOH (500
mL) and NH.sub.3.H.sub.2O (10 mL) was hydrogenated under 50 psi of
H.sub.2 at 50.degree. C. for 6 h. The catalyst was filtered off and
the filtrate was concentrated to dryness to give
(4'-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester,
which was used directly in next step.
Step c: [4'-(Methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic
acid tert-butyl ester
[0376] To a solution of crude
(4'-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester (8.2
g 27 mmol) and Et.sub.3N (4.2 g, 40 mmol) in dichloromethane (250
mL) was added dropwise MsCl (3.2 g, 27 mmol) at 0.degree. C. The
reaction mixture was stirred at this temperature for 30 min and was
then washed with water and saturated aqueous NaCl solution, dried
over Na.sub.2SO.sub.4, and concentrated to dryness. The residue was
recrystallized with DCM/pet ether (1:3) to give
[4'-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acid
tert-butyl ester (7.5 g, yield 73%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.67 (s, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.23-7.41
(m, 5H), 6.57 (s, 1H), 4.65-4.77 (m, 1H), 4.35 (d, J=6 Hz, 2H),
2.90 (s, 3H), 1.53 (s, 9H).
Step d: N((3'-Aminobiphenyl-4-yl)methyl)methanesulfonamide
[0377] A solution of
[4'-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acid
tert-butyl ester (5 g, 13 mmol) in HCl/MeOH (4M, 150 mL) was
stirred at room temperature overnight. The mixture was concentrated
to dryness and the residue was washed with ether to give the target
compound N-((3'-aminobiphenyl-4-yl)methyl)methanesulfonamide as its
HCl salt (3.0 g, 71%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
7.54-7.71 (m, 6H), 7.46 (d, J=7.8 Hz, 2H), 7.36 (d, J=7.5 Hz, 1H),
4.19 (s, 2H), 2.87 (s, 3H). MS (ESI) m/e (M+H.sup.+): 277.0.
Preparation 11
(R)-(1-(3'-Aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol
(C-2)
##STR01261##
[0378] Step a:
(R)-Bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol
[0379] To a mixture of sat aq. NaHCO.sub.3 (44 g, 0.53 mol),
CH.sub.2Cl.sub.2 (400 mL) and (R)-pyrrolidin-2-yl-methanol (53 g,
0.53 mol) was added 4-bromo-benzenesulfonyl chloride (130 g, 0.50
mol) in CH.sub.2Cl.sub.2 (100 mL). The reaction was stirred at
20.degree. C. overnight. The organic phase was separated and dried
over Na.sub.2SO.sub.4. Evaporation of the solvent under reduced
pressure provided
(R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (145 g,
crude), which was used in the next step without further
purification. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.66-7.73
(m, 4H), 3.59-3.71 (m, 3H), 3.43-3.51 (m, 1H), 3.18-3.26 (m, 1H),
1.680-1.88 (m, 3H), 1.45-1.53 (m, 1H).
Step b:
(R)-(1-(3'-Aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol
(C-2)
[0380] To a solution of
(R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (1.6 g,
5.0 mmol) in DMF (10 mL) was added 3-amino-phenyl boronic acid
(0.75 g, 5.5 mmol), Pd(PPh.sub.3).sub.4 (45 mg, 0.15 mmol),
potassium carbonate (0.75 g, 5.5 mmol) and water (5 mL). The
resulting mixture was degassed by gently bubbling argon through the
solution for 5 minutes at 20.degree. C. The reaction mixture was
then heated at 80.degree. C. overnight. The reaction was filtered
through a pad of silica gel, which was washed with CH.sub.2Cl.sub.2
(25 mL.times.3). The combined organics were concentrated under
reduced pressure to give the crude product, which was washed with
EtOAc to give pure
(R)-(1-(3'-aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol
(C-2) (810 mg, 49%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.88
(d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.23-7.28 (m, 1H), 6.98
(d, J=7.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.74 (dd, J=7.8, 1.2 Hz,
1H), 3.66-3.77 (m, 3H), 3.45-3.53 (m, 1H), 3.26-3.34 (m, 1H),
1.68-1.88 (m, 3H), 1.45-1.55 (m, 1H). MS (ESI) m/e (M+H.sup.+)
333.0.
Preparation 12
3'-Amino-N-methylbiphenyl-4-sulfonamide (C-3)
##STR01262##
[0381] Step a: 4-Bromo-N-methyl-benzenesulfonamide
[0382] To a mixture of sat aq. NaHCO.sub.3 (42 g, 0.50 mol),
CH.sub.2Cl.sub.2 (400 mL) and methylamine (51.7 g, 0.50 mol, 30% in
methanol) was added a solution of 4-bromo-benzenesulfonyl chloride
(130 g, 0.50 mol) in CH.sub.2Cl.sub.2 (100 mL). The reaction was
stirred at 20.degree. C. overnight. The organic phase was separated
and dried over Na.sub.2SO.sub.4. Evaporation of the solvent under
reduced pressure provided 4-bromo-N-methyl-benzenesulfonamide (121
g, crude), which was used in the next step without further
purification. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.65-7.74
(m, 4H), 4.40 (br, 1H), 2.67 (d, J=5.4 Hz, 3H).
Step b: 3'-Amino-N-methylbiphenyl-4-sulfonamide (C-3)
[0383] To a solution of 4-bromo-N-methyl-benzene sulfonamide (2.49
g, 10 mmol) in DMF (20 mL) was added 3-amino-phenyl boronic acid
(1.51 g, 11 mmol), Pd(PPh.sub.3).sub.4 (90 mg, 0.30 mmol),
potassium carbonate (1.52 g, 11 mmol) and water (5 mL). The
resulting mixture was degassed by gently bubbling argon through the
solution for 5 minutes at 20.degree. C. The reaction mixture was
then heated at 80.degree. C. overnight. The reaction was filtered
through a pad of silica gel, which was washed with CH.sub.2Cl.sub.2
(50 mL.times.3). The combined organics were concentrated under
reduced pressure to give crude product, which was washed with EtOAc
to give pure 3'-amino-N-methylbiphenyl-4-sulfonamide (C-3) (1.3 g,
50%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.85 (d, J=8.7 Hz,
2H), 7.75 (d, J=8.7 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H), 6.95-7.01 (m,
2H), 6.73-6.77 (m, 1H), 2.54 (s, 3H). MS (ESI) m/e (M+H.sup.+)
263.0.
Preparation 13
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(hydroxymethyl-
)-N,N-dimethylbiphenyl-4-carboxamide
##STR01263##
[0384] Step a:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cycloprop-
anecarboxamide
[0385] Methyl
4-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-bromobenzoate
(4.12 g, 9.9 mmol) was added to a solution of LiBH.sub.4 (429 mg,
19.8 mmol) in THF/ether/H.sub.2O (20/20/1 mL) and was allowed to
stir at 25.degree. C. After 16 hours, the reaction was quenched
with H.sub.2O (10 mL). The reaction mixture was diluted with
dichloromethane (25 mL) and was extracted with 1N HCl (30
mL.times.3) and brine (30 mL). The organic extracts were dried over
Na.sub.2SO.sub.4 and evaporated. The crude product was purified by
chromatography on silica gel (eluting with 0-100% ethyl acetate in
hexanes) to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cycloprop-
anecarboxamide (2.84 g, 74%). ESI-MS m/z calc. 389.0. found 390.1
(M+1).sup.1; retention time 2.91 minutes.
Step b:
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(hydro-
xymethyl)-N,N-dimethylbiphenyl-4-carboxamide
[0386]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)-phenyl)cy-
clopropanecarboxamide (39 mg, 0.10 mmol),
4-(dimethylcarbamoyl)-phenylboronic acid (29 mg, 0.15 mmol), 1 M
K.sub.2CO.sub.3 (0.3 mL, 0.3 mmol), Pd-FibreCat 1007 (8 mg, 0.1
mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture
was heated at 80.degree. C. for 3 h. After cooling, the mixture was
filtered and purified by reverse phase HPLC to yield
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(hydroxymethy-
l)-N,N-dimethylbiphenyl-4-carboxamide (16 mg, 34%). ESI-MS m/z
calc. 458.5. found 459.5 (M+1).sup.+; Retention time 2.71
minutes.
Preparation 14
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(ethoxymethyl)-
-N,N-dimethylbiphenyl-4-carboxamide
##STR01264##
[0388]
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(hydrox-
ymethyl)-N,N-dimethylbiphenyl-4-carboxamide (49 mg, 0.10 mmol) and
para-toluenesulfonic acid (38 mg, 0.2 mmol) were dissolved in
ethanol (1.0 mL) and irradiated in the microwave at 140.degree. C.
for 10 minutes. Volatiles were removed in vacuo and crude product
was purified by reverse phase HPLC to afford the pure product (6.4
mg, 13%). ESI-MS m/z calc. 486.2. found 487.5 (M+1).sup.+;
retention time 3.17 minutes.
Preparation 15
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-2'-(isopropoxyme-
thyl)-N,N-dimethylbiphenyl-4-carboxamide
##STR01265##
[0390]
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(hydrox-
ymethyl)-N,N-dimethylbiphenyl-4-carboxamide (46 mg, 0.10 mmol) and
para-toluenesulfonic acid (38 mg, 0.2 mmol) were dissolved in
isopropanol (1.0 mL) and irradiated in the microwave at 140.degree.
C. for 10 minutes. Volatiles were removed in vacuo and crude
product was purified by reverse phase HPLC to afford the pure
product (22 mg, 44%). ESI-MS m/z calc. 500.2. found 501.3
(M+1).sup.+; retention time 3.30 minutes.
Preparation 16
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(cyanomethyl)--
N,N-dimethylbiphenyl-4-carboxamide
##STR01266##
[0391] Step a:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclo-propa-
ne carboxamide
[0392]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyc-
lopropane-carboxamide (1.08 g, 2.78 mmol), methanesulfonyl chloride
(0.24 mL, 3.1 mmol), and N,N-diisopropylethylamine (0.72 mL, 4.1
mmol) were dissolved in acetonitrile (27 mL) at 25.degree. C. After
complete dissolution, KCN (450 mg, 6.95 mmol) was added and the
reaction was stirred for 14 d. The reaction was diluted with
dichloromethane (25 mL) and washed with water (25 mL). The organic
extracts were dried over Na.sub.2SO.sub.4 and evaporated. The crude
product was purified by chromatography on silica gel (eluting with
0-100% ethyl acetate in hexanes) to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclo-propa-
ne carboxamide (514 mg, 46%). ESI-MS m/z calc. 398.0. found 399.1
(M+1).sup.+; retention time 3.24 minutes.
Step b:
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(cyano-
methyl)-N,N-dimethylbiphenyl-4-carboxamide
[0393]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclo-
propane-carboxamide (40 mg, 0.10 mmol),
4-(dimethylcarbamoyl)phenylboronic acid (29 mg, 0.15 mmol), 1 M
K.sub.2CO.sub.3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1
mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture
was irradiated in the microwave at 150.degree. C. for 10 minutes.
Volatiles were removed in vacuo and crude product was purified by
chromatography on silica gel (eluting with 0-100% ethyl acetate in
hexanes) to afford
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(cyanomethyl)-
-N,N-dimethylbiphenyl-4-carboxamide (9.1 mg, 20%). ESI-MS m/z calc.
467.2. found 468.5 (M+1).sup.+; retention time 2.96 minutes.
Preparation 17
2'-((1H-Tetrazol-5-yl)methyl)-5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane
carboxamido)-N,N-dimethylbiphenyl-4-carboxamide
##STR01267##
[0395]
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(cyanom-
ethyl)-N,N-dimethylbiphenyl-4-carboxamide (32 mg, 0.070 mmol),
sodium azide (55 mg, 0.84 mmol), and ammonium chloride (45 mg, 0.84
mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and
irradiated in the microwave at 100.degree. C. for 2 hours. After
cooling, the mixture was filtered and purified by reverse phase
HPLC to yield
2'-((1H-tetrazol-5-yl)methyl)-5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropan-
e carboxamido)-N,N-dimethylbiphenyl-4-carboxamide (9.2 mg, 26%).
ESI-MS m/z calc. 510.2. found 511.5 (M+1).sup.+; Retention time
2.68 minutes.
Preparation 18
2'-(2-Amino-2-oxoethyl)-5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbox-
amido)-N,N-dimethylbiphenyl-4-carboxamide
##STR01268##
[0397]
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(cyanom-
ethyl)-N,N-dimethylbiphenyl-4-carboxamide (58 mg, 0.12 mmol),
H.sub.2O.sub.2 (30 wt % solution in water, 36 .mu.L, 1.2 mmol), and
NaOH (10 wt % in water, 0.15 mL, 0.42 mmol) were dissolved in MeOH
(1.2 mL) and stirred at 25.degree. C. for 2 hours. The reaction was
filtered and purified by reverse phase HPLC to yield
2'-(2-amino-2-oxoethyl)-5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbo-
xamido)-N,N-dimethylbiphenyl-4-carboxamide (14 mg, 23%). ESI-MS m/z
calc. 485.2. found 486.5 (M+1).sup.+; Retention time 2.54
minutes.
Preparation 19
N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyc-
lopropanecarboxamide
##STR01269##
[0399]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropane-
carboxamide (37 mg, 0.10 mmol),
4-((tert-butoxycarbonylamino)methyl)phenylboronic acid (37 mg, 0.15
mmol), 1 M K.sub.2CO.sub.3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8
mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The
mixture was irradiated in the microwave at 150.degree. C. for 10
minutes. The reaction was filtered and purified by reverse phase
HPLC. The obtained material was dissolved in dichloromethane (2 mL)
containing trifluoroacetic acid (2 mL) and stirred at 25.degree. C.
for 1 hour. The reaction was filtered and purified by reverse phase
HPLC to yield
N-(4'-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cy-
clopropanecarboxamide as the TFA salt (8.1 mg, 20%). ESI-MS m/z
calc. 400.2. found 401.5 (M+1).sup.+; retention time 2.55
minutes.
Preparation 20
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-(propionamidomethyl)biphenyl-3-
-yl)cyclopropanecarboxamide
##STR01270##
[0401]
N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-
-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), propionyl chloride
(8.7 .mu.L, 0.10 mmol) and Et.sub.3N (28 .mu.L, 0.20 mmol) were
dissolved in dichloromethane (1.0 mL) and allowed to stir at
25.degree. C. for 3 hours. Volatiles were removed in vacuo and
crude product was purified by reverse phase HPLC to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-(propionamidomethyl)biphenyl--
3-yl)cyclopropanecarboxamide (13 mg, 28%). ESI-MS m/z calc. 456.5.
found 457.5 (M+1).sup.+; retention time 3.22 minutes.
Preparation 21
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-(propylsulfonamidomethyl)biphe-
nyl-3-yl)cyclopropanecarboxamide
##STR01271##
[0403]
N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-
-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), 1-propanesulfonyl
chloride (11 .mu.L, 0.10 mmol) and Et.sub.3N (28 .mu.L, 0.20 mmol)
were dissolved in dichloromethane (1.0 mL) and allowed to stir at
25.degree. C. for 16 hours. Volatiles were removed in vacuo and
crude product was purified by reverse phase HPLC to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-(propylsulfonamidomethyl)biph-
enyl-3-yl)cyclopropanecarboxamide (5.3 mg, 10%). ESI-MS m/z calc.
506.6. found 507.3 (M+1).sup.+; retention time 3.48 minutes.
Preparation 22
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((propylamino)methyl)biphenyl--
3-yl)cyclopropanecarboxamide
##STR01272##
[0405]
N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-
-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), propionaldehyde
(5.1 .mu.L, 0.10 mmol) and Ti(OPr).sub.4 (82 .mu.L, 0.30 mmol) were
dissolved in dichloromethane (1.0 mL) and mono-glyme (1.0 mL). The
mixture was allowed to stir at 25.degree. C. for 16 hours.
NaBH.sub.4 (5.7 mg, 0.15 mmol) was added and the reaction was
stirred for an additional 1 h. The reaction was diluted to 5 mL
with dichloromethane before water (5 mL) was added. The reaction
was filtered through celite to remove the titanium salts and the
layers separated. The organic extracts were dried over
Na.sub.2SO.sub.4 and evaporated. The crude product was purified by
reverse phase HPLC to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((propylamino)methyl)biphenyl-
-3-yl)cyclopropanecarboxamide (7.8 mg, 14%). ESI-MS m/z calc.
442.6. found 443.5 (M+1).sup.+; retention time 2.54 minutes.
Preparation 23
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4'-((isopentylamino)methyl)-6-methylbiphen-
yl-3-yl)cyclopropanecarboxamide
##STR01273##
[0407]
N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-
-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), 3-methylbutanal
(8.6 mg, 0.10 mmol) and Ti(OPr).sub.4 (82 .mu.L, 0.30 mmol) were
dissolved in dichloromethane (1.0 mL) and mono-glyme (1.0 mL) and
allowed to stir at 25.degree. C. for 16 hours. NaBH.sub.4 (5.7 mg,
0.15 mmol) was added and the reaction was stirred for an additional
1 h. The reaction was diluted to 5 mL with dichloromethane before
water (5 mL) was added. The reaction was filtered through celite to
remove the titanium salts and the layers separated. The organic
extracts were dried over Na.sub.2SO.sub.4 and evaporated. The crude
product was purified by reverse phase HPLC to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(4'-((isopentylamino)methyl)-6-meth-
ylbiphenyl-3-yl)cyclopropanecarboxamide (5.7 mg, 10%). ESI-MS m/z
calc. 470.3. found 471.5 (M+1).sup.+; retention time 2.76
minutes.
Preparation 24
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4'-(hydroxymethyl)-6-methylbiphenyl-3-yl)c-
yclopropanecarboxamide
##STR01274##
[0409]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropane-
carboxamide (3.0 g, 8.1 mmol), 4-(hydroxymethyl)phenylboronic acid
(1.5 g, 9.7 mmol), 1 M K.sub.2CO.sub.3 (16 mL, 16 mmol),
Pd-FibreCat 1007 (640 mg), and N,N-dimethylformamide (80 mL) were
combined. The mixture was heated at 80.degree. C. for 3 h. The
volatiles were removed in vacuo and residue was redissolved in
dichloromethane (100 mL). The organics were washed with 1N HCl (100
mL.times.2), then dried over Na.sub.2SO.sub.4 and evaporated. The
crude product was purified by chromatography on silica gel to
afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(4'-(hydroxymethyl)-6-methylbiphenyl-3-yl)-
cyclopropanecarboxamide (1.9 g, 59%). ESI-MS m/z calc. 401.5. found
402.5 (M+1).sup.+; retention time 3.18 minutes.
Preparation 25
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4'-(methoxymethyl)-6-methylbiphenyl-3-yl)c-
yclopropanecarboxamide
##STR01275##
[0411]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4'-(hydroxymethyl)-6-methylbiphenyl-
-3-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol),
para-toluenesulfonic acid (24 mg, 0.13 mmol) and MeOH (53 .mu.L,
1.3 mmol) were dissolved in toluene (2.0 mL) and irradiated in the
microwave at 140.degree. C. for 10 minutes. Volatiles were removed
in vacuo and crude product was purified by reverse phase HPLC to
afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(4'-(methoxymethyl)-6-methylbiphenyl-3-yl)-
cyclopropanecarboxamide (9.6 mg, 23%). ESI-MS m/z calc. 415.5.
found 416.5 (M+1).sup.+; retention time 3.68 minutes.
Preparation 26
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((methylamino)methyl)biphenyl--
3-yl)cyclopropanecarboxamide
##STR01276##
[0413]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4'-(hydroxymethyl)-6-methylbiphenyl-
-3-yl)cyclopropanecarboxamide (610 mg, 1.52 mmol), methanesulfonyl
chloride (0.13 mL, 1.7 mmol), and N,N-diisopropylethylamine (0.79
mL, 4.6 mmol) were dissolved in dichloromethane (10 mL) at
25.degree. C. The reaction was stirred for 10 minutes before a 2.0
M solution of MeNH.sub.2 in THF (15 mL, 30 mmol) was added. The
mixture was stirred for 30 minutes at ambient temperature before it
was extracted with 1N HCl (20 mL.times.2) and saturated NaHCO.sub.3
(20 mL.times.2). The organic extracts were dried over
Na.sub.2SO.sub.4 and evaporated. The crude product was purified by
chromatography on silica gel (eluting with 0-20% methanol in
dichloromethane) to afford
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((methylamino)methyl)biphenyl-
-3-yl)cyclopropanecarboxamide (379 mg, 60%). ESI-MS m/z calc.
414.5. found 415.5 (M+1).sup.+; retention time 2.44 minutes.
Preparation 27
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((N-methylpivalamido)methyl)bi-
phenyl-3-yl)cyclopropanecarboxamide
##STR01277##
[0415]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((methylamino)methyl)bi-
phenyl-3-yl)cyclopropanecarboxamide (30 mg, 0.070 mmol), pivaloyl
chloride (12.3 .mu.L, 0.090 mmol) and Et.sub.3N (20 .mu.L, 0.14
mmol) were dissolved in N,N-dimethylformamide (1.0 mL) and allowed
to stir at 25.degree. C. for 3 hours. The crude reaction was
purified by reverse phase HPLC to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((N-methylpivalamido)methyl)b-
iphenyl-3-yl)cyclopropanecarboxamide (15 mg, 30%). ESI-MS m/z calc.
498.3. found 499.3 (M+1).sup.+; retention time 3.75 minutes.
Preparation 28
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((N-methylmethylsulfonamido)
methyl)biphenyl-3-yl)cyclopropanecarboxamide
##STR01278##
[0417]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((methylamino)-methyl)b-
iphenyl-3-yl)cyclopropane carboxamide (30 mg, 0.070 mmol),
methanesulfonyl chloride (7.8 .mu.L, 0.14 mmol) and Et.sub.3N (30
.mu.L, 0.22 mmol) were dissolved in N,N-dimethylformamide (1.0 mL)
and allowed to stir at 25.degree. C. for 16 hours. The crude
reaction was purified by reverse phase HPLC to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((N-methylmethylsulfonamido)
methyl)biphenyl-3-yl)cyclopropanecarboxamide (22 mg, 64%). ESI-MS
m/z calc. 492.2. found 493.3 (M+1).sup.+; retention time 3.45
minutes.
Preparation 29
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4'-((isobutyl(methyl)amino)-methyl)-6-meth-
ylbiphenyl-3-yl)cyclopropanecarboxamide
##STR01279##
[0419]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4'-((methylamino)methyl)bi-
phenyl-3-yl)cyclopropanecarboxamide (49 mg, 0.12 mmol),
isobutyraldehyde (11 .mu.L, 0.12 mmol) and NaBH(OAc).sub.3 (76 mg,
0.36 mmol) were dissolved in dichloroethane (2.0 mL) and heated at
70.degree. C. for 16 hours. The reaction was quenched with MeOH
(0.5 mL) and 1 N HCl (0.5 mL). The volatiles were removed in vacuo
and the crude product was purified by reverse phase HPLC to afford
1-(benzo[d][1,3]dioxol-5-yl)-N-(4'-((isobutyl(methyl)amino)-methyl)-6-met-
hylbiphenyl-3-yl)cyclopropanecarboxamide as the TFA salt (5.0 mg,
9%). ESI-MS m/z calc. 470.3. found 471.3 (M+1).sup.+; retention
time 2.64 minutes.
[0420] The following compounds were prepared using procedures 20-23
and 27-29 above: 6, 14, 24, 26, 70, 79, 84, 96, 114, 122, 159, 200,
206, 214, 223, 248, 284-5, 348, 355, 382, 389, 391, 447, 471, 505,
511, 524, 529-30, 534, 551, 562, 661, 682, 709, 783, 786, 801, 809,
828, 844, 846, 877, 937, 947, 1012, 1049, 1089.
Preparation 30
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)cyclopropan-
e-carboxamide
##STR01280##
[0422] 4-(2-Methylthiazol-4-yl)aniline (19 mg, 0.10 mmol) and
1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg,
0.100 mmol) were dissolved in acetonitrile (1.0 mL) containing
triethylamine (42 .mu.L, 0.30 mmol).
0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and
the resulting solution was allowed to stir for 16 hours. The crude
product was purified by reverse-phase preparative liquid
chromatography to yield
1-(benzo[d][1,3]dioxol-5-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)cyclopropa-
ne-carboxamide. ESI-MS m/z calc. 378.1. found; 379.1 (M+1).sup.+;
Retention time 2.72 minutes. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.04-1.10 (m, 2H), 1.40-1.44 (m, 2H), 2.70 (s, 3H), 6.03
(s, 2H), 6.88-6.96 (m, 2H), 7.01 (d, J=1.4 Hz, 1H), 7.57-7.61 (m,
2H), 7.81-7.84 (m, 3H), 8.87 (s, 1H).
Preparation 31
1-Benzo[1,3]dioxol-5-yl-N-[3-[4-(methylsulfamoyl)phenyl]phenyl]-cyclopropa-
ne-1-carboxamide
##STR01281##
[0424] To a solution of
1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride (0.97 mmol)
in CH.sub.2Cl.sub.2 (3 mL) at ambient temperature was added a
solution of 3'-amino-N-methylbiphenyl-4-sulfonamide (0.25 g, 0.97
mmol), Et.sub.3N (0.68 mL, 4.9 mmol), DMAP (0.050 g, 0.058 mmol),
and CH.sub.2Cl.sub.2 (1 mL) dropwise. The mixture was allowed to
stir for 16 h before it was diluted with CH.sub.2Cl.sub.2 (50 mL).
The solution was washed with 1N HCl (2.times.25 mL), sat. aq.
NaHCO.sub.3 (2.times.25 mL), then brine (25 mL). The organics were
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (5-25%
EtOAc/hexanes) to provide
1-benzo[1,3]dioxol-5-yl-N-[3-[4-(methylsulfamoyl)phenyl]phenyl]-cycloprop-
ane-1-carboxamide as a white solid. ESI-MS m/z calc. 450.5. found
451.3 (M+1).sup.+. Retention time of 3.13 minutes.
[0425] The following compounds were prepared using procedures 30
and 31 above: 4-5, 27, 35, 39, 51, 55, 75, 81, 90, 97-8, 101, 110,
132, 146, 155, 166, 186, 208, 211, 218, 230, 239, 245, 247, 258,
261, 283, 292, 308, 334, 339, 352, 356, 379, 405, 411, 433, 462,
477, 504, 514, 526, 536, 554, 563, 573, 590-2, 612, 619, 623, 627,
637, 648, 653, 660, 668-9, 692, 728, 740, 747, 748, 782, 814,
826-7, 834-6, 845, 916, 931-2, 938, 944, 950, 969, 975, 996, 1004,
1007, 1009, 1033, 1064, 1084-5, 1088, 1097, 1102, 1127, 1151, 1157,
1159, 1162, 1186, 1193.
Preparation 32
4-[5-(1-Benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]ben-
zoic acid
##STR01282##
[0427]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropane-
carbox-amide (B-8) (5.1 g, 14 mmol), 4-boronobenzoic acid (3.4 g,
20 mmol), 1 M K.sub.2CO.sub.3 (54 mL, 54 mmol), Pd-FibreCat 1007
(810 mg, 1.35 mmol), and DMF (135 mL) were combined. The mixture
was heated at 80.degree. C. for 3 h. After cooling, the mixture was
filtered and DMF was removed in vacuo. The residue was partitioned
between dichloromethane (250 mL) and 1N HCl (250 mL). The organics
were separated, washed with saturated NaCl solution (250 mL), and
dried over Na.sub.2SO.sub.4. Evaporation of organics yielded
4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]be-
nzoic acid (5.5 g, 98%). ESI-MS m/z calc. 415.1. found 416.5
(M+1).sup.+; Retention time 3.19 minutes. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 13.06 (s, 1H), 8.83 (s, 1H), 8.06-8.04 (m, 2H),
7.58-7.56 (m, 1H), 7.50-7.48 (m, 3H), 7.27-7.24 (m, 1H), 7.05-7.04
(m, 1H), 6.98-6.94 (m, 2H), 6.07 (s, 2H), 2.22 (s, 3H), 1.46-1.44
(m, 2H), 1.12-1.09 (m, 2H).
Preparation 33
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-methyl-N-(2-(p-
yridin-2-yl)ethyl)biphenyl-4-carboxamide
##STR01283##
[0429] 2-(Pyridin-2-yl)ethanamine (12 mg, 0.10 mmol) and
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-methylbipheny-
l-4-carboxylic acid (42 mg, 0.10 mmol) were dissolved in
N,N-dimethylformamide (1.0 mL) containing triethylamine (28 .mu.L,
0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and
the resulting solution was allowed to stir for 1 hour at ambient
temperature. The crude product was purified by reverse-phase
preparative liquid chromatography to yield
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-methyl-N-(2-(-
pyridin-2-yl)ethyl)biphenyl-4-carboxamide as the trifluoroacetic
acid salt (43 mg, 67%). ESI-MS m/z calc. 519.2. found 520.5
(M+1).sup.+; Retention time 2.41 minutes. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.77 (s, 1H), 8.75-8.74 (m, 1H), 8.68-8.65 (m,
1H), 8.23 (m, 1H), 7.83-7.82 (m, 2H), 7.75-7.68 (m, 2H), 7.48-7.37
(m, 4H), 7.20-7.18 (m, 1H), 6.99-6.98 (m, 1H), 6.90-6.89 (m, 2H),
6.01 (s, 2H), 3.72-3.67 (m, 2H), 3.20-3.17 (m, 2H), 2.15 (s, 3H),
1.40-1.37 (m, 2H), 1.06-1.03 (m, 2H).
[0430] The following compounds were prepared using procedure 33
above: 32, 78, 118, 134, 156, 171, 188, 237, 279, 291, 297, 309,
319, 338, 341, 362, 373, 376, 393, 406-7, 410, 448, 452-3, 474,
482, 494, 508, 577, 580, 593-4, 622, 629, 638, 651, 663-4, 681,
698, 704, 707, 710, 736-7, 739, 775, 806, 810, 825, 842, 853, 866,
871, 900, 905-7, 926, 935, 941, 966, 971, 973, 978-9, 1046, 1048,
1066, 1077, 1079, 1083, 1141, 1150, 1155-6, 1163, 1180, 1185, 1187,
1198, 1201.
Preparation 34
4-[5-(1-Benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]-N,-
N-dimethyl-benzamide
##STR01284##
[0432]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropane-
carbox-amide (0.10 mmol),
N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide
(0.11 mmol), K.sub.2CO.sub.3 (240 .mu.L, 1M), Pd-FibreCat (7 mg),
and DMF (1 mL) were combined. The mixture was heated at 150.degree.
C. for 5 min (5 min ramp time) in a microwave reactor. After
cooling, the mixture was filtered and purified by prep-HPLC to
provide
4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]-N-
,N-dimethyl-benzamide. ESI-MS m/z calc. 442.2. found 443.5
(M+1).sup.+; Retention time 3.12 minutes. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 1.02-1.08 (m, 2H), 1.37-1.44 (m, 2H), 2.17
(s, 3H), 2.96 (s, 3H), 3.00 (s, 3H), 6.01 (s, 2H), 6.87-6.93 (m,
2H), 6.98 (d, J=1.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.34-7.37 (m,
2H), 7.40-7.52 (m, 4H), 8.75 (s, 1H).
Preparation 35
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(isopropoxymet-
hyl)-N,N-dimethylbiphenyl-4-carboxamide
##STR01285##
[0434] Sodium hydride (2.2 mg, 0.055 mmol, 60% by weight dispersion
in oil) was slowly added to a stirred solution of
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N,2'-trimethyl-
biphenyl-4-carboxamide (21 mg, 0.048 mmol) in a mixture of 0.90 mL
of anhydrous tetrahydrofuran (THF) and 0.10 mL of anhydrous
N,N-dimethylformamide (DMF). The resulting suspension was allowed
to stir for 3 minutes before iodomethane (0.0048 mL, 0.072 mmol)
was added to the reaction mixture. An additional aliquot of sodium
hydride and iodomethane were required to consume all of the
starting material which was monitored by LCMS. The crude reaction
product was evaporated to dryness, redissolved in a minimum of DMF
and purified by preparative LCMS chromatography to yield
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(isopropoxyme-
thyl)-N,N-dimethylbiphenyl-4-carboxamide (9.1 mg, 42%) ESI-MS m/z
calc. 456.2. found 457.5 (M+1).sup.+. Retention time of 2.94
minutes. .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. 0.91-0.93 (m,
2H), 1.41-1.45 (m, 2H), 2.23 (s, 3H), 3.00 (s, 3H), 3.07 (s, 3H),
3.20 (s, 3H), 5.81 (s, 2H), 6.29-6.36 (m, 2H), 6.56 (d, J=8.0 Hz,
1H), 6.69 (s, 1H), 6.92 (dd, J=1.6, 7.9 Hz, 1H), 7.17 (d, J=8.1 Hz,
1H), 7.28 (d, J=8.1 Hz, 2H), 7.46 (dd, J=1.8, 6.4 Hz, 2H).
Preparation 36
(S)-1-(5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-methylb-
iphenyl-4-ylsulfonyl)pyrrolidine-2-carboxylic acid
##STR01286## ##STR01287##
[0435] Step a: 4-(4,4'-Dimethoxybenzhydryl)-thiophenyl boronic
acid
[0436] 4,4'-Dimethoxybenzhydrol (2.7 g, 11 mmol) and
4-mercaptophenylboronic acid (1.54 g, 10 mmol) were dissolved in
AcOH (20 mL) and heated at 60.degree. C. for 1 h. Solvent was
evaporated and the residue was dried under high vacuum. This
material was used without further purification.
Step b:
4'-[Bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylami-
ne
[0437] 4-(4,4'-Dimethoxybenzhydryl)-thiophenyl boronic acid (10
mmol) and 3-bromo-4-methylaniline (1.86 g, 10 mmol) were dissolved
in MeCN (40 mL). Pd (PPh.sub.3).sub.4 (.about.50 mg) and aqueous
solution K.sub.2CO.sub.3 (1M, 22 mL) were added before the reaction
mixture was heated portion-wise in a microwave oven (160.degree.
C., 400 sec). Products were distributed between ethyl acetate and
water. The organic layer was washed with water, brine and dried
over MgSO.sub.4. Evaporation yielded an oil that was used without
purification in the next step. ESI-MS m/z calc. 441.0. found 442.1
(M+1).
Step c: 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid
4'-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide
[0438]
4'-[Bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamin-
e (.about.10 mmol) and
1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11
mmol) were dissolved in chloroform (25 mL) followed by addition of
TCPH (4.1 g, 12 mmol) and DIEA (5.0 mL, 30 mmol). The reaction
mixture was heated at 65.degree. C. for 48 h. The volatiles were
removed under reduced pressure. The residue was distributed between
water (200 mL) and ethyl acetate (150 mL). The organic layer was
washed with 5% NaHCO.sub.3 (2.times.150 mL), water (1.times.150
mL), brine (1.times.150 mL) and dried over MgSO.sub.4. Evaporation
of the solvent yielded crude
1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid
4'-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide
as a pale oil, which was used without further purification. ESI-MS
m/z calc. 629.0. found 630.0 (M+1) (HPLC purity .about.85-90%,
UV254 nm).
Step d:
5'-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2'-methy-
lbiphenyl-4-sulfonic acid
[0439] 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid
4'-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide
(.about.8.5 mmol) was dissolved in acetic acid (75 mL) followed by
addition of 30% H.sub.2O.sub.2 (10 mL). Additional hydrogen
peroxide (10 mL) was added 2 h later. The reaction mixture was
stirred at 35-45.degree. C. overnight (-90% conversion, HPLC). The
volume of reaction mixture was reduced to a third by evaporation
(bath temperature below 40.degree. C.). The reaction mixture was
loaded directly onto a prep RP HPLC column (C-18) and purified. The
appropriate fractions with were collected and evaporated to provide
5'-[(1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2'-methylbiphen-
yl-4-sulfonic acid (2.1 g, 46%, cal. based on
4-mercaptophenylboronic acid). ESI-MS m/z calc. 451.0. found 452.2
(M+1).
Step e:
5'-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2'-methy-
lbiphenyl-4-sulfonyl chloride
[0440]
5'-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2'-methyl-
biphenyl-4-sulfonic acid (1.9 g, 4.3 mmol) was dissolved in
POCl.sub.3 (30 mL) followed by the addition of SOCl.sub.2 (3 mL)
and DMF (100 .mu.l). The reaction mixture was heated at
70-80.degree. C. for 15 min. The reagents were evaporated and
re-evaporated with chloroform-toluene. The residual brown oil was
diluted with chloroform (22 mL) and immediately used for
sulfonylation. ESI-MS m/z calc. 469.0. found 470.1 (M+1).
Step f:
(S)-1-{5'-[(1-Benzo[1,3]dioxol-5-yl-cyclopropane-carbonyl)-amino]--
2'-methyl-biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylic acid
[0441] L-Proline (57 mg, 0.50 mmol) was treated with
N,O-bis(trimethylsilyl)acetamide (250 .mu.l, 1.0 mmol) in 1 mL
dioxane overnight at 50.degree. C. To this mixture was added
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane
carboxamido)-2'-methylbiphenyl-4-sulfonyl chloride (.about.35 mmol,
400 .mu.l solution in chloroform) followed by DIEA (100 .mu.L). The
reaction mixture was kept at room temperature for 1 h, evaporated,
and diluted with DMSO (400 .mu.l). The resulting solution was
subjected to preparative HPLC purification. Fractions containing
the desired material were combined and concentrated in vacuum
centrifuge at 40.degree. C. to provide the trifluoroacetic salt of
(S)-1-{5'-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2'-methy-
l-biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylic acid. ESI-MS m/z
calc. 548.1. found 549.1 (M+1), retention time 3.40 min; .sup.1H
NMR (250 MHz, DMSO-d.sub.6) .delta. 1.04 (m. 2H), .delta. 1.38 (m,
2H), .delta. 1.60 (m, 1H), .delta. 1.80-1.97 (m, 3H) .delta. 2.16
(s, 3H), .delta. 3.21 (m, 1H), 3.39 (m, 1H), 4.15 (dd, 1H, J=4.1
Hz, J=7.8 Hz), .delta. 6.01 (s, 2H), .delta. 6.89 (s, 2H), .delta.
6.98 (s, 1H), .delta. 7.21 (d, 1H, J=8.3 Hz), .delta. 7.45 (d, 1H,
J=2 Hz), .delta. 7.52 (dd, 1H, J=2 Hz, J=8.3 Hz), .delta. 7.55 (d,
2H, J=8.3 Hz), .delta. 7.88 (d, 2H, J=8.3 Hz), .delta. 8.80 (s,
1H).
[0442] The following compounds were prepared using procedure 36
above: 9, 17, 30, 37, 41, 62, 88, 104, 130, 136, 169, 173, 184,
191, 216, 219, 259-60, 265, 275, 278, 281, 302, 306, 342, 350, 366,
371, 380, 387, 396, 404, 412, 430, 438, 449, 460, 478, 486, 496,
499-500, 503, 512, 517, 579, 581-2, 603, 610, 611, 615, 652, 676,
688, 701, 706, 712, 725, 727, 732, 734, 751, 764, 770, 778, 780,
790, 802, 829, 841, 854, 885, 889, 897, 902, 930, 951-2, 970, 986,
992, 994, 997, 1040, 1050-1, 1054, 1056, 1065, 1082, 1090, 1093,
1107, 1114, 1130, 1143, 1147, 1158, 1160, 1164, 1170, 1174-5.
Preparation 37
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro-2'-methy-
lbiphenyl-4-carboxamide
##STR01288##
[0443] Step a:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)cyclopropanecarboxamide
[0444]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropane-
carboxamide (5.0 g, 13 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.1 g,
16 mmol), Pd(dppf)Cl.sub.2 (0.66 g, 0.81 mmol), and DMF (100 mL)
were added to a flask containing oven-dried KOAc (3.9 g, 40 mmol).
The mixture was heated at 80.degree. C. for 2 h (.about.40%
conversion). The mixture was cooled to ambient temperature and the
volatiles were removed under vacuum. The residue was taken up in
CH.sub.2Cl.sub.2, filtered, and loaded onto a SiO.sub.2 column (750
g of SiO.sub.2). The product was eluted with EtOAc/Hexanes (0-25%,
70 min, 250 mL/min) to provide
1-(benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)cyclopropanecarboxamide (1.5 g, 27%) and
unreacted starting material:
1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarbox-
amide (3.0 g).
Step b:
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro--
2'-methylbiphenyl-4-carboxamide
[0445]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42 mg, 0.10
mmol), 4-bromo-3-fluorobenzamide (24 mg, 0.11 mmol), Pd-FibreCat
1007 (10 mg), K.sub.2CO.sub.3 (1M, 240 mL), and DMF (1 mL) were
combined in a scintillation vial and heated at 80.degree. C. for 3
hr. The mixture was filtered and purified using reverse-phase
preparative HPLC to provide
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro-2'-meth-
ylbiphenyl-4-carboxamide (ESI-MS m/z calc. 428.5. found 429.5
(M+1); retention time 3.30 min).
Preparation 38
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3'-(2H-tetrazol-5-yl)biphenyl-3-y-
l)cyclopropanecarboxamide
##STR01289##
[0446] Step a:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)cyclopropanecarboxamide
[0447] To a solution of
1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.74 g,
8.57 mmol) in DMF (10 mL) was added HATU (3.59 g, 9.45 mmol),
Et.sub.3N (3.60 mL, 25.8 mmol), then
4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(2.19 g, 9.40 mmol) at ambient temperature. The mixture was heated
at 70.degree. C. for 18 h. The mixture was cooled, then
concentrated under reduced pressure. The residue was taken up in
EtOAc before it was washed with H.sub.2O, then brine (2.times.).
The organics were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure to provide an orange-tan foam/semi-solid. Column
chromatography on the residue (5-15% EtOAc/hexanes) provided a
white foam. MeOH was added to the material and the slurry was
concentrated under reduced pressure to yield 3.10 g of
1-(benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)cyclopropanecarboxamide as a white, granular
solid, (85%).
Step b:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3'-(2H-tetrazol-5-yl)-bip-
henyl-3-yl)cyclopropane carboxamide
[0448]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42.1 mg, 0.100
mmol), 5-(3-bromophenyl)-tetrazole (22.5 mg, 0.100 mmol), a 1 M
aqueous solution of potassium carbonate (0.50 mL), Pd-FibreCat 1007
(6 mg), and ethanol (0.50 mL) were combined. The mixture was heated
at 110.degree. C. for 5 min (5 min ramp time) in a microwave
reactor. After cooling, the mixture was filtered and purified by
prep-HPLC to provide
1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3'-(2H-tetrazol-5-yl)-biphenyl-3-
-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 439.2. found 440.2
(M+1).sup.+; Retention time 2.59 minutes.
[0449] The following compounds were prepared using procedures 13,
24, 32, 34, 37 and 38 above: 1-3, 7-8, 10-13, 15-6, 18-23, 25,
28-9, 31, 33-4, 36, 38, 40, 42-50, 52-54, 56-61, 63-9, 71, 72(1),
73-4, 76-7, 80, 82-3, 85-7, 89, 91-5, 99-100, 102-3, 105-9,
111-113, 115(1), 116-7, 119-21, 123-4, 125(2), 126-9, 131, 133,
135, 137-45, 147-54, 157-8, 160-5, 167-8, 170, 172, 174-5, 176(1),
177-83, 185, 187, 189-90, 193-4, 195(1), 196, 197(1), 198-9, 201-5,
207, 209-10, 212-3, 215, 217, 220-2, 224-9, 231, 232(2), 233-6,
238, 240-4, 246, 249-52, 253(1), 254-7, 262-74, 276-7, 280, 282,
286-8, 290, 293-6, 298-301, 303-5, 307, 310, 312-8, 320-31, 332(2),
333, 335-7, 340, 340, 343-7, 349, 351, 353-4, 357-61, 363-4,
367-70, 372, 374, 375(2), 377(2), 378, 381, 383-6, 388, 390, 394-5,
397-403, 408, 409(2), 413, 414(1), 415-29, 431-2, 434-7, 439-46,
450-1, 454-8, 461, 463-4, 466-8, 469(2), 470, 472-3, 475-6, 479,
480-1, 483-5, 487-93, 497-8, 501-2, 506-7, 509-510, 513, 515-6,
518-21, 523, 525, 527-8, 531-3, 535, 537-8, 539(1), 540-50, 552-3,
555-561, 564-72, 574-6, 578, 583-89, 595-602, 604-5, 606(1), 607-9,
613-4, 616-8, 620, 624-6, 630, 631(1), 632-6, 639-42, 644-7,
649-50, 654-9, 662, 665-7, 670-1, 673-5, 677-80, 683-5, 686(1),
687, 689-91, 693-97, 699-700, 702-3, 705, 708, 711, 713-24, 726,
729(2), 730, 733, 735(1), 738, 741-6, 752-4, 756-63, 765-9, 771-4,
776-7, 779, 781, 784-5, 787-9, 791-6, 798-799, 800(1), 803-5,
807-8, 811, 813, 815-21, 822(1), 823-4, 830-3, 837-40, 847-52,
855-65, 867-70, 872-76, 878-84, 886-8, 890-6, 898-9, 901, 903-4,
908, 910-4, 915(1), 917-25, 927-8, 933-4, 936, 939-40, 942-3,
945-6, 948-9, 953-64, 967-8, 972, 974, 976-7, 980-5, 987-91, 993,
995, 998-1001, 1003, 1005-6, 1008, 1010-11, 1013-32, 1034-6,
1038-9, 1041-5, 1047, 1052-3, 1055, 1057-60, 1062-3, 1067-9,
1071-6, 1078, 1081, 1086-7, 1091-2, 1094-6, 1098-1101, 1103-6,
1108-13, 1115, 1116(2), 1117-26, 1128-9, 1131-40, 1142, 1144-6,
1148-9, 1152-4, 1161, 1165, 1167-9, 1171-3, 1176, 1177(1), 1178-9,
1181-4, 1188-92, 1194, 1197, 1199-1200, 1202-4, 1205(2). .sup.(1)
Following the coupling with
2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoindoline-1,3--
dione and
2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoindo-
line-1,3-dione, examples were obtained after removal of the
phthalimide group with hydrazine using known deprotecting
procedures..sup.(2) Following the coupling with
4-((tert-butoxycarbonylamino)methyl)phenylboronic acid, examples
were obtained after removal of the Boc-group with TFA using known
deprotecting procedures.
Preparation 39
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N2,N4',N4'-trimeth-
ylbiphenyl-2,4'-dicarboxamide
##STR01290##
[0450] Step a:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4'-(dimethylcarba-
moyl)biphenyl-2-carboxylic acid
[0451] Methyl
5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4'-(dimethylcarba-
moyl)biphenyl-2-carboxylate (84 mg, 0.20 mmol) was dissolved in DMF
(2.0 mL) with 1M K.sub.2CO.sub.3 (1.0 mL) and irradiated in the
microwave at 150.degree. C. for 10 minutes. Purification by reverse
phase HPLC yielded
5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4'-(dimethylcarba-
moyl)-biphenyl-2-carboxylic acid (7.3 mg, 8%). ESI-MS m/z calc.
472.5. found 473.3 (M+1).sup.+; retention time 2.79 minutes.
Step b:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N2,N4',N4'-
-trimethylbiphenyl-2,4'-dicarboxamide
[0452]
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4'-(dimethy-
lcarbamoyl)biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75
.mu.L of a 2.0 M solution of methylamine in tetrahydrofuran (0.15
mmol) were dissolved in DMF (1.0 mL) containing Et.sub.3N (28
.mu.L, 0.20 mmol).
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and
the resulting solution was allowed to stir for 3 hours. The mixture
was filtered and purified by reverse phase HPLC to yield
5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4',N4'-trime-
thylbiphenyl-2,4'-dicarboxamide (5.0 mg, 10%). ESI-MS m/z calc.
485.5. found 486.5 (M+1).sup.+; retention time 2.54 minutes.
[0453] The following compounds were prepared using procedure 39
above: 311, 495, 755, 812, 1070.
Preparation 40
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-((2-hydroxyeth-
ylamino)methyl)-N,N-dimethylbiphenyl-4-carboxamide
##STR01291##
[0455] To a solution of
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-(hydroxymethy-
l)-N,N-dimethylbiphenyl-4-carboxamide (46 mg, 0.10 mmol) and
diisopropylethylamine (30 .mu.L, 0.20 mmol) in DMF (1.0 mL) was
added methanesulfonyl chloride (8.5 .mu.L, 0.11 mmol). After
stirring at 25.degree. C. for 15 minutes, ethanolamine (13 .mu.L,
0.30 mmol) was added and the mixture was stirring for an additional
1 hour. The mixture was filtered and purified by reverse phase HPLC
to yield
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-((2-hydroxyet-
hyl-amino)methyl)-N,N-dimethylbiphenyl-4-carboxamide as the
trifluoroacetic acid salt (5.0 mg, 8%). ESI-MS m/z calc. 501.2.
found 502.5 (M+1).sup.+; retention time 2.28 minutes.
[0456] The following compounds were prepared using procedure 40
above: 843, 909, 1080.
Preparation 41
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2'-((2-hydroxyeth-
ylamino)methyl)-N,N-dimethylbiphenyl-4-carboxamide
##STR01292##
[0457] Step a: 4-Bromo-2-fluoro-N,N-dimethylbenzenesulfonamide
[0458] To 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7
mmol) and Et.sub.3N (1.5 mL, 11 mmol) in dichloromethane (10 mL)
was added a solution of dimethylamine 2.0 M in THF (2.2 mL, 4.4
mmol). The reaction was stirred at ambient temperature for 30
minutes. The reaction was washed with 10 mL of 1N aqueous HCl and
10 mL of brine. Organics were dried over Na.sub.2SO.sub.4 and
evaporated to dryness. Crude product was purified by chromatography
on silica gel (eluting with 0-25% ethyl acetate in hexanes) to
afford 4-bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (780 mg,
75%).
Step b: 4-Bromo-2-cyano-N,N-dimethylbenzenesulfonamide
[0459] 4-Bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (1.0 g, 3.5
mmol) and sodium cyanide (350 mg, 7.1 mmol) were dissolved in DMF
(3 mL) and irradiated in the microwave at 150.degree. C. for 20
minutes. DMF was removed in vacuo and the residue was redissolved
in dichloromethane (5 mL). The organics were washed with 5 mL of
each 1N aqueous HCl, saturated aqueous NaHCO.sub.3, and brine.
Organics were dried over Na.sub.2SO.sub.4 and evaporated to
dryness. Crude product was purified by chromatography on silica gel
(eluting with 0-50% ethyl acetate in hexanes) to afford
4-bromo-2-cyano-N,N-dimethylbenzenesulfonamide (72 mg, 7%). ESI-MS
m/z calc. 288.0. found 288.9 (M+1).sup.+; retention time 1.44
minutes.
Step c: 5-Bromo-2-(N,N-dimethylsulfamoyl)benzoic acid
[0460] A mixture of 4-bromo-2-cyano-N,N-dimethylbenzenesulfonamide
(110 mg, 0.38 mmol) and 1N aqueous NaOH (2.0 mL, 2.0 mmol) in
1,4-dioxane (2 mL) was heated at reflux. The cooled reaction
mixture was washed with dichloromethane (5 mL). The aqueous layer
was acidified by the addition of 1N aqueous HCl. The acidified
aqueous layer was extracted with dichloromethane (2.times.5 mL).
The combined organics were dried over Na.sub.2SO.sub.4 and
evaporated to dryness to yield
5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid in 34% yield (40 mg,
0.13 mmol). ESI-MS m/z calc. 307.0. found 308.1 (M+1).sup.+;
retention time 1.13 minutes.
Step d:
5'-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4-(N,N-di-
methylsulfamoyl)-2'-methylbiphenyl-3-carboxylic acid
[0461]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42 mg, 0.10
mmol), 5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid (31 mg, 0.10
mmol), 1 M K.sub.2CO.sub.3 (0.30 mL, 0.30 mmol), and Pd-FibreCat
1007 (8 mg, 0.004 mmol) were dissolved in DMF (1 mL) and heated at
80.degree. C. for 3 hr in an oil bath. The mixture was filtered and
purified by reverse phase HPLC to yield
5'-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4-(N,N-dimethyls-
ulfamoyl)-2'-methylbiphenyl-3-carboxylic acid. ESI-MS m/z calc.
522.6. found 523.5 (M+1).sup.+; retention time 1.79 minutes.
Preparation 42
3-Bromo-4-(3-methyloxetan-3-yl)aniline
##STR01293##
[0462] Step a: Diethyl
2-(2-bromo-4-nitrophenyl)-2-methylmalonate
[0463] Diethyl 2-methylmalonate (4.31 mL, 25.0 mmol) was dissolved
in 25 mL of anhydrous DMF. This solution was cooled to 0.degree. C.
under an atmosphere of nitrogen. Sodium hydride (1.04 g, 26 mmol,
60% by weight in mineral oil) was slowly added to the solution. The
resulting mixture was allowed to stir for 3 minutes at 0.degree.
C., and then at room temperature for 10 minutes.
2-Bromo-1-fluoro-4-nitrobenzene (5.00 g, 22.7 mmol) was quickly
added and the mixture turned bright red. After stirring for 10
minutes at room temperature, the crude mixture was evaporated to
dryness and then partitioned between dichloromethane and a
saturated aqueous solution of sodium chloride. The layers were
separated and the organic phase was washed twice with a saturated
aqueous solution of sodium chloride. The organics were concentrated
to yield diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.4 g,
99%) as a pale yellow oil which was used without further
purification. Retention time 1.86 min.
Step b: 2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol
[0464] Diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.12 g,
21.7 mmol) was dissolved in 80 mL of anhydrous tetrahydrofuran
(THF) under an atmosphere of nitrogen. The solution was then cooled
to 0.degree. C. before a solution of lithium aluminum hydride (23
mL, 23 mmol, 1.0 M in THF) was added slowly. The pale yellow
solution immediately turned bright red upon the addition of the
lithium aluminum hydride. After 5 min, the mixture was quenched by
the slow addition of methanol while maintaining the temperature at
0.degree. C. The reaction mixture was then partitioned between
dichloromethane and 1 N hydrochloric acid. The layers were
separated and the aqueous layer was extracted three times with
dichloromethane. The combined organics were evaporated to dryness
and then purified by column chromatography (SiO.sub.2, 120 g)
utilizing a gradient of 0-100% ethyl acetate in hexanes over 45
minutes. 2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol was
isolated as a red solid (2.0 g, 31%). .sup.1H NMR (400 MHz,
d.sub.6-DMSO) .delta. 8.34 (d, J=2.6 Hz, 1H), 8.16 (dd, J=2.6, 8.9
Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 4.78 (t, J=5.2 Hz, 2H), 3.98-3.93
(m, 2H), 3.84-3.79 (m, 2H), 1.42 (s, 3H). Retention time 0.89
min.
Step c: 3-Bromo-4-(3-methyloxetan-3-yl)aniline
[0465] 2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (0.145 g,
0.500 mmol) was dissolved in 2.5 mL of anhydrous benzene.
Cyanomethylenetributylphosphorane (CMBP) (0.181 g, 0.750 mmol) was
then added and the solution was allowed to stir at room temperature
for 72 hours. The mixture was evaporated to dryness and then
re-dissolved in 4 mL of EtOH. Tin(II) chloride dihydrate (0.564 g,
2.50 mmol) was then added and the resulting solution was heated at
70.degree. C. for 1 hour. The mixture was cooled to room
temperature and then quenched with a saturated aqueous solution of
sodium bicarbonate. The mixture was then extracted three times with
ethyl acetate. The combined ethyl acetate extracts were evaporated
to dryness and purified by preparative LC/MS to yield
3-bromo-4-(3-methyloxetan-3-yl)aniline as a pale yellow oil (0.032
g, 32%) .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. 7.13 (dd, J=0.7,
1.8 Hz, 1H), 6.94-6.88 (m, 2H), 6.75 (br s, 2H), 4.98 (d, J=5.6 Hz,
2H), 4.51 (d, J=6.1 Hz, 2H), 1.74 (s, 3H). ESI-MS m/z calc. 241.0.
found; 242.1 (M+1).sup.+ Retention time 0.53 minutes.
Preparation 43
3-Bromo-4-ethylaniline
##STR01294##
[0466] Step a: 2-Bromo-1-ethyl-4-nitrobenzene
[0467] To a mixture of 1-ethyl-4-nitro-benzene (30 g, 0.20 mol),
silver sulfate (62 g, 0.20 mol), concentrated sulfuric acid (180
mL) and water (20 g) was added bromine (20 mL, 0.40 mol) dropwise
at ambient temperature. After addition, the mixture was stirred for
2 hours at ambient temperature, and then was poured into dilute
sodium hydrogen sulfite solution (1 L, 10%). The mixture was
extracted with diethylether. The combined organics were dried over
Na.sub.2SO.sub.4 and then concentrated under vacuum to provide a
mixture of 2-bromo-1-ethyl-4-nitrobenzene and
1,3-dibromo-2-ethyl-5-nitro-benzene. The mixture was purified by
column chromatography (petroleum ether/EtOAc 100:1) to yield
2-bromo-1-ethyl-4-nitrobenzene (25 g) as a yellow oil with a purity
of 87%. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.39 (d, J=2.4
Hz, 1H), 8.09 (dd, J=2.4, 8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 2.83
(q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).
Step b: 3-Bromo-4-ethylaniline
[0468] To a solution of 2-bromo-1-ethyl-4-nitro-benzene (25 g,
0.019 mol) in MeOH (100 mL) was added Raney-Ni (2.5 g). The
reaction mixture was hydrogenated under hydrogen (1 atm) at room
temperature. After stirring for 3 hours, the mixture was filtered
and concentrated under reduced pressure. The crude material was
purified by preparative HPLC to give 3-bromo-4-ethylaniline (8.0 g,
48%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.92 (d, J=8.4 Hz,
1H), 6.83 (d, J=2.4 Hz, 1H), 6.52 (dd, J=2.4, 8.4 Hz, 1H), 2.57 (q,
J=7.6 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H). MS (ESI) m/e (M+H.sup.+)
200.
3-Bromo-4-iso-propylaniline and 3-bromo-4-tert-butylaniline were
synthesized following preparation 43 above.
Preparation 44
5-Bromo-2-fluoro-4-methylaniline
##STR01295##
[0469] Step a: 1-Bromo-4-fluoro-2-methyl-5-nitrobenzene
[0470] To a stirred solution of 1-bromo-4-fluoro-2-methyl-benzene
(15.0 g, 79.8 mmol) in dichloromethane (300 mL) was added nitronium
tetrafluoroborate (11.7 g, 87.8 mmol) in portions at 0.degree. C.
The mixture was heated at reflux for 5 h and was then poured into
ice water. The organic layer was separated and the aqueous phase
was extracted with dichloromethane (100 mL.times.3). The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4 and
evaporated under reduced pressure to give crude
1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g), which was used
directly in the next step.
Step b: 5-Bromo-2-fluoro-4-methylaniline
[0471] To a stirred solution of
1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g) in ethanol (300
mL) was added SnCl.sub.2.2H.sub.2O (51.8 g, 0.230 mol) at room
temperature. The mixture was heated at reflux for 3 h. The solvent
was evaporated under reduced pressure to give a residue, which was
poured into ice water. The aqueous phase was basified with sat.
NaHCO.sub.3 to pH 7. The solid was filtered off and the filtrate
was extracted with dichloromethane (200 mL.times.3). The combined
organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated
under reduced pressure. The residue was purified by column
chromatography (petroleum ether/EtOAc=10/1) to afford
5-bromo-2-fluoro-4-methylaniline (5.0 g, 30% yield for two steps).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.96 (d, J=8.8 Hz, 1H),
6.86 (d, J=11.6 Hz, 1H), 3.64 (br, 2H), 2.26 (s, 3H). MS (ESI) m/z
(M+H.sup.+) 204.0.
Preparation 45
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3'-chloro-6-methyl-4'-(2H-tetrazol-5-yl)bi-
phenyl-3-yl)cyclopropanecarboxamide
##STR01296##
[0472] Step a:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3'-chloro-6-methyl-4'-(2H-tetrazol-5-yl)b-
iphenyl-3-yl)cyclopropanecarboxamide
[0473]
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (0.084 g, 0.20
mmol), 4-bromo-2-chlorobenzonitrile (0.043 g, 0.20 mmol), aqueous
potassium carbonate (520 .mu.L, 1M), FibreCat 1007 (7 mg), and DMF
(1 mL) were combined. The mixture was heated at 80.degree. C. for
18 hours. After cooling, the mixture was filtered and purified by
preparative HPLC to provide
1-(benzo[d][1,3]dioxol-5-yl)-N-(3'-chloro-4'-cyano-6-methylbiphen-
yl-3-yl)cyclopropanecarboxamide.
Step b:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3'-chloro-6-methyl-4'-(2H-tetrazol-
-5-yl)biphenyl-3-yl)cyclopropanecarboxamide
[0474] To
1-(benzo[d][1,3]dioxol-5-yl)-N-(3'-chloro-4'-cyano-6-methylbiphe-
nyl-3-yl)-cyclopropanecarboxamide was added ammonium chloride (0.13
g, 2.4 mmol), sodium azide (0.156 g, 2.40 mmol) and 1 mL of DMF.
The mixture was heated at 110.degree. C. in a microwave reactor for
10 minutes. After cooling, the mixture was filtered and purified by
preparative HPLC to provide
1-(benzo[d][1,3]dioxol-5-yl)-N-(3'-chloro-6-methyl-4'-(2H-tetrazo-
l-5-yl)biphenyl-3-yl)cyclopropanecarboxamide (8.6 mg, 9%). ESI-MS
m/z calc. 473.1. found 474.3 (M+1).sup.+; retention time 1.86
minutes.
Preparation 46
3-Bromo-4-(3-methyloxetan-3-yl)aniline
##STR01297##
[0475] Step a: Diethyl 2-(4-bromophenyl)malonate
[0476] To a solution of ethyl 2-(4-bromophenyl)acetate (5.0 g, 21
mmol) in dry THF (40 mL) at -78.degree. C. was added a 2.0M
solution of lithium diisopropylamide in THF (11 mL, 22 mmol). After
stirring for 30 minutes at -78.degree. C., ethyl cyanoformate (2.0
mL, 21 mmol) was added and the mixture was allowed to warm to room
temperature. After stirring for 48 h at room temperature, the
mixture was quenched with water (10 mL). The reaction was
partitioned between 1 N HCl (50 mL) and dichloromethane (50 mL),
and the organic layer was separated. The organic layer was washed
with 1 N HCl (50 mL), dried over Na.sub.2SO.sub.4 and evaporated.
The crude material was purified by silica gel chromatography,
eluting with 0-20% ethyl acetate in hexanes to give diethyl
2-(4-bromophenyl)malonate (2.6 g, 41%) .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.60-7.58 (m, 2H), 7.36-7.34 (m, 2H), 5.03 (s,
1H), 4.21-4.09 (m, 4H), 1.20-1.16 (m, 6H).
Step b: Diethyl 2-(4-bromophenyl)-2-methylmalonate
[0477] To a solution of diethyl 2-(4-bromophenyl)malonate (1.5 g,
4.8 mmol) in dry THF (5 mL) at 0.degree. C. was added sodium
hydride (380 mg, 9.5 mmol). After stirring for 30 minutes at
0.degree. C., iodomethane (600 .mu.L, 9.5 mmol) was added and the
reaction was allowed to warm to room temperature. After stirring
for 12 h at room temperature, the reaction was quenched with water
(3 mL). The mixture was partitioned between 1 N HCl (10 mL) and
dichloromethane (10 mL), and the organic layer was separated. The
organic layer was washed with 1 N HCl (10 mL), dried over
Na.sub.2SO.sub.4 and evaporated. The crude material was purified by
silica gel chromatography, eluting with 0-20% ethyl acetate in
hexanes, to give diethyl 2-(4-bromophenyl)-2-methylmalonate (850
mg, 55%) .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.59-7.55 (m, 2H),
7.31-7.27 (m, 2H), 4.21-4.14 (m, 4H), 1.75 (s, 3H), 1.19-1.16 (m,
6H).
Step c: 2-(4-Bromophenyl)-2-methylpropane-1,3-diol
[0478] To a solution of diethyl 2-(4-bromophenyl)-2-methylmalonate
(850 mg, 2.6 mmol) in dry THF (5 mL) at 0.degree. C. was added a
1.0M solution of lithium aluminum hydride in THF (2.6 mL, 2.6
mmol). After stirring for 2 h at 0.degree. C., the mixture was
quenched by slow addition of water (5 mL). The mixture was made
acidic by addition of 1N HCl and was then extracted with
dichloromethane (2.times.20 mL). The organics were combined, dried
over Na.sub.2SO.sub.4 and evaporated to give
2-(4-bromophenyl)-2-methylpropane-1,3-diol (500 mg, 79%) .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 7.47-7.43 (m, 2H), 7.35-7.32 (m,
2H), 4.59-4.55 (m, 2H), 3.56-3.51 (m, 4H), 1.17 (s, 3H).
Step d: 3-(4-Bromophenyl)-3-methyloxetane
[0479] 2-(4-Bromophenyl)-2-methylpropane-1,3-diol (100 mg, 0.41
mmol), triphenyl phosphine (210 mg, 0.82 mmol), and diisopropyl
azodicarboxylate (160 .mu.L, 0.82 mmol) were combined in toluene (2
mL) and irradiated in the microwave at 140.degree. C. for 10
minutes. The mixture was directly purified by silica gel
chromatography eluting with 0-20% ethyl acetate in hexanes to give
3-(4-bromophenyl)-3-methyloxetane (39 mg, 42%) .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.38-7.34 (m, 2H), 7.26-7.22 (m, 2H),
4.82-4.80 (m, 2H), 4.55-4.54 (m, 2H), 1.62 (s, 3H).
Preparation 47
N-(4-bromophenylsulfonyl)acetamide
##STR01298##
[0481] 3-Bromobenzenesulfonamide (470 mg, 2.0 mmol) was dissolved
in pyridine (1 mL). To this solution was added DMAP (7.3 mg, 0.060
mmol) and then acetic anhydride (570 .mu.L, 6.0 mmol). The reaction
was stirred for 3 h at room temperature during which time the
reaction changed from a yellow solution to a clear solution. The
solution was diluted with ethyl acetate, and then washed with
aqueous NH.sub.4Cl solution (.times.3) and water. The organic layer
was dried over MgSO.sub.4 and concentrated. The resulting oil was
triturated with hexanes and the precipitate was collected by
filtration to obtain N-(3-bromophenylsulfonyl)-acetamide as a shiny
white solid (280 mg, 51%). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
12.43 (s, 1H), 8.01 (t, J=1.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.61 (t,
J=8.0 Hz, 1H), 1.95 (s, 3H); HPLC ret. time 1.06 min; ESI-MS 278.1
m/z (MH.sup.+).
[0482] Assays
Assays for Detecting and Measuring .DELTA.F508-CFTR Correction
Properties of Compounds
A. Membrane Potential Optical Methods for Assaying .DELTA.F508-CFTR
Modulation Properties of Compounds
[0483] The optical membrane potential assay utilized
voltage-sensitive FRET sensors described by Gonzalez and Tsien
(See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by
fluorescence resonance energy transfer in single cells" Biophys J
69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997)
"Improved indicators of cell membrane potential that use
fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in
combination with instrumentation for measuring fluorescence changes
such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E.,
K. Oades, et al. (1999) "Cell-based assays and instrumentation for
screening ion-channel targets" Drug Discov Today 4(9):
431-439).
[0484] These voltage sensitive assays are based on the change in
fluorescence resonant energy transfer (FRET) between the
membrane-soluble, voltage-sensitive dye, DiSBAC.sub.2(3), and a
fluorescent phospholipid, CC2-DMPE, which is attached to the outer
leaflet of the plasma membrane and acts as a FRET donor. Changes in
membrane potential (V.sub.m) cause the negatively charged
DiSBAC.sub.2(3) to redistribute across the plasma membrane and the
amount of energy transfer from CC2-DMPE changes accordingly. The
changes in fluorescence emission were monitored using VIPR.TM. II,
which is an integrated liquid handler and fluorescent detector
designed to conduct cell-based screens in 96- or 384-well
microtiter plates.
1. Identification of Correction Compounds
[0485] To identify small molecules that correct the trafficking
defect associated with .DELTA.F508-CFTR; a single-addition HTS
assay format was developed. The cells were incubated in serum-free
medium for 16 hrs at 37.degree. C. in the presence or absence
(negative control) of test compound. As a positive control, cells
plated in 384-well plates were incubated for 16 hrs at 27.degree.
C. to "temperature-correct" .DELTA.F508-CFTR. The cells were
subsequently rinsed 3.times. with Krebs Ringers solution and loaded
with the voltage-sensitive dyes. To activate .DELTA.F508-CFTR, 10
.mu.M forskolin and the CFTR potentiator, genistein (20 .mu.M),
were added along with Cl.sup.--free medium to each well. The
addition of Cl.sup.--free medium promoted Cl.sup.- efflux in
response to .DELTA.F508-CFTR activation and the resulting membrane
depolarization was optically monitored using the FRET-based
voltage-sensor dyes.
2. Identification of Potentiator Compounds
[0486] To identify potentiators of .DELTA.F508-CFTR, a
double-addition HTS assay format was developed. During the first
addition, a Cl.sup.--free medium with or without test compound was
added to each well. After 22 sec, a second addition of
Cl.sup.--free medium containing 2-10 .mu.M forskolin was added to
activate .DELTA.F508-CFTR. The extracellular Cl.sup.- concentration
following both additions was 28 mM, which promoted Cl.sup.- efflux
in response to .DELTA.F508-CFTR activation and the resulting
membrane depolarization was optically monitored using the
FRET-based voltage-sensor dyes.
3. Solutions
[0487] Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl.sub.2 2,
MgCl.sub.2 1, HEPES10, pH 7.4 with NaOH.
[0488] Chloride-free bath solution: Chloride salts in Bath Solution
#1 are substituted with gluconate salts.
[0489] CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and
stored at -20.degree. C.
[0490] DiSBAC.sub.2(3): Prepared as a 10 mM stock in DMSO and
stored at -20.degree. C.
4. Cell Culture
[0491] NIH3T3 mouse fibroblasts stably expressing .DELTA.F508-CFTR
are used for optical measurements of membrane potential. The cells
are maintained at 37.degree. C. in 5% CO.sub.2 and 90% humidity in
Dulbecco's modified Eagle's medium supplemented with 2 mM
glutamine, 10% fetal bovine serum, 1.times.NEAA, .beta.-ME,
1.times. pen/strep, and 25 mM HEPES in 175 cm.sup.2 culture flasks.
For all optical assays, the cells were seeded at 30,000/well in
384-well matrigel-coated plates and cultured for 2 hrs at
37.degree. C. before culturing at 27.degree. C. for 24 hrs for the
potentiator assay. For the correction assays, the cells are
cultured at 27.degree. C. or 37.degree. C. with and without
compounds for 16-24 hours
B. Electrophysiological Assays for Assaying .DELTA.F508-CFTR
Modulation Properties of Compounds
1. Using Chamber Assay
[0492] Using chamber experiments were performed on polarized
epithelial cells expressing .DELTA.F508-CFTR to further
characterize the .DELTA.F508-CFTR modulators identified in the
optical assays. FRT.sup..DELTA.F508-CFTR epithelial cells grown on
Costar Snapwell cell culture inserts were mounted in an Ussing
chamber (Physiologic Instruments, Inc., San Diego, Calif.), and the
monolayers were continuously short-circuited using a Voltage-clamp
System (Department of Bioengineering, University of Iowa, IA, and,
Physiologic Instruments, Inc., San Diego, Calif.). Transepithelial
resistance was measured by applying a 2-mV pulse. Under these
conditions, the FRT epithelia demonstrated resistances of 4
K.OMEGA./cm.sup.2 or more. The solutions were maintained at
27.degree. C. and bubbled with air. The electrode offset potential
and fluid resistance were corrected using a cell-free insert. Under
these conditions, the current reflects the flow of Cl.sup.- through
.DELTA.F508-CFTR expressed in the apical membrane. The I.sub.SC was
digitally acquired using an MP100A-CE interface and AcqKnowledge
software (v3.2.6; BIOPAC Systems, Santa Barbara, Calif.).
2. Identification of Correction Compounds
[0493] Typical protocol utilized a basolateral to apical membrane
Cl.sup.- concentration gradient. To set up this gradient, normal
ringer was used on the basolateral membrane, whereas apical NaCl
was replaced by equimolar sodium gluconate (titrated to pH 7.4 with
NaOH) to give a large Cl.sup.- concentration gradient across the
epithelium. All experiments were performed with intact monolayers.
To fully activate .DELTA.F508-CFTR, forskolin (10 .mu.M) and the
PDE inhibitor, IBMX (100 .mu.M), were applied followed by the
addition of the CFTR potentiator, genistein (50 .mu.M).
[0494] As observed in other cell types, incubation at low
temperatures of FRT cells stably expressing .DELTA.F508-CFTR
increases the functional density of CFTR in the plasma membrane. To
determine the activity of correction compounds, the cells were
incubated with 10 .mu.M of the test compound for 24 hours at
37.degree. C. and were subsequently washed 3.times. prior to
recording. The cAMP- and genistein-mediated I.sub.SC in
compound-treated cells was normalized to the 27.degree. C. and
37.degree. C. controls and expressed as percentage activity.
Preincubation of the cells with the correction compound
significantly increased the cAMP- and genistein-mediated I.sub.SC
compared to the 37.degree. C. controls.
3. Identification of Potentiator Compounds
[0495] Typical protocol utilized a basolateral to apical membrane
Cl.sup.- concentration gradient. To set up this gradient, normal
ringers was used on the basolateral membrane and was permeabilized
with nystatin (360 .mu.g/ml), whereas apical NaCl was replaced by
equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a
large Cl.sup.- concentration gradient across the epithelium. All
experiments were performed 30 min after nystatin permeabilization.
Forskolin (10 .mu.M) and all test compounds were added to both
sides of the cell culture inserts. The efficacy of the putative
.DELTA.F508-CFTR potentiators was compared to that of the known
potentiator, genistein.
4. Solutions
[0496] Basolateral solution (in mM):NaCl (135), CaCl.sub.2 (1.2),
MgCl.sub.2 (1.2), K.sub.2HPO.sub.4 (2.4), KHPO.sub.4 (0.6),
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) (10),
and dextrose (10). The solution was titrated to pH 7.4 with
NaOH.
[0497] Apical solution (in mM): Same as basolateral solution with
NaCl replaced with Na Gluconate (135).
5. Cell Culture
[0498] Fisher rat epithelial (FRT) cells expressing
.DELTA.F508-CFTR (FRT.sup..DELTA.F508-CFTR) were used for Ussing
chamber experiments for the putative .DELTA.F508-CFTR modulators
identified from our optical assays. The cells were cultured on
Costar Snapwell cell culture inserts and cultured for five days at
37.degree. C. and 5% CO.sub.2 in Coon's modified Ham's F-12 medium
supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100
.mu.g/ml streptomycin. Prior to use for characterizing the
potentiator activity of compounds, the cells were incubated at
27.degree. C. for 16-48 hrs to correct for the .DELTA.F508-CFTR. To
determine the activity of corrections compounds, the cells were
incubated at 27.degree. C. or 37.degree. C. with and without the
compounds for 24 hours.
6. Whole-Cell Recordings
[0499] The macroscopic .DELTA.F508-CFTR current (I.sub..DELTA.F508)
in temperature- and test compound-corrected NIH3T3 cells stably
expressing .DELTA.F508-CFTR were monitored using the
perforated-patch, whole-cell recording. Briefly, voltage-clamp
recordings of I.sub..DELTA.F508 were performed at room temperature
using an Axopatch 200B patch-clamp amplifier (Axon Instruments
Inc., Foster City, Calif.). All recordings were acquired at a
sampling frequency of 10 kHz and low-pass filtered at 1 kHz.
Pipettes had a resistance of 5-6 M.OMEGA. when filled with the
intracellular solution. Under these recording conditions, the
calculated reversal potential for Cl.sup.- (E.sub.Cl) at room
temperature was -28 mV. All recordings had a seal resistance >20
G.OMEGA. and a series resistance <15 M.OMEGA.. Pulse generation,
data acquisition, and analysis were performed using a PC equipped
with a Digidata 1320 A/D interface in conjunction with Clampex 8
(Axon Instruments Inc.). The bath contained <250 .mu.l of saline
and was continuously perifused at a rate of 2 ml/min using a
gravity-driven perfusion system.
7. Identification of Correction Compounds
[0500] To determine the activity of correction compounds for
increasing the density of functional .DELTA.F508-CFTR in the plasma
membrane, we used the above-described perforated-patch-recording
techniques to measure the current density following 24-hr treatment
with the correction compounds. To fully activate .DELTA.F508-CFTR,
10 .mu.M forskolin and 20 .mu.M genistein were added to the cells.
Under our recording conditions, the current density following 24-hr
incubation at 27.degree. C. was higher than that observed following
24-hr incubation at 37.degree. C. These results are consistent with
the known effects of low-temperature incubation on the density of
.DELTA.F508-CFTR in the plasma membrane. To determine the effects
of correction compounds on CFTR current density, the cells were
incubated with 10 .mu.M of the test compound for 24 hours at
37.degree. C. and the current density was compared to the
27.degree. C. and 37.degree. C. controls (% activity). Prior to
recording, the cells were washed 3.times. with extracellular
recording medium to remove any remaining test compound.
Preincubation with 10 .mu.M of correction compounds significantly
increased the cAMP- and genistein-dependent current compared to the
37.degree. C. controls.
8. Identification of Potentiator Compounds
[0501] The ability of .DELTA.F508-CFTR potentiators to increase the
macroscopic .DELTA.F508-CFTR Cl.sup.- current (I.sub..DELTA.F508)
in NIH3T3 cells stably expressing .DELTA.F508-CFTR was also
investigated using perforated-patch-recording techniques. The
potentiators identified from the optical assays evoked a
dose-dependent increase in I.sub..DELTA.F508 with similar potency
and efficacy observed in the optical assays. In all cells examined,
the reversal potential before and during potentiator application
was around -30 mV, which is the calculated E.sub.Cl (-28 mV).
9. Solutions
[0502] Intracellular solution (in mM): Cs-aspartate (90), CsCl
(50), MgCl.sub.2 (1), HEPES (10), and 240 .mu.g/ml amphotericin-B
(pH adjusted to 7.35 with CsOH).
[0503] Extracellular solution (in mM): N-methyl-D-glucamine
(NMDG)-Cl (150), MgCl.sub.2 (2), CaCl.sub.2 (2), HEPES (10) (pH
adjusted to 7.35 with HCl).
10. Cell Culture
[0504] NIH3T3 mouse fibroblasts stably expressing .DELTA.F508-CFTR
are used for whole-cell recordings. The cells are maintained at
37.degree. C. in 5% CO.sub.2 and 90% humidity in Dulbecco's
modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal
bovine serum, 1.times.NEAA, .beta.-ME, 1.times. pen/strep, and 25
mM HEPES in 175 cm.sup.2 culture flasks. For whole-cell recordings,
2,500-5,000 cells were seeded on poly-L-lysine-coated glass
coverslips and cultured for 24-48 hrs at 27.degree. C. before use
to test the activity of potentiators; and incubated with or without
the correction compound at 37.degree. C. for measuring the activity
of correctors.
11. Single-Channel Recordings
[0505] The single-channel activities of temperature-corrected
.DELTA.F508-CFTR stably expressed in NIH3T3 cells and activities of
potentiator compounds were observed using excised inside-out
membrane patch. Briefly, voltage-clamp recordings of single-channel
activity were performed at room temperature with an Axopatch 200B
patch-clamp amplifier (Axon Instruments Inc.). All recordings were
acquired at a sampling frequency of 10 kHz and low-pass filtered at
400 Hz. Patch pipettes were fabricated from Corning Kovar Sealing
#7052 glass (World Precision Instruments, Inc., Sarasota, Fla.) and
had a resistance of 5-8 M.OMEGA. when filled with the extracellular
solution. The .DELTA.F508-CFTR was activated after excision, by
adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase,
catalytic subunit (PKA; Promega Corp. Madison, Wis.). After channel
activity stabilized, the patch was perifused using a gravity-driven
microperfusion system. The inflow was placed adjacent to the patch,
resulting in complete solution exchange within 1-2 sec. To maintain
.DELTA.F508-CFTR activity during the rapid perifusion, the
nonspecific phosphatase inhibitor F.sup.- (10 mM NaF) was added to
the bath solution. Under these recording conditions, channel
activity remained constant throughout the duration of the patch
recording (up to 60 min). Currents produced by positive charge
moving from the intra-to extracellular solutions (anions moving in
the opposite direction) are shown as positive currents. The pipette
potential (V.sub.p) was maintained at 80 mV.
[0506] Channel activity was analyzed from membrane patches
containing .ltoreq.2 active channels. The maximum number of
simultaneous openings determined the number of active channels
during the course of an experiment. To determine the single-channel
current amplitude, the data recorded from 120 sec of
.DELTA.F508-CFTR activity was filtered "off-line" at 100 Hz and
then used to construct all-point amplitude histograms that were
fitted with multigaussian functions using Bio-Patch Analysis
software (Bio-Logic Comp. France). The total microscopic current
and open probability (P.sub.o) were determined from 120 sec of
channel activity. The P.sub.o was determined using the Bio-Patch
software or from the relationship P.sub.o=I/i(N), where I=mean
current, i=single-channel current amplitude, and N=number of active
channels in patch.
12. Solutions
[0507] Extracellular solution (in mM): NMDG (150), aspartic acid
(150), CaCl.sub.2 (5), MgCl.sub.2 (2), and HEPES (10) (pH adjusted
to 7.35 with Tris base). [0508] Intracellular solution (in mM):
NMDG-Cl (150), MgCl.sub.2 (2), EGTA (5), TES (10), and Tris base
(14) (pH adjusted to 7.35 with HCl).
13. Cell Culture
[0509] NIH3T3 mouse fibroblasts stably expressing .DELTA.F508-CFTR
are used for excised-membrane patch-clamp recordings. The cells are
maintained at 37.degree. C. in 5% CO.sub.2 and 90% humidity in
Dulbecco's modified Eagle's medium supplemented with 2 mM
glutamine, 10% fetal bovine serum, 1.times.NEAA, .beta.-ME,
1.times. pen/strep, and 25 mM HEPES in 175 cm.sup.2 culture flasks.
For single channel recordings, 2,500-5,000 cells were seeded on
poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at
27.degree. C. before use.
[0510] The exemplified compounds of Table 1 have an activity of
less than 20 mM as measured using the assays described
hereinabove.
VIII. Other Embodiments
[0511] It is to be understood that while the invention has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims.
* * * * *
References