U.S. patent application number 15/618937 was filed with the patent office on 2017-12-14 for fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives.
The applicant listed for this patent is SciFluor Life Sciences, Inc.. Invention is credited to Ben C. ASKEW, D. Scott EDWARDS, Takeru FURUYA.
Application Number | 20170355679 15/618937 |
Document ID | / |
Family ID | 60572305 |
Filed Date | 2017-12-14 |
United States Patent
Application |
20170355679 |
Kind Code |
A1 |
EDWARDS; D. Scott ; et
al. |
December 14, 2017 |
FLUORINATED 2-AMINO-4-(SUBSTITUTED AMINO)PHENYL CARBAMATE
DERIVATIVES
Abstract
The application relates to 2-amino-4-(substituted amino)phenyl
carbamate derivatives, or pharmaceutically acceptable salts or
solvates thereof, as KCNQ2/3 potassium channel modulators, and
methods of their uses.
Inventors: |
EDWARDS; D. Scott; (Bedford,
MA) ; ASKEW; Ben C.; (Marshfield, MA) ;
FURUYA; Takeru; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SciFluor Life Sciences, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
60572305 |
Appl. No.: |
15/618937 |
Filed: |
June 9, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62348481 |
Jun 10, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 233/43 20130101;
C07C 271/28 20130101; A61P 25/00 20180101; C07D 209/44 20130101;
C07D 217/04 20130101 |
International
Class: |
C07D 217/04 20060101
C07D217/04; C07D 209/44 20060101 C07D209/44; C07C 233/43 20060101
C07C233/43; C07C 271/28 20060101 C07C271/28 |
Claims
1. A compound of formula A: ##STR00113## or a pharmaceutically
acceptable salt or solvate thereof, wherein: X.sub.1, X.sub.2,
X.sub.3, and X.sub.9 are each independently H, deuterium, F,
NH.sub.2, or a C.sub.1-C.sub.4 alkyl optionally substituted with
one or more F; X.sub.10 is C(O)(C.sub.7X.sub.7).sub.nX.sub.6 or
CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6; X.sub.4 is H,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl; X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m, wherein the
phenyl is substituted with one or more substituents independently
selected from deuterium, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, and SF.sub.5, and wherein
at least one substituent is selected from C.sub.1-C.sub.4 alkyl
substituted with one or more F, F, and SF.sub.5, or X.sub.4 and
X.sub.5, together with the nitrogen atom to which they are
attached, form a 5- to 7-membered heterocyclic ring comprising 1 or
2 heteroatoms selected from N, O, and S, wherein the heterocyclic
ring is optionally substituted with one or more substituents
independently selected from deuterium, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5, wherein at least one substituent is selected from
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5, or two substituents attached to adjacent carbon atoms on
the heterocyclic ring, together with the carbon atoms to which they
are attached, form a phenyl substituted with one or more
substituents independently selected from deuterium, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5, wherein the phenyl is substituted with at least one
substituent selected from C.sub.1-C.sub.4 alkyl substituted with
one or more F, F, and SF.sub.5; X.sub.6 is H or deuterium; each
X.sub.7 is independently H, C.sub.1-C.sub.4 alkyl, or deuterium, or
two X.sub.7, together with the carbon atom to which they are
attached, form a 3- to 6-membered carbocyclic ring or a 3- to
6-membered heterocyclic ring comprising 1 or 2 heteroatoms selected
from N, O, and S; each X.sub.5 is independently H, deuterium,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, or F; m is 1, 2, or 3; and n is 1, 2, or 3, wherein when
X.sub.1, X.sub.2, X.sub.3, and X.sub.6 are each H, n is 2, each
X.sub.7 is H, X.sub.5 is 4-fluorobenzyl, X.sub.9 is NH.sub.2, and
X.sub.10 is CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6, then X.sub.4 is
not propenyl or propynyl.
2. The compound of claim 1, wherein at least one of X.sub.1,
X.sub.2, X.sub.3, and X.sub.9 is NH.sub.2.
3. The compound of claim 1, wherein one of X.sub.1, X.sub.2,
X.sub.3, and X.sub.9 is NH.sub.2.
4. The compound of claim 1, wherein X.sub.9 is NH.sub.2.
5. The compound of claim 1, wherein at least one of X.sub.1 and
X.sub.9 is methyl.
6. The compound of claim 1, wherein X.sub.1 and X.sub.9 are each
methyl.
7. The compound of claim 1, of formula I: ##STR00114## or a
pharmaceutically acceptable salt or solvate thereof, wherein
X.sub.1, X.sub.2, and X.sub.3 are each independently H, deuterium,
or F, wherein when X.sub.1, X.sub.2, X.sub.3, and X.sub.6 are each
H, n is 2, each X.sub.7 is H, and X.sub.5 is 4-fluorobenzyl, then
X.sub.4 is not propenyl or propynyl.
8. The compound of claim 1, of formula Ia: ##STR00115## or a
pharmaceutically acceptable salt or solvate thereof, wherein
X.sub.2 and X.sub.3 are each independently H, deuterium, or F.
9. The compound of claim 1, wherein X.sub.3 is F.
10. The compound of claim 1, wherein X.sub.4 is C.sub.2-C.sub.6
alkenyl.
11. The compound of claim 1, wherein X.sub.4 is C.sub.2-C.sub.6
alkynyl.
12. The compound of claim 1, wherein X.sub.5 is
phenyl-(CX.sub.8X.sub.8).
13. The compound of claim 1, wherein X.sub.4 and X.sub.5, together
with the nitrogen atom to which they are attached, form a 5- to
7-membered heterocyclic ring substituted with two or more
substituents, wherein two substituents attached to adjacent carbon
atoms on the heterocyclic ring, together with the carbon atoms to
which they are attached, form a phenyl substituted with one or more
substituents independently selected from deuterium, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5.
14. The compound of claim 1, of formula II or VI: ##STR00116## or a
pharmaceutically acceptable salt or solvate thereof.
15. The compound of claim 1, of formula V or VII: ##STR00117## or a
pharmaceutically acceptable salt or solvate thereof.
16. The compound of claim 1, of formula IIIa: ##STR00118## or a
pharmaceutically acceptable salt or solvate thereof, wherein: t1 is
1, 2, 3, 4, or 5; and each Z.sub.1 is independently C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F, F, or
SF.sub.5, wherein at least one Z.sub.1 is C.sub.1-C.sub.4 alkyl
substituted with one or more F, F, or SF.sub.5, wherein when
X.sub.3 is H, t1 is 1, and Z.sub.1 is 4-fluoro, then X.sub.4 is not
propenyl or propynyl.
17. The compound of claim 1, of formula IIIb or IIIc: ##STR00119##
or a pharmaceutically acceptable salt or solvate thereof, wherein:
t1 is 1, 2, 3, 4, or 5; and each Z.sub.1 is independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, F, or SF.sub.5, wherein at least one Z.sub.1 is
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, or
SF.sub.5.
18. The compound of claim 1, of formula IVa, IVb, or IVc:
##STR00120## or a pharmaceutically acceptable salt or solvate
thereof, wherein: q is 1, 2, or 3; t2 is 1, 2, 3, or 4; and each
Z.sub.2 is independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, or SF.sub.5, wherein at
least one Z.sub.2 is C.sub.1-C.sub.4 alkyl substituted with one or
more F, F, or SF.sub.5, or two Z.sub.2, together with adjacent
carbon atoms to which they are attached, form a phenyl substituted
with one or more substituents independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, F, and SF.sub.5, wherein the phenyl is substituted with
at least one substituent selected from C.sub.1-C.sub.4 alkyl
substituted with one or more F, F, and SF.sub.5.
19. A pharmaceutical composition comprising at least one compound
according to claim 1 or a pharmaceutically acceptable salt or
solvate thereof and one or more pharmaceutically acceptable carrier
or excipient.
20. A method of treating or preventing a disease or disorder which
can be ameliorated by KCNQ2/3 potassium channel opening, comprising
administering to a subject in need thereof a compound of claim 1 or
a pharmaceutically acceptable salt or solvate thereof.
Description
RELATED APPLICATION
[0001] This application claims priority to, and the benefit of,
U.S. Ser. No. 62/348,481, filed on Jun. 10, 2016, the entire
contents of which are incorporated herein by reference.
BACKGROUND
[0002] Epilepsy is one of the most common chronic neurological
disorders, and affects approximately 50 million people worldwide.
Epilepsy patients have significantly increased morbidity, including
closed head injury, fractures, burns, dental injury and soft tissue
injury. Decline in or worsening of memory, cognition, depression
and sexual function and other lifestyle limitations occur
frequently in epilepsy patients. Epilepsy patients also have an
increased risk of mortality compared to the general population.
[0003] Although various pharmacologic agents are approved to treat
epilepsy, many patients are not adequately treated with the
currently available options. It is estimated that nearly a third of
patients with epilepsy have either intractable or uncontrolled
seizures or significant adverse side effects.
[0004] Ezogabine or retigabine, also known as ethyl
N-[2-amino-4-[(4-fluorophenyl) methylamino]phenyl]carbamate, is an
anticonvulsant used as a treatment for partial epilepsies.
Ezogabine works primarily as a potassium channel opener, i.e., by
activating KCNQ2/3 voltage-gated potassium channels in the brain.
Ezogabine was approved by the FDA and is marketed as Potiga.TM. and
Trobalt.TM.. U.S. Pat. No. 5,384,330 and WO 01/01970 describe
ezogabine and its use. The most common adverse events with
ezogabine are central nervous system effects, particularly
dizziness and somnolence. Occasional instances of urinary
difficulty may require surveillance. Ezogabine is predominantly
metabolized via glucuronidation, with a half-life of 8 hours.
[0005] Despite the beneficial activities of ezogabine, there is a
continuing need for new compounds to treat epilepsy and other
conditions ameliorated by KCNQ2/3 potassium channel opening.
SUMMARY OF THE APPLICATION
[0006] The present application provides a compound of formula
A:
##STR00001##
or a pharmaceutically acceptable salt or solvate thereof, wherein
the compound of formula A is disclosed in detail herein below.
[0007] The application also relates to a pharmaceutical composition
comprising a compound of formula A, or a pharmaceutically
acceptable salt or solvate thereof, and a pharmaceutically
acceptable carrier.
[0008] The application also relates to a method of modulating a
KCNQ2/3 potassium channel, comprising administering to a subject in
need thereof, a therapeutically effective amount of a compound of
formula A, or a pharmaceutically acceptable salt or solvate
thereof.
[0009] The application also relates to a compound of formula A, or
a pharmaceutically acceptable salt or solvate thereof, for use in
modulating a KCNQ2/3 potassium channel.
[0010] The application also relates to a compound of formula A, or
a pharmaceutically acceptable salt or solvate thereof, for use in
the manufacture of a medicament for modulating a KCNQ2/3 potassium
channel.
[0011] The present application also relates to use of a compound of
formula A, or a pharmaceutically acceptable salt or solvate
thereof, in the manufacture of a medicament for modulation of a
KCNQ2/3 potassium channel.
[0012] The application further relates to a method of treating or
preventing a disease or disorder which can be ameliorated by
KCNQ2/3 potassium channel opening, comprising administering to a
subject in need thereof, a therapeutically effective amount of a
compound of formula A, or a pharmaceutically acceptable salt or
solvate thereof.
[0013] The application also relates to a compound of formula A, or
a pharmaceutically acceptable salt or solvate thereof, for use in
treating or preventing a disease or disorder which can be
ameliorated by KCNQ2/3 potassium channel opening.
[0014] The application also relates to a compound of formula A, or
a pharmaceutically acceptable salt or solvate thereof, for use in
the manufacture of a medicament for treating or preventing a
disease or disorder which can be ameliorated by KCNQ2/3 potassium
channel opening.
[0015] The present application also relates to use of a compound of
formula A, or a pharmaceutically acceptable salt or solvate
thereof, in the manufacture of a medicament for the treatment or
prevention of a disease or disorder which can be ameliorated by
KCNQ2/3 potassium channel opening.
[0016] The application further relates to a method of treating or
preventing epilepsy, comprising administering to a subject in need
thereof, a therapeutically effective amount of a compound of
formula A, or a pharmaceutically acceptable salt or solvate
thereof.
[0017] The application also relates to a compound of formula A, or
a pharmaceutically acceptable salt or solvate thereof, for use in
treating or preventing epilepsy.
[0018] The application also relates to a compound of formula A, or
a pharmaceutically acceptable salt or solvate thereof, for use in
the manufacture of a medicament for treating or preventing
epilepsy.
[0019] The present application also relates to the use of a
compound of formula A, or a pharmaceutically acceptable salt or
solvate thereof, in the manufacture of a medicament for the
treatment or prevention of epilepsy.
[0020] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this application belongs. In the
case of conflict, the present specification, including definitions,
will control. In the specification, the singular forms also include
the plural unless the context clearly dictates otherwise. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
application, suitable methods and materials are described below.
All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference. The
references cited herein are not admitted to be prior art to the
present application. In addition, the materials, methods, and
examples are illustrative only and are not intended to be
limiting.
[0021] Other features and advantages of the application will be
apparent from the following detailed description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a graph showing the schematic of voltage protocol
and sweep settings for SyncroPatch Recordings in the assessment of
exemplified compounds of the application.
[0023] FIG. 2A is a plot showing dose-dependent activation of
Kv7.2/7.3 channels by Compound 4 as measured by the SyncroPatch
platform.
[0024] FIG. 2B is a plot showing dose-dependent activation of
Kv7.2/7.3 channels by Compound 6 as measured by the SyncroPatch
platform.
[0025] FIG. 2C is a plot showing dose-dependent activation of
Kv7.2/7.3 channels by Compound 7 as measured by the SyncroPatch
platform.
[0026] FIG. 2D is a plot showing dose-dependent activation of
Kv7.2/7.3 channels by Compound 8 as measured by the SyncroPatch
platform.
[0027] FIG. 2E is a plot showing dose-dependent activation of
Kv7.2/7.3 channels by Compound 10 (control) as measured by the
SyncroPatch platform.
[0028] FIG. 2F is a plot showing dose-dependent activation of
Kv7.2/7.3 channels by Compound 12 as measured by the SyncroPatch
platform.
[0029] FIG. 2G is a plot showing dose-dependent activation of
Kv7.2/7.3 channels by Compound X (control) as measured by the
SyncroPatch platform.
DETAILED DESCRIPTION OF THE APPLICATION
[0030] For purposes of the present application, the following
definitions will be used (unless expressly stated otherwise):
[0031] The term "a compound of the application" or "compounds of
the application" refers to any compound disclosed herein, e.g., a
compound of any of the formulae described herein, including
formulae A, I, Ia, II, IIIa-IIIc, IVa-IVc, V, VI, and VII, and/or
an individual compound explicitly disclosed herein. Whenever the
term is used in the context of the present application it is to be
understood that the reference is being made to the free base, a
deuterium labeled compound, and the corresponding pharmaceutically
acceptable salts or solvates thereof, provided that such is
possible and/or appropriate under the circumstances.
[0032] The term "pharmaceutical" or "pharmaceutically acceptable"
when used herein as an adjective, means substantially non-toxic and
substantially non-deleterious to the recipient.
[0033] By "pharmaceutical formulation" it is further meant that the
carrier, solvent, excipient, and salt must be compatible with the
active ingredient of the formulation (e.g., a compound of the
application). It is understood by those of ordinary skill in this
art that the terms "pharmaceutical formulation" and "pharmaceutical
composition" are generally interchangeable, and they are so used
for the purposes of this application.
[0034] Some of the compounds of the present application may exist
in unsolvated as well as solvated forms such as, for example,
hydrates.
[0035] "Solvate" means a solvent addition form that contains either
a stoichiometric or non stoichiometric amounts of solvent. Some
compounds have a tendency to trap a fixed molar ratio of solvent
molecules in the crystalline solid state, thus forming a solvate.
If the solvent is water the solvate formed is a hydrate, when the
solvent is alcohol, the solvate formed is an alcoholate. Hydrates
are formed by the combination of one or more molecules of water
with one of the substances in which the water retains its molecular
state as H.sub.2O, such combination being able to form one or more
hydrate. In the hydrates, the water molecules are attached through
secondary valencies by intermolecular forces, in particular
hydrogen bridges. Solid hydrates contain water as so-called crystal
water in stoichiometric ratios, where the water molecules do not
have to be equivalent with respect to their binding state. Examples
of hydrates are sesquihydrates, monohydrates, dihydrates or
trihydrates. Equally suitable are the hydrates of salts of the
compounds of the application.
[0036] Physiologically acceptable, i.e., pharmaceutically
compatible or pharmaceutically acceptable, salts can be salts of
the compounds of the application with inorganic or organic acids.
Preference is given to salts with inorganic acids, such as, for
example, hydrochloric acid, hydrobromic acid, phosphoric acid or
sulphuric acid, or to salts with organic carboxylic or sulphonic
acids, such as, for example, acetic acid, trifluoroacetic acid,
propionic acid, maleic acid, fumaric acid, malic acid, citric acid,
tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid,
ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid
or naphthalenedisulphonic acid. Other pharmaceutically compatible
salts which may be mentioned are salts with customary bases, such
as, for example, alkali metal salts (for example sodium or
potassium salts), alkaline earth metal salts (for example calcium
or magnesium salts) or ammonium salts, derived from ammonia or
organic amines, such as, for example, diethylamine, triethylamine,
ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,
dihydroabietylamine or methylpiperidine. Representative salts
include the following: acetate, benzenesulfonate, benzoate,
bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate,
carbonate, chloride, clavulanate, citrate, dihydrochloride,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, oleate, oxalate, pamottle (embonate), palmitate,
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, sulfate, subacetate, succinate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate.
[0037] The compounds of the application may contain one or more
asymmetric centers and can thus occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. Additional asymmetric centers may be
present depending upon the nature of the various substituents on
the molecule. Each such asymmetric center will independently
produce two optical isomers. It is intended that all of the
possible optical isomers and diastereomers in mixtures and as pure
or partially purified compounds are included within the ambit of
the application. The application is meant to comprehend all such
isomeric forms of these compounds.
[0038] The independent syntheses of these diastereomers or their
chromatographic separations may be achieved as known in the art by
appropriate modification of the methodology disclosed herein. Their
absolute stereochemistry may be determined by the X-ray
crystallography of crystalline products or crystalline
intermediates which are derivatized, if necessary, with a reagent
containing an asymmetric center of known absolute
configuration.
[0039] In the present specification, the structural formula of the
compound represents a certain isomer for convenience in some cases,
but the present application includes all isomers, such as
geometrical isomers, optical isomers based on an asymmetrical
carbon, stereoisomers, tautomers, and the like.
[0040] "Isomerism" means compounds that have identical molecular
formulae but differ in the sequence of bonding of their atoms or in
the arrangement of their atoms in space. Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed
"diastereoisomers", and stereoisomers that are non-superimposable
mirror images of each other are termed "enantiomers" or sometimes
optical isomers. A mixture containing equal amounts of individual
enantiomeric forms of opposite chirality is termed a "racemic
mixture".
[0041] "Chiral isomer" means a compound with at least one chiral
center. Compounds with more than one chiral center may exist either
as an individual diastereomer or as a mixture of diastereomers,
termed "diastereomeric mixture". When one chiral center is present,
a stereoisomer may be characterized by the absolute configuration
(R or S) of that chiral center. Absolute configuration refers to
the arrangement in space of the substituents attached to the chiral
center. The substituents attached to the chiral center under
consideration are ranked in accordance with the Sequence Rule of
Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413;
Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al.,
Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
[0042] "Geometric isomer" means the diastereomers that owe their
existence to hindered rotation about double bonds. These
configurations are differentiated in their names by the prefixes
cis and trans, or Z and E, which indicate that the groups are on
the same or opposite side of the double bond in the molecule
according to the Cahn-Ingold-Prelog rules.
[0043] Furthermore, the structures and other compounds discussed in
this application include all atropic isomers thereof. "Atropic
isomers" are a type of stereoisomer in which the atoms of two
isomers are arranged differently in space. Atropic isomers owe
their existence to a restricted rotation caused by hindrance of
rotation of large groups about a central bond. Such atropic isomers
typically exist as a mixture, however as a result of recent
advances in chromatography techniques; it has been possible to
separate mixtures of two atropic isomers in select cases.
[0044] "Tautomer" is one of two or more structural isomers that
exist in equilibrium and is readily converted from one isomeric
form to another. This conversion results in the formal migration of
a hydrogen atom accompanied by a switch of adjacent conjugated
double bonds. Tautomers exist as a mixture of a tautomeric set in
solution. In solid form, usually one tautomer predominates. In
solutions where tautomerization is possible, a chemical equilibrium
of the tautomers will be reached. The exact ratio of the tautomers
depends on several factors, including temperature, solvent and pH.
The concept of tautomers that are interconvertable by
tautomerizations is called tautomerism.
[0045] Of the various types of tautomerism that are possible, two
are commonly observed. In keto-enol tautomerism a simultaneous
shift of electrons and a hydrogen atom occurs. Ring-chain
tautomerism arises as a result of the aldehyde group (--CHO) in a
sugar chain molecule reacting with one of the hydroxy groups (--OH)
in the same molecule to give it a cyclic (ring-shaped) form as
exhibited by glucose. Common tautomeric pairs are: ketone-enol,
amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in
heterocyclic rings (e.g., in nucleobases such as guanine, thymine
and cytosine), amine-enamine and enamine-enamine. In one
example,
##STR00002##
are tautomers to each other.
[0046] It is to be understood that the compounds of the present
application may be depicted as different tautomers. It should also
be understood that when compounds have tautomeric forms, all
tautomeric forms are intended to be included in the scope of the
present application, and the naming of the compounds does not
exclude any tautomer form.
[0047] If desired, racemic mixtures of the compounds may be
separated so that the individual enantiomers are isolated. The
separation can be carried out by methods well known in the art,
such as contacting a racemic mixture of compounds with an
enantiomerically pure compound to form a diastereomeric mixture,
followed by separation of the individual diastereomers by standard
methods, such as fractional crystallization or chromatography. The
diastereomeric mixture is often a mixture of diasteriomeric salts
formed by contacting a racemic mixture of compounds with an
enantiomerically pure acid or base. The diastereomeric derivatives
may then be converted to the pure enantiomers by cleavage of the
added chiral residue. The racemic mixture of the compounds can also
be separated directly by chromatographic methods utilizing chiral
stationary phases, which are well known in the art.
[0048] The application also includes one or more metabolites of a
compound of the application.
[0049] The present application also comprehends deuterium labeled
compounds of each of the formulae described herein or the
individual compounds specifically disclosed, wherein a hydrogen
atom is replaced by a deuterium atom. The deuterium labeled
compounds comprise a deuterium atom having an abundance of
deuterium that is substantially greater than the natural abundance
of deuterium, e.g., 0.015%.
[0050] The term "deuterium enrichment factor" as used herein means
the ratio between the deuterium abundance and the natural abundance
of a deuterium. In one aspect, a compound of the application has a
deuterium enrichment factor for each deuterium atom of at least
3500 (52.5% deuterium incorporation at each deuterium atom), at
least 4000 (60% deuterium incorporation), at least 4500 (67.5%
deuterium incorporation), at least 5000 (75% deuterium), at least
5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium
incorporation), at least 6333.3 (95% deuterium incorporation), at
least 6466.7 (97% deuterium incorporation), at least 6600 (99%
deuterium incorporation), or at least 6633.3 (99.5% deuterium
incorporation).
[0051] Deuterium labeled compounds can be prepared using any of a
variety of art-recognized techniques. For example, deuterium
labeled compounds of each of the formulae described herein or the
compounds listed in Table 1 can generally be prepared by carrying
out the procedures described herein, by substituting a readily
available deuterium labeled reagent for a non-deuterium labeled
reagent.
[0052] A compound of the application or a pharmaceutically
acceptable salt or solvate thereof that contains the aforementioned
deuterium atom(s) is within the scope of the application. Further,
substitution with deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example, increased in vivo half-life and/or reduced dosage
requirements.
[0053] As used herein, the term "treat", "treating", or "treatment"
herein, is meant decreasing the symptoms, markers, and/or any
negative effects of a disease, disorder or condition in any
appreciable degree in a patient who currently has the condition.
The term "treat", "treating", or "treatment" includes alleviating
symptoms of a disease, disorder, or condition, e.g., alleviating
the symptoms of epilepsy. In some embodiments, treatment may be
administered to a subject who exhibits only early signs of the
condition for the purpose of decreasing the risk of developing the
disease, disorder, and/or condition.
[0054] As used herein, the term "prevent", "prevention", or
"preventing" refers to any method to partially or completely
prevent or delay the onset of one or more symptoms or features of a
disease, disorder, and/or condition. Prevention may be administered
to a subject who does not exhibit signs of a disease, disorder,
and/or condition.
[0055] As used herein, "subject" means a human or animal (in the
case of an animal, more typically a mammal). In one embodiment, the
subject is a human. In one embodiment, the subject is a male. In
one embodiment, the subject is a female.
[0056] As used herein, the term a "fluorinated derivative" is a
derivative compound that has the same chemical structure as the
original compound, except that at least one atom is replaced with a
fluorine atom or with a group of atoms containing at least one
fluorine atom.
[0057] The problem to be solved by the present application is the
identification of novel compounds for the treatment and/or
prevention of epilepsy and/or other diseases or disorders
ameliorated by KCNQ2/3 potassium channel opening. Although drugs
for epilepsy and related disorders are available, these drugs are
often not suitable for many patients for a variety of reasons. Many
epilepsy drugs are associated with adverse effects. For example,
many of the available epilepsy drugs are believed to significantly
increase the risk of birth defects if taken during the first
trimester of pregnancy. Other adverse side effects include urinary
retention, neuro-psychiatric symptoms including hallucinations and
psychosis, dizziness and somnolence, QT-prolonging effect, and
increased risk of suicidal behavior and ideation. Some epilepsy
drugs require administration of high doses due to extensive
metabolism into inactive or less potent metabolites. The present
application provides the solution of new fluorinated
2-amino-4-(benzylamino)phenylcarbamate compounds for treating
epilepsy and other diseases or disorders ameliorated by KCNQ2/3
potassium channel opening. The compounds described herein have the
advantage of providing improved potency, selectivity, tissue
penetration, half-life, and/or metabolic stability.
Compounds of the Application
[0058] The present application relates to a compound of formula
A:
##STR00003##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0059] X.sub.1, X.sub.2, X.sub.3, and X.sub.9 are each
independently H, deuterium, F, NH.sub.2, or a C.sub.1-C.sub.4 alkyl
optionally substituted with one or more F;
[0060] X.sub.10 is C(O)(C.sub.7X.sub.7).sub.nX.sub.6 or
CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6;
[0061] X.sub.4 is H, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl;
[0062] X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m, wherein the
phenyl is substituted with one or more substituents independently
selected from deuterium, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, and SF.sub.5, and wherein
at least one substituent is selected from C.sub.1-C.sub.4 alkyl
substituted with one or more F, F, and SF.sub.5, or
[0063] X.sub.4 and X.sub.5, together with the nitrogen atom to
which they are attached, form a 5- to 7-membered heterocyclic ring
comprising 1 or 2 heteroatoms selected from N, O, and S, wherein
the heterocyclic ring is optionally substituted with one or more
substituents independently selected from deuterium, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5, wherein at least one substituent is selected from
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5, or two substituents attached to adjacent carbon atoms on
the heterocyclic ring, together with the carbon atoms to which they
are attached, form a phenyl substituted with one or more
substituents independently selected from deuterium, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5, wherein the phenyl is substituted with at least one
substituent selected from C.sub.1-C.sub.4 alkyl substituted with
one or more F, F, and SF.sub.5;
[0064] X.sub.6 is H or deuterium;
[0065] each X.sub.7 is independently H, C.sub.1-C.sub.4 alkyl, or
deuterium, or two X.sub.7, together with the carbon atom to which
they are attached, form a 3- to 6-membered carbocyclic ring or a 3-
to 6-membered heterocyclic ring comprising 1 or 2 heteroatoms
selected from N, O, and S;
[0066] each X.sub.8 is independently H, deuterium, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F, or
F;
[0067] m is 1, 2, or 3; and
[0068] n is 1, 2, or 3,
wherein when X.sub.1, X.sub.2, X.sub.3, and X.sub.6 are each H, n
is 2, each X.sub.7 is H, X.sub.5 is 4-fluorobenzyl, X.sub.9 is
NH.sub.2, and X.sub.10 is CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6,
then X.sub.4 is not propenyl or propynyl.
[0069] In one embodiment, the compound of the present application
is a compound of formula A, wherein when X.sub.1, X.sub.2, X.sub.3,
and X.sub.6 are each H, n is 2, each X.sub.7 is H, and X.sub.5 is
4-fluorobenzyl, then X.sub.4 is not propenyl or propynyl.
[0070] In one embodiment, the compound of the present application
is a compound of formula A, wherein when X.sub.10 is
CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6, then X.sub.4 is not H.
[0071] In one embodiment, the compound of formula A is of formula
I:
##STR00004##
or a pharmaceutically acceptable salt or solvate thereof, wherein
X.sub.1, X.sub.2, and X.sub.3 are each independently H, deuterium,
or F, and X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, m, and n are
each as defined above in formula A, wherein when X.sub.1, X.sub.2,
X.sub.3, and X.sub.6 are each H, n is 2, each X.sub.7 is H, and
X.sub.5 is 4-fluorobenzyl, then X.sub.4 is not propenyl or
propynyl.
[0072] In one embodiment, the compound of formula A is of formula
Ia:
##STR00005##
or a pharmaceutically acceptable salt or solvate thereof, wherein
X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, m,
and n are each as defined above in formula A.
[0073] For a compound of formula A, I, or Ia, X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9,
X.sub.10, m, and n can each be, where applicable, selected from the
groups described herein below, and any group described herein for
any of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6,
X.sub.7, X.sub.8, X.sub.9, X.sub.10, m, and n can be combined,
where applicable, with any group described herein for one or more
of the remainder of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10, m, and n.
[0074] In one embodiment, at least one of X.sub.1, X.sub.2,
X.sub.3, and X.sub.9 is NH.sub.2. In one embodiment, one of
X.sub.1, X.sub.2, X.sub.3, and X.sub.9 is NH.sub.2. In one
embodiment, X.sub.9 is NH.sub.2. In one embodiment, one of X.sub.1,
X.sub.2, X.sub.3, and X.sub.9 is NH.sub.2, and the remainder of
X.sub.1, X.sub.2, X.sub.3, and X.sub.9 are each independently H,
deuterium, F, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), or C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F). In one embodiment, X.sub.9 is NH.sub.2, and
X.sub.1, X.sub.2, and X.sub.3 are each independently H, deuterium,
F, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, propyl,
butyl, i-butyl, or t-butyl), or C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, X.sub.9 is NH.sub.2, and X.sub.1, X.sub.2,
and X.sub.3 are each independently H, deuterium, or F.
[0075] In one embodiment, X.sub.9 is NH.sub.2, and X.sub.3 is F. In
one embodiment, X.sub.9 is NH.sub.2, X.sub.3 is F, and X.sub.1 and
X.sub.2 are each independently H or deuterium.
[0076] In one embodiment, at least one of X.sub.1, X.sub.2,
X.sub.3, and X.sub.9 is C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, or t-butyl) or C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F). In one embodiment, at least two of X.sub.1,
X.sub.2, X.sub.3, and X.sub.9 is C.sub.1-C.sub.4 alkyl (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F). In one embodiment, X.sub.1 and
X.sub.9 are each independently C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) or
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), and X.sub.2 and X.sub.3 are
each independently H, deuterium, F, or NH.sub.2. In one embodiment,
X.sub.1 and X.sub.9 are each independently C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl)
or C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each
of which is substituted with one or more F), and X.sub.2 and
X.sub.3 are each independently H, deuterium, or F. In one
embodiment, X.sub.1 and X.sub.9 are each independently methyl,
CF.sub.3, CHF.sub.2, or CH.sub.2F, and X.sub.2 and X.sub.3 are each
independently H, deuterium, or F. In one embodiment, at least one
of X.sub.1 and X.sub.9 is methyl. In one embodiment, X.sub.1 and
X.sub.9 are each methyl. In one embodiment, X.sub.1 and X.sub.9 are
each methyl, and X.sub.2 and X.sub.3 are each independently H,
deuterium, or F.
[0077] In one embodiment, X.sub.10 is
CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6. In one embodiment, X.sub.10
is C(O)(C.sub.7X.sub.7).sub.nX.sub.6.
[0078] In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are each
H.
[0079] In one embodiment, at least one of X.sub.1, X.sub.2, and
X.sub.3 is deuterium or F. In one embodiment, X.sub.1 is deuterium
or F, and X.sub.2 and X.sub.3 are each H. In one embodiment,
X.sub.1 is F, and X.sub.2 and X.sub.3 are each H. In one
embodiment, X.sub.2 is deuterium or F, and X.sub.1 and X.sub.3 are
each H. In one embodiment, X.sub.2 is F, and X.sub.1 and X.sub.3
are each H. In one embodiment, X.sub.3 is deuterium or F, and
X.sub.1 and X.sub.2 are each H. In one embodiment, X.sub.3 is F,
and X.sub.1 and X.sub.2 are each H.
[0080] In one embodiment, at least two of X.sub.1, X.sub.2, and
X.sub.3 are deuterium or F. In one embodiment, X.sub.1 and X.sub.2
are each independently deuterium or F, and X.sub.3 is H. In one
embodiment, X.sub.1 and X.sub.2 are each F, and X.sub.3 is H. In
one embodiment, X.sub.1 and X.sub.3 are each independently
deuterium or F, and X.sub.2 is H. In one embodiment, X.sub.1 and
X.sub.3 are each F, and X.sub.2 is H. In one embodiment, X.sub.2
and X.sub.3 are each independently deuterium or F, and X.sub.1 is
H. In one embodiment, X.sub.2 and X.sub.3 are each F, and X.sub.1
is H.
[0081] In one embodiment, X.sub.4 is H. In one embodiment, X.sub.4
is H, only when X.sub.10 is C(O)(C.sub.7X.sub.7).sub.nX.sub.6.
[0082] In one embodiment, X.sub.4 is C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl. In one
embodiment, X.sub.4 is C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, when X.sub.10 is
CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6.
[0083] In one embodiment, X.sub.4 is C.sub.1-C.sub.4 alkyl selected
from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, and
t-butyl.
[0084] In one embodiment, X.sub.4 is C.sub.2-C.sub.6 alkenyl or
C.sub.2-C.sub.6 alkynyl.
[0085] In one embodiment, X.sub.4 is C.sub.2-C.sub.6 alkenyl
selected from ethenyl, propenyl (e.g., 1-propenyl or 2-propenyl),
butenyl (e.g., 1-butenyl, 2-butenyl, or 3-butenyl), pentenyl (e.g.,
1-pentenyl, 2-pentenyl, 3-pentenyl, or 4-pentenyl), and hexenyl
(e.g., 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl).
In one embodiment, X.sub.4 is 1-propenyl or 2-propenyl.
[0086] In one embodiment, X.sub.4 is C.sub.2-C.sub.6 alkynyl
selected from ethynyl, propynyl (e.g., 1-propynyl or 2-propynyl),
butynyl (e.g., 1-butynyl, 2-butynyl, or 3-butynyl), pentynyl (e.g.,
1-pentynyl, 2-pentynyl, 3-pentynyl, or 4-pentynyl), and hexynyl
(e.g., 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl).
In one embodiment, X.sub.4 is 1-propynyl or 2-propynyl.
[0087] In one embodiment, X.sub.5 is phenyl-(CX.sub.8X.sub.8),
phenyl-(CX.sub.8X.sub.8).sub.2, or phenyl-(CX.sub.8X.sub.8).sub.3,
wherein the phenyl is substituted with one or more substituents
independently selected from deuterium, C.sub.1-C.sub.4 alkyl (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl) and C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F). In one embodiment, the phenyl is substituted
with one or more substituents independently selected from
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F) and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, and F. In
one embodiment, the phenyl is substituted with one or more groups
independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F, and F.
In one embodiment, the phenyl is substituted with one or more
substituents independently selected from CF.sub.3 and F. In one
embodiment, the substituent is attached at the para-position on the
phenyl ring. In one embodiment, the substituent(s) are attached at
the meta-position(s) on the phenyl ring. In one embodiment, the
substituent(s) are attached at the ortho-position(s) on the phenyl
ring. In one embodiment, X.sub.5 is 4-fluoro-benzyl,
4-trifluoromethyl-benzyl, or 3-trifluoromethyl-benzyl.
[0088] In one embodiment, each X.sub.5 is H. In one embodiment, at
least one X.sub.5 is deuterium, C.sub.1-C.sub.4 alkyl (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), or F. In one embodiment, at
least one X.sub.5 is deuterium. In one embodiment, at least one
X.sub.8 is C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), or F. In one embodiment, at least one X.sub.8
is C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl) or C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, at least one X.sub.8 is C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F) or F. In one embodiment, at least one X.sub.8
is C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl). In one embodiment, at least one
X.sub.8 is C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F). In one
embodiment, at least one X.sub.8 is F.
[0089] In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- to 7-membered
heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O,
and S (e.g., pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,
piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiapyranyl,
dioxanyl, morpholinyl, oxazinanyl, thiazinanyl, or oxathianyl). In
one embodiment, X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a 5- to 7-membered
heterocyclic ring comprising 1 heteroatom selected from N, O, and
S. In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- or 6-membered
heterocyclic ring comprising 1 heteroatom selected from N, O, and
S. In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- or 6-membered
heterocyclic ring comprising 1 heteroatom selected from N and O. In
one embodiment, X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a pyrrolidinyl or piperidinyl
ring.
[0090] In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- to 7-membered
heterocyclic ring substituted with one or more substituents
independently selected from deuterium, C.sub.1-C.sub.4 alkyl (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, propyl, butyl, i-butyl, or t-butyl, each of which is
substituted with one or more F), F, and SF.sub.5. In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), and F. In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl)
and C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each
of which is substituted with one or more F). In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F) and F. In one embodiment, the heterocyclic ring is substituted
with one or more substituents independently selected from CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2,
CH.sub.2CH.sub.2F, F, and SF.sub.5. In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, and F. In
one embodiment, the heterocyclic ring is substituted with one or
more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, and F. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from CF.sub.3 and F.
[0091] In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- to 7-membered
heterocyclic ring substituted with two or more substituents,
wherein two substituents attached to adjacent carbon atoms on the
heterocyclic ring, together with the carbon atoms to which they are
attached, form a phenyl substituted with one or more substituents
independently selected from deuterium, C.sub.1-C.sub.4 alkyl (e.g.,
methyl, ethyl, propyl, propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl) and C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F). In one embodiment, the phenyl is substituted
with one or more substituents independently selected from
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F) and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, and F. In
one embodiment, the phenyl is substituted with one or more groups
independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F, and F.
In one embodiment, the phenyl is substituted with one or more
substituents independently selected from CF.sub.3 and F.
[0092] In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a heterocyclic ring
selected from
##STR00006##
wherein the nitrogen atom is the nitrogen atom bonded to X.sub.4
and X.sub.5.
[0093] In one embodiment, X.sub.6 is H. In one embodiment, X.sub.6
is deuterium.
[0094] In one embodiment, each X.sub.7 is H. In one embodiment, at
least one X.sub.7 is deuterium. In one embodiment, at least one
X.sub.7 is C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl). In one embodiment, at least
two X.sub.7, together with the carbon atom to which they are
attached, form a 3- to 6-membered carbocyclic ring (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In one
embodiment, at least two X.sub.7, together with the carbon atom to
which they are attached, form a 3- to 6-membered heterocyclic ring
comprising 1 or 2 heteroatoms selected from N, O, and S (e.g.,
aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,
piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiapyranyl,
dioxanyl, morpholinyl, oxazinanyl, thiazinanyl, or oxathianyl). In
one embodiment, at least two X.sub.7, together with the carbon atom
to which they are attached, form a 3- to 6-membered heterocyclic
ring comprising 1 heteroatom selected from N, O, and S. In one
embodiment, at least two X.sub.7, together with the carbon atom to
which they are attached, form a 3- or 4-membered heterocyclic ring
comprising 1 heteroatom selected from N, O, and S. In one
embodiment, at least two X.sub.7, together with the carbon atom to
which they are attached, form a 3- or 4-membered heterocyclic ring
comprising 1 heteroatom selected from N and 0.
[0095] In one embodiment, m is 1. In one embodiment, m is 2. In one
embodiment, m is 3.
[0096] In one embodiment, n is 1. In one embodiment, n is 2. In one
embodiment, n is 3.
[0097] Any of the substituent groups described above for any of
X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7,
X.sub.8, X.sub.9, X.sub.10, m, and n can be combined with any of
the substituent groups described above for one or more of the
remainder of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6,
X.sub.7, X.sub.8, X.sub.9, X.sub.10, m, and n.
[0098] (1a) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each H.
[0099] (1b) In one embodiment, X.sub.1 and X.sub.2 are each H, and
X.sub.3 is deuterium or F.
[0100] (1c) In one embodiment, X.sub.1 and X.sub.2 are each H, and
X.sub.3 is F.
[0101] (1d) In one embodiment, X.sub.1 and X.sub.9 are each methyl,
and X.sub.3 is F.
[0102] (2a) In one embodiment, X.sub.6 is H.
[0103] (2b) In one embodiment, X.sub.6 is deuterium.
[0104] (3a) In one embodiment, each X.sub.7 is H.
[0105] (3b) In one embodiment, at least one X.sub.7 is
C.sub.1-C.sub.4 alkyl.
[0106] (3c) In one embodiment, at least two X.sub.7, together with
the carbon atom to which they are attached, form a 3- to 6-membered
carbocyclic ring or a 3- to 6-membered heterocyclic ring comprising
1 to 2 heteroatoms selected from N, O, and S. In one embodiment, at
least two X.sub.7, together with the carbon atom to which they are
attached, form a 3- to 6-membered heterocyclic ring comprising 1
heteroatom selected from N, O, and S. In one embodiment, at least
two X.sub.7, together with the carbon atom to which they are
attached, form a 3- or 4-membered heterocyclic ring comprising 1
heteroatom selected from N, O, and S. In one embodiment, at least
two X.sub.7, together with the carbon atom to which they are
attached, form a 3- or 4-membered heterocyclic ring comprising 1
heteroatom selected from N and O.
[0107] (4a) In one embodiment, n is 1.
[0108] (4b) In one embodiment, n is 2.
[0109] (4c) In one embodiment, n is 3.
[0110] (A1) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1a), and X.sub.7 is as defined in (3a).
[0111] (A2) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1b), and X.sub.7 is as defined in (3a).
[0112] (A3) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1c), and X.sub.7 is as defined in (3a).
[0113] (A4) In one embodiment, X.sub.1, X.sub.3, and X.sub.9 are
each as defined in (1d), and X.sub.7 is as defined in (3a).
[0114] (B1) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1a), and X.sub.7 is as defined in (3b).
[0115] (B2) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1b), and X.sub.7 is as defined in (3b).
[0116] (B3) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1c), and X.sub.7 is as defined in (3b).
[0117] (B4) In one embodiment, X.sub.1, X.sub.3, and X.sub.9 are
each as defined in (1d), and X.sub.7 is as defined in (3b).
[0118] (C1) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1a), and X.sub.7 is as defined in (3c).
[0119] (C2) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1b), and X.sub.7 is as defined in (3c).
[0120] (C3) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1c), and X.sub.7 is as defined in (3c).
[0121] (C4) In one embodiment, X.sub.1, X.sub.3, and X.sub.9 are
each as defined in (1d), and X.sub.7 is as defined in (3c).
[0122] (D1) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
and X.sub.9 are each as defined in any one of (A1)-(A4), and
X.sub.6 is as defined in (2a) or (2b). In one embodiment, X.sub.6
is as defined in (2a).
[0123] (D2) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
and X.sub.9 are each as defined in any one of (B1)-(B4), and
X.sub.6 is as defined in (2a) or (2b). In one embodiment, X.sub.6
is as defined in (2a).
[0124] (D3) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
and X.sub.9 are each as defined in any one of (C.sub.1)-(C.sub.4),
and X.sub.6 is as defined in (2a) or (2b). In one embodiment,
X.sub.6 is as defined in (2a).
[0125] (E1) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
and X.sub.9 are each as defined in any one of (A1)-(A4), (B1)-(B4),
or (C.sub.1)-(C.sub.4), and n is as defined in (4a).
[0126] (E2) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
and X.sub.9 are each as defined in any one of (A1)-(A4), (B1)-(B4),
or (C.sub.1)-(C.sub.4), and n is as defined in (4b).
[0127] (E3) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
and X.sub.9 are each as defined in any one of (A1)-(A4), (B1)-(B4),
or (C.sub.1)-(C.sub.4), and n is as defined in (4c).
[0128] (5a) In one embodiment, X.sub.4 is C.sub.1-C.sub.4 alkyl,
and X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m. In a further
embodiment, the phenyl is substituted with one or more groups
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkyl
substituted with one or more F. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl substituted with one or more F and F. In
a further embodiment, the phenyl is substituted with one or more
groups independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and
SF.sub.5. In a further embodiment, the phenyl is substituted with
one or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
and F. In a further embodiment, the phenyl is substituted with one
or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, and F. In a further embodiment, the phenyl is
substituted with one or more groups independently selected from
CF.sub.3 and F.
[0129] (5b) In one embodiment, X.sub.4 is C.sub.2-C.sub.6 alkenyl,
and X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m. In a further
embodiment, the phenyl is substituted with one or more groups
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkyl
substituted with one or more F. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl substituted with one or more F and F. In
a further embodiment, the phenyl is substituted with one or more
groups independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and
SF.sub.5. In a further embodiment, the phenyl is substituted with
one or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
and F. In a further embodiment, the phenyl is substituted with one
or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, and F. In a further embodiment, the phenyl is
substituted with one or more groups independently selected from
CF.sub.3 and F.
[0130] (5c) In one embodiment, X.sub.4 is C.sub.2-C.sub.6 alkynyl,
and X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m. In a further
embodiment, the phenyl is substituted with one or more groups
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkyl
substituted with one or more F. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl substituted with one or more F and F. In
a further embodiment, the phenyl is substituted with one or more
groups independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and
SF.sub.5. In a further embodiment, the phenyl is substituted with
one or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
and F. In a further embodiment, the phenyl is substituted with one
or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, and F. In a further embodiment, the phenyl is
substituted with one or more groups independently selected from
CF.sub.3 and F.
[0131] (5d) In one embodiment, X.sub.4 and X.sub.5, together with
the nitrogen atom to which they are attached, form a 5- to
7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected
from N, O, and S, optionally substituted with one or more
substituents independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5. In one embodiment, the heterocyclic ring is optionally
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with
one or more F, and F. In one embodiment, the heterocyclic ring is
optionally substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkyl
substituted with one or more F. In one embodiment, the heterocyclic
ring is optionally substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl substituted with
one or more F and F. In one embodiment, the heterocyclic ring is
optionally substituted with one or more substituents independently
selected from CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and SF.sub.5. In one
embodiment, the heterocyclic ring is optionally substituted with
one or more substituents independently selected from CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2,
CH.sub.2CH.sub.2F, and F. In one embodiment, the heterocyclic ring
is optionally substituted with one or more groups independently
selected from CF.sub.3, CHF.sub.2, CH.sub.2F, and F. In one
embodiment, the heterocyclic ring is optionally substituted with
one or more substituents independently selected from CF.sub.3 and
F.
[0132] (5e) In one embodiment, X.sub.4 and X.sub.5, together with
the nitrogen atom to which they are attached, form a 5- to
7-membered heterocyclic ring comprising 1 to 2 heteroatoms selected
from N, O, and S, substituted with two or more substituents,
wherein two substituents attached to adjacent carbon atoms on the
heterocyclic ring, together with the carbon atoms to which they are
attached, form a phenyl substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, and SF.sub.5. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, and F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkyl
substituted with one or more F. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl substituted with one or more F and F. In
a further embodiment, the phenyl is substituted with one or more
groups independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and
SF.sub.5. In a further embodiment, the phenyl is substituted with
one or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
and F. In a further embodiment, the phenyl is substituted with one
or more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, and F. In one embodiment, the phenyl is substituted with
one or more substituents independently selected from CF.sub.3 and
F.
[0133] (6a) In one embodiment, m is 1.
[0134] (6b) In one embodiment, m is 2.
[0135] (6c) In one embodiment, m is 3.
[0136] (7a) In one embodiment, each X.sub.5 is H.
[0137] (7b) In one embodiment, at least one X.sub.5 is
deuterium.
[0138] (7c) In one embodiment, at least one X.sub.5 is
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, or F.
[0139] (F1a) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in (5a), and m is as defined in any one of (6a)-(6c). In a
further embodiment, m is as defined in (6a).
[0140] (F1b) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in (5b), and m is as defined in any one of (6a)-(6c). In a
further embodiment, m is as defined in (6a).
[0141] (F1c) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in (5c), and m is as defined in any one of (6a)-(6c). In a
further embodiment, m is as defined in (6a).
[0142] (G1a) In one embodiment, X.sub.4, X.sub.5, and m are each as
defined in any one of (F1a)-(F1c), and X.sub.5 is as defined in
(7a).
[0143] (G1b) In one embodiment, X.sub.4, X.sub.5, and m are each as
defined in any one of (F1a)-(F1c), and X.sub.5 is as defined in
(7b).
[0144] (G1c) In one embodiment, X.sub.4, X.sub.5, and m are each as
defined in any one of (F1a)-(F1c), and X.sub.5 is as defined in
(7c).
[0145] (H1a) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, and X.sub.3
are each as defined in (1a).
[0146] (H1b) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, and X.sub.3
are each as defined in (1b).
[0147] (H1c) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, and X.sub.3
are each as defined in (1c).
[0148] (H1d) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.3, and X.sub.9
are each as defined in (1d).
[0149] (H1e) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.7 is as defined in
(3a).
[0150] (H1f) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.7 is as defined in
(3b).
[0151] (H1g) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.7 is as defined in
(3c).
[0152] (H1h) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (A1).
[0153] (H1i) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (A2).
[0154] (H1j) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (A3).
[0155] (H1k) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.3, X.sub.7, and
X.sub.9 are each as defined (A4).
[0156] (H1l) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (B1).
[0157] (H1m) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (B2).
[0158] (H1n) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (B3).
[0159] (H1o) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.3, X.sub.7, and
X.sub.9 are each as defined (B4).
[0160] (H1p) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (C.sub.1).
[0161] (H1q) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (C.sub.2).
[0162] (H1r) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (C.sub.3).
[0163] (H1s) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.3, X.sub.7, and
X.sub.9 are each as defined (C.sub.4).
[0164] (H1t) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3,
X.sub.6, X.sub.7, and X.sub.9 are each as defined (D1).
[0165] (H1u) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3,
X.sub.6, X.sub.7, and X.sub.9 are each as defined (D2).
[0166] (H1v) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3,
X.sub.6, X.sub.7, and X.sub.9 are each as defined (D3).
[0167] (H1w) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3,
X.sub.7, X.sub.9, and n are each as defined (E1).
[0168] (H1x) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3,
X.sub.7, X.sub.9, and n are each as defined (E2).
[0169] (H1y) In one embodiment, X.sub.4 and X.sub.5 are each as
defined in any one of (5a)-(5e), and X.sub.1, X.sub.2, X.sub.3,
X.sub.7, X.sub.9, and n are each as defined (E3).
[0170] (I1a) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1a), and X.sub.4, X.sub.5, and m are each as
defined in any one of (F1a)-(F1c).
[0171] (I1b) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1b), and X.sub.4, X.sub.5, and m are each as
defined in any one of (F1a)-(F1c).
[0172] (I1c) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1c), and X.sub.4, X.sub.5, and m are each as
defined in any one of (F1a)-(F1c).
[0173] (I1d) In one embodiment, X.sub.1, X.sub.3, and X.sub.9 are
each as defined in (1d), and X.sub.4, X.sub.5, and m are each as
defined in any one of (F1a)-(F1c).
[0174] (I1e) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1a), and X.sub.4, X.sub.5, X.sub.8, and m are
each as defined in any one of (G1a)-(G1c).
[0175] (I1f) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1b), and X.sub.4, X.sub.5, X.sub.8, and m are
each as defined in any one of (G1a)-(G1c).
[0176] (I1g) In one embodiment, X.sub.1, X.sub.2, and X.sub.3 are
each as defined in (1c), and X.sub.4, X.sub.5, X.sub.8, and m are
each as defined in any one of (G1a)-(G1c).
[0177] (I1h) In one embodiment, X.sub.1, X.sub.3, and X.sub.9 are
each as defined in (1d), and X.sub.4, X.sub.5, X.sub.8, and m are
each as defined in any one of (G1a)-(G1c).
[0178] (I1i) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (A1), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0179] (I1j) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (A2), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0180] (I1k) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (A3), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0181] (I1l) In one embodiment, X.sub.1, X.sub.3, X.sub.7, and
X.sub.9 are each as defined (A4), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0182] (I1m) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (B1), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0183] (I1n) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (B2), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0184] (I1o) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (B3), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0185] (I1p) In one embodiment, X.sub.1, X.sub.3, X.sub.7, and
X.sub.9 are each as defined (B4), and X.sub.4, X.sub.5, and m are
each as defined in any one of (F1a)-(F1c).
[0186] (I1q) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (C.sub.1), and X.sub.4, X.sub.5, and m
are each as defined in any one of (F1a)-(F1c).
[0187] (I1r) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (C.sub.2), and X.sub.4, X.sub.5, and m
are each as defined in any one of (F1a)-(F1c).
[0188] (I1s) In one embodiment, X.sub.1, X.sub.2, X.sub.3, and
X.sub.7 are each as defined (C.sub.3), and X.sub.4, X.sub.5, and m
are each as defined in any one of (F1a)-(F1c).
[0189] (I1t) In one embodiment, X.sub.1, X.sub.3, X.sub.7, and
X.sub.9 are each as defined (C.sub.4), and X.sub.4, X.sub.5, and m
are each as defined in any one of (F1a)-(F1c).
[0190] (I1u) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.6,
X.sub.7, and X.sub.9 are each as defined (D1), and X.sub.4,
X.sub.5, and m are each as defined in any one of (F1a)-(F1c).
[0191] (I1v) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.6,
X.sub.7, and X.sub.9 are each as defined (D2), and X.sub.4,
X.sub.5, and m are each as defined in any one of (F1a)-(F1c).
[0192] (I1w) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.6,
X.sub.7, and X.sub.9 are each as defined (D3), and X.sub.4,
X.sub.5, and m are each as defined in any one of (F1a)-(F1c).
[0193] (I1x) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
X.sub.9, and n are each as defined (E1), and X.sub.4, X.sub.5, and
m are each as defined in any one of (F1a)-(F1c).
[0194] (I1y) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
X.sub.9, and n are each as defined (E2), and X.sub.4, X.sub.5, and
m are each as defined in any one of (F1a)-(F1c).
[0195] (I1z) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.7,
X.sub.9, and n are each as defined (E3), and X.sub.4, X.sub.5, and
m are each as defined in any one of (F1a)-(F1c).
[0196] (J1) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, m, and n are each,
where applicable, as defined in any one of (1a)-(I1z), X.sub.10 is
C(O)(C.sub.7X.sub.7).sub.nX.sub.6.
[0197] (J2) In one embodiment, X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, m, and n are each,
where applicable, as defined in any one of (1a)-(I1z), X.sub.10 is
CO.sub.2(C.sub.7X.sub.7).sub.nX.sub.6.
[0198] In one embodiment, the compound of formula A is of formula
II or VI:
##STR00007##
or a pharmaceutically acceptable salt or solvate thereof, wherein
X.sub.3, X.sub.4, X.sub.5, X.sub.8, and m are each as defined above
in formula A.
[0199] X.sub.3, X.sub.4, X.sub.5, X.sub.8, and m can each be
selected from any of the substituents described above in formula A,
and any of the substituents described above for any of X.sub.3,
X.sub.4, X.sub.5, X.sub.8, and m can be combined with any of the
substituents described above for one or more of the remainder of
X.sub.3, X.sub.4, X.sub.5, X.sub.8, and m.
[0200] In one embodiment, the compound of formula A is of formula V
or VII:
##STR00008##
or a pharmaceutically acceptable salt or solvate thereof, wherein
X.sub.3, X.sub.4, X.sub.5, X.sub.8, and m are each as defined above
in formula A.
[0201] X.sub.3, X.sub.4, X.sub.5, X.sub.8, and m can each be
selected from any of the substituents described above in formula A,
and any of the substituents described above for any of X.sub.3,
X.sub.4, X.sub.5, X.sub.8, and m can be combined with any of the
substituents described above for one or more of the remainder of
X.sub.3, X.sub.4, X.sub.5, X.sub.8, and m.
[0202] In one embodiment, the compound of formula A is of formula
IIIa:
##STR00009##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0203] X.sub.3, X.sub.4, and m are each as defined above in formula
A;
[0204] t1 is 1, 2, 3, 4, or 5; and
[0205] each Z.sub.1 is independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, or
SF.sub.5, wherein at least one Z.sub.1 is C.sub.1-C.sub.4 alkyl
substituted with one or more F, F, or SF.sub.5, wherein when
X.sub.3 is H, t1 is 1, and Z.sub.1 is 4-fluoro, then X.sub.4 is not
propenyl or propynyl.
[0206] In one embodiment, the compound of formula A is of formula
IIIb or IIIc:
##STR00010##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0207] X.sub.3, X.sub.4, and m are each as defined above in formula
A;
[0208] t1 is 1, 2, 3, 4, or 5; and
[0209] each Z.sub.1 is independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, or
SF.sub.5, wherein at least one Z.sub.1 is C.sub.1-C.sub.4 alkyl
substituted with one or more F, F, or SF.sub.5.
[0210] For a compound of formula IIIa, IIIb, or IIIc, t1 and
Z.sub.1 can each be, where applicable, selected from the groups
described herein below, and any group described herein for any of
t1 and Z.sub.1 can be combined, where applicable, with any group
described herein for the remainder of t1 and Z.sub.1.
[0211] In one embodiment, t1 is 1, 2, or 3.
[0212] In one embodiment, t1 is 1 or 2.
[0213] In one embodiment, t1 is 1.
[0214] In one embodiment, t1 is 2.
[0215] In one embodiment, t1 is 3.
[0216] In one embodiment, t1 is 4.
[0217] In one embodiment, t1 is 5.
[0218] In one embodiment, at least one Z.sub.1 is C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), F, or
SF.sub.5.
[0219] In one embodiment, at least one Z.sub.1 is C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), or F.
[0220] In one embodiment, at least one Z.sub.1 is C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl) or C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F).
[0221] In one embodiment, at least one Z.sub.1 is C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F) or F.
[0222] In one embodiment, at least one Z.sub.1 is CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2,
CH.sub.2CH.sub.2F, F, or SF.sub.5. In a further embodiment, at
least one Z.sub.1 is CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, or F. In a
further embodiment, at least one Z.sub.1 is CF.sub.3, CHF.sub.2,
CH.sub.2F, or F. In a further embodiment, at least one Z.sub.1 is
CF.sub.3 or F.
[0223] X.sub.3, X.sub.4, and m can each be selected from any of the
substituents described above in formula A, and any of the
substituents described above for any of X.sub.3, X.sub.4, and m can
be combined with any of the substituents described above for one or
more of the remainder of X.sub.3, X.sub.4, and m, and can further
be combined with any of the substituents described for any of t1
and Z.sub.1.
[0224] In one embodiment, t1 is 1, and Z.sub.1 is CF.sub.3 or
F.
[0225] In one embodiment, t1 is 1, Z.sub.1 is CF.sub.3 or F, and m
is 1.
[0226] In one embodiment, t1 is 1, Z.sub.1 is CF.sub.3 or F, and
X.sub.4 is propenyl or propynyl.
[0227] In one embodiment, t1 is 1, Z.sub.1 is CF.sub.3 or F, m is
1, and X.sub.4 is propenyl or propynyl.
[0228] In one embodiment, t1 is 1, Z.sub.1 is CF.sub.3 or F,
X.sub.4 is propenyl or propynyl, and X.sub.3 is H or F.
[0229] In one embodiment, t1 is 1, Z.sub.1 is CF.sub.3, m is 1,
X.sub.4 is propenyl or propynyl, and X.sub.3 is H or F.
[0230] In one embodiment, t1 is 1, Z.sub.1 is CF.sub.3 or F, m is
1, X.sub.4 is propenyl or propynyl, and X.sub.3 is F.
[0231] In one embodiment, the compound of formula A is of formula
IVa, IVb, or IVc:
##STR00011##
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
[0232] X.sub.3 is as defined above in formula A;
[0233] q is 1, 2, or 3;
[0234] t2 is 1, 2, 3, or 4; and
[0235] each Z.sub.2 is independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, or
SF.sub.5, wherein at least one Z.sub.2 is C.sub.1-C.sub.4 alkyl
substituted with one or more F, F, or SF.sub.5, or two Z.sub.2,
together with adjacent carbon atoms to which they are attached,
form a phenyl substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, F, and SF.sub.5, wherein the
phenyl is substituted with at least one substituent selected from
C.sub.1-C.sub.4 alkyl substituted with one or more F, F, and
SF.sub.5.
[0236] For a compound of formula IVa, IVb, or IVc, q, t2, and
Z.sub.2 can each be, where applicable, selected from the groups
described herein below, and any group described herein for any of
q, t2, and Z.sub.2 can be combined, where applicable, with any
group described herein for one or more of the remainder of q, t2,
and Z.sub.2.
[0237] In one embodiment, q is 1.
[0238] In one embodiment, q is 2.
[0239] In one embodiment, q is 3.
[0240] In one embodiment, t2 is 1, 2, or 3.
[0241] In one embodiment, t2 is 1 or 2.
[0242] In one embodiment, t2 is 1.
[0243] In one embodiment, t2 is 2.
[0244] In one embodiment, t2 is 3.
[0245] In one embodiment, t2 is 4.
[0246] In one embodiment, at least one Z.sub.2 is C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), F, or
SF.sub.5.
[0247] In one embodiment, at least one Z.sub.2 is C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), or F.
[0248] In one embodiment, at least one Z.sub.2 is C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl) or C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F).
[0249] In one embodiment, at least one Z.sub.2 is C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F) or F.
[0250] In one embodiment, at least one Z.sub.2 is CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2,
CH.sub.2CH.sub.2F, F, or SF.sub.5. In a further embodiment, at
least one Z.sub.2 is CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, or F. In a
further embodiment, at least one Z.sub.2 is CF.sub.3, CHF.sub.2,
CH.sub.2F, or F. In a further embodiment, at least one Z.sub.2 is
CF.sub.3 or F.
[0251] In one embodiment, two Z.sub.2, together with adjacent
carbon atoms to which they are attached, form a phenyl substituted
with one or more substituents independently selected from
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), F, and SF.sub.5. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), and F. In one embodiment, the phenyl is substituted with one or
more substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl)
and C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each
of which is substituted with one or more F). In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F) and F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, F, and
SF.sub.5. In one embodiment, the phenyl is substituted with one or
more substituents independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
and F. In one embodiment, the phenyl is substituted with one or
more groups independently selected from CF.sub.3, CHF.sub.2,
CH.sub.2F, and F. In one embodiment, the phenyl is substituted with
one or more substituents independently selected from CF.sub.3 and
F.
[0252] Any of the substituents described above for any of q, t2,
and Z.sub.2 can be combined with any of the substituents described
above for any of the remainder of q, t2, and Z.sub.2, and can
further be combined with any of the substituents described above
for X.sub.3.
[0253] In one embodiment, a compound of the present application is
selected from the compounds in Tables 1a and 1b.
TABLE-US-00001 TABLE 1a Cpmd No. Structure 1 ##STR00012## 2
##STR00013## 3 ##STR00014## 4 ##STR00015## 5 ##STR00016## 6
##STR00017## 7 ##STR00018## 8 ##STR00019## 9 ##STR00020## 11
##STR00021## 12 ##STR00022## 13 ##STR00023## 14 ##STR00024## 15
##STR00025## 16 ##STR00026## 17 ##STR00027## 18 ##STR00028## 19
##STR00029## 20 ##STR00030## 21 ##STR00031## 22 ##STR00032## 23
##STR00033## 24 ##STR00034## 25 ##STR00035## 26 ##STR00036##
TABLE-US-00002 TABLE 1b Cpmd No. Structure 27 ##STR00037## 28
##STR00038## 29 ##STR00039## 30 ##STR00040## 31 ##STR00041## 32
##STR00042## 33 ##STR00043## 34 ##STR00044## 35 ##STR00045## 36
##STR00046##
[0254] In one embodiment, a compound of the application is a
pharmaceutically acceptable salt. In one embodiment, a compound of
the application is a solvate. In one embodiment, a compound of the
application is a hydrate.
[0255] The present application relates to pharmaceutical
compositions comprising one of the compounds of the application as
an active ingredient. In one embodiment, the application provides a
pharmaceutical composition comprising at least one compound of
formula A, I, Ia, II, IIIa, IIIb, IIIc, IVa, IVb, IVc, V, VI, or
VII, or a pharmaceutically acceptable salt or solvate thereof, and
one or more pharmaceutically acceptable carrier or excipient. In
one embodiment, the application provides a pharmaceutical
composition comprising at least one compound of Table 1, or a
pharmaceutically acceptable salt or solvate thereof, and one or
more pharmaceutically acceptable carrier or excipient.
[0256] The present application relates to a method of synthesizing
a compound of the application or a pharmaceutically acceptable salt
or solvate thereof. A compound of the application can be
synthesized using a variety of methods known in the art, such as
those described in U.S. Pat. No. 8,916,133, the contents of which
are incorporated by reference in their entirety. The schemes and
description below depict general routes for the preparation of a
compound of the application. For example, compounds of the present
application can be synthesized by following the steps outlined in
Schemes 1-6 which comprise different sequences of assembling
intermediates 3a, 3b, 3c, 3d, 3e, 4a, 4b, 4c, 5a, 5b, 5c, 5d, 5e,
7a, 7b, 7c, 7d, 7e, 7f, 8a, 8b, 8c, 8d, 8e, 8f, 9a, 9b, 9c, 9d, 9e,
and 9f. Starting materials are either commercially available or
made by known procedures in the reported literature or as
illustrated.
##STR00047##
wherein X.sub.3, X.sub.4, Z.sub.1, t1, and m are as defined herein
above.
[0257] The general way of preparing representative compounds of the
present application using intermediates 3a, 3b, 3c, 3d, and 3e is
outlined in Scheme 1. Alkylation of amine 3a with bromide 3b (i.e.,
an alkyl bromide, allyl bromide, etc.) in the presence of a base,
e.g., diisopropylethylamine (DIPEA), in a solvent, e.g.,
dimethylformamide (DMF), and optionally at an elevated temperature
provides intermediate 3c. Nucleophilic addition of 3c to fluoride
3d in the presence of a base, e.g., triethylamine (Et.sub.3N), in a
solvent, e.g., dimethylsulfoxide (DMSO), and optionally at an
elevated temperature provides intermediate 3e. Reduction of 3e
using a metal catalyst, e.g., Zinc (Zn), and ammonium chloride
(NH.sub.4C.sub.1) in the presence of a base, e.g., DIPEA and in a
solvent, e.g., methanol (MeOH), and consequent esterification with
an agent, e.g., ethyl chloroformate, in the presence of a base,
e.g., diisopropylethylamine (DIPEA), and optionally at an elevated
temperature provides compounds of formula IIIa.
##STR00048##
wherein X.sub.3, Z.sub.2, and t2 are as defined herein above.
[0258] The general way of preparing representative compounds of the
present application using intermediates 4a, 4b, and 4c is outlined
in Scheme 2. Nucleophilic addition of 4a to fluoride 4b in the
presence of a base, e.g., triethylamine (Et.sub.3N), in a solvent,
e.g., dimethylsulfoxide (DMSO), and optionally at an elevated
temperature provides intermediate 4c. Reduction of 4c using a metal
catalyst, e.g., Zinc (Zn), and ammonium chloride (NH.sub.4C.sub.1)
in the presence of a base, i.e., DIPEA and in a solvent, i.e.,
methanol (MeOH), and consequent esterification with an agent, e.g.,
ethyl chloroformate, in the presence of a base, e.g.,
diisopropylethylamine (DIPEA), and optionally at an elevated
temperature provides compounds of formula IVa.
##STR00049##
wherein X.sub.3, X.sub.4, Z.sub.1, t1, and m are as defined herein
above.
[0259] The general way of preparing representative compounds of the
present application using intermediates 5a, 5b, 5c, 5d, and 5e is
outlined in Scheme 3. Nucleophilic addition of 5a to fluoride 5b in
the presence of a base, e.g., triethylamine (Et.sub.3N), in a
solvent, e.g., dimethylsulfoxide (DMSO), and optionally at an
elevated temperature provides intermediate 5c. Alkylation of amine
5c with bromide 5d (i.e., an alkyl bromide, allyl bromide, etc.) in
the presence of a base, e.g., diisopropylethylamine (DIPEA), in a
solvent, e.g., dimethylformamide (DMF), and optionally at an
elevated temperature provides intermediate 5e. Reduction of 5e
using a metal catalyst, e.g., Zinc (Zn), and ammonium chloride
(NH.sub.4C.sub.1) in the presence of a base, e.g., DIPEA and in a
solvent, e.g., water, and consequent esterification with an agent,
e.g., ethyl chloroformate, in the presence of a base, e.g.,
diisopropylethylamine (DIPEA), and optionally at an elevated
temperature provides compounds of formula IIIa.
##STR00050##
wherein X.sub.3, X.sub.4, Z.sub.1, t1, and m are as defined herein
above.
[0260] The general way of preparing representative compounds of the
present application using intermediates 7a, 7b, 7c, 7d, 7e, and 7f
is outlined in Scheme 5. Nucleophilic addition of 7a to fluoride 7b
in the presence of a base, e.g., triethylamine (Et.sub.3N), in a
solvent, e.g., dimethylsulfoxide (DMSO), and optionally at an
elevated temperature provides intermediate 7c. Reduction of 7c
using a metal catalyst, e.g., Zinc (Zn), and ammonium chloride
(NH.sub.4C.sub.1) in the presence of a base, e.g., DIPEA and in a
solvent, e.g., methanol (MeOH), and consequent protection using
BOC.sub.2O in the presence of a base, e.g., NaHCO.sub.3, provides
intermediate 7d. Alkylation of amine 7d with bromide 7e (i.e., an
alkyl bromide, allyl bromide, etc.) in the presence of a base,
e.g., diisopropylethylamine (DIPEA), in a solvent, e.g.,
dimethylformamide (DMF), and optionally at an elevated temperature
provides intermediate 7f. Deprotection of 7f in the presence of an
acid, e.g., trifluoroacetic acid (TFA), and optionally at an
elevated temperature, and consequent esterification with an agent,
e.g., ethyl chloroformate, in the presence of a base, e.g.,
diisopropylethylamine (DIPEA), and optionally at an elevated
temperature provides compounds of formula IIIa.
##STR00051##
wherein X.sub.3 and X.sub.5 are as defined herein above.
[0261] The general way of preparing representative compounds of the
present using intermediates 8a, 8b, 8c, 8d, 8e, 8f, and 8g is
outlined in Scheme 6. Nucleophilic addition of 8a to fluoride 8b in
the presence of a base, e.g., triethylamine (Et.sub.3N), in a
solvent, e.g., dimethylsulfoxide (DMSO), and optionally at an
elevated temperature provides intermediate 8c. Protection of 8c
with Boc.sub.2O in the presence of a base, e.g., sodium hydride
(NaH) and/or 4-dimethylaminopyridine (DMAP), in a solvent, e.g.,
tetrahydrofuran (THF), and optionally at an elevated temperature
provides intermediate 8d. Reduction of 8d using a metal catalyst,
e.g., Zinc (Zn), and ammonium chloride (NH.sub.4C.sub.1), in a
solvent, e.g., methanol (MeOH), and optionally at an elevated
temperature provides intermediate 8e. Acetylation of 8e with
tert-butylacetyl chloride in the presence of a base, e.g.,
diisopropylethylamine (DIPEA), in a solvent, e.g., dichloromethane
(DCM), and optionally at an elevated temperature provides
intermediate 8f. Deprotection of 7f in the presence of an acid,
e.g., hydrochloric acid (HCL), in a solvent, e.g., DCM and/or
diethyl ether (Et.sub.2O), and optionally at an elevated
temperature provides compounds of formula VIa.
##STR00052##
wherein X.sub.3, X.sub.4, and X.sub.5 are as defined herein
above.
[0262] The general way of preparing representative compounds of the
present application using intermediates 9a, 9b, 9c, 9d, 9e, 9f is
outlined in Scheme 7. Methylation of 9a with trimethylboroxine in
the presence of a metal catalyst, e.g.,
tetrakis(triphenylphosphine)palladium (Pd(PPh.sub.3).sub.4)), and a
base, e.g., potassium carbonate (K.sub.2CO.sub.3), in a solvent,
e.g., dimethylsulfoxide (DMSO), and optionally at an elevated
temperature provides intermediate 9b. Reduction of 9b using a metal
catalyst, e.g., Zinc (Zn), and ammonium chloride (NH.sub.4C.sub.1),
in a solvent, e.g., water and ethyl acetate (EtOAc), and optionally
at an elevated temperature provides intermediate 9c. Bromination of
9c with N-bromosuccinimide (NBS), in the presence of an acid, e.g.,
acetic acid, and optionally at an elevated temperature provides
intermediate 9d. Acetylation of 9d with tert-butylacetyl chloride
in the presence of a base, e.g., diisopropylethylamine (DIPEA), in
a solvent, e.g., acetonitrile (MeCN), and optionally at an elevated
temperature provides intermediate 9e. Coupling 9e with 9f in the
presence of a metal catalyst, e.g.,
tris(dibenzylideneacetone)dipalladium (Pd.sub.2(dba).sub.3), and in
the presence of a base, e.g., potassium tert-butoxide (t-BuOK), in
a solvent, e.g., toluene, and optionally at an elevated temperature
provides compounds of formula VII.
[0263] The present application also comprehends deuterium labeled
compounds, wherein one or more hydrogen atoms is replaced by a
deuterium atom having an abundance of deuterium at that position
that is substantially greater than the natural abundance of
deuterium, which is 0.015%.
[0264] Deuterium labeled compounds can be prepared by using any of
a variety of art-recognized techniques. For example, deuterium
labeled compounds of any of the formulae described herein and
compounds listed in Table 1 of this application can be
prepared.
[0265] In one aspect, a deuterium labeled compound of the
application is a pharmaceutically acceptable salt. In one aspect, a
deuterium labeled compound of the application is a solvate. In one
aspect, a deuterium labeled compound of the application is a
hydrate.
[0266] The present application relates to pharmaceutical
compositions comprising one of the deuterium labeled compounds of
the application as an active ingredient. In one aspect, the
application provides a pharmaceutical composition comprising at
least one deuterium labeled compound of any of the formulae
described herein or a pharmaceutically acceptable salt or solvate
thereof and one or more pharmaceutically acceptable carrier or
excipient.
[0267] The present application relates to a method of synthesizing
a deuterium labeled compound of the application or a
pharmaceutically acceptable salt or solvate thereof. The deuterium
labeled compounds of the application can be prepared using any of a
variety of art-recognized techniques, such as those described in
U.S. Pat. No. 8,916,133, the contents of which are incorporated by
reference in their entirety. For example, a deuterium labeled
compound can be prepared by starting with deuterium labeled
Compound 1 and/or substituting a readily available deuterium
labeled reagent for a non-deuterium labeled reagent.
[0268] The scheme and description below depicts a general route for
the incorporation of deuterium label to produce a deuterium labeled
compound of the application.
##STR00053##
[0269] Scheme 1A outlines a preparation for a deuterium labeled
compound of the application. The preparation begins with Compound A
(from Scheme 1A described herein). In Step 1, the nitro group of
Compound A is reduced and then the deuterium label is introduced
via formation of a carbamate containing one or more deuterium. For
example, the nitro group of Compound A can be reduced using zinc
powder and ammonium chloride in methanol and the carbamate can be
formed using ethyl-d.sub.5 chloroformate to provide a deuterium
labeled compound.
[0270] In some embodiments, temporary protecting groups may be used
to prevent other reactive functionality, such as amines, thiols,
alcohols, phenols, and carboxylic acids, from participating or
interfering in the fluorination reaction. Representative amine
protecting groups include, for example, tert-butoxycarbonyl and
trityl (removed under acid conditions), Fmoc (removed by the use of
secondary amines such as piperidine), and benzyloxycarbonyl
(removed by strong acid or by catalytic hydrogenolysis). The trityl
group may also be used for the protection of thiols, phenols, and
alcohols. In certain embodiments the carboxylic acid protecting
groups include, for example, tert-butyl ester (removed by mild
acid), benzyl ester (usually removed by catalytic hydrogenolysis),
and alkyl esters such as methyl or ethyl (usually removed by mild
base). All protecting groups may be removed at the conclusion of
the synthesis using the conditions described above for the
individual protecting groups, and the final product may be purified
by techniques which would be readily apparent to one of ordinary
skill in the art, in combination with the teachings described
herein.
Biological Assays
Assessment of KCNQ2/3 Channel Activation Activity
[0271] Biological activities of the compounds of the application
can be assessed by using various methods known in the art. For
example, the KCNQ2/3 channel activation activity of the compounds
of the application can be evaluated through an in vitro assay
described below.
[0272] The in vitro effects of a compound of the application on
cloned KCNQ2/3 potassium channels (e.g., encoded by the human
KCNQ2/3 gene) are evaluated using a patch clamp system. Compounds
of the application are tested at various concentrations (e.g.,
0.01, 0.1, 1, 10 and 100 .mu.M) for a certain duration of exposure
(e.g., 5 min). The baseline for each recording is established. A
single test compound concentration is applied for a certain
duration of exposure after the vehicle. Each recording ends with
treatment with a supramaximal dose of linopirdine. The % activation
is calculated using the following equation by using leak subtracted
responses:
vehicle_response - compound_response vehicle_response -
flupirtine_response ##EQU00001##
Maximal Electroshock Seizure Test (MES)
[0273] In MES test, the ability of different doses of the test
compound in preventing seizure induced by an electrical stimulus,
delivered through the corneal electrodes primed with a drop of
anesthetic/electrolyte solution is tested. Mice are restrained and
released immediately following corneal stimulation that allows for
the observation of the entire seizure episode. A maximal seizure in
a test animal includes four distinct phases that includes, hind leg
flexor component tonic phase (Phase I), hind leg extensor component
of the tonic phase (Phase II), intermittent, whole-body clonus
(Phase III), and muscular relaxation (Phase IV) followed by seizure
termination (Woodbury & Davenport, 1952; Racine et al., 1972).
Test compounds are tested for their ability to abolish hind limb
tonic extensor component that indicates the compound's ability to
inhibit MES-induced seizure spread. Compounds are pre-administered
(i.p) and tested at various time points for the abolishment of hind
limb tonic extensor component after electrical stimulus.
Corneal-Kindled Mouse Model of Partial Seizures
[0274] In corneal kindled seizure model, mice are kindled
electrically with stimulation delivered through corneal electrodes
primed with tetracaine hydrochloride in saline, twice daily, until
5 consecutive stage V seizures are induced. Mice are considered
kindled when they display at least 5 consecutive stage V seizures
according to the Racine scale (Racine et al., 1972) including,
mouth and facial clonus (stage I), Stage I plus head nodding (Stage
II), Stage II plus forelimb clonus (Stage III), Stage III plus
rearing (Stage IV), and stage IV plus repeated rearing and falling
(Stage V) (Racine et al., 1972). At the completion of the kindling
acquisition, mice are permitted a 3-day stimulation-free period
prior to any drug testing. On the day of the experiment, fully
kindled mice are pre-administered (i.p) with increasing doses of
the test compound and challenged with the corneal kindling
stimulus. Mice are scored as protected (seizure score of <3) or
not protected, (seizure score .gtoreq.4) based on the Racine
scoring (Racine et al., 1972).
Pharmaceutical Compositions
[0275] The present application relates to pharmaceutical
compositions comprising a compound of the application as an active
ingredient. In one embodiment, the application provides a
pharmaceutical composition comprising at least one compound of each
of the formulae described herein, or a pharmaceutically acceptable
salt or solvate thereof, and one or more pharmaceutically
acceptable carriers or excipients. In one embodiment, the
application provides a pharmaceutical composition comprising at
least one compound selected from Table 1.
[0276] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0277] The compounds of the application can be formulated for oral
administration in forms such as tablets, capsules (each of which
includes sustained release or timed release formulations), pills,
powders, granules, elixirs, tinctures, suspensions, syrups and
emulsions. The compounds of the application can also be formulated
for intravenous (bolus or in-fusion), intraperitoneal, topical,
subcutaneous, intramuscular or transdermal (e.g., patch)
administration, all using forms well known to those of ordinary
skill in the pharmaceutical arts.
[0278] The formulation of the present application may be in the
form of an aqueous solution comprising an aqueous vehicle. The
aqueous vehicle component may comprise water and at least one
pharmaceutically acceptable excipient. Suitable acceptable
excipients include those selected from the group consisting of a
solubility enhancing agent, chelating agent, preservative, tonicity
agent, viscosity/suspending agent, buffer, and pH modifying agent,
and a mixture thereof.
[0279] Any suitable solubility enhancing agent can be used.
Examples of a solubility enhancing agent include cyclodextrin, such
as those selected from the group consisting of
hydroxypropyl-.beta.-cyclodextrin, methyl-.beta.-cyclodextrin,
randomly methylated-.beta.-cyclodextrin,
ethylated-.beta.-cyclodextrin, triacetyl-.beta.-cyclodextrin,
peracetylated-.beta.-cyclodextrin,
carboxymethyl-.beta.-cyclodextrin,
hydroxyethyl-.beta.-cyclodextrin,
2-hydroxy-3-(trimethylammonio)propyl-.beta.-cyclodextrin,
glucosyl-.beta.-cyclodextrin, sulphated .beta.-cyclodextrin
(S-.beta.-CD), maltosyl-.beta.-cyclodextrin, .beta.-cyclodextrin
sulfobutyl ether, branched-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, randomly
methylated-.gamma.-cyclodextrin, and
trimethyl-.gamma.-cyclodextrin, and mixtures thereof.
[0280] Any suitable chelating agent can be used. Examples of a
suitable chelating agent include those selected from the group
consisting of ethylenediaminetetraacetic acid and metal salts
thereof, disodium edetate, trisodium edetate, and tetrasodium
edetate, and mixtures thereof.
[0281] Any suitable preservative can be used. Examples of a
preservative include those selected from the group consisting of
quaternary ammonium salts such as benzalkonium halides (preferably
benzalkonium chloride), chlorhexidine gluconate, benzethonium
chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury
nitrate, phenylmercury acetate, phenylmercury neodecanoate,
merthiolate, methylparaben, propylparaben, sorbic acid, potassium
sorbate, sodium benzoate, sodium propionate, ethyl
p-hydroxybenzoate, propylaminopropyl biguanide, and
butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
[0282] The aqueous vehicle may also include a tonicity agent to
adjust the tonicity (osmotic pressure). The tonicity agent can be
selected from the group consisting of a glycol (such as propylene
glycol, diethylene glycol, triethylene glycol), glycerol, dextrose,
glycerin, mannitol, potassium chloride, and sodium chloride, and a
mixture thereof.
[0283] The aqueous vehicle may also contain a viscosity/suspending
agent. Suitable viscosity/suspending agents include those selected
from the group consisting of cellulose derivatives, such as methyl
cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene
glycols (such as polyethylene glycol 300, polyethylene glycol 400),
carboxymethyl cellulose, hydroxypropylmethyl cellulose, and
cross-linked acrylic acid polymers (carbomers), such as polymers of
acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol
(Carbopols--such as Carbopol 934, Carbopol 934P, Carbopol 971,
Carbopol 974 and Carbopol 974P), and a mixture thereof.
[0284] In order to adjust the formulation to an acceptable pH
(typically a pH range of about 5.0 to about 9.0, more preferably
about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about
7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9,
or about 7.5 to about 8.0), the formulation may contain a pH
modifying agent. The pH modifying agent is typically a mineral acid
or metal hydroxide base, selected from the group of potassium
hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures
thereof, and preferably sodium hydroxide and/or hydrochloric acid.
These acidic and/or basic pH modifying agents are added to adjust
the formulation to the target acceptable pH range. Hence it may not
be necessary to use both acid and base--depending on the
formulation, the addition of one of the acid or base may be
sufficient to bring the mixture to the desired pH range.
[0285] The aqueous vehicle may also contain a buffering agent to
stabilize the pH. When used, the buffer is selected from the group
consisting of a phosphate buffer (such as sodium dihydrogen
phosphate and disodium hydrogen phosphate), a borate buffer (such
as boric acid, or salts thereof including disodium tetraborate), a
citrate buffer (such as citric acid, or salts thereof including
sodium citrate), and .epsilon.-aminocaproic acid, and mixtures
thereof.
[0286] The formulation may further comprise a wetting agent.
Suitable classes of wetting agents include those selected from the
group consisting of polyoxypropylene-polyoxyethylene block
copolymers (poloxamers), polyethoxylated ethers of castor oils,
polyoxyethylenated sorbitan esters (polysorbates), polymers of
oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty
acid glycol esters, fatty acid glyceryl esters, sucrose fatty
esters, and polyoxyethylene fatty esters, and mixtures thereof.
[0287] Oral compositions generally include an inert diluent or an
edible pharmaceutically acceptable carrier. They can be enclosed in
gelatin capsules or compressed into tablets. For the purpose of
oral therapeutic administration, the active compound can be
incorporated with excipients and used in the form of tablets,
troches, or capsules. Oral compositions can also be prepared using
a fluid carrier for use as a mouthwash, wherein the compound in the
fluid carrier is applied orally and swished and expectorated or
swallowed. Pharmaceutically compatible binding agents, and/or
adjuvant materials can be included as part of the composition. The
tablets, pills, capsules, troches and the like can contain any of
the following ingredients, or compounds of a similar nature: a
binder such as microcrystalline cellulose, gum tragacanth or
gelatin; an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterotes; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring.
Methods of Use
[0288] The present application relates to methods for the use of
compounds of the application. The compounds of the application have
a useful pharmacological activity spectrum and are therefore
particularly suitable for the prophylaxis and/or treatment of
diseases or disorders.
[0289] The present application provides a method of treating or
preventing diseases or disorders, comprising administering a
therapeutically effective amount of a compound of the application,
or a pharmaceutically acceptable salt or solvate thereof, to a
subject in need thereof. The present application also provides the
use of a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof, for the preparation of a
medicament for administration to a subject for the treatment or
prevention of diseases or disorders. The present application also
provides a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof, for treating or preventing
diseases or disorders.
[0290] In one embodiment, the disease or disorder is a condition
which can be ameliorated by KCNQ2/3 potassium channel opening. In
one embodiment, the disease or disorder is selected from epilepsy,
neurotransmission disorder, CNS disorder, neurodegenerative disease
(e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's
disease, macular degeneration, or glaucoma), cognitive disorder
(e.g., degenerative dementia (including senile dementia,
Alzheimer's disease, Pick's disease, Huntington's chorea,
Parkinson's disease, and Creutzfeldt-Jakob disease); vascular
dementia (including multi-infarct dementia); dementia associated
with intracranial space occupying lesions, trauma, infections or
related conditions (including HIV infection), metabolism, toxins,
anoxia, or vitamin deficiency; mild cognitive impairment associated
with ageing, particularly Age Associated Memory Loss, or learning
deficiencies), bipolar disorder (e.g., Type I or II bipolar
disorder), unipolar depression, anxiety, migraine, ataxia,
myokimia, tinnitus, functional bowel disorders (e.g., non-ulcer
dyspepsia, non-cardiac chest pain, or irritable bowel syndrome),
cancer, inflammatory disease, ophthalmic disease (e.g., retinitis,
retinopathies, uveitis, or acute injury to the eye tissue), asthma,
allergic rhinitis, respiratory distress syndrome, gastrointestinal
conditions (e.g., inflammatory bowel disease, Chron's disease,
gastritis, irritable bowel syndrome, or ulcerative colitis), and
inflammation in such diseases as vascular disease, migraine,
periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's
disease, sclerodoma, type I diabetes, myasthenia gravis, multiple
sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome,
polymyositis, gingivitis, conjunctivitis, and myocardial
ischemia.
[0291] In one embodiment, the application provides a method of
producing an anti-epileptic, muscle relaxing, fever reducing,
peripherally analgesic, and/or anti-convulsive effect in a subject
in need thereof, comprising administering to the subject an
effective amount of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof. The present
application also provides the use of a compound of the application,
or a pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
producing an anti-epileptic, muscle relaxing, fever reducing,
peripherally analgesic, and/or anti-convulsive effect. The present
application also provides a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for producing
an anti-epileptic, muscle relaxing, fever reducing, peripherally
analgesic, and/or anti-convulsive effect.
[0292] In one embodiment, the application provides compounds that
are useful as an anticonvulsant. They are therefore useful in
treating or preventing epilepsy. Compounds of the application may
be used to improve the condition of a host, typically a human
being, suffering from epilepsy. They may be employed to alleviate
the symptoms of epilepsy in a host. "Epilepsy" is intended to
include the following seizures: simple partial seizures, complex
partial seizures, secondary generalized seizures, generalized
seizures including absence seizures, myoclonic seizures, clonic
seizures, tonic seizures, tonic clonic seizures and atonic
seizures. Partial-onset seizures are the most common type of
seizure in adult patients. For partial seizures, there is a focal
epileptic zone (site of seizure onset), and seizure activity is
initially limited to one hemisphere. Partial seizures can be
further sub-divided into simple partial (without impairment of
consciousness), complex partial (with impairment of consciousness
with or following a simple partial onset) and secondarily
generalized (i.e., partial seizures, either simple or complex,
which evolve to generalized tonic-clonic seizures). Simple partial
seizures, depending on the anatomical site of origin of the
seizure, may have motor, somatosensory or special sensory,
autonomic or psychic signs or symptoms.
[0293] In one embodiment, the application provides a method of
treating a subject suffering from or susceptible to epilepsy,
comprising administering to the subject an effective amount of a
compound of the application or a pharmaceutically acceptable salt
or solvate thereof. The present application also provides the use
of a compound of the application, or a pharmaceutically acceptable
salt or solvate thereof, for the preparation of a medicament for
administration to a subject suffering from or susceptible to
epilepsy for the treatment of epilepsy. The present application
also provides a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof, for treating a subject
suffering from or susceptible to epilepsy. In one embodiment, the
application provides a method for the adjunctive treatment of
adults with partial-onset seizures, comprising administering to the
subject an effective amount of a compound of the application or a
pharmaceutically acceptable salt thereof. The present application
also provides the use of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for adjunctive treatment of adults with
partial-onset seizures. The present application also provides a
compound of the application, or a pharmaceutically acceptable salt
or solvate thereof, for adjunctive treatment of adults with
partial-onset seizures.
[0294] In one embodiment, the present application provides a method
of treating or preventing epilepsy, comprising administering a
therapeutically effective amount of a compound of the application,
or a pharmaceutically acceptable salt or solvate thereof, to a
subject in need thereof. The present application also provides the
use of a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof, for the preparation of a
medicament for administration to a subject for the treatment or
prevention of epilepsy. The present application also provides a
compound of the application, or a pharmaceutically acceptable salt
or solvate thereof, for treating or preventing epilepsy.
[0295] In one embodiment, a compound of the application is
administered in combination with one or more anti-epileptic drugs
(AEDs). There are different types of AEDs. For example,
narrow-spectrum AEDs include phenytoin (Dilantin), phenobarbital,
carbamazepine (Tegretol), oxcarbazepine (Trileptal), gabapentin
(Neurontin), pregabalin (Lyrica), lacosamide (Vimpat), and
vigabatrin (Sabril). Broad spectrum AEDs include valproic acid
(Depakote), lamotrigine (Lamictal), topiramate (Topamax),
zonisamide (Zonegran), levetiracetam (Keppra), clonazepam
(Klonopin), and rufinamide (Banzel). In one embodiment, the AED is
any AED. In one embodiment, the AED is a narrow spectrum AED. In
one embodiment, the AED is a broad spectrum AED.
[0296] In one embodiment, the application provides compounds that
are useful as analgesics. The compounds are therefore useful in
treating or preventing pain. They may be used to improve the
condition of a host, typically a human being, suffering from pain.
They may be employed to alleviate pain in a host. Thus, the
compounds may be used as a pre-emptive analgesic to treat acute
pain such as musculoskeletal pain, post-operative pain and surgical
pain, chronic pain such as chronic inflammatory pain (e.g.,
rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g.,
post herpetic neuralgia, trigeminal neuralgia and sympathetically
maintained pain) and pain associated with cancer and fibromyalgia.
The compounds may also be used in the treatment or prevention of
pain associated with migraine. The compounds may also be used in
the treatment of the pain (both chronic and acute), fever and
inflammation of conditions such as rheumatic fever; symptoms
associated with influenza or other viral infections, such as the
common cold; lower back and neck pain; headache; toothache; sprains
and strains; myositis; neuralgia; synovitis; arthritis, including
rheumatoid arthritis; degenerative joint diseases, including
osteoarthritis; gout and ankylosing spondylitis; tendinitis;
bursitis; skin related conditions, such as psoriasis, eczema, burns
and dermatitis; injuries, such as sports injuries and those arising
from surgical and dental procedures.
[0297] In one embodiment, the application provides a method of
producing an analgesic effect in a subject in need thereof,
comprising administering to the subject an effective amount of a
compound of the application or a pharmaceutically acceptable salt
or solvate thereof. The present application also provides the use
of a compound of the application, or a pharmaceutically acceptable
salt or solvate thereof, for the preparation of a medicament for
administration to a subject for producing an analgesic effect. The
present application also provides a compound of the application, or
a pharmaceutically acceptable salt or solvate thereof, for
producing an analgesic effect. In one embodiment, the analgesic
effect is a neuroprotective effect. In one embodiment, the
analgesic effect is a centrally acting analgesic effect.
[0298] In one embodiment, the application provides a method of
treating or preventing a neurotransmission disorder, CNS disorder,
neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor
neuron disease, Parkinson's disease, macular degeneration and
glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II
bipolar disorder), unipolar depression, or anxiety in a subject in
need thereof, comprising administering to the subject an effective
amount of a compound of the application or a pharmaceutically
acceptable salt or solvate thereof. The present application also
provides the use of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
treating or preventing a neurotransmission disorder, CNS disorder,
neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor
neuron disease, Parkinson's disease, macular degeneration and
glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II
bipolar disorder), unipolar depression, or anxiety. The present
application also provides a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for treating
or preventing a neurotransmission disorder, CNS disorder,
neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor
neuron disease, Parkinson's disease, macular degeneration and
glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II
bipolar disorder), unipolar depression, or anxiety.
[0299] In one embodiment, the application provides a method of
treating or preventing migraine, ataxia, myokimia, tinnitus, and
functional bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac
chest pain, or irritable bowel syndrome) in a subject in need
thereof, comprising administering to the subject an effective
amount of a compound of the application or a pharmaceutically
acceptable salt or solvate thereof. The present application also
provides the use of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
treating or preventing migraine, ataxia, myokimia, tinnitus, and
functional bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac
chest pain, or irritable bowel syndrome). The present application
also provides a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof, for treating or preventing
migraine, ataxia, myokimia, tinnitus, and functional bowel
disorders (e.g., non-ulcer dyspepsia, non-cardiac chest pain, or
irritable bowel syndrome).
[0300] In one embodiment, the application provides compounds that
are useful in the treatment of CNS disorders such as bipolar
disorder, alternatively known as manic depression. The compounds
may thus be used to improve the condition of a human patient
suffering from bipolar disorder. They may be used to alleviate the
symptoms of bipolar disorder in a host. The compounds may also be
used in the treatment of unipolar depression, ataxia, myokimia and
anxiety.
[0301] In one embodiment, the application provides compounds that
are useful in the treatment of neurodegenerative diseases, such as
Alzheimer's disease, ALS, motor neuron disease, Parkinson's
disease, macular degeneration and glaucoma. The compounds of the
application may also be useful in neuroprotection and in the
treatment of neurodegeneration following stroke, cardiac arrest,
pulmonary bypass, traumatic brain injury, spinal cord injury or the
like. In one embodiment, compounds of the application are further
useful in the treatment of tinnitus.
[0302] In one embodiment, the application provides compounds that
are useful in the treatment of functional bowel disorders which
include non-ulcer dyspepsia, non-cardiac chest pain and in
particular irritable bowel syndrome. Irritable bowel syndrome is a
gastrointestinal disorder characterized by the presence of
abdominal pain and altered bowel habits without any evidence of
organic disease. The compounds may thus be used to alleviate pain
associated with irritable bowel syndrome. The condition of a human
patient suffering from irritable bowel syndrome may thus be
improved.
[0303] In one embodiment, the application provides a method of
preventing or reducing dependence on, or preventing or reducing
tolerance, or reverse tolerance, to a dependence-inducing agent in
a subject in need thereof, comprising administering to the subject
an effective amount of a compound of the application or a
pharmaceutically acceptable salt or solvate thereof. The present
application also provides the use of a compound of the application,
or a pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
preventing or reducing dependence on, or preventing or reducing
tolerance, or reverse tolerance, to a dependence-inducing agent.
The present application also provides a compound of the
application, or a pharmaceutically acceptable salt or solvate
thereof, for preventing or reducing dependence on, or preventing or
reducing tolerance, or reverse tolerance, to a dependence-inducing
agent. Examples of dependence inducing agents include opioids
(e.g., morphine), CNS depressants (e.g., ethanol), psychostimulants
(e.g., cocaine) and nicotine.
[0304] In one embodiment, the application provides a method of
treating or preventing cancer, inflammatory disease, or ophthalmic
disease in a subject in need thereof comprising administering to
the subject an effective amount of a compound of the application or
a pharmaceutically acceptable salt or solvate thereof. The present
application also provides the use of a compound of the application,
or a pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
treating or preventing cancer, inflammatory disease, or ophthalmic
disease. The present application also provides a compound of the
application, or a pharmaceutically acceptable salt or solvate
thereof, for treating or preventing cancer, inflammatory disease,
or ophthalmic disease.
[0305] In one embodiment, the application provides compounds that
inhibit cellular and neoplastic transformation and metastatic tumor
growth and hence are useful in the treatment of certain cancerous
diseases, such as colonic cancer.
[0306] In one embodiment, the application provides compounds that
inhibit inflammatory processes and therefore are of use in the
treatment of asthma, allergic rhinitis and respiratory distress
syndrome; gastrointestinal conditions such as inflammatory bowel
disease, Chron's disease, gastritis, irritable bowel syndrome and
ulcerative colitis; and the inflammation in such diseases as
vascular disease, migraine, periarteritis nodosa, thyroiditis,
aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes,
myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic
syndrome, Bechet's syndrome, polymyositis, gingivitis,
conjunctivitis and myocardial ischemia.
[0307] In one embodiment, the application provides compounds that
are useful in the treatment of ophthalmic diseases such as
retinitis, retinopathies, uveitis, and acute injury to the eye
tissue.
[0308] In one embodiment, the application provides compounds that
are useful for the treatment of cognitive disorders such as
dementia, particularly degenerative dementia (including senile
dementia, Alzheimer's disease, Pick's disease, Huntington's chorea,
Parkinson's disease and Creutzfeldt-Jakob disease), and vascular
dementia (including multi-infarct dementia), as well as dementia
associated with intracranial space occupying lesions, trauma,
infections and related conditions (including HIV infection),
metabolism, toxins, anoxia and vitamin deficiency; and mild
cognitive impairment associated with ageing, particularly Age
Associated Memory Loss; and learning deficiencies.
[0309] In one embodiment, the application provides a method of
producing an anxiolytic effect in a subject in need thereof
comprising administering to the subject an effective amount of a
compound of the application or a pharmaceutically acceptable salt
or solvate thereof. In one embodiment, the application provides a
method for the treatment of anxiety and its related psychological
and physical symptoms. Anxiolytics have been shown to be useful in
the treatment of anxiety disorders. The present application also
provides the use of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
producing an anxiolytic effect. The present application also
provides a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof, for producing an anxiolytic
effect.
[0310] In one embodiment, the application provides compounds for
treatment. In one embodiment, the application provides compounds
for prophylaxis. In one embodiment, the application provides
compound for alleviation of established symptoms.
[0311] Administration may for example be in the form of tablets,
capsules, pills, coated tablets, suppositories, ointments, gels,
creams, powders, dusting powders, aerosols or in liquid form.
Liquid application forms that may for example be considered are:
oils or alcoholic or aqueous solutions as well as suspensions and
emulsions. In one embodiment, the application provides forms of
application that are tablets that contain between 30 and 60 mg or
solutions that contain between 0.1 to 5 percent by weight of active
substance.
[0312] In one embodiment, a compound of the application is used in
human medicine. In one embodiment, the compound of the application
is used in veterinary medicine. In one embodiment, a compound of
the application is used in agriculture. In one embodiment, a
compound of the application is used alone or mixed with other
pharmacologically active substances.
[0313] The following Examples are illustrative and should not be
interpreted in any way so as to limit the scope of the
application.
EXAMPLES
Example 1a: Compound 1
##STR00054##
[0314] Step 1: Synthesis of Compound a
[0315] To a stirred solution of 4-fluorobenzylamine (1 equivalent
(equiv)) dissolved in dimethylformamide (DMF) is added allyl
bromide (1.5 equiv) and diisopropyl ethylamine (2 equiv) dropwise,
and the resulting mixture is heated to 80.degree. C. After 2 hours,
the reaction mixture is cooled, diluted with water, and extracted
with ethyl acetate (EtOAc). The organic layer is then washed with
saturated brine, dried with anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The resulting residue is purified by
silica gel liquid chromatography to provide Compound a.
Step 2: Synthesis of Compound b
[0316] To a stirred suspension of 2,3-difluoro-6-nitroaniline (1
equiv) in dry dimethyl sulfoxide (DMSO) is added Compound a (3
equiv) followed by Et.sub.3N (1.2 equiv) and I.sub.2 (catalytic
amount). The resulting mixture is heated to 120.degree. C. and
stirred at 120.degree. C. for 24 hours. Upon complete consumption
of the starting material (as determined by thin layer
chromatography (TLC)), the reaction mixture is cooled to RT,
diluted with water (25 mL), and extracted with EtOAc (2.times.25
mL). The combined organic layers are dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to give a crude product, which is purified by silica gel column
chromatography to afford Compound b.
Step 3: Synthesis of Compound 1
[0317] To a stirred solution of Compound b (1 equiv) in methanol is
added zinc powder (5 equiv) followed by the dropwise addition of
ammonium chloride solution (5 equiv). After stirring at room
temperature (RT) for 5 hours, N,N-diisopropylethylamine (DIPEA)
(1.25 equiv) and ethyl chloroformate (1 equiv) are then added at
10.degree. C., and the stirring is continued for another 3 hours at
RT. Upon complete consumption of the starting material (as
determined by TLC), the reaction mixture is diluted with water and
stirred for 1 hour to give a solid product. The obtained solid is
filtered, dissolved in EtOAc, and any un-dissolved solid is removed
by filtration. The filtrate is concentrated to provide Compound 1
which is crystallized using n-hexane.
Example 1b: Compound 1
Step 1: Synthesis of
2-Fluoro-N.sup.1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine
[0318] 2,3-Difluoro-6-nitroaniline (10.0 g, 79.9 mmole) was
dissolved in anhydrous dimethylsulfoxide (90 mL).
4-fluorobenzylamine (9.3 g, 53.3 mmole) was added triethylamine
(17.7 mL) and solid iodine (80 mg) were added and the mixture was
heated at reflux for 4 h. under argon. The reaction was dissolved
in ethyl acetate (200 mL) and extracted with water (3.times.100
mL). A yellow solid precipitated out of the organic layer to give
2-fluoro-N.sup.1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (13.6
g, 91% yield).
Step 2: Synthesis of di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate
[0319] 2-Fluoro-N.sup.1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine
(13.55 g, 48.53 mmole) was dissolved in methanol (60 mL) and
tetrahydrofuran (60 mL). The mixture was cooled in an ice bath and
zinc powder (31.70 g, 485.3 mmole) was added followed by ammonium
chloride (26.0 g, 485.3 mmole) in DI water (64 mL) over 30 min.
Ethyl acetate (200 mL) was added and the mixture was extracted with
water (200 mL) and the organic layer was evaporated to dryness. The
residue was dissolved in tetrahydrofuran (200 mL) and
di-tert-butyldicarbonate (15.9 g, 72.8 mmole) was added followed by
solid sodium bicarbonate (8.15 g, 97.06 mmole) and then DI water
(150 mL). The reaction was stirred for an 18 h. at ambient
temperature. The reaction was filtered and evaporated to dryness.
Ethyl acetate (200 mL) was added and then 3M NH.sub.4OH
(2.times.200 mL). The organic layer was evaporated to dryness. It
was chromatographed on a silica gel column (200 g) packed in
hexane. The column polarity was increased to 16% ethyl acetate over
5 CV, held at 16% ethyl acetate for 2 CV, increased to 32% ethyl
acetate over 4 CV, and then to 53% ethyl acetate over 2 CV. Flow
rate at 100 mL/min. t 100 mL/min. Fractions (22 mL each) containing
the product were pooled and stripped to give di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (9.84
g, 45% yield).
Step 3: Synthesis of di-tert-butyl
(4-(allyl(4-fluorobenzyl)amino)-3-fluoro-1,2-phenylene)dicarbamate
[0320] Di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (2.03
g, 4.52 mmole) was dissolved in anhydrous dimethylformamide (10
mL). Diisopropylethylamine (1.6 mL, 9.0 mmole) was added followed
by allyl bromide (0.710 mg, 5.87 mmole). The mixture was heated in
an 110.degree. C. oil bath under argon for 6h. The reaction was
diluted in ethyl acetate (100 mL) and extracted with water (100
mL). The aqueous layer was washed with ethyl acetate (100 mL). The
organic layers were washed with water, 2.times.50 mL and then brine
(50 mL) and filtered through a 1PS filter to dry and evaporated to
dryness. The crude material was chromatographed on a silica gel
column (25 g) packed in hexanes. The column polarity was increased
to 9% ethyl acetate over 4 CV, held at 9% ethyl acetate over 7 CV
and then increased to 33% ethyl acetate over 12 CV. The flow rate
was 25 mL/min. Fractions (22 mL each) containing the first product
were pooled and stripped to give of di-tert-butyl
(4-(allyl(4-fluorobenzyl)amino)-3-fluoro-1,2-phenylene)dicarbamate
(1.35 g, 61% yield).
Step 4: Synthesis of ethyl
(4-(allyl(4-fluorobenzyl)amino)-2-amino-3-fluorophenyl)carbamate
(Compound 1)
[0321] The organic layer was evaporated to dryness, dissolved in
methanol (5 mL) and tetrahydrofuran (5 mL) and cooled in an ice
bath when N, N-diisopropylethylamine (1.2 mL, 6.72 mmole) was added
followed by ethyl chloroformate (0.128 mL, 1.19 mmole) dropwise.
The reaction was stirred at ambient temperature for 0.5 h and was
evaporated to dryness. The crude oil was dissolved in ethyl acetate
(10 mL) and extracted with water (10 mL). The organic layer was
then dried through a 1PS filter and evaporated to dryness. It was
chromatographed on a silica gel column (10 g) packed in chloroform.
The column polarity was increased to 30% ethyl acetate in
chloroform over 7 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(4-(allyl(4-fluorobenzyl)amino)-2-amino-3-fluorophenyl)carbamate
(0.115 g, 29% yield).
[0322] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.28 (m, 2H), 6.99 (t, 2H), 6.83 (d, 1H), 6.38 (t, 1H), 6.25 (br s,
1H), 5.80-5.89 (m, 1H), 5.18 (t, 2H), 4.30 (s, 2H), 4.25 (q, 2H),
3.84 (br s, 1H), 3.70 (d, 2H), 1.60 (br s, 1H), 1.32 (t, 3H).
[0323] HPLC: Grace Alltima C18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd1=8.2 min.
Example 2a: Compound 2
##STR00055##
[0324] Step 1: Synthesis of Compound c
[0325] To a stirred solution of 4-trifluoromethylbenzylamine (1
equiv) dissolved in DMF is added allyl bromide (1.5 equiv) and
diisopropyl ethylamine (2 equiv) dropwise, and the resulting
mixture is heated to 80.degree. C. After 2 hours, the reaction
mixture is cooled, diluted with water, and extracted with ethyl
acetate. The organic layer is then washed with saturated brine,
dried with anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The resulting residue is purified by silica gel
liquid chromatography to give Compound c.
Step 2: Synthesis of Compound d
[0326] To a stirred suspension of 2, 3-difluoro-6-nitroaniline (1
equiv) in dry DMSO is added Compound c (3 equiv) followed by
Et.sub.3N (1.2 equiv) and I.sub.2 (catalytic amount). The reaction
mixture is heated to 120.degree. C. and stirred at 120.degree. C.
for 24 h. Upon complete consumption of the starting material (as
determined by TLC), the reaction mixture is cooled to RT, diluted
with water (25 mL), and extracted with EtOAc (2.times.25 mL). The
combined organic layers are dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure to give a crude
product, which is purified by silica gel column chromatography to
afford Compound d.
Step 3: Synthesis of Compound 2
[0327] To a stirred solution of Compound d (1 equiv) in methanol is
added zinc powder (5 equiv) followed by the dropwise addition of
ammonium chloride solution (5 equiv). After stirring at RT for 5
hours, DIPEA (1.25 equiv) and ethyl chloroformate (1 equiv) are
then added to reaction mixture at 10.degree. C., and the stirring
is continued for another 3 hours at RT. Upon complete consumption
of the starting material (as determined by TLC), the reaction
mixture is diluted with water and stirred for 1h to give a solid
product. The obtained solid is filtered, dissolved in EtOAc, and
any un-dissolved solid is removed by filtration. The filtrate is
concentrated to provide Compound 2 which is crystallized using
n-hexane.
Example 2b: Compound 2
Step 1: Synthesis of
N-(4-(trifluoromethyl)benzyl)prop-2-en-1-amine
[0328] 4-(Trifluoromethyl)benzylamine (8.76 g, 50 mmole) was cooled
in an ice bath when allyl bromide (2.60 g, 20.0 mmole) in DCM (30
mL) was added dropwise over 1 h. The reaction was filtered and
evaporated to dryness. It was chromatographed on a silica gel
column (100 g) packed in hexanes. The column polarity was increased
to 100% ethyl acetate over 10 CV, at 50 mL/min. Fractions (22 mL
each) containing the second band were pooled and stripped to give
N-(4-(trifluoromethyl)benzyl)prop-2-en-1-amine (1.42 g, 10.5%
yield).
Step 2: Synthesis of
N.sup.1-allyl-2-fluoro-4-nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-
-1,3-diamine
[0329] 2,3-Difluoro-6-nitroaniline (0.377 g, 2.17 mmole) was
dissolved in anhydrous dimethylsulfoxide (4 mL).
N-(4-(trifluoromethyl)benzyl)prop-2-en-1-amine (0.700 g, 3.25
mmole) was added followed by triethylamine (0.722 mL) and solid
iodine (1 mg). The mixture was heated at reflux for 18 h. under
argon. The reaction was dissolved in ethyl acetate (10 mL) and
extracted with water (10 mL). The organic layer was washed with
3.times.30 mL water and then dried through a 1PS filter and
evaporated to dryness. The crude material was chromatographed on a
silica gel column (25 g) packed in hexanes. The column polarity was
increased to 100% ethyl acetate over 16 CV, at 25 mL/min. Fractions
(22 mL each) containing the product were pooled and stripped to
give
N.sup.1-allyl-2-fluoro-4-nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-
-1,3-diamine (0.58 g, 71% yield).
Step 3: Synthesis of ethyl
(4-(allyl(4-(trifluoromethyl)benzyl)amino)-2-amino-3-fluorophenyl)carbama-
te (Compound 2)
[0330]
N.sup.1-allyl-2-fluoro-4-nitro-N.sup.1-(4-(trifluoromethyl)benzyl)b-
enzene-1,3-diamine (0.392 g, 1.06 mmole) was dissolved in methanol
(10 mL). Zinc powder (347 mg, 5.30 mmole) was added followed by
ammonium chloride (284 mg, 5.30 mmole) in DI water (1.0 mL). The
mixture was stirred under argon at ambient temperature for 2 h. and
then cooled to 10.degree. C. in an ice bath. N,
N-diisopropylethylamine (0.221 mL, 1.27 mmole) was added, followed
by ethyl chloroformate, dropwise (285 mg, 2.66 mmole) and the
reaction was stirred at ambient temperature for 18 h. The reaction
was dissolved in ethyl acetate (10 mL) and extracted with water (10
mL). The organic layer was washed with 2.times.10 mL water and then
dried through a 1PS filter and evaporated to dryness. The crude
material was chromatographed on a silica gel column (25 g) packed
in chloroform. The column polarity was increased to 20% ethyl
acetate/chloroform over 10 CV, at 25 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(4-(allyl(4-(trifluoromethyl)benzyl)amino)-2-amino-3-fluorophenyl)carbama-
te (0.331 g, 51% yield).
[0331] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.
7.56 (d, 2H), 7.43 (d, 2H), 7.24 (s, 1H), 6.85 (d, 1H), 6.34 (t,
1H), 6.20 (br s, 1H), 5.80-5.94 (m, 1H), 5.16-5.22 (m, 2H), 4.39
(s, 2H), 4.22 (q, 2H), 3.80-4.17 (br s, 1H), 3.75 (d, 2H), 1.33 (t,
3H).
[0332] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd2=12.2 min.
Example 3: Compound 3
##STR00056##
[0333] Step 1: Synthesis of
N-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine
[0334] 3-(Trifluoromethyl)benzylamine (10.0 g, 57.1 mmole) was
dissolved in anhydrous acetonitrile (36 mL). Potassium carbonate
(7.90 g, 57.1 mmole) was added and the mixture was cooled in an ice
bath when allyl bromide (4.91 g, 40.6 mmole) in anhydrous
acetonitrile (3.5 mL) was added over 30 min. The reaction was
stirred for 2 h at 0.degree. C. and then warmed to ambient
temperature. After 1 h, the mixture was cooled in an ice bath and
allyl bromide (0.987 mL, 11.4 mmole) was added dropwise and then
warmed to ambient temperature. It was filtered on a glass fiber
filter and then evaporated. It was chromatographed on a silica gel
column (100 g) packed in hexanes. The column polarity was increased
to 100% ethyl acetate over 6 CV, at 50 mL/min. Fractions (22 mL
each) containing the second band were pooled and stripped to give
N-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine (3.0 g, 24%
yield).
Step 2: Synthesis of
N'-allyl-2-fluoro-4-nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-1,3--
diamine
[0335] 2,3-Difluoro-6-nitroaniline (270 mg, 2.32 mmole) was
dissolved in anhydrous dimethylsulfoxide (5 mL).
N-(3-(trifluoromethyl)benzyl)prop-2-en-1-amine (0.500 g, 2.32
mmole) was added triethylamine (0.708 mL) and solid iodine (1 mg).
The mixture was heated at reflux for 18 h. under argon. The
reaction was dissolved in dichloromethane (20 mL) and extracted
with water (20 mL). The aqueous layer was washed with
dichloromethane (20 mL). The organic layers were washed with water,
2.times.20 mL brine and evaporated to dryness. The crude material
was chromatographed on a silica gel column (10 g) packed in
hexanes. The column polarity was increased to 40% ethyl acetate
over 10 CV, at 12 mL/min. Fractions (22 mL each) containing the
product were pooled and stripped to give
N.sup.1-allyl-2-fluoro-4-nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-
-1,3-diamine (0.320 g, 56% yield).
Step 3: Synthesis of ethyl
(4-(allyl(3-(trifluoromethyl)benzyl)amino)-2-amino-3-fluorophenyl)carbama-
te (Compound 3)
[0336]
N.sup.1-allyl-2-fluoro-4-nitro-N.sup.1-(3-(trifluoromethyl)benzyl)b-
enzene-1,3-diamine (0.305 g, 0.826 mmole) was dissolved in methanol
(4 mL) and tetrahydrofuran (4 mL). Zinc powder (0.540 g, 8.26
mmole) was added followed by ammonium chloride (442 mg, 8.26 mmole)
in DI water (2 mL). The mixture was stirred under argon at ambient
temperature for 15 min. The reaction was cooled in an ice bath and
N, N-diisopropylethylamine (0.330 mL, 1.89 mmole) was added
followed by ethyl chloroformate (159 mg, 1.49 mmole) dropwise. The
reaction was stirred at ambient temperature for 12 h. The reaction
was cooled in an ice bath and N, N-diisopropylethylamine (0.460 mL,
2.63 mmole) was added followed by ethyl chloroformate (244 mg, 2.30
mmole) dropwise. The reaction was stirred at ambient temperature
for 18 h and was filtered and evaporated. The crude oil was
dissolved in ethyl acetate (20 mL) and extracted with water (20
mL). the organic layer was then dried through a 1PS filter and
evaporated to dryness. It was chromatographed on a silica gel
column (10 g) packed in chloroform. The column polarity was
increased to 45% ethyl acetate in chloroform over 15 CV, at 12
mL/min. Fractions (22 mL each) containing the product were pooled
and stripped to give ethyl
(4-(allyl(3-(trifluoromethyl)benzyl)amino)-2-amino-3-fluorophenyl)carbama-
te (0.119 g, 30% yield).
[0337] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.57 (s, 1H), 7.48 (m, 2H), 7.41 (t, 1H), 6.84 (d, 1H), 6.33 (t,
1H), 6.19 (br s, 1H), 5.80-5.89 (m, 1H), 5.16 (s, 1H), 5.13 (d,
1H), 4.35 (s, 2H), 4.21 (q, 2H), 3.85 (br s, 2H), 3.70 (d, 2H),
1.30 (t, 3H).
[0338] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd3=11.8 min.
##STR00057##
Example 4: Compound 4
Step 1: Synthesis of di-tert-butyl
(4-(allyl(4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate
[0339] Di-tert-butyl
(4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (0.937 g, 2.17
mmole) was dissolved in anhydrous dimethylformamide (10 mL).
Diisopropylethylamine (0.755 mL, 4.34 mmole) was added followed by
allyl bromide (0.237 mL, 2.82 mmole). The mixture was heated in an
110.degree. C. oil bath under argon for 2h. The reaction was
diluted in ethyl acetate (100 mL) and extracted with water (100
mL). The aqueous layer was washed with ethyl acetate (100 mL). The
organic layers were washed with water, 2.times.50 mL and then brine
(50 mL) and filtered through a 1PS filter to dry and evaporated to
dryness. The crude material was chromatographed on a silica gel
column (25 g) packed in hexanes. The column polarity was increased
to 12% ethyl acetate over 6 CV, held at 12% ethyl acetate over 2 CV
and then increased to 40% ethyl acetate over 14 CV. The flow rate
was 25 mL/min. Fractions (22 mL each) containing the first product
were pooled and stripped to give di-tert-butyl
(4-(allyl(4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (0.780 g,
76% yield).
Step 2: Synthesis of ethyl
(4-(allyl(4-fluorobenzyl)amino)-2-aminophenyl)carbamate (Compound
4)
[0340] Di-tert-butyl
(4-(allyl(4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (0.700 g,
1.48 mmole) was dissolved in dichloromethane (7 mL) and
trifluoroacetic acid (7 mL) was added and the reaction was stirred
at ambient temperature under argon for 65 min. The organic layer
was evaporated to dryness, dissolved in methanol (7 mL) and
tetrahydrofuran (7 mL) and cooled in an ice bath when N,
N-diisopropylethylamine (1.6 mL, 9.20 mmole) was added followed by
ethyl chloroformate (0.175 g, 1.63 mmole) dropwise. The reaction
was stirred at ambient temperature for 1 h and was evaporated. The
crude oil was dissolved in ethyl acetate (10 mL) and extracted with
water (10 mL). The organic layer was then dried through a 1PS
filter and evaporated to dryness. It was chromatographed on a
silica gel column (10 g) packed in hexanes. The column polarity was
increased to 39% ethyl acetate over 6CV, held at 39% ethyl acetate
over 2 CV and then increased to 100% ethyl acetate over 9 CV. Flow
rate at 12 mL/min. Fractions (22 mL each) containing the product
were pooled and stripped to give ethyl
(4-(allyl(4-fluorobenzyl)amino)-2-aminophenyl)carbamate (0.209 g,
41% yield).
[0341] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.21 (t, 2H), 7.00 (m, 3H), 6.18 (m, 3H), 5.90 (m, 1H), 5.21 (m,
2H), 4.47 (s, 2H), 4.20 (q, 2H), 3.95 (s, 3H), 1.30 (t, 3H).
[0342] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd4=6.4 min.
Example 5: Compound 5
##STR00058##
[0343] Step 1: Synthesis of
N.sup.1-allyl-4-nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-1,3-diam-
ine
[0344] 5-Fluoro-2-nitroaniline (0.566 g, 3.62 mmole) was dissolved
in anhydrous dimethylsulfoxide (5 mL).
N-(4-(trifluoromethyl)benzyl)prop-2-en-1-amine (1.17 g, 5.44 mmole)
was added triethylamine (1.80 mL) and solid iodine (1 mg) were
added and the mixture was heated at reflux for an additional 18 h.
under argon. The reaction was dissolved in ethyl acetate (10 mL)
and extracted with water (10 mL). The organic layer was washed with
3.times.30 mL water and then dried through a 1PS filter and
evaporated to dryness. The crude material was chromatographed on a
silica gel column (50 g) packed in hexanes. The column polarity was
increased to 40% ethyl acetate/chloroform over 8 CV, at 50 mL/min.
Fractions (22 mL each) containing the product were pooled and
stripped to give
N.sup.1-allyl-4-nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-1,3-diam-
ine (0.182 g, 14% yield).
Step 2: Synthesis of ethyl
(4-(allyl(4-(trifluoromethyl)benzyl)amino)-2-aminophenyl)carbamate
(Compound 5)
[0345]
N.sup.1-allyl-4-nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-1,-
3-diamine (0.182 g, 0.518 mmole) was dissolved in methanol (3 mL).
Zinc powder (169 mg, 2.59 mmole) was added followed by ammonium
chloride (139 mg, 2.59 mmole) in DI water (1.0 mL). The mixture was
stirred under argon at ambient temperature for 30 min., and then
zinc powder (169 mg, 2.59 mmole) was added followed by ammonium
chloride (139 mg, 2.59 mmole) in DI water (1.0 mL) and
tetrahydrofuran (3 mL). After 30 min., the mixture was cooled in an
ice bath. N, N-diisopropylethylamine (0.378 mL, 2.18 mmole) was
added, followed by ethyl chloroformate, dropwise (166 mg, 1.55
mmole) and the reaction was stirred at ambient temperature for 18
h. The reaction was filtered on a Buchner funnel with #4 Whatman
filter paper. The filtrate was diluted with ethyl acetate (15 mL)
and extracted with water (15 mL). The organic layer was washed with
brine (15 mL), dried through a 1PS filter and evaporated to
dryness. It was chromatographed on a silica gel column (10g) packed
in chloroform. The column polarity was increased to 3% ethyl
acetate/chloroform over 2 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(4-(allyl(4-(trifluoromethyl)benzyl)amino)-2-aminophenyl)carbamate
(0.017 g, 8.3% yield).
[0346] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.59 (d, 2H), 7.38 (d, 2H), 6.96 (m, 1H), 6.18 (m, 2H), 6.08 (br s,
1H), 5.87 (m, 1H), 5.21 (m, 2H), 4.55 (s, 2H), 4.22 (q, 2H), 3.99
(s, 2H), 1.32 (t, 3H).
[0347] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd5=9.3 min.
Example 6: Compound 6
##STR00059##
[0348] Step 1: Synthesis of
4-Nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
[0349] 5-Fluoro-2-nitroaniline (10.24 g, 58.46 mmole) was dissolved
in anhydrous dimethylsulfoxide (90 mL). 3-fluorobenzylamine (6.1 g,
39.0 mmole) was added triethylamine (13.0 mL) and solid iodine (90
mg) were added and the mixture was heated at reflux for 4 h. under
argon. The reaction was dissolved in ethyl acetate (200 mL) and
extracted with water (3.times.200 mL). The combined aqueous layers
were washed with (300 mL) ethyl acetate, combined and then
evaporated to dryness. The crude material was triturated with
hexane/ethyl acetate (7:3, 100 mL) and dried under high vacuum to
give 4-nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
(8.29 g, 77% yield).
Step 2: Synthesis of di-tert-butyl
(4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)-
dicarbamate
[0350]
4-Nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
(10.8 g, 34.7 mmole) was dissolved in methanol (50 mL) and
tetrahydrofuran (50 mL). Zinc powder (22.7 g, 347 mmole) was added
followed by ammonium chloride (18.6 g, 347 mmole) in DI water (46
mL) over 30 min. The mixture was stirred under argon at ambient
temperature for 30 min. The reaction was filtered on a celite pad
which was washed with methanol (200 mL) and the mixture was
evaporated to dryness. Ethyl acetate (200 mL) was added and the
mixture was extracted with water (200 mL) and brine (50 mL) and
evaporated to dryness. The residue was dissolved in tetrahydrofuran
(150 mL) and di-tert-butyldicarbonate (22.1 g, 101.3 mmole) was
added followed by solid sodium bicarbonate (11.63 g, 138.4 mmole)
and then DI water (100 mL). The reaction was stirred for an 18 h.
at ambient temperature. The reaction was evaporated to dryness. and
ethyl acetate (200 mL) was added. The organic layer was extracted
with water (3.times.200 mL) and brine (50 mL) and evaporated to
dryness. It was chromatographed on a silica gel column (200 g)
packed in hexane. The column polarity was increased to 35% ethyl
acetate in hexanes over 9 CV, at 100 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give
di-tert-butyl
(4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)-
dicarbamate (13.1 g, 65% yield).
Step 3: Synthesis of di-tert-butyl
(4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
[0351] Di-tert-butyl
(4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)-
dicarbamate (13.0 g, 22.4 mmole) was dissolved in dichloromethane
(75 mL) and trifluoroacetic acid (50 mL) was added and the reaction
was stirred at ambient temperature under argon for 60 min. The
reaction was evaporated to give an off-white solid. The solid was
dissolved in dioxane (125 mL) and di-tert-butyldicarbonate (10.24
g, 46.94 mmole) was added followed by solid sodium bicarbonate
(7.51 g, 89.4 mmole) and then DI water (50 mL). The reaction was
heated to 40.degree. C. with stirring for 18 h., under argon. The
reaction was evaporated and ethyl acetate (200 mL) was added. The
organic layer was extracted with 3M NH.sub.4OH (2.times.100 mL) and
brine (50 mL), dried through a 1PS filter and evaporated to
dryness. It was chromatographed on a silica gel column (200 g)
packed in hexane. The column polarity was increased to 45% ethyl
acetate in hexanes over 12 CV, at 100 mL/min. Fractions (22 mL
each) containing the product were pooled and stripped to give
di-tert-butyl
(4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(1.3 g, 65% yield).
Step 4: Synthesis of di-tert-butyl
(4-(allyl(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
[0352] Di-tert-butyl
(4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(2.0 g, 4.2 mmole) was dissolved in anhydrous dimethylformamide (20
mL). Diisopropylethylamine (2.2 mL, 12.5 mmole) was added followed
by allyl bromide (0.803 mL, 9.55 mmole). The mixture was heated in
an 110.degree. C. oil bath under argon for 2h. The reaction was
diluted in ethyl acetate (200 mL) and extracted with water (200
mL), and then brine (50 mL) and filtered through a 1PS filter to
dry and evaporated to dryness. The crude material was
chromatographed on a silica gel column (25 g) packed in hexanes.
The column polarity was increased to 37% ethyl acetate in hexanes
over 14 CV. The flow rate was 25 mL/min. Fractions (22 mL each)
containing the first product were pooled and stripped to give of
di-tert-butyl
(4-(allyl(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(1.63 g, 75% yield).
Step 5: Synthesis of ethyl
(4-(allyl(3-(trifluoromethyl)benzyl)amino)-2-aminophenyl)carbamate
(Compound 6)
[0353] Di-tert-butyl
(4-(allyl(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(1.0 g, 1.92 mmole) was dissolved in dichloromethane (7 mL) and
trifluoroacetic acid (7 mL) was added and the reaction was stirred
at ambient temperature under argon for 90 min. The organic layer
was evaporated to dryness, dissolved in methanol (5 mL) and
tetrahydrofuran (5 mL) and cooled in an ice bath when N,
N-diisopropylethylamine (2.1 mL, 11.9 mmole) was added followed by
ethyl chloroformate (0.225 mL, 2.11 mmole) dropwise. The reaction
was stirred at ambient temperature for 18 h and was filtered and
evaporated. The crude oil was dissolved in ethyl acetate (20 mL)
and extracted with water (20 mL). The organic layer was then dried
through a 1PS filter and evaporated to dryness. It was
chromatographed on a silica gel column (25 g) packed in chloroform.
The column polarity was increased to 100% ethyl acetate in hexanes
over 26 CV, at 25 mL/min. Fractions (22 mL each) containing the
product were pooled and stripped to give ethyl
(4-(allyl(3-(trifluoromethyl)benzyl)amino)-2-aminophenyl)carbamate
(0.150 g, 20% yield).
[0354] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.48 (s, 2H), 7.41 (s, 2H), 6.92 (d, 1H), 6.15 (d, 1H), 6.07 (s,
1H), 6.00 (br s, 1H), 5.85 (m, 1H), 5.15-5.20 (m, 2H), 4.50 (s,
2H), 4.18 (q, 2H), 3.95 (s, 2H), 3.75 (br s, 2H), 1.26 (t, 3H).
[0355] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd6=8.8 min.
##STR00060##
Example 7: Compound 7
Step 1: Synthesis of
2-Fluoro-N.sup.1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine
[0356] 2,3-Difluoro-6-nitroaniline (10.0 g, 79.9 mmole) was
dissolved in anhydrous dimethylsulfoxide (90 mL).
4-fluorobenzylamine (9.3 g, 53.3 mmole) was added triethylamine
(17.7 mL) and solid iodine (80 mg) were added and the mixture was
heated at reflux for 4 h. under argon. The reaction was dissolved
in ethyl acetate (200 mL) and extracted with water (3.times.100
mL). A yellow solid precipitated out of the organic layer to give
2-fluoro-N.sup.1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (13.6
g, 91% yield).
Step 2: Synthesis of di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate
[0357] 2-Fluoro-N.sup.1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine
(13.55 g, 48.53 mmole) was dissolved in methanol (60 mL) and
tetrahydrofuran (60 mL). The mixture was cooled in an ice bath and
zinc powder (31.70 g, 485.3 mmole) was added followed by ammonium
chloride (26.0 g, 485.3 mmole) in DI water (64 mL) over 30 min.
Ethyl acetate (200 mL) was added and the mixture was extracted with
water (200 mL) and the organic layer was evaporated to dryness. The
residue was dissolved in tetrahydrofuran (200 mL) and
di-tert-butyldicarbonate (15.9 g, 72.8 mmole) was added followed by
solid sodium bicarbonate (8.15 g, 97.06 mmole) and then DI water
(150 mL). The reaction was stirred for an 18 h. at ambient
temperature. The reaction was filtered and evaporated to dryness.
Ethyl acetate (200 mL) was added and then 3M NH.sub.4OH
(2.times.200 mL). The organic layer was evaporated to dryness. It
was chromatographed on a silica gel column (200 g) packed in
hexane. The column polarity was increased to 16% ethyl acetate over
5 CV, held at 16% ethyl acetate for 2 CV, increased to 32% ethyl
acetate over 4 CV, and then to 53% ethyl acetate over 2 CV. Flow
rate at 100 mL/min. t 100 mL/min. Fractions (22 mL each) containing
the product were pooled and stripped to give di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (9.84
g, 45% yield).
Step 3: Synthesis of di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-1,2-phenylene)dicarba-
mate
[0358] Di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate (2.00
g, 4.45 mmole) was dissolved in anhydrous dimethylformamide (20
mL), 80% propargyl bromide in toluene (0.618 mL, 5.78 mmole) and
diisopropylethylamine (1.50 mL, 8.90 mmole). The mixture was heated
in a 90.degree. C. oil bath, under argon, for 0.5 h. 80% propargyl
bromide in toluene (0.65 mL, 5.78 mmole) and diisopropylethylamine
(1.50 mL, 8.90 mmole) were added and heated at 100.degree. C. for
4.5h. 80% propargyl bromide in toluene (0.618 mL, 5.78 mmole) and
diisopropylethylamine (1.50 mL, 8.90 mmole) were added and the
reaction was heated at 100.degree. for 18 h. 80% propargyl bromide
in toluene (0.618 mL, 5.78 mmole) was added and the mixture was
heated for 2 h. at 100.degree. C. The reaction was diluted in ethyl
acetate (100 mL) and extracted with water (100 mL) and brine (50
mL), filtered through a 1PS filter and evaporated to dryness. The
crude material was chromatographed on a silica gel column (25 g)
packed in hexanes. The column polarity was increased to 40% ethyl
acetate over 15 CV, at 25 mL/min. Fractions (22 mL each) containing
the product were pooled and stripped to give (1.01 g, 47% yield)
di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-1,2-phenylene)dicarba-
mate (1.35 g, 61% yield).
Step 4: Synthesis of ethyl
(2-amino-3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)phenyl)carbama-
te (Compound 7)
[0359] Di-tert-butyl
(3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-1,2-phenylene)dicarba-
mate (0.480 g, 0.985 mmole) was dissolved in dichloromethane (5 mL)
and trifluoroacetic acid (5 mL) was added and the reaction was
stirred at ambient temperature under argon for 90 min. The reaction
was evaporated to give red oil which was dissolved in methanol (5
mL) and tetrahydrofuran (5 mL) and cooled in an ice bath when N,
N-diisopropylethylamine (1.2 mL, 6.1 mmole) was added followed by
ethyl chloroformate (129 mg, 1.2 mmole) dropwise. The reaction was
stirred at ambient temperature for 18 h and was filtered and
evaporated. The crude oil was dissolved in ethyl acetate (20 mL)
and extracted with water (20 mL). The organic layer was then dried
through a 1PS filter and evaporated to dryness. It was
chromatographed on a silica gel column (10 g) packed in chloroform.
The column polarity was increased to 30% ethyl acetate in
chloroform over 7 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(2-amino-3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)phenyl)carbama-
te (0.073 g, 20% yield).
[0360] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.41 (m, 2H), 7.12 (t, 2H), 6.88 (m, 1H), 6.61 (m, 1H), 6.22 (br s,
1H), 4.30 (s, 2H), 4.25 (m, 2H), 3.88 (s, 2H), 3.78 (s, 2H), 2.28
(s, 1H), 1.35 (t, 3H).
[0361] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd7=10.6 min.
Example 8: Compound 8
##STR00061##
[0362] Step 1: Synthesis of
N-(4-(trifluoromethyl)benzyl)prop-2-yn-1-amine
[0363] 4-(Trifluoromethyl)benzylamine (6.93 g, 40 mmole) was
dissolved in anhydrous acetonitrile (18 mL). Potassium carbonate
(5.5 g, 40 mmole) was added and the mixture was cooled in an ice
bath when 80% propargyl bromide in toluene (2.6 g, 20 mmole) was
added over 10 min. The reaction was warmed to ambient temperature
and stirred for 18 h. It was filtered and evaporated. The crude oil
was dissolved in ethyl acetate (50 mL) and extracted with water (50
mL) and then brine (50 mL) and dried over sodium sulfate. It was
chromatographed on a silica gel column (100g) packed in hexanes.
The column polarity was increased to 100% ethyl acetate over 10 CV,
at 50 mL/min. Fractions (22 mL each) containing the second band
were pooled and stripped to give
N-(4-(trifluoromethyl)benzyl)prop-2-yn-1-amine (3.0 g, 43%
yield).
Step 2: Synthesis of
2-Fluoro-4-nitro-N.sup.1-(prop-2-yn-1-yl)-N.sup.1-(4-(trifluoromethyl)ben-
zyl)benzene-1,3-diamine
[0364] 2,3-Difluoro-6-nitroaniline (0.681 g, 3.91 mmole) was
dissolved in anhydrous dimethylsulfoxide (5 mL).
N-(4-(trifluoromethyl)benzyl)prop-2-yn-1-amine (1.75 g, 8.21
mmole)) was added followed by triethylamine (2.3 mL) and solid
iodine (2 mg). The mixture was heated at reflux for 18 h. under
argon. The reaction was dissolved in dichloromethane (10 mL) and
extracted with water (10 mL). The aqueous layer was washed with
2.times.10 mL dichloromethane. The organic layers were combined and
washed with brine (30 mL) and evaporated to dryness. The crude
material was chromatographed on a silica gel column (25 g) packed
in hexanes. The column polarity was increased to 100% chloroform
over 20 CV, at 25 mL/min. Fractions (22 mL each) containing the
product were pooled and stripped to give of
2-fluoro-4-nitro-N.sup.1-(prop-2-yn-1-yl)-N.sup.1-(4-(trifluoromethyl)ben-
zyl)benzene-1,3-diamine (0.36 g, 25% yield).
Step 3: Synthesis of ethyl
(2-amino-3-fluoro-4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)pheny-
l)carbamate (Compound 8)
[0365]
2-Fluoro-4-nitro-N.sup.1-(prop-2-yn-1-yl)-N.sup.1-(4-(trifluorometh-
yl)benzyl)benzene-1,3-diamine (0.350 g, 0.953 mmole) was dissolved
in methanol (3 mL). Zinc powder (312 mg, 4.76 mmole) was added
followed by ammonium chloride (255 mg, 4.76 mmole) in DI water (1.0
mL). The mixture was stirred under argon at ambient temperature for
18 h., and then zinc powder (312 mg, 4.76 mmole) were added
followed by ammonium chloride (255 mg, 4.76 mmole) in DI water (1.0
mL). After 25 min., the mixture was cooled in an ice bath. N,
N-diisopropylethylamine (0.364 mL, 2.01 mmole) was added, followed
by ethyl chloroformate, dropwise (204 mg, 1.90 mmole) and the
reaction was stirred at ambient temperature for 0.5 h. The reaction
was dissolved in ethyl acetate (10 mL) and extracted with water (10
mL). The organic layer was dried through a 1PS filter and
evaporated to dryness. It was chromatographed on a silica gel
column (50g) packed in chloroform. The column polarity was
increased to 65% ethyl acetate/chloroform over 11 CV, at 50 mL/min.
Fractions (22 mL each) containing the product were pooled and
stripped to give ethyl
(2-amino-3-fluoro-4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)pheny-
l)-carbamate (0.087 g, 19% yield).
[0366] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.59
(q, 4H), 6.95 (d, 1H), 6.62 (t, 1H), 6.24 (br s, 1H), 4.40 (s, 2H),
4.24 (q, 2H), 3.80 (d, 2H), 2.05-2.50 (m, 2H), 1.38 (t, 3H).
[0367] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd8=12.3 min.
Example 9: Compound 9
##STR00062##
[0368] Step 1: Synthesis of
N-(3-(trifluoromethyl)benzyl)prop-2-yn-1-amine
[0369] 3-(Trifluoromethyl)benzylamine (5.0 g, 28.6 mmole) was
dissolved in anhydrous acetonitrile (18 mL). Potassium carbonate
(4.00 g, 28.6 mmole) was added and the mixture was cooled in an ice
bath when 80% propargyl bromide in toluene (3.0 mL, 19 mmole) was
added over 30 min. The reaction was warmed to ambient temperature
and stirred for 2 h. It was filtered and evaporated. It was
chromatographed on a silica gel column (50 g) packed in hexanes.
The column polarity was increased to 100% ethyl acetate over 9 CV,
at 50 mL/min. Fractions (22 mL each) containing the second band
were pooled and stripped to give
N-(3-(trifluoromethyl)benzyl)prop-2-yn-1-amine (2.72 g, 45%
yield).
Step 2: Synthesis of
2-Fluoro-4-nitro-N.sup.1-(prop-2-yn-1-yl)-N.sup.1-(3-(trifluoromethyl)ben-
zyl)benzene-1,3-diamine
[0370] 2,3-Difluoro-6-nitroaniline (1.09 g, 6.26 mmole) was
dissolved in anhydrous dimethylsulfoxide (8 mL).
N-(3-(trifluoromethyl)benzyl)prop-2-yn-1-amine (2.00 g, 9.39 mmole)
was added triethylamine (2.86 mL) and solid iodine (1 mg). The
mixture was heated at reflux for 23 h. under argon. The reaction
was dissolved in ethyl acetate (40 mL) and extracted with water (40
mL). The aqueous layer was washed with ethyl acetate (20 mL). The
organic layers were washed with water, 2.times.20 mL brine and
filtered through a 1PS filter to dry. The crude material was
chromatographed on a silica gel column (50 g) packed in hexanes.
The column polarity was increased to 40% ethyl acetate over 15 CV,
at 50 mL/min. Fractions (22 mL each) containing the product were
pooled and stripped to give
2-fluoro-4-nitro-N.sup.1-(prop-2-yn-1-yl)-N.sup.1-(3-(trifluoromethyl)ben-
zyl)benzene-1,3-diamine (0.393 g, 17% yield).
Step 3: Synthesis of ethyl
(2-amino-3-fluoro-4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)pheny-
l)carbamate (Compound 9)
[0371]
2-Fluoro-4-nitro-N.sup.1-(prop-2-yn-1-yl)-N.sup.1-(3-(trifluorometh-
yl)benzyl)benzene-1,3-diamine (0.380 g, 1.04 mmole) was dissolved
in methanol (6 mL) and tetrahydrofuran (6 mL). Zinc powder (0.677
g, 10.4 mmole) was added followed by ammonium chloride (553 mg,
10.35 mmole) in DI water (2 mL). The mixture was stirred under
argon at ambient temperature for 30 min. The reaction was cooled in
an ice bath and N, N-diisopropylethylamine (0.515 mL, 2.96 mmole)
was added followed by ethyl chloroformate (249 mg, 2.33 mmole)
dropwise. The reaction was stirred at ambient temperature for 18 h
and was filtered and evaporated. The crude oil was dissolved in
ethyl acetate (20 mL) and extracted with water (20 mL). the organic
layer was then dried through a 1PS filter and evaporated to
dryness. It was chromatographed on a silica gel column (10 g)
packed in chloroform. The column polarity was increased to 20%
ethyl acetate in chloroform over 7 CV, at 12 mL/min. Fractions (22
mL each) containing the product were pooled and stripped to give of
ethyl
(2-amino-3-fluoro-4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)pheny-
l)carbamate (0.249 g, 58% yield).
[0372] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.39-7.70 (m, 5H), 6.90 (d, 1H), 6.59 (t, 1H), 6.23 (br s, 1H),
4.35 (s, 2H), 4.19 (m, 2H), 3.56-3.92 (m, 3H), 2.25 (s, 1H), 1.25
(t, 3H).
[0373] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd9=12.0 min.
Example 10: Compound 11
##STR00063##
[0374] Step 1: Synthesis of
4-Nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-1,3-diamine
[0375] 5-Fluoro-2-nitroaniline (10.24 g, 58.46 mmole) was dissolved
in anhydrous dimethylsulfoxide (90 mL).
(4-(trifluoromethyl)phenyl)methanamine (6.1 g, 39.0 mmole) was
added followed by triethylamine (13.0 mL) and solid iodine (70 mg).
The mixture was heated at reflux for 1 h. under argon. Ethyl
acetate (150 mL) was added and the organics were extracted with
water (3.times.150 mL). The combined aqueous layers were washed
with dichloromethane (300 mL), all organics were combined, filtered
through a 1PS filter and then evaporated to dryness. The crude
material was dissolved in boiling ethyl acetate (20 mL) and hexanes
were added to cloud point. Upon cooling, crystals formed. The solid
was filtered off on a #54 Whatman filter paper on a Buchner filter
and dried under high vacuum to give
4-nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-1,3-diamine
(8.61 g, 71% yield).
Step 2: Synthesis of di-tert-butyl
(4-((4-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
[0376]
4-Nitro-N.sup.1-(4-(trifluoromethyl)benzyl)benzene-1,3-diamine
(8.17 g, 26.2 mmole) was dissolved in methanol (30 mL) and
tetrahydrofuran (30 mL). The mixture was cooled in an ice bath and
zinc powder (17.16 g, 262.5 mmole) was added followed by ammonium
chloride (14.0 g, 262.5 mmole) in DI water (40 mL) over 60 min. The
reaction was filtered on a celite pad and solids were washed with
methanol (200 mL) and the filtrate was evaporated to dryness. Ethyl
acetate (100 mL) was added and the mixture was extracted with water
(100 mL) and then brine (50 mL) The organic layer was evaporated to
dryness. The residue was dissolved in tetrahydrofuran (171 mL) and
di-tert-butyldicarbonate (8.60 g, 39.36 mmole) was added followed
by solid sodium bicarbonate (6.60 g, 78.75 mmole) and then DI water
(86 mL). The reaction was stirred for an 18 h. at ambient
temperature. The reaction was filtered and evaporated to dryness.
Ethyl acetate (200 mL) was added and then washed with 3M NH.sub.4OH
(2.times.200 mL). The organic layer was evaporated to dryness. It
was chromatographed on a silica gel column (100 g) packed in
hexane. The column polarity was increased to 60% ethyl acetate in
hexanes over 14 CV. Flow rate at 50 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give
di-tert-butyl
(4-((4-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(5.9 g, 47% yield).
Step 3: Synthesis of di-tert-butyl
(4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarba-
mate
[0377] Di-tert-butyl
(4-((4-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(4.88 g, 10.13 mmole) was dissolved in anhydrous dimethylformamide
(50 mL). 80% propargyl bromide in toluene (2.50 mL, 23.3 mmole) was
added followed by diisopropylethylamine (5.30 mL, 30.4 mmole). The
mixture was heated at reflux, under argon, for 2h. The reaction was
evaporated to dryness and the crude material was chromatographed on
a suction silica gel column (50 g) packed in hexanes. The column
was washed with hexanes (250 mL), 10% ethyl acetate in hexanes (250
mL), 10% ethyl acetate in hexanes (250 mL), 20% ethyl acetate in
hexanes (250 mL), 30% ethyl acetate in hexanes (500 mL), Fractions
(125 mL each) containing the product were pooled and stripped to
give di-tert-butyl
(4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)-amino)-1,2-phenylene)dicarb-
amate (1.42 g, 27% yield).
Step 4: Synthesis of ethyl
(2-amino-4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)phenyl)carbama-
te (Compound 11)
[0378] Di-tert-butyl
(4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarba-
mate (1.40 g, 2.69 mmole) was dissolved in dichloromethane (15 mL)
and trifluoroacetic acid (15 mL) was added and the reaction was
stirred at ambient temperature under argon for 45 min. The organic
layer was evaporated to dryness, dissolved in methanol (10 mL) and
tetrahydrofuran (10 mL) and cooled in an ice bath when N,
N-diisopropylethylamine (3.00 mL, 16.7 mmole) was added followed by
ethyl chloroformate (0.317 g, 2.63 mmole) dropwise. The reaction
was stirred at ambient temperature for 1 h and was evaporated. The
crude oil was dissolved in ethyl acetate (40 mL) and extracted with
water (40 mL). The organic layer was then dried through a 1PS
filter and evaporated to dryness. It was chromatographed on a
silica gel column (25 g) packed in hexanes. The column polarity was
increased to 33% ethyl acetate over 7CV, held at 33% ethyl acetate
over 4 CV and then increased to 84% ethyl acetate over 10 CV. Flow
rate at 25 mL/min. Fractions (22 mL each) containing the product
were pooled and stripped to give ethyl
(2-amino-4-(prop-2-yn-1-yl(4-(trifluoromethyl)benzyl)amino)phenyl)carbama-
te (0.462 g, 44% yield).
[0379] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.55 (d, 2H), 7.40 (d, 2H), 6.98 (d, 1H), 6.20-6.25 (m, 2H), 6.07
(br s, 1H), 4.53 (s, 2H), 4.18 (q, 2H), 3.95 (s, 2H), 3.78 (br s,
2H), 2.21 (s, 1H), 1.25 (t, 3H).
[0380] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd11=8.8 min.
Example 11: Compound 12
##STR00064##
[0381] Step 1: Synthesis of
4-Nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
[0382] 5-Fluoro-2-nitroaniline (10.24 g, 58.46 mmole) was dissolved
in anhydrous dimethylsulfoxide (90 mL). 3-fluorobenzylamine (6.1 g,
39.0 mmole) was added triethylamine (13.0 mL) and solid iodine (90
mg) were added and the mixture was heated at reflux for 4 h. under
argon. The reaction was dissolved in ethyl acetate (200 mL) and
extracted with water (3.times.200 mL). The combined aqueous layers
were washed with (300 mL) ethyl acetate, combined and then
evaporated to dryness. The crude material was triturated with
hexane/ethyl acetate (7:3, 100 mL) and dried under high vacuum to
give 4-nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
(8.29 g, 77% yield).
Step 2: Synthesis of di-tert-butyl
(4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)-
dicarbamate
[0383]
4-Nitro-N.sup.1-(3-(trifluoromethyl)benzyl)benzene-1,3-diamine
(10.8 g, 34.7 mmole) was dissolved in methanol (50 mL) and
tetrahydrofuran (50 mL). Zinc powder (22.7 g, 347 mmole) was added
followed by ammonium chloride (18.6 g, 347 mmole) in DI water (46
mL) over 30 min. The mixture was stirred under argon at ambient
temperature for 30 min. The reaction was filtered on a celite pad
which was washed with methanol (200 mL) and the mixture was
evaporated to dryness. Ethyl acetate (200 mL) was added and the
mixture was extracted with water (200 mL) and brine (50 mL) and
evaporated to dryness. The residue was dissolved in tetrahydrofuran
(150 mL) and di-tert-butyldicarbonate (22.1 g, 101.3 mmole) was
added followed by solid sodium bicarbonate (11.63 g, 138.4 mmole)
and then DI water (100 mL). The reaction was stirred for an 18 h.
at ambient temperature. The reaction was evaporated to dryness. and
ethyl acetate (200 mL) was added. The organic layer was extracted
with water (3.times.200 mL) and brine (50 mL) and evaporated to
dryness. It was chromatographed on a silica gel column (200 g)
packed in hexane. The column polarity was increased to 35% ethyl
acetate in hexanes over 9 CV, at 100 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give
di-tert-butyl
(4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)-
dicarbamate (13.1 g, 65% yield).
Step 3: Synthesis of di-tert-butyl
(4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
[0384] Di-tert-butyl
(4-((tert-butoxycarbonyl)(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)-
dicarbamate (13.0 g, 22.4 mmole) was dissolved in dichloromethane
(75 mL) and trifluoroacetic acid (50 mL) was added and the reaction
was stirred at ambient temperature under argon for 60 min. The
reaction was evaporated to give an off-white solid. The solid was
dissolved in dioxane (125 mL) and di-tert-butyldicarbonate (10.24
g, 46.94 mmole) was added followed by solid sodium bicarbonate
(7.51 g, 89.4 mmole) and then DI water (50 mL). The reaction was
heated to 40.degree. C. with stirring for 18 h., under argon. The
reaction was evaporated and ethyl acetate (200 mL) was added. The
organic layer was extracted with 3M NH.sub.4OH (2.times.100 mL) and
brine (50 mL), dried through a 1PS filter and evaporated to
dryness. It was chromatographed on a silica gel column (200 g)
packed in hexane. The column polarity was increased to 45% ethyl
acetate in hexanes over 12 CV, at 100 mL/min. Fractions (22 mL
each) containing the product were pooled and stripped to give
di-tert-butyl
(4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(1.3 g, 65% yield).
Step 4: Synthesis of Di-tert-butyl
(4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarba-
mate
[0385] Di-tert-butyl
(4-((3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate
(2.00 g, 4.15 mmole) was dissolved in anhydrous dimethylformamide
(20 mL). Diisopropylethylamine (2.20 mL, 12.5 mmole) was added
followed by 80% propargyl bromide in toluene (1.50 mL, 14.3 mmole).
The mixture was heated in a 110.degree. C. oil bath under argon for
2h. The reaction was diluted in ethyl acetate (200 mL) and
extracted with water (200 mL). The organic layer was evaporated to
dryness. The crude material was chromatographed on a silica gel
column (25 g) packed in hexanes. The column polarity was increased
to 40% ethyl acetate over 15 CV, at 25 mL/min. Fractions (22 mL
each) containing the product were pooled and stripped to give
di-tert-butyl
(4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarba-
mate (1.76 g, 82% yield).
Step 5: Synthesis of ethyl
(2-amino-4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)
phenyl)carbamate (Compound 12)
[0386] Di-tert-butyl (4-(prop-2-yn-1-yl
(3-(trifluoromethyl)benzyl)amino)-1,2-phenylene)dicarbamate (1.0 g,
1.9 mmole) was dissolved in dichloromethane (7 mL) and
trifluoroacetic acid (7 mL) was added and the reaction was stirred
at ambient temperature under argon for 90 min. The organic layer
was evaporated to dryness, dissolved in methanol (5 mL) and
tetrahydrofuran (5 mL) and cooled in an ice bath when N,
N-diisopropylethylamine (2.1 mL, 11.9 mmole) was added followed by
ethyl chloroformate (0.225 mL, 2.11 mmole) dropwise. The reaction
was stirred at ambient temperature for 18 h and was filtered and
evaporated. The crude oil was dissolved in ethyl acetate (20 mL)
and extracted with water (20 mL). The organic layer was then dried
through a 1PS filter and evaporated to dryness. It was
chromatographed on a silica gel column (25 g) packed in hexane. The
column polarity was increased to 33% ethyl acetate over 4 CV, held
at 33% ethyl acetate over 4 CV and then increased to 100% ethyl
acetate over 13 CV. Flow rate at 25 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(2-amino-4-(prop-2-yn-1-yl(3-(trifluoromethyl)benzyl)amino)phenyl)-carbam-
ate (0.360 g, 48% yield).
[0387] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.60 (s, 1H), 7.50 (m, 2H), 7.40-7.45 (m, 1H), 7.24 (s, 1H), 7.00
(t, 1H), 6.30 (d, 1H), 6.23 (s, 1H), 6.02 (br s, 1H), 4.60 (s, 2H),
4.2 (q, 2H), 3.87 (s, 2H), 2.30 (br s, H), 2.21 (s, 1H), 1.24 (t,
3H).
[0388] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd12=8.3 min.
Example 12: Compound 13
##STR00065##
[0389] Step 1: Synthesis of Compound e
[0390] To a stirred suspension of 2, 3-difluoro-6-nitroaniline (1
equiv) in dry DMSO is added 5-fluoroisoindoline (3 equiv) followed
by Et.sub.3N (1.2 equiv) and I.sub.2 (catalytic amount). The
reaction mixture is heated to 120.degree. C. and stirred at
120.degree. C. for 24 h. Upon complete consumption of the starting
material (as determined by TLC), the reaction mixture is cooled to
RT, diluted with water (25 mL), and extracted with EtOAc
(2.times.25 mL). The combined organic layers are dried over
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure to give a crude product, which is purified by
silica gel column chromatography to afford Compound e.
Step 2: Synthesis of Compound 13
[0391] To a stirred solution of Compound e (1 equiv) in methanol is
added zinc powder (5 equiv) followed by the dropwise addition of
ammonium chloride solution (5 equiv). After stirring at RT for 5
hours, DIPEA (1.25 equiv) and ethyl chloroformate (1 equiv) are
then added to reaction mixture at 10.degree. C., and the stirring
is continued for another 3 hours at RT. Upon complete consumption
of the starting material (as determined by TLC), the reaction
mixture is diluted with water and stirred for 1 hour to give a
solid product. The obtained solid is filtered, dissolved in EtOAc,
and any un-dissolved solid is removed by filtration. The filtrate
concentrated to provide Compound 13 which is crystallized using
n-hexane.
Example 13: Compound 13
Step 1: Synthesis of
2-Fluoro-3-(5-fluoroisoindolin-2-yl)-6-nitroaniline
[0392] 2,3-Difluoro-6-nitroaniline (0.311 g, 1.78 mmole) was
dissolved in anhydrous dimethylsulfoxide (6 mL).
5-fluoroisoindoline hydrochloride (0.465 g, 2.68 mmole) was added
triethylamine (0.814 mL) and solid iodine (1 mg). The mixture was
heated at reflux for 4 h. under argon. The reaction was slurried in
7:3 chloroform/isopropanol (5 mL) and filtered on a #54 Whatman
filter on a buchner funnel. The solid was washed with 7:3
chloroform/isopropanol (2.times.5 mL) and dried at ambient temp.
under high vacuum to give a white solid
2-fluoro-3-(5-fluoroisoindolin-2-yl)-6-nitroaniline (0.455 g, 88%
yield).
Step 2: Synthesis of Ethyl
(2-amino-3-fluoro-4-(5-fluoroisoindolin-2-yl)phenyl)carbamate
(Compound 13)
[0393] 2-Fluoro-3-(5-fluoroisoindolin-2-yl)-6-nitroaniline (0.440
g, 1.51 mmole) was dissolved in methanol (5 mL) and tetrahydrofuran
(5 mL). Zinc powder (0.988 g, 15.1 mmole) was added followed by
ammonium chloride (808 mg, 15.1 mmole) in DI water (2 mL). The
mixture was stirred under argon at ambient temperature for 45 min.
The reaction was cooled in an ice bath and N,
N-diisopropylethylamine (0.604 mL, 3.45 mmole) was added followed
by ethyl chloroformate (291 mg, 2.72 mmole) dropwise. The reaction
was stirred at ambient temperature for 12 h. The reaction was
cooled in an ice bath and N, N-diisopropylethylamine (0.300 mL,
1.74 mmole) was added followed by ethyl chloroformate (150 mg, 1.30
mmole) dropwise. The reaction was stirred at ambient temperature
for 2 h and was filtered and evaporated. The crude oil was
dissolved in ethyl acetate (10 mL) and extracted with water (10
mL). the organic layer was then dried through a 1PS filter and
evaporated to dryness. It was chromatographed on a silica gel
column (10 g) packed in chloroform. The column polarity was
increased to 45% ethyl acetate in chloroform over 14 CV, at 12
mL/min. Fractions (22 mL each) containing the product were pooled
and stripped to give ethyl
(2-amino-3-fluoro-4-(5-fluoroisoindolin-2-yl)phenyl)carbamate
(0.033 g, 6.3% yield).
[0394] NMR Spectroscopy: .sup.1H NMR (CD.sub.3OD, 500 MHz): .delta.
7.30 (m, 1H), 7.05 (d, 1H), 6.98 (m, 1H), 6.80 (s, 1H), 6.20 (m,
1H), 4.68 (m, 4H), 4.18 (m, 2H), 1.25 (s, 4H).
[0395] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd13=10.1 min.
Example 14a: Compound 14
##STR00066##
[0396] Step 1: Synthesis of Compound f
[0397] To a stirred suspension of 2, 3-difluoro-6-nitroaniline (1
equiv) in dry DMSO is added 5-trifluoromethylisoindoline (3 equiv)
followed by Et.sub.3N (1.2 equiv) and I2 (catalytic amount). The
reaction mixture is heated to 120.degree. C. and stirred at
120.degree. C. for 24 hours. Upon complete consumption of the
starting material (as determined by TLC), the reaction mixture is
diluted with water (25 mL), and extracted with EtOAc (2.times.25
mL). The combined organic layers are dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to give a crude product, which is purified by silica gel column
chromatography to afford Compound f.
Step 2: Synthesis of Compound 14
[0398] To a stirred solution of Compound f (1 equiv) in methanol is
added zinc powder (5 equiv) followed by the dropwise addition of
ammonium chloride solution (5 equiv). After stirring at RT for 5
hours, DIPEA (1.25 equiv) and ethyl chloroformate (1 equiv) are
added to reaction mixture at 10.degree. C., and the stirring is
continued for another 3 hours at RT. Upon complete consumption of
the starting material (as determined by TLC), the reaction mixture
is diluted with water and stirred for 1 hour to give a solid
product. The obtained solid is filtered, dissolved in EtOAc, and
any un-dissolved solid is removed by filtration. The filtrate is
concentrated to provide Compound 14 which is crystallized using
n-hexane.
Example 14b: Compound 14
Step 1: Synthesis of
2-Fluoro-6-nitro-3-(5-(trifluoromethyl)isoindolin-2-yl)aniline
[0399] 2,3-Difluoro-6-nitroaniline (0.233 g, 1.34 mmole) was
dissolved in anhydrous dimethylsulfoxide (6 mL).
5-(trifluoromethyl)isoindoline hydrochloride (0.448 g, 2.00 mmole)
was added triethylamine (0.61 mL) and solid iodine (1 mg). The
mixture was heated at reflux for 2 h. under argon. The reaction was
dissolved in dichloromethane (10 mL) and extracted with water (10
mL). The aqueous layer was washed with dichloromethane (10 mL),
organics pooled and washed with brine (5 mL) and then dried through
a 1PS filter and evaporated to dryness. The crude material was
chromatographed on a silica gel column (10 g) packed in hexane. The
column polarity was increased to 100% ethyl acetate over 12 CV, at
12 mL/min. Fractions (22 mL each) containing the product were
pooled and stripped to give
2-fluoro-6-nitro-3-(5-(trifluoromethyl)-isoindolin-2-yl)aniline
(0.480 g, 100% yield).
Step 2: Synthesis of ethyl
(2-amino-3-fluoro-4-(5-(trifluoromethyl)isoindolin-2-yl)phenyl)carbamate
(Compound 14)
[0400]
2-Fluoro-6-nitro-3-(5-(trifluoromethyl)isoindolin-2-yl)aniline
(0.470 g, 1.378 mmole) was dissolved in methanol (5 mL) and
tetrahydrofuran (5 mL). Zinc powder (0.900 g, 13.78 mmole) was
added followed by ammonium chloride (737 mg, 13.78 mmole) in DI
water (2 mL). The mixture was stirred under argon at ambient
temperature for 45 min. and then cooled in an ice bath.
Triethylamine (0.55 mL, 3.96 mmole) was added, followed by ethyl
chloroformate dropwise (265 mg, 2.48 mmole) and the reaction was
stirred at ambient temperature for 105 min. The reaction was
filtered and evaporated. The crude oil was dissolved in ethyl
acetate (10 mL) and extracted with water (10 mL). the organic layer
was then dried through a 1PS filter and evaporated to dryness. It
was chromatographed on a silica gel column (10 g) packed in
chloroform. The column was washed with 13 CV of chloroform and then
polarity was increased to 45% ethyl acetate/chloroform over 14 CV,
at 12 mL/min. Fractions (22 mL each) containing the product were
pooled and stripped to give ethyl
(2-amino-3-fluoro-4-(5-(trifluoromethyl)isoindolin-2-yl)phenyl)carbamate
(0.146 g, 28% yield).
[0401] NMR Spectroscopy: .sup.1H NMR (DMSO, 300 MHz): .delta. 8.50
(br s, 1H), 7.78 (s, 1H), 7.63 (q, 3H), 6.82 (d, 1H), 6.10 (t, 1H),
4.75 (s, 5H), 4.08 (q, 2H), 1.20 (t, 3H).
[0402] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd14=11.8 min.
Example 15: Compound 15
##STR00067##
[0404] 5-(5-Fluoroisoindolin-2-yl)-2-nitroaniline (0.334 g, 1.22
mmole) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL).
Zinc powder (0.800 g, 12.23 mmole) was added followed by ammonium
chloride (654 mg, 12.23 mmole) in DI water (2 mL). The mixture was
stirred under argon at ambient temperature for 2 h. The reaction
was cooled in an ice bath and N, N-diisopropylethylamine (0.489 mL,
2.81 mmole) was added followed by ethyl chloroformate (235 mg, 2.20
mmole) dropwise. The reaction was stirred at ambient temperature
for 60 min. and was filtered and evaporated. The crude oil was
dissolved in ethyl acetate (10 mL) and extracted with water (10
mL). the organic layer was then dried through a 1PS filter and
evaporated to dryness. It was chromatographed on a silica gel
column (10 g) packed in hexanes. The column polarity was increased
to 100% ethyl acetate over 20 CV, at 12 mL/min. Fractions (22 mL
each) containing the product were pooled and stripped to give ethyl
(2-amino-4-(5-fluoroisoindolin-2-yl)phenyl)carbamate (0.130 g, 34%
yield).
[0405] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.28 (m, 1H), 7.03 (m, 3H), 6.10 (d, 3H), 4.60 (m, 4H), 4.21 (m,
2H), 3.98 (br s, 2H), 1.32 (s, 3H).
[0406] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd15=6.5 min.
Example 16: Compound 16
##STR00068##
[0407] Step 1: Synthesis of
2-Nitro-5-(5-(trifluoromethyl)isoindolin-2-yl)aniline
[0408] 5-Fluoro-2-nitroaniline (0.237 g, 1.52 mmole) was dissolved
in anhydrous dimethylsulfoxide (6 mL).
5-(trifluoromethyl)isoindoline hydrochloride (0.510 g, 2.28 mmole)
was added triethylamine (0.72 mL) and solid iodine (1 mg). The
mixture was heated at reflux for 12 h. under argon. The reaction
was dissolved in dichloromethane (10 mL) and extracted with water
(10 mL). The reaction was dissolved in dichloromethane (10 mL) and
extracted with water (10 mL). The organic layer was washed with
3.times.30 mL water and then dried through a 1PS filter and
evaporated to dryness. The crude material was chromatographed on a
silica gel column (10 g) packed in hexanes. The column polarity was
increased to 100% ethyl acetate over 10 CV, at 12 mL/min. Fractions
(22 mL each) containing the product were pooled and stripped to
give of 2-nitro-5-(5-(trifluoromethyl)isoindolin-2-yl)aniline
(0.225 g, 46% yield).
Step 2: Synthesis of ethyl
(2-amino-4-(5-(trifluoromethyl)isoindolin-2-yl)phenyl)carbamate
(Compound 16)
[0409] 2-Nitro-5-(5-(trifluoromethyl)isoindolin-2-yl)aniline (0.252
g, 0.779 mmole) was dissolved in methanol (5 mL) and
tetrahydrofuran (5 mL). Zinc powder (0.509 g, 7.79 mmole) was added
followed by ammonium chloride (417 mg, 7.79 mmole) in DI water (2
mL). The mixture was stirred under argon at ambient temperature for
45 min triethylamine (0.55 mL, 3.96 mmole) was added, and the
reaction was cooled in an ice bath. Ethyl chloroformate was added
dropwise (150 mg, 1.40 mmole) and the reaction was stirred at
ambient temperature for 2 h. The reaction was filtered and
evaporated. The crude oil was dissolved in ethyl acetate (10 mL)
and extracted with water (10 mL). the organic layer was then dried
through a 1PS filter and evaporated to dryness. It was
chromatographed on a silica gel column (10 g) packed in chloroform.
The column was washed with 12 CV of chloroform and then polarity
was increased to 50% ethyl acetate/chloroform over 20 CV, at 12
mL/min. Fractions (22 mL each) containing the product were pooled
and stripped to give ethyl
(2-amino-4-(5-(trifluoromethyl)isoindolin-2-yl)phenyl)carbamate
(0.113 g, 40% yield).
[0410] NMR Spectroscopy: .sup.1H NMR (DMSO, 500 MHz): .delta. 8.28
(br s, 1H), 7.80 (m, 1H), 7.60-7.75 (m, 3H), 6.97 (s, 1H), 6.03 (s,
1H), 5.95 (m, 1H), 4.98 (d, 1H), 4.75 (s, 2H), 4.70 (s, 1H), 4.60
(s, 1H), 4.08 (q, 2H), 1.22 (s, 3H).
[0411] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd16=8.3 min.
Example 17: Compound 17
##STR00069##
[0412] Step 1: Synthesis of
2-Fluoro-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroaniline
[0413] 2,3-Difluoro-6-nitroaniline (0.31 g, 1.8 mmole) was
dissolved in anhydrous dimethylsulfoxide (3 mL).
6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.50 g, 2.7
mmole) was added followed by triethylamine (0.84 mL) and solid
iodine (1 mg). The mixture was heated at reflux for 3 h. under
argon. The reaction was dissolved in ethyl acetate (50 mL) and
extracted with water (50 mL). The aqueous layer was extracted with
2.times.25 mL chloroform/isopropanol (7:3). The organic layers were
washed with 3.times.25 mL water and then brine (50 mL) and dried
over sodium sulfate. The oily solid was chromatographed on a silica
gel column (25 g) packed in hexanes. The column polarity was
increased to 50% ethyl acetate/hexanes over 8 CV, at 25 mL/min.
Fractions (22 mL each) containing the product were pooled and
stripped to give
2-fluoro-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroaniline
(0.4 g, 74% yield).
Step 2: Synthesis of ethyl
(2-amino-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carb-
amate (Compound 17)
[0414]
2-Fluoro-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroanilin-
e (0.388 g, 1.27 mmole) was dissolved in methanol (10 mL) and
tetrahydrofuran (10 mL). Zinc powder (415 mg, 6.35 mmole) was added
followed by ammonium chloride (340 mg, 6.35 mmole) in DI water (1
mL). The mixture was stirred under argon at ambient temperature for
2 h. and then cooled to 10.degree. C. in an ice bath. N,
N-diisopropylethylamine (0.565 mL, 3.24 mmole) was added, followed
by ethyl chloroformate dropwise (406 mg, 3.80 mmole) and the
reaction was stirred at ambient temperature for 18 h. It was
filtered and evaporated. The crude oil was dissolved in
dichloromethane (10 mL) and extracted with water (10 mL). The
aqueous layer was extracted with additional dichloromethane
(3.times.10 mL), the organic layers were pooled and evaporated to
dryness. It was chromatographed on a silica gel column (25g) packed
in chloroform. The column polarity was increased to 20% ethyl
acetate/chloroform over 11 CV, at 25 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(2-amino-3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carb-
amate (0.225 g, 51% yield).
[0415] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.
7.05 (m, 1H), 6.80-7.00 (m, 3H), 6.47 (t, 1H), 6.25 (br s, 1H),
4.25 (m, 4H), 3.52-4.15 (br s, 2H), 3.40 (m, 2H), 2.98 (m, 2H),
1.30 (t, 3H).
[0416] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd17=8.4 min.
Example 18: Compound 18
##STR00070##
[0417] Step 1: Synthesis of
2-Fluoro-6-nitro-3-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)a-
niline
[0418] 2,3-Difluoro-6-nitroaniline (0.238 g, 1.37 mmole) was
dissolved in anhydrous dimethylsulfoxide (6 mL).
7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
(0.487 g, 2.05 mmole) was added triethylamine (0.643 mL) and solid
iodine (1 mg). The mixture was heated at reflux for 12 h. under
argon. The reaction was dissolved in dichloromethane (10 mL) and
extracted with water (10 mL). The aqueous layer was washed with
dichloromethane (10 mL), organics pooled and washed with brine (5
mL) and then dried through a 1PS filter and evaporated to dryness.
The crude material was chromatographed on a silica gel column (10
g) packed in hexanes. The column polarity was increased to 100%
ethyl acetate over 12 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give
2-fluoro-6-nitro-3-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)a-
niline (0.388 g, 80% yield).
Step 2: Synthesis of Ethyl
(2-amino-3-fluoro-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-
phenyl)carbamate (Compound 18)
[0419]
2-Fluoro-6-nitro-3-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H-
)-yl)aniline (0.430 g, 1.21 mmole) was dissolved in methanol (4 mL)
and tetrahydrofuran (6 mL). Zinc powder (791 mg, 12.1 mmole) was
added followed by ammonium chloride (647 mg, 12.1 mmole) in DI
water (2 mL). The mixture was stirred under argon at ambient
temperature for 45 min. and then cooled in an ice bath. N,
N-diisopropylethylamine (0.421 mL, 2.42 mmole) was added, followed
by ethyl chloroformate dropwise (194 mg, 1.82 mmole) and the
reaction was stirred at ambient temperature for 45 min. It was
filtered and evaporated. The crude oil was dissolved in
dichloromethane (10 mL) and extracted with water (10 mL). The
aqueous layer was extracted with additional dichloromethane
(3.times.10 mL), the organic layers were pooled and evaporated to
dryness. It was chromatographed on a silica gel column (10g) packed
in chloroform. The column polarity was increased to 50% ethyl
acetate/chloroform over 9 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give of ethyl
(2-amino-3-fluoro-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-
phenyl)carbamate (0.150 g, 31% yield).
[0420] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.42 (d, 1H), 7.39 (s, 1H), 7.28 (d, 1H), 6.98 (d, 1H), 6.45 (t,
1H), 6.25 (br s, 1H), 4.32 (s, 2H), 4.25 (q, 2H), 3.92 (br s, 2H),
3.45 (t, 2H), 3.06 (t, 2H), 1.38 (t, 3H).
[0421] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd18=7.5 min.
Example 19: Compound 19
##STR00071##
[0422] Step 1: Synthesis of
2-Fluoro-6-nitro-3-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)a-
niline
[0423] 2,3-Difluoro-6-nitroaniline (0.238 g, 1.37 mmole) was
dissolved in anhydrous dimethylsulfoxide (6 mL).
6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
(0.49 g, 2.05 mmole) was added triethylamine (0.64 mL) and solid
iodine (1 mg). The mixture was heated at reflux for 2 h. under
argon. The reaction was dissolved in dichloromethane (10 mL) and
extracted with water (10 mL). The aqueous layer was washed with
dichloromethane (10 mL), organics pooled and washed with brine (5
mL) and then dried through a 1PS filter and evaporated to dryness.
The crude material was chromatographed on a silica gel column (10
g) packed in hexanes. The column polarity was increased to 100%
ethyl acetate over 12 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give
2-fluoro-6-nitro-3-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)a-
niline (0.420 g, 87% yield)
Step 2: Synthesis of ethyl
(2-amino-3-fluoro-4-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-
phenyl)carbamate (Compound 19)
[0424]
2-Fluoro-6-nitro-3-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H-
)-yl)aniline (0.420 g, 1.18 mmole) was dissolved in methanol (5 mL)
and tetrahydrofuran (5 mL). Zinc powder (0.693 g, 10.6 mmole) was
added followed by ammonium chloride (567 mg, 10.6 mmole) in DI
water (2 mL). The mixture was stirred under argon at ambient
temperature for 0.5 h. and then cooled in an ice bath. N,
N-diisopropylethylamine (0.423 mL, 2.43 mmole) was added, followed
by ethyl chloroformate dropwise (227 mg, 2.12 mmole) and the
reaction was stirred at ambient temperature for 1 h. The reaction
was filtered and evaporated. The crude oil was dissolved in ethyl
acetate (10 mL) and extracted with water (10 mL). the organic layer
was then dried through a 1PS filter and evaporated to dryness. It
was chromatographed on a silica gel column (10 g) packed in
chloroform. The column polarity was increased to 37% ethyl
acetate/chloroform over 15 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(2-amino-3-fluoro-4-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-
phenyl)carbamate (0.153 g, 33% yield).
[0425] NMR Spectroscopy: .sup.1H NMR (DMSO, 300 MHz): .delta. 8.60
(br s, 1H), 7.55 (d, 2H), 7.40 (d, 1H), 6.85 (d, 1H), 6.30 (t, 1H),
4.80 (s, 2H), 4.21 (s, 2H), 4.10 (q, 2H), 3.30 (m, 2H), 2.99 (m,
2H), 1.32 (t, 3H).
[0426] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd19=11.4 min.
Example 20: Compound 20
##STR00072##
[0427] Step 1: Synthesis of
2-Fluoro-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroaniline
[0428] 2,3-Difluoro-6-nitroaniline (0.310 g, 1.78 mmole) was
dissolved in anhydrous dimethylsulfoxide (6 mL).
7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.50 g, 2.66
mmole) was added triethylamine (0.840 mL) and solid iodine (1 mg).
The mixture was heated at reflux for 12 h. under argon. The
reaction was dissolved in dichloromethane (10 mL) and extracted
with water (10 mL). The aqueous layer was washed with
dichloromethane (10 mL), organics pooled and washed with brine (5
mL) and then dried through a 1PS filter and evaporated to dryness.
The crude material was chromatographed on a silica gel column (10
g) packed in hexanes. The column polarity was increased to 100%
ethyl acetate over 12 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give
2-fluoro-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroaniline
(0.500 g, 92% yield).
Step 2: Synthesis of ethyl
(2-amino-3-fluoro-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carb-
amate (Compound 20)
[0429]
2-Fluoro-3-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroanilin-
e (0.500 g, 1.64 mmole) was dissolved in methanol (5 mL) and
tetrahydrofuran (5 mL). Zinc powder (1.07 g, 16.4 mmole) was added
followed by ammonium chloride (877 mg, 16.4 mmole) in DI water (2
mL). The mixture was stirred under argon at ambient temperature for
3.5 h. and then cooled in an ice bath. N, N-diisopropylethylamine
(0.666 mL, 3.77 mmole) was added, followed by ethyl chloroformate
dropwise (298 mg, 2.80 mmole) and the reaction was stirred at
ambient temperature for 12 h. The reaction was cooled in an ice
bath. N, N-diisopropylethylamine (0.350 mL) was added, followed by
ethyl chloroformate dropwise (162 mg,). The reaction was stirred at
ambient temperature for 1 h. It was filtered and evaporated. The
crude oil was dissolved in ethyl acetate (10 mL) and extracted with
water (10 mL). the organic layer was then dried through a 1PS
filter and evaporated to dryness. It was chromatographed on a
silica gel column (10g) packed in chloroform. The column polarity
was increased to 50% ethyl acetate/chloroform over 9 CV, at 12
mL/min. Fractions (22 mL each) containing the product were pooled
and stripped to give of ethyl
(2-amino-3-fluoro-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carb-
amate (0.150 g, 26% yield).
[0430] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.
7.10 (m, 1H), 6.80-7.00 (m, 3H), 6.48 (t, 1H), 6.25 (br s, 1H),
4.25 (m, 4H), 3.43 (m, 2H), 2.92 (t, 3H), 1.32 (t, 3H).
[0431] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd20=8.9 min.
Example 21: Compound 21
##STR00073##
[0432] Step 1: Synthesis of
5-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitroaniline
[0433] 5-Fluoro-2-nitroaniline (0.278 g, 1.78 mmole) was dissolved
in anhydrous dimethylsulfoxide (6 mL).
6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.50 g, 2.7
mmole) was added triethylamine (0.837 mL) and solid iodine (1 mg).
The mixture was heated at reflux for 1.5 h. under argon. The
reaction was dissolved in ethyl acetate (10 mL) and extracted with
water (10 mL). The organic layer was washed with 3.times.30 mL
water and then dried through a 1PS filter and evaporated to
dryness. The crude material was chromatographed on a silica gel
column (10 g) packed in chloroform. The column polarity was
increased to 15% ethyl acetate/chloroform over 10 CV, at 12 mL/min.
Fractions (22 mL each) containing the product were pooled and
stripped to give
5-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitroaniline (0.43
g, 72% yield).
Step 2: Synthesis of ethyl
(2-amino-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate
(Compound 21)
[0434] 5-(6-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitroaniline
(0.432 g, 1.28 mmole) was dissolved in methanol (4 mL) and dioxane
(4 mL). Zinc powder (837 mg, 12.8 mmole) was added followed by
ammonium chloride (685 mg, 12.8 mmole) in DI water (2.0 mL). The
mixture was stirred under argon at ambient temperature for 30 min.
The mixture was cooled in an ice bath. N, N-diisopropylethylamine
(0.556 mL, 3.20 mmole) was added, followed by ethyl chloroformate,
dropwise (274 mg, 2.56 mmole) and the reaction was stirred at
ambient temperature for 18 h. To the reaction was added ethyl
acetate (10 mL) and extracted with water (10 mL). The organic layer
was dried through a 1PS filter and evaporated to dryness. It was
chromatographed on a silica gel column (10 g) packed in chloroform.
The column polarity was increased to 100% ethyl acetate/chloroform
over 12 CV, at 12 mL/min. Fractions (22 mL each) containing the
product were pooled and stripped to give ethyl
(2-amino-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate
(0.065 g, 15.4% yield).
[0435] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.08 (m, 2H), 6.90 (m, 2H), 6.42 (m, 2H), 6.15 (br s, 1H), 4.36 (s,
2H), 4.22 (q, 2H), 2.50 (m, 2H), 2.98 (m, 2H), 1.32 (t, 3H).
[0436] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd21=5.4 min.
Example 22: Compound 22
##STR00074##
[0437] Step 1: Synthesis of
2-Nitro-5-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)aniline
[0438] 5-Fluoro-2-nitroaniline (0.219 g, 1.40 mmole) was dissolved
in anhydrous dimethylsulfoxide (5 mL).
7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
(0.500 g, 2.10 mmole) was added triethylamine (0.660 mL) and solid
iodine (1 mg) were added and the mixture was heated at reflux for
an additional 3 h. under argon. The reaction was diluted with
dichloromethane (10 mL) and extracted with water (10 mL). The
organic layer was washed with 3.times.30 mL water and then dried
through a 1PS filter and evaporated to dryness. The crude material
was chromatographed on a silica gel column (10 g) packed in
hexanes. The column polarity was increased to 100% ethyl
acetate/chloroform over 12 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give
2-nitro-5-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)aniline
(0.410 g, 76% yield).
Step 2: Synthesis of ethyl
(2-amino-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ca-
rbamate (Compound 22)
[0439]
2-Nitro-5-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)anil-
ine (0.380 g, 1.13 mmole) was dissolved in methanol (4 mL) and
tetrahydrofuran (6 mL). Zinc powder (737 mg, 11.3 mmole) was added
followed by ammonium chloride (604 mg, 11.3 mmole) in DI water (2
mL). The mixture was stirred under argon at ambient temperature for
20 min. and then cooled to 10.degree. C. in an ice bath. N,
N-diisopropylethylamine (0.393 mL, 2.26 mmole) was added, followed
by ethyl chloroformate dropwise (181 mg, 1.70 mmole) and the
reaction was stirred at ambient temperature for 45 min. It was
filtered and evaporated. The crude oil was dissolved in
dichloromethane (10 mL) and extracted with water (10 mL). The
aqueous layer was extracted with additional dichloromethane
(3.times.10 mL), the organic layers were pooled and evaporated to
dryness. It was chromatographed on a silica gel column (10g) packed
in chloroform. The column polarity was increased to 50% ethyl
acetate/chloroform over 9 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(2-amino-4-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ca-
rbamate (0.112 g, 26% yield).
[0440] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.43 (m, 2H), 7.28 (d, 1H), 7.08 (d, 1H), 6.39-6.44 (m, 2H), 6.17
(br s, 1H), 4.42 (s, 2H), 4.22 (q, 2H), 3.90 (br s, 2H), 3.55 (t,
2H), 3.02 (t, 2H), 1.32 (t, 3H).
[0441] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd22=11.3 min.
Example 23: Compound 23
##STR00075##
[0442] Step 1: Synthesis of
2-Nitro-5-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)aniline
[0443] 5-Fluoro-2-nitroaniline (0.219 g, 1.40 mmole) was dissolved
in anhydrous dimethylsulfoxide (6 mL).
6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
(0.50 g, 2.1 mmole) was added triethylamine (0.66 mL) and solid
iodine (1 mg). The mixture was heated at reflux for 5 h. under
argon. The reaction was dissolved in dichloromethane (10 mL) and
extracted with water (10 mL). The organic layer was washed with
3.times.30 mL water and then dried through a 1PS filter and
evaporated to dryness. The crude material was chromatographed on a
silica gel column (10 g) packed in hexanes. The column polarity was
increased to 100% ethyl acetate over 10 CV, at 12 mL/min. Fractions
(22 mL each) containing the product were pooled and stripped to
give
2-nitro-5-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)aniline
(0.23 g, 42% yield).
Step 2: Synthesis of ethyl
(2-amino-4-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ca-
rbamate (Compound 23)
[0444]
2-Nitro-5-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)anil-
ine (0.230 g, 0.682 mmole) was dissolved in methanol (5 mL) and
tetrahydrofuran (5 mL). Zinc powder (0.396 g, 6.06 mmole) was added
followed by ammonium chloride (324 mg, 6.06 mmole) in DI water (2
mL). The mixture was stirred under argon at ambient temperature for
0.5 h. and then cooled in an ice bath. N, N-diisopropylethylamine
(0.242 mL, 1.39 mmole) was added, followed by ethyl chloroformate
dropwise (313 mg, 1.23 mmole) and the reaction was stirred at
ambient temperature for 1 h. The reaction was filtered and
evaporated. The crude oil was dissolved in ethyl acetate (10 mL)
and extracted with water (10 mL). the organic layer was then dried
through a 1PS filter and evaporated to dryness. It was
chromatographed on a silica gel column (10 g) packed in chloroform.
The column polarity was increased to 50% ethyl acetate/chloroform
over 20 CV, at 12 mL/min. Fractions (22 mL each) containing the
product were pooled and stripped to give ethyl
(2-amino-4-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)ca-
rbamate (0.10 g, 39% yield).
[0445] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.
7.45 (m, 2H), 7.25 (d, 1H), 7.10 (d, 1H), 6.43 (m, 2H), 6.18 (br s,
1H), 4.42 (s, 2H), 4.22 (q, 2H), 3.58 (m, 2H), 3.05 (m, 2H), 1.30
(t, 3H).
[0446] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd23=7.6 min.
Example 24: Compound 24
##STR00076##
[0447] Step 1: Synthesis of
5-(7-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitroaniline
[0448] 5-Fluoro-2-nitroaniline (0.278 g, 1.78 mmole) was dissolved
in anhydrous dimethylsulfoxide (6 mL).
6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.50 g, 2.7
mmole) was added triethylamine (0.837 mL) and solid iodine (1 mg).
The mixture was heated at reflux for 1.5 h. under argon. The
reaction was dissolved in ethyl acetate (10 mL) and extracted with
water (10 mL). The organic layer was washed with 3.times.30 mL
water and then dried through a 1PS filter and evaporated to
dryness. The crude material was chromatographed on a silica gel
column (10 g) packed in chloroform. The column polarity was
increased to 15% ethyl acetate/chloroform over 10 CV, at 12 mL/min.
Fractions (22 mL each) containing the product were pooled and
stripped to give
5-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitroaniline (0.43
g, 84% yield).
Step 2: Synthesis of ethyl
(2-amino-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate
(Compound 24)
[0449] 5-(7-Fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-nitroaniline
(0.430 g, 1.49 mmole) was dissolved in methanol (15 mL) and
tetrahydrofuran (15 mL). Zinc powder (0.979 g, 15.0 mmole) was
added followed by ammonium chloride (800 mg, 15.0 mmole) in DI
water (2 mL). The mixture was stirred under argon at ambient
temperature for 4 h. and then cooled in an ice bath. N,
N-diisopropylethylamine (0.593 mL, 3.43 mmole) was added, followed
by ethyl chloroformate dropwise (271 mg, 2.53 mmole) and the
reaction was stirred at ambient temperature for 12 h. The reaction
was filtered and evaporated. The crude oil was dissolved in ethyl
acetate (10 mL) and extracted with water (10 mL). the organic layer
was then dried through a 1PS filter and evaporated to dryness. It
was chromatographed on a silica gel column (10g) packed in
chloroform. The column polarity was increased to 20% ethyl
acetate/chloroform over 8 CV, at 12 mL/min. Fractions (22 mL each)
containing the product were pooled and stripped to give ethyl
(2-amino-4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)carbamate
(0.028 g, 6% yield).
[0450] NMR Spectroscopy: .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.
7.10 (m, 2H), 6.80-6.98 (m, 2H), 6.48 (m, 2H), 6.15 (br s, 1H),
4.38 (s, 2H), 4.22 (q, 2H), 2.55 (m, 2H), 2.98 (t, 2H), 1.30 (m,
4H).
[0451] HPLC: Grace Alltima C.sub.18 reverse phase HPLC column
(250.times.4.6 mm); Mobile Phase A: 0.1% TFA in water; Mobile Phase
B: 0.1% TFA in 100% acetonitrile; Flow rate: 1 mL/min; Temperature:
30.degree. C.; Injection Volume: 0.1-5 .mu.L; Detection
Wavelengths: 215-260 nm; Gradient: 0 min (60% A, 40% B), 15 min
(10% A, 90% B), 18 min (10% A, 90% B), 18.1 min (60% A, 40% B), 20
min (60% A, 40% B). t.sub.Cmpd24=5.7 min.
Example 25: Compound 27
##STR00077##
[0453] Under nitrogen, to
N-(4-bromo-3-fluoro-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide
(316 mg, 1.00 mmol, 1.00 equiv) in toluene (5 mL) at 23.degree. C.
were added 6-fluoro-1,2,3,4-tetrahydroisoquinoline (166 mg, 1.10
mmol, 1.10 equiv), DavePhos (47 mg, 0.12 mmol, 12 mol %),
Pd.sub.2(dba).sub.3 (37 mg, 0.040 mmol, 4.0 mol %), and t-BuOK (168
mg, 1.50 mmol, 1.50 equiv). After stirring for 24 hr at 90.degree.
C., the reaction mixture was concentrated in vacuo and the residue
was purified by column chromatography on silica gel eluting with
hexanes/EtOAc to afford 70 mg the title compound (18% yield).
[0454] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.02 (dd, J=9.0, 8.7 Hz, 1H), 6.89-6.77
(m, 3H), 6.61 (br s, 1H), 4.27 (br s, 2H), 3.43 (br s, 2H), 3.03
(br s, 2H), 2.24 (s, 2H), 2.17-2.10 (m, 6H), 1.08 (s, 9H).
Example 26: Compound 28
##STR00078##
[0456] Under nitrogen, to
N-(4-bromo-3-fluoro-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide
(316 mg, 1.00 mmol, 1.00 equiv) in toluene (5 mL) at 23.degree. C.
were added N-(4-fluorobenzyl)prop-2-yn-1-amine (180 mg, 1.10 mmol,
1.10 equiv), DavePhos (47 mg, 0.12 mmol, 12 mol %),
Pd.sub.2(dba).sub.3 (37 mg, 0.040 mmol, 4.0 mol %), and t-BuOK (168
mg, 1.50 mmol, 1.50 equiv). After stirring for 2 d at 110.degree.
C., the reaction mixture was concentrated in vacuo and the residue
was purified by column chromatography on silica gel eluting with
hexanes/EtOAc to afford 25 mg the title compound (6% yield).
[0457] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.35 (dd, J=8.7, 5.7 Hz, 2H), 6.96 (dd,
J=9.0, 8.7 Hz, 2H), 7.08 (d, J=7.5 Hz, 1H), 6.96 (br s, 1H), 3.88
(s, 2H), 3.58 (s, 2H), 2.23 (s, 1H), 2.12-2.08 (m, 8H), 1.10 (s,
9H).
Example 27: Compound 29
##STR00079##
[0458] Step 1: Synthesis of
2-Fluoro-N1-[(4-fluorophenyl)methyl]-4-nitro-benzene-1,3-diamine
##STR00080##
[0460] Under air, to 2,3-difluoro-6-nitroaniline (335 g, 1.92 mol,
1.00 equiv) in DMSO (400 mL) at 23.degree. C. was added
4-fluorobenzylamine (395 mL, 3.46 mol, 1.80 equiv), Et.sub.3N (642
mL, 4.61 mol, 2.40 equiv), and 12 (243 mg, 0.960 mmol, 0.0500 mol
%). After stirring at 100.degree. C. with a reflux condenser for 3
hr, the reaction mixture was cooled to 23.degree. C. and was poured
into water (2 L). The resulting suspension was filtered and the
solids were washed with water (3.times.800 mL). The solids were
collected and dried inside an oven set to 110.degree. C. for 8 hr
to afford 530 g of the title compound as yellow solids (99%
yield).
[0461] NMR Spectroscopy: .sup.1H NMR (400 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.87 (dd, J=9.6, 1.6 Hz, 1H), 7.31-7.28
(m, 2H), 7.08-7.03 (m, 2H), 6.11-6.03 (m, 3H), 4.82 (br s, 1H),
4.44 (d, J=5.2 Hz, 2H).
Step 2: Synthesis of tert-Butyl
N-[3-[bis(tert-butoxycarbonyl)amino]-2-fluoro-4-nitro-phenyl]-N-[(4-fluor-
ophenyl)-methyl]carbamate
##STR00081##
[0463] Under nitrogen, to
2-fluoro-N1-[(4-fluorophenyl)methyl]-4-nitro-benzene-1,3-diamine
(5.58 g, 20.0 mmol, 1.00 equiv) in THF (200 mL) at 23.degree. C.
were added DMAP (244 mg, 2.00 mmol, 10.0 mol %), NaH (1.44 g, 60.0
mmol, 3.00 equiv), and Boc.sub.2O (13.8 mL, 60.0 mmol, 3.00 equiv).
After stirring for 1.5 hr at 60.degree. C., the reaction mixture
was cooled to 23.degree. C. and water (200 mL) was added dropwise.
The phases were separated and the aqueous phase was extracted with
EtOAc (2.times.200 mL). The combined organic phases were washed
with brine (200 mL) and dried (MgSO.sub.4). The filtrate was
concentrated in vacuo and the residue was purified by column
chromatography on silica gel eluting with hexanes/EtOAc to afford
8.35 g of the title compound (72% yield).
[0464] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.81 (dd, J=9.0, 1.8 Hz, 1H), 7.24-7.15
(m, 3H), 6.95 (dd, J=8.4, 8.4 Hz, 2H), 4.80 (s, 2H), 1.41 (s, 9H),
1.36 (s, 18H).
Step 3: Synthesis of tert-Butyl
N-[4-amino-3-[bis(tert-butoxycarbonyl)amino]-2-fluoro-phenyl]-N-[(4-fluor-
ophenyl)methyl]carbamate
##STR00082##
[0466] Under air, to tert-butyl
N-[3-[bis(tert-butoxycarbonyl)amino]-2-fluoro-4-nitro-phenyl]-N-[(4-fluor-
ophenyl)methyl]carbamate (8.35 g, 14.4 mmol, 1.00 equiv) in MeOH
(144 mL) at 23.degree. C. were added Zn powder (4.71 g, 72.1 mmol,
5.00 equiv) and NH.sub.4C.sub.1 (3.85 g, 72.1 mmol, 5.00 equiv) in
H.sub.2O (20 mL). After stirring for 3 hr at 23.degree. C., the
reaction mixture was filtered through a pad of celite. The filtrate
was concentrated in vacuo, and H.sub.2O (200 mL) and EtOAc (200 mL)
were added to the residue. The phases were separated and the
aqueous phase was extracted with EtOAc (2.times.200 mL). The
combined organic phases were washed with brine (200 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by column chromatography on silica gel eluting
with hexanes/EtOAc to afford 6.00 g of the title compound (76%
yield).
[0467] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.17 (dd, J=8.4, 5.4 Hz, 2H), 6.92 (dd,
J=8.4, 8.4 Hz, 2H), 6.69 (dd, J=5.1, 5.1 Hz, 1H), 6.38 (d, J=5.1
Hz, 1H), 4.66 (br s, 2H), 1.38 (s, 27H).
Step 4: Synthesis of tert-Butyl
N-[3-[bis(tert-butoxycarbonyl)amino]-4-(3,
3-dimethylbutanoylamino)-2-fluoro-phenyl]-N-[(4-fluorophenyl)methyl]carba-
mate
##STR00083##
[0469] Under nitrogen, to tert-butyl
N-[4-amino-3-[bis(tert-butoxycarbonyl)amino]-2-fluoro-phenyl]-N-[(4-fluor-
ophenyl)methyl]carbamate (5.90 g, 10.7 mmol, 1.00 equiv) in DCM (26
mL) at 0.degree. C. were added DIPEA (2.06 mL, 11.8 mmol, 1.10
equiv) and tert-butylacetyl chloride (1.65 mL, 11.8 mmol, 1.10
equiv). After stirring for 3 hr at 23.degree. C., the reaction
mixture was concentrated in vacuo, and the residue was purified by
column chromatography on silica gel eluting with hexanes/EtOAc to
afford 4.30 g of the title compound (62% yield).
[0470] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.98 (d, J=9.0 Hz, 1H), 7.21-6.90 (m, 6H),
4.71 (s, 2H), 2.18 (s, 2H), 1.39 (s, 9H), 1.34 (s, 18H), 1.06 (s,
9H).
Step 5: Synthesis of
N-[2-amino-3-fluoro-4-[(4-fluorophenyl)methylamino]phenyl]-3,
3-dimethyl-butanamide (Compound 29)
##STR00084##
[0472] Under nitrogen, to tert-butyl
N-[3-[bis(tert-butoxycarbonyl)amino]-4-(3,3-dimethylbutanoylamino)-2-fluo-
ro-phenyl]-N-[(4-fluorophenyl)methyl]carbamate (1.30 g, 2.01 mmol,
1.00 equiv) in DCM (10 mL) at 23.degree. C. was added HCl (2.0 M in
Et.sub.2O, 10.1 mL, 20.1 mmol, 10.0 equiv). After stirring for 15
hr at 23.degree. C., NaHCO.sub.3 (aq) (100 mL) was added to the
reaction mixture. The phases were separated and the aqueous phase
was extracted with EtOAc (2.times.100 mL). The combined organic
phases were washed with brine (100 mL) and dried (MgSO.sub.4). The
filtrate was concentrated in vacuo and the residue was purified by
column chromatography on silica gel eluting with hexanes/EtOAc to
afford 690 mg of the title compound (99% yield).
[0473] NMR Spectroscopy: .sup.1H NMR (300 MHz, DMSO-d6, 23.degree.
C., .delta.): 9.00 (s, 1H), 7.36 (dd, J=8.4, 5.4 Hz, 2H), 7.11 (dd,
J=8.4, 8.4 Hz, 2H), 6.56 (d, J=8.7 Hz, 1H), 5.92 (dd, J=6.0, 6.0
Hz, 1H), 5.83 (dd, J=8.7, 8.7 Hz, 1H), 4.54 (s, 2H), 4.27 (d, J=6.0
Hz, 2H), 2.09 (s, 2H), 1.00 (s, 9H).
Example 28: Compound 30
##STR00085##
[0474] Step 1: Synthesis of
1-Bis(tert-butoxylcarbonyl)amino-2,3-difluoro-6-nitrobenzene
##STR00086##
[0476] Under nitrogen, to 2,3-difluoro-6-nitroaniline (3.48 g, 20.0
mmol, 1.00 equiv) in THF (100 mL) at 23.degree. C. were added DMAP
(122 mg, 1.00 mmol, 5.00 mol %), NaH (1.44 g, 60.0 mmol, 3.00
equiv), and Boc.sub.2O (13.8 mL, 60 mmol, 3.00 equiv). After
stirring for 1 h at 60.degree. C., the reaction mixture was cooled
to 23.degree. C. and water (100 mL) was added. The solution was
then neutralized with 1N HCl (aq) and was extracted with EtOAc
(2.times.100 mL). The combined organic phases were washed with
brine (100 mL) and dried (MgSO.sub.4). The filtrate was
concentrated in vacuo and the residue was purified by
chromatography on silica gel eluting with hexanes/EtOAc to afford
6.20 g of the title compound (83% yield).
[0477] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.98-7.90 (m, 1H), 7.37-7.27 (m, 1H), 1.40
(s, 18H).
Step 2: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[2-fluoro-3-[(4-fluorophenyl)methylamino]-6-nitro-
-phenyl]carbamate
##STR00087##
[0479] Under nitrogen, to
1-bis(tert-butoxylcarbonyl)amino-2,3-difluoro-6-nitrobenzene (1.87
g, 5.00 mmol, 1.00 equiv) in DMSO (5 mL) at 23.degree. C. were
added 4-fluorobenzylamine (1.03 mL, 9.00 mmol, 1.80 equiv) and
Et.sub.3N (0.837 mL, 6.00 mmol, 1.20 equiv). After stirring for 1.5
hr at 23.degree. C., the reaction mixture was cooled to 23.degree.
C. and water (10 mL) was added. The solution was then neutralized
with 1N HCl (aq) and was extracted with EtOAc (2.times.10 mL). The
combined organic phases were washed with brine (10 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by chromatography on silica gel eluting with
hexanes/EtOAc to afford 2.00 g of the title compound (83%
yield).
[0480] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.97 (d, J=9.0 Hz, 1H), 7.31 (dd, J=8.7,
5.7 Hz, 2H), 7.07 (dd, J=8.7, 8.7 Hz, 2H), 6.59 (dd, J=8.4, 8.4 Hz,
1H), 4.98 (br s, 1H), 4.44 (br s, 2H), 1.42 (s, 18H).
Step 3: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[(4-flu-
orophenyl)methyl-prop-2-ynyl-amino]phenyl]carbamate
##STR00088##
[0482] Under nitrogen, to tert-butyl
N-tert-butoxycarbonyl-N-[2-fluoro-3-[(4-fluorophenyl)-methylamino]-6-nitr-
o-phenyl]carbamate (2.00 g, 4.17 mmol, 1.00 equiv) in THF (4.2 mL)
at 23.degree. C. were added propargyl bromide (0.948 mL, 12.5 mmol,
3.00 equiv) and NaH (300 mg, 12.5 mmol, 3.00 equiv). After stirring
for 1 hr at 23.degree. C., the reaction mixture was cooled to
0.degree. C. and water (10 mL) was added. The reaction mixture was
extracted with EtOAc (2.times.10 mL). The combined organic phases
were washed with brine (10 mL) and dried (MgSO.sub.4). The filtrate
was concentrated in vacuo to afford a crude alkylation product,
which was used in the next step without further purification.
[0483] Under air, to the crude product obtained above in MeOH (42
mL) at 23.degree. C. were added Zn powder (1.36 g, 20.9 mmol, 5.00
equiv) and NH.sub.4C.sub.1 (1.12 g, 20.9 mmol, 5.00 equiv) in
H.sub.2O (5 mL). After stirring for 3 hr at 23.degree. C., the
reaction mixture was filtered through a pad of celite. The filtrate
was concentrated in vacuo, and H.sub.2O (50 mL) and EtOAc (50 mL)
were added to the residue. The phases were separated and the
aqueous phase was extracted with EtOAc (2.times.50 mL). The
combined organic phases were washed with brine (100 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo to afford a
crude reduction product, which was used in the next step without
further purification.
[0484] Under nitrogen, to the crude reduction product obtained
above in MeCN (4.2 mL) at 23.degree. C. were added DIPEA (1.31 mL,
7.51 mmol, 1.80 equiv) and tert-butylacetyl chloride (1.05 mL, 7.51
mmol, 1.80 equiv). After stirring for 1 hr at 23.degree. C., the
reaction mixture was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel eluting with
hexanes/EtOAc to afford 1.90 g of the title compound (78% yield
over 3 steps).
[0485] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.90 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.7,
5.7 Hz, 2H), 7.16 (dd, J=9.0, 9.0 Hz, 1H), 7.06 (s, 1H), 6.99 (dd,
J=8.7, 8.4 Hz, 2H), 4.27 (s, 2H), 3.76 (d, J=2.4 Hz, 2H), 2.25 (t,
J=2.4 Hz, 1H), 2.19 (s, 2H), 1.40 (s, 18H), 1.07 (s, 9H).
Step 4: Synthesis of
N-(2-amino-3-fluoro-4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)phenyl)-3,3--
dimethylbutanamide (Compound 30)
##STR00089##
[0487] Under nitrogen, to tert-butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[(4-flu-
orophenyl)methyl-prop-2-ynyl-amino]phenyl]carbamate (1.90 g, 3.24
mmol, 1.00 equiv) in DCM (8 mL) at 23.degree. C. was added HCl (2.0
M in Et.sub.2O, 16.2 mL, 20.1 mmol, 10.0 equiv). After stirring for
15 hr at 23.degree. C., NaHCO.sub.3 (aq) (10 mL) was added to the
reaction mixture. The phases were separated and the aqueous phase
was extracted with EtOAc (2.times.10 mL). The combined organic
phases were washed with brine (10 mL) and dried (MgSO.sub.4). The
filtrate was concentrated in vacuo to afford 1.20 g of the title
compound (96% yield).
[0488] NMR Spectroscopy: .sup.1H NMR (300 MHz, methanol-d4,
23.degree. C., .delta.): 7.34 (dd, J=8.7, 5.7 Hz, 2H), 6.96 (dd,
J=9.0, 9.0 Hz, 2H), 6.71 (d, J=8.7 Hz, 1H), 6.50 (dd, J=9.0, 8.7
Hz, 1H), 4.22 (s, 2H), 3.69 (d, J=2.4 Hz, 2H), 2.56 (t, J=2.4 Hz,
1H), 2.19 (s, 2H), 1.07 (s, 9H).
Example 29: Compound 31
##STR00090##
[0489] Step 1: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[2-fluoro-6-nitro-3-[[4-(trifluoromethyl)phenyl]--
methylamino]phenyl]carbamate
##STR00091##
[0491] Under nitrogen, to
1-bis(tert-butoxylcarbonyl)amino-2,3-difluoro-6-nitrobenzene (1.87
g, 5.00 mmol, 1.00 equiv) in DMSO (5 mL) at 23.degree. C. were
added 4-(trifluoromethyl)benzylamine (1.28 mL, 9.00 mmol, 1.80
equiv) and Et.sub.3N (0.837 mL, 6.00 mmol, 1.20 equiv). After
stirring for 1.5 hr at 23.degree. C., the reaction mixture was
cooled to 23.degree. C. and water (10 mL) was added. The solution
was then neutralized with 1N HCl (aq) and was extracted with EtOAc
(2.times.10 mL). The combined organic phases were washed with brine
(10 mL) and dried (MgSO.sub.4). The filtrate was concentrated in
vacuo and the residue was purified by chromatography on silica gel
eluting with hexanes/EtOAc to afford 1.90 g of the title compound
(72% yield).
[0492] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.95 (d, J=9.0 Hz, 1H), 7.63 (d, J=7.8 Hz,
2H), 7.48 (d, J=7.8 Hz, 2H), 6.54 (dd, J=8.4, 8.4 Hz, 1H), 5.08 (br
s, 1H), 4.56 (br s, 2H), 1.41 (s, 18H).
Step 2: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[prop-2-
-ynyl-[[4-(trifluoromethyl)phenyl]methyl]amino]phenyl]carbamate
##STR00092##
[0494] Under nitrogen, to tert-butyl
N-tert-butoxycarbonyl-N-[2-fluoro-6-nitro-3-[[4-(trifluoromethyl)phenyl]m-
ethylamino]phenyl]carbamate (1.90 g, 3.59 mmol, 1.00 equiv) in THF
(3.6 mL) at 23.degree. C. were added propargyl bromide (0.816 mL,
10.8 mmol, 3.00 equiv) and NaH (258 mg, 10.8 mmol, 3.00 equiv).
After stirring for 1 hr at 23.degree. C., the reaction mixture was
cooled to 0.degree. C. and water (10 mL) was added. The reaction
mixture was extracted with EtOAc (2.times.10 mL). The combined
organic phases were washed with brine (10 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo to afford a
crude alkylation product, which was used in the next step without
further purification.
[0495] Under air, to the crude product obtained above in MeOH (36
mL) at 23.degree. C. were added Zn powder (1.17 g, 18.0 mmol, 5.00
equiv) and NH.sub.4C.sub.1 (960 mg, 18.0 mmol, 5.00 equiv) in
H.sub.2O (5 mL). After stirring for 3 hr at 23.degree. C., the
reaction mixture was filtered through a pad of celite. The filtrate
was concentrated in vacuo, and H.sub.2O (50 mL) and EtOAc (50 mL)
were added to the residue. The phases were separated and the
aqueous phase was extracted with EtOAc (2.times.50 mL). The
combined organic phases were washed with brine (100 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo to afford a
crude reduction product, which was used in the next step without
further purification.
[0496] Under nitrogen, to the crude reduction product obtained
above in MeCN (3.6 mL) at 23.degree. C. were added DIPEA (1.13 mL,
6.46 mmol, 1.80 equiv) and tert-butylacetyl chloride (0.902 mL,
6.46 mmol, 1.80 equiv). After stirring for 1 hr at 23.degree. C.,
the reaction mixture was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel eluting with
hexanes/EtOAc to afford 1.90 g of the title compound (83% yield
over 3 steps).
[0497] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.91 (d, J=8.7 Hz, 1H), 7.62-7.50 (m, 4H),
7.15 (dd, J=9.0, 9.0 Hz, 1H), 7.07 (s, 1H), 4.36 (s, 2H), 3.73 (d,
J=2.4 Hz, 2H), 2.25 (t, J=2.4 Hz, 1H), 2.19 (s, 2H), 1.40 (s, 18H),
1.07 (s, 9H).
Step 3: Synthesis of
N-[2-amino-3-fluoro-4-[prop-2-ynyl-[[4-(trifluoromethyl)phenyl]methyl]ami-
no]phenyl]-3,3-dimethyl-butanamide (Compound 31)
##STR00093##
[0499] Under nitrogen, to tert-butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[prop-2-
-ynyl-[[4-(trifluoromethyl)phenyl]methyl]amino]phenyl]carbamate
(1.90 g, 2.99 mmol, 1.00 equiv) in DCM (7.5 mL) at 23.degree. C.
was added HCl (2.0 M in Et.sub.2O, 15.0 mL, 29.9 mmol, 10.0 equiv).
After stirring for 15 hr at 23.degree. C., NaHCO.sub.3 (aq) (10 mL)
was added to the reaction mixture. The phases were separated and
the aqueous phase was extracted with EtOAc (2.times.10 mL). The
combined organic phases were washed with brine (10 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by chromatography on silica gel eluting with
hexanes/EtOAc to afford 600 mg of the title compound (46%
yield).
[0500] NMR Spectroscopy: .sup.1H NMR (300 MHz, methanol-d4,
23.degree. C., .delta.): 7.58-7.50 (m, 4H), 6.70 (d, J=9.0 Hz, 1H),
6.50 (dd, J=9.0, 8.7 Hz, 1H), 4.35 (s, 2H), 3.76 (d, J=2.4 Hz, 2H),
2.59 (t, J=2.4 Hz, 1H), 2.20 (s, 2H), 1.03 (s, 9H).
Example 30: Compound 32
##STR00094##
[0501] Step 1: Synthesis of
2-Fluoro-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroaniline
##STR00095##
[0503] Under nitrogen, to 2,3-difluoro-6-nitro-aniline (1.74 g,
10.0 mmol, 1.00 equiv) in DMSO (10 mL) at 23.degree. C. were added
N-[(4-fluoro-2-methyl-phenyl)methyl]ethanamine (1.67 g, 10.0 mmol,
1.00 equiv) and Et.sub.3N (1.67 mL, 12.0 mmol, 1.20 equiv). After
stirring for 1 hr at 100.degree. C., the reaction mixture was
cooled to 23.degree. C. and water (100 mL) was added. The solution
was then neutralized with 1N HCl (aq) and was extracted with EtOAc
(2.times.100 mL). The combined organic phases were washed with
brine (100 mL) and dried (MgSO.sub.4). The filtrate was
concentrated in vacuo and the residue was purified by
chromatography on silica gel eluting with hexanes/EtOAc to afford
1.38 g of the title compound (45% yield).
[0504] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.87 (d, J=9.0 Hz, 1H), 7.08 (dd, J=7.8
Hz, 7.8 Hz, 1H), 6.95-6.85 (m, 2H), 6.33 (dd, J=8.4, 8.4 Hz, 1H),
4.49 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.99 (t, J=6.0 Hz, 2H).
Step 2: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[3-[ethyl-[(4-fluoro-2-methyl-phenyl)methyl]amino-
]-2-fluoro-6-nitro-phenyl]carbamate
##STR00096##
[0506] Under nitrogen, to
2-fluoro-3-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-nitroaniline
(1.38 g, 4.29 mmol, 1.00 equiv) in THF (21 mL) at 23.degree. C.
were added DMAP (26.2 mg, 0.214 mmol, 5.00 mol %), NaH (309 mg,
12.9 mmol, 3.00 equiv), and Boc.sub.2O (2.96 mL, 12.9 mmol, 3.00
equiv). After stirring for 1 h at 60.degree. C., the reaction
mixture was cooled to 23.degree. C. and water (50 mL) was added.
The solution was then neutralized with 1N HCl (aq) and was
extracted with EtOAc (2.times.50 mL). The combined organic phases
were washed with brine (100 mL) and dried (MgSO.sub.4). The
filtrate was concentrated in vacuo and the residue was purified by
chromatography on silica gel eluting with hexanes/EtOAc to afford
2.17 g of the title compound (97% yield).
[0507] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.96 (d, J=9.0 Hz, 1H), 7.10 (dd, J=7.8
Hz, 7.8 Hz, 1H), 6.95-6.83 (m, 3H), 4.46 (s, 2H), 3.64 (t, J=6.0
Hz, 2H), 2.99 (t, J=6.0 Hz, 2H), 1.41 (s, 18H).
Step 3: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-(6-fluo-
ro-3,4-dihydro-1H-isoquinolin-2-yl)phenyl]carbamate
##STR00097##
[0509] Under air, to tert-butyl
N-tert-butoxycarbonyl-N-[3-[ethyl-[(4-fluoro-2-methyl-phenyl)methyl]amino-
]-2-fluoro-6-nitro-phenyl]carbamate (2.17 g, 4.29 mmol, 1.00 equiv)
in MeOH (43 mL) at 23.degree. C. were added Zn powder (1.40 g, 21.5
mmol, 5.00 equiv) and NH.sub.4C.sub.1 (1.15 g, 21.5 mmol, 5.00
equiv) in H.sub.2O (5 mL). After stirring for 3 hr at 23.degree.
C., the reaction mixture was filtered through a pad of celite. The
filtrate was concentrated in vacuo, and H.sub.2O (50 mL) and EtOAc
(50 mL) were added to the residue. The phases were separated and
the aqueous phase was extracted with EtOAc (2.times.50 mL). The
combined organic phases were washed with brine (100 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo to afford a
crude reduction product, which was used in the next step without
further purification.
[0510] Under nitrogen, to the crude reduction product obtained
above in MeCN (4.3 mL) at 23.degree. C. were added DIPEA (1.35 mL,
7.72 mmol, 1.80 equiv) and tert-butylacetyl chloride (1.08 mL, 7.72
mmol, 1.80 equiv). After stirring for 1 hr at 23.degree. C., the
reaction mixture was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel eluting with
hexanes/EtOAc to afford 2.20 g of the title compound (89% yield
over 2 steps).
[0511] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.87 (d, J=8.7 Hz, 1H), 7.10-6.80 (m, 4H),
4.23 (s, 2H), 3.38 (t, J=6.0 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 2.16
(s, 2H), 1.41 (s, 18H), 1.07 (s, 9H).
Step 4: Synthesis of ethyl
(3-fluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl-
)-carbamate (Compound 32)
##STR00098##
[0513] Under nitrogen, to tert-butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-(6-fluo-
ro-3,4-dihydro-1H-isoquinolin-2-yl)phenyl]carbamate (2.20 g, 3.83
mmol, 1.00 equiv) in DCM (10 mL) at 23.degree. C. was added HCl
(2.0 M in Et.sub.2O, 19.2 mL, 38.3 mmol, 10.0 equiv). After
stirring for 15 hr at 23.degree. C., NaHCO.sub.3 (aq) (100 mL) was
added to the reaction mixture. The phases were separated and the
aqueous phase was extracted with EtOAc (2.times.100 mL). The
combined organic phases were washed with brine (100 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo to afford 1.20
g of the title compound (84% yield).
[0514] NMR Spectroscopy: .sup.1H NMR (300 MHz, methanol-d4,
23.degree. C., .delta.): 7.16-7.10 (m, 1H), 6.94-6.79 (m, 3H), 6.46
(dd, J=8.7, 8.7 Hz, 1H), 4.19 (s, 2H), 3.36 (t, J=6.0 Hz, 2H), 2.96
(t, J=6.0 Hz, 2H), 2.27 (s, 2H), 1.11 (s, 9H).
Example 31: Compound 33
##STR00099##
[0515] Step 1: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[2-fluoro-6-nitro-3-[6-(trifluoromethyl)-3,4-dihy-
dro-1H-isoquinolin-2-yl]phenyl]carbamate
##STR00100##
[0517] Under nitrogen, to
1-bis(tert-butoxylcarbonyl)amino-2,3-difluoro-6-nitrobenzene (1.87
g, 5.00 mmol, 1.00 equiv) in DMSO (5 mL) at 23.degree. C. were
added 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (1.01 g,
5.00 mmol, 1.00 equiv) and Et.sub.3N (1.74 mL, 12.5 mmol, 2.50
equiv). After stirring for 1.5 hr at 23.degree. C., the reaction
mixture was cooled to 23.degree. C. and water (10 mL) was added.
The solution was then neutralized with 1N HCl (aq) and was
extracted with EtOAc (2.times.10 mL). The combined organic phases
were washed with brine (10 mL) and dried (MgSO.sub.4). The filtrate
was concentrated in vacuo and the residue was purified by
chromatography on silica gel eluting with hexanes/EtOAc to afford
1.39 g of the title compound (50% yield).
[0518] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.97 (d, J=9.0 Hz, 1H), 7.47 (d, J=8.1 Hz,
1H), 7.41 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.7, 8.4 Hz,
1H), 4.54 (s, 2H), 3.67 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2H),
1.42 (s, 18H).
Step 2: Synthesis of tert-Butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[6-(tri-
fluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]phenyl]carbamate
##STR00101##
[0520] Under air, to tert-butyl
N-tert-butoxycarbonyl-N-[2-fluoro-6-nitro-3-[6-(trifluoromethyl)-3,4-dihy-
dro-1H-isoquinolin-2-yl]phenyl]carbamate (1.39 g, 2.50 mmol, 1.00
equiv) in MeOH (25 mL) at 23.degree. C. were added Zn powder (817
mg, 12.5 mmol, 5.00 equiv) and NH.sub.4C.sub.1 (669 mg, 12.5 mmol,
5.00 equiv) in H.sub.2O (5 mL). After stirring for 3 hr at
23.degree. C., the reaction mixture was filtered through a pad of
celite. The filtrate was concentrated in vacuo, and H.sub.2O (50
mL) and EtOAc (50 mL) were added to the residue. The phases were
separated and the aqueous phase was extracted with EtOAc
(2.times.50 mL). The combined organic phases were washed with brine
(100 mL) and dried (MgSO.sub.4). The filtrate was concentrated in
vacuo to afford a crude reduction product, which was used in the
next step without further purification.
[0521] Under nitrogen, to the crude reduction product obtained
above in MeCN (2.5 mL) at 23.degree. C. were added DIPEA (0.784 mL,
4.50 mmol, 1.80 equiv) and tert-butylacetyl chloride (0.628 mL,
4.50 mmol, 1.80 equiv). After stirring for 1 hr at 23.degree. C.,
the reaction mixture was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel eluting with
hexanes/EtOAc to afford 1.25 g of the title compound (80% yield
over 2 steps).
[0522] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.95 (d, J=8.7 Hz, 1H), 7.44 (d, J=8.1 Hz,
1H), 7.37 (s, 1H), 7.30-7.18 (m, 2H), 7.09 (s, 1H), 4.37 (s, 2H),
3.48 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.0 Hz, 2H), 2.20 (s, 2H), 1.42
(s, 18H), 1.08 (s, 9H).
Step 3: Synthesis of
N-[2-amino-3-fluoro-4-[6-(trifluoromethyl)-3,4-dihydro-1H-isoquinolin-2-y-
l]phenyl]-3,3-dimethyl-butanamide (Compound 33)
##STR00102##
[0524] Under nitrogen, to tert-butyl
N-tert-butoxycarbonyl-N-[6-(3,3-dimethylbutanoylamino)-2-fluoro-3-[6-(tri-
fluoromethyl)-3,4-dihydro-1H-isoquinolin-2-yl]phenyl]carbamate
(1.25 g, 2.00 mmol, 1.00 equiv) in DCM (5 mL) at 23.degree. C. was
added HCl (2.0 M in Et.sub.2O, 10.0 mL, 20.0 mmol, 10.0 equiv).
After stirring for 15 hr at 23.degree. C., NaHCO.sub.3 (aq) (10 mL)
was added to the reaction mixture. The phases were separated and
the aqueous phase was extracted with EtOAc (2.times.10 mL). The
combined organic phases were washed with brine (10 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo to afford 570
mg of the title compound (67% yield).
[0525] NMR Spectroscopy: .sup.1H NMR (300 MHz, methanol-d4,
23.degree. C., .delta.): 7.42-7.25 (m, 3H), 6.75 (d, J=8.7 Hz, 1H),
6.41 (dd, J=8.7, 8.7 Hz, 1H), 4.23 (s, 2H), 3.36 (t, J=6.0 Hz, 2H),
2.96 (t, J=6.0 Hz, 2H), 2.21 (s, 2H), 1.04 (s, 9H).
Example 32: Compound 34
##STR00103##
[0526] Step 1: Synthesis of 1-Fluoro-2,
4-dimethyl-3-nitrobenzene
##STR00104##
[0528] Under air, to 1-bromo-4-fluoro-3-methyl-2-nitro-benzene
(4.68 g, 20.0 mmol, 1.00 equiv) in DME-H.sub.2O (10 mL-10 mL) at
23.degree. C. were added trimethylboroxine (1.76 g, 14.0 mmol,
0.700 equiv), K.sub.2CO.sub.3 (4.15 g, 30.0 mmol, 1.50 equiv), and
Pd(PPh.sub.3).sub.4 (2.31 g, 2.00 mmol, 10.0 mol %). After stirring
for 3 d at 100.degree. C., the reaction mixture was cooled to
23.degree. C. The phases were separated and the aqueous phase was
extracted with EtOAc (2.times.10 mL). The combined organic phases
were washed with brine (10 mL) and dried (MgSO.sub.4). The filtrate
was concentrated in vacuo and the residue was purified by column
chromatography on silica gel eluting with hexanes/EtOAc to afford
3.00 g of the title compound (89% yield).
[0529] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.05-6.99 (m, 2H), 2.21 (s, 3H), 2.15 (d,
J=1.8 Hz, 3H).
Step 2: Synthesis of 3-Fluoro-2, 6-dimethylaniline
##STR00105##
[0531] Under air, to 1-fluoro-2,4-dimethyl-3-nitrobenzene (3.00 g,
17.7 mmol, 1.00 equiv) in MeOH (177 mL) at 23.degree. C. were added
Zn powder (5.80 g, 88.7 mmol, 5.00 equiv) and NH.sub.4C.sub.1 (4.74
g, 5.00 mmol, 5.00 equiv) in H.sub.2O (10 mL). After stirring for 3
hr at 23.degree. C., the reaction mixture was filtered through a
pad of celite. The filtrate was concentrated in vacuo, and H.sub.2O
(100 mL) and EtOAc (100 mL) were added to the residue. The phases
were separated and the aqueous phase was extracted with EtOAc
(2.times.100 mL). The combined organic phases were washed with
brine (200 mL) and dried (MgSO.sub.4). The filtrate was
concentrated in vacuo and the residue was purified by column
chromatography on silica gel eluting with hexanes/EtOAc to afford
2.00 g of the title compound (81% yield).
[0532] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 6.87 (dd, J=7.5, 7.5 Hz, 1H), 6.48 (dd,
J=9.0, 7.5 Hz, 1H), 2.19 (s, 3H), 2.14 (d, J=1.8 Hz, 3H).
Step 3: Synthesis of 4-Bromo-3-fluoro-2,6-dimethylaniline
##STR00106##
[0534] Under air, to 3-fluoro-2,6-dimethylaniline (2.00g, 14.4
mmol, 1.00 equiv) in AcOH (14 mL) at 23.degree. C. was added NBS
(2.56 g, 14.4 mmol, 1.00 equiv). After stirring for 10 min at
23.degree. C., the reaction mixture was poured into water (100 mL).
Potassium carbonate was added to neutralize the solution, after
which was extracted with EtOAc (2.times.100 mL). The combined
organic phases were washed with brine (200 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by column chromatography on silica gel eluting
with hexanes/EtOAc to afford 1.66 g of the title compound (53%
yield).
[0535] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.07 (d, J=4.5 Hz, 1H), 2.14 (s, 6H).
Step 4: Synthesis of ethyl
(4-bromo-3-fluoro-2,6-dimethylphenyl)carbamate
##STR00107##
[0537] Under nitrogen, to 4-bromo-3-fluoro-2,6-dimethylaniline (830
mg, 3.81 mmol, 1.00 equiv) in MeCN (3.8 mL) at 0.degree. C. were
added DIPEA (797 .mu.l, 5.72 mmol, 1.50 equiv) and ethyl
chloroformate (798 .mu.l, 5.72 mmol, 1.50 equiv). After stirring
for 4 hr at 23.degree. C., NaHCO.sub.3 (aq) (10 mL) was added to
the reaction mixture. The phases were separated and the aqueous
phase was extracted with EtOAc (2.times.10 mL). The combined
organic phases were washed with brine (10 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by column chromatography on silica gel eluting
with hexanes/EtOAc to afford 935 mg of the title compound (78%
yield).
[0538] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.26 (d, J=4.5 Hz, 1H), 6.65 (br s, 1H),
2.18 (s, 2H), 2.14 (s, 6H), 1.14 (s, 9H).
Step 5: Synthesis of
N-(3-fluoro-4-((4-fluorobenzyl)amino)-2,6-dimethylphenyl)-3,3-dimethylbut-
anamide (Compound 34)
##STR00108##
[0540] Under nitrogen, to
N-(4-bromo-3-fluoro-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide
(316 mg, 1.00 mmol, 1.00 equiv) in toluene (5 mL) at 23.degree. C.
are added 4-fluorobenzylamine (125 mg, 1.00 mmol, 1.00 equiv),
DavePhos (47 mg, 0.12 mmol, 12 mol %), Pd.sub.2(dba).sub.3 (37 mg,
0.040 mmol, 4.0 mol %), and t-BuOK (168 mg, 1.50 mmol, 1.50 equiv).
After stirring for 2 hr at 90.degree. C., the reaction mixture is
concentrated in vacuo and the residue is purified by column
chromatography on silica gel eluting with hexanes/EtOAc to afford
the title compound.
Example 33: Compound 35
##STR00109##
[0542] Under nitrogen, to
N-(4-bromo-3-fluoro-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide
(316 mg, 1.00 mmol, 1.00 equiv) in toluene (5 mL) at 23.degree. C.
were added N-[[4-(trifluoromethyl)phenyl]methyl]prop-2-yn-1-amine
(235 mg, 1.10 mmol, 1.10 equiv), DavePhos (47 mg, 0.12 mmol, 12 mol
%), Pd.sub.2(dba).sub.3 (37 mg, 0.040 mmol, 4.0 mol %), and t-BuOK
(168 mg, 1.50 mmol, 1.50 equiv). After stirring for 2 d at
110.degree. C., the reaction mixture was concentrated in vacuo and
the residue was purified by column chromatography on silica gel
eluting with hexanes/EtOAc to afford 120 mg the title compound (27%
yield).
[0543] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.57 (d, J=8.7 Hz, 2H), 7.50 (d, J=8.7 Hz,
2H), 7.08 (d, J=7.5 Hz, 1H), 6.96 (br s, 1H), 4.00 (s, 2H), 3.65
(s, 2H), 2.27 (s, 1H), 2.13-2.10 (m, 8H), 1.12 (s, 9H).
Example 34: Compound 36
##STR00110##
[0545] Under nitrogen, to
N-(4-bromo-3-fluoro-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide
(158 mg, 0.500 mmol, 1.00 equiv) in toluene (2.5 mL) at 23.degree.
C. were added 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline
hydrochloric acid salt (178 mg, 0.750 mmol, 1.50 equiv), DavePhos
(47 mg, 0.12 mmol, 24 mol %), Pd.sub.2(dba).sub.3 (37 mg, 0.040
mmol, 8.0 mol %), and t-BuOK (168 mg, 1.50 mmol, 3.00 equiv). After
stirring for 1 hr at 100.degree. C., the reaction mixture was
concentrated in vacuo and the residue was purified by column
chromatography on silica gel eluting with hexanes/EtOAc to afford
72 mg the title compound (33% yield).
[0546] NMR Spectroscopy: .sup.1H NMR (300 MHz, CDCl.sub.3,
23.degree. C., .delta.): 7.40-7.32 (m, 2H), 7.14 (d, J=8.7 Hz, 1H),
6.79-6.70 (m, 1H), 6.54 (br s, 1H), 4.25 (br s, 2H), 3.37 (t, J=6.0
Hz, 2H), 3.03 (t, J=6.0 Hz, 2H), 2.23 (s, 2H), 2.13-2.08 (m, 6H),
1.08 (s, 9H).
Example 35: Assessment of KCNQ2/3 Channel Activation Activity
[0547] The in vitro effects of a compound of the application on
cloned KCNQ2/3 potassium channels (encoded by the human KCNQ2/3
gene and expressed in HEK293 cells) are evaluated at room
temperature using the QPatch HT.RTM. (Sophion Bioscience A/S,
Denmark), an automatic parallel patch clamp system. Each test
compound is evaluated at 0.01, 0.1, 1, 10 and 100 .mu.M with each
concentration tested in at least two cells (n>2). The duration
of exposure to each test compound concentration is 5 minutes.
[0548] The baseline for each recording is established using a 5-10
minute vehicle application (HBPS+0.3% DMSO). A single test compound
concentration is applied for a period of 5 minutes after the
vehicle, followed by a 3 minute application of 30 .mu.M flupirtine.
Each recording ends with a supramaximal dose of 30 .mu.M
linopirdine. The % activation is calculated using the following
equation by using leak subtracted responses:
vehicle_response - compound_response vehicle_response -
flupirtine_response ##EQU00002##
Example 36: Electrophysiology
[0549] (Kalappa et al., J. Neurosci., 35, 8829 (2015))
[0550] HEK293T cells are transfected with recombinant DNA (3-5
.mu.g) using Lipofectamine 2000 (Invitrogen, Carlsbad, Calif.) and
recorded 48 hours after transfection. All experiments are performed
at room temperature using conventional whole-cell patch clamp
technique. Recording electrodes are filled with internal solution
containing (in mM): 132 K-Gluconate, 10 KCl, 4 Mg.ATP, 20 HEPES,
and 1 EGTA.KOH, pH 7.2-7.3, and have resistances of 3-5 M.OMEGA..
The standard bath solution contains (in mM): 144 NaCl, 2.5 KCl,
2.25 CaCl.sub.2, 1.2 MgCl.sub.2, 10 HEPES, and 22 D-Glucose, pH
7.2-7.3. Series resistance is compensated by 75%. Osmolarity is
adjusted to 300-305 mOsm and pH to 7.2-7.3 with NaOH. Voltage
pulses are applied at 30s intervals from a holding potential of -85
mV to various test pulses before jumping down to -70 mV. These
values are adjusted for the calculated junction potential of -15
mV. Data are acquired through a Multiclamp 700B amplifier
(Molecular Devices, Sunnyvale, Calif.), low-pass filtered at 2 kHz
and sampled at 10 kHz. The construct for testing KCNQ2/3
electrophysiology is created as described previously (Soh and
Tzingounis, Mol. Pharmaco., 78, 1088 (2010)).
Example 37: Maximal Electroshock Seizure Test (MES)
[0551] In MES test, the ability of different doses of the test
compound in preventing seizure induced by an electrical stimulus of
0.2 s in duration (50 mA at 60 Hz), delivered through the corneal
electrodes primed with a drop of anesthetic/electrolyte solution
(0.5% tetracaine hydrochloride in 0.9% saline) is tested. Mice are
restrained by hand and released immediately following corneal
stimulation that allows for the observation of the entire seizure
episode. A maximal seizure in a test animal includes four distinct
phases that includes, hind leg flexor component tonic phase (Phase
I), hind leg extensor component of the tonic phase (Phase II),
intermittent, whole-body clonus (Phase III), and muscular
relaxation (Phase IV) followed by seizure termination (Woodbury
& Davenport, 1952; Racine et al., 1972). Test compounds are
tested for their ability to abolish hind limb tonic extensor
component that indicates the compound's ability to inhibit
MES-induced seizure spread. Compounds are pre-administered (i.p)
and tested at 0.25, 0.5, 1 and 4 h time points for the abolishment
of hind limb tonic extensor component after electrical
stimulus.
Example 38: Corneal-Kindled Mouse Model of Partial Seizures
[0552] In corneal kindled seizure model, mice are kindled
electrically with 3 s stimulation, 8 mA, 60 Hz delivered through
corneal electrodes primed with 0.5% tetracaine hydrochloride in
0.9% saline, twice daily, until 5 consecutive stage V seizures are
induced. Mice are considered kindled when they display at least 5
consecutive stage V seizures according to the Racine scale (Racine
et al., 1972) including, mouth and facial clonus (stage I), Stage I
plus head nodding (Stage II), Stage II plus forelimb clonus (Stage
III), Stage III plus rearing (Stage IV), and stage IV plus repeated
rearing and falling (Stage V) (Racine et al., 1972). At the
completion of the kindling acquisition, mice are permitted a 3-day
stimulation-free period prior to any drug testing. On the day of
the experiment, fully kindled mice are pre-administered (i.p) with
increasing doses of the test compound and challenged with the
corneal kindling stimulus of 3 mA for 3 seconds 15 min. Mice are
scored as protected (seizure score of <3) or not protected,
(seizure score .gtoreq.4) based on the Racine scoring (Racine et
al., 1972).
Example 39: Assessment of Recombinantly Expressed Human Kv7.2/7.3
Xhannels Activation Ability
[0553] The in vitro effects of a compound of the present
application recombinantly expressed human Kv7.2/7.3 channels are
assessed on Syncropatch high throughput electrophysiology
platform.
[0554] Cell Preparations:
[0555] CHO cells stably expressing human Kv7.2/7.3 channels were
cultured in Ham's F-12 media (Hyclone, Cat #SH30022.02)
supplemented with 10% Fetal Bovine Serum, 1.times.MEM non-essential
amino acids, and 400 .mu.g/ml G418 at 37.degree. C. in 5% CO.sub.2.
On the day of Syncropatch, the cells were washed once in DPBS
(Hyclone, Cat #SH30028.03) for approximately 30 seconds. 1 ml of
1.times.0.015% Trypsin-EDTA GIBCO Cat #25300-054) was added and
swirled around to cover the bottom of the flask, and allowed to sit
on the cells for about 4 minutes (approximately 90% of the cells
were lifted by light tapping of the flask). 10 ml of cold media
(Ham's F-12 media (Hyclone, Cat #SH30022.02) supplemented with 10%
Fetal Bovine Serum, 1.times.MEM non-essential amino acids, and 400
.mu.g/ml G418) was added to inactivate Trypsin. The cells were then
triturated until a single cell suspension was achieved, and the
cell count was performed. The cells were then diluted to a
concentration of 5.times.10.sup.5/ml and placed into the "cell
hotel" on the deck of the Syncropatch at 10.degree. C. for about 1
hour to recover. 40 .mu.L of the cell suspension was dispensed into
each well of a 384-well Syncropatch chip by the onboard pipettor at
the beginning of each Syncropatch assay.
[0556] Test Solution Preparations:
[0557] The compounds to be tested were dissolved in DMSO to give 10
mM stock solutions. Eight-point dose response curves were created
by performing semi-log serial dilutions from 10 mM compound stock
solutions in 100% DMSO. Concentration-response curves were
transferred to assay plates to give two-fold final compound
concentration to account for the two-fold dilution with drug
addition on the SyncroPatch. Final DMSO concentration in the assay
was 0.3%. Final assay test concentrations were 30 .mu.M to 0.01
.mu.M or 1 .mu.M to 0.0003 .mu.M. Negative (0.3% DMSO) and positive
(30 .mu.M ML213) controls were included in each test run to assess
pharmacological responsiveness.
[0558] Assessment Protocol:
[0559] Electrophysiological studies of the compounds were performed
using the Nanion SyncroPatch automated patch clamp platform.
Compound effects on Kv7 channels were assayed using a voltage
protocol as shown in FIG. 1.
[0560] Kv7 channels were evaluated using a voltage protocol in
which cells were voltage-clamped at a holding potential of -110 mV.
Potassium currents were activated with a series of voltage steps
from -110 mV to +50 mV in 10 mV intervals with 5.5 seconds between
successive voltage steps. Each voltage step was 3 seconds in
duration and immediately followed by a 1 second voltage step to
-120 mV to generate an inward "tail" current to allow construction
of activation (G-V) curves by plotting normalized peak tail current
versus the potential of the activating voltage step. To obtain
normalized values, peak current amplitudes for successive
depolarizing pulses were normalized against the maximum tail
current amplitude generated at +50 mV (Tatulian et al., Journal of
Neuroscience 2001, 21 (15)).
[0561] Data Analysis: Data was collected on the Syncropatch
platform using PatchControl software (Nanion) and processed and
analyzed using DataControl Software (Nanion). Normalized percent
activation was calculated and activation curves were fit with a
Boltzmann function to determine the midpoint voltage of activation
(G-V midpoint) for both pre-compound and post-compound conditions
for each of the 384-wells of a sealchip with Pipeline Pilot
(Accelrys). The difference in G-V midpoint between pre-compound and
post-compound conditions (.DELTA. V0.5) was plotted as a function
of concentration and concentration-response curves were fit with a
three-parameter logistic equation {Y=Bottom+(Top-Bottom)/(1+10 (Log
EC50-X))} for determination of the EC.sub.50 (Graphpad Prism).
[0562] Assessment Results:
[0563] Exemplary compounds of the present application were tested
for their ability to produce a concentration-dependent
hyperpolarizing shift in the midpoint of activation for heteromeric
Kv7.2/7.3 channels. Eight of the compounds produced a quantifiable
hyperpolarizing shift in activation as determined by a
concentration-dependent shift in the midpoint that could be fit
with a 3-parameter logistic equation. These data were combined with
the initial 8-point concentration-response data in a single fit.
Potency and efficacy data for each compound are summarized in Table
2 and FIGS. 2A-2F.
TABLE-US-00003 TABLE 2 Cmpd # EC.sub.50 (95% CI) 1 B 2 A 3 C 4 A 6
A 7 A 8 A 9 A 10 (control) B 11 A 12 A 17 A 18 A 19 B 20 A 21 B 22
A 23 B 24 B X (control) A A: 0.1 to 1.0 .mu.M, B: 1.0 to 5 .mu.M,
C: 5 to 25 .mu.M, D: 25 to 50 .mu.M ##STR00111## ##STR00112##
EQUIVALENTS
[0564] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically
herein. Such equivalents are intended to be encompassed in the
scope of the following claims.
* * * * *