U.S. patent application number 15/666719 was filed with the patent office on 2018-03-01 for fused dihydro-4h-pyrazolo[5,1-c][1,4]oxazinyl compounds and analogs for treating cns disorders.
This patent application is currently assigned to Sunovion Pharmaceuticals Inc.. The applicant listed for this patent is PGI Drug Discovery LLC, Sunovion Pharmaceuticals Inc.. Invention is credited to Vadim ALEXANDROV, Milan CHYTIL, Sharon Engel, Taleen G. HANANIA, Emer LEAHY.
Application Number | 20180057506 15/666719 |
Document ID | / |
Family ID | 55456906 |
Filed Date | 2018-03-01 |
United States Patent
Application |
20180057506 |
Kind Code |
A1 |
CHYTIL; Milan ; et
al. |
March 1, 2018 |
FUSED DIHYDRO-4H-PYRAZOLO[5,1-C][1,4]OXAZINYL COMPOUNDS AND ANALOGS
FOR TREATING CNS DISORDERS
Abstract
Disclosed are compounds of Formula (I): ##STR00001## and
pharmaceutically acceptable salts thereof, wherein Ring B, A.sup.1,
A.sup.2, R.sup.6, w and n1 are defined and described herein;
compositions thereof; and methods of use thereof. These compounds
are useful for treating a variety of neurological and psychiatric
disorders, such as those described herein.
Inventors: |
CHYTIL; Milan; (Acton,
MA) ; Engel; Sharon; (Hudson, MA) ; HANANIA;
Taleen G.; (Valhalla, NY) ; ALEXANDROV; Vadim;
(Hopewell Junction, NY) ; LEAHY; Emer; (Pound
Ridge, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sunovion Pharmaceuticals Inc.
PGI Drug Discovery LLC |
Marlborough
Tarrytown |
MA
NY |
US
US |
|
|
Assignee: |
Sunovion Pharmaceuticals
Inc.
Marlborough
MA
PGI Drug Discovery LLC
Tarrytown
NY
|
Family ID: |
55456906 |
Appl. No.: |
15/666719 |
Filed: |
August 2, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15041827 |
Feb 11, 2016 |
9758529 |
|
|
15666719 |
|
|
|
|
62115043 |
Feb 11, 2015 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/30 20180101;
A61P 25/00 20180101; A61P 29/00 20180101; A61P 25/24 20180101; C07D
498/22 20130101; C07D 498/04 20130101; C07D 498/20 20130101; A61P
25/22 20180101; C07D 231/56 20130101; A61P 25/18 20180101; A61P
25/28 20180101; C07D 498/14 20130101; A61P 25/04 20180101 |
International
Class: |
C07D 498/04 20060101
C07D498/04; C07D 498/22 20060101 C07D498/22; C07D 498/14 20060101
C07D498/14; C07D 498/20 20060101 C07D498/20 |
Claims
1-55. (canceled)
56. A process for preparing a compound of formula ##STR00257## as
its hydrochloride salt, comprising: combining ##STR00258## and
di-tert-butyl dicarbonate in the presence of a base to form
##STR00259## resolving ##STR00260## into its enantiomers
##STR00261## and isolating ##STR00262## and deprotecting
##STR00263## to obtain ##STR00264##
57. A process according to claim 56, wherein said resolving is
accomplished by chiral HPLC.
58. A process according to claim 56, further comprising combining
##STR00265## with 4-methylbenzenesulfonic acid to obtain
##STR00266##
59. A process according to claim 58, further comprising combining
##STR00267## with lithium diisopropylamide to form a mixture, then
combining the mixture with tert-butyl methyl (2-oxoethyl)carbamate
to obtain ##STR00268##
60. A process according to claim 58, further comprising combining
##STR00269## in 2-bromoethanol to obtain ##STR00270##
61. A process for preparing a compound of formula ##STR00271## as
its hydrochloride salt, comprising: a) combining ##STR00272## in
2-bromoethanol to obtain ##STR00273## b) combining ##STR00274##
with lithium diisopropylamide to form a mixture, then combining the
mixture with tert-butyl methyl(2-oxoethyl)carbamate to obtain
##STR00275## c) combining ##STR00276## with 4-methylbenzenesulfonic
acid to obtain ##STR00277## and d) combining ##STR00278## and
di-tert-butyl dicarbonate in the presence of a base to form
##STR00279## e) resolving ##STR00280## into its enantiomers
##STR00281## and isolating ##STR00282## and f) deprotecting
##STR00283## to obtain ##STR00284##
62. A process according to claim 61, wherein said resolving in step
e) is accomplished by chiral HPLC.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 15/041,827, filed Feb. 11, 2016, now
allowed, which claims the benefit of U.S. Provisional Application
No. 62/115,043, filed Feb. 11, 2015. The disclosures of each of
these prior applications are hereby incorporated herein by
reference in their entirety.
BACKGROUND
[0002] Central nervous system disorders affect a wide range of the
population with differing severity. Neurological and psychiatric
disorders include major depression, schizophrenia, bipolar
disorder, obsessive compulsive disorder (OCD), panic disorder, and
posttraumatic stress disorder (PTSD), among others. These disorders
affect a person's thoughts, mood, behavior and social interactions
and can significantly impair daily functioning. See, e.g.,
Diagnostic and Statistical Manual of Mental Disorders, 4.sup.th
Ed., American Psychiatric Association (2000) ("DSM-IV-TR");
Diagnostic and Statistical Manual of Mental Disorders, 5.sup.th
Ed., American Psychiatric Association (2013) ("DSM-5").
[0003] Bipolar disorder is a serious psychiatric disorder that has
a prevalence of approximately 2% of the population, and affects
both genders alike. It is a relapsing-remitting condition
characterized by cycling between elevated (i.e., manic) and
depressed moods, which distinguishes it from other disorders such
as major depressive disorder and schizophrenia. Bipolar I is
defined by the occurrence of a full manic episode, although most
individuals experience significant depression. Symptoms of mania
include elevated or irritable mood, hyperactivity, grandiosity,
decreased need for sleep, racing thoughts and in some cases,
psychosis. The depressive episodes are characterized by anhedonia,
sad mood, hopelessness, poor self-esteem, diminished concentration
and lethargy. Bipolar II is defined as the occurrence of a major
depressive episode and hypomanic (less severe mania) episode
although patients spend considerable more time in the depressive
state. Other related conditions include cyclothymic disorder.
[0004] Schizophrenia is a psychopathic disorder of unknown origin,
which usually appears for the first time in early adulthood and is
marked by characteristics such as psychotic symptoms, phasic
progression and development, and/or deterioration in social
behavior and professional capability. Characteristic psychotic
symptoms are disorders of thought content (e.g., multiple,
fragmentary, incoherent, implausible or simply delusional contents,
or ideas of persecution) and of mentality (e.g., loss of
association, flight of imagination, incoherence up to
incomprehensibility), as well as disorders of perceptibility (e.g.,
hallucinations), emotions (e.g., superficial or inadequate
emotions), self-perceptions, intentions, impulses, and/or
inter-human relationships, and psychomotoric disorders (e.g.,
catatonia). Other symptoms are also associated with this
disorder.
[0005] Schizophrenia is classified into subgroups: the paranoid
type, characterized by delusions and hallucinations and absence of
thought disorder, disorganized behavior, and affective flattening;
the disorganized type, also named "hebephrenic schizophrenia," in
which thought disorder and flat affect are present together; the
cataconic type, in which prominent psychomotor disturbances are
evident, and symptoms may include catatonic stupor and waxy
flexibility; and the undifferentiated type, in which psychotic
symptoms are present but the criteria for paranoid, disorganized,
or catatonic types have not been met. The symptoms of schizophrenia
normally manifest themselves in three broad categories: positive,
negative and cognitive symptoms. Positive symptoms are those which
represent an "excess" of normal experiences, such as hallucinations
and delusions. Negative symptoms are those where the patient
suffers from a lack of normal experiences, such as anhedonia and
lack of social interaction. The cognitive symptoms relate to
cognitive impairment in schizophrenics, such as lack of sustained
attention and deficits in decision making.
[0006] Neurological and psychiatric disorders can exhibit a variety
of symptoms, including cognitive impairment, depressive disorders,
and anxiety disorders.
[0007] Cognitive impairment includes a decline in cognitive
functions or cognitive domains, e.g., working memory, attention and
vigilance, verbal learning and memory, visual learning and memory,
reasoning and problem solving (e.g., executive function, speed of
processing and/or social cognition). In particular, cognitive
impairment may indicate deficits in attention, disorganized
thinking, slow thinking, difficulty in understanding, poor
concentration, impairment of problem solving, poor memory,
difficulties in expressing thoughts, and/or difficulties in
integrating thoughts, feelings and behavior, or difficulties in
extinction of irrelevant thoughts.
[0008] Depressive disorders include major depressive disorder and
dysthymia, and are associated with depressed mood (sadness), poor
concentration, insomnia, fatigue, appetite disturbances, excessive
guilt and thoughts of suicide.
[0009] Anxiety disorders are disorders characterized by fear,
worry, and uneasiness, usually generalized and unfocused as an
overreaction to a situation. Anxiety disorders differ in the
situations or types of objects that induce fear, anxiety, or
avoidance behavior, and the associated cognitive ideation. Anxiety
differs from fear in that anxiety is an emotional response to a
perceived future threat while fear is associated with a perceived
or real immediate threat. They also differ in the content of the
associated thoughts or beliefs.
SUMMARY
[0010] While medications exist for some aspects of these diseases,
there remains a need for effective treatments for various
neurological and psychiatric disorders, including mood disorders
such as bipolar and related disorders, psychosis and schizophrenia.
For example, while mood stabilizers such as lithium and valproate,
antidepressants and antipsychotic drugs are used to treat mood
disorders, more effective medications are necessary. And current
antipsychotics may be successful in treating the positive symptoms
of schizophrenia but fare less well for the negative and cognitive
symptoms. Additionally, current antidepressants are typically
effective only for a proportion of patients suffering from
depression.
[0011] In some embodiments, the present invention encompasses the
insight that compounds of Formula (I):
##STR00002##
and pharmaceutically acceptable salts thereof, wherein Ring B,
A.sup.1, A.sup.2, R.sup.6, w and n1 are defined and described
herein, are useful for treating a variety of neurological and
psychiatric disorders, such as those described herein.
[0012] Also provided herein are methods for the treatment of
various neurological and psychiatric disorders using the compounds
and compositions provided herein.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General Description of Compounds of the Invention
[0013] In some embodiments, the present invention provides a
compound of Formula (I):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein: Ring B is a
6-membered aromatic ring, which ring unsubstituted or substituted
with 1 to 4 substituents independently selected from halo, --OH,
--NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and --CF.sub.3; or
is a 5- or 6-membered heteroaromatic ring having 1 to 3 ring
heteroatoms independently selected from O, N and S, which ring is
unsubstituted or substituted with 1 to 3 substituents independently
selected from halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F,
--CHF.sub.2 and --CF.sub.3; A.sup.1 is --H or C.sub.1-3 alkyl; and
A.sup.2 is
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10; or
A.sup.1 and A.sup.2, together with the carbon atom to which they
are attached, form
##STR00004##
m is 0, 1 or 2; n1 is 1 or 2; n2 is 0 or 1; n3 is 0 or 1; p is 0 or
1; R is --H or C.sub.1-C.sub.3 alkyl; or R is --CH.sub.2--(X),
--CH.sub.2CH.sub.2--(X), --CH.sub.2--(Z) or
--CH.sub.2CH.sub.2--(Z); each instance of R.sup.5 independently is
halo, --CH.sub.3 or ethyl; each instance of R.sup.6 independently
is halo or --CH.sub.3; R.sup.7 is --H or C.sub.1-C.sub.3 alkyl;
R.sup.8 is --H or C.sub.1-C.sub.3 alkyl which is unsubstituted or
substituted with C.sub.3-C.sub.6 cycloalkyl; R.sup.9 is --H,
C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.6 cycloalkyl; and R.sup.10
is --H or C.sub.1-C.sub.3 alkyl; or R.sup.9 and R.sup.8, together
with the atoms to which they are attached, form (i.e., R.sup.9 and
R.sup.8, together with the atoms to which they are attached form a
ring such that
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10 is)
##STR00005##
or R.sup.9 and R.sup.10, together with the nitrogen atom to which
they are attached, form
##STR00006##
w is 0, 1 or 2;
X is CH or CH.sub.2; and
Z is CH, CH.sub.2 or O.
2. Compounds and Definitions
[0014] Compounds of this invention include those described
generally above, and are further illustrated by the classes,
subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated. For
purposes of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version,
Handbook of Chemistry and Physics, 75th Ed. Additionally, general
principles of organic chemistry are described in M. Loudon, Organic
Chemistry, 5th Ed., Roberts and Company, Greenwood Village, Colo.:
2009; and M. B. Smith, March's Advanced Organic Chemistry:
Reactions, Mechanisms and Structure, 7th Ed., John Wiley &
Sons, Hoboken: 2013, the entire contents of which are hereby
incorporated by reference.
[0015] As used herein, the term "halogen" or "halo" means F, Cl,
Br, or I.
[0016] As used herein, the term "alkylene" refers to a bivalent
alkyl group. An "alkylene chain" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n--, wherein n is a positive integer, preferably
from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
A substituted alkylene chain is a polymethylene group in which one
or more methylene hydrogen atoms are replaced with a substituent.
Suitable substituents include those described herein for a
substituted aliphatic group.
[0017] As used herein, the terms "heteroaryl" and "heteroar-," used
alone or as part of a larger moiety, e.g., "heteroaralkyl," or
"heteroaralkoxy," refer to groups having 5 to 10 ring atoms,
preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14
.quadrature. electrons shared in a cyclic array; and having, in
addition to carbon atoms, from one to five ring heteroatoms.
Heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, and pteridinyl. A heteroaryl group may be
monocyclic or bicyclic. The term "heteroaryl" may be used
interchangeably with the terms "heteroaryl ring," "heteroaryl
group," or "heteroaromatic," any of which terms include rings that
are optionally substituted. The term "heteroaralkyl" refers to an
alkyl group substituted by a heteroaryl, wherein the alkyl and
heteroaryl portions independently are optionally substituted.
[0018] As used herein, the terms "heterocycle," "heterocyclyl,"
"heterocyclic radical," and "heterocyclic ring" are used
interchangeably and refer to a stable 5- to 7-membered monocyclic
or 7- to 10-membered bicyclic heterocyclic moiety that is either
saturated or partially unsaturated, and having, in addition to ring
carbon atoms, one to four ring heteroatoms. When used in reference
to a ring atom of a heterocycle, the term "nitrogen" includes a
substituted nitrogen. As an example, in a saturated or partially
unsaturated ring having 0-3 heteroatoms selected from oxygen,
sulfur and nitrogen, the nitrogen may be N (as in
3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or .sup.+NR (as
in N-substituted pyrrolidinyl).
[0019] A heterocyclic ring can be attached to its pendant group at
any heteroatom or carbon atom that results in a stable structure
and any of the ring atoms can be optionally substituted. Examples
of such saturated or partially unsaturated heterocyclic radicals
include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,
piperidinyl, pyrrolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl,
piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,
thiazepinyl, morpholinyl, and quinuclidinyl. The terms
"heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic
group," "heterocyclic moiety," and "heterocyclic radical," are used
interchangeably herein. A heterocyclyl group may be monocyclic or
bicyclic. The term "heterocyclylalkyl" refers to an alkyl group
substituted by a heterocyclyl, wherein the alkyl and heterocyclyl
portions independently are optionally substituted.
[0020] As used herein, the term "unsaturated," as used herein,
means that a moiety has one or more units of unsaturation.
[0021] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond. The
term "partially unsaturated" is intended to encompass rings having
multiple sites of unsaturation, but is not intended to include aryl
or heteroaryl moieties, as herein defined.
[0022] As used herein, the term "heteroatom" means one or more of
oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any
oxidized form of nitrogen, sulfur, phosphorus, boron, or silicon;
the quaternized form of any basic nitrogen or; a substitutable
nitrogen of a heterocyclic ring, for example N (as in
3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or .sup.+NR (as
in N-substituted pyrrolidinyl)).
[0023] As used herein, the term "aryl" used alone or as part of a
larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl,"
refers to carbocyclic aromatic ring systems having a total of six
to fourteen ring atoms. The term "aryl" may be used interchangeably
with the term "aryl ring." Examples of "aryl" groups include
phenyl, naphthyl, anthracyl and the like, which may be optionally
substituted.
[0024] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge et al., describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66, 1-19, incorporated herein by reference.
Pharmaceutically acceptable salts of the compounds of this
invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition salts are salts of an amino group formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid or malonic acid or by using other
methods used in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, pivalate, propionate, stearate,
succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate,
undecanoate, valerate salts, and the like.
[0025] Salts derived from appropriate bases include alkali metal,
alkaline earth metal, ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4
salts. Representative alkali or alkaline earth metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0026] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, Z
and E double bond isomers, and Z and E conformational isomers.
Therefore, single stereochemical isomers as well as enantiomeric,
diastereomeric, and geometric (or conformational) mixtures of the
present compounds are within the scope of the invention. Unless
otherwise stated, all tautomeric forms of the compounds of the
invention are within the scope of the invention. Additionally,
unless otherwise stated, structures depicted herein are also meant
to include compounds that differ only in the presence of one or
more isotopically enriched atoms. For example, compounds having the
present structures including the replacement of hydrogen by
deuterium or tritium, or the replacement of a carbon by a .sup.13C-
or .sup.14C-enriched carbon are within the scope of this invention.
Such compounds are useful, for example, as analytical tools, as
probes in biological assays, or as therapeutic agents in accordance
with the present invention.
[0027] Unless otherwise specified, the word "includes" (or any
variation thereon, e.g., "include", "including", etc.) is intended
to be open-ended. For example, "A includes 1, 2 and 3" means that A
includes but is not limited to 1, 2 and 3.
[0028] Unless otherwise specified, the phrase "such as" is intended
to be open-ended. For example, "A can be a halogen, such as
chlorine or bromine" means that A can be, but is not limited to,
chlorine or bromine.
3. Description of Exemplary Embodiments
[0029] In some embodiments, the present invention provides a
compound of Formula (I):
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein: Ring B is a
6-membered aromatic ring, which ring is unsubstituted or
substituted with 1 to 4 substituents independently selected from
halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3; or is a 5- or 6-membered heteroaromatic ring having 1
to 3 ring heteroatoms independently selected from O, N and S, which
ring is unsubstituted or substituted with 1 to 3 substituents
independently selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3; A.sup.1 is --H or
C.sub.1-3 alkyl; and A.sup.2 is
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10; or
A.sup.1 and A.sup.2, together with the carbon atom to which they
are attached, form
##STR00008##
m is 0, 1 or 2; n1 is 1 or 2; n2 is 0 or 1; n3 is 0 or 1; p is 0 or
1; R is --H or C.sub.1-C.sub.3 alkyl; or R is --CH.sub.2--(X),
--CH.sub.2CH.sub.2--(X), --CH.sub.2--(Z) or
--CH.sub.2CH.sub.2--(Z); each instance of R.sup.5 independently is
halo, --CH.sub.3 or ethyl; each instance of R.sup.6 independently
is halo or --CH.sub.3; R.sup.7 is --H or C.sub.1-C.sub.3 alkyl;
R.sup.8 is --H or C.sub.1-C.sub.3 alkyl which is unsubstituted or
substituted with C.sub.3-C.sub.6 cycloalkyl; R.sup.9 is --H,
C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.6 cycloalkyl; and R.sup.10
is --H or C.sub.1-C.sub.3 alkyl; or R.sup.9 and R.sup.8, together
with the atoms to which they are attached, form (i.e., R.sup.9 and
R.sup.8, together with the atoms to which they are attached form a
ring such that
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10 is)
##STR00009##
or R.sup.9 and R.sup.10, together with the nitrogen atom to which
they are attached, form
##STR00010##
w is 0, 1 or 2;
X is CH or CH.sub.2; and
Z is CH, CH.sub.2 or O.
[0030] Such a compound (including pharmaceutically acceptable
salts) is referred to herein as a "provided compound". Provided
compounds are also described in U.S. Application No. 62/115,043,
filed Feb. 11, 2015, which is hereby incorporated by reference
herein in its entirety.
[0031] When R is "--CH.sub.2--(X)" or "--CH.sub.2CH.sub.2--(X)",
this means that the nitrogen atom bearing R is attached to the
carbon atom represented by X with --CH.sub.2-- or
--CH.sub.2CH.sub.2--, respectively. For example, when A.sup.1 and
A.sup.2, together with the carbon atom to which they are attached,
form
##STR00011##
("AA"), if n2 is 1, n3 is 1 and m is 0:
[0032] if R is --CH.sub.2--(X), then AA is
##STR00012##
and if R is --CH.sub.2CH.sub.2--(X), then AA is
##STR00013##
When R is --H or C.sub.1-C.sub.3 alkyl, then X is CH.sub.2.
[0033] When R is "--CH.sub.2--(Z)" or "--CH.sub.2CH.sub.2--(Z)",
this means that the nitrogen atom bearing R is attached to the
carbon atom represented by Z with --CH.sub.2-- or
--CH.sub.2CH.sub.2--, respectively. For example, when R.sup.9 and
R.sup.8, together with the atoms to which they are attached,
form
##STR00014##
("R98"), if n2 is 1, n3 is 1 and m is 0:
[0034] if R is --CH.sub.2--(Z), then R98 is
##STR00015##
and if R is --CH.sub.2CH.sub.2--(Z), then R98 is
##STR00016##
When R is --H or C.sub.1-C.sub.3 alkyl, then Z is CH.sub.2 or
O.
[0035] In some embodiments, the present invention provides a
compound of Formula (I):
##STR00017##
or a pharmaceutically acceptable salt thereof, wherein: Ring B is a
6-membered aromatic ring, which ring is unsubstituted or
substituted with 1 to 4 substituents independently selected from
halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3; or is a 5- or 6-membered heteroaromatic ring having 1
to 3 ring heteroatoms independently selected from O, N and S, which
ring is unsubstituted or substituted with 1 to 3 substituents
independently selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3; A.sup.1 is --H or
C.sub.1-3 alkyl; and A.sup.2 is
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10; or
A.sup.1 and A.sup.2, together with the carbon atom to which they
are attached, form
##STR00018##
m is 0, 1 or 2; n1 is 1 or 2; n2 is 0 or 1; n3 is 0 or 1; p is 0 or
1; R is --H or C.sub.1-C.sub.3 alkyl; or R is --CH.sub.2--(X),
--CH.sub.2CH.sub.2--(X), --CH.sub.2--(Z) or
--CH.sub.2CH.sub.2--(Z); each instance of R.sup.5 independently is
halo, --CH.sub.3 or ethyl; each instance of R.sup.6 independently
is halo or --CH.sub.3; R.sup.7 is --H or C.sub.1-C.sub.3 alkyl;
R.sup.8 is --H or C.sub.1-C.sub.3 alkyl which is unsubstituted or
substituted with C.sub.3-C.sub.6 cycloalkyl; R.sup.9 is --H,
C.sub.1-C.sub.4 alkyl or C.sub.3-C.sub.6 cycloalkyl; and R.sup.10
is --H or C.sub.1-C.sub.3 alkyl; or R.sup.9 and R.sup.8, together
with the atoms to which they are attached, form (i.e., R.sup.9 and
R.sup.8, together with the atoms to which they are attached form a
ring such that
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10 is)
##STR00019##
or R.sup.9 and R.sup.10, together with the nitrogen atom to which
they are attached, form
##STR00020##
w is 0, 1 or 2;
X is CH or CH.sub.2; and
Z is CH, CH.sub.2 or O.
[0036] As defined above, Ring B is a 6-membered aromatic ring,
which ring is unsubstituted or substituted with 1 to 4 substituents
independently selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3; or is a 5- or 6-membered
heteroaromatic ring having 1 to 3 ring heteroatoms independently
selected from O, N and S, which ring is unsubstituted or
substituted with 1 to 3 substituents independently selected from
halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3. This description of Ring B includes the 2 carbon atoms
shared with the pyrazole moiety of Formula (I).
[0037] In some embodiments, Ring B is a 6-membered aromatic ring,
which ring is unsubstituted or substituted with 1 to 4 substituents
independently selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some embodiments, Ring
B is a 6-membered aromatic ring, which ring is unsubstituted or
substituted with 1 to 3 substituents independently selected from
halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3. In some embodiments, Ring B is a 6-membered aromatic
ring, which ring is unsubstituted or substituted with 1 or 2
substituents independently selected from halo, --OH, --NH.sub.2,
--CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some embodiments, Ring
B is a 6-membered aromatic ring, which ring is unsubstituted or
substituted with 1 substituent selected from halo, --OH,
--NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In
some embodiments, Ring B is an unsubstituted 6-membered aromatic
ring.
[0038] In some embodiments, Ring B is a 5- or 6-membered
heteroaromatic ring having 1 to 3 ring heteroatoms independently
selected from O, N and S, which ring is unsubstituted or
substituted with 1 to 3 substituents independently selected from
halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3. When the resulting compound is stable, a ring N atom
can be substituted with --CH.sub.3.
[0039] In some embodiments, Ring B is a 5-membered heteroaromatic
ring having 1 to 3 ring heteroatoms independently selected from O,
N and S, which ring is unsubstituted or substituted with 1 to 3
substituents independently selected from halo, --OH, --NH.sub.2,
--CH.sub.3, --CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some
embodiments, Ring B is a 5-membered heteroaromatic ring having 1 or
2 ring heteroatoms independently selected from O, N and S, which
ring is unsubstituted or substituted with 1 to 3 substituents
independently selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some embodiments, Ring
B is a 5-membered heteroaromatic ring having 1 ring heteroatom
selected from O, N and S, which ring is unsubstituted or
substituted with 1 to 3 substituents independently selected from
halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3.
[0040] In some embodiments, Ring B is any 5-membered heteroaromatic
ring described in the preceding paragraph, which ring is
unsubstituted or substituted with 1 or 2 substituents independently
selected from halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F,
--CHF.sub.2 and --CF.sub.3. In some embodiments, Ring B is any
5-membered heteroaromatic ring described in the preceding
paragraph, which ring is unsubstituted or substituted with 1
substituent selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some embodiments, Ring
B is any 5-membered heteroaromatic ring described in the preceding
paragraph, which ring is unsubstituted.
[0041] In some embodiments, Ring B is a 6-membered heteroaromatic
ring having 1 to 3 ring heteroatoms independently selected from O,
N and S, which ring is unsubstituted or substituted with 1 to 3
substituents independently selected from halo, --OH, --NH.sub.2,
--CH.sub.3, --CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some
embodiments, Ring B is a 6-membered heteroaromatic ring having 1 or
2 ring heteroatoms independently selected from O, N and S, which
ring is unsubstituted or substituted with 1 to 3 substituents
independently selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some embodiments, Ring
B is a 6-membered heteroaromatic ring having 1 ring heteroatom
selected from O, N and S, which ring is unsubstituted or
substituted with 1 to 3 substituents independently selected from
halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2 and
--CF.sub.3.
[0042] In some embodiments, Ring B is any 6-membered heteroaromatic
ring described in the preceding paragraph, which ring is
unsubstituted or substituted with 1 or 2 substituents independently
selected from halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F,
--CHF.sub.2 and --CF.sub.3. In some embodiments, Ring B is any
6-membered heteroaromatic ring described in the preceding
paragraph, which ring is unsubstituted or substituted with 1
substituent selected from halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 and --CF.sub.3. In some embodiments, Ring
B is any 6-membered heteroaromatic ring described in the preceding
paragraph, which ring is unsubstituted.
[0043] As defined above, in some embodiments, A.sup.1 is --H or
C.sub.1-3 alkyl. In some embodiments, A.sup.1 is --H or --CH.sub.3.
In some embodiments, A.sup.1 is --H.
[0044] As defined above, n1 is 1 or 2. In some embodiments, n1 is
1. In some embodiments, n1 is 2.
[0045] As defined above, w is 0, 1 or 2. In some embodiments, w is
0 or 1. In some embodiments, w is 0. In some embodiments, w is 1 or
2. In some embodiments, w is 1.
[0046] As defined above, each instance of R.sup.6 independently is
halo or --CH.sub.3. In some embodiments, each instance of R.sup.6
independently is halo. In some embodiments, each instance of
R.sup.6 independently is --F or --Cl. In some embodiments, each
instance of R.sup.6 is --CH.sub.3.
[0047] As defined above, in some embodiments, A.sup.2 is
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10. In
some embodiments, p is 0. In some embodiments, R.sup.7 is --H or
--CH.sub.3; and R.sup.8 is H or unsubstituted C.sub.1-C.sub.3
alkyl. In some embodiments, R.sup.7 is --H; and R.sup.8 is H or
--CH.sub.3. In some embodiments, R.sup.9 is --H, C.sub.1-C.sub.3
alkyl, cyclopropyl or cyclobutyl; and R.sup.10 is --H or
C.sub.1-C.sub.2 alkyl. In some embodiments, R.sup.9 is --H or
C.sub.1-C.sub.3 alkyl; and R.sup.10 is --H or --CH.sub.3. In some
embodiments, p is 0; R.sup.7 is --H or --CH.sub.3; R.sup.8 is H or
unsubstituted C.sub.1-C.sub.3 alkyl; R.sup.9 is --H,
C.sub.1-C.sub.3 alkyl, cyclopropyl or cyclobutyl; and R.sup.10 is
--H or C.sub.1-C.sub.2 alkyl. In some embodiments, p is 0; R.sup.7
is --H; R.sup.8 is H or --CH.sub.3; R.sup.9 is --H or
C.sub.1-C.sub.3 alkyl; and R.sup.10 is --H or --CH.sub.3. In some
embodiments, R.sup.9 and R.sup.10, together with the nitrogen atom
to which they are attached, form
##STR00021##
In some embodiments, one of n2 and n3 is 0 and the other is 1. In
some embodiments, each of n2 and n3 is 1. In some embodiments, m is
0 or 1. In some embodiments, m is 0. In some embodiments, m is 1 or
2. In some embodiments, m is 1. In some embodiments, R.sup.5 is
halo. In some embodiments, R.sup.5 is --F or --Cl. In some
embodiments, R.sup.5 is --CH.sub.3 or ethyl. In some embodiments,
R.sup.5 is --CH.sub.3. In some embodiments, Z is CH or CH.sub.2. In
some embodiments, Z is O. In some embodiments, each of n2 and n3 is
1; and Z is O.
[0048] As defined above, in some embodiments, A.sup.2 is
--C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10. In
some embodiments, p is 0. In some embodiments, R.sup.7 is --H or
--CH.sub.3; and R.sup.8 is H or unsubstituted C.sub.1-C.sub.3
alkyl. In some embodiments, R.sup.7 is --H; and R.sup.8 is H or
--CH.sub.3. In some embodiments, R.sup.9 is --H, C.sub.1-C.sub.3
alkyl, cyclopropyl or cyclobutyl; and R.sup.10 is --H or
C.sub.1-C.sub.2 alkyl. In some embodiments, R.sup.9 is --H or
C.sub.1-C.sub.3 alkyl; and R.sup.10 is --H or --CH.sub.3. In some
embodiments, p is 0; R.sup.7 is --H or --CH.sub.3; R.sup.8 is H or
unsubstituted C.sub.1-C.sub.3 alkyl; R.sup.9 is --H,
C.sub.1-C.sub.3 alkyl, cyclopropyl or cyclobutyl; and R.sup.10 is
--H or C.sub.1-C.sub.2 alkyl. In some embodiments, p is 0; R.sup.7
is --H; R.sup.8 is H or --CH.sub.3; R.sup.9 is --H or
C.sub.1-C.sub.3 alkyl; and R.sup.10 is --H or --CH.sub.3. In some
embodiments, R.sup.9 and R.sup.10, together with the nitrogen atom
to which they are attached, form
##STR00022##
In some embodiments, m is 0 or 1. In some embodiments, m is 0. In
some embodiments, m is 1 or 2. In some embodiments, m is 1. In some
embodiments, R.sup.5 is halo. In some embodiments, R.sup.5 is --F
or --Cl. In some embodiments, R.sup.5 is --CH.sub.3 or ethyl. In
some embodiments, R.sup.5 is --CH.sub.3.
[0049] In some embodiments, R.sup.9 and R.sup.8, together with the
atoms to which they are attached, form (i.e., R.sup.9 and R.sup.8,
together with the atoms to which they are attached form a ring such
that --C(R.sup.7)(R.sup.8)--(CH.sub.2).sub.p--N(R.sup.9)R.sup.10
is)
##STR00023##
In some embodiments, each of n2 and n3 is 0. In some embodiments,
one of n2 and n3 is 0 and the other is 1. In some embodiments, each
of n2 and n3 is 1. In some embodiments, m is 0 or 1. In some
embodiments, m is 0. In some embodiments, m is 1 or 2. In some
embodiments, m is 1. In some embodiments, R.sup.5 is halo. In some
embodiments, R.sup.5 is --F or --Cl. In some embodiments, R.sup.5
is --CH.sub.3 or ethyl. In some embodiments, R.sup.5 is --CH.sub.3.
In some embodiments, R is --H or C.sub.1-C.sub.3 alkyl. In some
embodiments, R is --H or --CH.sub.3. In some embodiments, R is --H.
In some embodiments, R is --CH.sub.3. In some embodiments, R is
--CH.sub.2--(Z) or --CH.sub.2CH.sub.2--(Z). In some embodiments, R
is --CH.sub.2--(Z). In some embodiments, R is
--CH.sub.2CH.sub.2--(Z). In some embodiments, Z is CH or CH.sub.2.
In some embodiments, Z is O. In some embodiments, each of n2 and n3
is 1; and Z is O.
[0050] As defined above, in some embodiments, or A.sup.1 and
A.sup.2, together with the carbon atom to which they are attached,
form
##STR00024##
In some embodiments, each of n2 and n3 is 0. In some embodiments,
one of n2 and n3 is 0 and the other is 1. In some embodiments, each
of n2 and n3 is 1. In some embodiments, m is 0 or 1. In some
embodiments, m is 0. In some embodiments, m is 1 or 2. In some
embodiments, m is 1. In some embodiments, R.sup.5 is halo. In some
embodiments, R.sup.5 is --F or --Cl. In some embodiments, R.sup.5
is --CH.sub.3 or ethyl. In some embodiments, R.sup.5 is --CH.sub.3.
In some embodiments, R is --H or C.sub.1-C.sub.3 alkyl. In some
embodiments, R is --H or --CH.sub.3. In some embodiments, R is --H.
In some embodiments, R is --CH.sub.3. In some embodiments, R is
--CH.sub.2--(X) or --CH.sub.2CH.sub.2--(X). In some embodiments, R
is --CH.sub.2--(X).
[0051] In some embodiments, a provided compound is a compound of
Formula (I-1):
##STR00025##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, n1, R.sup.6 and w is as described in embodiments
for Formula (I), supra, or described in embodiments herein, both
singly and in combination; and R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are independently --H, halo, --OH, --NH.sub.2, --CH.sub.3,
--CH.sub.2F, --CHF.sub.2 or --CF.sub.3.
[0052] In some embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are --H. In some embodiments, at least three of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are --H. In some embodiments,
each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H. In some
embodiments, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently --H, halo or --CH.sub.3. In some embodiments,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently --H, --F or
--Cl. In some embodiments, each of R.sup.1, R.sup.3 and R.sup.4 is
--H. In some embodiments, each of R.sup.1, R.sup.3 and R.sup.4 is
--H; and R.sup.2 is --H, halo or --CH.sub.3. In some embodiments,
each of R.sup.1, R.sup.3 and R.sup.4 is --H; and R.sup.2 is H, --F
or --Cl. In some embodiments, each of R.sup.1, R.sup.2 and R.sup.4
is --H. In some embodiments, each of R.sup.1, R.sup.2 and R.sup.4
is --H; and R.sup.3 is --H, halo or --CH.sub.3. In some
embodiments, each of R.sup.1, R.sup.2 and R.sup.4 is --H; and
R.sup.3 is H, --F or --Cl.
[0053] In some embodiments, a provided compound is a compound of
Formula (I-1-A):
##STR00026##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, R.sup.6 and w is as described in embodiments for
Formula (I), supra, or described in embodiments herein, both singly
and in combination; and each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is as described in embodiments for Formula (I-1), supra, or
described in embodiments herein, both singly and in
combination.
[0054] In some embodiments, a provided compound is a compound of
Formula (I-1-B):
##STR00027##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, R.sup.6 and w is as described in embodiments for
Formula (I), supra, or described in embodiments herein, both singly
and in combination; and each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is as described in embodiments for Formula (I-1), supra, or
described in embodiments herein, both singly and in
combination.
[0055] In some embodiments, a provided compound is a compound of
Formula (I-2):
##STR00028##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, n1, R.sup.6 and w is as described in embodiments
for Formula (I), supra, or described in embodiments herein, both
singly and in combination; Y.sup.1 is N or CR.sup.1'; Y.sup.2 is N
or CR.sup.2'; Y.sup.3 is N or CR.sup.3'; and Y.sup.4 is N or
CR.sup.4'; wherein 1 to 3 of Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4
are N; and R.sup.1', R.sup.2', R.sup.3' and R.sup.4' are
independently --H, halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F,
--CHF.sub.2 or --CF.sub.3.
[0056] In some embodiments, R.sup.1', R.sup.2', R.sup.3' and
R.sup.4' are independently --H, halo or --CH.sub.3. In some
embodiments, R.sup.1', R.sup.2', R.sup.3' and R.sup.4' are
independently --H, --F or --Cl.
[0057] In some embodiments, 2 of Y.sup.1, Y.sup.2, Y.sup.3 and
Y.sup.4 are N. In some embodiments, 2 of Y.sup.1, Y.sup.2, Y.sup.3
and Y.sup.4 are N; and R.sup.1', R.sup.2', R.sup.3' and R.sup.4'
are independently --H, halo or --CH.sub.3. In some embodiments, 2
of Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are N; and R.sup.1',
R.sup.2', R.sup.3' and R.sup.4' are independently --H, --F or --Cl.
In some embodiments, 2 of Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are
N; and at least 1 of Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 is
CH.
[0058] In some embodiments, 1 of Y.sup.1, Y.sup.2, Y.sup.3 and
Y.sup.4 is N. In some embodiments, 1 of Y.sup.1, Y.sup.2, Y.sup.3
and Y.sup.4 is N; and R.sup.1', R.sup.2', R.sup.3' and R.sup.4' are
independently --H, halo or --CH.sub.3. In some embodiments, 1 of
Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 is N; and R.sup.1', R.sup.2',
R.sup.3' and R.sup.4' are independently --H, --F or --Cl. In some
embodiments, 1 of Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 is N; and
at least 2 of Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are CH. In some
embodiments, Y.sup.2 is N; and R.sup.1', R.sup.3' and R.sup.4' are
independently --H, halo or --CH.sub.3. In some embodiments, Y.sup.2
is N; and R.sup.1', R.sup.3' and R.sup.4' are independently --H,
--F or --Cl. In some embodiments, Y.sup.3 is N; and R.sup.1',
R.sup.2' and R.sup.4' are independently --H, halo or --CH.sub.3. In
some embodiments, Y.sup.3 is N; and R.sup.1', R.sup.2' and R.sup.4'
are independently --H, --F or --Cl.
[0059] In some embodiments, a provided compound is a compound of
Formula (I-2-A):
##STR00029##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, R.sup.6 and w is as described in embodiments for
Formula (I), supra, or described in embodiments herein, both singly
and in combination; and each of Y.sup.1, Y.sup.2, Y.sup.3 and
Y.sup.4 is as described in embodiments for Formula (I-2), supra, or
described in embodiments herein, both singly and in
combination.
[0060] In some embodiments, a provided compound is a compound of
Formula (I-2-B):
##STR00030##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, R.sup.6 and w is as described in embodiments for
Formula (I), supra, or described in embodiments herein, both singly
and in combination; and each of Y.sup.1, Y.sup.2, Y.sup.3 and
Y.sup.4 is as described in embodiments for Formula (I-2), supra, or
described in embodiments herein, both singly and in
combination.
[0061] In some embodiments, a provided compound is a compound of
Formula (I-2-i):
##STR00031##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, n1, R.sup.6 and w is as described in embodiments
for Formula (I), supra, or described in embodiments herein, both
singly and in combination; and each of Y.sup.1, Y.sup.2 and Y.sup.4
is as described in embodiments for Formula (I-2), supra, or
described in embodiments herein, both singly and in
combination.
[0062] In some embodiments, a provided compound is a compound of
Formula (I-3):
##STR00032##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, n1, R.sup.6 and w is as described in embodiments
for Formula (I), supra, or described in embodiments herein, both
singly and in combination; Y.sup.11 is CR.sup.1'' or a heteroatom
selected from O, S, N and NR.sup.11; Y.sup.12 is CR.sup.2'' or a
heteroatom selected from O, S, N and NR.sup.12; and Y.sup.13 is
CR.sup.3'' or a heteroatom selected from O, S, N and NR.sup.13;
wherein at least one of Y.sup.11, Y.sup.12 and Y.sup.13 is a
heteroatom; R.sup.1'', R.sup.2'' and R.sup.3'' are independently
--H, halo, --OH, --NH.sub.2, --CH.sub.3, --CH.sub.2F, --CHF.sub.2
or --CF.sub.3; and R.sup.11, R.sup.12 and R.sup.13 are
independently --H or --CH.sub.3.
[0063] In some embodiments, R.sup.1'', R.sup.2'' and R.sup.3'' are
independently --H, halo, or --CH.sub.3. In some embodiments,
R.sup.1'', R.sup.2'' and R.sup.3'' are independently --H, --F or
--Cl.
[0064] In some embodiments, 2 of Y.sup.1, Y.sup.12 and Y.sup.13 are
heteroatoms. In some embodiments, 2 of Y.sup.11, Y.sup.12 and
Y.sup.13 are heteroatoms; and R.sup.1'', R.sup.2'' and R.sup.3''
are independently --H, halo, or --CH.sub.3. In some embodiments, 2
of Y.sup.11, Y.sup.12 and Y.sup.13 are heteroatoms; and R.sup.1'',
R.sup.2'' and R.sup.3'' are independently --H, --F or --Cl. In some
embodiments, 2 of Y.sup.1, Y.sup.12 and Y.sup.13 are heteroatoms;
and 1 of Y.sup.11, Y.sup.12 and Y.sup.13 is CH.
[0065] In some embodiments, 1 of Y.sup.11, Y.sup.12 and Y.sup.13 is
a heteroatom. In some embodiments, 1 of Y.sup.1, Y.sup.12 and
Y.sup.13 is a heteroatom; and R.sup.1'', R.sup.2'' and R.sup.3''
are independently --H, halo, or --CH.sub.3. In some embodiments, 1
of Y.sup.1, Y.sup.12 and Y.sup.13 is a heteroatom; and R.sup.1'',
R.sup.2'' and R.sup.3'' are independently --H, --F or --Cl. In some
embodiments, 1 of Y.sup.1, Y.sup.12 and Y.sup.13 is a heteroatom;
and at least 1 of Y.sup.1, Y.sup.12 and Y.sup.13 is CH. In some
embodiments, Y.sup.11 is a heteroatom. In some embodiments,
Y.sup.11 is a heteroatom; and R.sup.2'' and R.sup.3'' are
independently --H, halo, or --CH.sub.3. In some embodiments,
Y.sup.11 is a heteroatom; and R.sup.2'' and R.sup.3'' are
independently --H, --F or --Cl. In some embodiments, Y.sup.11 is a
heteroatom; and at least 1 of Y.sup.12 and Y.sup.13 is CH.
[0066] In some embodiments, a provided compound is a compound of
Formula (I-3-A):
##STR00033##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, R.sup.6 and w is as described in embodiments for
Formula (I), supra, or described in embodiments herein, both singly
and in combination; and each of Y.sup.11, Y.sup.12 and Y.sup.13 is
as described in embodiments for Formula (I-3), supra, or described
in embodiments herein, both singly and in combination.
[0067] In some embodiments, a provided compound is a compound of
Formula (I-3-B):
##STR00034##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, R.sup.6 and w is as described in embodiments for
Formula (I), supra, or described in embodiments herein, both singly
and in combination; and each of Y.sup.11, Y.sup.12 and Y.sup.13 is
as described in embodiments for Formula (I-3), supra, or described
in embodiments herein, both singly and in combination.
[0068] In some embodiments, a provided compound is a compound of
Formula (I-3-i):
##STR00035##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, n1, R.sup.6 and w is as described in embodiments
for Formula (I), supra, or described in embodiments herein, both
singly and in combination; and each of Y.sup.12 and Y.sup.13 is as
described in embodiments for Formula (I-3), supra, or described in
embodiments herein, both singly and in combination.
[0069] In some embodiments, a provided compound is a compound of
Formula (I-3-ii):
##STR00036##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, n1, R.sup.6 and w is as described in embodiments
for Formula (I), supra, or described in embodiments herein, both
singly and in combination; and each of Y.sup.12 and Y.sup.13 is as
described in embodiments for Formula (I-3), supra, or described in
embodiments herein, both singly and in combination.
[0070] In some embodiments, a provided compound is a compound of
Formula (I-3-iii):
##STR00037##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, A.sup.2, n1, R.sup.6 and w is as described in embodiments
for Formula (I), supra, or described in embodiments herein, both
singly and in combination; and each of Y.sup.12 and Y.sup.13 is as
described in embodiments for Formula (I-3), supra, or described in
embodiments herein, both singly and in combination. In some
embodiments, R.sup.11 is --H.
[0071] In some embodiments, a provided compound is a compound of
Formula (II):
##STR00038##
or a pharmaceutically acceptable salt thereof, wherein each of Ring
B, A.sup.1, n1, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and w
is as described in embodiments for Formula (I), supra, or described
in embodiments herein, both singly and in combination.
[0072] In some embodiments, a provided compound is a compound of
Formula (II-1):
##STR00039##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, n1, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and w is
as described in embodiments for Formula (I), supra, or described in
embodiments herein, both singly and in combination; and each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described in
embodiments for Formula (I-1), supra, or described in embodiments
herein, both singly and in combination.
[0073] In some embodiments, w is 0. In some embodiments, each of
R.sup.1 and R.sup.4 is --H. In some embodiments, w is 0; and each
of R.sup.1 and R.sup.4 is --H. In some embodiments, R.sup.7 is --H;
and R.sup.8 is --H or --CH.sub.3. In some embodiments, w is 0; each
of R.sup.1 and R.sup.4 is --H; R.sup.7 is --H; and R.sup.8 is --H
or --CH.sub.3. In some embodiments, A.sup.1 is --H or --CH.sub.3.
In some embodiments, w is 0; each of R.sup.1 and R.sup.4 is --H;
R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H.
In some embodiments, w is 0; each of R.sup.1, R.sup.2 and R.sup.4
is --H; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1
is --H. In some embodiments, w is 0; each of R.sup.1, R.sup.2 and
R.sup.4 is --H; R.sup.3 is halo; R.sup.7 is --H; R.sup.8 is --H or
--CH.sub.3; and A.sup.1 is --H. In some embodiments, w is 0; each
of R.sup.1, R.sup.2 and R.sup.4 is --H; R.sup.3 is --F or --Cl;
R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H.
In some embodiments, w is 0; each of R.sup.1, R.sup.3 and R.sup.4
is --H; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1
is --H. In some embodiments, w is 0; each of R.sup.1, R.sup.3 and
R.sup.4 is --H; R.sup.2 is halo; R.sup.7 is --H; R.sup.8 is --H or
--CH.sub.3; and A.sup.1 is --H. In some embodiments, w is 0; each
of R.sup.1, R.sup.3 and R.sup.4 is --H; R.sup.2 is --F or --Cl;
R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H.
In some embodiments, w is 0; each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --H; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and
A.sup.1 is --H.
[0074] In some embodiments, n1 is 1. In some embodiments, n1 is 1;
w is 0; each of R.sup.1, R.sup.2 and R.sup.4 is --H; R.sup.7 is
--H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H. In some
embodiments, n1 is 1; w is 0; each of R.sup.1, R.sup.2 and R.sup.4
is --H; R.sup.3 is halo; R.sup.7 is --H; R.sup.8 is --H or
--CH.sub.3; and A.sup.1 is --H. In some embodiments, n1 is 1; w is
0; each of R.sup.1, R.sup.2 and R.sup.4 is --H; R.sup.3 is --F or
--Cl; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is
--H. In some embodiments, n1 is 1; w is 0; each of R.sup.1, R.sup.3
and R.sup.4 is --H; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3;
and A.sup.1 is --H. In some embodiments, n1 is 1; w is 0; each of
R.sup.1, R.sup.3 and R.sup.4 is --H; R.sup.2 is halo; R.sup.7 is
--H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H. In some
embodiments, n1 is 1; w is 0; each of R.sup.1, R.sup.3 and R.sup.4
is --H; R.sup.2 is --F or --Cl; R.sup.7 is --H; R.sup.8 is --H or
--CH.sub.3; and A.sup.1 is --H. In some embodiments, n1 is 1; w is
0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; R.sup.7 is
--H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H.
[0075] In some embodiments, n1 is 2. In some embodiments, n1 is 2;
w is 0; each of R.sup.1, R.sup.2 and R.sup.4 is --H; R.sup.7 is
--H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H. In some
embodiments, n1 is 2; w is 0; each of R.sup.1, R.sup.2 and R.sup.4
is --H; R.sup.3 is halo; R.sup.7 is --H; R.sup.8 is --H or
--CH.sub.3; and A.sup.1 is --H. In some embodiments, n1 is 2; w is
0; each of R.sup.1, R.sup.2 and R.sup.4 is --H; R.sup.3 is --F or
--Cl; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is
--H. In some embodiments, n1 is 2; w is 0; each of R.sup.1, R.sup.3
and R.sup.4 is --H; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3;
and A.sup.1 is --H. In some embodiments, n1 is 2; w is 0; each of
R.sup.1, R.sup.3 and R.sup.4 is --H; R.sup.2 is halo; R.sup.7 is
--H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H. In some
embodiments, n1 is 2; w is 0; each of R.sup.1, R.sup.3 and R.sup.4
is --H; R.sup.2 is --F or --Cl; R.sup.7 is --H; R.sup.8 is --H or
--CH.sub.3; and A.sup.1 is --H. In some embodiments, n1 is 2; w is
0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; R.sup.7 is
--H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H.
[0076] In some embodiments, R.sup.9 and R.sup.10, together with the
nitrogen atom to which they are attached, form
##STR00040##
In some embodiments, R.sup.9 and R.sup.10, together with the
nitrogen atom to which they are attached, form
##STR00041##
and (a) w is 0; (b) each of R.sup.1 and R.sup.4 is --H; (c) w is 0;
and each of R.sup.1 and R.sup.4 is --H; (d) A.sup.1 is --H or
--CH.sub.3; (e) w is 0; each of R.sup.1 and R.sup.4 is --H; and
A.sup.1 is --H; (f) m is 0; (g) w is 0; each of R.sup.1 and R.sup.4
is --H; A.sup.1 is --H; and m is 0; (h) w is 0; each of R.sup.1,
R.sup.2 and R.sup.4 is --H; A.sup.1 is --H; and m is 0; (i) w is 0;
each of R.sup.1, R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; and m
is 0; (j) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is
--H; A.sup.1 is --H; and m is 0; (k) one of n2 and n3 is 0 and the
other is 1; (1) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --H; A.sup.1 is --H; m is 0; and one of n2 and n3 is 0
and the other is 1; (m) w is 0; each of R.sup.1, R.sup.2, R.sup.3
and R.sup.4 is --H; A.sup.1 is --H; m is 0; one of n2 and n3 is 0
and the other is 1; and Z is CH.sub.2; (n) each of n2 and n3 is 1;
(o) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H;
A.sup.1 is --H; m is 0; and each of n2 and n3 is 1; or (p) w is 0;
each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; A.sup.1 is
--H; m is 0; each of n2 and n3 is 1; and Z is O.
[0077] In some embodiments, R.sup.9 and R.sup.10, together with the
nitrogen atom to which they are attached, form
##STR00042##
In some embodiments, R.sup.9 and R.sup.10, together with the
nitrogen atom to which they are attached, form
##STR00043##
and (a) w is 0; (b) each of R.sup.1 and R.sup.4 is --H; (c) w is 0;
and each of R.sup.1 and R.sup.4 is --H; (d) A.sup.1 is --H or
--CH.sub.3; (e) w is 0; each of R.sup.1 and R.sup.4 is --H; and
A.sup.1 is --H; (f) m is 0; (g) w is 0; each of R.sup.1 and R.sup.4
is --H; A.sup.1 is --H; and m is 0; (h) w is 0; each of R.sup.1,
R.sup.2 and R.sup.4 is --H; A.sup.1 is --H; and m is 0; (i) w is 0;
each of R.sup.1, R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; and m
is 0; or (j) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4
is --H; A.sup.1 is --H; and m is 0.
[0078] In some embodiments, a provided compound is a compound of
Formula (II-1a):
##STR00044##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, n1, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and w is
as described in embodiments for Formula (I) or (II-1), supra, or
described in embodiments herein, both singly and in combination;
and each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described
in embodiments for Formula (I-1) or (II-1), supra, or described in
embodiments herein, both singly and in combination.
[0079] In some embodiments, a provided compound is a compound of
Formula (II-1b):
##STR00045##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, n1, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and w is
as described in embodiments for Formula (I) or (II-1), supra, or
described in embodiments herein, both singly and in combination;
and each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described
in embodiments for Formula (I-1) or (II-1), supra, or described in
embodiments herein, both singly and in combination.
[0080] In some embodiments, a provided compound is a compound of
Formula (II-2):
##STR00046##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, n1, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and w is
as described in embodiments for Formula (I), supra, or described in
embodiments herein, both singly and in combination; and each of
Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 is as described in
embodiments for Formula (I-2), supra, or described in embodiments
herein, both singly and in combination.
[0081] In some embodiments, w is 0. In some embodiments, each of
Y.sup.1 and Y.sup.4 is CH. In some embodiments, w is 0; and each of
Y.sup.1 and Y.sup.4 is CH. In some embodiments, R.sup.7 is --H; and
R.sup.8 is --H or --CH.sub.3. In some embodiments, w is 0; each of
Y.sup.1 and Y.sup.4 is CH; and R.sup.8 is --H or --CH.sub.3. In
some embodiments, A.sup.1 is --H or --CH.sub.3. In some
embodiments, w is 0; each of Y.sup.1 and Y.sup.4 is CH; R.sup.7 is
--H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H. In some
embodiments, w is 0; each of Y.sup.1, Y.sup.2 and Y.sup.4 is CH;
R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H.
In some embodiments, w is 0; each of Y.sup.1, Y.sup.2 and Y.sup.4
is CH; R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; A.sup.1 is
--H; and n1 is 1.
[0082] In some embodiments, a provided compound is a compound of
Formula (II-3):
##STR00047##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, n1, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and w is
as described in embodiments for Formula (I), supra, or described in
embodiments herein, both singly and in combination; and each of
Y.sup.11, Y.sup.12 and Y.sup.13 is as described in embodiments for
Formula (I-3), supra, or described in embodiments herein, both
singly and in combination.
[0083] In some embodiments, w is 0. In some embodiments, each of
Y.sup.12 and Y.sup.13 is CH. In some embodiments, w is 0; and each
of Y.sup.12 and Y.sup.13 is CH. In some embodiments, R.sup.7 is
--H; and R.sup.8 is --H or --CH.sub.3. In some embodiments, w is 0;
each of Y.sup.12 and Y.sup.13 is CH; and R.sup.8 is --H or
--CH.sub.3. In some embodiments, A.sup.1 is --H or --CH.sub.3. In
some embodiments, w is 0; each of Y.sup.12 and Y.sup.13 is CH;
R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; and A.sup.1 is --H.
In some embodiments, w is 0; each of Y.sup.12 and Y.sup.13 is CH;
R.sup.7 is --H; R.sup.8 is --H or --CH.sub.3; A.sup.1 is --H; and
n1 is 1.
[0084] In some embodiments, a provided compound is a compound of
Formula (III):
##STR00048##
or a pharmaceutically acceptable salt thereof, wherein each of Ring
B, A.sup.1, m, n1, n2, n3, R, R.sup.5, R.sup.6, w and Z is as
described in embodiments for Formula (I), supra, or described in
embodiments herein, both singly and in combination.
[0085] In some embodiments, a provided compound is a compound of
Formula (III-1):
##STR00049##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, m, n1, n2, n3, R, R.sup.5, R.sup.6, w and Z is as
described in embodiments for Formula (I), supra, or described in
embodiments herein, both singly and in combination; and each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described in
embodiments for Formula (I-1), supra, or described in embodiments
herein, both singly and in combination.
[0086] In some embodiments, (a) w is 0; (b) each of R.sup.1 and
R.sup.4 is --H; (c) w is 0; and each of R.sup.1 and R.sup.4 is --H;
(d) A.sup.1 is --H or --CH.sub.3; (e) w is 0; each of R.sup.1 and
R.sup.4 is --H; and A.sup.1 is --H; (f) m is 0; (g) w is 0; each of
R.sup.1 and R.sup.4 is --H; A.sup.1 is --H; and m is 0; (h) w is 0;
each of R.sup.1, R.sup.2 and R.sup.4 is --H; A.sup.1 is --H; and m
is 0; (i) w is 0; each of R.sup.1, R.sup.3 and R.sup.4 is --H;
A.sup.1 is --H; and m is 0; (j) w is 0; each of R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; and m is 0; (k) R is
--H or --CH.sub.3; (1) w is 0; each of R.sup.1, R.sup.2, R.sup.3
and R.sup.4 is --H; A.sup.1 is --H; m is 0; and R is --H or
--CH.sub.3; (m) one of n2 and n3 is 0 and the other is 1; (n) w is
0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; A.sup.1 is
--H; m is 0; R is --H or --CH.sub.3; and one of n2 and n3 is 0 and
the other is 1; (o) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --H; A.sup.1 is --H; m is 0; R is --H or --CH.sub.3; one
of n2 and n3 is 0 and the other is 1; and Z is CH or CH.sub.2; (p)
each of n2 and n3 is 1; (q) w is 0; each of R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; m is 0; R is --H or
--CH.sub.3; and each of n2 and n3 is 1; (r) w is 0; each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; m is
0; R is --H or --CH.sub.3; each of n2 and n3 is 1; and Z is CH or
CH.sub.2; or (s) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --H; A.sup.1 is --H; m is 0; R is --H or --CH.sub.3;
each of n2 and n3 is 1; and Z is O.
[0087] In some embodiments, n1 is 1; and (a) w is 0; (b) each of
R.sup.1 and R.sup.4 is --H; (c) w is 0; and each of R.sup.1 and
R.sup.4 is --H; (d) A.sup.1 is --H or --CH.sub.3; (e) w is 0; each
of R.sup.1 and R.sup.4 is --H; and A.sup.1 is --H; (f) m is 0; (g)
w is 0; each of R.sup.1 and R.sup.4 is --H; A.sup.1 is --H; and m
is 0; (h) w is 0; each of R.sup.1, R.sup.2 and R.sup.4 is --H;
A.sup.1 is --H; and m is 0; (i) w is 0; each of R.sup.1, R.sup.3
and R.sup.4 is --H; A.sup.1 is --H; and m is 0; (j) w is 0; each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; and m
is 0; (k) R is --H or --CH.sub.3; (1) w is 0; each of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; m is 0; and R
is --H or --CH.sub.3; (m) one of n2 and n3 is 0 and the other is 1;
(n) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H;
A.sup.1 is --H; m is 0; R is --H or --CH.sub.3; and one of n2 and
n3 is 0 and the other is 1; (o) w is 0; each of R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; m is 0; R is --H or
--CH.sub.3; one of n2 and n3 is 0 and the other is 1; and Z is CH
or CH.sub.2; (p) each of n2 and n3 is 1; (q) w is 0; each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; A.sup.1 is --H; m is
0; R is --H or --CH.sub.3; and each of n2 and n3 is 1; (r) w is 0;
each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; A.sup.1 is
--H; m is 0; R is --H or --CH.sub.3; each of n2 and n3 is 1; and Z
is CH or CH.sub.2; or (s) w is 0; each of R.sup.1, R.sup.2, R.sup.3
and R.sup.4 is --H; A.sup.1 is --H; m is 0; R is --H or --CH.sub.3;
each of n2 and n3 is 1; and Z is O.
[0088] In some embodiments, a provided compound is a compound of
Formula (III-1a):
##STR00050##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, m, n1, n3, R, R.sup.5, R.sup.6, w and Z is as described in
embodiments for Formula (I) or (III-1), supra, or described in
embodiments herein, both singly and in combination; and each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described in
embodiments for Formula (I-1) or (III-1), supra, or described in
embodiments herein, both singly and in combination.
[0089] In some embodiments, a provided compound is a compound of
Formula (III-1b):
##STR00051##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, m, n1, n3, R, R.sup.5, R.sup.6, w and Z is as described in
embodiments for Formula (I) or (III-1), supra, or described in
embodiments herein, both singly and in combination; and each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described in
embodiments for Formula (I-1) or (III-1), supra, or described in
embodiments herein, both singly and in combination.
[0090] In some embodiments, a provided compound is a compound of
Formula (III-1c):
##STR00052##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, m, n1, n3, R, R.sup.5, R.sup.6, w and Z is as described in
embodiments for Formula (I) or (III-1), supra, or described in
embodiments herein, both singly and in combination; and each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described in
embodiments for Formula (I-1) or (III-1), supra, or described in
embodiments herein, both singly and in combination.
[0091] In some embodiments, a provided compound is a compound of
Formula (III-1d):
##STR00053##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, m, n1, n3, R, R.sup.5, R.sup.6, w and Z is as described in
embodiments for Formula (I) or (III-1), supra, or described in
embodiments herein, both singly and in combination; and each of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is as described in
embodiments for Formula (I-1) or (III-1), supra, or described in
embodiments herein, both singly and in combination.
[0092] In some embodiments, a provided compound is a compound of
Formula (III-2):
##STR00054##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, m, n1, n2, n3, R, R.sup.5, R.sup.6, w and Z is as
described in embodiments for Formula (I), supra, or described in
embodiments herein, both singly and in combination; and each of
Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 is as described in
embodiments for Formula (I-2), supra, or described in embodiments
herein, both singly and in combination.
[0093] In some embodiments, a provided compound is a compound of
Formula (III-3):
##STR00055##
or a pharmaceutically acceptable salt thereof, wherein each of
A.sup.1, m, n1, n2, n3, R, R.sup.5, R.sup.6, w and Z is as
described in embodiments for Formula (I), supra, or described in
embodiments herein, both singly and in combination; and each of
Y.sup.11, Y.sup.12 and Y.sup.13 is as described in embodiments for
Formula (I-3), supra, or described in embodiments herein, both
singly and in combination.
[0094] In some embodiments, a provided compound is a compound of
Formula (IV):
##STR00056##
or a pharmaceutically acceptable salt thereof, wherein each of Ring
B, m, n1, n2, n3, R, R.sup.5, R.sup.6, w and X is as described in
embodiments for Formula (I), supra, or described in embodiments
herein, both singly and in combination.
[0095] In some embodiments, a provided compound is a compound of
Formula (IV-1):
##STR00057##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, n2, n3, R, R.sup.5, R.sup.6, w and X is as described in
embodiments for Formula (I), supra, or described in embodiments
herein, both singly and in combination; and each of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 is as described in embodiments for
Formula (I-1), supra, or described in embodiments herein, both
singly and in combination.
[0096] In some embodiments, (a) w is 0; (b) each of R.sup.1 and
R.sup.4 is --H; (c) w is 0; and each of R.sup.1 and R.sup.4 is --H;
(d) m is 0; (e) w is 0; each of R.sup.1 and R.sup.4 is --H; and m
is 0; (f) w is 0; each of R.sup.1, R.sup.2 and R.sup.4 is --H; and
m is 0; (g) w is 0; each of R.sup.1, R.sup.3 and R.sup.4 is --H;
and m is 0; (h) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --H; and m is 0; (i) R is --H or --CH.sub.3; (j) w is 0;
each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; m is 0; and R
is --H or --CH.sub.3; (k) each of n2 and n3 is 0; (1) w is 0; each
of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; m is 0; R is --H
or --CH.sub.3; and each of n2 and n3 is 0; (m) one of n2 and n3 is
0 and the other is 1; (n) w is 0; each of R.sup.1, R.sup.2, R.sup.3
and R.sup.4 is --H; m is 0; R is --H or --CH.sub.3; and one of n2
and n3 is 0 and the other is 1; (o) each of n2 and n3 is 1; or (p)
w is 0; each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; m is
0; R is --H or --CH.sub.3; and each of n2 and n3 is 1.
[0097] In some embodiments, n1 is 1; and (a) w is 0; (b) each of
R.sup.1 and R.sup.4 is --H; (c) w is 0; and each of R.sup.1 and
R.sup.4 is --H; (d) m is 0; (e) w is 0; each of R.sup.1 and R.sup.4
is --H; and m is 0; (f) w is 0; each of R.sup.1, R.sup.2 and
R.sup.4 is --H; and m is 0; (g) w is 0; each of R.sup.1, R.sup.3
and R.sup.4 is --H; and m is 0; (h) w is 0; each of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 is --H; and m is 0; (i) R is --H or
--CH.sub.3; (j) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --H; m is 0; and R is --H or --CH.sub.3; (k) each of n2
and n3 is 0; (1) w is 0; each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --H; m is 0; R is --H or --CH.sub.3; and each of n2 and
n3 is 0; (m) one of n2 and n3 is 0 and the other is 1; (n) w is 0;
each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is --H; m is 0; R is
--H or --CH.sub.3; and one of n2 and n3 is 0 and the other is 1;
(o) each of n2 and n3 is 1; or (p) w is 0; each of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 is --H; m is 0; R is --H or
--CH.sub.3; and each of n2 and n3 is 1.
[0098] In some embodiments, a provided compound is a compound of
Formula (IV-2):
##STR00058##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, n2, n3, R, R.sup.5, R.sup.6, w and X is as described in
embodiments for Formula (I), supra, or described in embodiments
herein, both singly and in combination; and each of Y.sup.1,
Y.sup.2, Y.sup.3 and Y.sup.4 is as described in embodiments for
Formula (I-2), supra, or described in embodiments herein, both
singly and in combination.
[0099] In some embodiments, a provided compound is a compound of
Formula (IV-3):
##STR00059##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, n2, n3, R, R.sup.5, R.sup.6, w and X is as described in
embodiments for Formula (I), supra, or described in embodiments
herein, both singly and in combination; and each of Y.sup.1,
Y.sup.12 and Y.sup.13 is as described in embodiments for Formula
(I-3), supra, or described in embodiments herein, both singly and
in combination.
[0100] Exemplary compounds of formula (I) are set forth in Table 1,
below.
TABLE-US-00001 TABLE 1 ##STR00060## 1 ##STR00061## 2 ##STR00062## 3
##STR00063## 4 ##STR00064## 5 ##STR00065## 6 ##STR00066## 7
##STR00067## 8 ##STR00068## 9 ##STR00069## 10 ##STR00070## 11
##STR00071## 12 ##STR00072## 13 ##STR00073## 14 ##STR00074## 15
##STR00075## 16 ##STR00076## 17 ##STR00077## 18 ##STR00078## 19
##STR00079## 20 ##STR00080## 21 ##STR00081## 22 ##STR00082## 23
##STR00083## 24 ##STR00084## 25 ##STR00085## 26 ##STR00086## 27
##STR00087## 28 ##STR00088## 29 ##STR00089## 30 ##STR00090## 31
##STR00091## 32 ##STR00092## 33 ##STR00093## 34 ##STR00094## 35
##STR00095## 36 ##STR00096## 37 ##STR00097## 38 ##STR00098## 39
##STR00099## 40 ##STR00100## 41 ##STR00101## 42 ##STR00102## 43
##STR00103## 44 ##STR00104## 45 ##STR00105## 46 ##STR00106## 47
##STR00107## 48 ##STR00108## 49 ##STR00109## 50 ##STR00110## 51
##STR00111## 52 ##STR00112## 53 ##STR00113## 54 ##STR00114## 55
##STR00115## 56 ##STR00116## 57 ##STR00117## 58 ##STR00118## 59
##STR00119## 60 ##STR00120## 61 ##STR00121## 62 ##STR00122## 63
##STR00123## 64 ##STR00124## 65 ##STR00125## 66 ##STR00126## 67
##STR00127## 68 ##STR00128## 69
[0101] In some embodiments, the present invention provides a
compound selected from those depicted in Table 1, above, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
pharmaceutically acceptable salt is a hydrochloride salt.
4. Uses, Formulation and Administration and Pharmaceutically
Acceptable Compositions
[0102] According to another embodiment, the invention provides a
composition comprising a compound of this invention, or a
pharmaceutically acceptable salt, ester, or salt of ester thereof,
and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In
some embodiments, the amount of compound in compositions of this
invention is such that is effective to treat, prevent, and/or
manage various neurological and/or psychiatric disorders and/or
symptoms in a patient. In some embodiments, a composition of this
invention is formulated for administration to a patient in need of
such composition. In some embodiments, a composition of this
invention is formulated for oral administration to a patient.
[0103] The term "patient," as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0104] The term "pharmaceutically acceptable carrier, adjuvant, or
vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that
does not destroy the pharmacological activity of the compound with
which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the compositions of this
invention include ion exchangers, alumina, aluminum stearate,
lecithin, serum proteins, such as human serum albumin, buffer
substances such as phosphates, glycine, sorbic acid, potassium
sorbate, partial glyceride mixtures of saturated vegetable fatty
acids, water, salts or electrolytes, such as protamine sulfate,
disodium hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium trisilicate,
polyvinyl pyrrolidone, cellulose-based substances, polyethylene
glycol, sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat.
[0105] A "pharmaceutically acceptable derivative" means any
non-toxic salt, ester, salt of an ester or other derivative of a
compound of this invention that, upon administration to a
recipient, is capable of providing, either directly or indirectly,
a compound of this invention or an active metabolite or residue
thereof.
[0106] Compositions of the present invention may be administered
orally, parenterally, by inhalation spray, topically, rectally,
nasally, buccally, vaginally or via an implanted reservoir. The
term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or infusion techniques. Preferably, the
compositions are administered orally, intraperitoneally or
intravenously. Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium.
[0107] For this purpose, any bland fixed oil may be employed
including synthetic mono- or di-glycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents that are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0108] Pharmaceutically acceptable compositions of this invention
may be orally administered in any orally acceptable dosage form
including capsules, tablets, aqueous suspensions or solutions. In
the case of tablets for oral use, carriers commonly used include
lactose and corn starch. Lubricating agents, such as magnesium
stearate, are also typically added. For oral administration in a
capsule form, useful diluents include lactose and dried cornstarch.
When aqueous suspensions are required for oral use, the active
ingredient is combined with emulsifying and suspending agents. If
desired, certain sweetening, flavoring or coloring agents may also
be added.
[0109] Alternatively, pharmaceutically acceptable compositions of
this invention may be administered in the form of suppositories for
rectal administration. These can be prepared by mixing the agent
with a suitable non-irritating excipient that is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0110] Pharmaceutically acceptable compositions of this invention
may also be administered topically, especially when the target of
treatment includes areas or organs readily accessible by topical
application, including diseases of the eye, the skin, or the lower
intestinal tract. Suitable topical formulations are readily
prepared for each of these areas or organs.
[0111] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0112] For topical applications, provided pharmaceutically
acceptable compositions may be formulated in a suitable ointment
containing the active component suspended or dissolved in one or
more carriers. Carriers for topical administration of compounds of
this invention include mineral oil, liquid petrolatum, white
petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene
compound, emulsifying wax and water. Alternatively, provided
pharmaceutically acceptable compositions can be formulated in a
suitable lotion or cream containing the active components suspended
or dissolved in one or more pharmaceutically acceptable carriers.
Suitable carriers include mineral oil, sorbitan monostearate,
polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0113] For ophthalmic use, provided pharmaceutically acceptable
compositions may be formulated as micronized suspensions in
isotonic, pH adjusted sterile saline, or, preferably, as solutions
in isotonic, pH adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, for
ophthalmic uses, the pharmaceutically acceptable compositions may
be formulated in an ointment such as petrolatum.
[0114] Pharmaceutically acceptable compositions of this invention
may also be administered by nasal aerosol or inhalation. Such
compositions are prepared according to techniques well-known in the
art of pharmaceutical formulation and may be prepared as solutions
in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or dispersing
agents.
[0115] Most preferably, pharmaceutically acceptable compositions of
this invention are formulated for oral administration. Such
formulations may be administered with or without food. In some
embodiments, pharmaceutically acceptable compositions of this
invention are administered without food. In other embodiments,
pharmaceutically acceptable compositions of this invention are
administered with food.
[0116] The amount of compounds of the present invention that may be
combined with the carrier materials to produce a composition in a
single dosage form will vary depending upon a variety of factors,
including the host treated and the particular mode of
administration. Preferably, provided compositions should be
formulated so that a dosage of between 0.01-100 mg/kg body
weight/day of a compound of the present invention can be
administered to a patient receiving these compositions.
[0117] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease being treated. The amount of a compound of the
present invention in the composition will also depend upon the
particular compound in the composition.
5. Uses of Compounds and Pharmaceutically Acceptable
Compositions
[0118] As used herein, the terms "treatment," "treat," and
"treating" refer to reversing, alleviating, delaying the onset of,
or inhibiting the progress of a disease or disorder, or one or more
symptoms thereof, as described herein. In some embodiments,
treatment may be administered after one or more symptoms have
developed. In other embodiments, treatment may be administered in
the absence of symptoms. For example, treatment may be administered
to a susceptible individual prior to the onset of symptoms (e.g.,
in light of a history of symptoms and/or in light of genetic or
other susceptibility factors). Treatment may also be continued
after symptoms have resolved, for example to prevent or delay their
recurrence.
[0119] The compounds and compositions, according to the method of
the present invention, may be administered using any amount and any
route of administration effective for treating a neurological or
psychiatric disorder.
[0120] In some embodiments, the compounds and compositions,
according to the method of the present invention, may be
administered using any amount and any route of administration
effective for treating a neurological and/or psychiatric disorder
in a patient.
[0121] In some embodiments, the neurological or psychiatric
disorder is selected from a psychosis, including schizophrenia
(paranoid, disorganized, catatonic or undifferentiated),
schizophreniform disorder, schizoaffective disorder, delusional
disorder, brief psychotic disorder, shared psychotic disorder,
psychotic disorder due to a general medical condition and
substance-induced or drug-induced (phencyclidine, ketamine and
other dissociative anesthetics, amphetamine and other
psychostimulants and cocaine) psychosispsychotic disorder,
psychosis associated with affective disorders, brief reactive
psychosis, schizoaffective psychosis, "schizophrenia-spectrum"
disorders such as schizoid or schizotypal personality disorders, or
illness associated with psychosis (such as major depression, manic
depressive (bipolar) disorder, Alzheimer's disease and
post-traumatic stress syndrome), including both positive, negative,
and cognitive symptoms of schizophrenia and other psychoses;
cognitive disorders including dementia (associated with Alzheimer's
disease, ischemia, multi-infarct dementia, trauma, vascular
problems or stroke, HIV disease, Parkinson's disease, Huntington's
disease, Down syndrome, Pick's disease, Creutzfeldt-Jacob disease,
perinatal hypoxia, other general medical conditions or substance
abuse); delirium, amnestic disorders or age related cognitive
decline; anxiety disorders including acute stress disorder,
agoraphobia, generalized anxiety disorder, obsessive-compulsive
disorder, panic attack, panic disorder, post-traumatic stress
disorder, separation anxiety disorder, social phobia, specific
phobia, substance-induced anxiety disorder and anxiety due to a
general medical condition; substance-related disorders and
addictive behaviors (including substance-induced delirium,
persisting dementia, persisting amnestic disorder, psychotic
disorder or anxiety disorder; tolerance, dependence or withdrawal
from substances including alcohol, amphetamines, cannabis, cocaine,
hallucinogens, inhalants, nicotine, opioids, phencyclidine,
sedatives, hypnotics or anxiolytics); obesity, bulimia nervosa and
compulsive eating disorders; bipolar disorders, mood disorders
including depressive disorders; depression including unipolar
depression, seasonal depression and post-partum depression,
premenstrual syndrome (PMS) and premenstrual dysphoric disorder
(PDD), mood disorders due to a general medical condition, and
substance-induced mood disorders; learning disorders, pervasive
developmental disorder including autistic disorder, attention
disorders including attention-deficit hyperactivity disorder (ADHD)
and conduct disorder; disorders such as autism, depression, benign
forgetfulness, childhood learning disorders and closed head injury;
movement disorders, including akinesias and akinetic-rigid
syndromes (including Parkinson's disease, drug-induced
parkinsonism, postencephalitic parkinsonism, progressive
supranuclear palsy, multiple system atrophy, corticobasal
degeneration, Parkinsonism-ALS dementia complex and basal ganglia
calcification), medication-induced Parkinsonism (such as
neuroleptic-induced parkinsonism, neuroleptic malignant syndrome,
neuroleptic-induced acute dystonia, neuroleptic-induced acute
akathisia, neuroleptic-induced tardive dyskinesia and
medication-induced postural tremor), Gilles de la Tourette's
syndrome, epilepsy, muscular spasms and disorders associated with
muscular spasticity or weakness including tremors; dyskinesias
{including drug e.g. L-DOPA induced dyskinesia tremor (such as rest
tremor, postural tremor, intention tremor), chorea (such as
Sydenham's chorea, Huntington's disease, benign hereditary chorea,
neuroacanthocytosis, symptomatic chorea, drug-induced chorea and
hemiballism), myoclonus (including generalised myoclonus and focal
myoclonus), tics (including simple tics, complex tics and
symptomatic tics), and dystonia (including generalised dystonia
such as iodiopathic dystonia, drug-induced dystonia, symptomatic
dystonia and paroxymal dystonia, and focal dystonia such as
blepharospasm, oromandibular dystonia, spasmodic dysphonia,
spasmodic torticollis, axial dystonia, dystonic writer's cramp and
hemiplegic dystonia)}; urinary incontinence; neuronal damage
including ocular damage, retinopathy or macular degeneration of the
eye, tinnitus, hearing impairment and loss, and brain edema;
emesis; and sleep disorders including insomnia and narcolepsy.
[0122] In some embodiments, the neurological or psychiatric
disorder is Alzheimer's Disease, Parkinson's Disease, depression,
cognitive impairment, stroke, schizophrenia, Down Syndrome, or
Fetal Alcohol Syndrome. In some embodiments, the neurological or
psychiatric disorder is Alzheimer's Disease. In some embodiments,
the neurological or psychiatric disorder is Parkinson's Disease. In
some embodiments, the neurological or psychiatric disorder is
depression. In some embodiments, the neurological or psychiatric
disorder is cognitive impairment. In some embodiments, the
cognitive impairment is cognitive dysfunction associated with
depression, for example, major depressive disorder. In some
embodiments, the neurological or psychiatric disorder is stroke. In
some embodiments, the neurological or psychiatric disorder is
schizophrenia. In some embodiments, the neurological or psychiatric
disorder is Down Syndrome. In some embodiments, the neurological or
psychiatric disorder is Fetal Alcohol Syndrome.
[0123] In some embodiments, the neurological or psychiatric
disorder involves a deficit in cognition (cognitive domains as
defined by the DSM-5 are: complex attention, executive function,
learning and memory, language, perceptual-motor, social cognition).
In some embodiments, the neurological or psychiatric disorder is
associated with a deficit in dopamine signaling. In some
embodiments, the neurological or psychiatric disorder is associated
with basal ganglia dysfunction. In some embodiments, the
neurological or psychiatric disorder is associated with
dysregulated locomotor activity. In some embodiments, the
neurological or psychiatric disorder is associated with impairment
of prefrontal cortex functioning.
[0124] In some embodiments, the present invention provides a method
of treating one or more symptoms of a neurological and/or
psychiatric disorder provided herein. Such disorders include mood
disorders, including bipolar I disorder, bipolar II disorder,
bipolar depression, mania, cyclothymic disorder,
substance/medication-induced bipolar and related disorders, bipolar
and related disorder due to another medical condition, other
specified bipolar and related disorder, and unspecified bipolar and
related disorders; psychotic disorders, including schizophrenia,
schizophrenia spectrum disorder, acute schizophrenia, chronic
schizophrenia, NOS schizophrenia, schizoid personality disorder,
schizotypal personality disorder, delusional disorder, psychosis,
psychotic disorder, brief psychotic disorder, shared psychotic
disorder, psychotic disorder due to a general medical condition,
drug-induced psychosis (e.g., cocaine, alcohol, amphetamine),
schizoaffective disorder, aggression, delirium, Parkinson's
psychosis, excitative psychosis, Tourette's syndrome, and organic
or NOS psychosis; depressive disorders, including disruptive mood
dysregulation disorder, major depressive disorder (MDD) (including
major depressive episode), dysthymia, persistent depressive
disorder (dysthymia), treatment resistant depression, premenstrual
dysphoric disorder, sub stance/medication-induced depressive
disorder, depressive disorder due to another medical condition,
other specified depressive disorder, and unspecified depressive
disorder; anxiety disorders, including separation anxiety disorder,
selective mutism, specific phobia, social anxiety disorder (social
phobia), panic disorder, panic attack specifier, agoraphobia,
generalized anxiety disorder, substance/medication-induced anxiety
disorder, anxiety disorder due to another medical condition, other
specified anxiety disorder, and unspecified anxiety disorder;
stressor-related disorders, including reactive attachment disorder,
disinhibited social engagement disorder, posttraumatic stress
disorder (PTSD), acute stress disorder, and adjustment disorders;
and other disorders including substance abuse or dependency (e.g.,
nicotine, alcohol, cocaine), addiction, eating disorders, behavior
disorder, seizure, vertigo, epilepsy, agitation, aggression,
neurodegenerative disease, Alzheimer's disease, Parkinson's
disease, dyskinesias, Huntington's disease, dementia, premenstrual
dysphoria; and attention deficit disorder (ADD) and
neurodevelopmental disorders, including attention deficit
hyperactivity disorder (ADHD)), autism, autism spectrum disorder,
obsessive-compulsive disorder, pain (e.g., neuropathic pain,
sensitization accompanying neuropathic pain, and inflammatory
pain), fibromyalgia, migraine, cognitive impairment, movement
disorder, restless leg syndrome (RLS), multiple sclerosis,
Parkinson's disease, Huntington's disease, dyskinesias multiple
sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive
daytime sleepiness, jet lag, drowsy side effect of medications,
insomnia, sexual dysfunction, hypertension, emesis, Lesche-Nyhane
disease, Wilson's disease, and Huntington's chorea. In some
embodiments, the neurological and/or psychiatric disorders include
agitation and aggression. In some embodiments, the agitation and
aggression are associated with Alzheimer's Disease, Parkinson's
Disease, and/or autism. In some embodiments, the neurological
and/or psychiatric disorders are obsessive-compulsive disorder and
related disorders (e.g., body dysmorphic disorder, hoarding
disorder, trichotillomania, excoriation disorder). In some
embodiments, the neurological and/or psychiatric disorders are
disruptive, impulse-control, and conduct disorders including
oppositional defiant disorder, intermittent explosive disorder,
conduct disorder, antisocial personality disorder, pyromania,
kleptomania, other specified disruptive, impulse-control, and
conduct disorder, unspecified disruptive, impulse-control, and
conduct disorder.
[0125] In some embodiments, the present invention provides a method
of treating one or more symptoms including depression (e.g., major
depressive disorder or dysthymia); bipolar disorder, seasonal
affective disorder; cognitive deficit; sleep related disorder
(e.g., sleep apnea, insomnia, narcolepsy, cataplexy) including
those sleep disorders which are produced by psychiatric conditions;
chronic fatigue syndrome; anxieties (e.g., general anxiety
disorder, social anxiety disorder, panic disorder); obsessive
compulsive disorder; post-menopausal vasomotor symptoms (e.g., hot
flashes, night sweats); neurodegenerative disease (e.g.,
Parkinson's disease, Alzheimer's disease and amyotrophic lateral
sclerosis); manic disorder; dysthymic disorder; and obesity.
[0126] In some embodiments, a depressive disorder is associated
with acute suicidality or suicide ideation. The United States Food
and Drug Administration has adopted a "black box" label warning
indicating that antidepressants may increase the risk of suicidal
thinking and behavior in some children, adolescents and young
adults (up to age 24) with a depressive disorder such as MDD. In
some embodiments, a provided compound does not increase the risk of
suicidal thinking and/or behavior in children, adolescents and/or
young adults with a depressive disorder, e.g., with MDD. In some
embodiments, the present invention provides a method of treating
one or more symptoms of a depressive disorder (e.g., MDD) in
children, adolescents and/or young adults without increasing the
risk of suicidal thinking and/or behavior.
[0127] In some embodiments, the present invention provides a method
of treating one or more symptoms including senile dementia,
Alzheimer's type dementia, cognition, memory loss, amnesia/amnestic
syndrome, disturbances of consciousness, coma, lowering of
attention, speech disorder, Lennox syndrome, and hyperkinetic
syndrome.
[0128] In some embodiments, the present invention provides a method
of treating one or more symptoms of neuropathic pain, including
post herpetic (or post-shingles) neuralgia, reflex sympathetic
dystrophy/causalgia or nerve trauma, phantom limb pain, carpal
tunnel syndrome, and peripheral neuropathy (such as diabetic
neuropathy or neuropathy arising from chronic alcohol use).
[0129] In some embodiments, the present invention provides a method
of treating one or more symptoms including obesity; migraine or
migraine headache; and sexual dysfunction, in men or women,
including without limitation sexual dysfunction caused by
psychological and/or physiological factors, erectile dysfunction,
premature ejaculation, vaginal dryness, lack of sexual excitement,
inability to obtain orgasm, and psycho-sexual dysfunction,
including without limitation, inhibited sexual desire, inhibited
sexual excitement, inhibited female orgasm, inhibited male orgasm,
functional dyspareunia, functional vaginismus, and atypical
psychosexual dysfunction.
[0130] In some embodiments, the present invention provides a method
of suppressing rapid eye movement (REM) during both sleep and
daytime equivalent.
[0131] In some embodiments, the present invention provides a method
of suppressing or eliminating pathological or excessive REM during
the night or daytime equivalent.
[0132] In some embodiments, the present invention provides a method
of treating one or more symptoms including cataplexy (sudden
involuntary transient bouts of muscle weakness or paralysis while
awake); nighttime sleep disturbance/sleep fragmentation associated
with narcolepsy or other conditions; sleep paralysis associated
with narcolepsy or other conditions; hypnagogic and hypnapompic
hallucinations associated with narcolepsy or other conditions; and
excessive daytime sleepiness associated with narcolepsy, sleep
apnea or shift work disorder and other medical conditions such as
cancer, chronic fatigue syndrome and fibromyalgia.
[0133] In some embodiments, the present invention provides a method
of treating a neurological and/or psychiatric disorder described
herein, comprising administering a compound of the invention in
conjunction with one or more pharmaceutical agents. Suitable
pharmaceutical agents that may be used in combination with the
compounds of the present invention include anti-Parkinson's drugs,
anti-Alzheimer's drugs, anti-depressants, anti-psychotics,
anti-ischemics, CNS depressants, anti-cholinergics, and nootropics.
In some embodiments, suitable pharmaceutical agents are
anxiolytics.
[0134] Suitable anti-Parkinson's drugs include dopamine replacement
therapy (e.g. L-DOPA, carbidopa, COMT inhibitors such as
entacapone), dopamine agonists (e.g. D1 agonists, D2 agonists,
mixed D1/D2 agonists; bromocriptine, pergolide, cabergoline,
ropinirole, pramipexole, or apomorphine in combination with
domperidone), histamine H2 antagonists, and monoamine oxidase
inhibitors such as selegiline and tranylcypromine.
[0135] In some embodiments, compounds of the invention can be used
in combination with levodopa (with or without a selective
extracerebral decarboxylase inhibitor such as carbidopa or
benserazide), anticholinergics such as biperiden (optionally as its
hydrochloride or lactate salt) and
trihexyphenidyl(benzhexyl)hydrochloride, COMT inhibitors such as
entacapone, MAO A/B inhibitors, antioxidants, A2a adenosine
receptor antagonists, cholinergic agonists, NMDA receptor
antagonists, serotonin receptor antagonists and dopamine receptor
agonists such as alentemol, bromocriptine, fenoldopam, lisuride,
naxagolide, pergolide and pramipexole. It will be appreciated that
the dopamine agonist may be in the form of a pharmaceutically
acceptable salt, for example, alentemol hydrobromide, bromocriptine
mesylate, fenoldopam mesylate, naxagolide hydrochloride and
pergolide mesylate. Lisuride and pramipexole are commonly used in a
non-salt form.
[0136] Suitable anti-Alzheimer's drugs include beta-secretase
inhibitors, gamma-secretase inhibitors, HMG-CoA reductase
inhibitors, NSAID's including ibuprofen, vitamin E, and
anti-amyloid antibodies. In some embodiments, an anti-Alzheimer's
drug is memantine.
[0137] Suitable anti-depressants and anti-anxiety agents include
norepinephrine reuptake inhibitors (including tertiary amine
tricyclics and secondary amine tricyclics), selective serotonin
reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs),
reversible inhibitors of monoamine oxidase (RIMAs), serotonin and
noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing
factor (CRF) antagonists, .alpha.-adrenoreceptor antagonists,
neurokinin-1 receptor antagonists, atypical anti-depressants,
benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A
partial agonists, and corticotropin releasing factor (CRF)
antagonists.
[0138] Specific suitable anti-depressant and anti-anxiety agents
include amitriptyline, clomipramine, doxepin, imipramine and
trimipramine; amoxapine, desipramine, citalopram, escitalopram,
maprotiline, nortriptyline and protriptyline; fluoxetine,
fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine,
tranylcypromine and selegiline; moclobemide: venlafaxine;
desvenlafaxine, duloxetine; aprepitant; bupropion, vilazodone,
mirtazapine, lithium, nefazodone, trazodone and viloxazine;
alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,
halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan,
gepirone and ipsapirone, and pharmaceutically acceptable salts
thereof. In some embodiments, suitable anti-depressant and
anti-anxiety agents are tianeptine, or pharmaceutically acceptable
salts thereof.
[0139] Suitable anti-psychotic and mood stabilizer agents include
D2 antagonists, 5HT2A antagonists, atypical antipsychotics,
lithium, and anticonvulsants.
[0140] Specific suitable anti-psychotic and mood stabilizer agents
include chlorpromazine, fluphenazine, haloperidol, amisulpride,
chlorpromazine, perphenazine, thioridazine, trifluoperazine,
aripiprazole, asenapine, clozapine, olanzapine, paliperidone,
quetiapine, risperidone, ziprasidone, lurasidone, flupentixol,
levomepromazine, pericyazine, perphenazine, pimozide,
prochlorperazine, zuclopenthixol, olanzapine and fluoxetine,
lithium, carbamazepine, lamotrigine, valproic acid and
pharmaceutically acceptable salts thereof.
[0141] In some embodiments, compounds of the invention may be used
in combination with other therapies. Suitable therapies include
psychotherapy, cognitive behavioral therapy, electroconvulsive
therapy, transcranial magnetic stimulation, vagus nerve
stimulation, and deep-brain stimulation.
[0142] The exact amount required will vary from subject to subject,
depending on the species, age, and general condition of the
subject, the severity of the infection, the particular agent, its
mode of administration, and the like. The compounds of the
invention are preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed, and like
factors well known in the medical arts.
[0143] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In some embodiments, the
compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0144] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0145] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0146] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0147] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0148] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0149] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0150] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols and the like.
[0151] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0152] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0153] Depending upon the particular condition, or disease, to be
treated, additional therapeutic agents, which are normally
administered to treat that condition, may be administered in
combination with compounds and compositions of this invention. As
used herein, additional therapeutic agents that are normally
administered to treat a particular disease, or condition, are known
as "appropriate for the disease, or condition, being treated".
[0154] In some embodiments, a combination of 2 or more therapeutic
agents may be administered together with the compounds of the
invention. In some embodiments, a combination of 3 or more
therapeutic agents may be administered with the compounds of the
invention.
[0155] Other examples of agents the compounds of this invention may
also be combined with include: vitamins and nutritional
supplements, antiemetics (e.g. 5-HT3 receptor antagonists, dopamine
antagonists, NK1 receptor antagonists, histamine receptor
antagonists, cannabinoids, benzodiazepines, or anticholinergics),
agents for treating Multiple Sclerosis (MS) such as beta interferon
(e.g., Avonex.RTM. and Rebif.RTM.), Copaxone.RTM., and
mitoxantrone; treatments for asthma such as albuterol and
Singulair.RTM.; anti-inflammatory agents such as corticosteroids,
TNF blockers, IL-1 RA, azathioprine, and sulfasalazine;
immunomodulatory and immunosuppressive agents such as cyclosporin,
tacrolimus, rapamycin, mycophenolate mofetil, interferons,
corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine;
neurotrophic factors such as acetylcholinesterase inhibitors, MAO
inhibitors, interferons, anti-convulsants, ion channel blockers,
riluzole, agents for treating cardiovascular disease such as
beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel
blockers, and statins, fibrates, cholesterol absorption inhibitors,
bile acid sequestrants, and niacin; agents for treating liver
disease such as corticosteroids, cholestyramine, interferons, and
anti-viral agents; agents for treating blood disorders such as
corticosteroids, anti-leukemic agents, and growth factors; agents
for treating immunodeficiency disorders such as gamma globulin; and
anti-diabetic agents such as biguanides (metformin, phenformin,
buformin), thiazolidinediones (rosiglitazone, pioglitazone,
troglitazone), sulfonylureas (tolbutamide, acetohexamide,
tolazamide, chlorpropamide, glipizide, glyburide, glimepiride,
gliclazide), meglitinides (repaglinide, nateglinide),
alpha-glucosidase inhibitors (miglitol, acarbose), incretin
mimetics (exenatide, liraglutide, taspoglutide), gastric inhibitory
peptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin,
saxagliptin, linagliptin, alogliptin), amylin analogs
(pramlintide), and insulin and insulin analogs.
[0156] In some embodiments, a compound of the present invention, or
a pharmaceutically acceptable salt thereof, is administered in
combination with an antisense agent, a monoclonal or polyclonal
antibody, or an siRNA therapeutic.
[0157] Those additional agents may be administered separately from
an inventive compound-containing composition, as part of a multiple
dosage regimen. Alternatively, those agents may be part of a single
dosage form, mixed together with a compound of this invention in a
single composition. If administered as part of a multiple dosage
regime, the two active agents may be submitted simultaneously,
sequentially or within a period of time from one another, normally
within five hours from one another.
[0158] As used herein, the term "combination," "combined," and
related terms refers to the simultaneous or sequential
administration of therapeutic agents in accordance with this
invention. For example, a compound of the present invention may be
administered with another therapeutic agent simultaneously or
sequentially in separate unit dosage forms or together in a single
unit dosage form. Accordingly, the present invention provides a
single unit dosage form comprising a compound of formula I, or a
pharmaceutically acceptable salt thereof, an additional therapeutic
agent, and a pharmaceutically acceptable carrier, adjuvant, or
vehicle.
[0159] The amount of both, an inventive compound and additional
therapeutic agent (in those compositions which comprise an
additional therapeutic agent as described above) that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Preferably, compositions of this invention
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of an inventive can be administered.
[0160] In those compositions which comprise an additional
therapeutic agent, that additional therapeutic agent and the
compound of this invention may act synergistically. Therefore, the
amount of additional therapeutic agent in such compositions will be
less than that required in a monotherapy utilizing only that
therapeutic agent. In such compositions a dosage of between
0.01-100 mg/kg body weight/day of the additional therapeutic agent
can be administered.
[0161] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0162] In some embodiments, the present invention provides a
medicament comprising at least one compound of formula I, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, adjuvant, or vehicle.
[0163] In some embodiments, the present invention provides the use
of a compound of formula I, or a pharmaceutically acceptable salt
thereof, in the manufacture of a medicament for the treatment of a
neurological and/or psychiatric disorder.
EXAMPLES
Example 1. Compounds
[0164] As depicted in the Examples below, in some embodiments,
compounds are prepared according to the following procedures. It
will be appreciated that, although the general methods depict the
synthesis of certain compounds of the present invention, the
following methods, and other methods known to persons skilled in
the art, can be applied to all compounds and subclasses and species
of each of these, as described herein.
Example 1.A. Preparation of 2-(2H-indazol-2-yl)ethanol (I-2)
##STR00129##
[0166] A mixture of 1H-indazole (100 g 847 mmol) in 2-bromoethanol
(420 g 3.39 mol) was stirred at 140.degree. C. for 3 hour. The
mixture was cooled and concentrated. The residue was purified by
flash column chromatography on silica gel (ethyl acetate in
petroleum ether, 1/4 v/v) to give the desired product intermediate
I-2 (120 g, 87%); MS (ESI): m/z 163 [M+H].sup.+.
Example 1.B. Preparation of tert-butyl
2-hydroxy-2-(2-(2-hydroxyethyl)-2H-indazol-3-yl)ethyl(methyl)carbamate
(I-3)
##STR00130##
[0168] To a solution of intermediate I-2 (60 g, 0.37 mol) in THF
(300 mL) at -78.degree. C., LDA (296 mL, 2.5M, 0.74 mol) was added
dropwise over 40 minutes keeping the temperature below -78.degree.
C. the solution was allowed to come to -15.degree. C. when after
tert-butyl methyl(2-oxoethyl)carbamate (128 g, 0.74 mol) in THF
(100 mL) was added dropwise over 20 minutes keeping the temperature
below -78.degree. C. The mixture was allowed to come to rt
overnight and poured into ice water, extracted with ethyl acetate
(3.times.250 mL). The combined organic layers were washed with
brine (2.times.200 mL), dried over sodium sulfate and concentrated.
The crude intermediate I-3 was used in next step without
purification (120 g, 65%); MS (ESI): m/z 336 [M+H].sup.+.
Example 1.C. Preparation of
(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine
(I-4)
##STR00131##
[0170] To a solution of intermediate I-3 (120 g, 358 mmol) in
toluene (400 mL) was added 4-methylbenzenesulfonic acid (123 g, 716
mmol), The reaction was stirred at 0.degree. C. for 3 h, then
stirred at 120.degree. C. for 16 hrs. Upon the completion, the
mixture was washed with water (3.times.200 mL), then concentrated
and purified by column chromatography
(Dichloromethane:methanol=1:20) to give intermediate I-4 (26 g,
33%) as a yellow oil. MS (ESI): m/z 218 [M+H].sup.+; 1H NMR (400
MHz, CDCl3) .delta. 7.68-7.65 (m, 1H), 7.56-7.54 (m, 1H), 7.29-7.26
(m, 1H), 7.06-7.02 (m, 1H), 5.29-5.27 (m, 1H), 4.53-4.50 (m, 1H),
4.43-4.36 (m, 2H), 4.07-4.02 (m, 1H), 3.35-3.31 (m, 1H), 3.14-3.09
(m, 1H), 2.51 (s, 3H).
Example 1.D. Preparation of (tert-butyl
(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl(methyl)carbamate
(I-5)
##STR00132##
[0172] To a solution of intermediate I-4 (26 g, 120 mmol) in
dichloromethane (250 mL) was added triethylamine (24.2 g, 240 mmol)
and di-tert-butyl dicarbonate (52.3 g, 240 mmol) at 0.degree. C.,
the reaction was stirred at 0.degree. C. for 3 h, then stirred at
room temperature for 16 hrs. The mixture was washed with water
(3.times.200 mL), then concentrated and purified by column
chromatography (ethyl acetate/petroleum ether=1:20) to give
intermediate I-5 (32 g, 80%) as a white solid. MS (ESI): m/z 280
[M-56+H].sup.+.
Example 1.E. Preparation of tert-butyl
(R)-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(methyl)carba-
mate (I-6) and tert-butyl
(S)-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(methyl)carba-
mate (I-7)
##STR00133##
[0174] Intermediate I-5 (17 g, 50.7 mmol) was separated into its
enantiomers I-6 and I-7 by chiral HPLC using column CHIRALPAK IC
30*250 mm 5 .mu.m (Daicel) and mobile phase
CO.sub.2/methanol=70/30. The flow rate was 160 g/min, back pressure
was 100 Bar and cycle time of stack injections was 4.2 min.
Intermediate I-6 (7.0 g, 41%, retention time 3.96 min) was obtained
as yellow oil and intermediate I-7 (6.5 g, 38%, retention time 4.56
min) was obtained as yellow oil.
Example 1.F. Preparation of 5-8
(S)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanam-
ine (I-8)
##STR00134##
[0176] To a solution of compound 1 (1.2 g, 4.74 mmol) in methanol
(100 mL) was added paraformaldehyde (284.4 mg, 9.48 mmol) and
NaBH.sub.3CN (597.2 mg, 9.48 mmol) and the mixture was stirred at
40.degree. C. for 2 hours, water (100 mL) was added, extracted with
dichloromethane (3.times.100 mL), combined, dried and then purified
by preparative HPLC in 0.01% ammonia to give intermediate I-8 (1.01
g, 92%); MS (ESI): m/z 232 [M+H].sup.+; 1H NMR (400 MHz, CDCl3)
.delta. 7.67 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.31-7.27
(m, 1H), 7.07-7.04 (m, 1H), 5.32-5.29 (m, 1H), 4.57-4.51 (m, 1H),
4.45-4.39 (m, 2H), 4.08-4.02 (m, 1H), 3.04-3.00 (m, 1H), 2.91-2.85
(m, 1H), 2.44 (s, 6H).
Example 1.G. Preparation of 5-chloro-2H-indazole (I-10)
##STR00135##
[0178] 5-amino-1H-indazole 1-9 (15.41 g, 116 mmol) was suspended in
a mixture of water (250 mL), ice (250 g), and concentrated HCl (100
mL). The mixture was cooled in an ice-salt bath to an internal
temperature of -5.degree. C. To this mixture was added a solution
of sodium nitrite (8.78 g, 127 mmol) in water (75 mL), which had
been cooled to 0.degree. C. The resulting diazonium solution was
stirred for 15 minutes at -5.degree. C. A solution of copper (I)
chloride (14.9 g, 151 mmol) in concentrated HCl (150 mL) was cooled
to 0.degree. C. and then added to the diazonium solution dropwise,
causing an orange precipitate to form. The cooling bath was removed
to allow the reaction to warm to room temperature. Gas evolution
began at 10.degree. C. internal temperature. After stirring at room
temperature for 1.5 hours, the gas evolution subsided. The flask
was then heated to 60.degree. C. for 30 minutes, cooled to
-15.degree. C. while a brown precipitate formed. The precipitate
was collected by suction filtration and dried in a vacuum
desiccator over sodium hydroxide for 16 hours to give crude
intermediate I-10 (25.6 g) as a tan powder that was purified via
silicagel chromatography, eluting with dichloromethane:methanol
20:1 to give intermediate I-10 (8.0 g, 45%); MS (ESI): m/z 153
[M+H].sup.+.
Example 1.H. Preparation of 2-(5-chloro-2H-indazol-2-yl)ethanol
(I-11)
##STR00136##
[0180] Intermediate I-11 was prepared using a procedure analogous
to that described for intermediate I-2, but using intermediate I-10
in place of intermediate I-1 in the procedure of Example 1.A. (5.4
g, white solid, 55%); MS (ESI): m/z 197 [M+H].sup.+.
Example 1.I. Preparation of tert-butyl
(2-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-3-yl)-2-hydroxyethyl)(methyl)c-
arbamate (I-12)
##STR00137##
[0182] A solution of 2.5 M butyllithium in hexane (5.4 mL, 13.53
mmol) was added to a solution of intermediate I-11 (1.21 g, 6.15
mmol) in tetrahydrofuran (15 mL) at -78.degree. C. The solution was
stirred at -78.degree. C. for 30 min and then tert-butyl
methyl(2-oxoethyl)carbamate (2.13 g, 12.13 mmol) was added, the
reaction mixture was warmed slowly to room temperature. After
stirring for 2 h, H.sub.2O (15 mL) was added, the water phase was
extracted by ethyl acetate (30 mL) twice, the organic phase was
washed by brine and dried over Na.sub.2SO.sub.4, the solvent was
removed in vacuo and the residue was purified by reverse-phase
column chromatography to give intermediate I-12 (880 mg black oil,
purity: 62%, 214 nm, 24%) that was used in the following step
without further purification. MS (ESI): m/z 370 [M+H].sup.+.
Example 1.J. Preparation of
1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmetha-
namine (I-13)
##STR00138##
[0184] Intermediate I-13 was prepared using a procedure analogous
to that described for intermediate I-4, but using intermediate I-12
in place of intermediate I-3 in the procedure of Example 1.C. as
the starting material. (435 mg, colorless oil), MS (ESI): m/z 252
[M+H].sup.+. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 7.60 (d,
J=9.4 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.24-7.18 (m, 1H), 5.23 (dd,
J=7.9, 2.9 Hz, 1H), 4.58-4.47 (m, 1H), 4.45-4.36 (m, 2H), 4.06
(ddd, J=12.0, 9.8, 3.6 Hz, 1H), 3.28 (dd, J=13.0, 3.1 Hz, 1H), 3.10
(dd, J=12.8, 8.0 Hz, 1H), 2.53 (s, 3H).
Example 1.K. Preparation of
1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylm-
ethanamine (I-14)
##STR00139##
[0186] Intermediate I-14 was prepared using a procedure analogous
to that described for intermediate I-8, but using compound 5 in
place of compound 1 in the procedure of Example 1.F. as the
starting material. (120 mg, white solid); MS (ESI): m/z 265
[M+H].sup.+; .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 7.60 (d,
J=9.4 Hz, 2H), 7.21 (dd, J=9.1, 2.0 Hz, 1H), 5.24 (dd, J=8.3, 3.4
Hz, 1H), 4.58-4.48 (m, 1H), 4.42 (td, J=5.3, 2.7 Hz, 2H), 4.10-4.01
(m, 1H), 2.95 (dd, J=13.4, 3.6 Hz, 1H), 2.86 (dd, J=13.4, 8.4 Hz,
1H), 2.44 (s, 6H).
Example 1.L. Preparation of
5-fluoro-2-(2-hydroxyethyl)-2H-indazole-3-carbaldehyde (I-16)
##STR00140##
[0188] To a solution of intermediate I-15 (1.9 g, 10.6 mmol,
prepared using a procedure analogous to that described for
intermediate I-2, but using 5-fluoro-1H-indazole in place of
intermediate I-1 in the procedure of Example 1.A. in
tetrahydrofuran (100 mL) at -78.degree. C., n-butyllithium (13.2
mL, 31.7 mmol) was added dropwise. The resulting mixture was
stirred at -78.degree. C. for 30 min then warmed to -20.degree. C.
for 0.5 h and a solution of N,N-dimethylformamide (1.15 g, 15.9
mmol) in tetrahydrofuran (5 mL) was added dropwise. The resulting
mixture was stirred at -78.degree. C. for 1 h. Upon the completion,
the reaction mixture was neutralized with saturated ammonium
chloride solution and extracted with ethyl acetate (3.times.100
mL). The combined organic layers were washed with brine (200 mL),
the solvent was removed to give intermediate I-16 (2.2 g) as a
yellow oil that was used in the following step without further
purification. MS (ESI): m/z 209 [M+H].sup.+.
Example 1.M. Preparation of
9-fluoro-1-methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole
(I-17)
##STR00141##
[0190] To a solution of intermediate I-16 (2.2 g, 10.6 mmol) and
trimethoxymethane (5.6 g, 53.0 mmol) in methanol (50 mL),
p-toluenesulfonic acid (5.0 g, 26.5 mmol) was added in portions.
The resulting mixture was stirred at 45.degree. C. for 1.5 h. Upon
the completion, the reaction mixture was neutralized with saturated
sodium bicarbonate solution and extracted with dichloromethane
(3.times.80 mL). The combined organic layers were washed with brine
(150 mL), dried over sodium sulfate and concentrated and purified
by flash column chromatography on silica gel
(dichloromethane/petroleum ether, 1/1 v/v) to give the desired
product intermediate I-17 (1.4 g, 60%) as a yellow oil. MS (ESI):
m/z 223 [M+H].sup.+.
Example 1.N. Preparation of
9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole-1-carbonitrile
(I-18)
##STR00142##
[0192] To a solution of intermediate I-17 (1.4 g, 6.3 mmol) and
trimethylsilycyanide (3.9 ml, 31.5 mmol) in dichloromethane (50 mL)
at -78.degree. C. boron trifluoride etherate (3.9 ml, 31.5 mmol)
was added dropwise over the course of 10 min. The resulting mixture
was stirred at 30.degree. C. for 1.5 h. Upon the completion, the
reaction mixture was neutralized with saturated sodium bicarbonate
solution, extracted with dichloromethane (3.times.60 mL). The
combined organic layers were washed with brine (100 mL), dried over
sodium sulfate, concentrated and purified by flash column
chromatography on silica gel (dichloromethane/methanol, 100/5 v/v)
to give intermediate I-18 (0.40 g, 29%) as a yellow solid. MS
(ESI): m/z 218 [M+H].sup.+.
Example 1.O. Preparation of
(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanamine
(I-19)
##STR00143##
[0194] To a solution of intermediate I-18 (0.40 g, 1.84 mmol) in
tetrahydrofuran (20 mL) was added lithium tetrahydridoaluminate
(0.11 g, 2.76 mmol). The mixture was stirred at 0.degree. C. for 10
minutes and warmed to room temperature, the mixture was stirred at
room temperature for 0.5 hour. After completion, the reaction was
quenched with water (30 mL), diluted with dichloromethane
(3.times.30 mL) and washed with brine (3.times.30 mL), dried over
sodium sulfate, filtered and concentrated in vacuo to give crude
intermediate I-19 (0.3 g, yellow oil) that was used in the
following step without further purification. MS (ESI): m/z 222
[M+H].sup.+.
Example 1.P. Preparation of tert-butyl
(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methylcarbamate
(I-20)
##STR00144##
[0196] Intermediate I-20 was prepared using a procedure analogous
to that described for intermediate I-5, but using intermediate I-19
in place of intermediate I-4 in the procedure of Example 1.D. (0.20
g, yellow oil); MS (ESI): m/z 322 [M+H].sup.+.
Example 1.Q. Preparation of tert-butyl
((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)
methyl)(ethyl)carbamate (I-22)
##STR00145##
[0198] To a solution of intermediate I-21 (319 mg, 1.05 mmol,
prepared using a procedure analogous to that described for
intermediate I-20 but using intermediate I-2 in place of
intermediate I-15 in the procedure of Example 1.L) in
N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil,
63 mg, 1.58 mmol) at 0.degree. C. The reaction was stirred at
0.degree. C. for 1 hour. Iodoethane (164 mg, 1.05 mmol) was added.
The reaction was stirred at ambient temperature for 3 hours.
Saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (60
mL) were added and the organic phase was washed with water
(2.times.30 mL) and brine (3.times.60 mL). The combined organics
were dried over anhydrous sodium sulfate, filtered and concentrated
in vacuo to give intermediate I-22 (256 mg, amber oil, 74%) that
was used in the following step without further purification. MS
(ESI): m/z 332 [M+H].sup.+.
Example 1.R. Preparation of
1-(2-(2-hydroxyethyl)-2H-indazol-3-yl)ethanone (I-23)
##STR00146##
[0200] Intermediate I-23 was prepared using a procedure analogous
to that described for intermediate I-12, but using intermediate I-2
in place of intermediate I-11 and ethyl acetatein place of
tert-butyl methyl(2-oxoethyl)carbamate in the procedure of Example
1.I. (6.1 g, brown oil); MS (ESI): m/z 205 [M+H].sup.+.
Example 1.S. Preparation of 2-(3-acetyl-2H-indazol-2-yl)ethyl
acetate (I-24)
##STR00147##
[0202] To a solution of intermediate I-23 (6.1 g, 29.87 mmol) in
dichloromethane (200.0 mL) was added acetyl chloride (1.88 g, 23.9
mmol) in one portion at room temperature. To reaction mixture was
added triethylamine (3.02 g, 29.87 mmol) dropwise under nitrogen at
0.degree. C. over 15 min. The reaction mixture was stirred for 1.0
h at room temperature. The reaction mixture was quenched with
sodium hydrogen carbonate aqueous solution (50 mL). The aqueous
phase was extracted with dichloromethane (50 mL.times.3). The
combined organic phase was washed with brine (70 mL.times.3) and
dried over sodium sulphate and concentrated under reduced pressure
to afford the crude product which was purified through silica gel.
(Petroleum ether:ethyl acetate=5:1) to give intermediate I-24 (0.9
g 31%) as a brown oil. MS (ESI): m/z 247 [M+H].sup.+.
Example 1.T. Preparation of
2-(3-(2-bromoacetyl)-2H-indazol-2-yl)ethyl acetate (I-25)
##STR00148##
[0204] To a solution of intermediate I-24 (0.72 g, 2.92 mmol) in a
mixture of glacial acetic acid (2.5 mL) and HBr/glacial acetic acid
(2.5 mL) was added bromine (0.51 g, 3.21 mmol) dropwise under
nitrogen at 0.degree. C. over 10 min and the reaction mixture was
stirred at 40.degree. C. for 1.0 h. The reaction mixture was poured
into 150 g of ice and neutralized with solid sodium carbonate to
pH=7. The aqueous phase was extracted with dichloromethane (50
mL.times.3). The combined organic phase was washed with brine (50
mL.times.3), dried over sodium sulphate and concentrated under
reduced pressure to afford intermediate I-25 (0.95 g, 100%) as a
brown solid. MS (ESI): m/z 325, 327 [M+H].sup.+.
Example 1.U. Preparation of
1-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)pyrrolidin-1-iu-
m chloride (I-26)
##STR00149##
[0206] To a solution of intermediate I-25 (0.652 g, 2.00 mmol) in
acetonitrile (50 mL) was added pyrrolidine (4.9 ml, 60.0 mmol)
dropwise at -50.degree. C. and the reaction mixture was stirred at
room temperature for 2.0 h and then diluted with 25 mL of methanol.
To the reaction mixture was added sodium borohydride (0.304 g, 8.0
mmol) portion wise at room temperature. After 1.0 h, the reaction
mixture was quenched with 50.0 mL of sat. NH.sub.4Cl solution and
the crude reaction mixture was concentrated under reduced pressure.
The residue was dissolved in ethyl acetate (150 mL), washed with
brine (50 mL.times.3), the organic phase was dried over sodium
sulphate, the solids were removed by filtration and the filtrate
was concentrated under reduced pressure. The residue was dissolved
in a solution of methylamine in methanol (40.0 mL, 30%) at room
temperature and the solution was stirred at 70.degree. C. for 3.0
h. The reaction mixture was concentrated under reduced pressure.
4-methyl benzenesulfonic acid (1.548 g, 9.0 mmol) was added to the
solution of the residue in toluene (35.0 mL) in one portion at room
temperature and the reaction mixture was stirred at reflux for 16
hrs. The reaction mixture was poured into saturated sodium
carbonate aqueous solution (80.0 mL). The resulted mixture was
extracted with ethyl acetate (80.0 mL.times.3). The organic phase
was washed with brine (70.0 mL.times.3) and concentrated under
reduced pressure to afford the crude product which was purified
through silica gel. (Dichloromethane:methanol=30:1) to give
intermediate I-26 (87 mg, 17%) as a brown solid. MS (ESI): m/z 258
[M+H].sup.+.
Example 1.V. Preparation of
3,4-dihydrospiro[[1,4]oxazino[4,3-b]indazole-1,3'-pyrrolidin]-1'-ium
chloride (I-27)
##STR00150##
[0208] Intermediate I-27 was prepared using a procedure analogous
to that described for compound 5 but using intermediate I-2 in
place of intermediate I-11 and tert-butyl
3-oxopyrrolidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.I (740
mg, 91%) as a white solid. MS (ESI): m/z 230 [M+H].sup.+.
Example 1.W. Preparation of
(R)-1-((R)-4-methylmorpholin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]inda-
zole (I-29) and
(S)-1-((R)-4-methylmorpholin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]inda-
zole (I-30)
##STR00151##
[0210] Intermediate I-28 was prepared using a procedure analogous
to that described for compound 24 but using (R)-tert-butyl
2-formylmorpholine-4-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.I. The
two diastereomers 1-29 and 1-30 were separated by preparative HPLC
to provide intermediate I-29 (340 mg) and intermediate I-30 (420
mg).
Example 1.X. Preparation of tert-butyl
(+/-)-((R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethyl)ca-
rbamate (I-32) and
(+/-)-tert-butyl((S)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-y-
l)ethyl)carbamate (I-33)
##STR00152##
[0212] To a solution of intermediate I-31 (3.91 g, 11.53 mmol,
prepared using a procedure analogous to that described for
intermediate I-25 but using intermediate I-2 in place of
intermediate I-11 and methyl propionate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.1) in a
mixture of acetonitrile (50.0 mL) and methanol (10.0 mL) was added
a solution of NH.sub.3 in methanol (20.0 M) (80.0 mL) dropwise at
-78.degree. C. and the reaction mixture was stirred at room
temperature for 5.0 h. Sodium tetrahydroborate (1.1 g, 29.0 mmol)
was added portion-wise to the reaction mixture at room temperature
over 5.0 min. After 1 h, the reaction was quenched with water (50.0
mL) and concentrated under reduced pressure. The residue was
dissolved in toluene (250.0 mL) and to this solution was added
4-methylbenzenesulfonic acid (19.4 g, 112.5 mmol) in one portion at
room temperature. The reaction mixture was stirred at reflux for 16
hrs, concentrated under reduced pressure, the residue was dissolved
in methanol (300 mL) and neutralized with solid sodium carbonate
(11.93 g, 112.5 mmol). To this mixture was added triethylamine
(0.96 g, 9.5 mmol) and di-tert-butyl dicarbonate (3.69 g, 16.95
mmol) in one portion at room temperature, the reaction mixture was
stirred at room temperature for 1.5 h and concentrated under
reduced pressure. The residue was dissolved in dichloromethane
(500.0 mL), washed with brine (150.0 mL.times.3), the organic phase
was concentrated under reduced pressure to afford the crude product
which was purified through silica gel.
(dichloromethane:methanol=50:1) and then by preparative TLC
(dichloromethane:methanol=30:1) to provide the low polarity
intermediate I-32 (677 mg, yellow solid, 18%), MS (ESI): m/z 318
[M+H].sup.+ and the high polarity intermediate I-33 (360 mg, yellow
solid, 10%), MS (ESI): m/z 318 [M+H].sup.+.
Example 1.Y. Preparation of (+/-)-tert-butyl
((R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethyl)(methyl)-
carbamate (I-34)
##STR00153##
[0214] To a solution of intermediate I-32 (550.0 mg, 1.73 mmol) in
a mixture of N,N-dimethylformamide (5.0 mL) and tetrahydrofuran
(5.0 mL) was added sodium hydride (60% in oil, 0.139 g, 3.47 mmol)
and iodomethane (0.22 mL, 3.47 mmol) in one portion at room
temperature and the reaction mixture was stirred at room
temperature for 1.0 h. The reaction mixture was quenched with an
aqueous solution of NH.sub.4Cl (10 mL), diluted with
dichloromethane (50 mL) and washed with brine (30 mL.times.3). The
organic phase was dried over sodium sulphate and concentrated under
reduced pressure to afford intermediate I-34 (0.574 g, 100%) as a
brown solid. MS (ESI): m/z 332 [M+H].sup.+.
Example 1.Z. Preparation of tert-butyl
3-hydroxy-3-(2-(2-(methylsulfonyloxy)ethyl)-2H-indazol-3-yl)azetidine-1-c-
arboxylate (I-36)
##STR00154##
[0216] To a solution of intermediate I-35 (prepared using a
procedure analogous to that described for intermediate I-3 but
using tert-butyl 3-oxoazetidine-1-carboxylate in place of
tert-butyl methyl(2-oxoethyl)carbamate in the procedure of Example
1.B. (420 mg, 1.26 mmol) in ethyl acetate (20 ml) was added
triethylamine (0.48 g, 4.72 mmol) and the solution was cooled to
0.degree. C. Methanesulfonyl chloride (0.14 g, 1.26 mmol) was added
in several portions, the reaction mixture was stirred at 0.degree.
C. for 2 hrs and quenched with 30 ml of water. The crude reaction
mixture was extracted with ethyl acetate (3.times.30 mL), the
combined organic phase was dried over sodium sulfate and solids
were removed by filtration. The filtrate was concentrated in vacuo
to give intermediate I-36 (440 mg, 68%, white solid). MS (ESI): m/z
412.1 [M+H].sup.+.
Example 1.AA. Preparation of
(+/-)-1-((S)-morpholin-3-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole
(I-37)
##STR00155##
[0218] Intermediate I-37 was prepared using a procedure analogous
to that described for intermediate I-4 but using (S)-tert-butyl
3-formylmorpholine-4-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B. (1.09
g, brown oil); MS (ESI): m/z 260 [M+H].sup.+.
Example 1.AB. Preparation of tert-butyl (+/-)-(3
S)-3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholine-4-carboxy-
late (I-38)
##STR00156##
[0220] Intermediate I-38 was prepared using a procedure analogous
to that described for intermediate I-5 but using intermediate I-37
in place of intermediate I-4 in the procedure of Example 1.D. (0.72
g, colorless oil); MS (ESI): m/z 360 [M+H].sup.+.
Example 1.AC. Preparation of tert-butyl
(+/-)-(S)-3-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-
e-4-carboxylate (I-39) and tert-butyl
(+/-)-(S)-3-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-
e-4-carboxylate (I-40)
##STR00157##
[0222] Cis/trans diastereomers of intermediate I-38 were separated
by HPLC to provide intermediate I-39 (0.3 g, colorless oil) and
intermediate I-40 (0.21 g, colorless oil).
Example 1.AD. Preparation of 3-(2H-indazol-2-yl)propan-1-ol
(I-41)
##STR00158##
[0224] Intermediate I-41 was prepared using a procedure analogous
to that described for intermediate I-2 but using 3-bromopropan-1-ol
in place of 2-bromoethanol in the procedure of Example 1.A. (51.4
g, brown oil); MS (ESI): m/z 177 [M+H].sup.+.
Example 1.AE. Preparation of
2-(3-(tert-butyldimethylsilyloxy)propyl)-2H-indazole (I-42)
##STR00159##
[0226] To a solution of intermediate I-41 (30 g, 170 mmol) in
N,N-dimethylformamide (400 mL) was added
tert-butylchlorodimethylsilane (38.4 g, 255 mmol) and 1H-imidazole
(23.1 g, 340 mmol). The reaction mixture was stirred at room
temperature for 16 h, concentrated in vacuo and the residue was
purified by silica-gel chromatography (petroleum ether: EtOAc 9:1)
to provide intermediate I-42. (39.7 g, 81%, orange oil); MS (ESI):
m/z 291 [M+H].sup.+.
Example 1.AF. Preparation of tert-butyl
2-(2-(3-(tert-butyldimethylsilyloxy)propyl)-2H-indazol-3-yl)-2-hydroxyeth-
yl(methyl)carbamate (I-43)
##STR00160##
[0228] Intermediate I-43 was prepared using a procedure analogous
to that described for intermediate I-12 but using intermediate I-42
in place of intermediate I-11 in the procedure of Example 1.I. (11
g, orange oil); MS (ESI): m/z 464 [M+H].sup.+.
Example 1.AG. Preparation of tert-butyl
2-hydroxy-2-(2-(3-hydroxypropyl)-2H-indazol-3-yl)ethyl(methyl)carbamate
(I-44)
##STR00161##
[0230] To a solution of intermediate I-43 (1.0 g, 2.16 mmol) in
tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (0.52
g, 2.16 mmol) and the reaction mixture was stirred at ambient
temperature overnight. The crude reaction mixture was extracted
with ethyl acetate, the combined organic layers were dried with
Na.sub.2SO.sub.4. Solids were removed by filtration and the
filtrate was concentrated in vacuo. The resulting oil was purified
by flash column chromatography (dichloromethane/methanol=20/1) to
provide intermediate I-44. (500 mg, 66.2%, yellow oil); MS (ESI):
m/z 350 [M+H].sup.+.
Example 1.AH. Preparation of
N-methyl(1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methanamine
(I-45)
##STR00162##
[0232] Intermediate I-45 was prepared using a procedure analogous
to that described for intermediate I-4 but using intermediate I-44
in place of intermediate I-3 in the procedure of Example 1.C. MS
(ESI): m/z 232 [M+H].sup.+.
Example 1.AI. Preparation of tert-butyl
methyl((1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)carba-
mate (I-46)
##STR00163##
[0234] Intermediate I-46 was prepared using a procedure analogous
to that described for intermediate I-5 but using intermediate I-45
in place of intermediate I-4 in the procedure of Example 1.D. (4.0
g, orange oil); MS (ESI): m/z 332 [M+H].sup.+.
Example 1.AJ. Preparation of
2-(3-hydroxypropyl)-2H-indazole-3-carbaldehyde (I-47)
##STR00164##
[0236] Intermediate I-47 was prepared using a procedure analogous
to that described for intermediate I-16 but using intermediate I-41
in place of intermediate I-15 in the procedure of Example 1.L. (5.5
g, yellow oil); MS (ESI): m/z 286 [M+H].sup.+.
Example 1.AK. Preparation of
2-(2-(3-hydroxypropyl)-2H-indazol-3-yl)-2-(trimethylsilyloxy)acetonitrile
(I-48)
##STR00165##
[0238] To a solution of intermediate I-47 (3.17 g, 15.5 mmol) in
methanol (40 mL) was added zinc(II) iodide (4.94 g, 15.5 mmol) and
trimethylsilanecarbonitrile (3.07 g, 31 mmol). The reaction mixture
was stirred at room temperature for 1 h, concentrated in vacuo, the
crude residue used in the following step without further
purification.
Example 1.AL. Preparation of
3-(3-(2-amino-1-hydroxyethyl)-2H-indazol-2-yl)propan-1-ol
##STR00166##
[0240] To a solution of intermediate I-48 (5.9 g, 19.6 mmol) in
tetrahydrofuran (100 mL) was added Lithium aluminum hydride (1.48
g, 39.2 mmol) and the reaction mixture was stirred at room
temperature for 1 h. Water (20 mL) was added, solids were removed
by filtration and the filtrate was concentrated in vacuo. The crude
residue was used for in the following step without further
purification. MS (ESI): m/z 236 [M+H].sup.+.
Example 1.AM. Preparation of
(1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methanamine
(I-50)
##STR00167##
[0242] Intermediate I-50 was prepared using a procedure analogous
to that described for intermediate I-4 but using intermediate I-49
in place of intermediate I-3 in the procedure of Example 1.C. MS
(ESI): m/z 218 [M+H].sup.+.
Example 1.AN. Preparation of tert-butyl
(1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methylcarbamate
(I-51)
##STR00168##
[0244] Intermediate I-51 was prepared using a procedure analogous
to that described for intermediate I-5 but using intermediate I-50
in place of intermediate I-4 in the procedure of Example 1.D. (160
mg); MS (ESI): m/z 318 [M+H].sup.+.
Example 1.AO. Preparation of tert-butyl
ethyl((1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)carbam-
ate (I-52)
##STR00169##
[0246] To a solution of intermediate I-51 (140 mg, 441 .mu.mol) in
N,N-Dimethyl formamide (5 mL) was added sodium hydride (27 mg, 1.12
mmol) and iodoethane (232 mg, 1.49 mmol) and the reaction was
stirred at room temperature for 3 h. Water (5 mL) was added
followed by ethyl acetate (20 mL) and the resulting biphasic
mixture was transferred to a separatory funnel. The layers were
separated and the organic phase was washed with water (2.times.10
mL) and brine (2.times.10 mL). The combined organic layers were
dried over anhydrous sodium sulfate, solids were removed by
filtration and the filtrate was concentrated in vacuo. The residue
was purified by preparative thin layer chromatography with petrol
ether/ethyl acetate=3/1 to provide intermediate I-52. (120 mg, 79%,
clear oil); MS (ESI): m/z 346 [M+H].sup.+.
Example 1.AP. Preparation of 3-bromothiophene-2-carbaldehyde
(I-53)
##STR00170##
[0248] To a solution of 3-bromothiophene (25 g, 153 mmol) in
tetrahydrofuran (250 mL) was added 2 M Lithium diisopropylamide in
tetrahydrofuran (77 mL, 154 mmol) at 0.degree. C. and the reaction
mixture was stirred at 0.degree. C. for 1 h. N,N-dimethylformamide
(12.2 g, 168 mmol) was added and the reaction mixture was allowed
to warm to room temperature and stirred for additional 2 h. Water
(100 mL) was added and extracted with ethyl acetate (500
mL.times.3) was performed. The combined organic layer were dried
over anhydrous magnesium sulfate, solids were removed by filtration
and the filtrate was concentrated by evaporation in vacuo. The
residue was purified by silica gel chromatography (petrol
ether/ethyl acetate=10/1) to provide intermediate I-53 (20 g, 68%).
MS (ESI): m/z 190 [M+H].sup.+.
Example 1.AQ. Preparation of 3-azidothiophene-2-carbaldehyde
(I-54)
##STR00171##
[0250] To a solution of intermediate I-53 (2.0 g, 10.47 mmol) in
dimethyl sulfoxide (15 mL) was added sodium azide (2.72 g, 41.88
mmol) and the solution was stirred at 80.degree. C. for 4h. Water
(100 mL) was added, the aqueous layer was extracted by ethyl
acetate (2.times.100 mL), the organic phase was washed by brine and
dried over anhydrous sodium sulfate. Solids were removed by
filtration, and the filtrate was concentrated in vacuo. The residue
was purified by silica gel chromatography (petrol ether/ethyl
acetate=5/1) to provide intermediate I-54 (840 mg, 52%). MS (ESI):
m/z 154 [M+H].sup.+.
Example 1.AR. Preparation of
2-(2H-thieno[3,2-c]pyrazol-2-yl)ethanol (I-55)
##STR00172##
[0252] To a solution of intermediate I-54 (1.45 g, 9.47 mmol) in
toluene (20 mL) was added 2-aminoethanol (1.16 g, 18.94 mmol) and
the reaction mixture was stirred at 120.degree. C. for 3h. The
crude reaction mixture was concentrated in vacuo, water (20 mL) was
added, the aqueous phase was extracted by ethyl acetate (2.times.50
mL), the combined organic layers were washed with brine (50 mL) and
the dried over anhydrous sodium sulfate. Solids were removed by
filtration, the filtrate was concentrated in vacuo and the residue
was purified by silica gel column chromatography (petrol
ether:ethyl acetate=5:1) to provide intermediate I-55. (400 mg,
25%, yellow oil); MS (ESI): m/z 169 [M+H].sup.+.
Example 1.AS. Preparation of tert-butyl
2-hydroxy-2-(2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazol-3-yl)ethyl(methyl-
)carbamate (I-56)
##STR00173##
[0254] Intermediate I-56 was prepared using a procedure analogous
to that described for intermediate I-3 but using intermediate I-55
in place of intermediate I-2 in the procedure of Example 1.B. (170
mg, 12%, white solid); MS (ESI): m/z 342 [M+H].sup.+.
Example 1.AT. Preparation of
1-(7,9-dihydro-6H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-met-
hylmethanamine (I-57)
##STR00174##
[0256] Intermediate I-57 was prepared using a procedure analogous
to that described for intermediate I-4 but using intermediate I-56
in place of intermediate I-3 in the procedure of Example 1.C. MS
(ESI): m/z 224 [M+H].sup.+.
Example 1.AU. Preparation of tert-butyl
((7,9-dihydro-6H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)methyl)-
(methyl)carbamate (I-58)
##STR00175##
[0258] Intermediate I-58 was prepared using a procedure analogous
to that described for intermediate I-5 but using intermediate I-57
in place of intermediate I-4 in the procedure of Example 1.D. (95
mg, white solid); MS (ESI): m/z 324 [M+H].sup.+.
Example 1.AV. Synthesis of
2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazole-3-carbaldehyde
(I-59)
##STR00176##
[0260] Intermediate I-59 was prepared using a procedure analogous
to that described for intermediate I-16 but using intermediate I-55
in place of intermediate I-15 in the procedure of Example 1.L. (600
mg, yellow oil); MS (ESI): m/z 197 [M+H].sup.+.
Example 1.AW. Synthesis of
2-(2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazol-3-yl)-2-(trimethylsilyloxy)-
acetonitrile (I-60)
##STR00177##
[0262] Intermediate I-60 was prepared using a procedure analogous
to that described for intermediate I-48 but using intermediate I-59
in place of intermediate I-47 in the procedure of Example 1.AK.
Example 1.AX. Synthesis of
2-amino-1-(2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazol-3-yl)ethanol
(I-61)
##STR00178##
[0264] Intermediate I-61 was prepared using a procedure analogous
to that described for intermediate I-49 but using intermediate I-60
in place of intermediate I-48 in the procedure of Example 1.AL. MS
(ESI): m/z 228 [M+H].sup.+.
Example 1.AY. Synthesis of
(7,9-dihydro-6H-thieno[3',2':3,4]pyrazolo[5,
1-c][1,4]oxazin-9-yl)methanamine (I-62)
##STR00179##
[0266] Intermediate I-62 was prepared using a procedure analogous
to that described for intermediate I-4 but using intermediate I-61
in place of intermediate I-3 in the procedure of Example 1.C. MS
(ESI): m/z 210 [M+H].sup.+.
Example 1.AZ. Synthesis of tert-butyl
((7,9-dihydro-6H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)methyl)-
carbamate (I-63)
##STR00180##
[0268] Intermediate I-63 was prepared using a procedure analogous
to that described for intermediate I-5 but using intermediate I-62
in place of intermediate I-4 in the procedure of Example 1.D. (165
mg, 12%, yellow oil); MS (ESI): m/z 310 [M+H]+.
Example 1.BA. Synthesis of N-(4-methylpyridin-3-yl)acetamide
(I-64)
##STR00181##
[0270] Into a 250 mL round bottom flask was placed a solution of
4-methylpyridin-3-amine (10 g, 92.47 mmol, 1.00 equiv) in acetic
anhydride (50 mL). The resulting solution was stirred for 1 hour at
room temperature. Water (200 ml) was added, the pH of the solution
was adjusted to 7 by addition of sodium carbonate (1M solution in
water). The crude reaction mixture was extracted with ethyl acetate
(3.times.300 ml), the combined organic layers were dried over
anhydrous sodium sulfate, solids were removed by filtration and the
filtrate was concentrated in vacuo. The residue was purified by
silicagel-gel chromatography (dichloromethane/methanol: 20/1) to
provide intermediate I-64. (12 g, 94%); MS (ESI): m/z 151
[M+H].sup.+.
Example 1.BB. Synthesis of Preparation of tert-butyl
3-(3-acetamidopyridin-4-yl)-2-hydroxypropyl(methyl)carbamate
(I-65)
##STR00182##
[0272] To a solution of intermediate I-64 (2.5 g) in dry THF (70
mL) at -78.degree. C. under argon was added n-BuLi (17 mL, 2.5 M in
hexanes) and the reaction mixture was stirred at -78.degree. C. for
15 min and then at -25.degree. C. for additional 90 min. The
reaction mixture was cooled to -78.degree. C. and a solution of
tert-butyl methyl(2-oxoethyl)carbamate (3.46 g) in dry
tetrahydrofuran (20 mL) was added drop-wise. The reaction mixture
was stirred at -78.degree. C. for 10 min and then at -20.degree. C.
for additional 3 h. A saturated aqueous solution of ammonium
chloride was added to quench excess n-BuLi. The crude reaction
mixture was concentrated in vacuo, water was added to the residue
and extraction with dichloromethane (4.times.50 mL) was performed.
The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, solids were removed by filtration and the
filtrate was concentrated in vacuo. The orange oily residue was
purified by silicagel chromatography (dichloromethane/methanol
50/1) to provide intermediate I-65. (2.69 g, 50%, light-yellow
oil); MS (ESI): m/z 324 [M+H].sup.+.
Example 1.BC. Synthesis of
1-(1-acetyl-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-(tert-butoxycarbonyl(methyl-
)amino)ethyl acetate (I-66)
##STR00183##
[0274] To a suspension of intermediate I-65 (1.0 g, 3.09 mmol) in
dry toluene (30 mL) under argon were added potassium acetate (314
mg, 2.0 mmol) and acetic anhydride (0.8 mL, 8.1 mmol). The reaction
mixture was stirred at 80.degree. C. while isoamyl nitrite (1.1 mL,
7.72 mmol) was added drop-wise and the reaction mixture was heated
at 100.degree. C. for 16 h. Solids were removed by filtration, the
residue was washed with hot toluene and the combined filtrates were
concentrated in vacuo to afford intermediate I-66 that was used in
the following step without further purification. (1.0 g, dark oil);
MS (ESI): m/z 377 [M+H].sup.+.
Example 1.BD. Synthesis of tert-butyl
2-(2-hydroxyethoxy)-2-(2H-pyrazolo[3,4-c]pyridin-3-yl)ethyl(methyl)carbam-
ate (I-67)
##STR00184##
[0276] To a solution of intermediate I-66 (1.8 g, 4.78 mmol) in
ethane-1,2-diol (10 mL) was added sodium hydroxide (0.57 g, 14.34
mmol) and the reaction mixture was stirred at ambient temperature
for 24 h. Ethyl acetate (100 mL) was added and extraction was
performed. The combined organic layers were washed with brine
(3.times.20 mL), dried over anhydrous sodium sulfate, solids were
removed by filtration and the filtrate was concentrated in vacuo.
The residue was purified by silica gel chromatography
(dichloromethane/methanol) to provide intermediate 1-67 (0.03 g,
2%, oil); MS (ESI): m/z 337 [M+H].sup.+.
Example 1.BE. Synthesis of tert-butyl
((3,4-dihydro-1H-pyrido[3',4':3,4]pyrazolo[5,
1-c][1,4]oxazin-1-yl)methyl)(methyl)carbamate (I-68)
##STR00185##
[0278] To a solution of intermediate I-67 (500 mg) and
triphenylphosphine (776 mg) in dry tetrahydrofuran (50 mL) at
0.degree. C. under argon was added DIAD (600 mg) and the reaction
mixture was stirred at room temperature for 12 h. Water (30 mL) and
ethyl acetate (2.times.100 mL) were added and extraction was
performed. The combined organic layers were washed with brine
(2.times.30 mL), dried over anhydrous sodium sulfate, solids were
removed by filtration and the filtrate was concentrated in vacuo.
The residue was purified by silica gel chromatography (petroleum
ether/ethyl acetate) to provide intermediate I-68. (300 mg, 64%,
white solid); MS (ESI): m/z 319 [M+H].sup.+.
Example 1.BF. Preparation of tert-butyl
(S)-2-(2-(2-hydroxyethyl)-2H-indazole-3-carbonyl)-azetidine-1-carboxylate
(I-69)
##STR00186##
[0280] A solution of intermediate I-2 (3.24 g, 19.9 mmol) in THF
(60 mL) was cooled to -78.degree. C., a solution of n-BuLi (4.45 g,
69.6 mmol 2.5M in hexanes) was added dropwise and the reaction
mixture was stirred at -78.degree. C. for 1 hr. A solution of
(S)-tert-butyl 2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate
(4.86 g, 19.9 mmol) in THF (30 mL) was added to the mixture and
allowed to warm to room temperature over the course of 1 hr. The
reaction mixture was quenched with brine (50 mL), extracted with
ethyl acetate (50 mL.times.3), the combined organic phase was dried
over Na.sub.2SO.sub.4, solids were removed by filtration, the
filtrate was concentrated in vacuo and the residue was purified by
silicagel chromatography to give intermediate I-69 (552 mg, 8%) as
a yellow oil. MS (ESI): m/z 346 [M+H].sup.+.
Example 1.BG. Preparation of tert-butyl
(2S)-2-(hydroxy(2-(2-hydroxyethyl)-2H-indazol-3-yl)methyl)azetidine-1-car-
boxylate (I-70)
##STR00187##
[0282] To a solution of intermediate I-69 (700 mg, 2.02 mmol) in
MeOH (10 mL) was added solid NaBH.sub.4 (76.4 mg, 2.02 mmol) and
the reaction mixture was stirred at ambient temperature for 16 hrs.
The crude reaction mixture was concentrated in vacuo and the
residue was purified by silicagel chromatography to give
intermediate I-70 (402 mg, 57%) as yellow oil. MS (ESI): m/z 348
[M+H].sup.+.
Example 1.BH. Preparation of tert-butyl
(2S)-2-(hydroxy(2-(2-((methyl
sulfonyl)oxy)ethyl)-2H-indazol-3-yl)methyl)azetidine-1-carboxylate
(I-71)
##STR00188##
[0284] Intermediate I-71 was prepared using a procedure analogous
to that described for intermediate I-36 but using intermediate I-70
in place of intermediate I-35 in the procedure of Example 1.Z. (497
mg, 45%) as yellow oil. MS (ESI): m/z 426 [M+H].sup.+.
Example 1.1. Preparation of
(S)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanaminiu-
m chloride (1)
##STR00189##
[0286] To a solution of intermediate I-7 (2.0 g, 6.0 mmol) in
dichloromethane (20 mL) was added 4 M HCl/methanol (8 mL) dropwise,
the resulting solution was stirred for 10 min and concentrated to
give compound 1 (1.30 g, 86%) as a white solid. MS (ESI): m/z 218
[M+H].sup.+, .sup.1H-NMR (400 MHz, MeOD): .delta. 7.68-7.71 (d,
J=8.4 Hz, 1H), 7.48-7.57 (m, 2H), 7.23-7.27 (m, 1H), 5.61-5.63 (m,
1H), 4.36-4.53 (m, 3H), 4.08-4.14 (m, 1H), 3.77-3.81 (m, 1H),
3.50-3.56 (m, 1H), 2.67 (s, 3H).
Example 1.2. Preparation of
(R)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanaminiu-
m chloride (2)
##STR00190##
[0288] Compound 2 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-6 in place of
intermediate I-7 in the procedure of Example 1.1. (1.25 g, white
solid); MS (ESI): m/z 218 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD):
.delta. 7.64-7.66 (d, J=8.8 Hz, 1H), 7.46-7.55 (m, 2H), 7.19-7.24
(m, 1H), 5.56-5.59 (m, 1H), 4.38-4.71 (m, 3H), 4.09-4.15 (m, 1H),
3.76-3.81 (m, 1H), 3.50-3.56 (m, 1H), 2.71 (s, 3H).
Example 1.3.Preparation of 5-9
(S)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanam-
inium chloride (3)
##STR00191##
[0290] To a solution of intermediate I-8 (1.0 g, 4.33 mmol) in
dichloromethane (20 mL) was added 4 M HCl/methanol (8 mL) dropwise,
the resulting solution was stirred for 2 min and concentrated to
give compound 3 (1.1 g, 86%) as a white solid. MS (ESI): m/z 232
[M+H].sup.+, .sup.1H-NMR (400 MHz, MeOD): .delta. 7.58-7.64 (m,
2H), 7.42-7.44 (d, J=6.8 Hz, 1H), 7.18 (s, 1H), 5.64-5.69 (m, 1H),
4.39-4.53 (m, 3H), 4.11-4.17 (m, 1H), 3.88-3.91 (d, J=13.2 Hz, 1H),
3.59-3.65 (m, 1H), 3.02 (s, 3H), 2.87 (s, 3H).
Example 1.4. Preparation of
(R)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanam-
inium chloride (4)
##STR00192##
[0292] Compound 4 was prepared using a procedure analogous to that
described for compound 3 but using compound 2 in place of compound
1 in the procedure of Example 1.F. (1.1 g, white solid); MS (ESI):
m/z 232 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD): .delta. 7.51-7.53
(m, 2H), 7.33-7.37 (m, 1H), 7.10-7.13 (m, 1H), 5.44-5.47 (m, 1H),
4.28-4.44 (m, 3H), 4.03-4.09 (m, 1H), 3.78-3.82 (m, 1H), 3.46-3.52
(m, 1H), 2.99 (s, 3H), 2.86 (s, 3H).
Example 1.5. Preparation of
1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmetha-
naminium chloride (5)
##STR00193##
[0294] Compound 5 was prepared using a procedure analogous to that
described for compound 3 but using intermediate I-13 in place of
intermediate I-8 in the procedure of Example 1.3. (145 mg, white
solid); MS (ESI): m/z 252 [M+H].sup.+.
Example 1.6. Preparation of
1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylm-
ethanaminium chloride (6)
##STR00194##
[0296] Compound 6 was prepared using a procedure analogous to that
described for compound 3 but using intermediate I-14 in place of
intermediate I-8 in the procedure of Example 1.3. (115 mg, white
solid); MS (ESI): m/z 265 [M+H].sup.+.
Example 1.7. Preparation of
1-(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmetha-
naminium chloride (7)
##STR00195##
[0298] Compound 7 was prepared using a procedure analogous to that
described for compound 5 but using 5-fluoro-1H-indazole in place of
1H-indazole in the procedure of Example 1.A. (450 mg, white solid);
MS (ESI): m/z 236 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD): .delta.
7.70-7.74 (d, J=9.6, 1H), 7.58-7.60 (d, J=9.6, 1H), 7.25-7.39 (m,
1H), 5.64-5.67 (dd, J=8.8 Hz, J.sub.2=2.4 Hz, 1H), 4.60-4.64 (m,
1H), 4.53-4.58 (m, 2H), 4.24-4.29 (m, 1H), 3.91-3.95 (d, J=9.6,
1H), 3.59-3.65 (m, 1H), 2.85 (s, 3H).
Example 1.8. Preparation of
1-(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylm-
ethanaminium chloride (8)
##STR00196##
[0300] Compound 8 was prepared using a procedure analogous to that
described for compound 3 but using compound 7 in place of compound
1 in the procedure of Example 1.F. (240 mg, white solid); MS (ESI):
m/z 250 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD): .delta. 7.70-7.74
(d, J=9.6, 1H), 7.63-7.66 (d, J=9.6, 1H), 7.30-7.36 (m, 1H),
5.82-5.85 (dd, J=10.4, 2.8 Hz, 1H), 4.62-4.68 (m, 1H), 4.55-4.60
(m, 2H), 4.27-4.33 (m, 1H), 4.06-4.10 (d, J=13.6, 1H), 3.70-3.76
(m, 1H), 3.15 (s, 3H), 3.04 (s, 3H).
Example 1.9. Preparation of
(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanaminium
chloride (9)
##STR00197##
[0302] Compound 9 was prepared a procedure analogous to that
described for compound 1 but using intermediate I-20 in place of
intermediate I-7 in the procedure of Example 1.1. (60 mg, white
solid); MS (ESI): m/z 222 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD):
.delta. 7.70-7.73 (d, J=9.2, 1H), 7.49-7.52 (d, J=9.6, 1H),
7.27-7.32 (m, 1H), 5.55-5.58 (dd, J=7.8, 2.8 Hz, 1H), 4.59-4.62 (m,
1H), 4.52-4.56 (m, 2H), 4.22-4.28 (m, 1H), 3.79-3.83 (d, J=13.6 Hz,
1H), 3.51-3.57 (m, 1H).
Example 1.10. Preparation of
1-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmetha-
naminium (10)
##STR00198##
[0304] Compound 10 was prepared using a procedure analogous to that
described for compound 5 but using 6-fluoro-1H-indazole in place of
1H-indazole in the procedure of Example 1.A. (450 mg, white solid);
MS (ESI): m/z 236 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD): .delta.
8.07-8.03 (m, 1H), 7.41-7.38 (dd, J=9.6, 2.4 Hz, 1H), 7.20-7.15 (m,
1H), 5.76 (d, J=1.6 Hz, 1H), 4.65 (m, 1H), 4.57 (d, J=9.2 Hz, 2H),
4.29 (t, J=8.8 Hz, 1H), 4.01 (m, 1H), 3.67 (m, 1H), 3.33 (m, 1H),
2.86 (s, 3H).
Example 1.11. Preparation of
1-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylm-
ethanaminium (11)
##STR00199##
[0306] Compound 11 was prepared using a procedure analogous to that
described for compound 3 but using compound 10 in place of compound
1 in the procedure of Example 1.F. (240 mg, white solid); MS (ESI):
m/z 250 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD): .delta. 8.07-8.10
(m, 1H), 7.39-7.36 (dd, J=9.6, 2.4 Hz, 1H), 7.20-7.15 (m, 1H), 5.92
(d, J=2.4 Hz, 1H), 4.68 (m, 1H), 4.57-4.62 (m, 2H), 4.32 (m, 1H),
4.18-4.14 (d, J=3.2, 1H), 3.83-3.77 (m, 1H), 3.18 (s, 3H), 3.07 (s,
1H).
Example 1.12. Preparation of
(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanaminium
(12)
##STR00200##
[0308] Compound 12 was prepared using a procedure analogous to that
described for compound 9 but using 6-fluoro-1H-indazole in place of
1H-indazole in the procedure of Example 1.A. (60 mg, white solid);
MS (ESI): m/z 222 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD): .delta.
8.04-8.01 (m, 1H), 7.41-7.38 (dd, J=9.6, 2.4 Hz, 1H), 7.19-7.15 (m,
1H), 5.71 (d, J=6.0 Hz 1H), 4.68-4.57 (m, 3H), 4.29 (m, 1H), 3.89
(d, J=7.2 Hz, 1H), 3.63 (m, 1H).
Example 1.13. Preparation of
1-((S)-pyrrolidin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole
hydrochloride (13)
##STR00201##
[0310] Compound 13 was prepared using a procedure analogous to that
described for compound 5 but using (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B. (80
mg, yellow oil); MS (ESI): m/z 244 [M+H].sup.+; .sup.1H-NMR (400
MHz, MeOD): .delta. 7.89-7.91 (d, J=8.4, 1H), 7.69-7.71 (d, J=8.8,
1H), 7.47-7.51 (m, 1H), 7.26-7.29 (m, 1H), 5.62 (s, 1H), 4.71-4.74
(m, 2H), 4.54-4.62 (m, 2H), 4.24-4.28 (m, 1H), 3.28-3.32 (m, 2H),
2.41-2.45 (m, 2H), 2.08-2.26 (m, 2H).
Example 1.14. Preparation of
1-((S)-1-methylpyrrolidin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-
e hydrochloride (14)
##STR00202##
[0312] Compound 14 was prepared using a procedure analogous to that
described for compound 3 but using compound 13 in place of compound
1 in the procedure of Example 1.F. (60 mg, yellow oil); MS (ESI):
m/z 258 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): .delta. 7.70-7.72
(d, J=8.4 Hz, 1H), 7.58-7.60 (d, J=8.8 Hz, 1H), 7.31-7.35 (m, 1H),
7.08-7.12 (m, 1H), 5.44 (s, 1H), 4.42-4.61 (m, 3H), 4.08-4.15 (m,
1H), 3.33-3.35 (m, 1H), 3.14-3.16 (m, 1H), 2.59 (s, 3H), 2.40-2.44
(m, 1H), 1.68-1.76 (m, 3H), 1.49-1.54 (m, 1H).
Example 1.15. Preparation of
(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanamine
(15)
##STR00203##
[0314] Compound 15 was prepared using a procedure analogous to that
described for intermediate I-19 but using 1H-indazole in the
procedure of Example 1.A (as shown, in place of the
5-fluoro-1H-indazole used in Example 1.L. (4.2 g, white solid); MS
(ESI): m/z 204 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): .delta.
7.65 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.32 (t, J=7.2 Hz,
1H), 7.08 (t, J=7.2 Hz, 1H), 5.18 (d, J=6.8 Hz, 1H), 4.52-4.49 (m,
1H), 4.45-4.38 (m, 2H), 4.13-4.10 (m, 1H), 3.40 (dd, J=14.0, 2.0
Hz, 1H), 3.21-3.15 (m, 1H).
Example 1.16. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)
cyclobutanamine (16)
##STR00204##
[0316] Compound 16 was prepared using a procedure analogous to that
described for intermediate I-8 but using compound 15 in place of
compound 1 and cyclobutanone in place of paraformaldehyde in the
procedure of Example 1.F. (67 mg, white solid); MS (ESI): m/z 258
[M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD): .delta. 7.66 (d, J=8.8
Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.33 (t, J=7.2 Hz, 1H), 7.10 (t,
J=7.6 Hz, 1H), 5.31 (d, J=7.2 Hz, 1H), 4.54 (m, 1H), 4.44 (m, 2H),
4.13 (m, 1H), 3.38-3.30 (m, 2H), 3.12-3.10 (m, 1H), 2.25-2.21 (m,
2H), 1.87-1.70 (m, 4H).
Example 1.17. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)propan-2-amine
(17)
##STR00205##
[0318] Compound 17 was prepared using a procedure analogous to that
described for intermediate I-8 but using compound 15 in place of
compound 1 and propan-2-one in place of paraformaldehyde in the
procedure of Example 1.F. (97 mg, white solid); MS (ESI): m/z 246
[M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): .delta. 7.67 (d, J=8.4
Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.33 (t, J=6.8 Hz, 1H), 7.10 (t,
J=7.6 Hz, 1H), 5.35 (dd, J=8.4, 2.8 Hz, 1H), 4.54-4.51 (m, 1H),
4.48-4.41 (m, 2H), 4.17-4.11 (m, 1H), 3.43 (dd, J=12.8, 3.2 Hz,
1H), 3.15 (dd, J=12.8, 8.4 Hz, 1H), 2.98-2.95 (m, 1H), 1.14 (t,
J=5.6 Hz, 6H).
Example 1.18. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)
ethanamine hydrogen chloride salt (18)
##STR00206##
[0320] Compound 18 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-22 in place of
intermediate I-7 in the procedure of Example 1.1. (92 mg, white
solid); MS (ESI): m/z 232 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD):
.delta. 7.68 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.33 (t,
J=7.6 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 5.36 (dd, J=8.8, 2.8 Hz,
1H), 4.54-4.50 (m, 1H), 4.48-4.41 (m, 2H), 4.16-4.11 (m, 1H), 3.42
(dd, J=12.8, 3.2 Hz, 1H), 3.16 (dd, J=12.8, 8.4 Hz, 1H), 2.79-2.75
(m, 2H), 1.17 (t, J=7.2 Hz, 3H).
Example 1.19. Preparation of
1-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole
hydrogen chloride salt (19)
##STR00207##
[0322] Compound 19 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-26 in place of
intermediate I-7 in the procedure of Example 1.1. (white solid); MS
(ESI): m/z 258 [M+H].sup.+; 1H NMR (400 MHz, d.sup.4-methanol):
.delta. 8.01 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.60 (t,
J=7.7 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 5.82-5.94 (m, 1H), 4.66-4.78
(m, 1H), 4.55-4.66 (m, 2H), 4.27-4.40 (m, 1H), 4.14-4.25 (m, 1H),
3.84-3.99 (m, 2H), 3.67-3.81 (m, 1H), 3.39-3.54 (m, 1H), 3.22-3.31
(m, 1H), 1.96-2.38 (m, 4H).
Example 1.20. Preparation of
1-(morpholinomethyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole
hydrogen chloride salt (20)
##STR00208##
[0324] Compound 20 was prepared using a procedure analogous to that
described for compound 19 but using morpholine in place of
pyrrolidine in the procedure of Example 1.U. (White solid); MS
(ESI): m/z 274 [M+H].sup.+; 1H NMR (400 MHz, d.sup.4-methanol):
.delta. 8.01 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.60 (t,
J=7.7 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 5.99-6.07 (m, 1H), 4.57-4.66
(m, 1H), 4.66-4.76 (m, 2H), 4.26-4.38 (m, 1H), 4.05-4.21 (m, 3H),
3.90-4.03 (m, 2H), 3.76-3.88 (m, 2H), 3.60-3.70 (m, 1H), 3.38-3.56
(m, 2H).
Example 1.21. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)cyclopropan
amine hydrogen chloride salt (21)
##STR00209##
[0326] Compound 21 was prepared using a procedure analogous to that
described for compound 19 but using cyclopropylamine in place of
pyrrolidine in the procedure of Example 1.U. (White solid); MS
(ESI): m/z 244 [M+H].sup.+; 1H NMR (400 MHz, d.sup.4-methanol):
.delta. 7.85-8.10 (m, 1H), 7.46-7.79 (m, 2H), 7.24-7.44 (m, 1H),
5.69-5.89 (m, 1H), 4.50-4.77 (m, 3H), 4.22-4.37 (m, 1H), 4.03-4.15
(m, 1H), 3.74-3.89 (m, 1H), 2.86-2.99 (m, 1H), 0.84-1.14 (m,
4H).
Example 1.22. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylcyclop-
ropanamine hydrogen chloride salt (22)
##STR00210##
[0328] Compound 22 was prepared using a procedure analogous to that
described for compound 3 but using compound 21 in place of compound
1 in the procedure of Example 1.F. (50.0 mg); MS (ESI): m/z 258
[M+H].sup.+; 1H-NMR (400 MHz, d.sup.4-methanol): .delta. 8.10-8.20
(m, 1H), 7.69-7.79 (m, 2H), 7.42-7.47 (m, 1H), 5.95-6.25 (m, 1H),
4.57-4.80 (m, 3H), 4.30-4.40 (m, 2H), 3.89-4.14 (m, 1H), 3.10-3.30
(m, 4H), 1.16-1.46 (m, 2H), 0.94-1.14 (m, 2H).
Example 1.23.Preparation of
1'-methyl-3,4-dihydrospiro[[1,4]oxazino[4,3-b]indazole-1,3'-pyrrolidin]-1-
'-ium chloride (23)
##STR00211##
[0330] Compound 23 was prepared using a procedure analogous to that
described for compound 3 but using intermediate I-27 in place of
compound 1 in the procedure of Example 1.F. (160 mg, white solid,
95%); MS (ESI): m/z 244 [M+H].sup.+; 1H-NMR (400 MHz, CDCl.sub.3):
.delta. 7.69 (dd, J=19.6, 8.6 Hz, 2H), 7.29 (dd, J=13.5, 5.6 Hz,
1H), 7.11-7.01 (m, 1H), 4.47 (t, J=5.0 Hz, 2H), 4.23-4.15 (m, 2H),
3.12-2.98 (m, 3H), 2.83 (dd, J=14.8, 8.6 Hz, 1H), 2.59-2.50 (m,
1H), 2.49 (s, 3H), 2.45-2.35 (m, 1H).
Example 1.24. Preparation of
1'-methyl-3,4-dihydrospiro[[1,4]oxazino[4,3-b]indazole-1,4'-piperidin]-1'-
-ium chloride (24)
##STR00212##
[0332] Compound 24 was prepared using a procedure analogous to that
described for compound 23 but using tert-butyl
4-oxopiperidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.I. (160
mg, white solid); MS (ESI): m/z 258 [M+H].sup.+; 1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.75 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.7 Hz,
1H), 7.31-7.24 (m, 1H), 7.04 (ddd, J=8.4, 6.7, 0.7 Hz, 1H),
4.51-4.41 (m, 2H), 4.23-4.11 (m, 2H), 2.79 (dd, J=6.8, 5.4 Hz, 2H),
2.51-2.40 (m, 4H), 2.38 (s, 3H), 2.07-1.94 (m, 2H).
Example 1.25. Preparation of
(2R)-2-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorph-
olin-4-ium chloride (25)
##STR00213##
[0334] Compound 25 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-29 in place of
intermediate I-7 in the procedure of Example 1.1. (160 mg, white
solid); MS (ESI): m/z 274 [M+H].sup.+; 1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.69 (dd, J=12.1, 8.6 Hz, 2H), 7.32-7.24 (m,
1H), 7.04 (dd, J=7.9, 7.2 Hz, 1H), 5.17 (s, 1H), 4.55 (ddd, J=13.4,
9.3, 4.1 Hz, 1H), 4.50-4.35 (m, 2H), 4.24 (dt, J=10.4, 2.2 Hz, 1H),
4.06-3.94 (m, 1H), 3.88 (dd, J=11.5, 2.3 Hz, 1H), 3.64 (td, J=11.5,
2.4 Hz, 1H), 2.82 (d, J=11.2 Hz, 1H), 2.63 (d, J=11.6 Hz, 1H), 2.29
(s, 3H), 2.21 (t, J=10.9 Hz, 1H), 2.17-2.06 (m, 1H).
Example 1.26. Preparation of
(2R)-2-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorph-
olin-4-ium chloride (26)
##STR00214##
[0336] Compound 26 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-30 in place of
intermediate I-7 in the procedure of Example 1.1. (160 mg, white
solid); MS (ESI): m/z 274 [M+H].sup.+; 1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.74-7.63 (m, 2H), 7.35-7.26 (m, 1H),
7.09-7.02 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.61-4.49 (m, 1H),
4.49-4.39 (m, 2H), 4.26 (ddd, J=10.3, 4.5, 2.3 Hz, 1H), 4.10-3.97
(m, 2H), 3.81 (td, J=11.5, 2.5 Hz, 1H), 2.67 (d, J=11.7 Hz, 1H),
2.58-2.48 (m, 1H), 2.22 (s, 3H), 2.21-2.14 (m, 2H).
Example 1.27. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylpropan-
-2-aminium chloride (27)
##STR00215##
[0338] Compound 27 was prepared using a procedure analogous to that
described for compound 3 but using compound 17 in place of compound
1 in the procedure of Example 1.F. (95 mg, white solid); MS (ESI):
m/z 260 [M+H].sup.+; 1H-NMR (400 MHz, MeOD): .delta. 8.16 (dd,
J=28.7, 8.5 Hz, 1H), 7.83-7.70 (m, 2H), 7.51-7.43 (m, 1H),
6.20-6.01 (m, 1H), 4.89-4.74 (m, 1H), 4.76-4.59 (m, 2H), 4.39 (ddd,
J=12.5, 8.6, 3.7 Hz, 1H), 4.15-3.75 (m, 3H), 3.17 (s, 2H), 2.95 (s,
1H), 1.47 (ddd, J=23.4, 12.7, 6.7 Hz, 6H).
Example 1.28. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylethana-
minium chloride (28)
##STR00216##
[0340] Compound 28 was prepared using a procedure analogous to that
described for compound 3 but using compound 18 in place of compound
1 in the procedure of Example 1.F. (130 mg, white solid); MS (ESI):
m/z 246 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD): .delta. 8.17-8.01
(m, 1H), 7.82-7.63 (m, 2H), 7.49-7.36 (m, 1H), 6.03 (s, 1H),
4.84-4.72 (m, 1H), 4.72-4.57 (m, 2H), 4.42-4.30 (m, 1H), 4.14 (m,
1H), 3.87 (m, 1H), 3.53 (m, 2H), 3.11 (dd, J=55.7, 1.5 Hz, 3H),
1.46 (dt, J=33.4, 7.3 Hz, 3H).
Example 1.29. Preparation of
N-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylcyclob-
utanaminium chloride (29)
##STR00217##
[0342] Compound 29 was prepared using a procedure analogous to that
described for compound 3 but using compound 16 in place of compound
1 in the procedure of Example 1.F. (130 mg, white solid); MS (ESI):
m/z 272 [M+H].sup.+; .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
7.68 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.32-7.27 (m, 1H),
7.11-7.03 (m, 1H), 5.34 (d, J=8.1 Hz, 1H), 4.62-4.50 (m, 1H),
4.50-4.38 (m, 2H), 4.12-4.00 (m, 1H), 2.96 (m, 2H), 2.81 (dd,
J=13.7, 9.2 Hz, 1H), 2.37 (s, 3H), 2.09-1.91 (m, 3H), 1.77-1.58 (m,
3H).
Example 1.30. Preparation of
(+/-)-rel-(R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)
ethanaminium chloride (30)
##STR00218##
[0344] Compound 30 was prepared using a procedure analogous to that
described for compound 3 but using intermediate I-32 in place of
intermediate I-8 in the procedure of Example 1.3. (55.0 mg, white
solid); MS (ESI): m/z 218 [M+H].sup.+; 1H NMR (400 MHz,
d.sup.4-methanol): .delta. 7.80 (d, J=8.4 Hz, 1H), 7.70 (d, J=9.1
Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 5.58-5.63
(m, 1H), 4.51-4.75 (m, 3H), 4.36-4.46 (m, 1H), 4.18-4.29 (m, 1H),
1.12 (d, J=6.9 Hz, 3H).
Example 1.31. Preparation of
(+/-)-rel-(R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-me-
thylethanaminium chloride (31)
##STR00219##
[0346] Compound 31 was prepared using a procedure analogous to that
described for compound 3 but using intermediate I-34 in place of
intermediate I-8 in the procedure of Example 1.3. (300 mg, white
solid); MS (ESI): m/z 232 [M+H].sup.+; 1H-NMR (400 MHz,
d.sup.4-methanol): .delta. 7.79 (d, J=8.6 Hz, 1H), 7.68 (d, J=8.7
Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 5.67-5.76
(m, 1H), 4.48-4.72 (m, 3H), 4.17-4.34 (m, 2H), 2.93 (s, 3H), 1.12
(d, J=6.8 Hz, 3H).
Example 1.32. Preparation of
(+/-)-rel-(R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N--
dimethylethanaminium chloride (32)
##STR00220##
[0348] Compound 32 was prepared using a procedure analogous to that
described for compound 3 but using compound 31 in place of compound
1 in the procedure of Example 1.F. (150 mg, white solid); MS (ESI):
m/z 246 [M+H].sup.+; 1H-NMR (400 MHz, d.sup.4-methanol): .delta.
7.98 (d, J=8.6 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.61 (t, J=7.6 Hz,
1H), 7.36 (t, J=7.8 Hz, 1H), 6.00-6.10 (m, 1H), 4.68-4.80 (m, 1H),
4.55-4.67 (m, 2H), 4.35-4.45 (m, 1H), 4.28 (td, J=11.7, 3.5 Hz,
1H), 3.20 (s, 3H), 3.13 (s, 3H), 1.23 (d, J=6.8 Hz, 3H).
Example 1.33. Preparation of
(+/-)-rel-(R)-1-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)
ethanaminium chloride (33)
##STR00221##
[0350] Compound 33 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-33 in place of
intermediate I-7 in the procedure of Example 1.1. (100 mg, white
solid); MS (ESI): m/z 218 [M+H].sup.+; 1H-NMR (400 MHz,
d.sup.4-methanol): .delta. 7.93 (d, J=8.6 Hz, 1H), 7.74 (d, J=8.7
Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 5.52-5.56
(m, 1H), 4.53-4.73 (m, 3H), 4.32-4.41 (m, 1H), 4.18-4.28 (m, 1H),
1.67 (d, J=6.7 Hz, 3H).
Example 1.34. Preparation of
(+/-)-rel-(R)-1-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-me-
thylethanaminium chloride (34)
##STR00222##
[0352] Compound 34 was prepared using a procedure analogous to that
described for compound 31 but using intermediate I-33 in place of
intermediate I-32 in the procedure of Example 1.Y. (110 mg, white
solid); MS (ESI): m/z 232 [M+H].sup.+; 1H-NMR (400 MHz,
d.sup.4-Methanol): .delta. 7.95-8.12 (m, 1H), 7.59-7.86 (m, 2H),
7.35-7.54 (m, 1H), 5.57-5.73 (m, 1H), 4.56-4.86 (m, 3H), 4.21-4.42
(m, 2H), 2.62 (s, 3H), 1.72 (dd, J=6.9, 2.6 Hz, 3H).
Example 1.35. Preparation of
4-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)piperidin-1-ium
chloride (35)
##STR00223##
[0354] Compound 35 was prepared using a procedure analogous to that
described for intermediate I-4 but using tert-butyl
4-formylpiperidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (293 mg, white solid); MS (ESI): m/z
258.1 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4):
.quadrature. 8.16 (d, 1H), 7.83-7.78 (m, 2H), 5.44 (s, 1H),
4.77-4.74 (m, 1H), 4.64-4.55 (m, 2H), 4.23-4.17 (m, 1H), 3.56 (d,
1H), 3.31-3.39 (m, 1H), 3.19-3.29 (m, 1H), 3.01-2.94 (m, 2H),
2.22-2.17 (m, 2H), 1.86-1.81 (m, 1H), 1.37 (d, 1H).
Example 1.36. Preparation of
3',4'-dihydrospiro[piperidine-4,1'-[1,4]oxazino[4,3-b]indazol]-1-ium
chloride (36)
##STR00224##
[0356] Compound 36 was prepared using a procedure analogous to that
described for intermediate I-4 but using tert-butyl
4-oxopiperidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (175 mg, white solid); MS (ESI): m/z
244.2 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4):
.quadrature. 8.20 (d, 1H), 7.77-7.72 (m, 2H), 7.46 (t, 1H), 4.66
(br, 2H), 4.42 (br, 2H), 3.51 (br, 4H), 2.79 (br, 2H), 2.43 (d,
2H).
Example 1.37. Preparation of
3',4'-dihydro-4-azaspiro[bicyclo[2.2.1]heptane-2,1'-[1,4]oxazino[4,3-b]in-
dazol]-4-ium chloride (37)
##STR00225##
[0358] Compound 37 was prepared using a procedure analogous to that
described for intermediate I-4 but using
1-azabicyclo[2.2.1]heptan-3-one in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (240 mg, white solid); MS (ESI): m/z
256.2 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4);
.quadrature. 7.81-7.79 (m, 1H), 7.74-7.72 (m, 1H), 7.56-7.52 (m,
1H), 7.38-7.33 (m, 1H), 4.65-4.57 (m, 3H), 4.46-4.39 (m, 1H), 4.13
(dd, 1H), 3.96-3.89 (m, 2H), 3.80-3.70 (m, 3H), 3.50 (dd, 1H),
2.36-2.27 (m, 1H), 2.13-2.06 (m, 1H).
Example 1.38. Preparation of (3
S)-3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)piperidin-1-ium
(38)
##STR00226##
[0360] Compound 38 was prepared using a procedure analogous to that
described for intermediate I-4 but using (S)-tert-butyl
3-formylpiperidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (120 mg, pale-brown solid); MS (ESI): m/z
258.0 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .quadrature.
8.03-7.96 (m, 1H), 7.77-7.66 (m, 2H), 7.44-7.39 (m, 1H), 5.48-5.44
(m, 1H), 4.74-4.66 (m, 1H), 4.58-4.53 (m, 2H), 4.21-4.13 (m, 1H),
3.69-3.68 (m, 0.4H), 3.41-3.30 (m, 1.6H), 3.06-2.88 (m, 3H),
2.17-1.89 (m, 2.6H), 1.76-1.61 (m, 0.8H), 1.38-1.29 (m, 0.6H).
Example 1.39. Preparation of
(1-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanaminium
chloride (39)
##STR00227##
[0362] Compound 39 was prepared using a procedure analogous to that
described for intermediate I-4 but using tert-butyl
(2-oxopropyl)carbamate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (80 mg, pale-brown solid); MS (ESI): m/z
218.1 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .quadrature.
8.06 (d, 1H), 7.80-7.71 (m, 2H), 7.48-7.43 (m, 1H), 4.76-4.69 (m,
1H), 4.66-4.60 (m, 1H), 4.51-4.40 (m, 2H), 3.86 (d, 1H), 3.67-3.65
(m, 1H), 1.92 (s, 3H).
Example 1.40. Preparation of
3',4'-dihydrospiro[azetidine-3,1'-[1,4]oxazino[4,3-b]indazol]-1-ium
chloride (40)
##STR00228##
[0364] To a solution of intermediate I-36 (440 mg, 1.07 mmol) in
tetrahydrofuran (20 mL) was added potassium tert-butoxide (0.36 g,
3.21 mmol) at 0.degree. C. The mixture was stirred at 0.degree. C.
for 2 hrs and quenched with 10 ml of water. The crude reaction
mixture was extracted with ethyl acetate (3.times.30 mL), the
combined organic phase was dried over sodium sulfate and solids
were removed by filtration. The filtrate was concentrated in vacuo
and purified by preparative TLC (ethyl acetate:petrol ether=2:1) to
give a white foamy solid. To the solid was added 5 ml of
HCl-Methanol (3 N) and the reaction mixture was stirred at room
temperature for 4 hrs and concentrated in vacuo to give compound
40. (92 mg, 35%, pale-brown solid); MS (ESI): m/z 216.1
[M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .quadrature.
7.86-7.85 (m, 1H), 7.59-7.58 (m, 1H), 7.40-7.35 (m, 1H), 7.22-7.17
(m, 1H), 4.79-4.78 (m, 2H), 4.40-4.38 (m, 2H), 4.33-4.32 (m, 2H),
4.25-4.23 (m, 2H).
Example 1.41. Preparation of
(1R)-2-cyclobutyl-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethan-
-1-aminium (41)
##STR00229##
[0366] Compound 41 was prepared using a procedure analogous to that
described for intermediate I-4 but using (R)-tert-butyl
(1-cyclobutyl-3-oxopropan-2-yl)carbamate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (97 mg, pale-brown solid); MS (ESI): m/z
272.1 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .quadrature.
7.90-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.65-7.63 (m, 1H), 7.39-7.34
(m, 1H), 5.69 & 5.60 (s & s, 1H), 4.78-4.57 (m, 3H),
4.26-4.06 (m, 2H), 2.71-2.65 (m, 0.5H), 2.33-2.19 (m, 2H),
2.09-1.76 (m, 4.5H), 1.68-1.48 (m, 1H), 1.38-1.25 (m, 1H).
Example 1.42. Preparation of
(2R)-2-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-4-ium
chloride (42)
##STR00230##
[0368] Compound 42 was prepared using a procedure analogous to that
described for intermediate I-4 but using (R)-tert-butyl
2-formylmorpholine-4-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (41 mg, pale-white solid); MS (ESI): m/z
260.0 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .quadrature.
8.05-8.03 (m, 1H), 7.74-7.61 (m, 2H), 7.44-7.32 (m, 1H), 5.65-5.47
(m, 1H), 4.77-4.46 (m, 4H), 4.30-4.21 (m, 1.4H), 4.04-3.90 (m, 1H),
3.85-3.78 (m, 0.6H), 3.66-3.64 (m, 0.6H), 3.49-3.13 (m, 3.4H).
Example 1.43. Preparation (3
S)-3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-4-ium
chloride (43)
##STR00231##
[0370] Compound 43 was prepared using a procedure analogous to that
described for intermediate I-4 but using (S)-tert-butyl
3-formylmorpholine-4-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (75 mg, pale-white solid); MS (ESI): m/z
260.1 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .quadrature.
7.95-7.94 (m, 1H), 7.73-7.72 (m, 1H), 7.56-7.55 (m, 1H), 7.34-7.33
(m, 1H), 4.71-4.50 (m, 4H), 4.27-4.20 (m, 1H), 4.06-4.04 (m, 1H),
3.81-3.72 (m, 2H), 3.61-3.43 (m, 3H).
Example 1.44. Preparation of
3',4'-dihydrospiro[pyrrolidine-3,1'-[1,4]oxazino[4,3-b]indazol]-1-ium
chloride (44)
##STR00232##
[0372] Compound 44 was prepared using a procedure analogous to that
described for intermediate I-4 but using tert-butyl
3-oxopyrrolidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B,
followed by hydrochlorination using a procedure analogous to that
described in Example 1.3. (90 mg, pale-yellow solid); MS (ESI): m/z
229.9 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.4) .quadrature.
8.08-8.07 (m, 1H), 7.75-7.74 (m, 1H), 7.65-7.63 (m, 1H), 7.40-7.38
(m, 1H), 4.66-4.65 (m, 2H), 4.46-4.45 (m, 2H), 3.89-3.65 (m, 4H),
2.80-2.79 (m, 2H).
Example 1.45. Preparation of
(+/-)-(S)-3-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-
-4-ium chloride (45)
##STR00233##
[0374] Compound 45 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-39 in place of
intermediate I-7 in the procedure of Example 1.1. (0.19 g); MS
(ESI): m/z 260 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD-d4) .delta.
7.66-7.60 (m, 2H), 7.29-7.25 (m, 1H), 7.07-7.03 (m, 1H), 5.15-5.14
(d, J=3.6 Hz, 1H), 4.48-4.35 (m, 3H), 3.95-3.94 (m, 1H), 3.77-3.73
(m, 1H), 3.66-3.64 (m, 1H), 3.50-3.49 (m, 1H), 3.44-3.38 (m, 2H),
3.06-2.99 (m, 2H).
Example 1.46. Preparation of
(+/-)-(S)-3-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-
-4-ium chloride (46)
##STR00234##
[0376] Compound 46 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-40 in place of
intermediate I-7 in the procedure of Example 1.1. (0.12 g); MS
(ESI): m/z 260 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD-d4) .delta.
7.70-7.60 (m, 2H), 7.31-7.29 (m, 1H), 7.11-7.09 (m, 1H), 5.13-5.12
(d, J=3.6 Hz, 1H), 4.65-4.55 (m, 1H), 4.48-4.38 (m, 2H), 4.01-3.98
(m, 2H), 3.86-3.78 (m, 2H), 3.68-3.64 (m, 1H), 3.58-3.52 (m, 1H),
2.96-2.84 (m, 2H).
Example 1.47. Preparation of (+/-)-(3
S,4R)-3-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorp-
holin-4-ium chloride (47)
##STR00235##
[0378] Compound 47 was prepared using a procedure analogous to that
described for compound 3 but using intermediate I-39 in place of
compound 1 in the procedure of Example 1.F. (0.08 g); MS (ESI): m/z
274 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD-d4) .delta. 7.71-7.68
(d, J=8.8 Hz, 1H), 7.64-7.62 (d, J=8.8 Hz, 1H), 7.34-7.30 (m, 1H),
7.12-7.10 (d, J=8.8 Hz, 1H), 5.62 (d, J=2.4 Hz, 1H), 4.52-4.45 (m,
3H), 4.02-3.94 (m, 1H), 3.79-3.78 (m, 1H), 3.70-3.69 (m, 1H),
3.60-3.54 (m, 1H), 3.35-3.34 (m, 1H), 3.02-3.00 (m, 1H), 2.89-2.86
(m, 1H), 2.60 (s, 3H), 2.55-2.54 (m, 1H).
Example 1.48. Preparation of (+/-)-(3
S,4R)-3-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorp-
holin-4-ium chloride (48)
##STR00236##
[0380] Compound 48 was prepared using a procedure analogous to that
described for compound 3 but using intermediate I-40 in place of
compound 1 in the procedure of Example 1.F. (0.11 g); MS (ESI): m/z
274 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD-d4) .delta. 7.98-7.95
(d, J=8.4 Hz, 1H), 7.66-7.63 (d, J=8.4 Hz, 1H), 7.29-7.27 (m, 1H),
7.07-7.05 (m, 1H), 5.21 (s, 1H), 4.56-4.39 (m, 3H), 3.96-3.95 (m,
1H), 3.90-3.87 (m, 1H), 3.78-3.76 (m, 1H), 3.61-3.60 (m, 1H),
3.52-3.47 (m, 1H), 2.99-2.97 (m, 1H), 2.76-2.74 (m, 1H), 2.45-2.44
(m, 1H), 2.13 (s, 3H).
Example 1.49. Preparation of
N--(((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methyle-
thanaminium chloride (49)
##STR00237##
[0382] Compound 49 was prepared using a procedure analogous to that
described for compound 3 but using acetaldehyde in place of
paraformaldehyde in the procedure of Example 1.F. (1.5 g, Yield
88%); MS (ESI): m/z 246 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD-d4)
.delta. 8.13-8.08 (m, 1H), 7.78-7.76 (m, 1H), 7.74-7.68 (m, 1H),
7.45-7.42 (m, 1H), 6.05-6.03 (m, 1H), 4.80-4.74 (m, 1H), 4.69-4.61
(m, 2H), 4.40-4.33 (m, 1H), 4.21-4.17 (m, 1H), 4.11-4.08 (m, 1H),
3.93-3.86 (m, 1H), 3.69-3.64 (m, 0.41H), 3.55-3.36 (m, 1.57H), 3.18
(s, 1.77H), 3.04 (s, 1.21H), 1.50 (t, J=7.3 Hz, 1.24H), 1.42 (t,
J=7.3 Hz, 1.76H).
Example 1.50. Preparation of
N--(((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methyle-
thanaminium chloride (50)
##STR00238##
[0384] Compound 50 was prepared using a procedure analogous to that
described for compound 4 but using acetaldehyde in place of
paraformaldehyde in the procedure of Example 1.F. (1.4 g); MS
(ESI): m/z 246 [M+H].sup.+; .sup.1H NMR (400 MHz, MeOD-d4) .delta.
8.12-8.07 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.69 (m, 1H), 7.46-7.42
(m, 1H), 6.04-6.00 (m, 1H), 4.80-4.73 (m, 1H), 4.69-4.61 (m, 2H),
4.40-4.33 (m, 1H), 4.21-4.09 (m, 1H), 4.11-4.07 (m, 1H), 3.93-3.80
(m, 1H), 3.67-3.64 (m, 0.41H), 3.49-3.36 (m, 1.63H), 3.18 (s,
1.78H), 3.04 (s, 1.19H), 1.50 (t, J=7.3 Hz, 1.23H), 1.42 (t, J=7.3
Hz, 1.77H).
Example 1.51. Preparation of
1-(4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)-N-methylmethanami-
nium chloride (51)
##STR00239##
[0386] Compound 51 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-46 in place of
intermediate I-7 in the procedure of Example 1.1. (60 mg, white
solid); MS (ESI): m/z 232 [M+H].sup.+; .sup.1H-NMR (400 MHz,
MeOD-d4) .delta. 7.98 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H),
7.63 (t, J=8.4 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 5.70 (d, J=10.0 Hz,
1H), 5.00-4.98 (m, 2H), 4.48-4.43 (m, 1H), 4.22-4.00 (m, 3H), 2.96
(s, 3H), 2.27 (br-s, 2H).
Example 1.52. Preparation of
1-(4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)-N,N-dimethylmetha-
naminium chloride (52)
##STR00240##
[0388] Compound 52 was prepared using a procedure analogous to that
described for compound 3 but using compound 51 in place of compound
1 in the procedure of Example 1.F. (128 mg, white solid); MS (ESI):
m/z 246 [M+H].sup.+; .sup.1H-NMR (400 MHz, MeOD-d4) .delta. 8.05
(d, J=8.7 Hz, 1H), 7.79-7.67 (m, 2H), 7.51-7.40 (m, 1H), 6.01-5.83
(m, 1H), 5.05 (s, 2H), 4.47 (dt, J=12.4, 4.6 Hz, 1H), 4.33-4.19 (m,
3H), 3.18 (d, J=5.7 Hz, 6H), 2.36-2.22 (m, 2H).
Example 1.53. Preparation
N-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)-N-methyle-
thanaminium chloride (53)
##STR00241##
[0390] Compound 53 was prepared using a procedure analogous to that
described for compound 52 but using acetaldehyde in place of
paraformaldehyde in the procedure of Example 1.F. (118 mg, white
solid); MS (ESI): m/z 260 [M+H].sup.+; .sup.1H-NMR (400 MHz,
MeOD-d4) .delta. 7.65 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H),
7.24 (t, J=8.8 Hz, 1H), 7.06-7.02 (m, 1H), 5.20-5.17 (m, 1H),
4.92-4.89 (m, 1H), 4.73-4.65 (m, 1H), 4.35-4.30 (m, 1H), 3.82-3.78
(m, 1H), 3.27-3.21 (m, 1H), 3.07-3.03 (m, 1H), 2.68-2.59 (m, 2H),
2.42 (s, 3H), 2.17-1.85 (m, 2H), 1.11 (t, J=7.2 Hz, 3H).
Example 1.54. Preparation of
N-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)-N-methylp-
ropan-2-aminium chloride (54)
##STR00242##
[0392] Compound 54 was prepared using a procedure analogous to that
described for compound 52 but using acetone in place of
paraformaldehyde in the procedure of Example 1.F. (142 mg, white
solid); MS (ESI): m/z 274 [M+H].sup.+; .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.59-7.50 (m, 1H), 7.51-7.43 (m, 1H), 7.18-7.07
(m, 1H), 7.01-6.87 (m, 1H), 5.05 (dd, J=5.5, 3.4 Hz, 1H), 4.87-4.71
(m, 1H), 4.61-4.46 (m, 1H), 4.24-4.13 (m, 1H), 3.66 (dd, J=13.5,
9.1 Hz, 1H), 3.13-2.99 (m, 1H), 2.94 (d, J=13.5 Hz, 1H), 2.89-2.76
(m, 1H), 2.29 (d, J=2.9 Hz, 3H), 1.94 (dd, J=41.8, 2.9 Hz, 2H),
0.92 (ddd, J=9.5, 6.6, 2.8 Hz, 6H).
Example 1.55. Preparation of
N-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)-N-methylc-
yclobutanaminium chloride (55)
##STR00243##
[0394] Compound 55 was prepared using a procedure analogous to that
described for compound 52 but using cyclobutanone in place of
paraformaldehyde in the procedure of Example 1.F. (99 mg, white
solid); MS (ESI): m/z 286 [M+H].sup.+; .sup.1H-NMR (400 MHz,
D.sub.2O) .delta. 7.56 (dd, J=18.2, 8.7 Hz, 2H), 7.33 (dd, J=8.2,
7.4 Hz, 1H), 7.16-7.09 (m, 1H), 5.49 (dd, J=11.1, 2.9 Hz, 1H),
4.76-4.72 (m, 2H), 4.33 (dt, J=12.5, 3.8 Hz, 1H), 4.14-3.83 (m,
4H), 2.88 (d, J=10.5 Hz, 3H), 2.48-2.12 (m, 4H), 2.00 (dd, J=18.7,
4.1 Hz, 2H), 1.77 (dd, J=18.2, 10.2 Hz, 2H).
Example 1.56. Preparation of
(4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methanaminium
chloride (56)
##STR00244##
[0396] Compound 56 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-51 in place of
intermediate I-7 in the procedure of Example 1.1. (89 mg, white
solid); MS (ESI): m/z 218 [M+H].sup.+. .sup.1H-NMR (400 MHz,
MeOD-d4) .delta. 7.76 (d, J=8.7 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H),
7.51-7.41 (m, 1H), 7.29-7.20 (m, 1H), 5.38 (dd, J=10.8, 3.0 Hz,
1H), 4.91-4.79 (m, 2H), 4.43 (s, 1H), 4.14-3.98 (m, 2H), 3.84 (s,
1H), 2.26-2.10 (m, 2H).
Example 1.57. Preparation of
N-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)ethanamini-
um chloride (57)
##STR00245##
[0398] Compound 57 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-52 in place of
intermediate I-7 in the procedure of Example 1.1. (72 mg, white
solid) as white solid; MS (ESI): m/z 246 [M+H].sup.+; .sup.1H-NMR
(400 MHz, MeOD-d4) .delta. 7.90 (d, J=8.7 Hz, 1H), 7.70 (d, J=8.8
Hz, 1H), 7.59-7.51 (m, 1H), 7.34 (dd, J=8.1, 7.0 Hz, 1H), 5.58 (dd,
J=10.8, 2.8 Hz, 1H), 4.92 (s, 2H), 4.55-4.37 (m, 1H), 4.22-4.04 (m,
2H), 4.01 (d, J=11.2 Hz, 1H), 3.33-3.27 (m, 2H), 2.24 (dd, J=10.5,
5.8 Hz, 2H), 1.46 (t, J=7.3 Hz, 3H).
Example 1.58. Preparation of
1-(6,7-dihydro-9H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-met-
hylmethanaminium chloride (58)
##STR00246##
[0400] Compound 58 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-58 in place of
intermediate I-7 in the procedure of Example 1.1. (53 mg, white
solid); MS (ESI): m/z 224 [M+H].sup.+; .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.60 (d, J=5.2 Hz, 1H), 7.12 (d, J=5.2 Hz,
1H), 5.44-5.42 (m, 1H), 4.54-4.38 (m, 3H), 4.27-4.21 (m, 1H),
3.74-3.70 (m, 1H), 3.54-3.49 (m, 1H), 2.82 (s, 3H).
Example 1.59. Preparation of
1-(6,7-dihydro-9H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N,N-d-
imethylmethanaminium chloride (59)
##STR00247##
[0402] Compound 59 was prepared using a procedure analogous to that
described for compound 3 but using compound 58 in place of compound
1 in the procedure of Example 1.F. (56 mg, white solid); MS (ESI):
m/z 238 [M+H].sup.+; .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
7.31 (d, J=5.5 Hz, 1H), 7.05 (d, J=5.5 Hz, 1H), 4.98 (t, J=6.8 Hz,
1H), 4.48-4.34 (m, 2H), 4.33-4.26 (m, 1H), 4.07 (td, J=11.4, 3.5
Hz, 1H), 2.79 (qd, J=12.5, 6.8 Hz, 2H), 2.40 (s, 6H).
Example 1.60. Synthesis of
(6,7-dihydro-9H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)methanam-
inium chloride (60)
##STR00248##
[0404] Compound 60 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-63 in place of
intermediate I-7 in the procedure of Example 1.1. (56 mg, white
solid); MS (ESI): m/z 210 [M+H].sup.+; .sup.1H-NMR (400 MHz,
MeOD-d4): .delta. 7.63 (d, J=5.3 Hz, 1H), 7.13 (d, J=5.4 Hz, 1H),
5.38 (dd, J=7.7, 2.8 Hz, 1H), 4.57-4.45 (m, 2H), 4.44-4.36 (m, 1H),
4.29-4.19 (m, 1H), 3.65 (dd, J=13.4, 2.7 Hz, 1H), 3.42 (dd, J=13.5,
7.8 Hz, 1H).
Example 1.61. Synthesis of
1-((methylammonio)methyl)-3,4-dihydro-1H-pyrido[3',4':3,4]pyrazolo[5,1-c]-
[1,4]oxazin-8-ium chloride (61)
##STR00249##
[0406] Compound 61 was prepared using a procedure analogous to that
described for compound 1 but using intermediate I-68 in place of
intermediate I-7 in the procedure of Example 1.1. (55.4 mg, yellow
solid); MS (ESI): m/z 219 [M+H].sup.+; .sup.1H-NMR (400 MHz,
MeOD-d4): .delta. 9.79 (s, 1H), 8.54 (d, J=6.8 Hz, 1H), 8.28 (d,
J=6.8 Hz, 1H), 5.82-5.79 (m, 1H), 4.86-4.84 (m, 2H), 4.67-4.63 (m,
1H), 4.39-4.35 (m, 1H), 4.07-4.03 (m, 1H), 3.71-3.68 (m, 1H), 2.89
(s, 3H).
Example 1.62. Synthesis of
1-((dimethylammonio)methyl)-3,4-dihydro-1H-pyrido[3',4':3,4]pyrazolo[5,1--
c][1,4]oxazin-8-ium chloride (62)
##STR00250##
[0408] Compound 62 was prepared using a procedure analogous to that
as described for compound 3 but using compound 61 in place of
compound 1 in the procedure of Example 1.F. (60 mg, yellow solid);
MS (ESI): m/z 233 [M+H].sup.+, .sup.1H-NMR (400 MHz, MeOD-d4):
.delta. 9.79 (s, 1H), 8.58 (d, J=6.8 Hz, 1H), 8.28 (d, J=6.8 Hz,
1H), 5.98-5.94 (m, 1H), 5.45-5.42 (m, 1H), 4.68-4.65 (m, 1H),
4.58-4.55 (m, 1H), 4.44-4.38 (m, 2H), 4.30-4.22 (m, 2H), 4.19-4.13
(m, 1H), 3.07 (s, 3H), 3.02 (s, 3H).
Example 1.63. Preparation of
1-(aziridin-1-ylmethyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole
(63)
##STR00251##
[0410] To a solution of compound 15 (0.34 g, 1.67 mmol) in a
mixture of dichloroethane/acetonitrile (4 mL/2 mL) was added solid
K.sub.3PO.sub.4 (354 mg, 1.67 .mu.mol) in a sealed tube. The
reaction mixture was stirred at 130.degree. C. for 3 hrs. The crude
reaction mixture was filtered, the filtrate was concentrated in
vacuo and the residue was purified by silica gel chromatography.
Compound 63 was obtained as yellow oil (90 mg, 20%, MS (ESI): m/z
230 [M+H].sup.+. .sup.1H-NMR (500 MHz CDCl.sub.3): .delta. 7.68 (d,
J=8.8 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.36-7.26 (m, 1H), 7.13-7.00
(m, 1H), 5.55-5.32 (m, 1H), 4.61-4.56 (m, 1H), 4.51-4.47 (m, 2H),
4.18-4.05 (m, 1H), 3.11-3.08 (m, 1H), 2.76-2.72 (m, 1H), 1.89-1.87
(m, 2H), 1.36-1.30 (m, 2H).
Example 1.64. Preparation of
(2S)-2-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)azetidin-1-ium
chloride (64)
##STR00252##
[0412] Compound 64 was prepared using a procedure analogous to that
described for compound 40 but using intermediate I-71 in place of
intermediate I-36 in the procedure of Example 1.40. (129 mg as
white solid). MS (ESI): m/z 230 [M+H].sup.+. 1H-NMR (500 MHz,
DMSO-d6): .delta. 7.78 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H),
7.28 (t, J=8.5 Hz, 1H), 7.08 (t, J=8.5 Hz, 1H), 5.52 (s, 1H), 5.33
(br-s, 1H), 4.74-4.69 (m, 1H), 4.54-4.51 (m, 1H), 4.44-4.42 (m,
1H), 4.21-4.16 (m, 1H), 3.88-3.85 (m, 1H), 3.75-3.72 (m, 1H),
2.79-2.76 (m, 1H), 2.57-2.54 (m, 1H).
Example 1.65. Preparation of
((2S)-2-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-1-methylazetidin-
-1-ium chloride (65)
##STR00253##
[0414] Compound 65 was prepared using a procedure analogous to that
described for compound 3 but using compound 64 in place of compound
1 in the procedure of Example 1.F. (49.8 mg, as colorless oil). MS
(ESI): m/z 244 [M+H].sup.+. 1H-NMR (500 MHz, CD.sub.3OD): .delta.
7.79 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.40 (t, J=8.5 Hz,
1H), 7.22 (t, J=8.5 Hz, 1H), 5.57 (s, 1H), 5.43-5.41 (m, 1H),
4.74-4.65 (m, 2H), 4.54-4.51 (m, 1H), 4.33-4.26 (m, 1H), 4.19-4.14
(m, 1H), 3.99-3.92 (m, 1H), 3.03-2.97 (m, 1H), 2.74-2.70 (m, 1H),
2.49 (s, 3H).
Example 1.66. Preparation of
3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)azetidin-1-ium
chloride (66)
##STR00254##
[0416] Compound 66 was prepared using a procedure analogous to that
described for compound 3, but using tert-butyl
3-formylazetidine-1-carboxylate in place of tert-butyl
methyl(2-oxoethyl)carbamate in the procedure of Example 1.B. MS
(ESI): m/z 230 [M+H].sup.+. .sup.1H NMR (500 MHz, CD.sub.3OD):
.delta. 7.80 (m, 1H), 7.68 (m, 1H), 7.52 (m, 1H), 7.26 (m, 1H),
5.47 (brs, 1H), 4.71-4.68 (m, 3H), 4.40-4.30 (m, 3H), 4.05-3.87 (m,
3H).
Example 1.67. Preparation of
3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-1-methylazetidin-1-ium
chloride (67)
##STR00255##
[0418] Compound 67 was prepared using a procedure analogous to that
described for compound 3, but using compound 66 in place of
compound 1 in the procedure of Example 1.F. MS (ESI): m/z 244
[M+H]+. 1H NMR (400 MHz, CD.sub.3OD): .delta. 7.87-7.80 (m, 1H),
7.69 (d, J=8.8 Hz, 1H), 7.58-7.54 (m, 1H), 7.33-7.28 (m, 1H), 5.55
(s, 1H), 4.81-4.58 (m, 4H), 4.35-4.29 (m, 2H), 4.13-3.98 (m, 3H),
2.92 (s, 3H).
Example 1.68. Preparation of
(S)-1-(6,7-dihydro-9H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-
-methylmethanamine (68) and
(R)-1-(6,7-dihydro-9H-thieno[3',2':3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-
-methylmethanamine (69)
##STR00256##
[0420] Compound 58 (4.0 g, 17.9 mmol) was separated into its
enantiomers 68 and 69 by chiral HPLC using column IC 20*250 mm, 5
.mu.m (Daicel) and mobile phase CO.sub.2/MeOH (0.2%
NH.sub.4OH)=65/35. The flow rate was 80 g/min, back pressure was
100 Bar and cycle time of stack injections was 5.3 min. Compound 68
(2.0 g, 50%, retention time 2.74 min) was obtained as colorless
oil. MS (ESI): m/z 224 [M+H].sup.+. .sup.1H-NMR (500 MHz,
CD.sub.3OD): .delta. 7.85 (d, J=5.0 Hz, 1H), 7.21 (d, J=5.0 Hz,
1H), 5.57-5.55 (m, 1H), 4.58-4.48 (m, 3H), 4.32-4.27 (m, 1H),
3.80-3.77 (m, 1H), 3.59-3.55 (m, 1H), 2.84 (s, 3H). Compound 69
(2.0 g, 50%, retention time 4.46 min) was obtained as white solid.
MS (ESI): m/z 224 [M+H].sup.+. .sup.1H-NMR (500 MHz, CD.sub.3OD):
.delta. 7.63 (d, J=5.0 Hz, 1H), 7.12 (d, J=5.0 Hz, 1H), 5.47-5.45
(m, 1H), 4.54-4.39 (m, 3H), 4.27-4.22 (m, 1H), 3.75-3.72 (m, 1H),
3.54-3.50 (m, 1H), 2.83 (s, 3H).
Example 2. Biological Assays
Example 2.1. Tail Suspension Test
[0421] The tail suspension test (TST) is a rodent screening test
for potential (human) antidepressant drugs. It is based on the
assumption that an animal will actively try to escape an aversive
(stressful) stimulus. If escape is impossible, the animal will
eventually stop trying ("give up"). In the TST, a mouse is
suspended by the tail so that its body dangles in the air, head
downward. Mice initially struggle to face upward and climb to a
solid surface. When the animal stops struggling and hangs immobile
it is considered to have "given up". Shorter periods of immobility
are characteristic of anti-depressant-like activity. Accordingly,
longer periods of immobility are considered indicative of a
depressive-like state. It has been shown that treatment with an
antidepressant drug will decrease the time the animal spends
immobile. See generally L. Steru et al., Psychopharmacology (Berl).
1985; 85(3):367-70; B. Thierry et al., Psychopharmacology 1986;
90:284-85.
[0422] Procedure. Adult male CD 1 mice (Charles River Laboratories)
receive either vehicle (sterile water or saline, 10 mL/kg) or
compound (30 mg/kg) by ip injection 30 min before being subjected
to the Tail Suspension Test. In this test animals are suspended by
the tail for 10 min during which the time spent immobile is
measured.
TABLE-US-00002 Mean Standard p value Total Time Error of (compound
Compound Immobile (sec) the Mean vs vehicle) 2 76.6 25.9 <0.0001
4 74.9 13.0 <0.0001 6 175.2 35.1 0.020 7 132.9 20.7 0.0012 8
237.5 30.0 0.12 9 189.4 18.8 0.0078 22 374.0 27.8 0.73 27 144.2
34.5 0.0002 28 98.0 33.9 <0.0001 29 115.0 25.1 <0.0001 50
84.5 18.9 0.0005 61 162.0 26.6 <0.0001 68 86.1 30.6
<0.0001
Example 2.2. Neuropharmacological Assay (SmartCube.TM.)
[0423] In order to further demonstrate the utility of the provided
compounds to treat neurological and psychiatric diseases and
disorders, exemplary compounds were evaluated using the
neuropharmacological screen described in S. L. Roberds et al.,
Front. Neurosci. 2011 Sep. 9; 5:103 (doi: 10.3389/fnins.2011.00103)
("Roberds"). As reported in Roberds, because psychiatric diseases
generally result from disorders of cell-cell communication or
circuitry, intact systems are useful in detecting improvement in
disease-relevant endpoints. These endpoints are typically
behavioral in nature, often requiring human observation and
interpretation. To facilitate testing of multiple compounds for
behavioral effects relevant to psychiatric disease, PsychoGenics,
Inc. (Tarrytown, N.Y., "PGI") developed SmartCube.TM., an automated
system in which behaviors of compound-treated mice are captured by
digital video and analyzed with computer algorithms. (D. Brunner et
al., Drug Discov. Today 2002, 7:S107-S112). PGI Analytical Systems
uses data from SmartCube.TM. to compare the behavioral signature of
a test compound to a database of behavioral signatures obtained
using a large set of diverse reference compounds. (The composition
of the database as well as validation of the method is further
described in Roberds). In this way, the neuropharmacological
effects of a test compound can be predicted by similarity to major
classes of compounds, such as antipsychotics, anxiolytics and
antidepressants.
[0424] The SmartCube.TM. system produces an activity signature
indicating the probability that the activity of the test compound
at the administered dose matches a given class of
neuropharmacological agents. (See, e.g., Roberds, FIGS. 2 and 3).
The test compound is simultaneously compared against multiple
classes of agents; thus, a separate probability is generated for
each behavioral effect measured (e.g., anxiolytic activity,
analgesic activity, etc.). In Table 2 and 2B, these probabilities
are reported for each behavioral effect measured as follows:
TABLE-US-00003 LOQ.ltoreq. + <5% 5%.ltoreq. ++ <25%
25%.ltoreq. +++ <50% 50%.ltoreq. ++++
where LOQ is the limit of quantification.
[0425] Provided compounds were dissolved in a mixture of
Pharmasolve.TM. (N-methyl-2-pyrrolidone), polyethylene glycol and
propylene glycol, and were injected i.p. 15 min. before the
behavioral test. For each compound, injections were administered at
3 different doses. For each behavioral effect measured, results for
the most efficacious dose(s) are presented.
TABLE-US-00004 TABLE 2 Compound DP AX SD PS MS AD CE AG XG HA UN 1
+ ++ + + + + + + + + + 2 ++++ ++ + + + ++ + + + ++++ + 3 ++ + + ++
+ + + + + + +++ 4 ++++ + + + + ++ ++ ++ + ++ ++ 5 ++ + + + + + + ++
+ + + 6 +++ ++ + ++ + + ++ ++ + + + 7 ++++ + + + + + + ++ + + + 8
+++ ++ + ++ + + ++ ++ ++ + + 9 ++ + + + + ++ ++ ++ + + +++ 10 ++++
++ + ++ + + + ++ ++ + + 11 +++ + ++ ++ + + + + + + + 12 + + + + + +
+ + + + + 13 ++ ++ + + ++ + ++ +++ + + + 14 ++ +++ + ++ + + ++ + +
+ + 15 ++ + + + + ++++ + ++ + + + 16 + + + + + + + + + + + 17 ++ ++
+ + + + + + + + ++ 18 + ++ + ++ + + ++ ++ + + + 19 +++ ++ + + + +
++ ++ + + + 20 ++ +++ + ++ + + ++ ++ + + + 21 ++ ++ + ++ + + + ++ +
+ + 22 ++++ ++ + + + ++ + + + ++ ++ 23 ++ ++++ + + + + ++ ++ + + +
24 ++ ++ + ++ + + ++ ++ + + + 25 ++ ++ + + + ++ + ++ + + + 26 ++ +
+ + + + + ++ + + + 27 ++++ + + + + + + ++ + + + 28 ++++ ++ + + + +
++ + + ++ ++ 29 +++ ++ + + + + ++ + + ++ + 30 ++ +++ + + + ++ + ++
+ ++ + 31 ++ +++ + ++ + + ++ ++ + + +++ 32 ++ ++ + +++ + + ++ + + +
++ 33 ++ ++ + + + ++++ + ++ + ++ +++ 34 + ++ + + + + + + + + + 35 +
+ + + + + + + + + + 36 +++ ++ ++ ++ + + ++ ++ + + ++ 37 ++ ++ ++ ++
+ + ++ ++ + + +++ 38 + ++ + ++ ++ + + ++ + + + 39 ++ ++ + + + + + +
+ + + 40 ++ +++ ++ ++ + + ++ ++ + + + 41 + + + + + + + + + + + 42 +
+ + + + + + + + + + 43 + + + + + + + + + + + 44 ++ +++ + ++ + + ++
++ + + + 45 + + + + + + + + + + + 46 + ++ ++ ++ + + + ++ + + ++ 47
+ ++ + + + + + ++ + + + 48 + + + + + + + + + + + 49 ++ ++ ++ + + +
++ +++ + + + 50 ++++ +++ + + + ++ + + + ++ + 51 +++ ++ + + + ++ + +
+ + + 52 ++ ++ + + + + + + + + ++ 53 ++ ++ ++ + + + + + + + ++ 54 +
++ + + + + + + + + + 55 + ++ + + + + + + + + +++ 56 + + + + + + + +
+ + + 57 + + + + + + + + + + + 58 ++++ ++ ++ + + ++ + + + ++ + 59
++ ++ + ++ + + ++ ++ + + +++ 60 ++ +++ ++ + + ++ + + + + + 61 ++++
+ + + + ++ + + + ++ ++ 62 + ++ + + + + + + + + + I-4 ++++ +++ ++ +
+ ++ + + + ++ + 63 ++ + ++ + + + + +++ + + + 64 ++ ++ + + + ++++ +
++ + + +++ 65 ++ ++ ++ + + + ++ +++ ++ + + 66 ++ ++ + + + + + ++ +
+ + 67 ++ ++ + + + + + + + + + 68 ++++ ++ ++ + + ++ + ++ + ++++ ++
69 ++ ++ + + + + + + + + ++ DP: anti-depressant; AX: anxiolytic;
SD: sedative hypnotic; PS: anti-psychotic; MS: mood stabilizer; AD:
ADHD; CE: cognitive enhancer; AG: analgesic; XG: anxiogenic; HA:
hallucinogen; UN: uncharacterized CNS activity
[0426] Some embodiments of the present invention are enumerated
below. In such presentations, an embodiment reciting a "compound"
with reference to another enumerated embodiment either that itself
explicitly recites "or a pharmaceutically acceptable salt thereof"
or that refers ultimately to an enumerated embodiment that does, is
intended to encompass both free compounds and pharmaceutically
acceptable salts thereof. As a convention, the phrase "or a
pharmaceutically acceptable salt thereof" is explicitly recited
when the structural formula of the compound is explicitly recited,
but no difference in inclusion or exclusion of pharmaceutically
acceptable salts is thereby intended. For example, both embodiments
1 and 2 are intended to encompass both the free compounds and
pharmaceutically acceptable salts thereof.
* * * * *