U.S. patent application number 17/452786 was filed with the patent office on 2022-06-16 for 1-heterocyclyl isochromanyl 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, Taleen G. HANANIA, Philip Glyn JONES, Noel Aaron POWELL, Kerry L. SPEAR, Linghong XIE.
Application Number | 20220185799 17/452786 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-16 |
United States Patent
Application |
20220185799 |
Kind Code |
A1 |
XIE; Linghong ; et
al. |
June 16, 2022 |
1-HETEROCYCLYL ISOCHROMANYL COMPOUNDS AND ANALOGS FOR TREATING CNS
DISORDERS
Abstract
Disclosed are compounds of Formula (I): ##STR00001## and
pharmaceutically acceptable salts thereof, wherein A, R.sup.a,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, 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: |
XIE; Linghong;
(Southborough, MA) ; JONES; Philip Glyn; (Danvers,
MA) ; SPEAR; Kerry L.; (Concord, MA) ; POWELL;
Noel Aaron; (Westford, MA) ; HANANIA; Taleen G.;
(Valhalla, NY) ; ALEXANDROV; Vadim; (Hopewell
Junction, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sunovion Pharmaceuticals Inc.
PGI Drug Discovery LLC |
Marlborough
Paramus |
MA
NJ |
US
US |
|
|
Assignee: |
Sunovion Pharmaceuticals
Inc.
Marlborough
MA
PGI Drug Discovery LLC
Paramus
NJ
|
Appl. No.: |
17/452786 |
Filed: |
October 29, 2021 |
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Application
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16403698 |
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11192885 |
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17452786 |
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15819372 |
Nov 21, 2017 |
10336732 |
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15819372 |
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International
Class: |
C07D 405/04 20060101
C07D405/04; C07D 405/14 20060101 C07D405/14; C07D 413/14 20060101
C07D413/14; C07D 493/04 20060101 C07D493/04; C07D 413/04 20060101
C07D413/04 |
Claims
1. A compound of formula I: ##STR00341## or a pharmaceutically
acceptable salt thereof, wherein: A is ##STR00342## m is 0, 1, or
2; n1 is 1, 2, or 3; R is --H or C.sub.1-C.sub.3 alkyl; R.sup.a is
--H or C.sub.1-C.sub.3 alkyl; R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, --OH, --NH.sub.2,
C.sub.1-C.sub.3 alkyl, --OR.sup.7, --NHR.sup.7,
--N(R.sup.7)R.sup.7, --CN, phenyl, or 5- or 6-membered heteroaryl,
wherein: each instance of R.sup.7 independently is unsubstituted
C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 alkyl substituted with 1-3
halo, each instance of C.sub.1-C.sub.3 alkyl independently is
unsubstituted or substituted with 1-3 halo, and the phenyl or
heteroaryl is unsubstituted or substituted with 1 or 2 groups
independently selected from halo, --OH, --OCH.sub.3, --OCF.sub.3,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, ethyl,
--CF.sub.3, and --CN, optionally wherein two adjacent instances of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--,
--O--C(CH.sub.3).sub.2--O--, --O--CH.sub.2--CH.sub.2--O--, or
--O--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--O--; each instance of
R.sup.5 independently is halo, --CH.sub.3, or ethyl; each instance
of R.sup.6 independently is halo, --CH.sub.3, ethyl or --OH; and w
is 0, 1, or 2.
2. The compound of claim 1 of formula (III): ##STR00343## or a
pharmaceutically acceptable salt thereof.
3. The compound of claim 2 of formula (IIIa), formula (IIIb),
formula (IIIc), or formula (IIId): ##STR00344## or a
pharmaceutically acceptable salt thereof.
4-11. (canceled)
12. The compound of claim 1 of formula (I-C): ##STR00345## or a
pharmaceutically acceptable salt thereof.
13. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein n1 is 1.
14. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein n1 is 2.
15. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein n1 is 3.
16. (canceled)
17. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein at least three of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are --H.
18-20. (canceled)
21. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein two adjacent instances of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--.
22. (canceled)
23. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.a is --H and/or wherein R is --H.
24-27. (canceled)
28. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein m is 0 and/or w is 0.
29-31. (canceled)
32. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently --H, --F, --CH.sub.3, --OCH.sub.3, or --CN.
33-36. (canceled)
37. The compound of claim 17, or a pharmaceutically acceptable salt
thereof, wherein: n1 is 2; R.sup.a is H; m is 0; w is 0; R is H;
and R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently --H,
--F, --CH.sub.3, --OCH.sub.3, or --CN.
38. The compound of claim 1, selected from those depicted in Table
1: TABLE-US-00006 TABLE 1 ##STR00346## I-79 ##STR00347## I-80
##STR00348## I-81 ##STR00349## I-82 ##STR00350## I-83 ##STR00351##
I-84 ##STR00352## I-85 ##STR00353## I-86 ##STR00354## I-87
##STR00355## I-88 ##STR00356## I-89 ##STR00357## I-90 ##STR00358##
I-91 ##STR00359## I-92 ##STR00360## I-93 ##STR00361## I-94
##STR00362## I-95 ##STR00363## I-96 ##STR00364## I-114 ##STR00365##
I-115 ##STR00366## I-116 ##STR00367## I-117 ##STR00368## I-126
##STR00369## I-127 ##STR00370## I-128 ##STR00371## I-133
##STR00372## I-135 ##STR00373## I-136 ##STR00374## I-143
##STR00375## I-144
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1, wherein the compound is: ##STR00376##
or a pharmaceutically acceptable salt thereof.
40. The compound of claim 39, selected from: ##STR00377## or a
pharmaceutically acceptable salt thereof, or a mixture of two or
more thereof.
41. The compound of claim 1, wherein the compound is: ##STR00378##
or a pharmaceutically acceptable salt thereof.
42. The compound of claim 45, selected from: ##STR00379## or a
pharmaceutically acceptable salt thereof, or a mixture of two or
more thereof.
43. A composition comprising a compound according to claim 1, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier, adjuvant, or vehicle.
44. A method for treating a neurological or psychiatric disorder in
a patient, comprising administering to said patient an effective
amount of the compound according to claim 1, or a pharmaceutically
acceptable salt thereof.
Description
BACKGROUND
[0001] 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, 4th Ed.,
American Psychiatric Association (2000) ("DSM-IV-TR"); Diagnostic
and Statistical Manual of Mental Disorders, 5th Ed., American
Psychiatric Association (2013) ("DSM-5").
[0002] 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.
[0003] 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.
[0004] 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.
[0005] Neurological and psychiatric disorders can exhibit a variety
of symptoms, including cognitive impairment, depressive disorders,
and anxiety disorders.
[0006] 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.
[0007] 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.
[0008] 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
[0009] 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.
[0010] In some embodiments, the present invention encompasses the
insight that compounds of Formula (I):
##STR00002##
[0011] and pharmaceutically acceptable salts thereof, wherein A,
R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, 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: [0014] A
is
[0014] ##STR00004## [0015] m is 0, 1, or 2; [0016] n1 is 1, 2, or
3; [0017] n2 is 0 or 1; [0018] n3 is 0 or 1; [0019] R is --H or
C.sub.1-C.sub.3 alkyl; [0020] R.sup.a is --H or C.sub.1-C.sub.3
alkyl; [0021] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently --H, halo, --OH, --NH.sub.2, C.sub.1-C.sub.3 alkyl,
--OR.sup.7, --NHR.sup.7, --N(R.sup.7)R.sup.7, --CN, phenyl, or 5-
or 6-membered heteroaryl, wherein: [0022] each instance of R.sup.7
independently is unsubstituted C.sub.1-C.sub.2 alkyl or
C.sub.1-C.sub.2 alkyl substituted with 1-3 halo, [0023] each
instance of C.sub.1-C.sub.3 alkyl independently is unsubstituted or
substituted with 1-3 halo, [0024] and [0025] the phenyl or
heteroaryl is unsubstituted or substituted with 1 or 2 groups
independently selected from halo, --OH, --OCH.sub.3, --OCF.sub.3,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, ethyl,
--CF.sub.3, and --CN,
[0026] optionally wherein [0027] two adjacent instances of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, --O--C(CH.sub.3).sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, or
--O--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--O--; [0028] each
instance of R.sup.5 independently is halo, --CH.sub.3, or ethyl;
[0029] each instance of R.sup.6 independently is halo, --CH.sub.3,
ethyl or --OH; [0030] w is 0, 1, or 2; and [0031] Z is C or 0;
provided that the compound is not
##STR00005##
[0031] 2. Compounds and Definitions
[0032] 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.
[0033] As used herein, the term "halogen" or "halo" means F, Cl,
Br, or I.
[0034] 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.
[0035] 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 .pi.
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.
[0036] 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).
[0037] 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.
[0038] As used herein, the term "unsaturated," as used herein,
means that a moiety has one or more units of unsaturation.
[0039] 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.
[0040] 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 NR.sup.+ (as
in N-substituted pyrrolidinyl)).
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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
[0047] In some embodiments, the present invention provides a
compound of formula I:
##STR00006##
or a pharmaceutically acceptable salt thereof, wherein: [0048] A
is
[0048] ##STR00007## [0049] m is 0, 1, or 2; [0050] n1 is 1, 2, or
3; [0051] n2 is 0 or 1; [0052] n3 is 0 or 1; [0053] R is --H or
C.sub.1-C.sub.3 alkyl; [0054] R.sup.a is --H or C.sub.1-C.sub.3
alkyl; [0055] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently --H, halo, --OH, --NH.sub.2, C.sub.1-C.sub.3 alkyl,
--OR.sup.7, --NHR.sup.7, --N(R.sup.7)R.sup.7, --CN, phenyl, or 5-
or 6-membered heteroaryl, wherein: [0056] each instance of R.sup.7
independently is unsubstituted C.sub.1-C.sub.2 alkyl or
C.sub.1-C.sub.2 alkyl substituted with 1-3 halo, [0057] each
instance of C.sub.1-C.sub.3 alkyl independently is unsubstituted or
substituted with 1-3 halo, [0058] and [0059] the phenyl or
heteroaryl is unsubstituted or substituted with 1 or 2 groups
independently selected from halo, --OH, --OCH.sub.3, --OCF.sub.3,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, ethyl,
--CF.sub.3, and --CN,
[0060] optionally wherein [0061] two adjacent instances of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, --O--C(CH.sub.3).sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, or
--O--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--O--; [0062] each
instance of R.sup.5 independently is halo, --CH.sub.3, or ethyl;
[0063] each instance of R.sup.6 independently is halo, --CH.sub.3,
ethyl or --OH; [0064] w is 0, 1, or 2; and [0065] Z is C or 0;
[0066] with the proviso that the compound is not:
##STR00008##
[0066] 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. 62/115,064,
filed Feb. 11, 2015, which is hereby incorporated by reference
herein in its entirety.
[0067] As defined above, A is
##STR00009##
[0068] In some embodiments, A is
##STR00010##
[0069] As defined above, m is 0, 1, or 2. In some embodiments, m is
0. In some embodiments, m is 1. In some embodiments, m is 2. In
some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In
some embodiments, m is 0 or 2.
[0070] As defined above, n1 is 1, 2, or 3. In some embodiments, n1
is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3.
In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 1 or
3. In some embodiments, n1 is 2 or 3.
[0071] As defined above, n2 is 0 or 1. In some embodiments, n2 is
0. In some embodiments, n2 is 1.
[0072] As defined above, n3 is 0 or 1. In some embodiments, n3 is
0. In some embodiments, n3 is 1.
[0073] As defined above, R is --H or C.sub.1-C.sub.3 alkyl. In some
embodiments, R is --H. In some embodiments, R is C.sub.1-C.sub.3
alkyl. In some embodiments, R is --H or --CH.sub.3.
[0074] As defined above, R.sup.a is --H or C.sub.1-C.sub.3 alkyl.
In some embodiments, R.sup.a is --H. In some embodiments, R.sup.a
is C.sub.1-C.sub.3 alkyl. In some embodiments, R.sup.a is --H or
--CH.sub.3.
[0075] As defined above, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently --H, halo, --OH, --NH.sub.2, C.sub.1-C.sub.3 alkyl,
--OR.sup.7, --NHR.sup.7, --N(R.sup.7)R.sup.7, --CN, phenyl, or 5-
or 6-membered heteroaryl, wherein:
[0076] each instance of R.sup.7 independently is unsubstituted
C.sub.1-C.sub.2 alkyl or C.sub.1-C.sub.2 alkyl substituted with 1-3
halo,
[0077] each instance of C.sub.1-C.sub.3 alkyl independently is
unsubstituted or substituted with 1-3 halo, and
[0078] the phenyl or heteroaryl is unsubstituted or substituted
with 1 or 2 groups independently selected from halo, --OH,
--OCH.sub.3, --OCF.sub.3, --NH.sub.2, --NH(CH.sub.3),
--N(CH.sub.3).sub.2, --CH.sub.3, ethyl, --CF.sub.3, and --CN,
optionally wherein two adjacent instances of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, --O--C(CH.sub.3).sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, or
--O--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--O--
[0079] 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, the 5- or 6-membered heteroaryl of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 has at least 1 nitrogen ring atom and is
unsubstituted or substituted with 1 group selected from halo, --OH,
--OCH.sub.3, --OCF.sub.3, --NH.sub.2, --NH(CH.sub.3),
--N(CH.sub.3).sub.2, --CH.sub.3, ethyl, --CF.sub.3, and --CN. In
some embodiments, the 5- or 6-membered heteroaryl of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 is unsubstituted pyridyl,
pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl, or
oxazolyl. In some embodiments, the 5- or 6-membered heteroaryl of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is unsubstituted pyridyl or
isoxazolyl. In some embodiments, two adjacent instances of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--. In some
embodiments, two adjacent instances of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 together form --O--CH.sub.2--O--. In some embodiments,
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently --H, halo,
C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN. In some embodiments,
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently --H, --F,
--CH.sub.3, --OCH.sub.3, or --CN.
[0080] As defined above, each instance of R.sup.5 independently is
halo, --CH.sub.3, or ethyl. In some embodiments, each instance of
R.sup.5 independently is halo. In some embodiments, each instance
of R.sup.5 independently is --CH.sub.3. In some embodiments, each
instance of R.sup.5 independently is ethyl. In some embodiments,
each instance of R.sup.5 independently is halo or --CH.sub.3. In
some embodiments, each instance of R.sup.5 independently is halo or
ethyl. In some embodiments, each instance of R.sup.5 independently
is --CH.sub.3 or ethyl. In some embodiments, each instance of
R.sup.5 independently is --F or --CH.sub.3.
[0081] As defined above, each instance of R.sup.6 independently is
halo, --CH.sub.3, ethyl or --OH. In some embodiments, each instance
of R.sup.6 independently is halo. In some embodiments, each
instance of R.sup.6 independently is --CH.sub.3. In some
embodiments, each instance of R.sup.6 independently is ethyl. In
some embodiments, each instance of R.sup.6 independently is --OH.
In some embodiments, 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 or ethyl. In some embodiments, each instance
of R.sup.6 independently is --CH.sub.3 or ethyl. In some
embodiments, each instance of R.sup.6 independently is --F or
--CH.sub.3.
[0082] As defined above, w is 0, 1, or 2. In some embodiments, w is
0. In some embodiments, w is 1. In some embodiments, w is 2. In
some embodiments, w is 0 or 1. In some embodiments, w is 1 or 2. In
some embodiments, w is 0 or 2.
[0083] As defined above, Z is C or O. In some embodiments, Z is C.
In some embodiments, Z is O.
[0084] In some embodiments, a provided compound is a compound of
formula (I-A) or (I-B):
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
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 (I-A1) or (I-B1):
##STR00012##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n2, n3, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, 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.
[0086] In some embodiments, a provided compound is a compound of
formula (I-A2) or (I-B2):
##STR00013##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n2, n3, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, 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.
[0087] In some embodiments, a provided compound is a compound of
formula (I-A3) or (I-B3):
##STR00014##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n2, n3, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, 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.
[0088] In some embodiments, a provided compound is a compound of
formula (I-A), or a pharmaceutically acceptable salt thereof,
wherein each of m, n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, 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. In some such embodiments, Z
is C. In some such embodiments, Z is C, n2 is 0 and n3 is 0. In
some such embodiments, Z is C, and one of n2 and n3 is 0 and the
other is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1.
In some such embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. In some such embodiments, at least
three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some
such embodiments, R.sup.a is --H. In some such embodiments, R is
--H. In some such embodiments, R.sup.a is --H and R is --H. In some
such embodiments, each instance of R.sup.5 is --F or --CH.sub.3. In
some such embodiments, R.sup.a is --H, R is --H, and each instance
of R.sup.5 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --F or --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --F or --CH.sub.3. In
some such embodiments, each instance of R.sup.6 is --CH.sub.3. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is
--CH.sub.3. In some such embodiments, m is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3;
and m is 0. In some such embodiments, w is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3; m
is 0; and w is 0. In some such embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, halo, C.sub.1-C.sub.3
alkyl, --OR.sup.7 or --CN. In some such embodiments, w is 0. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, C.sub.1-C.sub.3 alkyl,
--OR.sup.7 or --CN. In some such embodiments, two adjacent
instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. In some such embodiments, R.sup.a is
--H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and two
adjacent instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
together form --O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--.
[0089] In some embodiments, a provided compound is a compound of
formula (I-A1), (I-A2), or (I-A3), or a pharmaceutically acceptable
salt thereof, wherein each of m, n2, n3, R, R.sup.a, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, 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. In some such
embodiments, Z is C. In some such embodiments, Z is C, n2 is 0 and
n3 is 0. In some such embodiments, Z is C, and one of n2 and n3 is
0 and the other is 1. In some such embodiments, Z is C, n2 is 1 and
n3 is 1. In some such embodiments, at least two of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are --H. In some such embodiments, at
least three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In
some such embodiments, R.sup.a is --H. In some such embodiments, R
is --H. In some such embodiments, R.sup.a is --H and R is --H. In
some such embodiments, each instance of R.sup.5 is --F or
--CH.sub.3. In some such embodiments, R.sup.a is --H, R is --H, and
each instance of R.sup.5 is --F or --CH.sub.3. In some such
embodiments, each instance of R.sup.6 is --F or --CH.sub.3. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is --F
or --CH.sub.3. In some such embodiments, each instance of R.sup.6
is --CH.sub.3. In some such embodiments, R.sup.a is --H; R is --H;
each instance of R.sup.5 is --F or --CH.sub.3; and each instance of
R.sup.6 is --CH.sub.3. In some such embodiments, m is 0. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; and m is 0. In some such embodiments, w is 0. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; and w is 0. In some such embodiments, R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are independently --H, halo,
C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN. In some such
embodiments, w is 0. In some such embodiments, R.sup.a is --H; R is
--H; each instance of R.sup.5 is --F or --CH.sub.3; each instance
of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are independently --H, halo,
C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN. In some such
embodiments, two adjacent instances of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and two adjacent instances of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--.
[0090] In some embodiments, a provided compound is a compound of
formula (I-B), or a pharmaceutically acceptable salt thereof,
wherein each of m, n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, 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. In some such embodiments, Z
is C. In some such embodiments, Z is C, n2 is 0 and n3 is 0. In
some such embodiments, Z is C, and one of n2 and n3 is 0 and the
other is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1.
In some such embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. In some such embodiments, at least
three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some
such embodiments, R.sup.a is --H. In some such embodiments, R is
--H. In some such embodiments, R.sup.a is --H and R is --H. In some
such embodiments, each instance of R.sup.5 is --F or --CH.sub.3. In
some such embodiments, R.sup.a is --H, R is --H, and each instance
of R.sup.5 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --F or --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --F or --CH.sub.3. In
some such embodiments, each instance of R.sup.6 is --CH.sub.3. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is
--CH.sub.3. In some such embodiments, m is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3;
and m is 0. In some such embodiments, w is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3; m
is 0; and w is 0. In some such embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, halo, C.sub.1-C.sub.3
alkyl, --OR.sup.7 or --CN. In some such embodiments, w is 0. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, C.sub.1-C.sub.3 alkyl,
--OR.sup.7 or --CN. In some such embodiments, two adjacent
instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. In some such embodiments, R.sup.a is
--H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and two
adjacent instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
together form --O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--.
[0091] In some embodiments, a provided compound is a compound of
formula (I-B1), (I-B2), or (I-B3), or a pharmaceutically acceptable
salt thereof, wherein each of m, n2, n3, R, R.sup.a, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, 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. In some such
embodiments, Z is C. In some such embodiments, Z is C, n2 is 0 and
n3 is 0. In some such embodiments, Z is C, and one of n2 and n3 is
0 and the other is 1. In some such embodiments, Z is C, n2 is 1 and
n3 is 1. In some such embodiments, at least two of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are --H. In some such embodiments, at
least three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In
some such embodiments, R.sup.a is --H. In some such embodiments, R
is --H. In some such embodiments, R.sup.a is --H and R is --H. In
some such embodiments, each instance of R.sup.5 is --F or
--CH.sub.3. In some such embodiments, R.sup.a is --H, R is --H, and
each instance of R.sup.5 is --F or --CH.sub.3. In some such
embodiments, each instance of R.sup.6 is --F or --CH.sub.3. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is --F
or --CH.sub.3. In some such embodiments, each instance of R.sup.6
is --CH.sub.3. In some such embodiments, R.sup.a is --H; R is --H;
each instance of R.sup.5 is --F or --CH.sub.3; and each instance of
R.sup.6 is --CH.sub.3. In some such embodiments, m is 0. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; and m is 0. In some such embodiments, w is 0. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; and w is 0. In some such embodiments, R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are independently --H, halo,
C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN. In some such
embodiments, w is 0. In some such embodiments, R.sup.a is --H; R is
--H; each instance of R.sup.5 is --F or --CH.sub.3; each instance
of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are independently --H, halo,
C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN. In some such
embodiments, two adjacent instances of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and two adjacent instances of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--.
[0092] In some embodiments, a provided compound is a compound of
formula (Ia), (Ib), (Ic), or (Id):
##STR00015##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
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 where the depictions of stereochemistry at
the stereocenters marked with an asterisk (*) are absolute.
[0093] In some embodiments, a provided compound is a compound of
formula (Ia), or a pharmaceutically acceptable salt thereof,
wherein each of m, n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, 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. In some such embodiments, Z
is C. In some such embodiments, Z is C, n2 is 0 and n3 is 0. In
some such embodiments, Z is C, and one of n2 and n3 is 0 and the
other is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1.
In some such embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. In some such embodiments, at least
three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some
such embodiments, R.sup.a is --H. In some such embodiments, R is
--H. In some such embodiments, R.sup.a is --H and R is --H. In some
such embodiments, each instance of R.sup.5 is --F or --CH.sub.3. In
some such embodiments, R.sup.a is --H, R is --H, and each instance
of R.sup.5 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --F or --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --F or --CH.sub.3. In
some such embodiments, each instance of R.sup.6 is --CH.sub.3. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is
--CH.sub.3. In some such embodiments, m is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3;
and m is 0. In some such embodiments, w is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3; m
is 0; and w is 0. In some such embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, halo, C.sub.1-C.sub.3
alkyl, --OR.sup.7 or --CN. In some such embodiments, w is 0. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, C.sub.1-C.sub.3 alkyl,
--OR.sup.7 or --CN. In some such embodiments, two adjacent
instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. In some such embodiments, R.sup.a is
--H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and two
adjacent instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
together form --O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--.
[0094] In some embodiments, a provided compound is a compound of
formula (Ib), or a pharmaceutically acceptable salt thereof,
wherein each of m, n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, 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. In some such embodiments, Z
is C. In some such embodiments, Z is C, n2 is 0 and n3 is 0. In
some such embodiments, Z is C, and one of n2 and n3 is 0 and the
other is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1.
In some such embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. In some such embodiments, at least
three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some
such embodiments, R.sup.a is --H. In some such embodiments, R is
--H. In some such embodiments, R.sup.a is --H and R is --H. In some
such embodiments, each instance of R.sup.5 is --F or --CH.sub.3. In
some such embodiments, R.sup.a is --H, R is --H, and each instance
of R.sup.5 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --F or --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --F or --CH.sub.3. In
some such embodiments, each instance of R.sup.6 is --CH.sub.3. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is
--CH.sub.3. In some such embodiments, m is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3;
and m is 0. In some such embodiments, w is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3; m
is 0; and w is 0. In some such embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, halo, C.sub.1-C.sub.3
alkyl, --OR.sup.7 or --CN. In some such embodiments, w is 0. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, C.sub.1-C.sub.3 alkyl,
--OR.sup.7 or --CN. In some such embodiments, two adjacent
instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. In some such embodiments, R.sup.a is
--H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and two
adjacent instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
together form --O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--.
[0095] In some embodiments, a provided compound is a compound of
formula (Ic), or a pharmaceutically acceptable salt thereof,
wherein each of m, n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, 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. In some such embodiments, Z
is C. In some such embodiments, Z is C, n2 is 0 and n3 is 0. In
some such embodiments, Z is C, and one of n2 and n3 is 0 and the
other is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1.
In some such embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. In some such embodiments, at least
three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some
such embodiments, R.sup.a is --H. In some such embodiments, R is
--H. In some such embodiments, R.sup.a is --H and R is --H. In some
such embodiments, each instance of R.sup.5 is --F or --CH.sub.3. In
some such embodiments, R.sup.a is --H, R is --H, and each instance
of R.sup.5 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --F or --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --F or --CH.sub.3. In
some such embodiments, each instance of R.sup.6 is --CH.sub.3. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is
--CH.sub.3. In some such embodiments, m is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3;
and m is 0. In some such embodiments, w is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3; m
is 0; and w is 0. In some such embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, halo, C.sub.1-C.sub.3
alkyl, --OR.sup.7 or --CN. In some such embodiments, w is 0. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, C.sub.1-C.sub.3 alkyl,
--OR.sup.7 or --CN. In some such embodiments, two adjacent
instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. In some such embodiments, R.sup.a is
--H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and two
adjacent instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
together form --O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--.
[0096] In some embodiments, a provided compound is a compound of
formula (Id), or a pharmaceutically acceptable salt thereof,
wherein each of m, n1, n2, n3, R, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, 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. In some such embodiments, Z
is C. In some such embodiments, Z is C, n2 is 0 and n3 is 0. In
some such embodiments, Z is C, and one of n2 and n3 is 0 and the
other is 1. In some such embodiments, Z is C, n2 is 1 and n3 is 1.
In some such embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. In some such embodiments, at least
three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some
such embodiments, R.sup.a is --H. In some such embodiments, R is
--H. In some such embodiments, R.sup.a is --H and R is --H. In some
such embodiments, each instance of R.sup.5 is --F or --CH.sub.3. In
some such embodiments, R.sup.a is --H, R is --H, and each instance
of R.sup.5 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --F or --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --F or --CH.sub.3. In
some such embodiments, each instance of R.sup.6 is --CH.sub.3. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is
--CH.sub.3. In some such embodiments, m is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3;
and m is 0. In some such embodiments, w is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3; m
is 0; and w is 0. In some such embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, halo, C.sub.1-C.sub.3
alkyl, --OR.sup.7 or --CN. In some such embodiments, w is 0. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, C.sub.1-C.sub.3 alkyl,
--OR.sup.7 or --CN. In some such embodiments, two adjacent
instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. In some such embodiments, R.sup.a is
--H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and two
adjacent instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
together form --O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--.
[0097] In some embodiments, a provided compound is a compound of
formula (I-C):
##STR00016##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, and w is as described in embodiments for formula I, supra,
or described in embodiments herein, both singly and in
combination.
[0098] In some embodiments, a provided compound is a compound of
formula (I-C), or a pharmaceutically acceptable salt thereof,
wherein each of m, n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and w is as described in embodiments for
formula I, supra, or described in embodiments herein, both singly
and in combination. In some such embodiments, at least two of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some such
embodiments, at least three of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are --H. In some such embodiments, R.sup.a is --H. In some
such embodiments, R is --H. In some such embodiments, R.sup.a is
--H and R is --H. In some such embodiments, each instance of
R.sup.5 is --F or --CH.sub.3. In some such embodiments, R.sup.a is
--H, R is --H, and each instance of R.sup.5 is --F or --CH.sub.3.
In some such embodiments, each instance of R.sup.6 is --F or
--CH.sub.3. In some such embodiments, R.sup.a is --H; R is --H;
each instance of R.sup.5 is --F or --CH.sub.3; and each instance of
R.sup.6 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --CH.sub.3. In some
such embodiments, m is 0. In some such embodiments, R.sup.a is --H;
R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; and m is 0. In some such
embodiments, w is 0. In some such embodiments, R.sup.a is --H; R is
--H; each instance of R.sup.5 is --F or --CH.sub.3; each instance
of R.sup.6 is --F or --CH.sub.3; m is 0; and w is 0. In some such
embodiments, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently --H, halo, C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN.
In some such embodiments, w is 0. In some such embodiments, R.sup.a
is --H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3;
each instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently --H, halo,
C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN. In some such
embodiments, two adjacent instances of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--. In some
such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and two adjacent instances of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 together form --O--CH.sub.2--O--,
--O--CH(CH.sub.3)--O--, or --O--C(CH.sub.3).sub.2--O--.
[0099] In some embodiments, a provided compound is a compound of
formula II:
##STR00017##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, and w is as described in embodiments for formula I, supra,
or described in embodiments herein, both singly and in combination.
In some such embodiments, at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. In some such embodiments, at least
three of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are --H. In some
such embodiments, R.sup.a is --H. In some such embodiments, R is
--H. In some such embodiments, R.sup.a is --H and R is --H. In some
such embodiments, each instance of R.sup.5 is --F or --CH.sub.3. In
some such embodiments, R.sup.a is --H, R is --H, and each instance
of R.sup.5 is --F or --CH.sub.3. In some such embodiments, each
instance of R.sup.6 is --F or --CH.sub.3. In some such embodiments,
R.sup.a is --H; R is --H; each instance of R.sup.5 is --F or
--CH.sub.3; and each instance of R.sup.6 is --F or --CH.sub.3. In
some such embodiments, each instance of R.sup.6 is --CH.sub.3. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; and each instance of R.sup.6 is
--CH.sub.3. In some such embodiments, m is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3;
and m is 0. In some such embodiments, w is 0. In some such
embodiments, R.sup.a is --H; R is --H; each instance of R.sup.5 is
--F or --CH.sub.3; each instance of R.sup.6 is --F or --CH.sub.3; m
is 0; and w is 0. In some such embodiments, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, halo, C.sub.1-C.sub.3
alkyl, --OR.sup.7 or --CN. In some such embodiments, w is 0. In
some such embodiments, R.sup.a is --H; R is --H; each instance of
R.sup.5 is --F or --CH.sub.3; each instance of R.sup.6 is --F or
--CH.sub.3; m is 0; w is 0; and R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are independently --H, halo, C.sub.1-C.sub.3 alkyl,
--OR.sup.7 or --CN. In some such embodiments, two adjacent
instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. In some such embodiments, R.sup.a is
--H; R is --H; each instance of R.sup.5 is --F or --CH.sub.3; each
instance of R.sup.6 is --F or --CH.sub.3; m is 0; w is 0; and two
adjacent instances of R.sup.1, R.sup.2, R.sup.3, and R.sup.4
together form --O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--.
[0100] In some embodiments, a provided compound is a compound of
formula (IIa), (IIb), (IIc), or (IId):
##STR00018##
or a pharmaceutically acceptable salt thereof, with the proviso as
described in embodiments for formula I, wherein each of m, n1, R,
R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and
w is as described in embodiments for formula I, supra, or described
in embodiments herein, both singly and in combination.
[0101] In some embodiments, the present invention provides a
compound of formula I, or a pharmaceutically acceptable salt
thereof, wherein the compound of formula I is a compound of formula
III:
##STR00019##
wherein each of m, n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and w is as described in embodiments for
formula I, supra, or described in embodiments herein, both singly
and in combination.
[0102] In some embodiments, the present invention provides a
compound of formula I selected from formulas (IIIa), (IIIb),
(IIIc), and (IIId):
##STR00020##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, and w is as described in embodiments for formula I, supra,
or described in embodiments herein, both singly and in
combination.
[0103] In some embodiments, the present invention provides a
compound of formula I, or a pharmaceutically acceptable salt
thereof, wherein the compound of formula I is a compound of formula
IV:
##STR00021##
wherein each of m, n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and w is as described in embodiments for
formula I, supra, or described in embodiments herein, both singly
and in combination.
[0104] In some embodiments, the present invention provides a
compound of formula I selected from formulas (IVa), (IVb), (IVc),
and (IVd):
##STR00022##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, and w is as described in embodiments for formula I, supra,
or described in embodiments herein, both singly and in
combination.
[0105] In some embodiments, the present invention provides a
compound of formula I, or a pharmaceutically acceptable salt
thereof, wherein the compound of formula I is a compound of formula
V:
##STR00023##
wherein each of m, n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and w is as described in embodiments for
formula I, supra, or described in embodiments herein, both singly
and in combination.
[0106] In some embodiments, the present invention provides a
compound of formula I selected from formulas (Va), (Vb), (Vc), and
(Vd):
##STR00024##
or a pharmaceutically acceptable salt thereof, wherein each of m,
n1, R, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, and w is as described in embodiments for formula I, supra,
or described in embodiments herein, both singly and in
combination.
[0107] Exemplary compounds of formula I are set forth in Table 1,
below.
TABLE-US-00001 TABLE 1 ##STR00025## I-1 ##STR00026## I-2
##STR00027## I-3 ##STR00028## I-4 ##STR00029## I-5 ##STR00030## I-6
##STR00031## I-7 ##STR00032## I-8 ##STR00033## I-9 ##STR00034##
I-10 ##STR00035## I-11 ##STR00036## I-12 ##STR00037## I-13
##STR00038## I-14 ##STR00039## I-15 ##STR00040## I-16 ##STR00041##
I-17 ##STR00042## I-18 ##STR00043## I-19 ##STR00044## I-20
##STR00045## I-21 ##STR00046## I-22 ##STR00047## I-23 ##STR00048##
I-24 ##STR00049## I-25 ##STR00050## I-26 ##STR00051## I-27
##STR00052## I-28 ##STR00053## I-29 ##STR00054## I-30 ##STR00055##
I-31 ##STR00056## I-32 ##STR00057## I-33 ##STR00058## I-34
##STR00059## I-35 ##STR00060## I-36 ##STR00061## I-37 ##STR00062##
I-38 ##STR00063## I-39 ##STR00064## I-40 ##STR00065## I-41
##STR00066## I-42 ##STR00067## I-43 ##STR00068## I-44 ##STR00069##
I-45 ##STR00070## I-46 ##STR00071## I-47 ##STR00072## I-48
##STR00073## I-49 ##STR00074## I-50 ##STR00075## I-51 ##STR00076##
I-52 ##STR00077## I-53 ##STR00078## I-54 ##STR00079## I-55
##STR00080## I-56 ##STR00081## I-57 ##STR00082## I-58 ##STR00083##
I-59 ##STR00084## I-60 ##STR00085## I-61 ##STR00086## I-62
##STR00087## I-63 ##STR00088## I-64 ##STR00089## I-65 ##STR00090##
I-66 ##STR00091## I-67 ##STR00092## I-68 ##STR00093## I-69
##STR00094## I-70 ##STR00095## I-71 ##STR00096## I-72 ##STR00097##
I-73 ##STR00098## I-74 ##STR00099## I-75 ##STR00100## I-76
##STR00101## I-77 ##STR00102## I-78 ##STR00103## I-79 ##STR00104##
I-80 ##STR00105## I-81 ##STR00106## I-82 ##STR00107## I-83
##STR00108## I-84 ##STR00109## I-85 ##STR00110## I-86 ##STR00111##
I-87 ##STR00112## I-88 ##STR00113## I-89 ##STR00114## I-90
##STR00115## I-91 ##STR00116## I-92 ##STR00117## I-93 ##STR00118##
I-94 ##STR00119## I-95 ##STR00120## I-96 ##STR00121## I-97
##STR00122## I-98 ##STR00123## I-99 ##STR00124## I-100 ##STR00125##
I-101 ##STR00126## I-102 ##STR00127## I-103 ##STR00128## I-104
##STR00129## I-105 ##STR00130## I-106 ##STR00131## I-107
##STR00132## I-108 ##STR00133## I-109 ##STR00134## I-110
##STR00135## I-111 ##STR00136## I-112 ##STR00137## I-113
##STR00138## I-114 ##STR00139## I-115 ##STR00140## I-116
##STR00141## I-117 ##STR00142## I-118 ##STR00143## I-119
##STR00144## I-120 ##STR00145## I-121 ##STR00146## I-122
##STR00147## I-123 ##STR00148## I-124
##STR00149## I-125 ##STR00150## I-126 ##STR00151## I-127
##STR00152## I-128 ##STR00153## I-129 ##STR00154## I-130
##STR00155## I-131 ##STR00156## I-132 ##STR00157## I-133
##STR00158## I-134 ##STR00159## I-135 ##STR00160## I-136
##STR00161## I-137 ##STR00162## I-138 ##STR00163## I-139
##STR00164## I-140 ##STR00165## I-141 ##STR00166## I-142
##STR00167## I-143 ##STR00168## I-144 ##STR00169## I-145
[0108] In some embodiments, the present invention provides a
compound selected from those depicted in Table 1, above, or a
pharmaceutically acceptable salt thereof.
[0109] Schemes below provide exemplary synthetic methods for the
preparation of the compounds provided herein. One skilled in the
art will understand that suitable adjustments to reagents,
protecting groups, reaction conditions, and reaction sequences may
be employed to prepare the compounds provided herein.
[0110] The compounds of formula (I) may be prepared following
Schemes A-D, using suitable starting materials known in the art
and/or available from a commercial source. The starting materials
of Schemes A-D may be prepared from commercially available
compounds using procedures and conditions known in the art.
##STR00170##
[0111] As shown in Scheme A, a suitable hydroxyalkyl substituted
benzene (1-1) is reacted with a suitable N-protected aminoaldehyde
(1-2) in the presence of an acid or a Lewis acid such as
trifluoromethanesulfonic acid or trimethylsilyl
trifluoromethanesulfonate to afford a cyclized product (1-3), which
can be deprotected to afford a compound of formula (I). Chiral HPLC
may be used to separate the enantiomers of a compound of formula
(I)
##STR00171##
[0112] As shown in Scheme B, a suitable 0-protected
1-hydroxyalkyl-2-bromo-benzene (2-1) is treated with a lithium or
Grignard reagent. The anion formed is reacted with a suitable
N-protected aminoketone (2-2), followed by 0-deprotection with a
suitable deprotecting reagent to afford a diol (2-3). Cyclization
of the diol (2-3) to a cyclized product (2-4) is achieved under
various conditions (for example, MsCl/Et.sub.3N followed by t-BuOK
treatment; TMSOTf treatment, etc.). The cyclized product (2-4) can
be N-deprotected to afford a compound of formula (I). Chiral HPLC
may be used to separate the enantiomers of a compound of formula
(I)
##STR00172##
[0113] As shown in Scheme C, a suitable bromo- or OTf-substituted
N-protected cyclized product (3-1) is converted to the
corresponding CN, aryl or heteroaryl substituted product (3-2)
under various organometallic cross-coupling conditions known in the
art. The cyclized product (3-2) can be N-deprotected to afford a
compound of formula (I). Chiral HPLC may be used to separate the
enantiomers of a compound of formula (I)
##STR00173##
[0114] As shown in Scheme D, a suitable N-unsubstituted product
(4-1) is alkylated under any reductive amination condition known in
the art to afford the corresponding compound of formula (I).
4. Uses, Formulation and Administration and Pharmaceutically
Acceptable Compositions
[0115] 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.
[0116] The term "patient," as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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 may be combined with emulsifying and suspending agents.
If desired, certain sweetening, flavoring or coloring agents may
also be added.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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, substance/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.
[0138] 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.
[0139] 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.
[0140] 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.
[0141] 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).
[0142] 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.
[0143] In some embodiments, the present invention provides a method
of suppressing rapid eye movement (REM) during both sleep and
daytime equivalent.
[0144] In some embodiments, the present invention provides a method
of suppressing or eliminating pathological or excessive REM during
the night or daytime equivalent.
[0145] 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.
[0146] 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, mood
stabilizers, anti-ischemics, CNS depressants, anticholinergics, and
nootropics. In some embodiments, suitable pharmaceutical agents are
anxiolytics.
[0147] 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.
[0148] 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.
[0149] 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.
[0150] 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), serotonin,
norepinephrine and dopamine reuptake inhibitors, 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.
[0151] 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, mirtazapine,
vilazodone, 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.
[0152] Suitable anti-psychotic and mood stabilizer agents include
D2 antagonists, 5HT2A antagonists, atypical antipsychotics,
lithium, and anticonvulsants.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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".
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] 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 may 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.
[0174] 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.
[0175] 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.
[0176] 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
[0177] 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 one of ordinary skill
in the art, can be applied to all compounds and subclasses and
species of each of these compounds, as described herein.
[0178] In the examples below, unless otherwise indicated, all
temperatures are set forth in degrees Celsius and all parts and
percentages are by weight. Reagents were purchased from commercial
suppliers, such as Sigma-Aldrich Chemical Company, and were used
without further purification unless otherwise indicated. Reagents
were prepared following standard literature procedures known to
those skilled in the art. All solvents requiring purification or
drying were treated using standard methods known to those skilled
in the art, unless otherwise indicated.
[0179] The reactions set forth below were done generally at ambient
temperature, unless otherwise indicated. The reaction flasks were
fitted with rubber septa for introduction of substrates and
reagents via syringe. Analytical thin layer chromatography (TLC)
was performed using glass-backed silica gel pre-coated plates
(Merck Art 5719) and eluted with appropriate solvent ratios (v/v).
Reactions were assayed by TLC or LCMS, and terminated as judged by
the consumption of starting material. Visualization of the TLC
plates was done with UV light (254 wavelength) or with an
appropriate TLC visualizing solvent, such as basic aqueous
KMnO.sub.4 solution activated with heat. Flash column
chromatography (See, e.g., Still et al., J. Org. Chem., 43: 2923
(1978)) was performed using silica gel 60 (Merck Art 9385) or
various MPLC systems.
[0180] The compound structures in the examples below were confirmed
by one or more of the following methods: proton magnetic resonance
spectroscopy, mass spectroscopy, and melting point. Proton magnetic
resonance (.sup.1H NMR) spectra were determined using an NMR
spectrometer operating at 400 MHz field strength. Chemical shifts
are reported in the form of delta (.delta.) values given in parts
per million (ppm) relative to an internal standard, such as
tetramethylsilane (TMS). Alternatively, .sup.1H NMR spectra were
referenced to signals from residual protons in deuterated solvents
as follows: CDCl.sub.3=7.25 ppm; DMSO-d.sub.6=2.49 ppm;
C.sub.6D.sub.6=7.16 ppm; CD.sub.3OD=3.30 ppm. Peak multiplicities
are designated as follows: s, singlet; d, doublet; dd, doublet of
doublets; t, triplet; dt, doublet of triplets; q, quartet; quint,
quintet; sept, septet; br, broadened; and m, multiplet. Coupling
constants are given in Hertz (Hz). Mass spectra (MS) data were
obtained using a mass spectrometer with APCI or ESI ionization.
[0181] As used herein, and unless otherwise specified, "Me" means
methyl, "Et" means ethyl, "Ac" means acetyl, "BINAP" means
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, "Dess-Martin reagent"
means 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one,
"DCM" means dichloromethane, "DIEA" means diisopropylethylamine,
"DMF" means dimethylformamide, "EDCl" means
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride,
"EtOAc" means ethyl acetate, "EtOH" means ethanol, "HATU" means
O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium
hexafluorophosphate, "HOBt" means hydroxybenzotriazole, "m-CPBA"
means 3-chloro-perbenzoic acid, "MeCN" means acetonitrile, "MeOH"
means methanol, "PE" means petroleum ether, "RT" or "rt" means room
temperature, "t-BuOH" means tert-butanol, "t-BuONa" means sodium
tert-butoxide, "TBDMSCI" means tert-butyldimethylsilyl chloride,
"TEA" means triethylamine, "THF" means tetrahydrofuran, "TMSI"
means iodotrimethylsilane, "Xantphos" means
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "h" or "hr" means
hour(s), "min" means minute(s), "cat." means catalytic, "aq" means
aqueous, and "TFA" means trifluoroacetic acid.
Example 1. Preparation of Compounds
Example 1.1. Procedure A. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.1.1
Example 1.1.1. (S)-2-((S)-isochroman-1-yl)pyrrolidine (I-17) and
(S)-2-((R)-isochroman-1-yl)pyrrolidine (I-18)
##STR00174##
[0182] (a). (2S)-2-(isochroman-1-yl)pyrrolidine
##STR00175##
[0184] To a mixture of 2-phenylethanol (2 g, 16.38 mmol) and
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (6.52 g, 32.76
mmol) was added trifluoromethanesulphonic acid (3 mL) at 0.degree.
C. slowly. After the reaction was stirred at room temperature for 2
h, ice-water (50 mL) was added. The mixture was extracted with
dichloromethane/MeOH (10:1, 50 mL.times.3). The organic layers were
combined, dried and concentrated to give the crude product (2.65 g)
as brown oil. ESI: m/z=204[M+H].sup.+.
(b). (2S)-tert-butyl 2-(isochroman-1-yl)
pyrrolidine-1-carboxylate
##STR00176##
[0186] To crude (2S)-2-(isochroman-1-yl) pyrrolidine (2.65 g, 13
mmol) obtained above was added water (50 mL), sodium hydroxide (1
g, 26 mmol), and then di-tert-butyl dicarbonate (5.69 g, 26 mmol).
The mixture was stirred at room temperature for 1 h. The mixture
was extracted with EtOAc (30 mL.times.3), and the organic layers
were combined, dried and concentrated. The crude was purified by
reverse gel column chromatography (eluted with
water/CH.sub.3CN=100:65, 0.01% NH.sub.4OH) to give the desired
compound (3.65 g as a colorless oil).
(c). TFA Salt of (2S)-2-(isochroman-1-yl) pyrrolidine
##STR00177##
[0188] To a solution of TFA (5 mL) in methylene chloride (20 mL)
was added (2S)-tert-butyl 2-(isochroman-1-yl)
pyrrolidine-1-carboxylate (3.65 g, 12 mmol). The mixture was
stirred at room temperature for 3 h and the solvent was removed to
yield the crude product 2.3 g, as colorless oil. MS (ESI):
m/z=204[M+H].sup.+.
(d). (S)-2-((S)-isochroman-1-yl) pyrrolidine and
(S)-2-((R)-isochroman-1-yl) pyrrolidine
##STR00178##
[0190] The mixture from previous step (1.95 g, 9.6 mmol) was
purified and separated by prep. HPLC in 0.01% aqueous TFA to give
the two diastereoisomers, which were separately further purified by
chiral HPLC using Column: AY-H (250*4.6 mm 5 .mu.m) and Mobile
Phase: n-Hexane (0.1% DEA):EtOH (0.1% DEA)=90:10 to give
(S)-2-((S)-isochroman-1-yl)pyrrolidine (86 mg yellow oil, R.T.:
7.042 min, ee %: 98%) and (S)-2-((R)-6-fluoroisochroman-1-yl)
pyrrolidine (360 mg yellow oil, R.T.: 7.408 min, ee %: 100%).
[0191] .sup.1HNMR of (S)-2-((S)-isochroman-1-yl)pyrrolidine (I-17)
(400 MHz, CDCl.sub.3) .delta. 7.26.about.7.11 (m, 4H), 4.78 (d,
J=3.2 Hz, 1H), 4.24.about.4.20 (m, 1H), 3.79.about.3.76 (td,
J.sub.1=10.8, J.sub.2=3.5 Hz, 1H), 3.59.about.3.57 (td,
J.sub.1=7.5, J.sub.2=3.9 Hz, 1H), 3.11.about.2.98 (m, 2H),
2.79.about.2.76 (m, 1H), 2.69.about.2.65 (m, 1H), 2.28 (s, 1H),
1.96.about.1.73 (m, 4H).
[0192] .sup.1HNMR of (S)-2-((R)-isochroman-1-yl)pyrrolidine (I-18)
(400 MHz, CDCl.sub.3) .delta. 7.19.about.7.12 (m, 4H), 5.00 (d,
J=2.5 Hz, 1H), 4.23.about.4.18 (m, 1H), 3.78.about.3.72 (td,
J.sub.1=11.3, J.sub.1=3.0 Hz, 1H), 3.59.about.3.57 (td,
J.sub.1=7.9, J.sub.1=3.5 Hz, 1H), 3.22.about.2.99 (m, 2H),
2.86.about.2.81 (m, 1H), 2.63.about.2.61 (m, 1H), 2.27 (s, 1H),
1.71.about.1.66 (m, 2H), 1.50.about.1.44 (m, 2H).
Example 1.1.2. (R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine
(I-16) and (R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine
(I-15)
##STR00179##
[0194] (R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-16) and
(R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-15) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(2-fluoro-phenyl)-ethanol in place of 2-phenylethanol and
(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0195] (R)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-16): MS
(ESI): m/z 222 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.21-7.10 (m, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.89 (t, J=8.7
Hz, 1H), 4.94 (s, 1H), 4.23 (ddd, J=11.3, 5.8, 1.9 Hz, 1H), 3.69
(td, J=11.1, 3.7 Hz, 1H), 3.57 (td, J=7.9, 3.5 Hz, 1H), 3.19-3.06
(m, 1H), 2.91-2.68 (m, 3H), 1.76-1.62 (m, 2H), 1.53-1.37 (m,
2H).
[0196] (R)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-15): MS
(ESI): m/z 222 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.21-7.10 (m, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.89 (t, J=8.7
Hz, 1H), 4.72 (d, J=3.2 Hz, 1H), 4.24 (ddd, J=11.3, 5.8, 2.9 Hz,
1H), 3.73 (ddd, J=11.2, 10.3, 4.0 Hz, 1H), 3.58 (td, J=7.5, 3.8 Hz,
1H), 3.03 (ddd, J=10.3, 6.9, 5.4 Hz, 1H), 2.87 (ddd, J=16.1, 10.1,
5.8 Hz, 1H), 2.76 (dt, J=10.4, 7.5 Hz, 2H), 1.90 (dd, J=11.6, 4.2
Hz, 2H), 1.84-1.71 (m, 2H).
Example 1.1.3. (S)-2-((S)-isochroman-1-yl)azetidine (I-79) and
(S)-2-((R)-iso-chroman-1-yl)azetidine (I-80)
##STR00180##
[0198] (S)-2-((S)-isochroman-1-yl)azetidine (I-79) and
(S)-2-((R)-iso-chroman-1-yl)azetidine (I-80) were prepared using a
procedure analogous to that described in Example 1.1.1, but using
(S)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0199] (S)-2-((S)-isochroman-1-yl)azetidine (I-79): MS (ESI): m/z
190 [M+H].sup.+, .sup.1HNMR (400 MHz, CDCL3): .delta. 7.10-7.21 (m,
4H), 4.73-4.74 (d, J=6.0 Hz, 1H), 4.18-4.26 (m, 2H), 3.78-3.85 (dt,
J.sub.1=3.6 Hz, J.sub.2=10.0 Hz, 1H), 3.59-3.65 (q, J=7.6 Hz, 1H),
3.42-3.47 (m, 1H), 3.00-3.06 (m, 1H), 2.55-2.74 (m, 2H), 2.35-2.43
(m, 1H), 2.11 (br, 1H).
[0200] (S)-2-((R)-iso-chroman-1-yl)azetidine (I-80): MS (ESI): m/z
190 [M+H].sup.+, .sup.1HNMR (400 MHz, MeOD): .delta. 7.20-7.271 (m,
3H), 7.10-7.12 (m, 1H), 5.10-5.14 (m, 2H), 4.39-4.44 (m, 1H),
3.85-4.05 (m, 3H), 3.14-3.23 (m, 1H), 2.72-2.76 (m, 1H), 2.21-39
(m, 2H).
Example 1.1.4. (S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94)
and (S)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-93)
##STR00181##
[0202] (S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94) and
(S)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-93) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(2-fluorophenyl)ethanol in place of 2-phenylethanol and
(S)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0203] (S)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-94): MS
(ESI): m/z 208 [M+H].sup.+, .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.27-7.33 (m, 1H), 7.04-7.08 (m, 2H), 5.13-5.18 (dt,
J.sub.1=3.6 Hz, J.sub.2=8.4 Hz, 1H), 5.02 (s, 1H), 4.39-4.44 (m,
1H), 4.04-4.11 (q, J=8.8 Hz, 1H), 3.81-3.91 (m, 2H), 2.94-3.08 (m,
2H), 2.79-2.93 (m, 1H), 2.51-2.66 (m, 1H).
[0204] (S)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-93): MS
(ESI): m/z 208 [M+H].sup.+, .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.24-7.29 (m, 1H), 7.02-7.06 (t, J=8.8 Hz, 1H), 6.94-6.96
(d, J=7.6 Hz, 1H), 5.13-5.16 (m, 2H), 4.44-4.49 (m, 1H), 3.83-4.04
(m, 3H), 2.95-3.03 (m, 1H), 2.83-2.88 (m, 1H), 2.10-2.36 (m,
2H).
Example 1.1.5. (S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89)
and (S)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-90)
##STR00182##
[0206] (S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89) and
(S)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-90) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(3-fluorophenyl) ethanol in place of 2-phenylethanol and
(S)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0207] (S)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-89): MS
(ESI) m/z 208 (M+H).sup.+ 1H NMR (HCl salt, 400 MHz, MeOD) .delta.
7.13 (m, 1H), 6.90 (m, 2H), 4.69 (d, J=6.0 Hz, 1H), 4.28 (m, 1H),
4.19 (m, 1H), 3.77 (m, 1H), 3.58 (m, 1H), 3.37 (m, 1H), 3.05 (m,
1H), 2.72 (m, 2H), 2.38 (m, 1H).
[0208] (S)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-90): MS
(ESI) m/z 208 (M+H).sup.+ 1H NMR (HCl salt, 400 MHz, MeOD) .delta.
7.17-7.14 (m, 1H), 7.01-6.99 (m, 2H), 5.10-5.12 (m, 2H), 4.39-4.44
(m, 1H), 3.98-4.03 (m, 1H), 3.92-3.85 (m, 2H), 3.18 (m, 1H),
2.78-2.79 (m, 1H), 2.30-2.34 (m, 2H).
Example 1.1.6. (S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85)
and (S)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-86)
##STR00183##
[0210] (S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85) and
(S)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-86) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(4-fluorophenyl)ethanol in place of 2-phenylethanol and
(S)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0211] (S)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-85): MS
(ESI) m/z 208 (M+H).sup.+, .sup.1H NMR (400 MHz, MeOD) .delta. 7.26
(m, 1H), 7.03 (m, 2H), 5.11 (m, 1H), 4.98 (m, 1H), 4.36 (m, 1H),
4.08 (m, 1H), 3.87 (m, 2H), 3.16 (m, 1H), 2.98 (m, 1H), 2.73 (m,
1H), 2.61 (m, 1H).
[0212] (S)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-86): MS
(ESI) m/z 208 (M+H).sup.+, .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.15 (m, 1H), 6.93 (m, 2H), 4.73 (d, J=5.2 Hz, 1H), 4.30
(m, 1H), 4.23 (m, 1H), 3.74 (m, 1H), 3.59 (m, 1H), 3.39 (m, 1H),
2.98 (m, 1H), 2.69 (m, 1H), 2.31 (m, 1H), 2.15 (m, 1H).
Example 1.1.7. (R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88)
and (R)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-87)
##STR00184##
[0214] (R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88) and
(R)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-87) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(4-fluorophenyl)ethanol in place of 2-phenylethanol and
(R)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0215] (R)-2-((S)-7-fluoroisochroman-1-yl)azetidine (I-88): MS
(ESI) m/z: 208 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.20.about.7.16 (q, J=6.4 Hz, 1H), 6.96.about.6.91 (m, 2H),
4.77 (d, J=4.8 Hz, 1H), 4.40.about.4.34 (m, 1H), 4.28.about.4.24
(m, 1H), 3.80.about.3.73 (m, 1H), 3.65.about.3.59 (q, J=8.4 Hz,
1H), 3.48.about.3.42 (m, 1H), 3.04.about.2.96 (m, 1H),
2.71.about.2.67 (m, 1H), 2.35.about.2.21 (m, 1H), 2.19.about.2.12
(m, 1H).
[0216] (R)-2-((R)-7-fluoroisochroman-1-yl)azetidine (I-87): MS
(ESI) m/z: 208 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.18.about.7.15 (q, J=5.6 Hz, 1H), 6.95.about.6.87 (m, 2H),
4.69 (d, J=5.6 Hz, 1H), 4.32.about.4.21 (m, 2H), 3.80.about.3.74
(m, 1H), 3.61.about.3.55 (q, J=8.4 Hz, 1H), 3.40.about.3.32 (m,
1H), 3.06.about.2.98 (m, 1H), 2.72.about.2.63 (m, 2H),
2.43.about.2.35 (m, 1H).
Example 1.1.8. (R)-2-((S)-isochroman-1-yl)azetidine (I-81) and
(R)-2-((R)-isochroman-1-yl)azetidine (I-82)
##STR00185##
[0218] (R)-2-((S)-isochroman-1-yl)azetidine (I-81) and
(R)-2-((R)-isochroman-1-yl)azetidine (I-82) were prepared using a
procedure analogous to that described in Example 1.1.1, but using
(R)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0219] (R)-2-((S)-isochroman-1-yl)azetidine (I-81): MS (ESI) m/z:
190 (M+H).sup.+. .sup.1H NMR 400 MHz, CDCl.sub.3) .delta.
7.25.about.7.09 (m, 4H), 4.79.about.4.78 (d, J=5.6 Hz, 1H),
4.35.about. 4.18 (m, 2H), 3.78 (td, J.sub.1=10.9, J.sub.2=3.2 Hz,
1H), 3.62 (q, J=8.1 Hz, 1H), 3.44.about.3.39 (m, 1H),
3.07.about.3.0 (m, 1H), 2.69.about.2.65 (m, 1H), 2.59 (s, 1H),
2.43.about.2.31 (m, 1H), 2.18.about.2.14 (m, 1H).
[0220] (R)-2-((R)-isochroman-1-yl)azetidine (I-82): MS (ESI) m/z:
190 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.25.about.7.06 (m, 4H), 4.75.about.4.739 (d, J=6.3 Hz, 1H),
4.26.about.4.21 (m, 2H), 3.87.about.3.78 (m, 1H), 3.63 (dd,
J.sub.1=15.5, J.sub.2=8.0 Hz, 1H), 3.50.about.3.42 (m, 1H),
3.08.about.3.01 (m, 1H), 2.74.about.2.69 (m, 1H), 2.66-2.55 (m,
1H), 2.42.about.2.36 (m, 2H).
Example 1.1.9. (R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96)
and (R)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-95)
##STR00186##
[0222] (R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96) and
(R)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-95) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(2-fluorophenyl)ethanol in place of 2-phenylethanol and
(R)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0223] (R)-2-((S)-5-fluoroisochroman-1-yl)azetidine (I-96): MS
(ESI) m/z: 208 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.30.about.7.24 (m, 1H), 7.04 (t, J=8.8 Hz, 1H), 6.97 (d,
J=7.8 Hz, 1H), 5.16 (d, J=13.4 Hz, 2H), 4.53-4.42 (m, 1H),
4.07-3.97 (m, 1H), 3.92.about.3.84 (m, 2H), 2.99.about.2.95 (m,
1H), 2.88.about.2.83 (m, 1H), 2.42-2.19 (m, 2H).
[0224] (R)-2-((R)-5-fluoroisochroman-1-yl)azetidine (I-95): MS
(ESI) m/z: 208 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.33.about.7.27 (m, 1H), 7.08.about.7.03 (m, 1H), 5.15 (s,
1H), 5.02 (s, 1H), 4.43.about.4.38 (m, 1H), 4.09.about.4.06 (m,
1H), 3.91.about.3.84 (m, 2H), 3.03.about.2.96 (m, 1H),
2.83.about.2.79 (m, 1H), 2.64.about.2.62 (m, 1H).
Example 1.1.10. (R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91)
and (R)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-92)
##STR00187##
[0226] (R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91) and
(R)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-92) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(3-fluorophenyl)ethanol in place of 2-phenylethanol and
(R)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0227] (R)-2-((S)-6-fluoroisochroman-1-yl)azetidine (I-91): MS
(ESI) m/z: 208 (M+H).sup.+1. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.25 (dd, J=8.5, 5.7 Hz, 1H), 7.02 (dd, J=13.0, 5.7 Hz,
2H), 5.11 (td, J=8.6, 3.7 Hz, 1H), 4.99 (s, 1H), 4.35 (ddd, J=11.3,
6.0, 1.7 Hz, 1H), 4.17-3.99 (m, 1H), 3.97-3.75 (m, 2H), 3.22 (ddd,
J=17.1, 11.4, 6.0 Hz, 1H), 3.08-2.88 (m, 1H), 2.74 (d, J=16.7 Hz,
1H), 2.68-2.50 (m, 1H).
[0228] (R)-2-((R)-6-fluoroisochroman-1-yl)azetidine (I-92): MS
(ESI) m/z: 208 (M+H).sup.+1. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.15 (dd, J=8.3, 5.5 Hz, 1H), 6.98 (dd, J=15.4, 6.3 Hz,
2H), 5.12 (p, J=3.2 Hz, 2H), 4.41 (dd, J=11.3, 5.9 Hz, 1H), 4.02
(td, J=9.8, 8.0 Hz, 1H), 3.96-3.78 (m, 2H), 3.28-3.09 (m, 1H), 2.76
(d, J=16.6 Hz, 1H), 2.44-2.18 (m, 2H).
Example 1.1.11. (S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine
(I-30) and (S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine
(I-29)
##STR00188##
[0230] (S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-30) and
(S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-29) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(4-chlorophenyl)ethanol in place of 2-phenylethanol.
[0231] (S)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-30): MS
(ESI) m/z: 238 (M+H).sup.+1. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.32-7.33 (m, 1H), 7.13-7.21 (m, 2H), 4.79 (s, 1H),
4.20-4.25 (m, 1H), 3.70-3.77 (m, 1H), 3.61-3.66 (m, 1H), 2.98-3.08
(m, 2H), 2.64-2.77 (m, 2H), 1.95-2.01 (m, 2H), 1.81-1.88 (m,
2H).
[0232] (S)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-29): MS
(ESI) m/z: 238 (M+H).sup.+1. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.23 (s, 1H), 7.14-7.21 (m, 2H), 4.93 (s, 1H), 4.20-4.24
(m, 1H), 3.67-3.74 (m, 1H), 3.59-3.64 (m, 1H), 3.08-3.14 (m, 1H),
2.95-3.04 (m, 1H), 2.78-2.84 (m, 1H), 2.63-2.67 (J=16.4 Hz, d, 1H),
1.70-1.78 (m, 2H), 1.45-1.51 (m, 2H).
Example 1.1.12. (S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine
(I-26) and (S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine
(I-25)
##STR00189##
[0234] (S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-26) and
(S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-25) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(p-tolyl)ethanol in place of 2-phenylethanol.
[0235] (S)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-26): MS
(ESI) m/z: 218 (M+H).sup.+1.
[0236] (S)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-25): MS
(ESI) m/z: 218 (M+H).sup.+1.
Example 1.1.13. (R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine
(I-27) and (R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine
(I-28)
##STR00190##
[0238] (R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-27) and
(R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-28) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(p-tolyl)ethanol in place of 2-phenylethanol and
(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0239] (R)-2-((S)-7-methylisochroman-1-yl)pyrrolidine (I-27): MS
(ESI) m/z: 218 (M+H).sup.+1.
[0240] (R)-2-((R)-7-methylisochroman-1-yl)pyrrolidine (I-28): MS
(ESI) m/z: 218 (M+H).sup.+1.
Example 1.1.14. (R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine
(I-32) and (R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine
(I-31)
##STR00191##
[0242] (R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-32) and
(R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-31) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(4-chlorophenyl)ethanol in place of 2-phenylethanol and
(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0243] (R)-2-((S)-7-chloroisochroman-1-yl)pyrrolidine (I-32): MS
(ESI) m/z: 238 (M+H).sup.+1.
[0244] (R)-2-((R)-7-chloroisochroman-1-yl)pyrrolidine (I-31): MS
(ESI) m/z: 238 (M+H).sup.+1.
Example 1.1.15. (S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine
(I-33) and (S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine
(I-34)
##STR00192##
[0246] (S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-33) and
(S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-34) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(3-chlorophenyl)ethanol in place of 2-phenylethanol.
[0247] (S)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-33): (ESI)
m/z: 238[M+H].sup.+. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
7.21-7.15 (m, 2H), 7.12 (s, 1H), 4.74 (d, J=3.6 Hz, 1H), 4.24-4.19
(m, 1H), 3.77-3.71 (m, 1H), 3.63-3.58 (m, 1H), 3.08-3.00 (m, 2H),
2.82-2.76 (m, 2H), 2.66 (m, 1H), 1.94-1.77 (m, 4H).
[0248] (S)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-34): (ESI)
m/z: 238[M+H].sup.+. .sup.1H-NMR (400 MHz, MeOD): .delta. 7.28-7.21
(m, 3H), 5.19 (s, 1H), 4.38-4.29 (m, 2H), 3.83-3.76 (td,
J.sup.1=2.8 Hz, J.sup.2=12.0 Hz, 1H), 3.38-3.32 (m, 2H), 3.14-3.06
(m, 1H), 2.73-2.69 (m, 1H), 2.09-1.93 (m, 2H), 1.80-1.74 (m,
2H).
Example 1.1.16. (R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine
(I-36) and ((R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine
(I-35)
##STR00193##
[0250] (R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-36) and
(R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-35) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(3-chlorophenyl)ethanol in place of 2-phenylethanol and
(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0251] (R)-2-((S)-6-chloroisochroman-1-yl)pyrrolidine (I-36): MS
(ESI+): m/z 238 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
39.65 (s, 1H), 8.70 (s, 1H), 7.40-7.20 (m, 3H), 5.12 (s, 1H),
4.40-4.10 (m, 2H), 3.71 (td, J=11.5, 2.9 Hz, 1H), 3.27-3.06 (m,
2H), 3.06-2.92 (m, 1H), 2.69 (d, J=16.7 Hz, 1H), 1.97-1.45 (m,
4H).
[0252] (R)-2-((R)-6-chloroisochroman-1-yl)pyrrolidine (I-35): MS
(ESI): m/z 238 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
39.55 (s, 1H), 8.28 (s, 1H), 7.37-7.24 (m, 3H), 4.94 (d, J=4.1 Hz,
1H), 4.21-4.06 (m, 2H), 3.73 (td, J=10.9, 3.6 Hz, 1H), 3.15-3.00
(m, 3H), 2.70 (d, J=16.7 Hz, 1H), 2.09-1.79 (m, 4H).
Example 1.1.17. (S)-2-((S)-isochroman-1-yl)piperidine (I-71) and
(S)-2-((R)-isochroman-1-yl)piperidine (I-72)
##STR00194##
[0254] (S)-2-((S)-isochroman-1-yl)piperidine (I-71) and
(S)-2-((R)-isochroman-1-yl)piperidine (I-72) were prepared using a
procedure analogous to that described in Example 1.1.1, but using
(S)-tert-butyl 2-formylpiperidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0255] (S)-2-((S)-isochroman-1-yl)piperidine (I-71): MS (ESI): m/z
218 [M+H]+. .sup.1HNMR (400 MHz, MeOD): .delta. 7.30-7.32 (m, 3H),
7.25 (m, 1H), 4.88 (s, 1H), 4.28-4.30 (m, 1H), 3.71-3.79 (m, 2H),
3.23-3.26 (m, 1H), 3.07-3.13 (m, 1H), 2.90-2.96 (m, 1H), 2.69-2.73
(d, J=16, 1H), 2.05-2.07 (m, 3H), 1.99-2.01 (m, 1H), 1.69-1.91 (m,
2H).
[0256] (S)-2-((R)-isochroman-1-yl)piperidine (I-72): MS (ESI): m/z
218 [M+H]+. .sup.1HNMR (400 MHz, MeOD): .delta. 7.18-7.29 (m, 4H),
5.10 (s, 1H), 4.28-4.32 (m, 1H), 3.74-3.80 (m, 2H), 3.41-3.45 (m,
1H), 3.02-3.19 (m, 2H), 2.66-2.70 (d, J=16, 1H), 1.81-2.03 (m, 2H),
2.05-2.07 (m, 3H), 1.99-2.01 (m, 1H).
Example 1.1.18. (S)-2-((S)-6-fluoroisochroman-1-yl)piperidine
(I-73) and (S)-2-((R)-6-fluoroisochroman-1-yl)piperidine (I-74)
##STR00195##
[0258] (S)-2-((S)-6-fluoroisochroman-1-yl)piperidine (I-73) and
(S)-2-((R)-6-fluoroisochroman-1-yl)piperidine (I-74) were prepared
using a procedure analogous to that described in Example 1.1.1, but
using 2-(3-fluorophenyl)ethanol in place of 2-phenylethanol and
(S)-tert-butyl 2-formylpiperidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0259] (S)-2-((S)-6-fluoroisochroman-1-yl)piperidine (I-73): MS
(ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (400 MHz, MeOD): .delta.
7.34-7.37 (m, 1H), 6.99-7.09 (m, 2H), 4.87 (s, 1H), 4.27-4.32 (m,
1H), 3.71-3.80 (m, 2H), 3.24-3.28 (m, 1H), 3.05-3.13 (m, 1H),
2.92-2.97 (m, 1H), 2.70-2.74 (d, J=16, 1H), 1.89-2.08 (m, 4H),
1.66-1.72 (m, 2H).
[0260] (S)-2-((R)-6-fluoroisochroman-1-yl)piperidine (I-74): MS
(ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (400 MHz, MeOD): .delta.
7.21-7.24 (m, 1H), 6.98-7.05 (m, 2H), 5.07 (s, 1H), 4.28-4.32 (m,
1H), 3.73-3.79 (m, 2H), 3.41-3.45 (m, 1H), 3.02-3.18 (m, 2H),
2.67-2.71 (d, J=16, 1H), 1.82-1.91 (m, 2H), 1.49-1.72 (m, 3H),
1.36-1.40 (m, 1H).
Example 1.1.19.
(S)-2-((S)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine
(I-53) and
(S)-2-((R)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine
(I-54)
##STR00196##
[0262]
(S)-2-((S)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrol-
idine (I-53) and
(S)-2-((R)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrolidine
(I-54) were prepared using a procedure analogous to that described
in Example 1.1.1, but using 2-(benzo[d][1,3]dioxol-5-yl)ethanol in
place of 2-phenylethanol.
[0263]
(S)-2-((S)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrol-
idine (I-53): MS (ESI): m/z 248 (M+H).sup.+. .sup.1H NMR (HCl salt,
400 MHz, MeOD) .delta. 6.81 (t, J=40.4 Hz, 2H), 5.95 (d, J=0.5 Hz,
2H), 4.94 (s, 1H), 4.25 (ddd, J=11.2, 5.8, 1.7 Hz, 1H), 4.22-4.03
(m, 1H), 3.77 (td, J=11.3, 3.2 Hz, 1H), 3.31-3.17 (m, 2H),
3.16-3.02 (m, 1H), 2.59 (d, J=16.3 Hz, 1H), 2.33-2.19 (m, 2H),
2.20-1.98 (m, 2H).
[0264]
(S)-2-((R)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromen-5-yl)pyrrol-
idine (I-54): MS (ESI): m/z 248 (M+H).sup.+. .sup.1H NMR (HCl salt,
400 MHz, MeOD) .delta. 6.70 (d, J=9.1 Hz, 2H), 5.94 (d, J=1.7 Hz,
2H), 5.11 (s, 1H), 4.36-4.12 (m, 2H), 3.84-3.61 (m, 1H), 3.35 (d,
J=8.3 Hz, 2H), 3.10-2.90 (m, 1H), 2.59 (d, J=16.2 Hz, 1H),
2.15-1.86 (m, 2H), 1.78 (td, J=8.4, 3.8 Hz, 2H).
Example 1.1.20. (S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine
(I-145)
##STR00197##
[0266] (S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (I-145) were
prepared using a procedure analogous to that described in Example
1.1.1, but using 2-(3-bromophenyl)ethanol in place of
2-phenylethanol.
[0267] (S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (I-145): MS
(ESI): m/z 282 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl3) .delta.
7.29-7.03 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 4.86 (d, J=2.4 Hz, 1H),
4.18-4.13 (m, 1H), 3.71-3.64 (m, 1H), 3.53-3.48 (m, 1H), 3.12-2.96
(m, 2H), 2.83-2.76 (m, 1H), 2.58 (d, J=16.4 Hz, 1H), 2.17 (br, 1H),
1.70-1.63 (m, 2H), 1.45-1.39 (m, 2H).
Example 1.2. Procedure B. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.2.1
Example 1.2.1. (S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine
(I-10) and (S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9)
##STR00198##
[0268] (a).
(2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane
##STR00199##
[0270] To a solution of 2-(2-bromo-5-fluorophenyl)ethanol (23.2 g,
105.91 mmol) in DCM (300 mL) was added 1H-imidazole (14.4 g, 211.8
mmol) and tert-butylchlorodimethylsilane (20.8 g, 137.7 mmol).
After the mixture was stirred at room temperature overnight, it was
quenched with H.sub.2O (300 mL) at 0.degree. C. The resulting
mixture was extracted with DCM (2.times.100 mL). The combined
organic layers were washed with brine (400 mL), dried over sodium
sulfate, filtered, and concentrated. The crude product was purified
by silica gel chromatography (eluted with petroleum ether:ethyl
acetate=40:1) to give (2-bromo-5-fluorophenethoxy)
(tert-butyl)dimethylsilane. MS (ESI): m/z 333 [M+H].sup.+, 32.3 g
colorless oil.
(b). (2S)-tert-butyl
2-((2-(2-(tert-butyldimethylsilyloxy)ethyl)-4-fluorophenyl)(hydroxy)-meth-
yl)pyrrolidine-1-carboxylate
##STR00200##
[0272] To a mixture of
(2-bromo-5-fluorophenethoxy)(tert-butyl)dimethylsilane (5.0 g, 15.0
mmol) in toluene (60 mL) was added n-butyllithium (2.4 M, 12.5 mL,
30.0 mmol) at -78.degree. C. After stirred at -78.degree. C. for 1
h, (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (4.48 g, 22.5
mmol) in toluene (10 mL) was added at -78.degree. C. The mixture
was stirred at -78.degree. C. for 2 h. Upon completion, sat.
NH.sub.4Cl solution (100 mL) and EtOAc (50 mL) was added. The
organic layer was separated, washed with brine, dried, filtered,
and concentrated. The crude product was purified by silica gel
(eluted from PE:EtOAc=100:1 to PE:EtOAc=20:1) to yield the desired
compound: 2.5 g colorless oil. (ESI) m/z: 454 (M+H).sup.+.
(c). (2S)-tert-butyl
2-((4-fluoro-2-(2-hydroxyethyl)phenyl)(hydroxy)methyl)
pyrrolidine-1-carboxylate
##STR00201##
[0274] To a solution of (2S)-tert-butyl
2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)(hydroxy)met-
hyl)pyrrolidine-1-carboxylate (2.5 g, 5.07 mmol) in THF (50 mL) was
added TBAF (2.64 g, 10.14 mmol) at room temperature. The mixture
was stirred at room temperature for 3 h. The mixture was evaporated
in vacuo. The residue was dissolved in EtOAc (100 mL) and washed
with water (80 mL.times.2). The organic layer was dried, filtered
and concentrated in vacuo to give the crude product. The crude was
purified by reverse flash column (mobile phase: MeCN and 0.1%
aqueous ammonia) to afford the desired product: 1.2 g yellow
oil.
(d). (2S)-tert-butyl
2-((4-fluoro-2-(2-(methylsulfonyloxy)ethyl)phenyl)
(hydroxy)methyl)-pyrrolidine-1-carboxylate
##STR00202##
[0276] To a solution of (2S)-tert-butyl
2-((4-fluoro-2-(2-hydroxyethyl)phenyl)(hydroxy)
methyl)pyrrolidine-1-carboxylate (1.0 g, 2.95 mmol) in ethyl
acetate (50 mL) was added methanesulfonyl chloride (372 mg, 3.2
mmol) and triethylamine (894 mg, 8.85 mmol) at 0.degree. C. The
mixture was stirred at room temperature for 2 h. Upon completion,
aq NaHCO.sub.3 (10 mL) was added to the mixture. The organic layer
was separated, washed with water (3.times.150 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the product:
1.2 g light yellow oil.
(e). (2S)-tert-butyl
2-(6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00203##
[0278] To a solution of (2S)-tert-butyl
2-((4-fluoro-2-(2-((methylsulfonyl)oxy)ethyl)phenyl)
(hydroxy)methyl)pyrrolidine-1-carboxylate (1.2 g, 2.44 mmol) in
tetrahydrofuran (80 mL) was added potassium t-butoxide (0.55 g, 4.9
mmol) at 0.degree. C. The mixture was stirred at room temperature
for 2 h. Upon completion, the mixture was concentrated, diluted
with EtOAc (60 mL), washed with water (3.times.40 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to
give the crude product as a yellow oil (600 mg).
(f). (2S)-2-(6-fluoroisochroman-1-yl)pyrrolidine
##STR00204##
[0280] A solution of (2S)-tert-butyl
2-(6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate (600 mg, 1.87
mmol) in 4 N HCl/dioxane (10 mL) was stirred at room temperature
for 3 h. The mixture was evaporated in vacuo to give the crude
product: 390 mg off-white solid. (ESI) m/z: 222[M+H].sup.+.
(g). (S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-10) and
(S)-2-((R)-6-fluoroiso-chroman-1-yl)pyrrolidine (I-9)
##STR00205##
[0282] (2S)-2-(6-fluoroisochroman-1-yl)pyrrolidine from previous
step (2 batches) (780 mg, 3.52 mmol) was separated by preparative
HPLC to give the two diastereoisomers, which were separately
further purified by chiral column chromatography: Column AY-H
(250*4.6 mm 5 .mu.m) and Mobile Phase: n-Hexane (0.1% DEA):EtOH
(0.1% DEA)=80:20 to give
(S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (160 mg yellow oil,
(ESI) m/z: 222[M+H].sup.+) and (S)-2-((R)-6-fluoroisochroman-1-yl)
pyrrolidine (180 mg yellow oil, (ESI) m/z: 222[M+H].sup.+).
[0283] .sup.1HNMR of (S)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine
(I-10) (400 MHz, CDCl.sub.3): .delta. 7.23-7.19 (m, 1H), 6.90-6.85
(m, 1H), 6.81-6.79 (m, 1H), 4.71 (d, J=2.4 Hz, 1H), 4.21-4.16 (m,
1H), 3.76-3.69 (m, 1H), 3.57-3.52 (m, 1H), 3.06-2.98 (m, 2H),
2.79-2.73 (m, 1H), 2.65 (d, J=16.4 Hz, 1H), 2.45 (brs, 1H),
1.90-1.73 (m, 4H).
[0284] .sup.1HNMR of (S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine
(I-9) (400 MHz, CDCl.sub.3): .delta. 7.17-7.14 (m, 1H), 6.92-6.82
(m, 2H), 4.93 (s, 1H), 4.22-4.17 (m, 1H), 3.76-3.69 (m, 1H),
3.58-3.53 (m, 1H), 3.17-3.00 (m, 2H), 2.87-2.80 (m, 1H), 2.64-2.60
(m, 1H), 2.20 (brs, 1H), 1.74-1.66 (m, 2H), 1.49-1.43 (m, 2H).
Example 1.2.2. (2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine
(I-6) and (2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-5)
##STR00206##
[0286] (2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-6) and
(2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-5) were prepared
using a procedure analogous to that described in Example 1.2.1, but
using 2-(2-bromo-4-fluorophenyl) ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol.
[0287] (2S)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-6): MS
(ESI): m/z 222 [M+H].sup.+, .sup.1H NMR (400 MHz, CDCl3): .delta.
7.06-7.09 (m, 1H), 6.85-6.92 (m, 2H), 4.92 (s, 1H), 4.18-4.22 (m,
1H), 3.67-3.74 (m, 1H), 3.51-3.56 (m, 1H), 3.10-3.16 (m, 1H),
2.94-3.03 (m, 1H), 2.81-2.87 (m, 1H), 2.51-2.62 (m, 2H), 1.67-1.74
(m, 2H), 1.44-1.50 (m, 2H).
[0288] (2S)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-5): MS
(ESI): m/z 222 [M+H].sup.+, .sup.1H NMR (400 MHz, CDCl3): .delta.
7.06-7.09 (m, 1H), 6.93-6.86 (m, 2H), 4.93 (s, 1H), 4.23-4.18 (m,
1H), 3.74-3.68 (m, 1H), 3.56-3.51 (m, 1H), 3.17-3.11 (m, 1H),
3.03-2.94 (m, 1H), 2.88-2.81 (m, 1H), 2.61 (d, 1H), 2.52 (s, br.
1H), 1.74-1.67 (m, 2H), 1.51-1.45 (m, 2H).
Example 1.2.3. ((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine
(I-14) and (S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine
(I-13)
##STR00207##
[0290] ((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-14) and
(S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-13) were prepared
using a procedure analogous to that described in Example 1.2.1, but
using 2-(2-bromo-6-fluorophenyl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol.
[0291] ((S)-2-((S)-5-fluoroisochroman-1-yl)pyrrolidine (I-14): MS
(ESI) m/z 222.1 (M+H).sup.+1. .sup.1H NMR (400 MHz, MeOD): .delta.
7.28.about.7.22 (m, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.99.about.6.95
(q, J=4.4 Hz, 1H), 4.82 (d, J=2.4 Hz, 1H), 4.30.about.4.25 (m, 1H),
3.79.about.3.72 (m, 2H), 3.07.about.3.01 (m, 1H), 2.95.about.2.75
(m, 3H), 2.06.about.2.00 (m, 2H) 1.96.about.1.79 (m, 2H).
[0292] (S)-2-((R)-5-fluoroisochroman-1-yl)pyrrolidine (I-13): MS
(ESI) m/z 222.1 (M+H).sup.+1. .sup.1H NMR (400 MHz, MeOD): .delta.
7.25.about.7.19 (m, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.97.about.6.92
(q, J=4.4 Hz, 1H), 4.96 (d, J=0.8 Hz, 1H), 4.28.about.4.23 (m, 1H),
3.73.about.3.63 (m, 2H), 3.14.about.3.09 (m, 1H), 2.88.about.2.73
(m, 3H), 1.76.about.1.69 (m, 2H) 1.51.about.1.41 (m, 2H).
Example 1.2.4. (R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20) and
(R)-2-((R)-isochroman-1-yl)pyrrolidine (I-19)
##STR00208##
[0294] (R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20) and
(R)-2-((R)-isochroman-1-yl)pyrrolidine (I-19) were prepared using a
procedure analogous to that described in Example 1.2.1, but using
2-(2-bromophenyl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol and (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0295] (R)-2-((S)-isochroman-1-yl)pyrrolidine (I-20):
m/z=204[M+1].sup.+. .sup.1H NMR (400 MHz, CDCl3) .delta. 7.24-7.05
(m, 4H), 4.98 (d, J=1.7 Hz, 1H), 4.21.about.4.16 (m, 1H),
3.76.about.3.69 (td, J=11.3, 3.0 Hz, 1H), 3.60.about.3.57 (td,
J=7.9, 3.5 Hz, 1H), 3.14.about.3.04 (m, 2H), 2.85.about.2.81 (m,
1H), 2.73 (s, 1H), 2.62.about.2.58 (d, J=16.1 Hz, 1H), 1.75-1.61
(m, 2H), 1.53-1.38 (m, 2H).
[0296] (R)-2-((R)-isochroman-1-yl)pyrrolidine (I-19):
m/z=204[M+1].sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD) .delta.
7.36-7.18 (m, 4H), 5.04 (d, J=2.4 Hz, 1H), 4.34-4.22 (m, 2H), 3.83
(td, J=11.3, 3.3 Hz, 1H), 3.32-3.14 (m, 3H), 2.71 (d, J=16.4 Hz,
1H), 2.34-2.03 (m, 4H).
Example 1.2.5. (R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8)
and (R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-7)
##STR00209##
[0298] (R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8) and
(R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-7) were prepared
using a procedure analogous to that described in Example 1.2.1, but
using 2-(2-bromo-4-fluorophenyl) ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol and (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0299] (R)-2-((S)-7-fluoroisochroman-1-yl)pyrrolidine (I-8):
m/z=222 [M+1].sup.+. .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
7.07-7.11 (m, 1H), 6.87-6.93 (m, 2H), 4.93 (s, 1H), 4.19-4.23 (m,
1H), 3.69-3.75 (m, 1H), 3.51-3.55 (m, 1H), 3.11-3.17 (m, 1H),
2.99-3.00 (m, 1H), 2.81-2.88 (m, 1H), 2.60-2.63 (J=15.6 Hz, d, 1H),
1.68-1.73 (m, 2H), 1.45-1.49 (m, 2H).
[0300] (R)-2-((R)-7-fluoroisochroman-1-yl)pyrrolidine (I-7):
m/z=222[M+1.sup.+. .sup.1HNMR (HCl salt, 400 MHz, MeOD): .delta.
7.14-7.18 (m, 1H), 7.03-7.06 (m, 1H), 6.91-6.96 (m, 1H), 4.77 (s,
1H), 4.20-4.24 (m, 1H), 3.70-3.76 (m, 1H), 3.58-3.62 (m, 1H),
2.99-3.03 (m, 2H), 2.63-2.75 (m, 2H), 1.94-2.00 (m, 2H), 1.80-1.87
(m, 2H).
Example 1.2.6. (R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine
(I-11) and (R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine
(I-12)
##STR00210##
[0302] (R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-11) and
(R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-12) were prepared
using a procedure analogous to that described in Example 1.2.1, but
using (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0303] (R)-2-((S)-6-fluoroisochroman-1-yl)pyrrolidine (I-11): ESI:
m/z=222 (M+H.sup.+). .sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 7.21
(dd, J.sup.1=5.6 Hz, J.sup.2=8.4 Hz, 1H), 6.88 (td, J.sup.1=2.8 Hz,
J.sup.2=8.4 Hz, 1H), 6.79 (dd, J.sup.1=2.4 Hz, J.sup.2=9.2 Hz, 1H),
4.69 (d, J=3.2 Hz, 1H), 4.19 (m, 1H), 3.73 (m, 1H), 3.56 (m, 1H),
3.03 (m, 2H), 2.77 (m, 1H), 2.63 (m, 1H), 2.48 (brs, 1H), 1.87-1.68
(m, 4H).
[0304] (R)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-12): ESI:
m/z=222 (M+H.sup.+). .sup.1HNMR of freebase (400 MHz, CDCl.sub.3):
.delta. 7.11 (dd, J.sup.1=5.6 Hz, J.sup.2=8.8 Hz, 1H), 6.85 (td,
J.sup.1=2.8 Hz, J.sup.2=8.8 Hz, 1H), 6.77 (dd, J.sup.1=2.4 Hz,
J.sup.2=9.2 Hz, 1H), 4.87 (s, 1H), 4.15 (m, 1H), 3.69 (td,
J.sup.1=2.8 Hz, J.sup.2=11.2 Hz, 1H), 3.53 (m, 1H), 3.10-2.95 (m,
2H), 2.81-2.74 (m, 1H), 2.58-2.53 (m, 2H), 1.67-1.60 (m, 2H),
1.45-1.38 (m, 2H).
Example 1.2.7. (S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine
(I-139) and (S)-2-((R)-4,4-difluoroisochroman-1-yl)pyrrolidine
(I-140)
##STR00211##
[0306] (S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-139)
and (S)-2-((R)-4,4-difluoro-isochroman-1-yl)pyrrolidine (I-140)
were prepared using a procedure analogous to that described in
Example 1.2.1, but using 2-(2-bromophenyl)-2,2-difluoroethanol in
place of 2-(2-bromo-5-fluorophenyl)ethanol.
[0307] (S)-2-((S)-4,4-difluoroisochroman-1-yl)pyrrolidine (I-139):
MS (ESI): m/z=240[M+H].sup.+; 1H NMR (HCl salt, 400 MHz, MeOD)
7.80.about.7.78 (m, 1H), 7.65.about.7.54 (m, 2H), 7.50.about.7.48
(m, 1H), 5.16 (brs, 1H), 4.47.about.4.39 (m, 1H), 4.38.about.4.34
(m, 1H), 4.17.about.4.07 (m, 1H), 3.27.about.3.22 (m, 2H),
2.39.about.2.23 (m, 2H), 2.18.about.2.08 (m, 2H).
[0308] (S)-2-((R)-4,4-difluoro-isochroman-1-yl)pyrrolidine (I-140):
MS (ESI): m/z=240[M+H].sup.+; 1H NMR (HCl salt, 400 MHz, MeOD)
7.76.about.7.75 (m, 1H), 7.60.about.7.50 (m, 2H), 7.41.about.7.39
(m, 1H), 5.34 (brs, 1H), 4.54.about.4.50 (m, 1H), 4.45.about.4.39
(m, 1H), 4.10.about.4.00 (m, 1H), 3.41.about.3.30 (m, 2H),
2.07.about.1.95 (m, 2H), 1.82.about.1.60 (m, 2H).
Example 1.3. Procedure C. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.3.1
Example 1.3.1. (S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2)
and (S)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-1)
##STR00212##
[0309] (a). (2S)-tert-butyl 2-(5-bromo-8-fluoroisochroman-1-yl)
pyrrolidine-1-carboxylate
##STR00213##
[0311] (2S)-tert-butyl 2-(5-bromo-8-fluoroisochroman-1-yl)
pyrrolidine-1-carboxylate was prepared using a procedure analogous
to that described in Example 1.1.1 (step a and step b), but using
2-(2-bromo-5-fluorophenyl)ethanol in place of 2-phenylethanol.
(b). (2S)-tert-butyl 2-(8-fluoroisochroman-1-yl)
pyrrolidine-1-carboxylate
##STR00214##
[0313] A mixture of
(2S)-tert-butyl-2-(5-bromo-8-fluoroisochroman-1-yl)pyrrolidine-1-carboxyl-
ate (2.0 g, 5.0 mmol) and 10% dry Pd/C (320 mg) in methanol (40 mL)
was stirred at room temperature under hydrogen for 2 h. The
reaction mixture was filtered and the filtrate was concentrated in
vacuo to give the crude, which was purified by preparative HPLC to
give the desired product, 1.3 g, as a light yellow oil.
(c). (S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and
(S)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-1)
##STR00215##
[0315] (S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2) and
(S)-2-((R)-8-fluoroiso-chroman-1-yl)-pyrrolidine (I-1) were
prepared using a procedure similar to that described in Example
1.1.1 (step c and step d).
[0316] (S)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-2): (ESI)
m/z: 222[M+H]+. .sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 7.19-7.14
(q, J=5.6 Hz, 1H), 6.93-6.87 (m, 2H), 5.42 (brs, 1H), 5.03 (d,
J=4.0 Hz, 1H), 4.27-4.20 (m, 1H), 3.87-3.82 (m, 1H), 3.71-3.65 (td,
J.sup.1=3.6 Hz, J.sup.2=10.4 Hz, 1H), 3.15-3.01 (m, 2H), 2.89-2.83
(m, 1H), 2.70-2.64 (m, 1H), 2.05-1.75 (m, 4H).
[0317] (S)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-1): (ESI)
m/z: 222[M+H]+. .sup.1HNMR (HCl salt, 400 MHz, MeOD): .delta.
7.35-7.30 (q, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.04 (t, J=9.6
Hz, 1H), 5.37 (s, 1H), 4.45-4.41 (td, J.sup.1=2.4 Hz, J.sup.2=8.0
Hz, 1H), 4.33 (q, J=5.6 Hz, 1H), 3.78-3.72 (td, J.sup.1=2.0 Hz,
J.sup.2=11.6 Hz, 1H), 3.37 (m, 2H), 3.14 (m, 1H), 2.77 (d, J=16.4
Hz, 1H), 2.11-1.93 (m, 2H), 1.83-1.71 (m, 2H).
Example 1.3.2. (R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3)
and (R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-4)
##STR00216##
[0319] (R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3) and
(R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-4) were prepared
using a procedure analogous to that described in Example 1.3.1, but
using (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0320] (R)-2-((S)-8-fluoroisochroman-1-yl)pyrrolidine (I-3): ESI:
m/z=222 (M+H.sup.+). .sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 7.18
(m, 1H), 6.93 (m, 2H), 5.19 (s, 1H), 4.20 (m, 1H), 3.84 (m, 1H),
3.67 (td, J.sup.1=2.8 Hz, J.sup.2=11.6 Hz, 1H), 3.14-2.97 (m, 2H),
2.87 (m, 1H), 2.64 (s, 1H), 2.60 (brs, 1H), 1.74-1.65 (m, 2H),
1.49-1.37 (m, 2H).
[0321] (R)-2-((R)-8-fluoroisochroman-1-yl)pyrrolidine (I-4): ESI:
m/z=222 (M+H.sup.+). .sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 7.18
(m, 1H), 6.93 (m, 2H), 4.99 (d, J=3.2 Hz, 1H), 4.26 (m, 1H), 3.72
(m, 2H), 3.08 (m, 2H), 2.80 (m, 2H), 2.16 (brs, 1H), 1.93-1.72 (m,
4H).
Example 1.3.3. (S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84)
and (S)-2-((R)-8-fluoroisochroman-1-yl)azetidine (I-83)
##STR00217##
[0323] (S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84) and
(S)-2-((R)-8-fluoroisochroman-1-yl)azetidine (I-83) were prepared
using a procedure analogous to that described in Example 1.3.1, but
using (S)-tert-butyl 2-formylazetidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0324] (S)-2-((S)-8-fluoroisochroman-1-yl)azetidine (I-84): MS
(ESI): m/z 208 [M+H].sup.+, .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.24-7.18 (m, 1H), 6.99 (d, J=7.6, 1H), 6.93 (t, 1H), 5.08
(s, 2H), 4.23-4.18 (m, 1H), 3.99-3.92 (d, J=9.6 Hz, 1H), 3.74-3.67
(m, 2H), 3.14-3.05 (m, 1H), 2.89-2.84 (m, 1H), 2.66 (d, J=11.6,
1H), 2.43 (m, 1H).
[0325] (S)-2-((R)-8-fluoroisochroman-1-yl)azetidine (I-83): MS
(ESI): m/z 208 [M+H].sup.+, .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.35-7.29 (m, 1H), 7.09 (d, J=7.6, 1H), 6.98 (t, 1H), 5.29
(s, 1H), 5.19 (t, 1H), 4.44-4.39 (m, 1H), 4.04 (d, J=9.6 Hz, 1H),
3.93-3.78 (m, 2H), 3.18 (m, 1H), 2.82 (d, J=16, 1H), 2.38 (m,
2H).
Example 1.3.4. (S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine
(I-21) and (S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine
(I-22)
##STR00218##
[0327] (S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-21) and
(S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-22) were prepared
using a procedure analogous to that described in Example 1.3.1, but
using 2-(2-bromo-5-methylphenyl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol.
[0328] (S)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-21): ESI:
m/z=218 (M+H.sup.+). .sup.1HNMR (HCl salt, 400 MHz, MeOD): .delta.
7.14-7.22 (m, 2H), 7.08-7.09 (J=7.2 Hz, d, 1H), 5.31 (s, 1H),
4.24-4.29 (m, 1H), 4.01-4.05 (m, 1H), 3.60-3.66 (m, 1H), 3.36-3.38
(m, 1H), 3.20-3.24 (m, 2H), 2.66-2.70 (J=16 Hz, d, 1H), 2.38 (s,
3H), 2.03-2.24 (m, 4H).
[0329] (S)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-22): ESI:
m/z=218 (M+H.sup.+). .sup.1HNMR (HCl salt, 400 MHz, MeOD): .delta.
7.16-7.19 (J=14.8 Hz, t, 1H), 7.05-7.11 (m, 2H), 5.44 (s, 1H),
4.21-4.27 (m, 2H), 3.60-2.67 (m, 1H), 3.35-3.38 (m, 2H), 3.04-3.13
(m, 1H), 2.65-2.69 (J=16 Hz, d, 1H), 2.35 (s, 3H), 1.90-2.06 (m,
2H), 1.76-1.83 (m, 1H), 1.56-1.59 (m, 1H).
Example 1.3.5. (R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine
(I-24) and (R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine
(I-23)
##STR00219##
[0331] (R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-24) and
(R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-23) were prepared
using a procedure analogous to that described in Example 1.3.1, but
using 2-(2-bromo-5-methylphenyl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol and (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0332] (R)-2-((S)-8-methylisochroman-1-yl)pyrrolidine (I-24): ESI:
m/z=218 (M+H.sup.+). .sup.1H NMR (HCl salt, 400 MHz, MeOD): .delta.
7.05-7.19 (m, 3H), 5.44 (s, 1H), 4.21-4.27 (m, 2H), 3.60-3.66 (m,
1H), 3.35-3.39 (m, 2H), 3.04-3.13 (m, 1H), 2.65-2.69 (J=16.4 Hz, d,
1H), 2.35 (s, 3H), 1.90-2.06 (m, 2H), 1.76-1.83 (m, 1H), 1.53-1.59
(m, 1H).
[0333] (R)-2-((R)-8-methylisochroman-1-yl)pyrrolidine (I-23): ESI:
m/z=218 (M+H.sup.+). .sup.1H NMR (HCl salt, 400 MHz, MeOD): .delta.
7.19-7.23 (J=14.8 Hz, t, 1H), 7.14-7.16 (J=7.2 Hz, d, 1H),
7.08-7.09 (J=7.6 Hz, d, 1H), 5.31 (s, 1H), 4.24-4.28 (m, 1H),
4.00-4.04 (m, 1H), 3.60-3.66 (m, 1H), 3.35-3.39 (m, 1H), 3.17-3.26
(m, 2H), 2.66-2.70 (J=16 Hz, d, 1H), 2.36 (s, 3H), 2.03-2.25 (m,
4H).
Example 1.3.6.
((S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine
(I-51) and
(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine
(I-52)
##STR00220##
[0335]
(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrol-
idine (I-51) and
(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrolidine
(I-52) were prepared using a procedure analogous to that described
in Example 1.3.1, but using
2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol.
[0336]
(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrol-
idine (I-51): ESI: M/Z=248[M+H].sup.+. 1H NMR (400 MHz, CDCl3)
.delta. 6.68 (d, J=7.9 Hz, 1H), 6.60 (d, J=7.9 Hz, 1H), 5.99 (d,
J=1.5 Hz, 1H), 5.88 (d, J=1.5 Hz, 1H), 4.86 (d, J=2.2 Hz, 1H),
4.21.about.4.17 (m, 2.7 Hz, 1H), 3.85 (td, J.sub.1=7.6, J.sub.2=2.9
Hz, 1H), 3.68 (td, J.sub.1=10.9, J.sub.2=3.1 Hz, 1H),
3.08.about.3.02 (m, 1H), 3.00-2.89 (m, 1H), 2.79.about.2.74 (m,
1H), 2.61.about.2.56 (m, 1H), 2.17 (s, 1H), 1.91.about.1.75 (m,
4H).
[0337]
(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)pyrrol-
idine (I-52): ESI: M/Z=248[M+H].sup.+. H NMR (400 MHz, MeOD)
.delta. 6.70 (d, J=8.0 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 5.94 (d,
J=1.1 Hz, 1H), 5.86 (d, J=1.1 Hz, 1H), 5.03 (s, 1H),
4.18.about.4.14 (m, 1H), 3.96 (td, J.sub.1=7.9, J.sub.2=3.0 Hz,
1H), 3.64 (td, J.sub.1=11.5, J.sub.2=2.7 Hz, 1H), 3.17-3.05 (m,
1H), 3.00-2.85 (m, 1H), 2.81.about.2.75 (m, 1H), 2.59.about.2.55
(m, 1H), 1.75.about.1.70 (m, 2H), 1.56.about.1.48 (m, 2H).
Example 1.3.7. (S)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine
(I-47) and (S)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine
(I-48)
##STR00221##
[0339] (S)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-47) and
(S)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-48) were
prepared using a procedure analogous to that described in Example
1.3.1, but using 2-(2-bromo-5-methoxyphenyl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol.
[0340] (S)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-47): MS
(ESI): m/z 234.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl3): .delta.
10.42 (s, 1H), 8.23 (s, 1H), 7.19 (t, J=8.0 Hz, 1H),
6.76.about.6.70 (q, J=7.6 Hz, 2H), 5.41 (s, 1H), 4.81 (s, 1H),
4.26.about.4.22 (q, J=5.2 Hz, 1H), 3.98.about.3.82 (m, 1H), 3.70
(s, 3H), 3.50.about.3.44 (m, 2H), 3.05.about.2.96 (m, 1H), 2.58 (d,
J=16.0 Hz, 1H), 2.07.about.1.88 (m, 2H), 1.75.about.1.61 (m,
1H).
[0341] (S)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-48): MS
(ESI): m/z 234.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 9.46 (s, 1H), 7.87 (s, 1H), 7.15 (t, J=8.0 Hz, 1H),
6.74.about.6.71 (m, 2H), 5.02 (s, 1H), 4.46.about.4.41 (m, 1H),
4.23.about.4.18 (m, 1H), 3.87 (s, 3H), 3.75.about.3.67 (m, 1H),
3.61.about.3.55 (m, 1H), 3.11.about.3.042 (m, 1H), 2.78.about.2.72
(m, 1H), 2.51 (d, J=16.0 Hz, 1H), 2.24.about.2.16 (m, 1H),
2.04.about.1.86 (m, 2H), 1.84.about.1.78 (m, 1H).
Example 1.3.8. (R)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine
(I-49) and (R)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine
(I-50)
##STR00222##
[0343] (R)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-49) and
(R)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-50) were
prepared using a procedure analogous to that described in Example
1.3.1, but using 2-(2-bromo-5-methoxyphenyl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol and (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0344] (R)-2-((R)-8-methoxyisochroman-1-yl)pyrrolidine (I-49): MS
(ESI): m/z 234.1 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz,
MeOD): .delta. 7.19 (t, J=7.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.77
(d, J=7.6 Hz, 1H), 5.04 (s, 1H), 4.19.about.4.14 (m, 1H),
3.86.about.3.82 (m, 4H), 3.63.about.3.56 (m, 1H), 3.09.about.2.98
(m, 2H), 2.74.about.2.60 (m, 2H), 1.99.about.1.81 (m, 4H).
[0345] (R)-2-((S)-8-methoxyisochroman-1-yl)pyrrolidine (I-50): MS
(ESI): m/z 234.1 (M+H).sup.+. .sup.1H NMR (400 MHz, MeOD): .delta.
7.18 (t, J=7.6 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz,
1H), 5.18 (s, 1H), 4.16.about.4.12 (m, 1H), 4.03.about.4.01 (m,
1H), 3.99 (s, 3H), 3.82.about.3.54 (m, 1H), 3.16.about.3.10 (m,
1H), 3.02.about.2.93 (m, 1H), 2.60 (d, J=16.0 Hz, 1H),
1.78.about.1.70 (m, 2H), 1.69.about.1.53 (m, 1H), 1.52.about.1.48
(m, 1H).
Example 1.3.9.
(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine
(I-143) and
(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine
(I-144)
##STR00223##
[0347]
(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetid-
ine (I-143) and
(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetidine
(I-144) were prepared using a procedure analogous to that described
in Example 1.3.1, but using
2-(6-bromobenzo[d][1,3]dioxol-5-yl)ethanol in place of
2-(2-bromo-5-fluorophenyl)ethanol and (S)-tert-butyl
2-formylazetidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0348]
(S)-2-((S)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetid-
ine (I-143): MS (ESI): m/z 234.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) 6.69.about.6.59 (m, 2H), 5.95 (s, 1H), 5.88 (s, 1H),
4.75.about.4.74 (m, 1H), 4.61.about.4.56 (m, 1H), 4.29.about.4.24
(m, 1H), 3.76.about.3.72 (m, 1H), 3.58.about.3.54 (m, 1H),
3.46.about.3.41 (m, 1H), 3.01.about.2.93 (m, 1H), 2.70.about.2.62
(m, 2H), 2.32.about.2.02 (m, 1H).
[0349]
(S)-2-((R)-7,9-dihydro-6H-[1,3]dioxolo[4,5-h]isochromen-9-yl)azetid-
ine (I-144): MS (ESI): m/z 234.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
MeOD) 6.78.about.6.71 (m, 2H), 5.98 (s, 1H), 5.93 (s, 1H),
5.28.about.5.23 (m, 1H), 5.14.about.5.13 (m, 1H), 4.39.about.4.36
(m, 1H), 4.02.about.3.98 (m, 1H), 3.92.about.3.80 (m, 2H),
3.08.about.3.01 (m, 1H), 2.71.about.2.66 (m, 1H), 2.18.about.2.08
(m, 2H).
Example 1.4. Procedure D. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.4.1
Example 1.4.1.
(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-106) and
(S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-107)
##STR00224##
[0350] (a).
(3-(2-bromo-4-fluorophenyl)propoxy)(tert-butyl)dimethylsilane
##STR00225##
[0352] To a solution of 3-(2-bromo-4-fluorophenyl)propanol (14.2 g,
60.9 mmol) in DCM (150 mL) was added imidazole (8.29 g, 121.8 mmol)
and TBDMSCI (11.9 g, 79.2 mmol). The mixture was stirred at room
temperature for 2 h and water (300 mL) was added. The mixture was
extracted with DCM (3.times.150 mL) and the organic layers were
combined, washed, dried, filtered, and concentrated in vacuo to
give the crude product, which was purified by column chromatography
(PE) to give
3-(2-bromo-4-fluorophenylpropoxy)(tert-butyl)dimethylsilane (19.6
g) as a colorless oil. MS (ESI): m/z 329 (M+H).sup.+.
(b) (2S)-tert-butyl
2-((2-(3-(tert-butyldimethylsilyloxy)propyl)-5-fluorophenyl)
(hydroxy)-methyl)pyrrolidine-1-carboxylate
##STR00226##
[0354] To a solution of
(3-(2-bromo-4-fluorophenyl)propoxy)(tert-butyl)dimethylsilane (6.95
g, 20 mmol) in toluene (60 mL) at -78.degree. C. was added n-BuLi
(16 mL, 40 mmol). After the mixture was stirred at this temperature
for 2 h, (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (5.98 g,
30 mmol) was added. The mixture was stirred at this temperature for
an additional 3 h, and quenched with ammonium chloride (aq. sat. 20
mL). The mixture was extracted with ethyl acetate (20 mL.times.2),
and the organic phase was washed with saturated aqueous brine
(2.times.20 mL). The combined organic layers were dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
crude was purified by silica gel chromatography (petro ether:ethyl
acetate=10:1) to give the desired product (3.2 g) as orange
oil.
(c). (2S)-tert-butyl
2-((5-fluoro-2-(3-hydroxypropyl)phenyl)(hydroxy)-methyl)pyrrolidine-1-car-
boxylate
##STR00227##
[0356] To a solution of (2S)-tert-butyl
2-((2-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-fluorophenyl)(hydroxy)me-
thyl)pyrrolidine-1-carboxylate (3.2 g, 6.84 mmol) in THF (30 mL)
was added TBAF (3.58 g, 13.68 mmol). After the mixture was stirred
at room temperature for 3 h, the solvent was evaporated in vacuo to
give an oil. EtOAc (150 mL) was added to the reaction vessel and
the resulting biphasic mixture was transferred to a separatory
funnel. The layers were separated and the organic phase was washed
with water (3.times.100 mL). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give the crude product, which was used in the next step without
further purification. MS (ESI) m/z 354 (M+H).sup.+
(d).
(2S)-2-(8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
##STR00228##
[0358] To a solution of (2S)-tert-butyl
2-((5-fluoro-2-(3-hydroxypropyl)phenyl)(hydroxy)
methyl)pyrrolidine-1-carboxylate (2 g, 5.66 mmol) in DCM (10 mL)
was added trimethylsilyl trifluoromethanesulfonate (3.77 g, 16.98
mmol). After the mixture was stirred at room temperature for 3 h,
solvent was evaporated in vacuo to give the crude product. To the
crude product, water (50 mL) was added. The mixture was washed with
PE (50 mL.times.3). NaOH (aq. 40%,) was added to the mixture until
basic (pH >9). The mixture was then extracted with DCM (100
mL.times.3). The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
crude product as a mixture of diastereoisomers. MS (ESI) m/z 236
(M+H)+.
(e).
(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-106) and
(S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)
pyrrolidine (I-107)
##STR00229##
[0360]
(S)-2-(8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
from previous step (800 mg) was purified by Prep-HPLC to give
(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-106, 200 mg) and
(S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)
pyrrolidine (I-107, 250 mg).
[0361]
(S)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-106): MS (ESI) m/z 236 (M+H)+. .sup.1H NMR (HCl salt, 400
MHz, MeOD) .delta. 7.26.about.7.23 (m, 1H), 7.02.about.6.95 (m,
2H), 5.06 (m, 1H), 4.28.about.4.20 (m, 2H), 3.93.about.3.86 (m,
1H), 3.44.about.3.31 (m, 2H), 3.17.about.3.10 (m, 1H),
2.97.about.2.91 (m, 1H), 2.24.about.2.05 (m, 4H), 1.98.about.1.92
(m, 2H).
[0362] (S)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)
pyrrolidine (I-107): MS (ESI) m/z 236 (M+H).sup.+. .sup.1H NMR (HCl
salt, 400 MHz, MeOD) .delta. 7.28.about.7.25 (m, 1H),
7.05.about.6.78 (m, 2H), 4.85 (d, J=8.8 Hz, 1H), 4.28.about.4.15
(m, 2H), 4.06.about.3.99 (m, 1H), 3.45.about.3.39 (m, 2H),
3.1.about.3.04 (m, 1H), 2.31.about.2.11 (m, 3H), 1.86.about.1.81
(m, 3H)
Example 1.4.2.
(S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-97)
and (S)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-98)
##STR00230##
[0364] (S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-97) and
(S)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-98)
were prepared using a procedure analogous to that described in
Example 1.4.1, but using 3-(2-bromophenyl)propan-1-ol in place of
3-(2-bromo-4-fluorophenyl)propan-1-ol.
[0365] (S)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-97): MS (ESI): m/z 218 [M+H].sup.+, .sup.1HNMR (HCl salt, 400
MHz, MeOD): .delta. 7.35-7.11 (m, 4H), 4.83 (d, J=8.6 Hz, 1H),
4.31-4.13 (m, 2H), 4.02-3.95 (m, 1H), 3.47-3.34 (m, 2H), 3.17-3.06
(m, 2H), 2.37-2.21 (m, 1H), 2.19-2.06 (m, 2H), 1.96-1.74 (m,
3H).
[0366] (S)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-98): MS (ESI): m/z 218 [M+H].sup.+, .sup.1HNMR (HCl salt, 400
MHz, MeOD): .delta. 7.36-7.12 (m, 4H), 5.08 (d, J=3.4 Hz, 1H),
4.37-4.18 (m, 2H), 4.02-3.81 (m, 1H), 3.54-3.38 (m, 2H), 3.22-3.16
(m, 1H), 3.10-2.92 (m, 1H), 2.32-1.87 (m, 6H).
Example 1.4.3.
(R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine (I-99)
and (R)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-100)
##STR00231##
[0368] (R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-99) and
(R)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-100) were prepared using a procedure analogous to that described
in Example 1.4.1, but using 3-(2-bromophenyl)propan-1-ol in place
of 3-(2-bromo-4-fluorophenyl)propan-1-ol and (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0369] (R)-2-((S)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-99): MS (ESI): m/z 218 [M+H].sup.+, .sup.1HNMR (HCl salt, 400
MHz, MeOD): .delta. 7.30-7.16 (m, 4H), 5.07 (d, J=3.5 Hz, 1H), 4.25
(tt, J=8.5, 3.2 Hz, 2H), 3.90 (ddd, J=12.2, 10.5, 4.4 Hz, 1H),
3.47-3.33 (m, 2H), 3.15 (ddd, J=14.4, 8.7, 3.4 Hz, 1H), 2.97 (ddd,
J=14.5, 8.5, 3.2 Hz, 1H), 2.28-2.04 (m, 4H), 2.02-1.82 (m, 2H).
[0370] (R)-2-((R)-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-100): MS (ESI): m/z 218 [M+H].sup.+, .sup.1HNMR (HCl salt, 400
MHz, MeOD): .delta. 7.37-7.12 (m, 4H), 4.85 (t, J=6.4 Hz, 1H),
4.34-4.12 (m, 2H), 3.99 (ddd, J=12.2, 10.7, 4.2 Hz, 1H), 3.40 (ddd,
J=24.0, 12.0, 7.5 Hz, 2H), 3.21-2.95 (m, 2H), 2.27 (dtd, J=12.6,
7.8, 4.8 Hz, 1H), 2.20-2.05 (m, 2H), 1.96-1.72 (m, 3H).
Example 1.4.4.
(R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-108) and
(R)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-109)
##STR00232##
[0372]
(R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-108) and
(R)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-109) were prepared using a procedure analogous to that described
in Example 1.4.1, but using (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0373]
(R)-2-((S)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-108): MS (ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (HCl salt,
400 MHz, MeOD): .delta. 7.08.about.7.04 (m, 1H), 6.92.about.6.89
(m, 1H), 6.80.about.6.75 (m, 1H), 4.36 (m, 1H), 4.09 (m, 1H), 3.81
(m, 1H), 3.51 (m, 1H), 2.94 (m, 2H), 2.80 (m, 2H), 1.88 (m, 1H),
1.73 (m, 2H), 1.64 (m, 2H), 1.40 (m, 1H).
[0374]
(R)-2-((R)-8-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-109): MS (ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (HCl salt,
400 MHz, MeOD): .delta. 7.27.about.7.23 (m, 1H), 7.01.about.6.98
(m, 2H), 5.06 (d, J=3.6 Hz, 1H), 4.24 (m, 2H), 3.92 (m, 1H), 3.40
(m, 2H), 3.14 (m, 1H), 2.97 (m, 1H), 2.11 (m, 4H), 1.93 (m,
2H).
Example 1.4.5.
(S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-110) and
(S)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-111)
##STR00233##
[0376]
(S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-110) and
(S)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-111) were prepared using a procedure analogous to that described
in Example 1.4.1, but using 3-(2-bromo-5-fluorophenyl)propan-1-ol
in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol.
[0377]
(S)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-110): MS (ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. 7.24 (dd, J.sup.1=5.2 Hz, J.sup.2=8.0 Hz, 1H),
6.91-6.83 (m, 2H), 5.53 (brs, 1H), 4.55 (d, J=8.0 Hz, 1H),
4.25-4.20 (m, 1H), 3.94-3.87 (td, J.sup.1=3.2 Hz, J.sup.2=12.0 Hz,
1H), 3.85-3.79 (q, J=8.0 Hz, 1H), 3.27-3.21 (m, 1H), 3.12-3.01 (m,
2H), 2.97-2.91 (m, 1H), 2.06-1.72 (m, 5H), 1.66-1.54 (m, 1H).
[0378]
(S)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-111): MS (ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. 7.25-7.22 (dd, J.sup.1=6.0 Hz, J.sup.2=8.0 Hz,
1H), 6.90-6.84 (m, 2H), 4.52 (d, J=6.4 Hz, 1H), 4.24-4.19 (m, 1H),
3.85-3.79 (td, J.sup.1=3.6 Hz, J.sup.2=11.2 Hz, 1H), 3.61-3.55 (m,
1H), 3.10-2.86 (m, 4H), 2.21 (brs, 1H), 2.06-1.75 (m, 6H).
Example 1.4.6.
(R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-112) and
(R)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-113)
##STR00234##
[0380]
(R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-112) and
(R)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-113) were prepared using a procedure analogous to that described
in Example 1.4.1, but using 3-(2-bromo-5-fluorophenyl)propan-1-ol
in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol and
(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0381]
(R)-2-((S)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-112): MS (ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (HCl salt,
400 MHz, MeOD): .delta. 7.24-7.21 (dd, J.sup.1=5.6 Hz, J.sup.2=8.4
Hz, 1H), 7.04-6.95 (m, 2H), 5.03 (d, J=3.2 Hz, 1H), 4.29-4.20 (m,
2H), 3.93-3.86 (m, 1H), 3.44-3.33 (m, 2H), 3.16-3.10 (m, 1H),
3.01-2.95 (m, 1H), 2.27-2.06 (m, 4H), 1.97-1.85 (m, 2H).
[0382]
(R)-2-((R)-7-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-113): MS (ESI): m/z 236 [M+H].sup.+, .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. 7.24 (dd, J.sup.1=5.6 Hz, J.sup.2=8.0 Hz, 1H),
6.91-6.83 (m, 2H), 5.57 (brs, 1H), 4.55 (d, J=8.0 Hz, 1H),
4.25-4.20 (m, 1H), 3.94-3.79 (m, 2H), 3.27-3.21 (m, 1H), 3.12-3.01
(m, 2H), 2.97-2.91 (m, 1H), 2.06-1.72 (m, 5H), 1.66-1.54 (m,
1H).
Example 1.4.7.
(S)-2-((R)-9-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-105)
##STR00235##
[0384]
(S)-2-((R)-9-fluoro-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-105) was prepared using a procedure analogous to that
described in Example 1.4.1, but using
3-(2-bromo-3-fluorophenyl)propan-1-ol in place of
3-(2-bromo-4-fluorophenyl)propan-1-ol. ESI: m/z=236 (M+H).sup.+.
.sup.1H NMR (HCl salt, 400 MHz, MeOD): .delta. 7.33.about.7.28 (m,
1H), 7.06.about.7.01 (m, 2H), 5.37 (s, 1H), 4.20.about.4.15 (m,
1H), 4.09.about.4.06 (m, 1H), 3.68.about.3.60 (m, 1H),
3.46.about.3.35 (m, 3H), 2.69.about.2.66 (m, 1H), 2.26.about.2.15
(m, 3H), 2.01.about.1.96 (m, 1H), 1.89.about.1.84 (m, 2H).
Example 1.4.8.
((S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-101) and
(S)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-102)
##STR00236##
[0386]
(S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-101) and
(S)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-102) were prepared using a procedure analogous to that described
in Example 1.4.1, but using 3-(2-bromo-3-methylphenyl)propan-1-ol
in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol.
[0387]
(S)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-101): (ESI) m/z: 232[M+H].sup.+. .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. 7.11-7.07 (t, J=7.6 Hz, 1H), 7.04-7.02 (d,
J=7.2 Hz, 1H), 6.97-6.95 (d, J=7.6 Hz, 1H), 5.06-5.04 (d, J=6.0 Hz,
1H), 4.02-3.96 (m, 1H), 3.61-3.46 (m, 3H), 3.17-3.11 (m, 1H),
2.90-2.83 (m, 1H), 2.56-2.51 (m, 1H), 2.34 (s, 3H), 2.10-2.05 (m,
1H), 2.04 (brs, 1H), 1.84-1.57 (m, 5H).
[0388]
(S)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-102): (ESI) m/z: 232[M+H].sup.+. .sup.1HNMR (400 MHz, MeOD):
.delta. 7.18-7.15 (t, J=7.6 Hz, 1H), 7.12-7.10 (d, J=6.8 Hz, 1H),
7.04-7.02 (d, J=7.2 Hz, 1H), 5.39-5.38 (d, J=3.2 Hz, 1H), 4.14-4.08
(m, 1H), 3.99-3.94 (m, 1H), 3.61-3.35 (m, 4H), 2.58-2.53 (m, 1H),
2.37 (s, 3H), 2.35-2.10 (m, 3H), 2.04-1.92 (m, 1H), 1.83-1.72 (m,
2H).
Example 1.4.9.
(R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-104) and
(R)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-103)
##STR00237##
[0390]
(R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-104) and
(R)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidine
(I-103) were prepared using a procedure analogous to that described
in Example 1.4.1, but using 3-(2-bromo-3-methylphenyl)propan-1-ol
in place of 3-(2-bromo-4-fluorophenyl)propan-1-ol and
(R)-tert-butyl 2-formylpyrrolidine-1-carboxylate in place of
(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0391]
(R)-2-((S)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-104): (ESI) m/z: 232[M+H].sup.+. .sup.1HNMR (400 MHz, MeOD):
.delta. 7.18-7.15 (t, J=7.6 Hz, 1H), 7.12-7.10 (d, J=6.8 Hz, 1H),
7.04-7.02 (d, J=7.2 Hz, 1H), 5.39-5.38 (d, J=3.2 Hz, 1H), 4.14-4.08
(m, 1H), 3.99-3.94 (m, 1H), 3.61-3.35 (m, 4H), 2.58-2.53 (m, 1H),
2.37 (s, 3H), 2.35-2.10 (m, 3H), 2.04-1.92 (m, 1H), 1.83-1.72 (m,
2H).
[0392]
(R)-2-((R)-9-methyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)pyrrolidi-
ne (I-103): (ESI) m/z: 232 [M+H].sup.+. .sup.1HNMR (400 MHz,
CDCl.sub.3): .delta. 7.11-7.07 (t, J=7.6 Hz, 1H), 7.04-7.02 (d,
J=7.2 Hz, 1H), 6.97-6.95 (d, J=7.6 Hz, 1H), 5.06-5.04 (d, J=6.0 Hz,
1H), 4.02-3.96 (m, 1H), 3.61-3.46 (m, 3H), 3.17-3.11 (m, 1H),
2.90-2.83 (m, 1H), 2.56-2.51 (m, 1H), 2.34 (s, 3H), 2.17 (brs, 1H),
2.10-2.05 (m, 1H), 1.84-1.57 (m, 5H).
Example 1.5. Procedure E. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.5.1
Example 1.5.1. (S)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine
(I-65) and (S)-2-((R)-3,3-dimethylisochroman-1-yl)pyrrolidine
(I-66)
##STR00238##
[0393] (a). 1-(2-bromophenyl)-2-methylpropan-2-ol
##STR00239##
[0395] To a solution of methyl 2-(2-bromophenyl)acetate (5 g, 21.83
mmol) in THF (100 mL) at -78.degree. C. was added dropwise
methylmagnesium bromide (21.83 mL, 3M in Et.sub.2O). The mixture
was stirred at this temperature for 16 h, then gradually warmed to
room temperature. The mixture was then cooled to 0.degree. C., and
saturated aqueous ammonium chloride (2 mL) was added. After 10
minutes, the mixture was extracted with EtOAc (3.times.120 mL). The
organic layers were combined, dried, filtered and concentrated. The
crude material was purified by silica gel chromatography
(PE:EtOAc=20:1) to yield 1-(2-bromophenyl)-2-methylpropan-2-ol (4.5
g) as a colorless oil.
(b). (2S)-tert-butyl
2-(hydroxy(2-(2-hydroxy-2-methylpropyl)phenyl)methyl)pyrrolidine-1-carbox-
ylate
##STR00240##
[0397] To a solution of 1-(2-bromophenyl)-2-methylpropan-2-ol (4.5
g, 15.71 mmol) in toluene (80 mL) was added butyllithium (2.21 g,
34.56 mmol) at -78.degree. C. After stirring at -78.degree. C. for
1 h, (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (4.07 g,
20.42 mmol) in toluene (20 mL) was added. The mixture was stirred
at -78.degree. C. for an additional 3 h. The mixture was poured
into iced water and extracted with EtOAc (3.times.100 mL). The
organic layers were combined, dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was then purified by column
chromatography to give the crude product (0.99 g). ESI: m/z=350
(M+H.sup.+).
(c). (2S)-2-(3,3-dimethylisochroman-1-yl)pyrrolidine
##STR00241##
[0399] To a solution of (2S)-tert-butyl
2-(hydroxy(2-(2-hydroxy-2-methylpropyl)phenyl)
methyl)pyrrolidine-1-carboxylate (4 g, 5.95 mmol) in toluene (100
mL) was added 85% phosphoric acid (10 mL). The reaction mixture was
heated at 110.degree. C. for 16 h. Toluene was removed by
distillation and to the resulting residue was added water (100 mL),
and washed with ethyl acetate (2.times.80 mL). The aqueous layer
was used for next step without further purification. ESI: m/z=232
(M+H.sup.+).
(d). (2S)-tert-butyl 2-(3,3-dimethylisochroman-1-yl)
pyrrolidine-1-carboxylate
##STR00242##
[0401] To a solution of
(2S)-2-(3,3-dimethylisochroman-1-yl)pyrrolidine in water from
previous step was added NaOH (0.31 g, 7.86 mmol) and di-tert-butyl
dicarbonate (1.72 g, 7.86 mmol) at 0.degree. C. The mixture was
stirred at room temperature for 2 h and then was extracted with
EtOAc (3.times.100 mL). The organic layers were combined, washed
with brine (2.times.60 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated to give the residue, which was purified by
prep-HPLC to give (2S)-tert-butyl
2-(3,3-dimethylisochroman-1-yl)pyrrolidine-1-carboxylate 780 mg as
a yellow oil. ESI: m/z=332 (M+H.sup.+).
(e). (S)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-65) and
(S)-2-((R)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I-66)
##STR00243##
[0403] To a solution of (2S)-tert-butyl
2-(3,3-dimethylisochroman-1-yl)pyrrolidine-1-carboxylate (780 mg,
2.35 mmol) in ethyl acetate (20 mL) was added HCl/dioxane (1.44 g,
40 mmol). The reaction mixture was stirred at room temperature for
4 h. Upon completion, the mixture was concentrated and the residue
separated by PREP-HPLC to give two diastereoisomers, which were
each purified again by chiral HPLC: AS-H (250*4.6 mm 5 .mu.m) and
mobile phase: MeOH (0.1% DEA) to give
(S)-2-((S)-3,3-dimethylisochroman-1-yl) pyrrolidine (I-65) (120 mg)
and (S)-2-((R)-3,3-dimethylisochroman1-yl) pyrrolidine (I-66) (80
mg).
[0404] (S)-2-((S)-3,3-dimethylisochroman-1-yl) pyrrolidine (I-65):
ESI: m/z=232 (M+H.sup.+). .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.28-7.37 (m, 3H), 7.19-7.21 (m, 1H), 5.03 (s, 1H),
4.23-4.28 (m, 1H), 3.30-3.33 (m, 2H), 3.06-3.10 (J=15.6 Hz, d, 1H),
2.64-2.68 (J=16 Hz, d, 1H), 2.26-2.32 (m, 2H), 2.02-2.18 (m, 2H),
1.43 (s, 3H), 1.20 (s, 3H).
[0405] (S)-2-((R)-3,3-dimethylisochromanl-yl) pyrrolidine (I-66):
ESI: m/z=232 (M+H.sup.+). .sup.1HNMR (400 MHz, MeOD): .delta.
7.17-7.28 (m, 4H), 5.23 (s, 1H), 4.31-4.35 (m, 1H), 3.32-3.37 (m,
2H), 2.89-2.94 (J=16.4 Hz, d, 1H), 2.65-2.69 (J=16 Hz, d, 1H),
2.03-2.08 (m, 1H), 1.93-1.98 (m, 1H), 1.70-1.76 (m, 2H), 1.44 (s,
3H), 1.21 (s, 3H).
Example 1.5.2. ((R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine
(I-67) and (R)-2-((R)-3,3-dimethylisochroman-1-yl)pyrrolidine
(I-68)
##STR00244##
[0407] (R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-67)
and (R)-2-((R)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I-68) were
prepared using a procedure analogous to that described in Example
1.5.1, but using (R)-tert-butyl 2-formylpyrrolidine-1-carboxylate
in place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0408] (R)-2-((S)-3,3-dimethylisochroman-1-yl)pyrrolidine (I-67):
ESI: m/z=232 (M+H.sup.+). .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.14-7.25 (m, 4H), 5.15 (s, 1H), 4.01-4.06 (m, 1H),
3.24-3.32 (m, 1H), 3.10-3.16 (m, 1H), 2.87-2.91 (J=15.6 Hz, d, 1H),
2.62-2.66 (J=15.6 Hz, d, 1H), 1.83-1.95 (m, 2H), 1.56-1.67 (m, 2H),
1.41 (s, 3H), 1.19 (s, 3H).
[0409] (R)-2-((R)-3,3-dimethyl-isochroman-1-yl)pyrrolidine (I-68):
ESI: m/z=232 (M+H.sup.+). .sup.1HNMR (400 MHz, MeOD): .delta.
7.28-7.36 (m, 3H), 7.19-7.21 (m, 1H), 5.03 (s, 1H), 4.23-4.27 (m,
1H), 3.23-3.32 (m, 2H), 3.05-3.09 (J=16 Hz, d, 1H), 2.64-2.68 (J=16
Hz, d, 1H), 2.26-2.32 (m, 2H), 2.04-2.17 (m, 2H), 1.44 (s, 3H),
1.20 (s, 3H).
Example 1.6. General Procedure F. Certain Provided Compounds were
Made Following a Procedure Exemplified by Example 1.6.1
Example 1.6.1. (R)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine
(I-62) and (R)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine
(I-61)
##STR00245##
[0410] (a). (R)-(9H-fluoren-9-yl)methyl
2-(hydroxymethyl)-4,4-dimethyl-pyrrolidine-1-carboxylate
##STR00246##
[0412] To a solution of (R)-(4,4-dimethylpyrrolidin-2-yl)methanol
(3.2 g, 24.77 mmole) in THF (100 mL) and water (30 mL) was added
Na.sub.2CO.sub.3 (7.87 g, 74.30 mmole) as solid. The suspension was
cooled to 0.degree. C. and Fmoc-Cl (9.61 g, 37.15 mmole) was added
dropwise. After the addition, the cold bath was removed and the
reaction mixture was stirred at room temperature for 2 h. Water
(200 mL) was added. The resulting solid was filtered off through a
pad of Celite. The filtrate was separated and extracted with ethyl
acetate (200 mL.times.2). The combined organic layers were washed
with dilute brine (50 mL.times.2), dried over sodium sulfate,
filtered and concentrated to give a crude product which was
purified through column chromatography (EtOAc/PE=1:10) to give the
product (7.1 g) as a colorless oil. LC/MS (ESI+): m/z=352.3
(M+H).
(b). (R)-(9H-fluoren-9-yl)methyl
2-formyl-4,4-dimethylpyrrolidine-1-carboxylate
##STR00247##
[0414] To a solution of (R)-(9H-fluoren-9-yl)methyl
2-(hydroxymethyl)-4,4-dimethylpyrrolidine-1-carboxylate (7.1 g,
20.20 mmole) in DCM (80 mL) was added Dess-Martin reagent (25.71 g,
60.61 mmole) slowly at 0.degree. C. The mixture was stirred at room
temperature overnight and the reaction was then quenched with
NaHCO.sub.3 (sat. aq. 100 mL). The resulting mixture was then
extracted with DCM (200 mL.times.2). The combined organic layers
were washed with brine (50 mL.times.2), dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the crude
product, which was purified by column chromatography
(EtOAc/PE=1:10) to give the product (3.25 g) as a colorless oil.
LC/MS (ESI+): m/z=351.2 (M+H).
(c). (R)-(9H-fluoren-9-yl)methyl
2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate and
(R)-(9H-fluoren-9-yl)methyl
2-((R)-isochroman-1-yl)-4,4-dimethyl-pyrrolidine-1-carboxylate
##STR00248##
[0416] To a solution of (R)-(9H-fluoren-9-yl)methyl
2-formyl-4,4-dimethylpyrrolidine-1-carboxylate (3.25 g, 9.30 mmole)
in DCM (16 mL) was added 2-phenylethanol (1.136 g, 9.30 mmole) and
TfOH (2 mL) at 0.degree. C. The mixture was stirred at room
temperature for 1 h. Solid Na.sub.2CO.sub.3 was added to adjust the
pH to 7-8, and EtOAc (300 mL) was added. The mixture was washed
with water (100 mL.times.2), sat.NaCl (100 mL.times.2), dried and
concentrated to give the crude product, which was purified by
Prep-HPLC to give (R)-(9H-fluoren-9-yl)methyl
2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (1.02
g) and (R)-(9H-fluoren-9-yl)methyl
2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate
(I-11) (805 mg). LC-MS: 454.1 (M+H).
(d). (R)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine
##STR00249##
[0418] To a solution of (R)-(9H-fluoren-9-yl)methyl
2-((S)-isochroman-1-yl)-4,4-dimethyl-pyrrolidine-1-carboxylate
(1.02 g) in DMF (8 mL) was added morpholine (8 mL). The mixture was
stirred at room temperature for 2 h. The resulting solid was
filtered off. To the filtrate was added EtOAc (200 mL) and the
mixture was then washed with water (30 mL.times.3), sat. NaCl (30
mL.times.3), dried, and concentrated to give a residue, which was
purified by prep-HPLC to give the product (300 mg). LC-MS: 232.2
(M+H). .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.28-7.10 (m, 4H), 4.96
(d, J=3.2 Hz, 1H), 4.25-4.20 (m, 1H), 3.80-3.72 (m, 2H), 3.10-3.02
(m, 1H), 2.80 (d, J=10.8 Hz, 1H), 2.70-2.61 (m, 2H), 1.40-1.26 (m,
1H), 1.24-1.19 (m, 1H), 1.03 (s, 3H), 1.01 (s, 3H).
(e). (R)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine
##STR00250##
[0420] To a solution of (R)-(9H-fluoren-9-yl)methyl
2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine-1-carboxylate (805
mg) in DMF (8 mL) was added morpholine (8 mL). The mixture was
stirred at room temperature for 2 h. The resulting solid was
filtered off and to the filtrate was added EtOAc (200 mL). The
mixture was washed with water (30 mL.times.3), sat. NaCl (30
mL.times.3), dried and concentrated to give a residue, which was
purified by prep-HPLC to give the product (242 mg). LC-MS: 232.2
(M+H). .sup.1H NMR (CDCl3,400 MHz): 7.28-7.10 (m, 4H), 4.71 (d,
J=4.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.80-3.72 (m, 2H), 3.07-2.98 (m,
1H), 2.80 (d, J=10.8 Hz, 1H), 2.70-2.61 (m, 2H), 1.79-1.74 (m, 1H),
1.68-1.63 (m, 1H), 1.10 (s, 3H), 1.08 (s, 3H).
Example 1.6.2. (S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine
(I-60) and (S)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine
(I-59)
##STR00251##
[0422] (S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-60)
and(S)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-59) were
prepared using a procedure analogous to that described in Example
1.6.1, but using (S)-(4,4-dimethylpyrrolidin-2-yl)methanol in place
of (R)-(4,4-dimethylpyrrolidin-2-yl)methanol.
[0423] (S)-2-((S)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-60):
LC-MS: 232.2 (M+H). .sup.1HNMR (HCl salt, DMSO-d6,400 MHz): 9.62
(s, 1H), 8.45 (s, 1H), 7.33-7.18 (m, 4H), 4.90 (s, 1H), 4.32-4.28
(m, 1H), 4.27-4.18 (m, 1H), 3.78-3.73 (m, 1H), 3.17-3.04 (m, 1H),
2.83-2.66 (m, 2H), 2.58-2.53 (m, 1H), 2.12-1.93 (m, 1H), 1.89-1.78
(m, 1H), 1.17 (s, 3H), 1.12 (s, 3H).
[0424] (S)-2-((R)-isochroman-1-yl)-4,4-dimethylpyrrolidine (I-59):
LC-MS: 232.2 (M+H). .sup.1HNMR (HCl salt, DMSO-d6,400 MHz): 9.62
(s, 1H), 8.45 (s, 1H), 7.33-7.18 (m, 4H), 4.90 (s, 1H), 4.32-4.28
(m, 1H), 4.27-4.18 (m, 1H), 3.78-3.73 (m, 1H), 3.17-3.04 (m, 1H),
2.83-2.66 (m, 2H), 2.58-2.53 (m, 1H), 2.12-1.93 (m, 1H), 1.89-1.78
(m, 1H), 1.17 (s, 3H), 1.12 (s, 3H).
Example 1.7. Procedure G. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.7.1
Example 1.7.1. (R)-3-(isochroman-1-yl)azetidine (I-114) and
(S)-3-(isochroman-1-yl)azetidine (I-115)
##STR00252##
[0425] (a). tert-butyl
3-(2-(2-(tert-butyldimethylsilyloxy)ethyl)benzoyl)azetidine-1-carboxylate
##STR00253##
[0427] To a stirred solution of
(2-bromophenethoxy)(tert-butyl)dimethylsilane (15.77 g, 50 mmol) in
dry THF (200 mL) was added dropwise n-Butyl lithium (25 mL, 60
mmol, 2.4 M solution in hexane) at -78.degree. C. under nitrogen,
and the reaction mixture was stirred at this temperature for 1 h.
To the reaction mixture, a solution of tert-butyl
3-(methoxy(methyl) carbamoyl)azetidine-1-carboxylate (12.2 g, 50
mmol) in dry THF (50 mL) was added dropwise. The reaction mixture
was stirred at -78.degree. C. for 1 h and then quenched by addition
of a saturated aqueous NH.sub.4Cl solution (50 mL). The aqueous
phase was extracted with ethyl acetate and the combined organic
phase were washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo to give a residue, which was
purified by column chromatography (petroleum ether/ethyl acetate:
5/1) to afford
butyldimethylsilyl)oxy)ethyl)benzoyl)azetidine-1-carboxylate (13.3
g) as colorless oil.
(b). tert-butyl
3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)(hydroxy)methyl)-azet-
idine-1-carboxylate
##STR00254##
[0429] To a solution of tert-butyl
3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzoyl)azetidine-1-carboxyla-
te (13.22 g, 31.5 mmol) in methanol (157 mL) was added sodium
borohydride (1.79 g, 47.25 mmol) slowly at 0.degree. C. Then
mixture was stirred at room temperature for 1 h. The solvent was
removed and the residue was added water (100 mL) and ethyl acetate
(100 mL). The resulting biphasic mixture was transferred to a
separatory funnel. The layers were separated and the organic phase
was washed with brine (50 mL), dried over anhydrous sodium sulfate,
filtered, concentrated to give a residue, which was purified by
column chromatography (ethyl acetate/petroleum ether=1:5) to give
the product (13 g) as a colorless oil.
(c). (tert-butyl
3-(hydroxy(2-(2-hydroxyethyl)phenyl)methyl)azetidine-1-carboxylate
##STR00255##
[0431] To a solution of tert-butyl
3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)
(hydroxy)methyl)azetidine-1-carboxylate (6.5 g, 15.42 mmol) in
tetrahydrofuran (75 mL) was added tetrabutylammonium fluoride (4.03
g, 15.42 mmol) at 0.degree. C. The mixture was stirred at room
temperature overnight and solvent removed. The residue was diluted
with EtOAc (500 mL), washed with brine (4.times.50 mL), dried over
sodium sulfate and concentrated. The crude product was purified by
silica gel chromatography (ethyl acetate/petroleum ether=1:5) to
give the product as a colorless oil (4.7 g).
(d). (R)-tert-butyl 3-(isochroman-1-yl)azetidine-1-carboxylate and
(S)-tert-butyl 3-(isochroman-1-yl)azetidine-1-carboxylate
##STR00256##
[0433] To a solution of tert-butyl
3-(hydroxy(2-(2-hydroxyethyl)phenyl)methyl)azetidine-1-carboxylate
(4.5 g, 14.64 mmol) in toluene (100 mL) was added n-butyllithium
(6.89 mL, 16.54 mmol) at 0.degree. C. After 30 min,
4-methyl-benzenesulfonyl chloride (3.15 g, 16.54 mmol) was added to
the mixture. The mixture was stirred at this temperature for
another 1 h and n-butyllithium (9.15 mL, 21.96 mmol) was added. The
reaction mixture was stirred at 40.degree. C. for 16 h and then
poured into iced-water, and extracted with EtOAc (3.times.100 mL).
The combined organic layers were washed with brine (2.times.100
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give
a residue, which was purified by pre-HPLC to give the racemic
mixture of tert-butyl 3-(isochroman-1-yl)azetidine-1-carboxylate as
yellow oi (1.5 g). The racemate was then separated by chiral HPLC,
column: OZ--H (250*4.6 mm 5 .mu.m) and mobile phase: MeOH (0.1%
DEA) to give
(R)-tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate and
(S)-tert-butyl-3-(isochroman-1-yl)azetidine-1-carboxylate as
colorless oil.
(e). (R)-3-(isochroman-1-yl)azetidine (I-114)
##STR00257##
[0435] To a solution of (R)-tert-butyl
3-(isochroman-1-yl)azetidine-1-carboxylate (0.4 g, 1.38 mmol) in
DCM (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL) dropwise.
The mixture was stirred at room temperature for 2 h and solvent was
removed. The residue was dissolved in water (15 mL), followed by
addition of aqueous NH.sub.4OH. The resulting mixture was extracted
with DCM (20 mL.times.5). The organic phase was combined, dried
over Na.sub.2SO.sub.4, filtered, and concentrated to give
(R)-3-(isochroman-1-yl)azetidine (I-114) (0.25 g) as a yellow oil.
MS (ESI): m/z 190 [M+H].sup.+, .sup.1H NMR (HCl salt, 400 MHz,
MeOD) .delta. 7.26-7.17 (m, 3H), 7.13-7.06 (m, 1H), 4.94 (s, 1H),
4.38 (m, 1H), 4.34-4.22 (m, 2H), 3.98-3.82 (m, 2H), 3.77 (dd,
J=10.4, 6.3 Hz, 1H), 3.69-3.55 (m, 1H), 3.17 (m, 1H), 2.79-2.67 (m,
1H).
(f). (S)-3-(isochroman-1-yl)azetidine (I-115)
##STR00258##
[0437] To a solution of (S)-tert-butyl
3-(isochroman-1-yl)azetidine-1-carboxylate (0.45 g, 1.56 mmol) in
DCM (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL) dropwise.
The mixture was stirred at room temperature for 2 h, and solvent
was removed. The residue was dissolved in water (15 mL), followed
by addition of aqueous NH.sub.4OH. The resulting mixture was
extracted with DCM (20 mL.times.5). The organic phase was combined,
dried over Na.sub.2SO.sub.4, and concentrated to give
(S)-3-(isochroman-1-yl)azetidine (0.27 gas a yellow oil. MS (ESI):
m/z 190 [M+H].sup.+, .sup.1H NMR (HCl salt, 400 MHz, MeOD) .delta.
7.15-7.04 (m, 3H), 7.00-6.92 (m, 1H), 4.82 (s, 1H), 4.26 (m, 1H),
4.16 (p, J=10.2 Hz, 2H), 3.76 (m, 2H), 3.65 (dd, J=10.3, 6.4 Hz,
1H), 3.55-3.44 (m, 1H), 3.05 (m, 1H), 2.61 (d, J=16.5 Hz, 1H).
Example 1.7.2. ((R)-3-(7-methylisochroman-1-yl)azetidine (I-116)
and (S)-3-(7-methylisochroman-1-yl)azetidine (I-117)
##STR00259##
[0439] (R)-3-(7-methylisochroman-1-yl)azetidine (I-116) and
(S)-3-(7-methylisochroman-1-yl)azetidine (I-117) were prepared
using a procedure analogous to that described in Example 1.7.1, but
using (2-bromo-4-methylphenethoxy)(tert-butyl)dimethylsilane in
place of (2-bromophenethoxy)(tert-butyl)dimethylsilane.
[0440] (R)-3-(7-methylisochroman-1-yl)azetidine (I-116): MS m/z 204
[M+H].sup.+, .sup.1H NMR (HCl salt, 400 MHz, MeOD) .delta. 7.06 (M,
2H), 6.91 (s, 1H), 4.90 (s, 1H), 4.36 (M, 1H), 4.33-4.20 (m, 2H),
3.98-3.89 (m, 1H), 3.88-3.72 (m, 2H), 3.67-3.54 (m, 1H), 3.19-3.04
(m, 1H), 2.67 (d, J=15.5 Hz, 1H), 2.30 (s, 3H).
[0441] (S)-3-(7-methylisochroman-1-yl)azetidine (I-117): MS m/z 204
[M+H].sup.+, .sup.1H NMR (HCl salt, 400 MHz, MeOD) .delta. 7.05 (m,
2H), 6.91 (s, 1H), 4.89 (s, 1H), 4.36 (m 1H), 4.27 (dd, J=15.6, 7.1
Hz, 2H), 3.93 (t, J=9.6 Hz, 1H), 3.89-3.72 (m, 2H), 3.66-3.54 (m,
1H), 3.20-3.05 (m, 1H), 2.67 (d, J=15.3 Hz, 1H), 2.30 (s, 3H).
Example 1.8. Procedure H. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.8.1
Example 1.8.1. (S)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile
(I-43) and (R)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile
(I-44)
(c). (S)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43)
and (R)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44)
##STR00260##
[0443] (2S)-tert-butyl
2-(6-cyanoisochroman-1-yl)pyrrolidine-1-carboxylate (2.1 g, 6.39
mmol) was stirred in HCl/dioxane (3 M) (20 mL) at room temperature
for about 2 h. To the mixture was added NH.sub.4OH (aq.) till pH
8.about.9 and the mixture was concentrated in vacuo. The crude
product was purified by Prep-HPLC to give the two diastereoisomers,
which then were each separately purified by chiral separation using
column: AY-H (250*4.6 mm 5 .mu.m); Mobile Phase: n-Hexane (0.1%
DEA):EtOH (0.1% DEA)=80:20, followed by another chiral separation
using column: OJ-H 4.6*250 mm 5 .mu.m, Mobile Phase: MeOH (0.1%
DEA), to afford I-43 and I-44. MS (ESI) m/z 229.1 (M+H).sup.+.
[0444] (S)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-43):
MS (ESI) m/z 229.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.49.about.7.40 (m, 3H), 4.79 (s, 1H), 4.27.about.4.22 (m,
1H), 3.78.about.3.72 (m, 1H), 3.60.about.3.55 (m, 1H),
3.11.about.3.06 (m, 2H), 2.80.about.2.67 (m, 2H), 1.95.about.1.75
(m, 5H).
[0445] (R)-1-((S)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-44):
MS (ESI) m/z: 229.1 (M+H)+.sup.1. H NMR (HCl salt, 400 MHz, MeOD):
.delta. 7.62 (d, J=7.2 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 5.27 (s,
1H), 4.42.about.4.33 (m, 2H), 3.86.about.3.79 (m, 1H),
3.38.about.3.33 (m, 2H), 3.19.about.3.11 (m, 1H), 2.79 (d, J=16.8
Hz, 1H), 2.11.about.1.93 (m, 2H), 1.79.about.1.72 (m, 2H).
Example 1.8.2. (S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile
(I-46) and (R)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile
(I-45)
##STR00261##
[0447] (S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46)
and (R)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45)
were prepared using a procedure analogous to that described in
Example 1.8.1, but using (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0448] (S)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-46):
ESI: m/z=229 (M+H.sup.+). .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.62-7.63 (J=6.8 Hz, d, 1H), 7.43-7.45 (J=8.4 Hz, d, 1H),
5.28 (s, 1H), 4.33-4.43 (m, 2H), 3.79-3.86 (m, 1H), 3.34-3.39 (m,
2H), 3.11-3.19 (m, 1H), 2.64-2.77 (m, 2H), 2.77-2.81 (J=16 Hz, d,
1H), 1.94-2.10 (m, 2H), 1.65-1.79 (m, 2H).
[0449] (R)-1-((R)-pyrrolidin-2-yl)isochroman-6-carbonitrile (I-45):
ESI: m/z=229 (M+H.sup.+). .sup.1HNMR (HCl salt, 400 MHz, MeOD):
.delta. 7.65-7.67 (J=13.2 Hz, d, 1H), 7.53-7.55 (m, 1H), 5.10 (s,
1H), 4.28-4.35 (m, 2H), 3.83-3.89 (m, 1H), 3.20-3.30 (m, 3H),
2.77-2.82 (J=17.2 Hz, d, 1H), 2.07-2.35 (m, 4H).
Example 1.8.3. (S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile
(I-39) and (R)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile
(I-40)
##STR00262##
[0451] (S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39)
and (R)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40)
were prepared using a procedure analogous to that described in
Example 1.8.1, but using 2-(4-bromophenyl)ethanol in place of
2-(3-bromophenyl) ethanol.
[0452] (S)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-39):
MS (ESI): m/z 229 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz,
MeOD) .delta. 7.78 (s, 1H), 7.66 (dd, J=7.9, 0.9 Hz, 1H), 7.44 (d,
J=8.0 Hz, 1H), 5.08 (s, 1H), 4.45-4.24 (m, 2H), 3.87 (td, J=11.4,
3.3 Hz, 1H), 3.32-3.19 (m, 3H), 2.82 (d, J=17.2 Hz, 1H), 2.41-2.23
(m, 2H), 2.22-1.97 (m, 2H).
[0453] (R)-1-((S)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-40):
MS (ESI): m/z 229 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz,
MeOD) .delta. 7.72 (d, J=23.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.43
(d, J=8.0 Hz, 1H), 5.25 (s, 1H), 4.43 (td, J=8.3, 2.7 Hz, 1H), 4.35
(dd, J=11.4, 6.0 Hz, 1H), 3.83 (td, J=11.7, 2.9 Hz, 1H), 3.38 (ddd,
J=11.9, 10.4, 7.6 Hz, 2H), 3.18 (ddd, J=17.8, 11.9, 6.2 Hz, 1H),
2.82 (d, J=17.0 Hz, 1H), 2.14-1.90 (m, 2H), 1.87-1.66 (m, 2H).
Example 1.8.4. (S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile
(I-42) and (R)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile
(I-41)
##STR00263##
[0455] (S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42)
and (R)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41)
were prepared using a procedure analogous to that described in
Example 1.8.1, but using 2-(4-bromophenyl)ethanol in place of
2-(3-bromophenyl) ethanol and (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0456] (S)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-42):
MS (ESI) m/z: 229.1 (M+H).sup.+1. .sup.1H NMR (HCl salt, 400 MHz,
MeOD): .delta. 7.70 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0
Hz, 1H), 5.25 (s, 1H), 4.46.about.4.42 (m, 1H), 4.37.about.4.11 (m,
1H), 3.87.about.3.80 (m, 1H), 3.42.about.3.32 (m, 2H),
3.22.about.3.14 (m, 1H), 2.81 (d, J=16.4 Hz, 1H), 2.10.about.1.82
(m, 2H), 1.80.about.1.71 (m, 2H).
[0457] (R)-1-((R)-pyrrolidin-2-yl)isochroman-7-carbonitrile (I-41):
MS (ESI) m/z: 229.1 (M+H).sup.+1 1H NMR (HCl salt, 400 MHz, MeOD):
.delta. 7.78 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.44 (d, J=8.0 Hz,
1H), 5.08 (s, 1H), 4.36.about.4.59 (m, 2H), 3.90.about.3.83 (m,
1H), 3.32.about.3.22 (m, 3H), 2.81 (d, J=17.2 Hz, 1H),
2.34.about.2.03 (m, 4H).
Example 1.9. Procedure I. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.9.1
Example 1.9.1. (S)-3-((S)-isochroman-1-yl)morpholine (I-75) and
(S)-3-((R)-isochroman-1-yl)morpholine (I-76)
##STR00264##
[0459] To a solution of (S)-tert-butyl
3-formylmorpholine-4-carboxylate (0.5 g, 2.32 mmol) in DCM (10 mL)
was added TMSOTf (2.06 g, 9.28 mmol) and 2-phenylethanol (0.28 g,
2.32 mmol). The mixture was stirred at room temperature for 2 h,
poured into ice-water, extracted with DCM (2.times.20 ml). The
combined organic layers were dried, filtered, and solvent removed.
The crude was purified by Prep-HPLC to provide
(S)-3-((S)-isochroman-1-yl) morpholine (I-75) (70 mg) and
(S)-3-((R)-isochroman-1-yl) morpholine (I-76) (50 mg) as orange
oil.
[0460] (S)-3-((S)-isochroman-1-yl) morpholine (I-75): MS (ESI) m/z
220 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD) .delta. 7.33
(m, 3H), 7.26 (m, 1H), 4.99 (s, 1H), 4.23 (m, 2H), 3.98 (m, 3H),
3.77 (m, 2H), 3.18 (m, 3H), 2.73 (m, 1H).
[0461] (S)-3-((R)-isochroman-1-yl) morpholine (I-76): MS (ESI) m/z
220 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD) .delta. 7.22
(m, 3H), 7.15 (m, 1H), 4.82 (s, 1H), 4.18 (m, 1H), 3.72 (m, 2H),
3.38 (m, 4H), 2.98 (m, 3H), 2.63 (m, 1H).
Example 1.9.2. (S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77)
and (S)-3-((R)-6-fluoroisochroman-1-yl)morpholine (I-78)
##STR00265##
[0463] (S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77) and
(S)-3-((R)-6-fluoroisochroman-1-yl)morpholine (I-78) were prepared
using a procedure analogous to that described in Example 1.9.1, but
using 2-(3-fluorophenyl)ethanol in place of 2-phenylethanol.
[0464] (S)-3-((S)-6-fluoroisochroman-1-yl)morpholine (I-77): MS
(ESI) m/z 238 (M+H).sup.+, .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.23 (m, 1H), 6.97 (m, 1H), 6.90 (m, 1H), 4.79 (s, 1H),
4.17 (m, 1H), 3.76 (m, 1H), 3.64 (m, 1H), 3.39 (m, 4H), 3.00 (m,
3H), 2.65 (m, 1H).
[0465] (S)-3-((R)-6-fluoroisochroman-1-yl)morpholine (I-78): MS
(ESI) m/z 238 (M+H).sup.+, H NMR HCl salt, (400 MHz, MeOD) .delta.
7.23 (m, 1H), 6.97 (m, 1H), 6.90 (m, 1H), 4.69 (s, 1H), 4.17 (m,
1H), 3.91 (m, 1H), 3.70 (m, 3H), 3.47 (m, 1H), 3.29 (m, 1H), 3.03
(m, 1H), 2.82 (m, 2H), 2.67 (m, 1H).
Example 1.10. Procedure J
Example 1.10.1.
(S)-1-((S)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-37) and
(R)-1-((S)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38)
##STR00266##
[0466] (a). (25)-(9H-fluoren-9-yl)methyl
2-(5-bromo-8-hydroxylisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00267##
[0468] 4-bromo-3-(2-hydroxyethyl)phenol (4.0 g, 18.43 mmol),
(S)-(9H-fluoren-9-yl)methyl 2-formylpyrrolidine-1-carboxylate (8.88
g, 27.65 mmol) in toluene (40 mL) was stirred at 0.degree. C.
Trifluoromethanesulfonic acid (10 mL) was added dropwise to the
solution at this temperature. The mixture was stirred at 0.degree.
C. for an additional 2-3 h and ice water (100 mL) was added. The
mixture was filtered under reduced pressure, washed with methanol
(100 mL). The filtrate was concentrated in vacuo and then extracted
with ethyl acetate (3.times.100 mL). The combined organic layers
were washed with brine (80 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to afford the crude
product, which was purified by column chromatography (petroleum
ether:ethyl acetate=20:1-10:1-5:1) to yield the desired product as
a colorless solid. MS (ESI) m/z 520.1 (M+H).sup.+
(b). (S)-(9H-fluoren-9-yl)methyl
2-((S)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate and
(S)-(9H-fluoren-9-yl)methyl
2-((R)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00268##
[0470] Palladium on activated carbon 10% Pd/C (3.2 g) was added to
a solution of (2S)-(9H-fluoren-9-yl)methyl
2-(5-bromo-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (10.3
g, 19.80 mmol) in methanol (150 mL). The mixture was stirred at
room temperature under hydrogen overnight. The mixture was filtered
through a celite pad under reduced pressure, washed with methanol
(3.times.100 mL). The combined filtrate was concentrated in vacuum
to afford the crude product, which was purified by column
chromatography (petroleum ether:ethyl acetate=20:1-10:1-5:1) to
afford the two stereoisomers, (S)-(9H-fluoren-9-yl)methyl
2-((S)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxy-late (1.1 g)
and (S)-(9H-fluoren-9-yl)methyl
2-((R)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxyl-ate (2.1 g)
as white solid. MS (ESI) m/z 442.1 (M+H).sup.+
(c). (S)-(9H-fluoren-9-yl)methyl
2-((S)-8-(trifluoromethylsulfonyloxy)
isochroman-1-yl)pyrrolidine-1-carboxylate
##STR00269##
[0472] Trifluoromethanesulfonic anhydride (1.35 mL, 2.26 mmol) was
added to a solution of (2S)-(9H-fluoren-9-yl)methyl
2-(8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (500 mg, 1.13
mmol), pyridine (890 mg, 11.3 mmol) in dichloromethane (60 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for about
2.about.3 h and ice water (80 mL) was added. The mixture was
extracted with dichloromethane (3.times.100 mL). The organic layers
were combined, washed, dried, filtered, and concentrated in vacuo
to afford the crude product (850 mg) as a light yellow oil, which
was used in the next step without further purification. MS (ESI)
m/z 573.9 (M+H).sup.+.
(d). (S)-1-((S)-pyrrolidin-2-yl)isochroman-8-carbonitrile
(I-37)
##STR00270##
[0474] A mixture of (S)-(9H-fluoren-9-yl)methyl
2-((S)-8-(trifluoromethylsulfonyloxy)
isochroman-1-yl)pyrrolidine-1-carboxylate (850 mg, 1.48 mmol),
dicyanozinc (350 mg, 2.96 mmol),
tetrakis(triphenylphosphine)platinum (350 mg, 0.30 mmol) in
dimethyl sulfoxide (6 mL) was stirred at 120.degree. C. under
microwave reactor for 6.5 h. The mixture was filtered through a
celite pad, washed with methanol (100 mL). The filtrate was
concentrated and water (10 mL) was added. The mixture was extracted
with dichloromethane:methanol=20:1 (3.times.80 mL). The organic
layers were combined, washed with brine (80 mL), dried, filtered,
and concentrated in vacuo to afford the crude product, which was
purified by Pre-HPLC to afford 1-37 (158 mg) as a light yellow oil.
MS (ESI) m/z 228.9 (M+H).sup.+. .sup.1H NMR (HCl salt, 400 MHz,
MeOD): .delta. 7.81 (d, J=7.6 Hz, 1H), 7.60.about.7.49 (m, 2H),
4.69 (d, J=11.6 Hz, 1H), 4.37.about.4.32 (q, J=6.4 Hz, 1H),
3.97.about.3.89 (m, 1H), 3.85.about.3.78 (m, 2H), 3.74.about.3.66
(m, 1H), 3.19.about.3.10 (m, 1H), 2.86.about.2.82 (dd, J.sup.1=3.2
Hz, J.sup.2=13.6 Hz, 1H), 2.57.about.2.52 (m, 1H), 2.38.about.2.31
(m, 1H), 2.14.about.1.98 (m, 2H).
(e). (S)-(9H-fluoren-9-yl)methyl
2-((R)-8-(trifluoromethylsulfonyloxy)
isochroman-1-yl)pyrrolidine-1-carboxylate
##STR00271##
[0476] Trifluoromethanesulfonic anhydride (0.33 mL, 2 mmol) was
added to a solution of (2S)-(9H-fluoren-9-yl)methyl
2-((R)-8-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate (441 mg,
1 mmol), pyridine (790 mg, 10.0 mmol) in dichloromethane (60 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for about
2.about.3 h and ice water (60 mL) was added. The mixture was
extracted with dichloromethane (3.times.80 mL). The combined
organic layers were washed with brine, dried, filtered, and
concentrated in vacuo to afford the crude product (713 mg) as a
light yellow oil, which was used in the next step without further
purification. MS (ESI) m/z 573.9 (M+H).sup.+.
(f). (S)-1-((R)-pyrrolidin-2-yl)isochroman-8-carbonitrile
(I-38)
##STR00272##
[0478] A mixture of (S)-(9H-fluoren-9-yl)methyl
2-((R)-8-(trifluoromethylsulfonyloxy)
isochroman-1-yl)pyrrolidine-1-carboxylate (713 mg, 1.24 mmol),
dicyanozinc (291 mg, 2.48 mmol),
tetrakis(triphenylphosphine)platinum (1.43 g, 1.24 mmol) in
dimethyl sulfoxide (6 mL) was stirred at 120.degree. C. under
microwave reactor for 6.5 h. The mixture was filtered through a
celite pad, washed with methanol (100 mL). The filtrate was
concentrated and water (10 mL) was added. The mixture was extracted
with dichloromethane:methanol=20:1 (3.times.80 mL). The combined
organic layers were washed with brine (80 mL), dried, filtered, and
concentrated in vacuo to afford the crude product, which was
purified by Pre-HPLC, followed by chiral HPLC purification using
column: OZ--H 250*4.6 mm 5 .mu.m; solvent: MeOH (0.1% DEA) to
afford (S)-1-((R)-pyrrolidin-2-yl)isochroman-8-carbonitrile (I-38)
as a light yellow oil (86 mg). MS (ESI) m/z 228.9 (M+H).sup.+.
.sup.1H NMR (HCl, 400 MHz, MeOD): .delta. 8.03 (d, J=8.4 Hz, 1H),
7.71.about.7.60 (m, 2H), 4.93 (d, J=8.4 Hz, 1H), 4.32.about.4.24
(m, 2H), 3.88.about.3.83 (m, 1H), 3.72.about.3.67 (m, 1H),
3.62.about.3.56 (m, 1H), 3.28.about.3.20 (m, 1H), 3.09.about.3.03
(m, 1H), 2.30.about.2.12 (m, 4H).
Example 1.11. Procedure K
Example 1.11.1. (S)-4,4-difluoro-2-((S)-isochroman-1-yl)pyrrolidine
(I-63) and (S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine
(I-64)
##STR00273##
[0480] To a solution of (S)-tert-butyl
4,4-difluoro-2-formylpyrrolidine-1-carboxylate (800 mg, 3.4 mmol))
was added 2-phenylethanol (0.42 g, 3.4 mmol) and trimethylsilyl
trifluoromethanesulfonate (2.27 g, 10.2 mmol). The reaction mixture
was stirred at room temperature for 12 h. Water (100 mL) was added
to the reaction vessel, and the resulting biphasic mixture was
transferred to a separatory funnel. The layers were separated, and
the aqeuous phase was extracted with DCM (2.times.100 mL). The
combined organics were dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo to afford the crude product,
which was purified by PREP-HPLC to afford
(S)-4,4-difluoro-2-((S)-isochroman-1-yl)pyrrolidine (I-63, 200 mg)
and (S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine (I-64, 180
mg).
[0481] (S)-4,4-difluoro-2-((S)-isochroman-1-yl)pyrrolidine (I-63):
ESI: m/z=240 (M+H.sup.+). .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
7.25-7.18 (m, 2H), 7.17-7.10 (m, 2H), 5.01 (s, 1H), 4.25 (ddd,
J=11.1, 5.8, 1.3 Hz, 1H), 3.97-3.86 (m, 1H), 3.81-3.74 (m, 1H),
3.46-3.38 (m, 1H), 3.22-3.00 (m, 2H), 2.64 (d, J=16.2 Hz, 1H),
2.21-2.01 (m, 2H), 1.96-1.84 (m, 1H).
[0482] (S)-4,4-difluoro-2-((R)-isochroman-1-yl)pyrrolidine (I-64):
ESI: m/z=240 (M+H.sup.+). .sup.1HNMR (400 MHz, CDCl.sub.3): .delta.
7.25-7.18 (m, 2H), 7.17-7.10 (m, 2H), 5.01 (s, 1H), 4.25 (ddd,
J=11.1, 5.8, 1.3 Hz, 1H), 3.97-3.86 (m, 1H), 3.81-3.74 (m, 1H),
3.46-3.38 (m, 1H), 3.22-3.00 (m, 2H), 2.64 (d, J=16.2 Hz, 1H),
2.21-2.01 (m, 2H), 1.96-1.84 (m, 1H).
Example 1.12. Procedure L. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.12.1
Example 1.12.1.
(S)-2-((R)-6-fluoroisochroman-1-yl)-1-methylpyrrolidine (I-69)
##STR00274##
[0484] To a solution of
(S)-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-9, 0.13 g, 0.6
mmol) in methanol (10 mL) was added (HCHO).sub.n (0.09 g, 3 mmol)
and NaCNBH.sub.3 (0.15 g, 2.4 mmol) at room temperature. The
mixture was stirred at this temperature overnight. The mixture was
concentrated in vacuo to give the residue, which was purified by
prep-HPLC, followed by neutralization with NaHCO.sub.3 (aq. sat.).
The solution was extraction with DCM (50 mL.times.2). The organic
layers were dried, filtered, and solvent evaporated in vacuo to
give the desired product as yellow oil (80 mg). (ESI) m/z:
236[M+H].sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD) .delta.
7.27.about.7.23 (dd, J.sup.1=5.6 Hz, J.sup.2=8.8 Hz, 1H),
7.04.about.6.98 (m, 2H), 5.33 (s, 1H), 4.34.about.4.30 (m, 1H),
4.18.about.4.13 (m, 1H), 3.87.about.3.80 (m, 1H), 3.73.about.3.67
(m, 1H), 3.28.about.3.21 (q, J=8.8 Hz, 1H), 3.16.about.3.10 (m,
4H), 2.75.about.2.71 (d, J=16.4 Hz), 2.11.about.1.67 (m, 4H).
Example 1.12.2.
(S)-1-ethyl-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine (I-70)
##STR00275##
[0486] (S)-1-ethyl-2-((R)-6-fluoroisochroman-1-yl)pyrrolidine
(I-70) was prepared using a procedure analogous to that described
in Example 1.12.1, but using acetaldehyde in place of (HCHO).sub.n.
ESI) m/z: 250[M+H].sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD)
.delta. 7.27.about.7.24 (dd, J.sup.1=5.6 Hz, J.sup.2=8.4 Hz, 1H),
7.05.about.6.98 (m, 2H), 5.31 (s, 1H), 4.37.about.4.30 (m, 1H),
4.23.about.4.18 (m, 1H), 3.86.about.3.59 (m, 3H), 3.30.about.3.08
(m, 3H), 2.75.about.2.71 (d, J=16.4 Hz, 1H), 2.08.about.1.94 (m,
2H), 1.87.about.1.75 (m, 2H), 1.49.about.1.43 (t, 3H).
Example 1.13. Procedure M. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.13.1
Example 1.13.1.
(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-118) and
(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-119)
##STR00276##
[0487] (a).
(2-bromo-5-fluorobenzyloxy)(tert-butyl)dimethylsilane
##STR00277##
[0489] To a solution of (2-bromo-5-fluorophenyl)methanol (25.6 g,
124.86 mmol) in dichloromethane (750 mL) was added 1H-imidazole (17
g, 249.72 mmol) and tert-butylchlorodimethylsilane (37.64 g, 249.72
mmol). The reaction mixture was stirred at room temperature for 16
h and was then washed with brine (3.times.200 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. The crude
product was purified by silica gel column chromatography (eluted
with petroleum ether) to give the product as a colorless oil (36.2
g).
(b).
(2S)-tert-butyl2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorop-
henyl)(hydroxy) methyl)pyrrolidine-1-carboxylate
##STR00278##
[0491] To a solution of
((2-bromo-5-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (3.19 g, 10
mmol) in toluene (25 mL) was added dropwise tert-butyllithium (0.96
g, 15 mmol) at -78.degree. C. The reaction was stirred at 0.degree.
C. for 1 h. (S)-tert-Butyl 2-formylpyrrolidine-1-carboxylate (2.99
g, 15 mmol)) in toluene (10 mL) was added dropwise. The reaction
mixture was stirred at -78.degree. C. for 3 h and poured into
iced-water. The organic phase was separated and washed with brine
(3.times.70 mL), dried over sodium sulfate and evaporated in vacuo
to give the crude, which was purified by column chromatography
(PE:EtOAc=15:1) to give the tittle compound (4 g) as colorless
oil.
(c).
(S)-tert-butyl2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)methyl)py-
rrolidine-1-carboxylate
##STR00279##
[0493] To a solution of (2S)-tert-butyl
2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluorophenyl)(hydroxy)meth-
yl)pyrrolidine-1-carboxylate (5.5 g, 11.4 mmol) in tetrahydrofuran
(100 mL) was added tetrabutylammonium fluoride (2.98 g, 11.4 mmol).
The reaction mixture was stirred at ambient temperature for 16 h
and then concentrated to give a residue, which was diluted with
ethyl acetate (200 mL), neutralized with saturated sodium
bicarbonate solution, washed with brine (4.times.50 mL), dried over
sodium sulfate and concentrated in vacuo. The crude product was
purified by silica gel column chromatography (eluted with petroleum
ether:ethyl acetate=5:1) to give the title compound as a colorless
oil (3.3 g), MS (ESI): m/z 326 [M+H].sup.+.
(d). (S)-tert-butyl
2-((4-fluoro-2-((methylsulfonyloxy)methyl)phenyl)(hydroxy)
methyl)pyrrolidine-1-carboxylate
##STR00280##
[0495] To a solution of (2S)-tert-butyl
2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)
methyl)pyrrolidine-1-carboxylate (3 g, 7.38 mmol) in ethyl acetate
(150 mL) was added methanesulfonyl chloride (0.8 g, 7.01 mmol). The
reaction mixture was stirred at room temperature for 30 min and
then washed with water (3.times.100 mL). The organic layer was
dried over sodium sulfate, filtered and concentrated to give the
crude product (3.4 g), which was used in the next step without
further purification.
(e). (S)-tert-butyl2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)
pyrrolidine-1-carboxylate
##STR00281##
[0497] To a solution of (2S)-tert-butyl
2-((4-fluoro-2-(((methylsulfonyl)oxy)methyl)phenyl)
(hydroxy)methyl)pyrrolidine-1-carboxylate (3 g, 7.44 mmol) in
tetrahydrofuran (150 mL) was added potassium 2-methylpropan-2-olate
(2.5 g, 22.32 mmol). The reaction mixture was stirred at room
temperature for 1 h. Upon completion, water (100 mL) and ethyl
acetate (100 mL) were added to the mixture. The organic layer was
separated, washed with water (3.times.80 mL), dried over sodium
sulfate, filtered and then concentrated to give the residue. The
residue was purified by silica gel column chromatography (eluted
with petroleum ether:ethyl acetate=20:1) to give the title compound
(1.9 g) as colorless oil.
(f). (S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-118) and
(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-119)
##STR00282##
[0499] To a solution of (2S)-tert-butyl
2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)
pyrrolidine-1-carboxylate (100 mg, 0.33 mmol) in methanol (10 mL)
was added HCl/1,4-dioxane (0.58 g, 16 mmol). The reaction mixture
was stirred at room temperature for 1 h to yield the a mixture of
two diastereoisomers, which was separated by HPLC to give
(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-118) and
(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-119).
[0500]
(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-118): ESI: m/z=208 (M+H).sup.+. .sup.1HNMR (HCl salt, 400 MHz,
MeOD): .delta. 7.39-7.43 (m, 1H), 7.11-7.14 (m, 2H), 5.38 (s, 1H),
5.08-5.26 (m, 2H), 3.90-3.95 (m, 1H), 3.29-3.33 (m, 1H), 2.01-2.33
(m, 6H).
[0501]
(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-119): ESI: m/z=208 (M+H).sup.+. .sup.1HNMR (HCl salt, 400 MHz,
MeOD): .delta. 7.35-7.38 (m, 1H), 7.10-7.14 (m, 2H), 5.63 (s, 1H),
5.15-5.26 (m, 2H), 4.12-4.16 (m, 1H), 3.34-3.38 (m, 1H), 1.95-2.12
(m, 2H), 1.62-1.79 (m, 4H).
Example 1.13.2.
(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-120) and
(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(121)
##STR00283##
[0503]
(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-120) and
(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-121) were prepared using a procedure analogous to that described
in Example 1.13.1, but using (R)-tert-butyl
2-formylpyrrolidine-1-carboxylate in place of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate.
[0504]
(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-120): ESI: m/z=208 (M+H).sup.+. .sup.1HNMR (400 MHz, MeOD):
.delta. 7.36-7.40 (m, 1H), 7.11-7.13 (m, 2H), 5.63 (s, 1H),
5.15-5.25 (m, 2H), 4.14-4.18 (m, 1H), 3.33-3.38 (m, 1H), 1.95-2.10
(m, 2H), 1.62-1.81 (m, 4H).
[0505]
(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-121): ESI: m/z=208 (M+H).sup.+. .sup.1HNMR (400 MHz, MeOD):
.delta. 7.40-7.43 (m, 1H), 7.10-7.14 (m, 2H), 5.39 (s, 1H),
5.08-5.37 (m, 2H), 3.90-3.96 (m, 1H), 3.28-3.33 (m, 1H), 2.08-2.35
(m, 6H).
Example 1.14. Procedure N. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.14.1
Example 1.14.1.
(S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-126) and
(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-133)
##STR00284## ##STR00285##
[0506] (a). 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran
##STR00286##
[0508] To a solution of (2-bromo-5-fluorophenyl)methanol (40 g, 195
mmol) in dichloromethane (200 ml) at 0.degree. C. was added
4-methylbenzenesulfonic acid (1 g, 5.85 mmol) and
3,4-dihydro-2H-pyran (24.5 g, 292 mmol). The mixture was stirred at
room temperature for 6 h. Saturated aqueous NaHCO.sub.3 (300 mL)
was added to the reaction vessel, and the resulting biphasic
mixture was transferred to a separatory funnel. The layers were
separated, and the organic phase was washed with saturated aqueous
NaCl (2.times.100 mL). The combined organics were dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
resulting oil was purified by flash column chromatography with an
isocratic elution of EtOAc (5%) and petroleum ether (95%) to
provide 2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (41.9 g,
145 mmol) as a colorless oil.
(b).
(2S)-tert-butyl-2-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)
benzoyl)azetidine-1-carboxylate
##STR00287##
[0510] To a solution of
2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (11.5 g, 40
mmol) in THF (40 ml) was added magnesium (1.94 g, 80 mmol) and a
grain of iodine. The mixture was stirred at reflux for 2 h. Upon
completion,
(S)-tert-butyl-2-(methoxy-(methyl)carbamoyl)azetidine-1-carboxylate
(4.88 g, 20 mmol) was added at 0.degree. C. The reaction mixture
was stirred at this temperature for 3 h. Water (100 mL) was added
to the reaction vessel, and the resulting biphasic mixture was
transferred to a separatory funnel. The organic layer was separated
and the aqueous layer was extraction with EtOAc (2.times.100 mL).
The combined organics were dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo to afford the crude product,
which was purified by flash column chromatography with an isocratic
elution of EtOAc (20%) and petroleum ether (80%) to afford the
title compound (6 g) as a colorless oil.
(c).
(2S)-tert-butyl-2-((4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)
phenyl)-(hydroxy)methyl)azetidine-1-carboxylate
##STR00288##
[0512] To a solution of (2S)-tert-butyl
2-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl) oxy)methyl)
benzoyl)azetidine-1-carboxylate (6 g, 15.2 mmol) in MeOH (30 ml)
was added NaBH.sub.4 (0.575 g, 15.2 mmol). The mixture was stirred
at room temperature for 3 h. Water (100 mL) was added to the
reaction vessel, and the resulting biphasic mixture was transferred
to a separatory funnel and extracted with EtOAc (2.times.200 mL).
The combined organics were dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The resulting oil was purified
by reverse phase HPLC to provide the title compound (5.2 g) as a
white solid.
(d). (2S)-tert-butyl 2-((4-fluoro-2-(hydroxymethyl)phenyl)
(hydroxy) methyl)azetidine-1-carboxylate
##STR00289##
[0514] To a solution of (2S)-tert-butyl
2-((4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)
phenyl)(hydroxy)methyl)azetidine-1-carboxylate (3 g, 7.58 mmol) in
MeOH (50 ml) was added 4-methylbenzenesulfonic acid (130 mg, 0.758
mmol). The mixture was stirred at room temperature for 3 h.
Saturated aqueous NaHCO.sub.3 (60 mL) was added to the reaction
vessel, and the resulting biphasic mixture was transferred to a
separatory funnel and extracted with DCM (2.times.50 mL). The
combined organics were dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. Crude product was used in next
step without further purification.
(e). (2S)-tert-butyl
2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine-1-carboxylate
##STR00290##
[0516] To a solution of ((2S)-tert-butyl
2-((4-fluoro-2-(hydroxymethyl)phenyl)(hydroxy)
methyl)azetidine-1-carboxylate (8 g, 25.7 mmol) in DCM (30 ml) was
added MsCl (5 g, 30.1 mmol), Et.sub.3N (0.35 g, 2.57 mmol). The
mixture was stirred at room temperature for 3 h. Solvent was
removed and to the residue t-BuOK (3.37 g, 30.1 mmol) in THF (30
mL) was added. The mixture was stirred at room temperature for 5 h
and then transferred to a separatory funnel and extracted with DCM
(2.times.200 mL). The combined organics were dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The resulting
oil was purified by flash column chromatography with an isocratic
elution of EtOAc (10%) and petroleum ether (90%) to provide the
title compound (5.6 g) as a white solid. ESI: m/z=605 (M+1)
(f). ((S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-126) and
(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-133)
##STR00291##
[0518] To a solution of (2S)-tert-butyl
2-(5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine-1-carboxylate
(5.6 g, 19.3 mmol) in DCM (30 ml) was added TFA (2.1 g, 21.2 mmol).
The mixture was stirred at 0.degree. C. for 3 h. Water (50 mL) was
added to the reaction vessel, and the mixture was adjusted to pH=9
with solid NaHCO.sub.3. The resulting biphasic mixture was
transferred to a separatory funnel and extracted with DCM
(3.times.100 mL). The combined organics were dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to give crude,
which was purified by PREP-HPLC to give
((S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-126) (200 mg) and
(S)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-133)
as oil. ESI: m/z=194 (M+H.sup.+).
[0519] ((S)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-126): .sup.1H NMR (400 MHz, MeOD) .delta. 7.21 (dd, J=8.3, 4.8
Hz, 1H), 7.07-6.89 (m, 2H), 5.29 (s, 1H), 5.16 (dd, J=12.7, 2.1 Hz,
1H), 5.01 (d, J=12.8 Hz, 1H), 4.75-4.72 (m, 1H), 3.94-3.91 (m, 1H),
3.75-3.68 (m, 1H), 2.51-2.43 (m, 1H), 2.58-2.40 (m, 1H).
Example 1.14.2.
(R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-127)
and (R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-128)
##STR00292##
[0521] (R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-127) and
(R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine (I-128)
were prepared using a procedure analogous to that described in
Example 1.14.1, but using (R)-tert-butyl
2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate in place of
(S)-tert-butyl
2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate.
[0522] (R)-2-((S)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-127): ESI: m/z=194 (M+H.sup.+). .sup.1H NMR (400 MHz, MeOD)
.delta. 7.25 (dd, J=8.3, 4.8 Hz, 1H), 7.09-6.96 (m, 2H), 5.33 (s,
1H), 5.20 (dd, J=12.7, 1.9 Hz, 1H), 5.03 (dd, J=12.7, 1.1 Hz, 1H),
4.90-4.81 (m, 1H), 4.01 (dd, J=18.9, 9.3 Hz, 1H), 3.78 (td, J=10.1,
5.5 Hz, 1H), 3.23 (dt, J=3.3, 1.6 Hz, 1H), 2.77 (ddt, J=11.9, 9.9,
8.6 Hz, 1H), 2.59-2.47 (m, 1H), 1.92-1.91 (m, 1H).
[0523] (R)-2-((R)-5-fluoro-1,3-dihydroisobenzofuran-1-yl)azetidine
(I-128): ESI: m/z=194 (M+H.sup.+). .sup.1H NMR (400 MHz, MeOD)
.delta. 7.25 (dd, J=8.3, 4.8 Hz, 1H), 7.09-6.96 (m, 2H), 5.33 (s,
1H), 5.20 (dd, J=12.7, 1.9 Hz, 1H), 5.03 (dd, J=12.7, 1.1 Hz, 1H),
6.84-4.36 (m, 8H), 4.90-4.81 (m, 1H), 4.01 (dd, J=18.9, 9.3 Hz,
1H), 5.34-2.59 (m, 1H), 3.78 (td, J=10.1, 5.5 Hz, 1H), 3.23 (dt,
J=3.3, 1.6 Hz, 1H), 2.77 (ddt, J=11.9, 9.9, 8.6 Hz, 1H), 2.59-2.47
(m, 1H), 1.92-1.91 (m, 1H), 1.08-0.90 (m, 1H).
Example 1.15. Procedure O. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.15.1
Example 1.15.1.
(R)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-125)
##STR00293##
[0524] (a). 2-(2-bromo-5-fluorobenzyloxy)tetrahydro-2H-pyran
##STR00294##
[0526] To a solution of (2-bromo-5-fluorophenyl)methanol (20 g,
97.5 mmol) in CH.sub.2Cl.sub.2 (100 ml) was added
4-methylbenzenesulfonic acid (0.502 g, 2.92 mmol) and
3,4-dihydro-2H-pyran (12.2 g, 146 mmol) at 0.degree. C. The
reaction was stirred at ambient temperature for 2 h. Upon
completion, saturated aqueous NaHCO.sub.3 (100 mL) was added to the
reaction vessel, and the resulting biphasic mixture was transferred
to a separatory funnel. The layers were separated, and the organic
phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The resulting oil was purified by flash
column chromatography with an isocratic elution of petroleum ether
(100%) and EtOAc (5%) to provide the title compound (22.9 g) as a
colorless oil.
(b). (2R)-tert-butyl
2-(1-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)
phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate
##STR00295##
[0528] To a solution of
2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (8.67 g, 30
mmol) in THF (40 ml) was added magnesium (1.45 g, 60 mmol) and one
grain of iodine. The reaction was stirred at reflux for 2 h. Upon
completion, (R)-tert-butyl 2-acetylpyrrolidine-1-carboxylate (6.12
g, 28.7 mmol) was added at 0.degree. C. The mixture was stirred at
this temperature for 3 h. Upon completion, water (50 mL) was added
to the reaction vessel, and the resulting biphasic mixture was
transferred to a separatory funnel and extracted with EtOAc
(2.times.50 mL). The combined organics were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford an
oil, which was purified by flash column chromatography with an
isocratic elution of EtOAc (10%) and petroleum ether (90%) to
provide the title compound (3.49 g) as a colorless oil.
(c). (2R)-tert-butyl
2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carb-
oxylate
##STR00296##
[0530] To a solution of (2R)-tert-butyl
2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)
methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (4 g, 9.44
mmol) in MeOH (100 mL) was added 4-methylbenzenesulfonic acid (323
mg, 1.88 mmol). The mixture was stirred at ambient temperature for
6 h. Upon completion, the solvent was evaporated in vacuo to afford
an oil. Water (100 mL) was added to the reaction vessel, and the
resulting biphasic mixture was transferred to a separatory funnel
and extracted with DCM (2.times.100 mL). The combined organics were
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to afford a white solid, which was used in the next step
without further purification. ESI: m/z=340 (M+H.sup.+).
(d). (R)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)
pyrrolidine (I-125)
##STR00297##
[0532] To a solution of (2R)-tert-butyl
2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carb-
oxylate (1.2 g, 3.53 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added
trimethylsilyl trifluoromethanesulfonate (2.33 g, 10.5 mmol). The
mixture was stirred at ambient temperature for 3 h. Water (60 mL)
was added to the reaction vessel, and the resulting biphasic
mixture was transferred to a separatory funnel and extracted with
DCM (2.times.60 mL). The combined organics were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
resulting oil was purified by reverse phase HPLC to provide 1-125
(497 mg). ESI: m/z=222 (M+H+). .sup.1H NMR (400 MHz, MeOD) .delta.
7.46-7.37 (m, 1H), 7.20-7.07 (m, 2H), 5.22 (d, J=13.0 Hz, 1H), 5.11
(d, J=13.0 Hz, 1H), 4.14 (dd, J=12.1, 4.7 Hz, 1H), 3.28 (t, J=6.9
Hz, 2H), 2.43-2.27 (m, 1H), 2.24-2.01 (m, 3H), 1.51 (s, 3H).
Example 1.15.2.
(S)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-122)
##STR00298##
[0534]
(S)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolid-
ine (I-122) was prepared using a procedure analogous to that
described in Example 1.15.1, but using (S)-tert-butyl
2-acetylpyrrolidine-1-carboxylate in place of (R)-tert-butyl
2-acetylpyrrolidine-1-carboxylate. ESI: m/z=222 (M+H.sup.+).
.sup.1H NMR (400 MHz, MeOD) .delta. 7.32 (dd, J=8.3, 4.8 Hz, 1H),
7.18-7.02 (m, 2H), 5.26-5.07 (m, 2H), 4.09-3.96 (m, 1H), 3.40-3.33
(m, 2H), 2.09-1.91 (m, 2H), 1.71-1.67 m, 1H), 1.65-1.52 (m,
4H).
Example 1.16. Procedure P. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.16.1
Example 1.16.1.
((R)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-124)
##STR00299##
[0535] (a). (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic
anhydride
##STR00300##
[0537] To a solution of
(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (20 g,
92.9 mmol) in CH.sub.2Cl.sub.2 (100 ml) was added
N,N'-methanediylidenedicyclohexanamine (9.57 g, 46.4 mmol). The
reaction was stirred at room temperature for 24 h. Upon completion,
the white solid was filtered off. The filtrate was evaporated in
vacuo to give an oil. After addition of ether (100 mL), the solid
precipitation was filtered off. The filtrate was evaporated in
vacuo to give the crude product, which was used in next step
without further purification.
(b). (2R)-tert-butyl
2-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)
benzoyl)-pyrrolidine-1-carboxylate
##STR00301##
[0539] To a solution of
2-((2-bromo-5-fluorobenzyl)oxy)tetrahydro-2H-pyran (7 g, 24.2 mmol)
in THF (20 ml) was added magnesium (1.17 g, 48.4 mmol). The mixture
was stirred at reflux for 2 h. Upon completion,
(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)magnesium
bromide (7.58 g, 24.2 mmol) was added. The reaction was stirred at
this temperature for 3 h. Upon completion, water (50 mL) was added
to the reaction vessel, and the resulting biphasic mixture was
transferred to a separatory funnel and extracted with EtOAc
(2.times.50 mL). The combined organics were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The resulting
oil was purified by flash column chromatography with an isocratic
elution of EtOAc (10%) and petroleum ether (90%) to provide the
title compound (5 g) as a colorless oil.
(c). (2R)-tert-butyl
2-(1-(4-fluoro-2-((tetrahydro-2H-pyran-2-yloxy)methyl)
phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate
##STR00302##
[0541] To a solution of (2R)-tert-butyl
2-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)
benzoyl)pyrrolidine-1-carboxylate (2.0 g, 4.90 mmol) in THF (20 ml)
was added methylmagnesium bromide (4.89 mL, 14.7 mmol). The mixture
was stirred at ambient temperature for 3 h. Saturated aqueous
NH.sub.4Cl (100 mL) was added to the reaction vessel, and the
resulting biphasic mixture was transferred to a separatory funnel,
and extracted with EtOAc (2.times.100 mL). The combined organics
were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give the crude product, which was used in
next step without further purification. ESI: m/z=446
(M+Na.sup.+).
(d). Preparation of (2R)-tert-butyl
2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxyl-ethyl)pyrrolidine-1-ca-
rboxylate
##STR00303##
[0543] To a solution of (2R)-tert-butyl
2-(1-(4-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)
methyl)phenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (2.1 g,
4.95 mmol) in MeOH (80 ml) was added 4-methylbenzenesulfonic acid
(85.2 mg, 495 .mu.mol). The mixture was stirred at room temperature
for 3 h, and then solvent evaporated in vacuo to give an oil.
Saturated aqueous NaHCO.sub.3 (10 mL) was then added to the
reaction vessel, and the resulting biphasic mixture was transferred
to a separatory funnel and extracted with EtOAc (2.times.100 mL).
The combined organics were dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The resulting oil was purified
by flash column chromatography with an isocratic elution of EtOAc
(20%) and petroleum ether (80%) to provide the title compound (1.49
g) as a colorless oil. ESI: m/z=340 (M+H.sup.+).
(e). (R)-tert-butyl
2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine-1-carb-
oxylate
##STR00304##
[0545] To a solution of (2R)-tert-butyl
2-(1-(4-fluoro-2-(hydroxymethyl)phenyl)-1-hydroxy
ethyl)pyrrolidine-1-carboxylate (1.6 g, 4.71 mmol) in
CH.sub.2Cl.sub.2 (30 ml) at 0.degree. C. was added triethylamine
(2.37 g, 23.5 mmol) and then followed by methanesulfonyl chloride
(1.61 g, 14.1 mmol). The mixture was stirred at ambient temperature
for 3 h. Water (100 mL) was added to the reaction vessel, and the
resulting biphasic mixture was transferred to a separatory funnel.
The layers were separated, and the organic phase was washed with
saturated aqueous NaCl (2.times.50 mL). The combined organics were
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The resulting oil was purified by flash column
chromatography with an isocratic elution of EtOAc (10%) and
petroleum ether (90%) to provide the title compound (1.09 g) as a
white solid.
(f). (R)-2-((R)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)
pyrrolidine (I-124)
##STR00305##
[0547] To a solution of (2R)-tert-butyl
2-(5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine-1-carboxyl-
ate (500 mg, 1.55 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added
2,2,2-trifluoroacetic acid (1.76 g, 15.5 mmol). The reaction was
stirred at room temperature for 2 h. Upon completion, the reaction
mixture was evaporated in vacuo to afford the crude product. The
resulting oil was purified by reverse phase HPLC to provide 1-124
(200 mg) as a colorless oil. ESI: m/z=222 (M+1). .sup.1H NMR (500
MHz, MeOD): .delta. 7.25 (dd, J=8.3, 4.8 Hz, 1H), 7.05 (dd, J=15.0,
8.6 Hz, 2H), 5.18-5.03 (m, 2H), 3.58-3.41 (m, 1H), 3.14-3.09 (m,
1H), 2.96-2.91 (m, 1H), 1.83-1.74 (m, 2H), 1.62-1.49 (m, 4H),
1.45-1.37 (1H).
Example 1.16.2.
(S)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolidine
(I-123)
##STR00306##
[0549]
(S)-2-((S)-5-fluoro-1-methyl-1,3-dihydroisobenzofuran-1-yl)pyrrolid-
ine (I-123) was prepared using a procedure analogous to that
described in Example 1.16.1, but using
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid in place
of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. ESI:
m/z=222 (M+H.sup.+). .sup.1H NMR (400 MHz, MeOD) .delta. 7.22 (dd,
J=8.2, 4.9 Hz, 1H), 7.11-6.90 (m, 2H), 5.19-5.00 (m, 2H), 3.13-2.94
(m, 1H), 2.81-2.77 (m, 1H), 1.83-1.64 (m, 2H), 1.53 (s, 3H),
1.49-1.41 (m, 1H), 1.39-1.29 (m, 1H).
Example 1.17. Procedure Q
Example 1.17.1.
2-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57) and
2-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-58)
[0550] MeOH (0.1% DEA) to yield
(S)-2-((S)-6-bromoisochroman-1-yl)pyrrolidine (6.12 g) and
(S)-2-((R)-6-bromoisochroman-1-yl)pyrrolidine (6.13 g). MS (ESI)
m/z 284 [M+H].sup.+.
(b). (S)-tert-butyl
2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00307##
[0552] To a solution of
(S)-2-((S)-6-bromoisochroman-1-yl)pyrrolidine (6 g, 21.2 mmol) in
NaOH/Water (30 ml) at room temperature was added ditertbutyl
dicarbonate (5.54 g, 25.4 mmol). The reaction was stirred at this
temperature for 2 h. Upon completion, the resulting biphasic
mixture was transferred to a separatory funnel. The layers were
separated and the aqeuous phase was washed with DCM (2.times.50
mL). The combined organics were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. MS (ESI) m/z:
384 [M+H].sup.+.
(c). (S)-tert-butyl 2-((S)-6-(pyridin-2-yl)isochroman-1-yl)
pyrrolidine-1-carboxylate
##STR00308##
[0554] To a solution of (S)-tert-butyl
2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (2 g, 5.23
mmol) in toluene (50 ml) was added 2-(tributylstannyl)pyridine (2.3
g, 6.27 mmol) and palladium-triphenylphosphane (1:4) (6.04 mg,
0.523 mmol). The mixture was stirred at 110.degree. C. for 6 h.
Upon completion, water (5 mL) was added to the reaction vessel and
the resulting biphasic mixture was transferred to a separatory
funnel. The layers were separated and the aqueous phase was washed
with EtOAc (2.times.50 mL). The combined organics were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
resulting oil was purified by flash column chromatography
(petroleum ether/EtOAc from 20:1 to 5:1) to provide the title
product (1.36 g) as a colorless oil. MS (ESI) m/z: 381
[M+H].sup.+.
(d). 2-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine
(I-57)
##STR00309##
[0556] To a solution of (S)-tert-butyl
2-((S)-6-(pyridin-2-yl)isochroman-1-yl)pyrrolidine-1-carboxylate
(500 mg, 1.31 mmol) in dichloromethane (50 mL), trifluoroacetic
acid (224 mg, 1.97 mmol) was added dropwise at 0.degree. C. After
addition, the mixture was stirred at this temperature for about 3
h. After workup,
2-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine (I-57) was
obtained. MS (ESI) m/z: 281 [M+H].sup.+. .sup.1H NMR (HCl salt, 400
MHz, MeOD): .delta. 8.89 (d, J=5.8 Hz, 1H), 8.78-8.68 (m, 1H), 8.46
(d, J=8.2 Hz, 1H), 8.10 (t, J=6.8 Hz, 1H), 7.97-7.86 (m, 2H), 7.70
(d, J=8.2 Hz, 1H), 5.17 (d, J=2.2 Hz, 1H), 4.91 (s, 11H), 4.45-4.33
(m, 2H), 3.92 (td, J=11.3, 3.3 Hz, 1H), 3.66-3.14 (m, 6H), 2.92 (d,
J=16.6 Hz, 1H), 2.35 (dt, J=16.8, 6.9 Hz, 2H), 2.15 (ddd, J=21.1,
13.0, 6.0 Hz, 2H).
(e). 2-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)pyridine
(I-58)
##STR00310##
[0558] I-58 was synthesized using the same method as Compound I-57
as described above. (ESI) m/z: 281 [M+H].sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.72-8.65 (m, 1H), 7.82-7.68 (m, 3H),
7.31-7.19 (m, 3H), 5.04 (d, J=2.4 Hz, 1H), 4.23 (ddd, J=11.1, 5.7,
1.6 Hz, 1H), 3.77 (td, J=11.3, 3.0 Hz, 1H), 3.69-3.60 (m, 1H), 3.48
(s, 1H), 3.20-2.95 (m, 2H), 2.85 (dt, J=11.1, 7.6 Hz, 1H), 2.73 (d,
J=16.2 Hz, 1H), 2.01 (s, 4H), 1.70 (dd, J=14.3, 7.0 Hz, 2H), 1.49
(ddd, J=15.0, 7.7, 2.7 Hz, 2H).
Example 1.18. Procedure R. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.18.1
Example 1.18.1.
5-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-55)
##STR00311##
[0559] (a). (S)-tert-butyl
2-((S)-6-acetylisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00312##
[0561] To a solution of (S)-tert-butyl
2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate (1.5 g,
3.32 mmol) in THF (25 mL) was added n-BuLi (1.6 N in hexane) (3.1
mL) at -78.degree. C. under nitrogen. After the mixture was stirred
at this temperature for 1 h, a solution of
N-methoxy-N-methylacetamide (444 mg, 4.31 mmol) in THF (2 mL) was
added. The mixture was allowed to warm to room temperature and
stirred for another 1 h. The mixture was quenched with water (100
mL), extracted with EtOAc (70 mL.times.2), dried and concentrated
in vacuo to give the crude, which was purified by prep-TLC, eluted
with PE:EtOAc=5:1 to yield the title compound.
(b). (5)-tert-butyl 2-((S)-6-((E)-3-(dimethylamino)acryloyl)
isochroman-1-yl)pyrrolidine-1-carboxylate
##STR00313##
[0563] A solution of (S)-tert-butyl
2-((S)-6-acetylisochroman-1-yl)pyrrolidine-1-carboxylate (520 mg,
1.50 mmol) and DMF-DMA (0.535 g, 4.5 mmol) was heated to
100.degree. C. with stirring overnight. The mixture was
concentrated in vacuo to give the crude, which was used directly in
the next step. (ESI) m/z: 401[M+H].sup.+.
(c). (5)-tert-butyl 2-((S)-6-(isoxazol-5-yl)isochroman-1-yl)
pyrrolidine-1-carboxylate
##STR00314##
[0565] To a solution of (S)-tert-butyl 2-((S)-6-((E)-3-(dimethyl
amino)acryloyl) isochroman-1-yl)pyrrolidine-1-carboxylate (720 mg,
0.876 mmol) in MeOH (30 mL) was added hydroxylamine hydrochloride
(182 mg, 2.62 mmol). The mixture was heated to 70.degree. C. with
stirring for 3 h. The mixture was concentrated in vacuo to give the
crude, which was diluted with water (100 mL), extracted with DCM
(70 mL.times.2). The organic phase was dried, filtered and
concentrated in vacuo to give the crude product. (ESI) m/z:
315[M-56+H].sup.+.
(d). 5-((S)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole
(I-55)
##STR00315##
[0567] To a solution of (S)-tert-butyl
2-((S)-6-(isoxazol-5-yl)isochroman-1-yl) pyrrolidine-1-carboxylate
(420 mg, 0.812 mmol) in DCM (5 mL) was added 3N HCl/dioxane (6 mL)
at room temperature. The mixture was stirred at room temperature
for 3 h and then concentrated in vacuo to give the crude, which was
purified by prep. HPLC to give a residue. The residue was
freeze-dried to give the TFA salt, which was basified with sat.
NaHCO.sub.3, extracted with DCM/MeOH=20:1 (50 mL.times.2), dried
and concentrated in vacuo to yield 1-55. (ESI) m/z: 271[M+H].sup.+.
.sup.1HNMR(HCl salt, 400 MHz, MeOD): .delta. 8.46 (s, 1H),
7.81-7.79 (d, J=8.0 Hz, 1H), 7.75 (s, 1H), 7.51-7.49 (d, J=8.0 Hz,
1H), 6.85 (s, 1H), 5.09 (s, 1H), 4.37-4.28 (m, 2H), 3.91-3.85 (m,
1H), 3.30-3.23 (m, 3H), 2.84-2.80 (d, J=16.4 Hz, 1H), 2.34-2.25 (m,
2H), 2.20-2.04 (m, 2H).
Example 1.18.2.
5-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole (I-56)
##STR00316##
[0569] 5-((R)-1-((S)-pyrrolidin-2-yl)isochroman-6-yl)isoxazole
(I-56) was prepared using a procedure analogous to that described
in Example 1.18.1, but using (S)-tert-butyl
2-((R)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate in place of
(S)-tert-butyl
2-((S)-6-bromoisochroman-1-yl)pyrrolidine-1-carboxylate. (ESI) m/z:
271[M+H].sup.+. .sup.1HNMR (400 MHz, MeOD): .delta. 8.46-8.45 (d,
J=2.0 Hz, 1H), 7.76-7.74 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.41-7.39
(d, J=7.6 Hz, 1H), 6.84-6.83 (d, J=1.6 Hz, 1H), 5.28 (s, 1H),
4.46-4.41 (m, 1H), 4.37-4.33 (m, 1H), 3.88-3.81 (m, 1H), 3.40-3.37
(m, 2H), 3.21-3.13 (m, 1H), 2.83-2.79 (d, J=16.4 Hz, 1H), 2.09-1.95
(m, 2H), 1.83-1.77 (m, 2H).
Example 1.19. Procedure S
Example 1.19.1. 3-(6-fluoroisochroman-1-yl)pyrrolidine (I-129,
I-130, I-131, I-132)
##STR00317##
[0571] To a mixture of tert-butyl 3-formylpyrrolidine-1-carboxylate
(550 mg, 2.76 mmol) and 2-(3-fluorophenyl)ethanol (386 mg, 2.76
mmol) was added trifluoromethanesulfonic acid (1.24 g, 8.28 mmol)
at 0.degree. C. The mixture was stirred at room temperature for
another 2 h. Upon completion, the mixture was quenched with sat.
NaHCO.sub.3 (100 mL) till pH>7, extracted with DCM (80
mL.times.2). The organic layers were dried and concentrated to give
the crude, which was purified by prep-HPLC to give the desired
product as TFA salt, which was basified with sat. NaHCO.sub.3 (30
mL) again, extracted with DCM (2.times.20 mL), dried and
concentrated in vacuo to yield the mixture of 4 stereoisomers.
(ESI) m/z: 222[M+H].sup.+. .sup.1HNMR (400 MHz, CDCl.sub.3):
.delta. 7.11-7.06 (m, 1H), 6.92-6.87 (m, 1H), 6.84-6.82 (m, 1H),
4.80-4.78 (d, J=6.8 Hz, 1H), 4.21-4.16 (m, 1H), 3.87 (s, 1H),
3.72-3.64 (m, 1H), 3.25-2.76 (m, 6H), 2.63-2.58 (d, J=16.8 Hz, 1H),
2.07-1.99 (m, 1H), 1.66-1.46 (m, 1H).
Example 1.20. Procedure T
Example 1.20.1.
(S)-2-((R)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)-pyrrolidine
(I-141) and
(S)-2-((S)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)-pyrrolidine
(I-142)
##STR00318## ##STR00319##
[0572] (a).
4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)benzo[d][1-
,3]dioxole-5-carboxylic acid
##STR00320##
[0574] To a solution of benzo[d][1,3]dioxole-5-carboxylic acid
(3.32 g, 20 mmol) in tetrahydrofuran (30 mL) at -78.degree. C. was
added n-butyllithium in n-hexane (2.5 M, 17.5 mL, 44.0 mmol)
dropwise over a period of 15 min. The reaction temperature was
allowed to rise to -20.degree. C. slowly. The mixture was stirred
at this temperature for 1 h and cooled to -78.degree. C. again. To
the mixture was added a solution of (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate (5.97 g, 15 mmol) in
tetrahydrofuran (5 mL) dropwise over a period of 5 min. The
reaction mixture was stirred for 6 h and then quenched with water
(100 mL) at -78.degree. C. The mixture was washed with ethyl
acetate (3.times.50 mL) and the combined organic phase was
extracted with water (50 mL). The combined aqueous layers were
adjusted to pH=5 carefully with 0.5 M HCl solution at 0.degree. C.,
extracted with dichloromethane (3.times.50 mL), dried over sodium
sulfate and concentrated in vacuo to give crude
4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)
(hydroxy)methyl)benzo[d][1,3]dioxole-5-carboxylic acid as a yellow
oil (5.5 g, purity ca. 50%); MS (ESI): m/z=366 [M+H].sup.+.
(b).
(2S)-tert-butyl2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran--
8-yl)pyrroledine-1-carboxylate
##STR00321##
[0576] To a solution of
4-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)(hydroxy)methyl)
benzo[d][1,3]dioxole-5-carboxylic acid (5.5 g, Purity: 50%, 7.52
mmol) in methanol (100 mL) was added 4 M HCl/1,4-dioxane (2.74 g,
75.2 mmol). The reaction mixture was stirred at room temperature
for 16 h and concentrated to give a residue. To the residue was
added water (30 mL), tetrahydrofuran (30 mL), sodium bicarbonate
(2.48 g, 29.6 mmol), and di-tert-butyl dicarbonate (3.23 g, 14.8
mmol). The reaction mixture was stirred at room temperature for 3 h
and then extracted with ethyl acetate (3.times.60 mL). The combined
organic layers were dried over sodium sulfate and concentrated in
vacuo. The crude product was purified by silica gel column
chromatography (eluted with petroleum ether:ethyl acetate=3:1) to
give (2S)-tert-butyl
2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)
pyrrolidine-1-carboxylate as a white solid (2.4 g). MS (ESI):
m/z=292 [M-55].sup.+.
(c) (2S)-tert-butyl
2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3]dioxol-4-yl)methyl)pyrrolidine-1-
-carboxylate
##STR00322##
[0578] To a solution of (2S)-tert-butyl
2-(6-oxo-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1--
carboxylate (2.1 g, 6.04 mmol) in tetrahydrofuran (100 mL) at
0.degree. C. was added lithium aluminium hydride (229 mg, 6.04
mmol) in portions. The reaction was stirred at 0.degree. C. for 1 h
and then quenched with water (0.5 mL in 10 mL tetrahydrofuran,
dropwise at 0.degree. C. over 5 mins) and then 15% sodium hydroxide
solution (0.5 mL). The mixture was stirred at 0.degree. C. for 30
min and filtered through celite. The filtered cake was washed with
dichloromethane (200 mL). The combined filtrate was concentrated to
give a residue which was diluted with brine (50 mL), extracted with
ethyl acetate (3.times.100 mL). The organic layers were dried over
sodium sulfate and concentrated in vacuo. The crude product was
purified by silica gel column chromatography (eluted with petroleum
ether:ethyl acetate=1:1) to give (2S)-tert-butyl
2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3]dioxol-4-yl)methyl)
pyrrolidine-1-carboxylate as a white solid (2.0 g). MS (ESI):
m/z=352 [M+H].sup.+.
(d). (2S)-tert-butyl
2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carbox-
ylate
##STR00323##
[0580] To a solution of (2S)-tert-butyl
2-(hydroxy(5-(hydroxymethyl)benzo[d][1,3]dioxol-4-yl)methyl)pyrrolidine-1-
-carboxylate (1.9 g, 5.40 mmol) in tetrahydrofuran (120 mL) at
-78.degree. C. was added n-butyllithium in n-hexane (2.5 M, 2.37
mL, 5.94 mmol). The reaction was stirred at this temperature for 30
min. Then a solution of 4-methylbenzene-1-sulfonyl chloride (1.13
g, 5.94 mmol) in tetrahydrofuran (12 mL) was added. After the
reaction mixture was stirred at this temperature for 1 h, a
solution of n-butyllithium in n-hexane (2.5 M, 2.37 mL, 5.94 mmol)
was added. The mixture was allowed to warm to room temperature
slowly, stirred at room temperature for an additional 16 h and then
quenched with water (150 mL) at 0.degree. C. It was extracted with
ethyl acetate (3.times.100 mL) and the organic layers were dried
over sodium sulfate and concentrated in vacuo. The crude product
was purified by Prep-TLC (eluted with petroleum ether:ethyl
acetate=4:1) to give (2S)-tert-butyl
2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine-1-carbox-
ylate as a yellow oil (680 mg). MS (ESI): m/z=334 [M+H].sup.+.
(e).
(S)-2-((R)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolid-
ine (I-141) and
(S)-2-((S)-6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine
(I-142)
##STR00324##
[0582] To a solution of (2S)-tert-butyl
2-(6,8-dihydro-[1,3]dioxolo[4,5-e]
isobenzofuran-8-yl)pyrrolidine-1-carboxylate (1.1 g, 3.3 mmol) in
dichloromethane (10 mL) was added 4 M hydrochloric acid/1,4-dioxane
solution (4 M, 2 mL, 8 mmol). The mixture was stirred at room
temperature for 6 h and concentrated in vacuo to give a residue,
which was washed with petroleum ether (50 mL), followed by ethyl
acetate (5 mL) to give the hydrochloride salt of
(2S)-2-(6,8-dihydro-[1,3]dioxolo[4,5-e]isobenzofuran-8-yl)pyrrolidine
as a yellow solid (0.7 g). This mixture of two diastereoisomers was
separated by Chiral HPLC (Co-Solvent: MeOH (0.5% NH4OH), Column:
AS-H 4.6.times.250 mm 5 .mu.m) to give
(S)-2-((R)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine
(I-141, 282 mg colorless oil) and
(S)-2-((S)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidine
(I-142, 124 mg colorless oil).
[0583]
(S)-2-((R)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidi-
ne (I-141): MS (ESI): m/z 233 [M+H].sup.+; .sup.1HNMR (HCl salt,
400 MHz, MeOD): .delta. 6.87-6.89 (d, J=8 Hz, 1H), 6.78-6.80 (d,
J=8 Hz, 1H), 6.01-6.04 (dd, J=11.6 Hz, 2H), 5.61-5.61 (d, J=2 Hz,
1H), 4.90-5.18 (m, 2H), 4.04-4.09 (m, 1H), 3.31-3.34 (m, 1H),
1.74-2.07 (m, 4H).
[0584]
(S)-2-((S)-6,8-dihydroisobenzofuro[4,5-d][1,3]dioxol-8-yl)pyrrolidi-
ne (I-142): MS (ESI): m/z 233 [M+H].sup.+, .sup.1HNMR (HCl salt,
400 MHz, MeOD): .delta. 6.88-6.90 (d, J=8 Hz, 1H), 6.80-6.82 (d,
J=8 Hz, 1H), 6.02-6.06 (dd, J=15.2 Hz, 2H), 5.40-5.41 (d, J=4 Hz,
1H), 5.16-5.19 (d, J=12 Hz, 1H), 5.02-5.04 (d, J=8 Hz, 1H),
3.87-3.91 (m, 1H), 3.25-3.36 (m, 2H), 2.28-2.31 (m, 1H), 2.06-2.17
(m, 3H).
Example 1.21. Procedure U. Certain Provided Compounds were Made
Following a Procedure Exemplified by Example 1.21.1
Example 1.21.1.
(S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137) and
(S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-138)
##STR00325## ##STR00326##
[0585] (a). (2S)-tert-butyl
2-(4-chloro-6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00327##
[0587] To a solution of 2-chloro-2-(3-fluorophenyl)ethanol (50 g,
287 mmol) in dichloromethane (300 ml) in ice salt bath was added
trifluoromethanesulfonic acid (129 g, 861 mmol) and (S)-tert-butyl
2-formylpyrrolidine-1-carboxylate (114 g, 574 mmol) dropwise (inner
temperature was kept <-5.degree. C.). After the addition, the
mixture was stirred at room temperature for 3 h and was then
basified with sodium hydroxide (20% aq.) to pH=10. Di-tert-butyl
dicarbonate (188 g, 861 mmol) was added. The mixture was stirred at
room temperature for 3 h, quenched with water (300 mL), and
extracted with dichloromethane (200 mL.times.2). The combined
organic layers were dried and concentrated in vacuo to give a
residue, which was purified by silica gel chromatography eluted
with petroleum ether:ethyl acetate=10:1 to give the desired product
(65 g) as a yellow oil.
(b). (2S)-tert-butyl
2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00328##
[0589] To a solution of (2S)-tert-butyl
2-(4-chloro-6-fluoroisochroman-1-yl)pyrrolidine-1-carboxylate (50
g, 140.8 mmol) in tetrahydrofuran/water (200 mL, 1:1) was added
silver nitrate (119.7 g, 704 mmol). The mixture was heated to
reflux for 4 h. Upon cooling to room temperature, the mixture was
extracted with ethyl acetate (200 mL.times.3) and the organic
layers were dried and concentrated in vacuo to give a residue. To
the residue was added acetic acid (200 mL) and zinc powder (45.8 g,
704 mmol) at room temperature. The mixture was stirred at room
temperature for 2 h and then filtered over celite. The filtrate was
evaporated in vacuo to give an oil, which was dissolved in water
(500 mL) and extracted with ethyl acetate (200 mL). The organic
layers were washed with sodium bicarbonate (aq. Sat.), dried and
concentrated in vacuo to give the crude product which was purified
by flash column chromatography with petroleum ether:ethyl
acetate=2:1 to provide (2S)-tert-butyl
2-(6-fluoro-4-hydroxyisochroman-1-yl)pyrrolidine-1-carboxylate
(35.0 g) as a yellow oil.
(c). (2S)-tert-butyl
2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate
##STR00329##
[0591] To a solution of (2S)-tert-butyl
2-(6-fluoro-4-hydroxyisochroman-1-yl) pyrrolidine-1-carboxylate (30
g, 88.9 mmol) in dichloromethane (60 mL) in ice salt bath was added
diethylaminosulfurtrifluoride (21.5 g, 133 mmol) dropwise. The
mixture was stirred at this temperature for 1 h and then poured
into saturated aqueous sodium bicarbonate (300 mL). The resulting
biphasic mixture was transferred to a separatory funnel. The layers
were separated and the water phase was extracted with
dichloromethane (2.times.200 mL). The combined organic layers were
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The resulting oil was purified by flash column
chromatography with a gradient elution of petroleum ether:ethyl
acetate=10:1 to provide (2S)-tert-butyl
2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate (16 g) as
a yellow oil.
(d). (S)-2-((1R,4)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137)
and (S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine
(I-138)
##STR00330##
[0593] To a solution of (2S)-tert-butyl
2-(4,6-difluoroisochroman-1-yl)pyrrolidine-1-carboxylate (5.8 g,
17.1 mmol) in dichloromethane (L) was added trifluoroacetic acid
(30 mL). The mixture was stirred at room temperature for 3 h and
then evaporated in vacuo to give the crude product, which was
purified by Prep-HPLC, followed by chiral separation: Column: AY-H
(250.times.4.6 mm 5 .mu.m); Mobile Phase: n-Hexane (0.1% DEA): EtOH
(0.1% DEA)=90:10 to give
(S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine (I-137, 900
mg) and (S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine
(I-138, 860 mg).
[0594] (S)-2-((1R,4S)-4,6-difluoroisochroman-1-yl)pyrrolidine
(I-137): MS (ESI): m/z=240[M+H].sup.+; .sup.1H NMR (HCl salt, 400
MHz, MeOD): .delta. 7.35.about.7.30 (m, 1H), 7.20.about.7.16 (m,
1H), 5.81.about.5.65 (m, 1H), 5.24 (s, 1H), 4.51.about.4.48 (m,
1H), 4.41.about.4.36 (m, 1H) 3.75.about.3.69 (m, 1H),
3.37.about.3.31 (m, 2H), 2.06.about.2.1.91 (m, 2H), 1.83.about.1.68
(m, 2H).
[0595] (S)-2-((1R,4R)-4,6-difluoroisochroman-1-yl)pyrrolidine
(I-138): MS (ESI): m/z=240[M+H].sup.+; 1H NMR (HCl salt, 400 MHz,
MeOD): .delta. 7.38-7.42 (m, 1H), 7.23-7.32 (m, 2H), 5.33-5.45 (m,
1H), 5.16-5.18 (m, 1H), 4.44-4.51 (m, 2H), 3.90-4.03 (m, 1H),
3.34-3.42 (m, 2H), 1.78-2.07 (m, 4H).
Example 1.21.2. (2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine
(I-135) and (2S)-2-((1S)-4,6-difluoroisochroman-1-yl)azetidine
(I-136)
##STR00331##
[0597] (2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine (I-135)
and (2S)-2-((1S)-4,6-difluoroisochroman-1-yl)azetidine (136) were
prepared using a procedure analogous to that described in Example
1.21.1, but using (S)-tert-butyl 2-formylazetidine-1-carboxylate in
place of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate.
[0598] (2S)-2-((1R)-4,6-difluoroisochroman-1-yl)azetidine (I-135):
MS (ESI): m/z=224 [M+H].sup.+; .sup.1H NMR (HCl salt, 400 MHz,
MeOD): .delta. 7.35.about.7.32 (m, 1H), 7.25.about.7.22 (m, 1H),
7.18.about.7.13 (m, 1H) 5.89.about.5.72 (m, 1H), 5.17.about.5.12
(m, 2H), 4.62.about.4.57 (m, 1H), 4.03.about.3.77 (m, 3H)
2.32.about.2.26 (m, 2H).
[0599] (2S)-2-((1S)-4,6-difluoroisochroman-1-yl)azetidine (136): MS
(ESI): m/z=224 [M+H].sup.+; .sup.1H NMR (HCl slat, 400 MHz, MeOD):
.delta. 7.35.about.7.30 (m, 2H), 7.22.about.7.17 (m, 1H),
5.72.about.5.61 (m, 1H), 5.11.about.5.08 (m, 2H), 4.49.about.4.43
(m, 1H), 4.11.about.4.04 (m, 1H), 3.93.about.3.81 (m, 2H),
2.98.about.2.94 (m, 1H), 2.60.about.2.56 (m, 1H).
Example 1.22. Procedure V
Example 1.22.1.
(1R)-6-fluoro-1-((S)-pyrrolidin-2-yl)isochroman-4-ol (I-134)
##STR00332##
[0601] To a solution of (S)-tert-butyl
2-((R)-6-fluoro-4-hydroxyisochroman-1-yl) pyrrolidine-1-carboxylate
(2.2 g, 6.5 mmol, prepared in Example 21.1) in dichloromethane (20
mL) was added trifluoroacetic acid (6 mL). The mixture was stirred
at room temperature for 3 h and then evaporated in vacuo to get a
residue, which was purified by Prep-HPLC to give
(1R)-6-fluoro-1-((S)-pyrrolidin-2-yl)isochroman-4-ol (650 mg).
m/z=238[M+H].sup.+. .sup.1H NMR (HCl salt, 400 MHz, MeOD): .delta.
7.36.about.7.33 (m, 1H), 7.28.about.7.25 (m, 1H), 7.08.about.7.03
(m, 1H) 5.22 (s, 1H), 4.82.about.4.78 (m, 1H), 4.39.about.4.35 (m,
1H) 4.30.about.4.26 (m, 1H), 3.46 (t, J=10.4 Hz, 1H),
3.38.about.3.28 (m, 2H), 2.05.about.1.91 (m, 2H), 1.77.about.1.68
(m, 2H).
Example 2. Biological Assays
Example 2.1 In Vitro Assay
[0602] Certain compounds were tested by in vitro binding assays
using standard procedures. Table 2 shows the membrane source,
radioligand, ligand used to define non-specific binding and
incubation conditions for each receptor. These receptors and assays
are well known to those skilled in the art, as exemplified by the
following: Abramovitz, M. et al. (2000), Biochem. Biophys. Acta.,
1483: 285-293 (EP4, IP (PGI.sub.2)); Aharony, D. et al. (1993),
Mol. Pharmacol., 44: 356-363 (NK2); Ardati, A. et al. (1997), Mol.
Pharmacol., 51: 816-824 (NOP (ORL1)); Bignon, E. et al. (1999), J.
Pharmacol. Exp. Ther. 289: 742-751 (CCK.sub.1 (CCK.sub.A));
Bloomquist, B. T. et al. (1998), Biochem. Biophys. Res. Commun.,
243: 474-479 (GAL.sub.2); Brockhaus, M. et al. (1990), Proc. Natl.
Acad. Sci. U.S.A., 87: 3127-3131 (TNF-.alpha.); Brown, G. B.
(1986), J. Neurosci., 6: 2064-2070 (Na+ channel (site 2)); Buchan,
K. W. et al. (1994), Brit. J. Pharmacol., 112:1251-1257 (ETA);
Cesura, A. M. et al. (1990), Mol. Pharmacol., 37: 358-366 (MAO-A);
Choi, D. S. et al. (1994), FEBS Lett., 352: 393-399 (5-HT2B);
Clark, A. F. et al. (1996), Invest. Ophtalmol. Vis. Sci., 37:
805-813 (GR); Couvineau, A. et al. (1985), Biochem. J., 231:
139-143 (VPAC.sub.1 (VIP.sub.1)); Dorje, F. et al. (1991), J.
Pharmacol. Exp. Ther., 256: 727-733 (M1, M2, M3, M4); Ferry, G. et
al. (2001), Eur. J. Pharmacol., 417: 77-89 (PPAR.gamma.); Fuchs, S.
et al. (2001), Mol. Med., 7: 115-124 (ETB); Fuhlendorff, J. et al.
(1990), Proc. Natl. Acad. Sci. U.S.A., 87: 182-186 (Y2); Ganapathy
M E. et al. (1999), J. Pharmacol. Exp. Ther., 289: 251-260 (sigma
(non-selective)); Gopalakrishnan, M. et al. (1996), J. Pharmacol.
Exp. Ther., 276: 289-297 (N neuronal .alpha.4.beta.2); Greengrass,
P. and Bremner, R. (1979), Eur. J. Pharmacol., 55: 323-326
(.alpha..sub.1 (non-selective)); Grandy, D. K. et al. (1989), Proc.
Natl. Acad. Sci. U.S.A., 86: 9762-9766 (D25); Guard, S. et al.
(1993), Eur. J. Pharmacol., 240: 177-184 (BB (non-selective));
Heuillet, E. et al. (1993), J. Neurochem., 60: 868-876 (NK1, P2X);
Hope, A. G. et al. (1996), Brit. J. Pharmacol., 118: 1237-1245
(5-HT3); Hoyer, D. et al. (1985), Eur. J. Pharmacol., 118: 1-12
(5-HT1B); Hugues, M. et al. (1982), J. Biol. Chem., 257: 2762-2769
(5-HT2A, SKCa channel); Joseph, S. S. et al. (2004), Naun.-Sch.
Arch. Pharm., 369: 525-532 (P2); Le, M. T. et al. (2005), Eur. J.
Pharmacol., 513: 35-45 (AT1); Le Fur, G. et al. (1983), Life Sci.,
33: 449-457) (BZD (peripheral); Lee, Y. M. et al. (1993), J. Biol.
Chem., 268: 8164-8169 (CCK.sub.2 (CCK.sub.B)); Leurs, R. et al.
(1994), Brit. J. Pharmacol., 112: 847-854 (H2); Levin, M. C. et al.
(2002), J. Biol. Chem., 277: 30429-30435 (.sctn. 1); Lewin, A. H.
et al. (1989), Mol. Pharmacol., 35: 189-194 (Cl- channel
(GABA-gated)); Lukas, R. J. (1986), J. Neurochem., 46: 1936-1941 (N
muscle-type); Luthin, D. R. et al. (1995), Mol. Pharmacol., 47:
307-313; (A2A); Mackenzie, R. G. et al. (1994), Eur. J. Pharmacol.,
266: 79-85 (D3); Mulheron, J. G. et al. (1994), J. Biol. Chem.,
269: 12954-12962 (5-HT1A); Meng, F. et al. (1993), Proc. Natl.
Acad. Sci. U.S.A., 90: 9954-9958 (K (KOP)); Monsma, F. J. et al.
(1993), Mol. Pharmacol., 43: 320-327 (5-HT6); Neote, K. et al.
(1993), Cell, 72: 415-425 (CCR1); Pacholczyk, T. et al. (1991),
Nature, 350: 350-354 (sst (non-selective, norepinephrine
transporter)); Peralta, E. G. et al. (1987), Embo. J., 6: 3923-3929
(M3); Pristupa, Z. B. et al. (1994), Mol. Pharmacol., 45: 125-135
(dopamine transporter); Pruneau, D. et al. (1998), Brit. J.
Pharmacol., 125: 365-372 (B2); Rees, S. et al. (1994), FEBS Lett.,
355: 242-246 (5-HT5a); Reynolds, I. J. et al. (1986), J. Pharmacol.
Exp. Ther., 237: 731-738 (Ca2+ channel (L, verapamil site));
Rinaldi-Carmona, M. et al. (1996), J. Pharmacol. Exp. Ther., 278:
871-878 (CB1); Salvatore, C. A. et al. (1993), Proc. Natl. Acad.
Sci. U.S.A., 90: 10365-10369 (A3); Sarau, H. M. et al. (1997), J.
Pharmacol. Exp. Ther., 281: 1303-1311 (NK3); Schioth, H. B. et al.
(1997), Neuropeptides, 31: 565-571 (MC4); Sharples, C. G. V. et al.
(2000), J. Neurosci., 20: 2783-2791 (N neuronal .alpha.7); Shen, Y.
et al. (1993), J. Biol. Chem., 268: 18200-18204 (5-HT7); Sills, M.
A. et al. (1991), Eur. J. Pharmacol., 192: 19-24 (NMDA); Simon, J.
et al. (1995), Pharmacol. Toxicol., 76: 302-307 (P2Y); Simonin, F.
et al. (1994), Mol. Pharmacol., 46: 1015-1021 (.delta..sub.2
(DOP)); Smit, M. J. et al. (1996), Brit. J. Pharmacol., 117:
1071-1080 (H1); Sorensen, R. G. and Blaustein, M. P. (1989), Mol.
Pharmacol., 36: 689-698 (KV channel); Speth, R. C. et al. (1979),
Life Sci., 24: 351-358 (BZD (central)); Stam, N.J. et al. (1994),
Eur. J. Pharmacol., 269: 339-348 (5-HT2C); Sullivan, K. A. et al.
(1997), Biochem. Biophys. Res. Commun., 233: 823-828 (GAL.sub.1);
Tahara, A. et al. (1998), Brit. J. Pharmacol., 125: 1463-1470
(Via); Tatsumi, M. et al. (1999), Eur. J. Pharmacol., 368: 277-283
(5-HT transporter); Townsend-Nicholson, A. and Schofield, P. R.
(1994), J. Biol. Chem., 269: 2373-2376 (A1); Tsuji, A. et al.
(1988), Antimicrob. Agents Chemother., 32: 190-194 (GABA
(non-selective)); Tsuzuki, S. et al. (1994), Biochem. Biophys. Res.
Commun., 200:1449-1454 (AT2); Uhlen, S. and Wikberg, J. E. (1991),
Pharmacol. Toxicol., 69: 341-350 (.alpha..sub.2 (non-selective));
Van Tol, H. H. M. et al. (1992), Nature, 358: 149-152 (D.sub.4.4);
Vignon, J. et al. (1986), Brain Res., 378: 133-141 (PCP); Vita, N.
et al. (1993), FEBS Lett., 317: 139-142 (NTS.sub.1 (NT.sub.1));
White, J. R. et al. (1998), J. Biol. Chem., 273:10095-10098 (CXCR2
(IL-8B), .mu. (MOP)); Wieland, H. A. et al. (1995), J. Pharmacol.
Exp. Ther., 275: 143-149 (Y1); Witt-Enderby, P. A. and Dubocovich,
M. L. (1996), Mol. Pharmacol., 50: 166-174 (MT.sub.1 (ML.sub.1A));
Zhou, Q. Y. et al. (1990), Nature, 347: 76-80 (D1).
[0603] Briefly, a membrane was incubated with a radioligand in the
presence and absence of a test compound under the relevant
condition, prior to filtration and washing. The amount of the
radioligand bound to a membrane was determined using liquid
scintillation counting. Total binding (the binding of a radioligand
to both receptor and non-receptor sites) was determined by
incubating a membrane with a radioligand alone. Non-specific
binding (binding to non-receptor sites) of a radioligand was
determined by incubating a membrane in the presence of a saturating
concentration of an unlabeled ligand (the ligand used to define
non-specific binding). Specific binding (binding to receptor sites
only) was calculated by subtracting non-specific binding from total
binding.
TABLE-US-00002 TABLE 2 Conc. Assay Source Ligand (nM) Non Specific
Incubation A1 human [3H]DPCPX 1 DPCPX 60 min recombinant (1 .mu.M)
RT (CHO cells) A2A human [3H]CGS 21680 6 NECA 120 min recombinant
(10 .mu.M) RT (HEK-293 cells) A3 human [125I]AB-MECA 0.15 IB-MECA
120 min recombinant (1 .mu.M) RT (HEK-293 cells) .alpha..sub.1
(non- rat cerebral [3H]prazosin 0.25 prazosin 60 min selective)
cortex (0.5 .mu.M) RT .alpha..sub.2 (non- rat cerebral [3H]RX
821002 0.5 (-)epinephrine 60 min selective) cortex (100 .mu.M) RT
.beta.1 human [3H](-)CGP 12177 0.3 alprenolol 60 min recombinant
(50 .mu.M) RT (HEK-293 cells) .beta.2 human [3H](-)CGP 12177 0.3
alprenolol 120 min recombinant (50 .mu.M) RT (CHO cells) AT1 human
[125I][Sar1, IIe8]-AT-II 0.05 angiotensin-II 120 min recombinant
(10 .mu.M) 37.degree. C. (HEK-293 cells) AT2 human [125I]CGP 42112A
0.01 angiotensin-II 4 hr recombinant (1 .mu.M) 37.degree. C.
(HEK-293 cells) BZD rat heart [3H]PK 11195 0.2 PK 11195 15 min
(peripheral) (10 .mu.M) RT BB (non- rat cerebral
[125I][Tyr4]bombesin 0.01 bombesin 60 min selective) cortex (1
.mu.M) RT B2 human [3H]bradykinin 0.3 bradykinin 60 min recombinant
(1 .mu.M) RT (CHO cells) CB1 human [3H]CP 55940 0.5 WIN 55212-2 120
min recombinant (10 .mu.M) 37.degree. C. (CHO cells) CCK.sub.1
(CCK.sub.A) human [125I]CCK-8s 0.08 CCK-8s 60 min recombinant (1
.mu.M) RT (CHO cells) CCK.sub.2 (CCK.sub.B) human [125I]CCK-8s 0.08
CCK-8s 60 min recombinant (1 .mu.M) RT (CHO cells) D1 human [3H]SCH
23390 0.3 SCH 23390 60 min recombinant (1 .mu.M) RT (CHO cells) D2S
human [3H]methyl- 0.3 (+)butaclamol 60 min recombinant spiperone
(10 .mu.M) RT (HEK-293 cells) D3 human [3H]methyl- 0.3
(+)butaclamol 60 min recombinant spiperone (10 .mu.M) RT (CHO
cells) D.sub.4.4 human [3H]methyl- 0.3 (+)butaclamol 60 min
recombinant spiperone (10 .mu.M) RT (CHO cells) ETA human
[125I]endothelin-1 0.03 endothelin-1 120 min recombinant (100 nM)
37.degree. C. (CHO cells) ETB human [125I]endothelin-1 0.03
endothelin-1 120 min recombinant (0.1 .mu.M) 37.degree. C. (CHO
cells) GABA rat cerebral [3H]GABA 10 GABA 60 min (non-selective)
cortex (100 .mu.M) RT GAL.sub.1 human [125I]galanin 0.1 galanin 80
min recombinant (1 .mu.M) RT (HEK-293 cells) GAL.sub.2 human
[125I]galanin 0.05 galanin 120 min recombinant (1 .mu.M) RT (CHO
cells) CXCR2 human [125I]IL-8 0.025 IL-8 60 min (IL-8B) recombinant
(30 nM) RT (HEK-293 cells) CCR1 human [125I]MIP-1.alpha. 0.01
MIP-1.alpha. 120 min recombinant (100 nM) RT (HEK-293 cells)
TNF-.alpha. U-937 cells [125I]TNF-.alpha. 0.1 TNF-.alpha. 120 min
(10 nM) 4.degree. C. H1 human [3H]pyrilamine 1 pyrilamine 60 min
recombinant (1 .mu.M) RT (HEK-293 cells) H2 human [125I]APT 0.075
tiotidine 120 min recombinant (100 .mu.M) RT (CHO cells) MC4 human
[125I]NDP-.alpha.-MSH 0.05 NDP-.alpha.-MSH 120 min recombinant (1
.mu.M) 37.degree. C. (CHO cells) MT.sub.1 (ML.sub.1A) human
[125I]2- 0.01 melatonin 60 min recombinant iodomelatonin (1 .mu.M)
RT (CHO cells) M1 human [3H]pirenzepine 2 atropine 60 min
recombinant (1 .mu.M) RT (CHO cells) M2 human [3H]AF-DX 384 2
atropine 60 min recombinant (1 .mu.M) RT (CHO cells) M3 human
[3H]4-DAMP 0.2 atropine 60 min recombinant (1 .mu.M) RT (CHO cells)
M4 human [3H]4-DAMP 0.2 atropine 60 min recombinant (1 .mu.M) RT
(CHO cells) M5 human [3H]4-DAMP 0.3 atropine 60 min recombinant (1
.mu.M) RT (CHO cells) NK1 U-373MG [125I]BH-SP 0.15 [Sar9,
Met(O2)11]-SP 60 min cells (1 .mu.M) RT (endogenous) NK2 human
[125I]NKA 0.1 [Nleu10]-NKA (4-10) 60 min recombinant (300 nM) RT
(CHO cells) NK3 human [3H]SR 142801 0.4 SB 222200 120 min
recombinant (10 .mu.M) RT (CHO cells) Y1 SK-N-MC cells
[125I]peptide YY 0.025 NPY 120 min (endogenous) (1 .mu.M)
37.degree. C. Y2 KAN-TS cells [125I]peptide YY 0.015 NPY 60 min (1
.mu.M) 37.degree. C. NT5.sub.1 (NT.sub.1) human [125I]Tyr3- 0.05
neurotensin 60 min recombinant neurotensin (1 .mu.M) 4.degree. C.
(CHO cells) N neuronal SH-SY5Y cells [3H]cytisine 0.6 nicotine 120
min .alpha.4.beta.2 (human (10 .mu.M) 4.degree. C. recombinant) N
neuronal .alpha.7 SH-SY5Y cells [125I].alpha.-bungarotoxin 0.05
.alpha.-bungarotoxin 120 min (human (1 .mu.M) 37.degree. C.
recombinant) N muscle-type TE671 cells [125I].alpha.-bungarotoxin
0.5 .alpha.-bungarotoxin 120 min (endogenous) (5 .mu.M) RT
.delta..sub.2 (DOP) human [3H]DADLE 0.5 naltrexone 120 min
recombinant (10 .mu.M) RT (CHO cells) .kappa. (KOP) rat [3H]U 69593
1 naloxone 60 min recombinant (10 .mu.M) RT (CHO cells) .mu. (MOP)
human [3H]DAMGO 0.5 naloxone 120 min recombinant (10 .mu.M) RT
(HEK-293 cells) NOP (ORL1) human [3H]nociceptin 0.2 nociceptin 60
min recombinant (1 .mu.M) RT (HEK-293 cells) PPAR.gamma. human
[3H]rosiglitazone 5 rosiglitazone 120 min recombinant (10 .mu.M)
4.degree. C. (E. coli) EP4 human [3H]PGE2 0.5 PGE2 120 min
recombinant (10 .mu.M) RT (HEK-293 cells) IP (PGI.sub.2) human
[3H]iloprost 6 iloprost 60 min recombinant (10 .mu.M) RT (HEK-293
cells) P2Y rat cerebral [35S]dATP.alpha.S 10 dATP.alpha.S 60 min
cortex RT 5-HT1A human [3H]8-OH-DPAT 0.3 8-OH-DPAT 60 min
recombinant (10 .mu.M) RT (HEK-293 cells) 5-HT1B rat cerebral
[125I]CYP 0.1 serotonin 120 min cortex (+30 .mu.M (10 .mu.M)
37.degree. C. isoproterenol) 5-HT2A human [3H]ketanserin 0.5
ketanserin 60 min recombinant (1 .mu.M) RT (HEK-293 cells) 5-HT2B
human [125I](.+-.)DOI 0.2 (.+-.)DOI 60 min recombinant (1 .mu.M) RT
(CHO cells) 5-HT2C human [3H]mesulergine 1 RS 102221 120 min
recombinant (10 .mu.M) 37.degree. C. (HEK-293 cells) 5-HT5a human
[3H]LSD 1.5 serotonin 120 min recombinant (100 .mu.M) 37.degree. C.
(HEK-293 cells) 5-HT6 human [3H]LSD 2 serotonin 120 min recombinant
(100 .mu.M) 37.degree. C. (CHO cells) 5-HT7 human [3H]LSD 4
serotonin 120 min recombinant (10 .mu.M) RT (CHO cells) sigma (non-
Jurkat cells [3H]DTG 10 Haloperidol 120 min selective) (endogenous)
(10 .mu.M) RT sst (non- AtT-20 cells [125I]Tyr11- 0.05
somatostatin-14 60 min selective) somatostatin-14 (300 nM)
37.degree. C. GR IM-9 cells [3H]dexamethasone 1.5 triamcinolone 6
hr (cytosol) (10 .mu.M) 4.degree. C. VPAC.sub.1 (VIP.sub.1) human
[125I]VIP 0.04 VIP 60 min recombinant (1 .mu.M) RT (CHO cells) V1a
human [3H]AVP 0.3 AVP 60 min recombinant (1 .mu.M) RT (CHO cells)
BZD (central) rat cerebral [3H]flunitrazepam 0.4 diazepam 60 min
cortex (3 .mu.M) 4.degree. C. NMDA rat cerebral [3H]CGP 39653 5
L-glutamate 60 min cortex (100 .mu.M) 4.degree. C. PCP rat cerebral
[3H]TCP 10 MK 801 120 min cortex (10 .mu.M) 37.degree. C. P2X rat
urinary [3H].alpha.,.beta.-MeATP 3 .alpha.,.beta.-MeATP 120 min
bladder (10 .mu.M) 4.degree. C. 5-HT3 human [3H]BRL 43694 0.5 MDL
72222 120 min recombinant (10 .mu.M) RT (CHO cells) Ca2+ channel
rat cerebral [3H]D888 3 D 600 120 min (L, verapamil cortex (10
.mu.M) RT site) KV channel rat cerebral [125I].alpha.-dendrotoxin
0.01 .alpha.-dendrotoxin 80 min cortex (50 nM) RT 5KCa channel rat
cerebral [125I]apannin 0.007 apamin 60 min cortex (100 nM)
4.degree. C. Na+ channel rat cerebral [3H]batrachotoxinin 10
veratridine 60 min (site 2) cortex (300 .mu.M) 37.degree. C.
Cl-channel rat cerebral [35S]IBPS 3 picrotoxinin 120 min
(GABA-gated) cortex (20 .mu.M) RT norepinephrine human
[3H]nisoxetine 1 desipramine 120 min transporter recombinant (1
.mu.M) 4.degree. C. (CHO cells) dopamine human [3H]BTCP 4 BTCP 120
min transporter recombinant (10 .mu.M) 4.degree. C. (CHO cells)
5-HT human [3H]imipramine 2 imipramine 60 min transporter
recombinant (10 .mu.M) RT (CHO cells) MAO-A rat cerebral [3H]Ro
41-1049 10 clorgyline 60 min cortex (1 .mu.M) 37.degree. C.
[0604] Table 3 shows certain compounds and receptors for which the
test compound's specific binding (measured by percentage
inhibition) was greater than 50%.
TABLE-US-00003 TABLE 3 Compound Receptor (percent inhibition) I-1
.alpha.1 (55%); .alpha.2 (95%); 5HT1a (79%); 5HT2b (79%); 5HT2c
(63%); 5HT7 (88%) I-5 .alpha.1 (59%); .alpha.2 (96%); GABA (57%);
KOP (71%); 5HT1a (52%); 5HT2b (72%); 5HT7 (60%) I-9 5HT7 (80%);
.alpha.1 (73%); .alpha.2 (91%); 5HT1a (77%); 5HT2b (76%); 5HT2c
(61%) I-29 .alpha.1 (69%); .alpha.2 (97%); k (89%); 5HT1a (71%);
5HT2b (80%); 5HT2c (67%); 5HT7 (52%) I-83 .alpha.2 (77%); 5HT1a
(87%); 5HT2b (83%); 5HT2c (64%); 5HT5a (58%); 5HT7 (99%) I-90
.alpha.1 (64%); .alpha.2 (71%); 5HT1a (64%); 5HT2b (77%); 5HT2c
(59%); 5HT7 (96%); Sert (80%); sigma (63%) I-94 .alpha.1 (72%);
.kappa. (67%); 5HT2b (76%); 5HT7 (74%); sigma (85%) I-96 .alpha.1
(81%); .alpha.2 (81%); 5HT2b (58%); 5HT7 (69%); M4 (53%)
Example 2.2. Neuropharmacological Assay (SmartCube.TM.)
[0605] 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.
[0606] 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 4, these probabilities are
reported for each behavioral effect measured as follows:
TABLE-US-00004 LOQ.ltoreq. + <5% 5%.ltoreq. ++ <25%
25%.ltoreq. +++ <50% 50%.ltoreq. ++++
where LOQ is the limit of quantification.
[0607] 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-00005 TABLE 4 Compound DP AX SD PS MS AD CE AG XG HA UN
I-1 ++ ++ ++ +++ ++ + ++ ++ + + ++ I-2 + ++ ++ ++ ++ + + + + + +
I-3 +++ ++ ++ ++ ++ + ++ ++ + + +++ I-4 ++ +++ + ++ + + ++ ++ + + +
I-5 ++ ++ + +++ ++ + ++ ++ + + +++ I-6 ++ ++ + ++ + + + + + + +++
I-7 ++ ++ + ++ + + ++ ++ + + +++ I-8 +++ ++ ++ +++ + + ++ + + + ++
I-9 ++ ++ ++ +++ ++ + ++ ++ + + +++ I-10 ++ ++ + ++ + + ++ ++ + + +
I-11 ++ ++ + +++ + + ++ ++ + + ++ I-12 ++ ++ + ++ + + + ++ + + ++++
I-13 +++ ++ + ++++ ++ + ++ ++ + + ++ I-14 +++ ++ + +++ ++ + ++ ++ +
+ + I-15 ++ +++ + ++ + + ++ ++ + + + I-16 ++ ++ + +++ ++ + ++ + + +
+++ I-17 +++ ++ + ++ + + ++ + + + + I-18 ++ +++ ++ +++ ++ + ++ ++ +
+ ++ I-19 + ++ + ++++ + + ++ + + + ++++ I-20 ++ ++ ++ ++++ ++ + ++
++ + + +++ I-21 ++ ++ + ++ + + + ++ + + +++ I-22 +++ ++ + +++ + +
++ ++ + + + I-23 ++ ++ ++ +++ ++ + ++ +++ + + + I-24 +++ ++ ++ ++
++ + ++ ++ + + + I-25 ++ ++ + ++ + + ++ +++ + + ++ I-26 + ++ + + +
+ + + + + + I-27 ++ +++ + ++ ++ + ++ ++ + + + I-28 ++ +++ + ++ + +
+ ++ + + ++ I-29 ++ +++ + ++ ++ + +++ ++ + + ++ I-30 ++ +++ ++ +++
+ + ++ ++ + + + I-31 ++ +++ ++ +++ ++ + ++ ++ + + + I-32 ++ ++ ++
+++ + + ++ +++ + + + I-33 ++ ++ ++ +++ + + ++ + + + + I-34 ++ ++ ++
++ + + ++ ++ + + +++ I-35 ++ ++ ++ +++ + + ++ + + + ++ I-36 ++ ++ +
+++ ++ + ++ ++ + + ++ I-37 ++ ++ + ++ + + + + + + +++ I-38 ++ ++ +
+ + + + ++ + + + I-39 + ++ + + + + ++ ++ + + ++ I-40 ++ ++ + +++ +
+ ++ + + + + I-41 +++ ++ ++ ++ ++ + ++ ++ + + + I-42 +++ ++ ++ ++ +
+ ++ ++ + + + I-43 ++ +++ + ++ + + ++ ++ + + + I-44 ++ +++ + +++ ++
+ ++ ++ + + + I-45 ++ +++ + + + + + ++ + + + I-46 ++ ++ ++ ++++ + +
++ ++ + + + I-47 + ++ + + + + + + + + + I-48 ++ ++ + ++ + + ++ +++
+ + + I-49 ++ ++ ++ ++ ++ + ++ ++ + + ++ I-50 ++ +++ + ++ + + ++ ++
+ + +++ I-51 + ++ + + + + + ++ + + ++ I-52 ++ ++++ + ++ + + ++ ++ +
+ +++ I-53 + + + + + + + + + + + I-54 +++ +++ + ++ ++ + ++ ++ + + +
I-55 + + + + + + + + + + + I-56 +++ ++ + ++ ++ ++ ++ +++ + + + I-57
+ + + + + + + + + + + I-58 +++ ++ + ++ ++ + + ++ + + + I-59 ++ ++ +
++ ++ + ++ + + + + I-60 ++ ++ ++ +++ + + ++ ++ + + ++ I-61 ++ ++ +
++ ++ + + +++ ++ + + I-62 ++ ++ + ++ + + +++ ++ + + + I-63 + + + +
+ + + + + + + I-64 + ++ + + + + + + + + + I-65 ++ ++ ++ ++ + + ++
+++ + + + I-66 ++ ++ + +++ + + ++ ++ + + ++ I-67 + + + + + + + + +
+ + I-68 + + + + + + + + + + + I-69 ++ ++ + ++ + + ++ +++ + + +
I-70 ++ +++ + + + + + ++ + + + I-71 ++ +++ + ++ ++ + ++ + + + +
I-72 + ++ + + + + + ++ ++ + +++ I-73 ++ ++ + + ++ + ++ ++ + + +++
I-74 ++ ++ ++ +++ + + ++ ++ + + + I-75 +++ ++ ++ ++ ++ + ++ + + + +
I-76 ++ ++ + ++ + + + ++ + + + I-77 + ++ + + + + + + + + + I-78 ++
+++ + ++ + + ++ ++ + + + I-79 ++ +++ + +++ ++ ++ ++ ++ + + + I-80
+++ ++ + ++ ++ + ++ ++ + + +++ I-81 ++ +++ +++ ++ + + ++ ++ + + +
I-82 +++ ++ ++ ++ ++ + ++ ++ + + ++ I-83 ++ ++ + +++ ++ ++ +++ ++ +
+ + I-84 ++ ++ ++ ++++ ++ + + + + + + I-85 ++ ++ ++ +++ + + ++ + +
+ ++ I-86 ++ +++ ++ +++ + + ++ +++ + + ++ I-87 ++ ++ + +++ + + + ++
+ + ++ I-88 ++ +++ + ++ + + ++ ++ + + +++ I-89 +++ ++ + +++ ++ ++
++ ++ + + + I-90 +++ +++ ++ ++ + + ++ ++ + + ++ I-91 ++ ++ ++ +++ +
+ ++ ++ + + ++ I-92 ++ ++ + +++ ++ + +++ ++ + + + I-93 +++ ++ ++ ++
+ ++ ++ +++ + + ++ I-94 +++ ++ + +++ + + ++ ++ + + ++ I-95 ++ ++ +
++ + + ++ +++ + + + I-96 +++ ++ + +++ ++ + ++ +++ + + + I-97 ++ ++
++ +++ ++ + ++ +++ + + + I-98 +++ ++ ++ +++ ++ + + + + + + I-99 +++
++ ++ ++ + + ++ ++ + + + I-100 ++ ++ ++ +++ ++ + +++ ++ + + + I-101
++ ++ + + + + + + + + + I-102 ++ +++ + ++ ++ + ++ ++ + + + I-103 ++
++ ++ + + + + ++ + + +++ I-104 ++ ++ ++ + + + + +++ + + ++ I-105 ++
+++ ++ ++ + + ++ ++ + + ++++ I-106 + ++ + ++ + + +++ ++ + + + I-107
++ +++ ++ +++ ++ + ++ ++ + + ++ I-108 ++ ++ ++ +++ + + ++ ++ + + ++
I-109 +++ ++ ++ ++ ++ + + ++ + + ++ I-110 ++ ++ ++ ++++ + + ++ ++ +
+ +++ I-111 ++ ++ ++ ++++ + + ++ ++ + + +++ I-112 ++ ++ + +++ + +
++ + + + + I-113 +++ ++ ++ ++ + + ++ ++ + + + I-114 +++ ++ ++ ++ +
+ ++ ++ + + + I-115 ++ ++ ++ ++ + + ++ ++ + + +++ I-116 ++ ++ ++
+++ + + + + + + + I-117 ++ ++ + +++ + + ++ + + + + I-118 ++ +++ ++
+++ ++ + ++ ++ + + + I-119 ++ ++ + +++ + + ++ +++ + + + I-120 ++ ++
++ ++ ++ + +++ ++ + + ++ I-121 ++ +++ ++ ++ + + ++ +++ + + ++ I-122
++ ++ + + + + + + + + + I-123 + + + + + + + + + + + I-124 + + + + +
+ + + + + + I-125 ++++ ++ ++ + + + ++ ++ + + + I-126 +++ ++ ++ +++
+ + ++ ++ + + ++ I-127 ++ ++ + ++ + + ++ ++ + + ++ I-128 ++ ++ +
++++ + + + ++ + + + I-134 + ++ + + + + + + + + + I-135 ++ ++ ++ +++
++ + ++ ++ + + ++ I-137 ++ ++ ++ ++++ ++ + ++ ++ + + ++ I-138 ++ ++
+ +++ + + + + + + ++ I-139 ++ ++ + +++ + + ++ + + + + I-140 ++ ++
+++ ++ ++ + +++ ++ + + ++ I-141 ++ ++ + ++ + ++ +++ ++ + ++ ++++
I-142 ++ +++ + ++ + + ++ ++ + + ++ I-143 ++ ++ + ++ + + + ++ + +
+++ I-144 +++ ++ + +++ ++ ++ ++ ++ + + +++ 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.
[0608] 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 6 are intended to encompass both the free compounds and
pharmaceutically acceptable salts thereof. [0609] 1. A compound of
formula I:
[0609] ##STR00333## [0610] or a pharmaceutically acceptable salt
thereof, wherein: [0611] A is
[0611] ##STR00334## [0612] m is 0, 1, or 2; [0613] n1 is 1, 2, or
3; [0614] n2 is 0 or 1; [0615] n3 is 0 or 1; [0616] R is --H or
C.sub.1-C.sub.3 alkyl; [0617] R.sup.a is --H or C.sub.1-C.sub.3
alkyl; [0618] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently --H, halo, --OH, --NH.sub.2, C.sub.1-C.sub.3
alkyl,--OR.sup.7,--NHR.sup.7, --N(R.sup.7)R.sup.7, --CN, phenyl, or
5- or 6-membered heteroaryl, wherein: [0619] each instance of
R.sup.7 independently is unsubstituted C.sub.1-C.sub.2 alkyl or
C.sub.1-C.sub.2 alkyl substituted with 1-3 halo, [0620] each
instance of C.sub.1-C.sub.3 alkyl independently is unsubstituted or
substituted with 1-3 halo, and [0621] the phenyl or heteroaryl is
unsubstituted or substituted with 1 or 2 groups independently
selected from halo, --OH, --OCH.sub.3, --OCF.sub.3, --NH.sub.2,
--NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, ethyl, --CF.sub.3,
and --CN, [0622] optionally wherein [0623] two adjacent instances
of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--,
--O--C(CH.sub.3).sub.2--O--, --O--CH.sub.2--CH.sub.2--O--, or
--O--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--O--; [0624] each
instance of R.sup.5 independently is halo, --CH.sub.3, or ethyl;
[0625] each instance of R.sup.6 independently is halo, --CH.sub.3,
ethyl or --OH; [0626] w is 0, 1, or 2; and [0627] Z is C or O;
[0628] provided that the compound is not:
[0628] ##STR00335## [0629] 2. The compound of embodiment 1 of
formula (Ia):
[0629] ##STR00336## [0630] or a pharmaceutically acceptable salt
thereof. [0631] 3. The compound of embodiment 1 of formula
(Ib):
[0631] ##STR00337## [0632] or a pharmaceutically acceptable salt
thereof. [0633] 4. The compound of embodiment 1 of formula
(Ic):
[0633] ##STR00338## [0634] or a pharmaceutically acceptable salt
thereof. [0635] 5. The compound of embodiment 1 of formula
(Id):
[0635] ##STR00339## [0636] or a pharmaceutically acceptable salt
thereof. [0637] 6. The compound of any of embodiments 1-5, wherein
Z is C. [0638] 7. The compound of embodiment 6, wherein n2 is 0 and
n3 is 0. [0639] 8. The compound of embodiment 6, wherein one of n2
and n3 is 0 and the other is 1. [0640] 9. The compound of
embodiment 6, wherein n2 is 1 and n3 is 1. [0641] 10. The compound
of any of embodiments 1-5, wherein n2 is 1 and Z is O. [0642] 11.
The compound of embodiment 10, wherein n3 is 1. [0643] 12. The
compound of embodiment 1 of formula (I-C):
[0643] ##STR00340## [0644] or a pharmaceutically acceptable salt
thereof. [0645] 13. The compound of any of embodiments 1-12,
wherein n1 is 1. [0646] 14. The compound of any of embodiments
1-12, wherein n1 is 2. [0647] 15. The compound of any of
embodiments 1-12, wherein n1 is 3. [0648] 16. The compound of any
of embodiments 1-15, wherein at least two of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. [0649] 17. The compound of any of
embodiments 1-15, wherein at least three of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are --H. [0650] 18. The compound of any of
embodiments 1-17, wherein the 5- or 6-membered heteroaryl has at
least 1 nitrogen ring atom and is unsubstituted or substituted with
1 group selected from halo, --OH, --OCH.sub.3, --OCF.sub.3,
--NH.sub.2, --NH(CH.sub.3), --N(CH.sub.3).sub.2, --CH.sub.3, ethyl,
--CF.sub.3, and --CN. [0651] 19. The compound of embodiment 18,
wherein the heteroaryl is unsubstituted pyridyl, pyrimidinyl,
pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl, or oxazolyl. [0652]
20. The compound of embodiment 18, wherein the heteroaryl is
unsubstituted pyridyl or isoxazolyl. [0653] 21. The compound of any
of embodiments 1-16 or 18-20, wherein two adjacent instances of
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 together form
--O--CH.sub.2--O--, --O--CH(CH.sub.3)--O--, or
--O--C(CH.sub.3).sub.2--O--. [0654] 22. The compound of embodiment
21, wherein two adjacent instances of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 together form --O--CH.sub.2--O--. [0655] 23. The
compound of any of embodiments 1-22, wherein R.sup.a is --H. [0656]
24. The compound of any of embodiments 1-23, wherein R is --H.
[0657] 25. The compound of any of embodiments 1-24, wherein each
instance of R.sup.5 is --F or --CH.sub.3. [0658] 26. The compound
of any of embodiments 1-25, wherein each instance of R.sup.6 is --F
or --CH.sub.3. [0659] 27. The compound of any of embodiments 1-25,
wherein each instance of R.sup.6 is --CH.sub.3. [0660] 28. The
compound of any of embodiments 1-24, 26, or 27, wherein m is 0.
[0661] 29. The compound of any of embodiments 1-25, wherein w is 0.
[0662] 30. The compound of any of embodiments 1-24, wherein m is 0
and w is 0. [0663] 31. The compound of any of embodiments 1-30,
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
--H, halo, C.sub.1-C.sub.3 alkyl, --OR.sup.7 or --CN. [0664] 32.
The compound of any of embodiments 1-30, wherein R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are independently --H, --F, --CH.sub.3,
--OCH.sub.3, or --CN. [0665] 33. A composition comprising a
compound according to any one of embodiments 1 to 32 and a
pharmaceutically acceptable carrier, adjuvant, or vehicle. [0666]
34. A method for treating a neurological or psychiatric disorder in
a patient, comprising administering to said patient an effective
amount of the compound according to any of embodiments 1-32. [0667]
35. The method according to embodiment 34, wherein the neurological
or psychiatric disorder is major depression, schizophrenia, bipolar
disorder, obsessive compulsive disorder (OCD), panic disorder, or
posttraumatic stress disorder (PTSD). [0668] 36. The method
according to embodiment 34, wherein the neurological or psychiatric
disorder is bipolar disorder, mania, psychosis, or
schizophrenia.
* * * * *