U.S. patent application number 17/045152 was filed with the patent office on 2021-05-20 for opioid receptor modulators and products and methods related thereto.
The applicant listed for this patent is Epiodyne, Inc.. Invention is credited to Ulhas BHATT, Pingyu DING, Jason DUQUETTE, Yihong LI, Larry McGEE, Julio Cesar MEDINA, Alok NERURKAR, Thomas NGUYEN, Corinne SADLOWSKI, Frederick SEIDL, David SPERANDIO, Xiaodong WANG, Zhi-Liang WEI.
Application Number | 20210147343 17/045152 |
Document ID | / |
Family ID | 1000005406985 |
Filed Date | 2021-05-20 |
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United States Patent
Application |
20210147343 |
Kind Code |
A1 |
MEDINA; Julio Cesar ; et
al. |
May 20, 2021 |
OPIOID RECEPTOR MODULATORS AND PRODUCTS AND METHODS RELATED
THERETO
Abstract
Compounds are provided having the structure of Formula (I): or a
pharmaceutically acceptable isomer, racemate, hydrate, solvate,
isotope, or salt thereof, wherein A, B, L, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.8, m and n are as defined herein. Such
compounds modulate the opioid receptor, particulate the mu-opioid
receptor (MOR) and/or the kappa-opioid receptor (KOR), and/or the
delta-opioid receptor (DOR). Products containing such compounds, as
well as methods for their use and preparation, are also provided.
##STR00001##
Inventors: |
MEDINA; Julio Cesar; (South
San Francisco, CA) ; McGEE; Larry; (South San
Francisco, CA) ; WEI; Zhi-Liang; (South San
Francisco, CA) ; SADLOWSKI; Corinne; (South San
Francisco, CA) ; SEIDL; Frederick; (South San
Francisco, CA) ; BHATT; Ulhas; (South San Francisco,
CA) ; WANG; Xiaodong; (South San Francisco, CA)
; NGUYEN; Thomas; (South San Francisco, CA) ;
SPERANDIO; David; (South San Francisco, CA) ; DING;
Pingyu; (South San Francisco, CA) ; NERURKAR;
Alok; (South San Francisco, CA) ; LI; Yihong;
(South San Francisco, CA) ; DUQUETTE; Jason;
(Union City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Epiodyne, Inc. |
San Francisco |
CA |
US |
|
|
Family ID: |
1000005406985 |
Appl. No.: |
17/045152 |
Filed: |
April 4, 2019 |
PCT Filed: |
April 4, 2019 |
PCT NO: |
PCT/US2019/025910 |
371 Date: |
October 2, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62792754 |
Jan 15, 2019 |
|
|
|
62652819 |
Apr 4, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 241/24 20130101;
C07C 235/60 20130101; A61P 23/00 20180101; C07D 263/58 20130101;
C07D 231/56 20130101; C07D 217/14 20130101; C07D 209/14 20130101;
C07D 471/04 20130101; C07C 233/78 20130101; C07D 295/13 20130101;
C07C 233/62 20130101; C07D 207/16 20130101; C07D 217/06 20130101;
C07C 237/42 20130101; C07D 403/06 20130101; C07C 233/63
20130101 |
International
Class: |
C07C 233/78 20060101
C07C233/78; C07D 231/56 20060101 C07D231/56; C07C 235/60 20060101
C07C235/60; C07C 237/42 20060101 C07C237/42; C07D 241/24 20060101
C07D241/24; C07D 217/06 20060101 C07D217/06; C07D 403/06 20060101
C07D403/06; C07D 217/14 20060101 C07D217/14; A61P 23/00 20060101
A61P023/00; C07D 471/04 20060101 C07D471/04; C07C 233/62 20060101
C07C233/62; C07C 233/63 20060101 C07C233/63; C07D 207/16 20060101
C07D207/16; C07D 209/14 20060101 C07D209/14; C07D 263/58 20060101
C07D263/58; C07D 295/13 20060101 C07D295/13 |
Claims
1. A compound having the structure of Formula (I): ##STR00478## or
a pharmaceutically acceptable isomer, racemate, hydrate, solvate,
isotope, or salt thereof, wherein: ring A is carbocycle or
heterocycle; ring B is carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; m is 0-5; n is 0-5; q is 0-5; r is 0-5; and
t is 0-2; with the provisos that: when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, m is not 0 and
at least one R.sup.5 is not --OH, halo, or alkoxy when ring B is an
aromatic monocyclic carbocycle or heterocyle, or at least one
R.sup.5 is not halo or alkoxy when ring B is an aromatic monocyclic
carbocycle or heterocyle and m is 2-5, or R.sup.3 and R.sup.4 are
not both H and ring A is not thiophene when ring B is an aromatic
polycyclic carbocycle or heterocyle; when L is ring C, m is not 0
when ring B is phenyl or pyrrolyl and R.sup.3 is H,
(C.sub.1-C.sub.6)alkyl, or forms a 5-7 membered heterocycle
together with one R.sup.5, or R.sup.5 is not halo when R.sup.3 and
R.sup.4, together with the N to which they are connected, form a
4-7 membered heterocycle, one R.sup.6 is halo, and m is 1; and when
L is a bond, m is not 0 when ring B is phenyl or pyrrolyl and
R.sup.3 is H or (C.sub.1-C.sub.6)alkyl, or m' is not 0 when R.sup.3
and one R.sup.5, together with the atoms to which they are
connected, form a 5-7 membered heterocycle, R.sup.5 is not halo or
alkoxy when ring B is phenyl, R.sup.3 and one R.sup.5, together
with the atoms to which they are connected, form a 5-7 membered
heterocycle, and m' is 1, or R.sup.5 is not --OH when ring B is a
7-membered carbocycle, R.sup.3 and one R.sup.5, together with the
atoms to which they are connected, form a 5-7 membered heterocycle,
and m' is 1, or m is not 0 when ring B is a monocyclic carbocycle
or heterocyle and R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl or R.sup.3 and R.sup.4, together with the N to
which they are connected, form a 4-7 membered heterocycle, or
R.sup.5 is not halo when ring B is phenyl and R.sup.3 and R.sup.4
are each H or R.sup.3 and R.sup.4, together with the N to which
they are connected, form a 4-7 membered heterocycle, or n is not 0
when ring A is imidazolyl and ring B is phenyl.
2. The compound of claim 1 having the structure of formula (II):
##STR00479## or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, isotope, or salt thereof, wherein: ring A is
carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and
Q.sup.5 are each, independently, C or N; wherein 0, 1, or 2 of
Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5 is N; m is 0-5; n
is 0-5; q is 0-5; r is 0-5; and t is 0-2; with the provisos that:
when L is --(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, m is
not 0 and at least one R.sup.5 is not --OH, halo, or alkoxy, or at
least one R.sup.5 is not halo when m is 2-5; or when L is ring C, m
is not 0 when Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5 are
each, independently, C and R.sup.3 is H, (C.sub.1-C.sub.6)alkyl, or
forms a 5-7 membered heterocycle together with one R.sup.5, or
R.sup.5 is not halo when R.sup.3 and R.sup.4, together with the N
to which they are connected, form a 4-7 membered heterocycle, one
R.sup.6 is halo, and m is 1; and when L is a bond, m is not 0 when
Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5 are each,
independently, C and and R.sup.3 is H or (C.sub.1-C.sub.6)alkyl, or
m' is not 0 when R.sup.3 and one R.sup.5, together with the atoms
to which they are connected, form a 5-7 membered heterocycle,
R.sup.5 is not halo or alkoxy when Q.sup.1, Q.sup.2, Q.sup.3,
Q.sup.4, and Q.sup.5 are each, independently, C and, R.sup.3 and
one R.sup.5, together with the atoms to which they are connected,
form a 5-7 membered heterocycle, and m' is 1, or m is not 0 when
R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl or R.sup.3 and R.sup.4, together with the N to
which they are connected, form a 4-7 membered heterocycle, or
R.sup.5 is not halo when Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and
Q.sup.5 are each, independently, C and R.sup.3 and R.sup.4 are each
H or R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or n is not 0 when ring
A is imidazolyl and Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5
are each, independently, C.
3. The compound of claim 1 or 2 having the structure of Formula
(III): ##STR00480## or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein: ring
A is carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; m is 0-5; n is 0-5; q is 0-5; r is 0-5; and
t is 0-2; with the provisos that: when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, m is not 0 and
at least one R.sup.5 is not --OH, halo, or alkoxy, or at least one
R.sup.5 is not halo when m is 2-5; or when L is ring C, m is not 0
when R.sup.3 is H, (C.sub.1-C.sub.6)alkyl, or forms a 5-7 membered
heterocycle together with one R.sup.5, or R.sup.5 is not halo when
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, one R.sup.6 is halo,
and m is 1; and when L is a bond, m is not 0 when R.sup.3 is H or
(C.sub.1-C.sub.6)alkyl, or m' is not 0 when R.sup.3 and one
R.sup.5, together with the atoms to which they are connected, form
a 5-7 membered heterocycle, R.sup.5 is not halo or alkoxy when
R.sup.3 and one R.sup.5, together with the atoms to which they are
connected, form a 5-7 membered heterocycle, and m' is 1, or m is
not 0 when R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl or R.sup.3 and R.sup.4, together with the N to
which they are connected, form a 4-7 membered heterocycle, or
R.sup.5 is not halo when R.sup.3 and R.sup.4 are each H or R.sup.3
and R.sup.4, together with the N to which they are connected, form
a 4-7 membered heterocycle, or n is not 0 when ring A is
imidazolyl.
4. The compound of any one of claims 1-3, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.5 is --C(O)NR.sup.1R.sup.2 and
having the structure of Formula (IV): ##STR00481## or a
pharmaceutically acceptable isomer, racemate, hydrate, solvate,
isotope, or salt thereof, wherein: ring A is carbocycle or
heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; m' is 0-4; n is 0-5; q is 0-5; r is 0-5;
and t is 0-2.
5. The compound of claim any one of claims 1-4 having the structure
of Formula (V): ##STR00482## or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein: ring A is carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; m' is 0-4; n is 0-5; q is 0-5; r is 0-5;
and t is 0-2.
6. The compound of claim any one of claims 1-4 having the structure
of Formula (VI): ##STR00483## or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein: ring A is carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; m' is 0-4; n is 0-5; q is 0-5; r is 0-5;
and t is 0-2.
7. The compound of claim 2, wherein Q.sup.1, Q.sup.2, Q.sup.3, and
Q.sup.4 are each C, and Q.sup.5 is N and having the structure of
Formula (VII): ##STR00484## or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein: ring A is carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; m is 0-5; n is 0-5; q is 0-5; r is 0-5; and
t is 0-2; with the provisos that: when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, m is not 0 and
at least one R.sup.5 is not --OH, halo, or alkoxy, or at least one
R.sup.5 is not halo when m is 2-5; and when L is ring C, R.sup.5 is
not halo when R.sup.3 and R.sup.4, together with the N to which
they are connected, form a 4-7 membered heterocycle, one R.sup.6 is
halo, and m is 1; and when L is a bond, m' is not 0 when R.sup.3
and one R.sup.5, together with the atoms to which they are
connected, form a 5-7 membered heterocycle, or m is not 0 when ring
B is a monocyclic carbocycle or heterocyle and R.sup.3 and R.sup.4
are each, independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle.
8. The compound of claim 7 having the structure of Formula (VIII):
##STR00485## or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, isotope, or salt thereof, wherein: ring A is
carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; m' is 0-4; n is 0-5; q is 0-5; r is 0-5;
and t is 0-2.
9. The compound of claim 1 having the structure of Formula (IX):
##STR00486## or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, isotope, or salt thereof, wherein: ring A is
carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; Q.sup.1, Q.sup.4, and Q.sup.5 are each,
independently, C or N; Q.sup.2 and Q.sup.3 are each C; ring D is a
5-6 membered carbocycle or heterocycle which forms, together with
Q.sup.2 and Q.sup.3, a fused bicyclic ring B; m is 0-5; n is 0-5; q
is 0-5; r is 0-5; and t is 0-2; with the proviso that: when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, R.sup.3 and
R.sup.4 are not both H, and ring A is not thiophene.
10. The compound of claim 1 having the structure of Formula (X):
##STR00487## or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, isotope, or salt thereof, wherein: ring A is
carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; Q.sup.1, Q.sup.4, and Q.sup.5 are each,
independently, C or N; m is 0-5; n is 0-5; q is 0-5; r is 0-5; and
t is 0-2.
11. The compound of claim 1 having the structure of Formula (XI):
##STR00488## or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, isotope, or salt thereof, wherein: ring A is
carbocycle or heterocycle; L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C; Q
is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--; ring C is a
C.sub.3-C.sub.7 cycloalkyl or 3-7 membered heterocycloalkyl,
substituted with 0-5 R.sup.7; each R.sup.a is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 and R.sup.2 are each,
independently, H, or (C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7
cycloalkyl substituted with 0-5 halo; R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl; or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle; R.sup.5, R.sup.6, and
R.sup.7 are each, independently, --C(O)NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1, --C(O)OR.sup.1,
--S(O).sub.tNR.sup.1R.sup.2, --NR.sup.1S(O).sub.tR.sup.2, --OH,
--CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or carbocycle;
or R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle; R.sup.8 is H or
(C.sub.1-C.sub.6)alkyl; Q.sup.1, Q.sup.4, and Q.sup.5 are each,
independently, C or N; m is 0-5; n is 0-5; q is 0-5; r is 0-5; and
t is 0-2.
12. The compound of any one of claims 1-11, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein ring A is an aromatic carbocycle.
13. The compound of claim 12, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein ring A is phenyl.
14. The compound of any one of claims 1-11, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein ring A is an aromatic heterocycle.
15. The compound of claim 14, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein ring A is pyrrolyl, furanyl, pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl,
indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl,
benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydro indolyl,
benzoxazolone, or pyrazolopyridine.
16. The compound of claim 1, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein ring B is pyrrolyl, furanyl, pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl,
azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl,
benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydro indolyl,
benzoxazolone, or pyrazolopyridine.
17. The compound of any one of claims 1-16, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r.
18. The compound of claim 17, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein q is 0.
19. The compound of any one of claims 1-18, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein Q is --O--.
20. The compound of any one of claims 1-18, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein Q is --C(R.sup.a).sub.2--.
21. The compound of any one of claims 1-18, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein Q is --NR.sup.a--.
22. The compound of any one of claims 1-16, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein L is ring C.
23. The compound of claim 22, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein ring C is cyclopropyl.
24. The compound of claim 22, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein ring C is pyrrolidinyl.
25. The compound of any one of claims 1-16, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein L is a bond.
26. The compound of any one of claims 1-25, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, carbocycle, or carbocyclealkyl.
27. The compound of any one of claims 1-26, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.3 and R.sup.4 are each methyl or ethyl.
28. The compound of any one of 1-26, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.3 and R.sup.4 are each H.
29. The compound of any one of claims 1-26, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.3 is methyl and R.sup.4 is
cyclopropylmethyl.
30. The compound of any one of claims 1-25, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.3 and R.sup.4, together with the N to which
they are connected, form a 4-7 membered heterocycle.
31. The compound of claim 30, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein R.sup.3 and R.sup.4, together with the N to which they are
connected, form pyrrolidinyl or mopholinyl.
32. The compound of any one of claims 1-25, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.3 and one R.sup.5, together with the atoms
to which they are connected, form a 5-7 membered heterocycle.
33. The compound of any one of claims 1-32, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.5 is --OH.
34. The compound of any one of claims 1-32, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.5 is --C(O)NR.sup.1R.sup.2.
35. The compound of any one of claims 1-32, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.5 is halo.
36. The compound of claim 35, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.5 is Cl or F.
37. The compound of any one of claims 1-32, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.5 is
(C.sub.1-C.sub.6)alkyl.
38. The compound of claim 37, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.5 is methyl.
39. The compound of any one of claims 1-32, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.5 is --OC(O)R.sup.1.
40. The compound of any one of claims 1-39, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.6 is carbocycle.
41. The compound of claim 40, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.6 is cycloalkyl.
42. The compound of claim 41, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.6 is cyclopropyl.
43. The compound of claim 1-39, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.6 is an aromatic carbocycle.
44. The compound of claim 43, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.6 is phenyl.
45. The compound of any one of claims 1-39, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.6 is halo.
46. The compound of claim 39, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.6 is Cl, F or Br.
47. The compound of any one of claims 1-39, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.6 is
(C.sub.1-C.sub.6)alkyl.
48. The compound of claim 47, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein the at least one R.sup.6 is methyl.
49. The compound of any one of claims 1-39, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein at least one R.sup.6 is
(C.sub.1-C.sub.6)alkoxy.
50. The compound of claim 49, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein the at least one R.sup.6 is methoxy.
51. The compound of any one of claims 1-16 and 22-24, or a
pharmaceutically acceptable isomer, racemate, hydrate, solvate,
isotope, or salt thereof, wherein at least one R.sup.7 is
(C.sub.1-C.sub.6)alkyl.
52. The compound of claim 51, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.7 is methyl, ethyl, isopropyl, or
t-butyl.
53. The compound of any one of claims 1-16 and 22-24, or a
pharmaceutically acceptable isomer, racemate, hydrate, solvate,
isotope, or salt thereof, wherein at least one R.sup.7 is
carbocycle.
54. The compound of claim 53, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.7 is cycloalkyl.
55. The compound of claim 54, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein at least one R.sup.7 is cyclopropyl.
56. The compound of any one of claims 1-55, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.8 is H.
57. The compound of any one of claims 1-55, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein R.sup.8 is methyl.
58. The compound of claim 1, or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
having the structure of any one of the compounds listed in Table 1,
Table 2, or Table 3.
59. A pharmaceutical composition comprising a compound of any one
of claims 1-58, or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, isotope, or salt thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient.
60. A method of modulating an opioid receptor comprising contacting
the opioid receptor with an effective amount of a compound of any
one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
61. The method of claim 60, wherein the compound is mu opioid
receptor agonist.
62. The method of claim 60 or 61, wherein the compound is a kappa
opioid receptor antagonist.
63. The method of any one of claims 60-62, wherein the method does
not modulate arrestin function.
64. A method of treating pain, comprising administering to a
subject in need thereof an effective amount of a compound of any
one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
65. The method of claim 64, wherein the method does not increase
the risk of respiratory depression or constipation in the
subject.
66. The method of claim 64, wherein the pain is acute pain.
67. The method of claim 64, wherein the pain is chronic pain.
68. The method of claim 64, wherein the pain is fibromyalgia,
neuropathic pain, chronic low back pain, surgical pain, cancer
pain, or severe pain.
69. A method of treating opioid overdose, comprising administering
to a subject in need thereof an effective amount of a compound of
any one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
70. A method of treating addiction, comprising administering to a
subject in need thereof an effective amount of a compound of any
one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
71. The method of claim 70, wherein the addiction is opioid use
disorder.
72. The method of claim 70, wherein the method comprises
maintenance of the opioid use disorder in a subject in need
thereof.
73. A method of treating a neuropsychiatric disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of any one of claims 1-58, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof.
74. The method of claim 73, wherein the neuropsychiatric disorder
is characterized by compulsive behavior.
75. The method of claim 73, wherein the neuropsychiatric disorder
characterized by compulsive behavior is obsessive compulsive
disorder, trichotillomania, or skin picking.
76. The method of claim 75, wherein the compulsive behavior is
associated with a neurodegenerative disorder.
77. The method of claim 76, wherein the neurodegenerative disorder
is Huntington's disease or Parkinson's disease.
78. The method of claim 73, wherein the neuropsychiatric disorder
is characterized by impulsive behavior.
79. The method of claim 78, wherein the neuropsychiatric disorder
characterized by impulsive behavior is addiction, pathological
gambling, alcohol use disorder, nicotine addiction, sex addiction,
Tourette syndrome, or kleptomania.
80. The method of claim 78, wherein the impulsive behaviour is
associated with a neurodegenerative disorder.
81. The method of claim 80, wherein the neurodegenerative disorder
is frontotemporal dementia or Alzheimer's disorder.
82. The method of claim 73, wherein the neuropsychiatric disorder
is characterized by depressive mood.
83. The method of claim 82, wherein the neuropsychiatric disorder
characterized by depressive mood is major depressive disorder,
anxiety disorder, panic disorder, dysphoria, or anhedonia.
84. The method of claim 73, wherein the neuropsychiatric disorder
is an eating disorder.
85. The method of claim 84, wherein the eating disorder is anorexia
nervosa, bulimia nervosa, binge eating disorder, or obesity.
86. A method of treating a sleep disorder, comprising administering
to a subject in need thereof an effective amount of a compound of
any one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
87. The method of claim 86, wherein the sleep disorder is sleep
disruption.
88. The method of claim 87, wherein the sleep disruption is
associated with a neurodegenerative disorder.
89. The method of claim 88, wherein the neurodegenerative disorder
is supranuclear palsy.
90. A method of treating a gastrointestinal disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of any one of claims 1-58, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof.
91. The method of claim 90, wherein the gastrointestinal disorder
is constipation, diarrhea, irritable bowel syndrome, inflammatory
bowel disease, or Crohn's disease.
92. A method of treating a skin disorder, comprising administering
to a subject in need thereof an effective amount of a compound of
any one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
93. The method of claim 92, wherein the skin disorder is itching or
urticaria.
94. A method of treating dyspnea, comprising administering to a
subject in need thereof an effective amount of a compound of any
one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
95. The method of claim 73, wherein the neuropsychiatric disorder
is Schizophrenia, psychosis, or bipolar disorder.
96. A method of treating autism spectrum disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of any one of claims 1-58, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof.
97. A method of treating Prader-Willi Syndrome, comprising
administering to a subject in need thereof an effective amount of a
compound of any one of claims 1-58, or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof.
98. A method of treating headache, comprising administering to a
subject in need thereof an effective amount of a compound of any
one of claims 1-58, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof.
99. The method of claim 98, wherein the headache is migraine.
100. A method of treating temporomandibular joint dysfunction,
comprising administering to a subject in need thereof an effective
amount of a compound of any one of claims 1-58, or a
pharmaceutically acceptable isomer, racemate, hydrate, solvate,
isotope, or salt thereof.
Description
FIELD OF THE INVENTION
[0001] The invention relates to opioid receptor modulators, and
particularly to compounds that modulate the mu-opioid receptor
(MOR) and/or the kappa-opioid receptor (KOR), and/or the
delta-opioid receptor (DOR), as well as to products containing the
same and to methods of their use and preparation.
BACKGROUND
[0002] Opioid receptors are a group of inhibitory G protein-coupled
receptors with opioids as ligands, which have long been used to
treat pain. Opioids generally act on these receptors as agonists,
antagonists, or partial agonists. There are three classical opioid
receptors, originally named mu (after morphine, its most commonly
recognized exogenous ligand), delta (after vas deferens, the tissue
within which it was first isolated) and kappa (after the first
ligand to act at this receptor, ketocyclazocine). These opioid
receptors are distributed widely within the central nervous system
and, to a lesser extent, throughout the periphery. Opioids, whether
naturally occurring or synthetic, exhibit any number of problematic
side effects, such as constipation, addiction and respiratory
depression, and efforts to eliminate such attributes have been meet
with only limited successes. Accordingly, there remains a need in
the art for agents that can modulate opioid receptors in a manner
that limit the side effects normally associated with such
agents.
BRIEF SUMMARY
[0003] In one embodiment, compounds are provided having the
structure of Formula (I):
##STR00002##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein A, B, L, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.8, m and n are as defined
below.
[0004] In more specific embodiments, compounds are provided having
the structure of any one of Formulas (II) through (XI), or any one
of the compounds listed in any one of Tables 1, 2 or 3. In further
embodiments, compounds are provided of Formula (I), or any one of
Formulas (II) through (XI), with the various applicable provisos
provided below.
[0005] In another embodiment, a pharmaceutical composition is
provided comprising a compound of any of the embodiments disclosed
herein in combination with a pharmaceutically acceptable carrier,
diluent, or excipient.
[0006] In another embodiment, a method is provided for modulating
an opioid receptor comprising contacting the opioid receptor with
an effective amount of a compound as provided herein, or a
pharmaceutically acceptable isomer, racemate, hydrate, solvate,
isotope, or salt thereof, or a pharmaceutical composition
comprising the same. In more specific embodiments, the compound is
a mu opioid receptor agonist and/or a kappa opioid receptor
antagonist.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 illustrates that MOR agonist Compound B-56 is an
analgesic in the hotplate test, increasing the time to exhibit a
withdrawal response. FIG. 1 also illustrates that MOR antagonists
Compound B-15 blocks in vivo the analgesic activity of the agonist
Compound B-56 when co-dosed, but has no effect on its own.
[0008] FIG. 2 illustrates that MOR antagonist Compound B-15 blocks
in vivo the respiratory depression of the MOR agonist fentanyl.
DETAILED DESCRIPTION
[0009] Unless specifically defined otherwise, the technical terms,
as used herein, have their normal meaning as understood in the art.
The following explanations of terms and methods are provided to
better describe the present compounds, compositions and methods,
and to guide those of ordinary skill in the art in the practice of
the present disclosure. It is also to be understood that the
terminology used in the disclosure is for the purpose of describing
particular embodiments and examples only and is not intended to be
limiting.
[0010] As used herein, the singular terms "a," "an," and "the"
include plural referents unless context clearly indicates
otherwise. Similarly, the word "or" is intended to include "and"
unless the context clearly indicates otherwise. Also, as used
herein, the term "comprises" means "includes." Thus the phrase
"comprising A or B" means including A, B, or A and B.
[0011] As mentioned above, the invention relates to compounds that
modulate one, two or three of the mu opioid receptor (MOR), the
kappa opioid receptor (KOR) and/or the delta opioid receptor (DOR).
As used herein, a "modulator" of MOR and/or KOR and/or DOR a
compound which, when administered to a subject, provides the
desired modulation of the target receptor. For example, the
compound may function as a full or partial antagonist or agonist of
the receptor, either by interacting directly or indirectly with the
target receptor. In one embodiment, the compounds is a MOR agonist,
a KOR antagonist, or both a MOR agonist and a KOR antagonist.
[0012] In one embodiment, compounds are provided having the
structure of Formula (I):
##STR00003##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0013] ring A is carbocycle or heterocycle;
[0014] ring B is carbocycle or heterocycle;
[0015] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0016] Q is --C(R.sup.a), --NR.sup.a--, or --O--;
[0017] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0018] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0019] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0020] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0021] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0022] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0023] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0024] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0025] m is 0-5;
[0026] n is 0-5;
[0027] q is 0-5;
[0028] r is 0-5; and
[0029] t is 0-2.
[0030] As used herein, "alkyl" means a straight chain or branched
saturated hydrocarbon group. "Lower alkyl" means a straight chain
or branched alkyl group having from 1 to 8 carbon atoms, in some
embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to
4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms.
Examples of straight chain lower alkyl groups include, but are not
limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,
n-heptyl, and n-octyl groups. Examples of branched lower alkyl
groups include, but are not limited to, isopropyl, iso-butyl,
sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl
groups.
[0031] As used herein, "alkylene" means a divalent alkyl group.
Examples of straight chain lower alkylene groups include, but are
not limited to, methylene (i.e., --CH.sub.2--), ethylene (i.e.,
--CH.sub.2CH.sub.2--), propylene (i.e.,
--CH.sub.2CH.sub.2CH.sub.2--), and butylene (i.e.,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2-). As used herein,
"heteroalkylene" is an alkylene group of which one or more carbon
atoms is replaced with a heteroatom such as, but not limited to, N,
O, S, or P.
[0032] "Alkoxy" refers to an alkyl as defined above joined by way
of an oxygen atom (i.e., --O-alkyl). Examples of lower alkoxy
groups include, but are not limited to, methoxy, ethoxy, n-propoxy,
n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.
[0033] The terms "carbocyclic" and "carbocycle" denote a ring
structure wherein the atoms of the ring are carbon. Carbocycles may
be monocyclic or polycyclic. Carbocycle encompasses both saturated
and unsaturated rings. Carbocycle encompasses both cycloalkyl and
aryl groups. In some embodiments, the carbocycle has 3 to 8 ring
members, whereas in other embodiments the number of ring carbon
atoms is 4, 5, 6, or 7. Unless specifically indicated to the
contrary, the carbocyclic ring can be substituted with as many as N
substituents wherein N is the size of the carbocyclic ring with for
example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and
halogen groups.
[0034] "Cycloalkyl" groups are alkyl groups forming a ring
structure, which can be substituted or unsubstituted. Examples of
cycloalkyl include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl
groups. In some embodiments, the cycloalkyl group has 3 to 8 ring
members, whereas in other embodiments the number of ring carbon
atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups
further include polycyclic cycloalkyl groups such as, but not
limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl,
and carenyl groups, and fused rings such as, but not limited to,
decalinyl, and the like. Cycloalkyl groups also include rings that
are substituted with straight or branched chain alkyl groups as
defined above. Representative substituted cycloalkyl groups can be
mono-substituted or substituted more than once, such as, but not
limited to, 2,2-, 2,3-, 2,4-2,5- or 2,6-disubstituted cyclohexyl
groups or mono-, di- or tri-substituted norbornyl or cycloheptyl
groups, which can be substituted with, for example, amino, hydroxy,
cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
[0035] "Aryl" groups are cyclic aromatic hydrocarbons that do not
contain heteroatoms. Thus aryl groups include, but are not limited
to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,
phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,
biphenylenyl, anthracenyl, and naphthyl groups. In some
embodiments, aryl groups contain 6-14 carbons in the ring portions
of the groups. The terms "aryl" and "aryl groups" include include
fused rings wherein at least one ring, but not necessarily all
rings, are aromatic, such as fused aromatic-aliphatic ring systems
(e.g., indanyl, tetrahydronaphthyl, and the like).
[0036] As used herein, "heterocycle" or "heterocyclyl" groups
include aromatic and non-aromatic ring compounds (heterocyclic
rings) containing 3 or more ring members, of which one or more is a
heteroatom such as, but not limited to, N, O, S, or P. A
heterocyclyl group as defined herein can be a heteroaryl group or a
partially or completely saturated cyclic group including at least
one ring heteroatom. In some embodiments, heterocyclyl groups
include 3 to 20 ring members, whereas other such groups have 3 to
15 ring members. At least one ring contains a heteroatom, but every
ring in a polycyclic system need not contain a heteroatom. For
example, a dioxolanyl ring and a benzdioxolanyl ring system
(methylenedioxyphenyl ring system) are both heterocyclyl groups
within the meaning herein. A heterocyclyl group designated as a
C.sub.2-heterocyclyl can be a 5-membered ring with two carbon atoms
and three heteroatoms, a 6-membered ring with two carbon atoms and
four heteroatoms and so forth. Likewise a C.sub.4-heterocyclyl can
be a 5-membered ring with one heteroatom, a 6-membered ring with
two heteroatoms, and so forth. The number of carbon atoms plus the
number of heteroatoms sums up to equal the total number of ring
atoms. A saturated heterocyclic ring refers to a heterocyclic ring
containing no unsaturated carbon atoms.
[0037] "Heteroaryl" groups are aromatic ring compounds containing 5
or more ring members, of which, one or more is a heteroatom such
as, but not limited to, N, O, and S. A heteroaryl group designated
as a C2-heteroaryl can be a 5-membered ring with two carbon atoms
and three heteroatoms, a 6-membered ring with two carbon atoms and
four heteroatoms and so forth. Likewise a C4-heteroaryl can be a
5-membered ring with one heteroatom, a 6-membered ring with two
heteroatoms, and so forth. The number of carbon atoms plus the
number of heteroatoms sums up to equal the total number of ring
atoms. Heteroaryl groups include, but are not limited to, groups
such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,
isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,
benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,
azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,
xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and
quinazolinyl groups. The terms "heteroaryl" and "heteroaryl groups"
include fused ring compounds such as wherein at least one ring, but
not necessarily all rings, are aromatic, including
tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and
2,3-dihydro indolyl.
[0038] "Halo" or "halogen" refers to fluorine, chlorine, bromine
and iodine.
[0039] "Haloalkyl" refers to an alkyl as defined above with one or
more hydrogen atoms replaced with halogen. Examples of lower
haloalkyl groups include, but are not limited to, --CF.sub.3,
--CH.sub.2CF.sub.3, and the like.
[0040] As used herein, the term "optionally substituted" refers to
a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1,
or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents.
Substituents include, but are not limited to, halo, cyano, --OR',
--NR'R'', --S(O).sub.2R' or --S(O).sub.2OR', wherein each R' and
R'' is, independently, H or alkyl.
[0041] In one embodiment, compounds are provided having the
structure of Formula (I):
##STR00004##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0042] ring A is carbocycle or heterocycle;
[0043] ring B is carbocycle or heterocycle;
[0044] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0045] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0046] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0047] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0048] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0049] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0050] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0051] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0052] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0053] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0054] m is 0-5;
[0055] n is 0-5;
[0056] q is 0-5;
[0057] r is 0-5; and
[0058] t is 0-2;
with the provisos that:
[0059] when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, [0060] m is
not 0 and at least one R.sup.5 is not --OH, halo, or alkoxy when
ring B is an aromatic monocyclic carbocycle or heterocyle, or
[0061] at least one R.sup.5 is not halo when ring B is an aromatic
monocyclic carbocycle or heterocyle and m is 2-5, or [0062] R.sup.3
and R.sup.4 are not both H and ring A is not thiophene when ring B
is an aromatic polycyclic carbocycle or heterocyle;
[0063] when L is ring C, [0064] m is not 0 when ring B is phenyl or
pyrrolyl and R.sup.3 is H, (C.sub.1-C.sub.6)alkyl, or forms a 5-7
membered heterocycle together with one R.sup.5, or [0065] R.sup.5
is not halo when R.sup.3 and R.sup.4, together with the N to which
they are connected, form a 4-7 membered heterocycle, one R.sup.6 is
halo, and m is 1; and
[0066] when L is a bond, [0067] m is not 0 when ring B is phenyl or
pyrrolyl and R.sup.3 is H or (C.sub.1-C.sub.6)alkyl, or [0068] m'
is not 0 when R.sup.3 and one R.sup.5, together with the atoms to
which they are connected, form a 5-7 membered heterocycle, [0069]
R.sup.5 is not halo or alkoxy when ring B is phenyl, R.sup.3 and
one R.sup.5, together with the atoms to which they are connected,
form a 5-7 membered heterocycle, and m' is 1, or [0070] R.sup.5 is
not --OH when ring B is a 7-membered carbocycle, R.sup.3 and one
R.sup.5, together with the atoms to which they are connected, form
a 5-7 membered heterocycle, and m' is 1, or [0071] m is not 0 when
ring B is a monocyclic carbocycle or heterocyle and R.sup.3 and
R.sup.4 are each, independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or [0072] R.sup.5 is
not halo when ring B is phenyl and R.sup.3 and R.sup.4 are each H
or R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or [0073] n is not 0
when ring A is imidazolyl and ring B is phenyl.
[0074] Accordingly, in one embodiment compounds are provided having
the structure of Formula (I), or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, isotope, or salt thereof,
wherein L is --(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r and
with the provisos that: [0075] m is not 0 and at least one R.sup.5
is not --OH, halo, or alkoxy when ring B is an aromatic monocyclic
carbocycle or heterocyle, or [0076] at least one R.sup.5 is not
halo when ring B is an aromatic monocyclic carbocycle or heterocyle
and m is 2-5, or [0077] R.sup.3 and R.sup.4 are not both H and ring
A is not thiophene when ring B is an aromatic polycyclic carbocycle
or heterocyle.
[0078] Accordingly, in another embodiment compounds are provided
having the structure of Formula (I), or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein L is ring C and with the provisos that: [0079] m
is not 0 when ring B is phenyl or pyrrolyl and R.sup.3 is H,
(C.sub.1-C.sub.6)alkyl, or forms a 5-7 membered heterocycle
together with one R.sup.5, or [0080] R.sup.5 is not halo when
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, one R.sup.6 is halo,
and m is 1.
[0081] Accordingly, in another embodiment compounds are provided
having the structure of Formula (I), or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, isotope, or salt
thereof, wherein L is a bond and with the proviso that: [0082] m is
not 0 when ring B is phenyl or pyrrolyl and R.sup.3 is H or
(C.sub.1-C.sub.6)alkyl, or [0083] m' is not 0 when R.sup.3 and one
R.sup.5, together with the atoms to which they are connected, form
a 5-7 membered heterocycle, [0084] R.sup.5 is not halo or alkoxy
when ring B is phenyl, R.sup.3 and one R.sup.5, together with the
atoms to which they are connected, form a 5-7 membered heterocycle,
and m' is 1, or [0085] R.sup.5 is not --OH when ring B is a
7-membered carbocycle, R.sup.3 and one R.sup.5, together with the
atoms to which they are connected, form a 5-7 membered heterocycle,
and m' is 1, or [0086] m is not 0 when ring B is a monocyclic
carbocycle or heterocyle and R.sup.3 and R.sup.4 are each,
independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or [0087] R.sup.5 is
not halo when ring B is phenyl and R.sup.3 and R.sup.4 are each H
or R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or [0088] n is not 0
when ring A is imidazolyl and ring B is phenyl.
[0089] In one embodiment, compounds are provided having the
structure of Formula (II):
##STR00005##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0090] ring A is carbocycle or heterocycle;
[0091] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0092] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0093] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0094] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0095] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0096] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0097] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0098] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0099] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0100] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0101] Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5 are each,
independently, C or N; wherein 0, 1, or 2 of Q.sup.1, Q.sup.2,
Q.sup.3, Q.sup.4, and Q.sup.5 is N;
[0102] m is 0-5;
[0103] n is 0-5;
[0104] q is 0-5;
[0105] r is 0-5; and
[0106] t is 0-2;
with the provisos that:
[0107] when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, [0108] m is
not 0 and at least one R.sup.5 is not --OH, halo, or alkoxy, or
[0109] at least one R.sup.5 is not halo when m is 2-5; or
[0110] when L is ring C, [0111] m is not 0 when Q.sup.1, Q.sup.2,
Q.sup.3, Q.sup.4, and Q.sup.5 are each, independently, C and
R.sup.3 is H, (C.sub.1-C.sub.6)alkyl, or forms a 5-7 membered
heterocycle together with one R.sup.5, or [0112] R.sup.5 is not
halo when R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle, one R.sup.6 is
halo, and m is 1; and
[0113] when L is a bond, [0114] m is not 0 when Q.sup.1, Q.sup.2,
Q.sup.3, Q.sup.4, and Q.sup.5 are each, independently, C and and
R.sup.3 is H or (C.sub.1-C.sub.6)alkyl, or [0115] m' is not 0 when
R.sup.3 and one R.sup.5, together with the atoms to which they are
connected, form a 5-7 membered heterocycle, [0116] R.sup.5 is not
halo or alkoxy when Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5
are each, independently, C and, R.sup.3 and one R.sup.5, together
with the atoms to which they are connected, form a 5-7 membered
heterocycle, and m' is 1, or [0117] m is not 0 when R.sup.3 and
R.sup.4 are each, independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or [0118] R.sup.5 is
not halo when Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4, and Q.sup.5 are
each, independently, C and R.sup.3 and R.sup.4 are each H or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or [0119] n is not 0
when ring A is imidazolyl and Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4,
and Q.sup.5 are each, independently, C.
[0120] In one embodiment, compounds are provided having the
structure of Formula (III):
##STR00006##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0121] ring A is carbocycle or heterocycle;
[0122] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0123] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0124] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0125] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0126] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0127] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0128] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0129] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0130] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0131] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0132] m is 0-5;
[0133] n is 0-5;
[0134] q is 0-5;
[0135] r is 0-5; and
[0136] t is 0-2;
with the provisos that:
[0137] when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, [0138] m is
not 0 and at least one R.sup.5 is not --OH, halo, or alkoxy, or
[0139] at least one R.sup.5 is not halo when m is 2-5; or
[0140] when L is ring C, [0141] m is not 0 when R.sup.3 is H,
(C.sub.1-C.sub.6)alkyl, or forms a 5-7 membered heterocycle
together with one R.sup.5, or [0142] R.sup.5 is not halo when
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, one R.sup.6 is halo,
and m is 1; and
[0143] when L is a bond, [0144] m is not 0 when R.sup.3 is H or
(C.sub.1-C.sub.6)alkyl, or [0145] m' is not 0 when R.sup.3 and one
R.sup.5, together with the atoms to which they are connected, form
a 5-7 membered heterocycle, [0146] R.sup.5 is not halo or alkoxy
when R.sup.3 and one R.sup.5, together with the atoms to which they
are connected, form a 5-7 membered heterocycle, and m' is 1, or
[0147] m is not 0 when R.sup.3 and R.sup.4 are each, independently,
H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle,
or carbocyclealkyl or R.sup.3 and R.sup.4, together with the N to
which they are connected, form a 4-7 membered heterocycle, or
[0148] R.sup.5 is not halo when R.sup.3 and R.sup.4 are each H or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle, or [0149] n is not 0
when ring A is imidazolyl.
[0150] In one embodiment, compounds are provided having the
structure of Formula (IV):
##STR00007##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0151] ring A is carbocycle or heterocycle;
[0152] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0153] Q is --C(R.sup.a)--, --NR.sup.a--, or --O--;
[0154] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0155] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0156] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0157] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0158] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0159] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0160] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0161] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0162] m' is 0-4;
[0163] n is 0-5;
[0164] q is 0-5;
[0165] r is 0-5; and
[0166] t is 0-2.
[0167] In one embodiment, compounds are provided having the
structure of Formula (V):
##STR00008##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0168] ring A is carbocycle or heterocycle;
[0169] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0170] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0171] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0172] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0173] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0174] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0175] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0176] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0177] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0178] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0179] m' is 0-4;
[0180] n is 0-5;
[0181] q is 0-5;
[0182] r is 0-5; and
[0183] t is 0-2.
[0184] In one embodiment, compounds are provided having the
structure of Formula (VI):
##STR00009##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0185] ring A is carbocycle or heterocycle;
[0186] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0187] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0188] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0189] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0190] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0191] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0192] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0193] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0194] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0195] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0196] m' is 0-4;
[0197] n is 0-5;
[0198] q is 0-5;
[0199] r is 0-5; and
[0200] t is 0-2.
[0201] In one embodiment, compounds are provided wherein Q.sup.1,
Q.sup.2, Q.sup.3, and Q.sup.4 are each C, and Q.sup.5 is N and
having the structure of Formula (VII):
##STR00010##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0202] ring A is carbocycle or heterocycle;
[0203] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0204] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0205] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0206] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0207] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0208] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0209] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0210] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2, --NRS(O).sub.tR.sup.2,
--OH, --CN, halo, oxo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, or
carbocycle;
[0211] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0212] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0213] m is 0-5;
[0214] n is 0-5;
[0215] q is 0-5;
[0216] r is 0-5; and
[0217] t is 0-2;
with the provisos that:
[0218] when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, [0219] m is
not 0 and at least one R.sup.5 is not --OH, halo, or alkoxy, or
[0220] at least one R.sup.5 is not halo when m is 2-5; and
[0221] when L is ring C, [0222] R.sup.5 is not halo when R.sup.3
and R.sup.4, together with the N to which they are connected, form
a 4-7 membered heterocycle, one R.sup.6 is halo, and m is 1;
and
[0223] when L is a bond, [0224] m' is not 0 when R.sup.3 and one
R.sup.5, together with the atoms to which they are connected, form
a 5-7 membered heterocycle, or [0225] m is not 0 when ring B is a
monocyclic carbocycle or heterocyle and R.sup.3 and R.sup.4 are
each, independently, H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, carbocycle, or carbocyclealkyl or
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle.
[0226] In one embodiment, compounds are provided having the
structure of Formula (VIII):
##STR00011##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0227] ring A is carbocycle or heterocycle;
[0228] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0229] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0230] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0231] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0232] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0233] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0234] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0235] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0236] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0237] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0238] m' is 0-4;
[0239] n is 0-5;
[0240] q is 0-5;
[0241] r is 0-5; and
[0242] t is 0-2.
[0243] In one embodiment, compounds are provided having the
structure of Formula (IX):
##STR00012##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0244] ring A is carbocycle or heterocycle;
[0245] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0246] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0247] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0248] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0249] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0250] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0251] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0252] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0253] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0254] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0255] Q.sup.1, Q.sup.4, and Q.sup.5 are each, independently, C or
N;
[0256] Q.sup.2 and Q.sup.3 are each C;
[0257] ring D is a 5-6 membered carbocycle or heterocycle which
forms, together with Q.sup.2 and Q.sup.3, a fused bicyclic ring
B;
[0258] m is 0-5;
[0259] n is 0-5;
[0260] q is 0-5;
[0261] r is 0-5; and
[0262] t is 0-2;
with the proviso that:
[0263] when L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, [0264] R.sup.3
and R.sup.4 are not both H, and ring A is not thiophene.
[0265] In one embodiment, compounds are provided having the
structure of Formula (X):
##STR00013##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0266] ring A is carbocycle or heterocycle;
[0267] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0268] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0269] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0270] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0271] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0272] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0273] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0274] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0275] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0276] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0277] Q.sup.1, Q.sup.4, and Q.sup.5 are each, independently, C or
N;
[0278] m is 0-5;
[0279] n is 0-5;
[0280] q is 0-5;
[0281] r is 0-5; and
[0282] t is 0-2.
[0283] In one embodiment, compounds are provided having the
structure of Formula (XI):
##STR00014##
or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, isotope, or salt thereof, wherein:
[0284] ring A is carbocycle or heterocycle;
[0285] L is a bond,
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--, or ring C;
[0286] Q is --C(R.sup.a).sub.2--, --NR.sup.a--, or --O--;
[0287] ring C is a C.sub.3-C.sub.7 cycloalkyl or 3-7 membered
heterocycloalkyl, substituted with 0-5 R.sup.7;
[0288] each R.sup.a is H or (C.sub.1-C.sub.6)alkyl;
[0289] R.sup.1 and R.sup.2 are each, independently, H, or
(C.sub.1-C.sub.6)alkyl or C.sub.3-C.sub.7 cycloalkyl substituted
with 0-5 halo;
[0290] R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, carbocycle, or
carbocyclealkyl;
[0291] or R.sup.3 and R.sup.4, together with the N to which they
are connected, form a 4-7 membered heterocycle;
[0292] R.sup.5, R.sup.6, and R.sup.7 are each, independently,
--C(O)NR.sup.1R.sup.2, --NR.sup.1C(O)R.sup.2, --OC(O)R.sup.1,
--C(O)OR.sup.1, --S(O).sub.tNR.sup.1R.sup.2,
--NR.sup.1S(O).sub.tR.sup.2, --OH, --CN, halo, oxo,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or carbocycle;
[0293] or R.sup.3 and one R.sup.5, together with the atoms to which
they are connected, form a 5-7 membered heterocycle;
[0294] R.sup.8 is H or (C.sub.1-C.sub.6)alkyl;
[0295] Q.sup.1, Q.sup.4, and Q.sup.5 are each, independently, C or
N;
[0296] m is 0-5;
[0297] n is 0-5;
[0298] q is 0-5;
[0299] r is 0-5; and
[0300] t is 0-2.
[0301] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein ring
A is an aromatic carbocycle.
[0302] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein ring
A is phenyl.
[0303] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein ring
A is an aromatic heterocycle.
[0304] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein ring
A is pyrrolyl, furanyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl,
azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl,
benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydro indolyl,
benzoxazolone, or pyrazolopyridine.
[0305] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein ring
B is pyrrolyl, furanyl, pyrazolyl, imidazolyl, triazolyl,
tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl,
indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,
benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydro indolyl,
benzoxazolone, or pyrazolopyridine.
[0306] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein L is
--(CR.sup.7.sub.2).sub.q-Q-(CR.sup.7.sub.2).sub.r--.
[0307] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein q is
0.
[0308] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein Q is
--O--.
[0309] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein Q is
--C(R.sup.a).sub.2--.
[0310] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein Q is
--NR.sup.a--.
[0311] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein L is
ring C.
[0312] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein ring
C is cyclopropyl.
[0313] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein ring
C is pyrrolidinyl.
[0314] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein L is
a bond.
[0315] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.3 and R.sup.4 are each, independently, H,
(C.sub.1-C.sub.6)alkyl, carbocycle, or carbocyclealkyl.
[0316] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.3 and R.sup.4 are each methyl or ethyl.
[0317] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.3 and R.sup.4 are each H.
[0318] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.3 is methyl and R.sup.4 is cyclopropylmethyl.
[0319] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.3 and R.sup.4, together with the N to which they are
connected, form a 4-7 membered heterocycle.
[0320] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.3 and R.sup.4, together with the N to which they are
connected, form pyrrolidinyl or mopholinyl.
[0321] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.3 and one R.sup.5, together with the atoms to which they are
connected, form a 5-7 membered heterocycle.
[0322] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.5 is --OH.
[0323] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.5 is --C(O)NR.sup.1R.sup.2.
[0324] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.5 is halo.
[0325] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.5 is Cl or F.
[0326] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.5 is (C.sub.1-C.sub.6)alkyl.
[0327] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.5 is methyl.
[0328] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.5 is --OC(O)R.sup.1.
[0329] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is carbocycle.
[0330] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is cycloalkyl.
[0331] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is cyclopropyl.
[0332] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is an aromatic carbocycle.
[0333] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is phenyl.
[0334] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is halo.
[0335] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is Cl, F or Br.
[0336] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is (C.sub.1-C.sub.6)alkyl.
[0337] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein the
at least one R.sup.6 is methyl.
[0338] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.6 is (C.sub.1-C.sub.6)alkoxy.
[0339] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein the
at least one R.sup.6 is methoxy.
[0340] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.7 is (C.sub.1-C.sub.6)alkyl.
[0341] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.7 is methyl, ethyl, isopropyl, or tert-butyl.
[0342] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.7 is carbocycle.
[0343] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.7 is cycloalkyl.
[0344] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein at
least one R.sup.7 is cyclopropyl.
[0345] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.8 is H.
[0346] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, wherein
R.sup.8 is methyl.
[0347] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, having the
structure of any one of the compounds listed in Table 1.
[0348] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, having the
structure of any one of the compounds listed in Table 2.
[0349] In one embodiment, a compound of any one of Formulas
(I)-(XI) is provided, or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, having the
structure of any one of the compounds listed in Table 3.
[0350] Representative compounds of Formulas (I)-(XI) as applicable,
include the compounds listed in Table 1 below, as well as
pharmaceutically acceptable isomers, racemates, hydrates, solvates,
homologs, and salts thereof
TABLE-US-00001 TABLE 1 REPRESENTATIVE COMPOUNDS Structure Compound
No. ##STR00015## A-1 ##STR00016## A-2 ##STR00017## A-3 ##STR00018##
A-4 ##STR00019## A-5 ##STR00020## A-6 ##STR00021## A-7 ##STR00022##
A-8 ##STR00023## A-9 ##STR00024## A-10 ##STR00025## A-11
##STR00026## A-12 ##STR00027## A-13 ##STR00028## A-14 ##STR00029##
A-15 ##STR00030## A-16 ##STR00031## A-17 ##STR00032## A-18
##STR00033## A-19 ##STR00034## A-20 ##STR00035## A-21 ##STR00036##
A-22 ##STR00037## A-23
[0351] Representative compounds of Formulas (I)-(XI) as applicable,
include the compounds listed in Table 2 below, as well as
pharmaceutically acceptable isomers, racemates, hydrates, solvates,
homologs, and salts thereof.
TABLE-US-00002 TABLE 2 REPRESENTATIVE COMPOUNDS Com- pound
Structure No. ##STR00038## B-1 ##STR00039## B-2 ##STR00040## B-3
##STR00041## B-4 ##STR00042## B-5 ##STR00043## B-6 ##STR00044## B-7
##STR00045## B-8 ##STR00046## B-9 ##STR00047## B-10 ##STR00048##
B-11 ##STR00049## B-12 ##STR00050## B-13 ##STR00051## B-14
##STR00052## B-15 ##STR00053## B-16 ##STR00054## B-17 ##STR00055##
B-18 ##STR00056## B-19 ##STR00057## B-20 ##STR00058## B-21
##STR00059## B-22 ##STR00060## B-23 ##STR00061## B-24 ##STR00062##
B-25 ##STR00063## B-26 ##STR00064## B-27 ##STR00065## B-28
##STR00066## B-29 ##STR00067## B-30 ##STR00068## B-31 ##STR00069##
B-32 ##STR00070## B-33 ##STR00071## B-34 ##STR00072## B-35
##STR00073## B-36 ##STR00074## B-37 ##STR00075## B-38 ##STR00076##
B-39 ##STR00077## B-40 ##STR00078## B-41 ##STR00079## B-42
##STR00080## B-43 ##STR00081## B-44 ##STR00082## B-45 ##STR00083##
B-46 ##STR00084## B-47 ##STR00085## B-48 ##STR00086## B-49
##STR00087## B-50 ##STR00088## B-51 ##STR00089## B-52 ##STR00090##
B-53 ##STR00091## B-54 ##STR00092## B-55 ##STR00093## B-56
##STR00094## B-57 ##STR00095## B-58 ##STR00096## B-59 ##STR00097##
B-60 ##STR00098## B-61 ##STR00099## B-62 ##STR00100## B-63
##STR00101## B-64 ##STR00102## B-65 ##STR00103## B-66 ##STR00104##
B-67 ##STR00105## B-68 ##STR00106## B-69 ##STR00107## B-70
##STR00108## B-71 ##STR00109## B-72
[0352] Representative compounds of Formulas (I)-(XI) as applicable,
include the compounds listed in Table 3 below, as well as
pharmaceutically acceptable isomers, racemates, hydrates, solvates,
homologs, and salts thereof.
TABLE-US-00003 TABLE 3 REPRESENTATIVE COMPOUNDS Compd. Structure
No. ##STR00110## C-1 ##STR00111## C-2 ##STR00112## C-3 ##STR00113##
C-4 ##STR00114## C-5 ##STR00115## C-6 ##STR00116## C-7 ##STR00117##
C-8 ##STR00118## C-10 ##STR00119## C-11 ##STR00120## C-12
##STR00121## C-13 ##STR00122## C-14 ##STR00123## C-15 ##STR00124##
C-16 ##STR00125## C-17 ##STR00126## C-18 ##STR00127## C-19
##STR00128## C-20 ##STR00129## C-21 ##STR00130## C-22 ##STR00131##
C-23 ##STR00132## C-24 ##STR00133## C-25 ##STR00134## C-26
##STR00135## C-27 ##STR00136## C-28 ##STR00137## C-29 ##STR00138##
C-30 ##STR00139## C-31 ##STR00140## C-32 ##STR00141## C-33
##STR00142## C-34 ##STR00143## C-35 ##STR00144## C-36 ##STR00145##
C-37 ##STR00146## C-38 ##STR00147## C-39 ##STR00148## C-40
##STR00149## C-41 ##STR00150## C-42 ##STR00151## C-43 ##STR00152##
C-44 ##STR00153## C-45 ##STR00154## C-46 ##STR00155## C-47
##STR00156## C-48 ##STR00157## C-49 ##STR00158## C-50 ##STR00159##
C-51 ##STR00160## C-52 ##STR00161## C-53 ##STR00162## C-54
##STR00163## C-55 ##STR00164## C-56 ##STR00165## C-57 ##STR00166##
C-58 ##STR00167## C-59 ##STR00168## C-60 ##STR00169## C-61
##STR00170## C-62 ##STR00171## C-63 ##STR00172## C-64 ##STR00173##
C-65 ##STR00174## C-66 ##STR00175## C-67 ##STR00176## C-68
##STR00177## C-69
[0353] "Isomer" is used herein to encompass all chiral,
diastereomeric or racemic forms of a structure, unless a particular
stereochemistry or isomeric form is specifically indicated. Such
compounds can be enriched or resolved optical isomers at any or all
asymmetric atoms as are apparent from the depictions, at any degree
of enrichment. Both racemic and diastereomeric mixtures, as well as
the individual optical isomers can be synthesized so as to be
substantially free of their enantiomeric or diastereomeric
partners, and these are all within the scope of certain embodiments
of the disclosure. The isomers resulting from the presence of a
chiral center comprise a pair of non-superimposable isomers that
are called "enantiomers." Single enantiomers of a pure compound are
optically active (i.e., they are capable of rotating the plane of
plane polarized light and designated R or S).
[0354] "Isolated optical isomer" means a compound which has been
substantially purified from the corresponding optical isomer(s) of
the same formula. For example, the isolated isomer may be at least
about 80%, at least 80% or at least 85% pure. In other embodiments,
the isolated isomer is at least 90% pure or at least 98% pure, or
at least 99% pure by weight.
[0355] "Substantially enantiomerically or diasteromerically" pure
means a level of enantiomeric or diastereomeric enrichment of one
enantiomer with respect to the other enantiomer or diasteromer of
at least about 80%, and more specifically in excess of 80%, 85%,
90%, 95%, 98%, 99%, 99.5% or 99.9%.
[0356] The terms "racemate" and "racemic mixture" refer to an equal
mixture of two enantiomers. A racemate is labeled "(.+-.)" because
it is not optically active (i.e., will not rotate plane-polarized
light in either direction since its constituent enantiomers cancel
each other out).
[0357] A "hydrate" is a compound that exists in combination with
water molecules. The combination can include water in
stoichiometric quantities, such as a monohydrate or a dihydrate, or
can include water in random amounts. As the term is used herein a
"hydrate" refers to a solid form; that is, a compound in a water
solution, while it may be hydrated, is not a hydrate as the term is
used herein.
[0358] A "solvate" is similar to a hydrate except that a solvent
other that water is present. For example, methanol or ethanol can
form an "alcoholate", which can again be stoichiometric or
non-stoichiometric. As the term is used herein a "solvate" refers
to a solid form; that is, a compound in a solvent solution, while
it may be solvated, is not a solvate as the term is used
herein.
[0359] "Isotope" refers to atoms with the same number of protons
but a different number of neutrons, and an isotope of a compound of
Formulas (I)-(X) includes any such compound wherein one or more
atoms are replaced by an isotope of that atom. For example, carbon
12, the most common form of carbon, has six protons and six
neutrons, whereas carbon 13 has six protons and seven neutrons, and
carbon 14 has six protons and eight neutrons. Hydrogen has two
stable isotopes, deuterium (one proton and one neutron) and tritium
(one proton and two neutrons). While fluorine has a number of
isotopes, fluorine 19 is longest-lived. Thus, an isotope of a
compound having the structure of Formulas (I)-(X) includes, but not
limited to, compounds of Formulas (I)-(X) wherein one or more
carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms,
wherein one or more hydrogen atoms are replaced with deuterium
and/or tritium, and/or wherein one or more fluorine atoms are
replaced by fluorine-19.
[0360] "Salt" generally refers to an organic compound, such as a
carboxylic acid or an amine, in ionic form, in combination with a
counter ion. For example, salts formed between acids in their
anionic form and cations are referred to as "acid addition salts".
Conversely, salts formed between bases in the cationic form and
anions are referred to as "base addition salts."
[0361] The term "pharmaceutically acceptable" refers an agent that
has been approved for human consumption and is generally non-toxic.
For example, the term "pharmaceutically acceptable salt" refers to
nontoxic inorganic or organic acid and/or base addition salts (see,
e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm.,
33, 201-217, 1986) (incorporated by reference herein).
[0362] Pharmaceutically acceptable base addition salts of compounds
of the disclosure include, for example, metallic salts including
alkali metal, alkaline earth metal, and transition metal salts such
as, for example, calcium, magnesium, potassium, sodium, and zinc
salts. Pharmaceutically acceptable base addition salts also include
organic salts made from basic amines such as, for example,
N,N'dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and
procaine.
[0363] Pharmaceutically acceptable acid addition salts may be
prepared from an inorganic acid or from an organic acid. Examples
of inorganic acids include hydrochloric, hydrobromic, hydriodic,
nitric, carbonic, sulfuric, and phosphoric acids. Appropriate
organic acids may be selected from aliphatic, cycloaliphatic,
aromatic, aromatic aliphatic, heterocyclic, carboxylic, and
sulfonic classes of organic acids, examples of which include
formic, acetic, propionic, succinic, glycolic, gluconic, lactic,
malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,
pyruvic, aspartic, glutamic, benzoic, anthranilic,
4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic,
oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, panthothenic, trifluoromethanesulfonic,
2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, alginic, Phydroxybutyric,
salicylic, -galactaric, and galacturonic acid.
[0364] Although pharmaceutically unacceptable salts are not
generally useful as medicaments, such salts may be useful, for
example as intermediates in the synthesis of compounds having the
structure of Formulas (I)-(XI), for example in their purification
by recrystallization.
[0365] In certain embodiments, the disclosure provides a
pharmaceutical composition comprising a compound of any one of
Formulas (I)-(XI), or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, together with
at least one pharmaceutically acceptable carrier, diluent, or
excipient. For example, the active compound will usually be mixed
with a carrier, or diluted by a carrier, or enclosed within a
carrier which can be in the form of an ampoule, capsule, sachet,
paper, or other container. When the active compound is mixed with a
carrier, or when the carrier serves as a diluent, it can be solid,
semi-solid, or liquid material that acts as a vehicle, excipient,
or medium for the active compound. The active compound can be
adsorbed on a granular solid carrier, for example contained in a
sachet. Some examples of suitable carriers are water, salt
solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated
castor oil, peanut oil, olive oil, gelatin, lactose, terra alba,
sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin,
amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia,
stearic acid, or lower alkyl ethers of cellulose, silicic acid,
fatty acids, fatty acid amines, fatty acid monoglycerides and
diglycerides, pentaerythritol fatty acid esters, polyoxyethylene,
hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the
carrier or diluent can include any sustained release material known
in the art, such as glyceryl monostearate or glyceryl distearate,
alone or mixed with a wax.
[0366] As used herein, the term "pharmaceutical composition" refers
to a composition containing one or more of the compounds described
herein, or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, homolog or salt thereof, formulated with a
pharmaceutically acceptable carrier, which can also include other
additives, and manufactured or sold with the approval of a
governmental regulatory agency as part of a therapeutic regimen for
the treatment of disease in a mammal. Pharmaceutical compositions
can be formulated, for example, for oral administration in unit
dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);
for topical administration (e.g., as a cream, gel, lotion, or
ointment); for intravenous administration (e.g., as a sterile
solution free of particulate emboli and in a solvent system
suitable for intravenous use); or in any other formulation
described herein. Conventional procedures and ingredients for the
selection and preparation of suitable formulations are described,
for example, in Remington: The Science and Practice of Pharmacy,
21.sup.st Ed., Gennaro, Ed., Lippencott Williams & Wilkins
(2005) and in The United States Pharmacopeia: The National
Formulary (USP 36 NF31), published in 2013.
[0367] In another embodiment, there are provided methods of making
a composition of a compound described herein including formulating
a compound of the disclosure with a pharmaceutically acceptable
carrier or diluent. In some embodiments, the pharmaceutically
acceptable carrier or diluent is suitable for oral administration.
In some such embodiments, the methods can further include the step
of formulating the composition into a tablet or capsule. In other
embodiments, the pharmaceutically acceptable carrier or diluent is
suitable for parenteral administration. In some such embodiments,
the methods further include the step of lyophilizing the
composition to form a lyophilized preparation.
[0368] As used herein, the term "pharmaceutically acceptable
carrier" refers to any ingredient other than the disclosed
compounds, or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, homolog or salt thereof (e.g., a carrier capable
of suspending or dissolving the active compound) and having the
properties of being nontoxic and non-inflammatory in a patient.
Excipients may include, for example: antiadherents, antioxidants,
binders, coatings, compression aids, disintegrants, dyes (colors),
emollients, emulsifiers, fillers (diluents), film formers or
coatings, flavors, fragrances, glidants (flow enhancers),
lubricants, preservatives, printing inks, sorbents, suspensing or
dispersing agents, sweeteners, or waters of hydration. Exemplary
excipients include, but are not limited to: butylated
hydroxytoluene (BHT), calcium carbonate, calcium phosphate
(dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl
pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose,
gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
lactose, magnesium stearate, maltitol, mannitol, methionine,
methylcellulose, methyl paraben, microcrystalline cellulose,
polyethylene glycol, polyvinyl pyrrolidone, povidone,
pregelatinized starch, propyl paraben, retinyl palmitate, shellac,
silicon dioxide, sodium carboxymethyl cellulose, sodium citrate,
sodium starch glycolate, sorbitol, starch (corn), stearic acid,
stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin
E, vitamin C, and xylitol.
[0369] The formulations can be mixed with auxiliary agents which do
not deleteriously react with the active compounds. Such additives
can include wetting agents, emulsifying and suspending agents, salt
for influencing osmotic pressure, buffers and/or coloring
substances, preserving agents, sweetening agents, or flavoring
agents. The compositions can also be sterilized if desired.
[0370] The route of administration can be any route which
effectively transports the active compound of the disclosure to the
appropriate or desired site of action, such as oral, nasal,
pulmonary, buccal, subdermal, intradermal, transdermal, or
parenteral, e.g., rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscular, intranasal, ophthalmic solution, or
an ointment, the oral route being preferred.
[0371] Dosage forms can be administered once a day, or more than
once a day, such as twice or thrice daily. Alternatively, dosage
forms can be administered less frequently than daily, such as every
other day, or weekly, if found to be advisable by a prescribing
physician. Dosing regimens include, for example, dose titration to
the extent necessary or useful for the indication to be treated,
thus allowing the patient's body to adapt to the treatment and/or
to minimize or avoid unwanted side effects associated with the
treatment. Other dosage forms include delayed or controlled-release
forms. Suitable dosage regimens and/or forms include those set out,
for example, in the latest edition of the Physicians' Desk
Reference, incorporated herein by reference.
[0372] As used herein, the term "administering" or "administration"
refers to providing a compound, a pharmaceutical composition
comprising the same, to a subject by any acceptable means or route,
including (for example) by oral, parenteral (e.g., intravenous), or
topical administration.
[0373] As used herein, the term "treatment" refers to an
intervention that ameliorates a sign or symptom of a disease or
pathological condition. As used herein, the terms "treatment",
"treat" and "treating," with reference to a disease, pathological
condition or symptom, also refers to any observable beneficial
effect of the treatment. The beneficial effect can be evidenced,
for example, by a delayed onset of clinical symptoms of the disease
in a susceptible subject, a reduction in severity of some or all
clinical symptoms of the disease, a slower progression of the
disease, a reduction in the number of relapses of the disease, an
improvement in the overall health or well-being of the subject, or
by other parameters well known in the art that are specific to the
particular disease. A prophylactic treatment is a treatment
administered to a subject who does not exhibit signs of a disease
or exhibits only early signs, for the purpose of decreasing the
risk of developing pathology. A therapeutic treatment is a
treatment administered to a subject after signs and symptoms of the
disease have developed.
[0374] As used herein, the term "subject" refers to an animal
(e.g., a mammal, such as a human). A subject to be treated
according to the methods described herein may be one who has been
diagnosed with a neurodegenerative disease involving demyelination,
insufficient myelination, or underdevelopment of a myelin sheath,
e.g., a subject diagnosed with multiple sclerosis or cerebral
palsy, or one at risk of developing the condition. Diagnosis may be
performed by any method or technique known in the art. One skilled
in the art will understand that a subject to be treated according
to the present disclosure may have been subjected to standard tests
or may have been identified, without examination, as one at risk
due to the presence of one or more risk factors associated with the
disease or condition.
[0375] As used herein, the term "effective amount" refers to a
quantity of a specified agent sufficient to achieve a desired
effect in a subject being treated with that agent. Ideally, an
effective amount of an agent is an amount sufficient to inhibit or
treat the disease without causing substantial toxicity in the
subject. The effective amount of an agent will be dependent on the
subject being treated, the severity of the affliction, and the
manner of administration of the pharmaceutical composition. Methods
of determining an effective amount of the disclosed compound
sufficient to achieve a desired effect in a subject will be
understood by those of skill in the art in light of this
disclosure.
[0376] In one embodiment, a method is provided of modulating an
opioid receptor comprising contacting the opioid receptor with an
effective amount of a compound having the structure of Formulas (I)
through (XI), or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, homolog, salt, or composition thereof. In another
embodiment, the opioid receptor is the kappa opioid receptor (KOR),
and in a further embodiment the compound is a KOR antagonist. In
another embodiment, the opioid receptor is the mu opioid receptor
(MOR), and in a further embodiment the compound is a MOR agonist.
In another embodiment, the compound is both a KOR antagonist and a
MOR agonist. In another embodiment, the method does not modulate
arrestin function.
[0377] In one embodiment, a method is provided for treating pain,
opioid overdose, addiction, a neuropsychiatric disorder, a sleep
disorder, a gastrointestinal disorder, a skin disorder, dyspnea,
autism spectrum disorder, Prader-Willi Syndrome, headache, or
temporomandibular joint dysfunction, comprising administering to a
subject in need thereof an effective amount of a compound of
Formulas (I) through (XI), or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, isotope, or salt thereof, or a
pharmaceutical composition comprising the same.
[0378] In one embodiment, a method is provided of treating pain,
comprising administering to a subject in need thereof an effective
amount of a compound having the structure of Formulas (I) through
(XI), or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, homolog, salt, or composition thereof. In one embodiment,
the method of treating pain does not increase the risk of
respiratory depression or constipation in the subject. In one
embodiment, the pain is acute pain. In one embodiment, the pain is
chronic pain. In another embodiment, the pain is fibromyalgia,
neuropathic pain, chronic low back pain, surgical pain, cancer
pain, or severe pain.
[0379] In one embodiment, a method is provided of treating opioid
overdose, comprising administering to a subject in need thereof an
effective amount of a compound having the structure of Formulas (I)
through (XI), or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, homolog, salt, or composition thereof.
[0380] In one embodiment, a method is provided of treating
addiction, comprising administering to a subject in need thereof an
effective amount of a compound having the structure of Formulas (I)
through (XI), or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, homolog, salt, or composition thereof. In one
embodiment, the addiction is opioid use disorder. In one
embodiment, the method of treating addiction comprises maintenance
of opioid use disorder.
[0381] In one embodiment, a method is provided of treating a
neuropsychiatric disorder, comprising administering to a subject in
need thereof an effective amount of a compound having the structure
of Formulas (I) through (XI), or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, homolog, salt, or composition
thereof.
[0382] In one embodiment, the neuropsychiatric disorder is
characterized by compulsive behavior. In one embodiment, the
neuropsychiatric disorder characterized by compulsive behavior is
obsessive compulsive disorder, trichotillomania, or skin picking.
In one embodiment, the compulsive behavior is associated with a
neurodegenerative disorder. In one embodiment, the
neurodegenerative disorder is Huntington's disease or Parkinson's
disease.
[0383] In one embodiment, the neuropsychiatric disorder is
characterized by impulsive behavior. In one embodiment, the
neuropsychiatric disorder characterized by impulsive behavior is
addiction, pathological gambling, alcohol use disorder, nicotine
addiction, sex addiction, Tourette syndrome, or kleptomania. In one
embodiment, the impulsive behavior is associated with a
neurodegenerative disorder. In one embodiment, the
neurodegenerative disorder is frontotemporal dementia or
Alzheimer's disorder.
[0384] In one embodiment, the neuropsychiatric disorder is
characterized by depressive mood. In one embodiment, the
neuropsychiatric disorder characterized by depressive mood is major
depressive disorder, anxiety disorder, panic disorder, dysphoria,
or anhedonia.
[0385] In one embodiment, the neuropsychiatric disorder is an
eating disorder. In one embodiment, the eating disorder is anorexia
nervosa, bulimia nervosa, binge eating disorder, or obesity.
[0386] In one embodiment, the neuropsychiatric disorder is
Schizophrenia, psychosis, or bipolar disorder.
[0387] In one embodiment, a method is provided of treating a sleep
disorder, comprising administering to a subject in need thereof an
effective amount of a compound having the structure of Formulas (I)
through (XI), or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, homolog, salt, or composition thereof. In one
embodiment, the sleep disorder is sleep disruption. In one
embodiment, the sleep disruption is associated with a
neurodegenerative disorder. In one embodiment, the
neurodegenerative disorder is supranuclear palsy.
[0388] In one embodiment, a method is provided of treating a
gastrointestinal disorder, comprising administering to a subject in
need thereof an effective amount of a compound having the structure
of Formulas (I) through (XI), or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, homolog, salt, or composition
thereof. In one embodiment, the gastrointestinal disorder is
constipation, diarrhea, irritable bowel syndrome, inflammatory
bowel disease, or Crohn's disease.
[0389] In one embodiment, a method is provided of treating a skin
disorder, comprising administering to a subject in need thereof an
effective amount of a compound having the structure of Formulas (I)
through (XI), or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, homolog, salt, or composition thereof. In one
embodiment, the skin disorder is itching or urticaria.
[0390] In one embodiment, a method is provided of treating dyspnea,
comprising administering to a subject in need thereof an effective
amount of a compound having the structure of Formulas (I) through
(XI), or a pharmaceutically acceptable isomer, racemate, hydrate,
solvate, homolog, salt, or composition thereof.
[0391] In one embodiment, a method is provided of treating autism
spectrum disorder, comprising administering to a subject in need
thereof an effective amount of a compound having the structure of
Formulas (I) through (XI), or a pharmaceutically acceptable isomer,
racemate, hydrate, solvate, homolog, salt, or composition
thereof.
[0392] In one embodiment, a method is provided of treating
Prader-Willi Syndrome, comprising administering to a subject in
need thereof an effective amount of a compound having the structure
of Formulas (I) through (XI), or a pharmaceutically acceptable
isomer, racemate, hydrate, solvate, homolog, salt, or composition
thereof.
[0393] In one embodiment, a method is provided of treating
headache, comprising administering to a subject in need thereof an
effective amount of a compound having the structure of Formulas (I)
through (XI), or a pharmaceutically acceptable isomer, racemate,
hydrate, solvate, homolog, salt, or composition thereof. In one
embodiment, the headache is migraine.
[0394] In one embodiment, a method is provided of treating
temporomandibular joint dysfunction, comprising administering to a
subject in need thereof an effective amount of a compound having
the structure of Formulas (I) through (XI), or a pharmaceutically
acceptable isomer, racemate, hydrate, solvate, homolog, salt, or
composition thereof.
[0395] Compounds having the structure of Formulas (I) through (XI)
can be synthesized using standard synthetic techniques known to
those of skill in the art. For examples, compounds of the present
disclosure can be synthesized using the general synthetic
procedures set forth in Schemes 1-2.
[0396] To this end, the reactions, processes and synthetic methods
described herein are not limited to the specific conditions
described in the following experimental section, but rather are
intended as a guide to one with suitable skill in this field. For
example, reactions may be carried out in any suitable solvent, or
other reagents to perform the transformation[s] necessary.
Generally, suitable solvents are protic or aprotic solvents which
are substantially non-reactive with the reactants, the
intermediates or products at the temperatures at which the
reactions are carried out (i.e., temperatures which may range from
the freezing to boiling temperatures). A given reaction may be
carried out in one solvent or a mixture of more than one solvent.
Depending on the particular reaction, suitable solvents for a
particular work-up following the reaction may be employed.
##STR00178##
##STR00179##
EXAMPLES
[0397] The invention is further illustrated by the following
examples. The examples below are non-limiting are merely
representative of various aspects of the invention. Solid and
dotted wedges within the structures herein disclosed illustrate
relative stereochemistry, with absolute stereochemistry depicted
only when specifically stated or delineated.
General Methods
[0398] All reagents, for which the synthesis is not described in
the experimental part, are either commercially available, or are
known compounds or may be formed from known compounds by known
methods by a person skilled in the art.
[0399] The compounds and intermediates produced according to the
methods of the invention may require purification. Purification of
organic compounds is well known to a person skilled in the art and
there may be several ways of purifying the same compound. In some
cases, no purification may be necessary. In some cases, the
compounds may be purified by crystallization. In some cases,
impurities may be stirred out using a suitable solvent. In some
cases, the compounds may be purified by chromatography,
particularly flash column chromatography or reverse phase column
chromatography, using prepacked silica gel cartridges. In some
cases, the compounds may be purified by preparative HPLC using
prepacked silica gel cartridges, e.g. RediSep.RTM.R.sub.f and
eluents such as gradients of 0-100% ethyl acetate in hexanes or
0-100% of 10% MeOH in CH.sub.2Cl.sub.2.
[0400] Purification methods as described herein may provide
compounds of the present disclosure which possess a sufficiently
basic or acidic functionality in the form of a salt, such as, in
the case of a compound of the present disclosure which is
sufficiently basic, a trifluoroacetate or formate salt, or, in the
case of a compound of the present disclosure which is sufficiently
acidic, an ammonium salt. A salt of this type can either be
transformed into its free base or free acid form, respectively, by
various methods known to a person skilled in the art, or be used as
salts in subsequent biological assays. It is to be understood that
the specific form of a compound of the present disclosure as
isolated and as described herein is not necessarily the only form
in which said compound can be applied to a biological assay in
order to quantify the specific biological activity.
[0401] All the starting materials and reagents are commercially
available and were used as is. .sup.1H Nuclear magnetic resonance
(NMR) spectroscopy was carried out using a Bruker Avance III
instrument operating at 400 MHz using the stated solvent at around
room temperature unless otherwise stated. In all cases, NMR data
were consistent with the proposed structures. Characteristic
chemical shifts (.delta.) are given in parts-per-million using
conventional abbreviations for designation of major peaks: e.g. s,
singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; dt, doublet of triplets; m, multiplet; br, broad.
Preparative HPLC purification was performed by reverse phase HPLC
using Agilent Technologies 1200 Infinity Series or an equivalent
HPLC system such as Teledyne ISCO CombiFlash R.sub.f.
[0402] Chemical names were generated using the ChemDraw naming
software (Version 17.0.0.206) by PerkinElmer Informatics, Inc. In
some cases, generally accepted names of commercially available
reagents were used in place of names generated by the naming
software.
Abbreviations
[0403] The following abbreviations are used in the examples, while
other abbreviations have their customary meaning in the art: [0404]
BOC: tert-butoxycarbonyl protecting group [0405] DIAD: Diisopropyl
azodicarboxylate [0406] EDCl:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride [0407]
EtOH: Ethanol [0408] EtOC(O)Cl Ethyl chloroformate [0409] h hour(s)
[0410] HOBt: Hydroxybenzotriazole [0411] KO.sup.tBu: Potassium
t-butoxide [0412] l: Liter [0413] LCMS: liquid chromatography--mass
spectrometry [0414] M: Molar [0415] MeOH: Methanol [0416] min:
Minute(s) [0417] .mu.l: Microliter [0418] ml: Millliliter [0419]
N.sub.2: Nitrogen [0420] N.sub.2H.sub.4: Hydrazine monohydrate
[0421] NaBH.sub.4: Sodium borohydride [0422] N.sub.2CHCO.sub.2Et
ethyl diazoacetate [0423] NMR: nuclear magnetic resonance
spectroscopy [0424] Pd.sub.2(dba).sub.3:
Tris(dibenzylideneacetone)dipalladium(0) [0425] PPh.sub.3:
Triphenylphosphine [0426] ppm: parts per million [0427]
Rh.sub.2(OAc).sub.4 Rhodium (II) acetate dimer [0428] rt: Room
temperature [0429] Rt: Retention time [0430] sat.: Saturated [0431]
Sphos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl [0432] TEA:
Triethylamine [0433] THF: Tetrahydrofuran
Analytical LC-MS Methods
[0434] Analytical Method A: Column: Eclipse Plus C18 4.6.times.3.5
.mu.m; eluent A: 0.1% TFA in H.sub.2O; eluent B: 0.1% TFA in
CH.sub.3CN; gradient: 20-100% over 4 minutes; flow: 1.5 mL/min;
injection volume 1-5 .mu.L; temperature: 23.degree. C.; UV scan:220
and 250 nm; signal settings--scan positive mode.
Preparative HPLC
[0435] Preparative Method A: Instrument: Agilent Technologies 1200
Infinity Series Column: Gemini 5 .mu.m NX-C18 110 .ANG.,
250.times.21.2 mm; eluent A: 0.1% TFA in H.sub.2O, eluent B: 0.1%
TFA in CH.sub.3CN; gradient: 10-100%; flow: 20 mL/min; injection
volume 0.5-2 mL; temperature: 23.degree. C.; UV scan: 254 and 220
nm.
A. Synthesis of Compounds Having the Structure of Formula (I-A)
[0436] Representative Compounds having the structure of Formula
(I-A) can be synthesized by using the general synthetic procedures
set forth in Schemes A1-A5.
##STR00180## ##STR00181##
##STR00182##
##STR00183##
##STR00184##
##STR00185##
EXAMPLE A1
##STR00186##
[0437] Synthesis of
4-((S)-2-(dimethylamino)-3-(3-((S)-1-phenylethyl)ureido)propyl)
benzamide (Compound A-1)
Step 1: Synthesis of tert-butyl
(S)-(1-amino-3-(4-bromophenyl)-1-oxopropan-2-yl)carbamate
(A-1b)
##STR00187##
[0439] 14.8 grams of the starting Boc-protected amino acid (A-1a)
(1.00 equiv., 43.0 mmol), 24.5 grams of HBTU (1.50 equiv., 64.5
mmol), and 6.58 grams of 1-hydroxybenzotriazole (1.00 equiv., 43.0
mmol) were dissolved in 50 mL of DMF (6.76 volEquiv.). To this
reaction mixture, 22.5 mL of N,N-diisopropylethylamine (3.00
equiv., 129 mmol) was added. Next, 20.7 grams of ammonium carbonate
(5.00 Equiv., 215 mmol) was added to the reaction mixture. Finally,
another 50 mL of DMF was added and the reaction mixture was allowed
to continue overnight. Diethyl ether was added, and a solid formed
that blocked the separatory funnel. The solution was transferred to
another flask where it was concentrated, diluted with ethyl acetate
(500 mL), and washed with water (5.times.300 mL), saturated
ammonium chloride (1.times.300 mL), and brine (1.times.300 mL). The
organic layer was dried over sodium sulfate and concentrated. The
resulting product (A-1b) was evaluated using TLC with a mobile
phase of 20:80 MeOH:DCM. This step yielded 11 g of product (74.5%
yield).
Step 2: Synthesis of (S)-2-amino-3-(4-bromophenyl)propenamide
(A-1c
##STR00188##
[0441] To a solution of starting material (A-1b) 11.0 grams (1.00
equiv., 32.0 mmol) in 66.0 mL of THE (6.0 volEquiv.) was added 48.1
mL of 4M HCl in dioxane (6.00 equiv., 192 mmol). Solvent was
evaporated under reduced pressure and the resulting product was
dissolved in ether and triturated. This reaction yielded 7 grams of
product (A-1c) (89.8% yield). (M+H=243.1)
Step 3: Synthesis of
(S)-3-(4-bromophenyl)-2-(dimethylamino)propenamide (A-1d)
##STR00189##
[0443] A solution of starting material (A-1c) 3.00 grams (1 equiv.,
12.3 mmol) in 63.0 mL of acetonitrile (21.0 volEquiv.) was cooled
to 0.degree. C. To this reaction mixture 6.34 mL of formaldehyde
(2.11 volEquiv) and 6.54 grams of sodium triacetoxyborohydride (2.5
equiv., 30.9 mmol) was added slowly. The residue was dissolved in
10 mL of isopropanol and treated with 4M HCl in dioxane. The
resulting solution was then concentrated and triturated with
diethyl ether. The resulting product was dried under a vacuum
yielding 3.2 grams of (A-1d) as an off white solid (95.6% yield).
(M+H=271.2)
Step 4: Synthesis of (S)-3-(4-bromophenyl)-N2,
N2-dimethylpropane-1,2-diamine dihydrochloride (A-1f)
##STR00190##
[0445] To a solution of starting material (A-1d) 3.10 grams (1.00
equiv., 11.4 mmol) in 28.0 mL of THF (9.03 vol. equiv.) was added
68.6 mL of 1M borane in THE (6.00 equiv., 68.6 mmol). After the
reaction reached completion it was quenched with 50 mL of MeOH. The
solvent was then removed under vacuum and the resulting residue
dissolved in isopropanol. Next, 6.0 mL of 4M HCl in dioxane was
added (22.8 mmol). The resulting solution was diluted with ether
and a solid crashed out. The resulting solid was filtered yielding
1.8 grams of product (A-1f) (61.2% yield). (M+H=257.2)
Step 5: Synthesis of tert-butyl
(S)-(3-(4-bromophenyl)-2-(dimethylamino) propyl)carbamate
(A-1g)
##STR00191##
[0447] To a solution of starting material (A-1f), 2.00 grams (1.00
equiv., 6.06 mmol) in 10 mL of DCM (5.00 volEquiv.) was added 2.53
mL of Triethylamine (3.00 equiv., 18.2 mmol), 1.39 grams
di-tert-butyl-dicarbonate (1.05 equiv., 6.36 mmol), and 222 mg of
DMAP (0.30 equiv., 1.82 mmol). The pH of the reaction mixture was
adjusted to 7 using 1M HCl. The resulting solution was extracted
using DCM (3.times.20 mL). The organic extracts were dried over
anhydrous sodium sulfate, filtered and concentrated under vacuum to
give a colorless oil. The resultant crude product was purified via
column chromatography eluting with 10% MeOH in DCM yielding 1.2
grams of product (A-1 g) (55.4% yield). .sup.1H NMR (300 MHz,
CHLOROFORM-d) 6=7.39-7.36 (d, 2H), 7.01-6.98 (d, J=8.28 Hz, 2H),
2.30 (s, 6H), 1.40 (s, 9H).
Step 6: Synthesis of tert-butyl
(S)-(3-(4-cyanophenyl)-2-(dimethylamino) propyl)carbamate
(A-1h)
##STR00192##
[0449] In a dry flask backfilled with Argon, 900 mg of starting
material (A-1g) (1.00 equiv., 2.52 mmol), 396 mg of Palladium Xphos
(0.20 equiv., 503 .mu.mol), and 532 mg of Potassium
hexacyanoferrate trihydrate (0.5 equiv., 1.26 mmol) were added.
Next, 6.3 mL of dioxane was added. Then, 6.3 mL of 0.05M solution
of Potassium acetate (0.125 equiv., 315 .mu.mol) was added. The
reaction mixture was then stirred at reflux for 6 hours. The
reaction was then quenched with ethyl acetate and then washed with
brine. The blue colored dye was discarded and the resulting product
purified via column chromatography eluting with DCM:MeOH 9:1
yielding 821 mg of product (A-1h). (M+H=304.3)
Step 7: Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)benzonitrile dihydrochloride
(A-1i)
##STR00193##
[0451] 2.71 mL of 4M HCl in dioxane (4.00 equiv., 10.8 mmol) was
added to 821 mg of starting material (A-1h) (1.00 equiv., 2.71
mmol). The reaction was stirred overnight. The next afternoon LCMS
showed the presence of starting material in the reaction mixture
(likely due to do poor stirring conditions). 1 mL of HCl in dioxane
(1.48 equiv., 4.00 mmol) was added and the reaction was allowed to
stir for another two hours. The reaction mixture was washed with
ether and decanted three times. The solvent was then evaporated
under vacuum yielding 826 mg of product. The product (A-1i) was
used for the next step without further purification.
(M+H=204.3)
Step 8: Synthesis of
1-((S)-3-(4-cyanophenyl)-2-(dimethylamino)propyl)-3-((S)-1-phenylethyl)ur-
ea (A-1k)
##STR00194##
[0453] (S)-4-(3-amino-2-(dimethylamino)propyl)benzonitrile
dihydrochloride (A-1i) (225 mg, 0.815 mmol, 1 eq.) was dissolved in
acetonitrile (10 mL) followed by triethyl amine (0.454 mL, 3.26
mmol, 4 eq.) was added. The reaction mixture was heated at
60.degree. C. and solution of 4-nitrophenyl
(S)-(1-phenylethyl)carbamate (A-1j) (0.233 g, 0.815 mmol, 1 eq)
dissolved in acetonitrile (3 mL) was added. The reaction was
stirred at 60.degree. C. for 2 h. The reaction mixture was
evaporated and diluted with ethyl acetate. The solid was filtered
off and the organic layer was washed with carbonate buffer
(3.times.5 mL), brine (10 mL), dried with Na.sub.2SO.sub.4 and
concentrated to get crude. The crude was purified using DCM and
methanol to yield (A-1k) as a yellow solid (0.088 g, 31%,
GA-00478). (M+H=351.2) H NMR (300 MHz, METHANOL-d.sub.4)
.delta.=7.60 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.32-7.25
(m, 4H), 7.23-7.16 (m, 1H), 4.73 (q, J=6.9 Hz, 1H), 3.20-2.93 (m,
3H), 2.91-2.81 (m, 1H), 2.52 (dd, J=8.7, 13.4 Hz, 1H), 2.33 (s,
6H), 1.37 (d, J=7.0 Hz, 3H).
Step 9: Synthesis of
4-((S)-2-(dimethylamino)-3-(3-((S)-1-phenylethyl)ureido)
propyl)benzamide (Compound A-1)
##STR00195##
[0455]
1-((S)-3-(4-cyanophenyl)-2-(dimethylamino)propyl)-3-((S)-1-phenylet-
hyl)urea (A-1k) (0.04 g, 0.114 mmol) was dissolved in
methanol/water (0.4 ml, 5:1) and cooled to 0.degree. C.
K.sub.2CO.sub.3 (0.0789 g, 0.571 mmol, 5 eq.) was added to the
reaction mixture followed by H.sub.2O.sub.2 (0.089 mL, 30%, 1.14
mmol, 10 eq.) was added dropwise. The reaction mixture was stirred
for 10 minutes. The reaction mixture was diluted with ethyl acetate
and water. The organic layer was separated and washed with water,
brine, dried over Na.sub.2SO.sub.4 and concentrated to get crude.
The crude was purified using DCM and methanol to yield Compound A-1
(5 mg, 12%). (M+H=369.3).sup.1H NMR (300 MHz, METHANOL-d.sub.4)
.delta.=7.79 (d, J=8.4 Hz, 2H), 7.34-7.25 (m, 6H), 7.24-7.16 (m,
1H), 4.73 (q, J=6.9 Hz, 1H), 3.21-2.87 (m, 4H), 2.52 (dd, J=8.9,
13.0 Hz, 1H), 2.38 (s, 6H), 1.37 (d, J=7.0 Hz, 3H)
Example A2
##STR00196##
[0456] Synthesis of (S)-1-phenylethyl
((S)-2-amino-3-(4-carbamoylphenyl)propyl)carbamate (Compound
A-2)
Step 1: Synthesis of tert-butyl
(S)-(1-amino-3-(4-carbamoylphenyl)propan-2-yl) carbamate
intermediate (A-2g)
##STR00197##
[0457] Step 2: Synthesis of tert-butyl ((S)-1-phenylethyl)
((S)-3-(4-carbamoylphenyl)propane-1,2-diyl)dicarbamate (A-2i)
##STR00198##
[0459] To a stirred solution of tert-butyl
(S)-(1-amino-3-(4-carbamoylphenyl)propan-2-yl)carbamate (A-2 g)
(190 mg), in anhydrous acetonitrile (5 mL) and DMF (3 mL) was added
(S)-4-nitrophenyl (1-phenylethyl) carbonate (A-2h) (200 mg)
(prepared similarly by using the previous procedures: Ronald G.
Sherrill, et al, J. Org. Chem. 1995, 60, 730; Miriam Crowe, et al,
WO2011054844). The reaction mixture was stirred at rt overnight and
then concentrated in vacuo. The residue was purified by flash
column chromatography over silica gel (100% EtOAc) to afford (A-2i)
as a white solid (210 mg, 73%). LC-MS: 464.2 [M+Na].sup.+; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (d, 2H, J=8.2 Hz), 7.40-7.25
(m, 7H), 6.06 (br s, 1H), 5.78 (q, 1H, J=6.5 Hz), 5.60 (br s, 1H),
5.03 (t, 1H, J=5.8 Hz), 4.77 (d, 1H, J=7.6 Hz), 3.90 (m, 1H), 3.23
(m, 2H), 2.87 (m, 1H), 2.79 (dd, 1H, J=13.6, 6.9 Hz), 1.53 (d, 3H,
J=6.5 Hz), 1.40 (s, 9H).
Step 3: Synthesis of (S)-1-phenylethyl
((S)-2-amino-3-(4-carbamoylphenyl) propyl)carbamate (Compound
A-2)
##STR00199##
[0461] To a stirred solution of tert-butyl ((S)-1-phenylethyl)
((S)-3-(4-carbamoylphenyl)propane-1,2-diyl)dicarbamate (A-2i) (200
mg) and phenol (200 mg) in 1,4-dioxane (15 mL) was added 4N HCl
solution in 1,4-dioxane (1 mL). The reaction mixture was stirred
overnight and then concentrated in vacuo. The residue was treated
with dichloromethane and ammonia and purified by flash column
chromatography over silica gel (0-10% MeOH/CH.sub.2Cl.sub.2 with 5%
ammonia) to afford Compound A-2 a white solid (75 mg, 48%). LC-MS:
342.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.90 (br
s, 1H), 7.77 (d, 2H, J=8.1 Hz), 7.40-7.15 (m, 9H), 5.66 (q, 1H,
J=6.6 Hz), 3.00-2.80 (m, 3H), 2.68 (dd, 1H, J=13.2, 5.0 Hz), 2.45
(dd, 1H, J=13.4, 7.3 Hz), 1.50 (br s, 2H), 1.44 (d, 3H, J=6.6
Hz).
Example A3
##STR00200##
[0462] Synthesis (S)-1-phenylethyl
((S)-3-(4-carbamoylphenyl)-2-(dimethylamino)propyl) carbamate
(Compound A-3)
##STR00201##
[0464] To a stirred suspension of (S)-1-phenylethyl
((S)-2-amino-3-(4-carbamoylphenyl)propyl)carbamate, Compound A-2
(40 mg, 0.12 mmol) in acetonitrile (10 mL) and water (0.5 mL) at
0.degree. C. was added 37% aqueous solution of formaldehyde (0.047
mL, 0.6 mmol), followed by sodium cyanoborohydride (22 mg, 0.35
mmol). After 10 min, acetic acid (0.036 mL, 0.6 mmol) was added.
The reaction mixture was warmed to rt and stirred for 3 h. The
mixture was diluted with water and adjusted to pH 10 with aq.
Na.sub.2CO.sub.3 and extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous sodium sulfate,
and concentrated. The residue was purified by flash column
chromatography over silica gel (0-5% MeOH/CH.sub.2Cl.sub.2 with 5%
ammonia) to afford Compound A-3, as a white foam (30 mg, 69%).
LC-MS: 370.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.89 (br s, 1H), 7.82 and 7.76 (d, 2H, J=8.0 Hz), 7.35-7.10 (m,
8H), 6.93 and 6.65 (t, 1H, J=5.4 Hz), 5.62 (q, 1H, J=6.6 Hz), 3.06
(m, 1H), 2.95-2.70 (m, 3H), 2.47 (dd, 1H, J=15.8, 6.1 Hz), 2.22 (s,
6H), 1.41 and 1.33 (d, 3H, J=6.6 Hz).
Example A4
##STR00202##
[0465] Synthesis of
4-((S)-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)-2-(dimethylamino)
propyl)benzamide (Compound A-4)
Step 1: Synthesis of tert-butyl
(S)-(1-(4-cyanophenyl)-3-hydroxypropan-2-yl) carbamate (A-2d)
##STR00203##
[0467] To a stirred solution of the commercially available
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid
(A-4a) (5.0 g, 17.2 mmol) in anhydrous THF (50 mL) at -10.degree.
C. under nitrogen was added N-methylmorpholine (1.89 mL, 17.2
mmol), followed by slow addition of ethyl chloroformate (1.65 mL,
17.2 mmol). After stirring at -10.degree. C. for 10 min, the
reaction mixture was warmed to rt and stirred for 1 h. The
precipitates were filtered off and the filter cake was washed with
THF. The filtrate was cooled to -10.degree. C. and a solution of
sodium borohydride (0.98 g, 25.9 mmol) in water (3 mL) was slowly
added. After 1 h, the reaction was carefully quenched with 1N aq.
HCl. The mixture was adjusted to pH 8-9 and extracted with EtOAc
(3.times.). The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, and concentrated. The
residue was purified by flash column chromatography over silica gel
(0-80% EtOAc/CH.sub.2Cl.sub.2) to afford (A-2d) as a white powder
(3.25 g, 68%). LC-MS: 299.2 [M+Na].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.60 (d, 2H, J=7.7 Hz), 7.35 (d, 2H, J=7.7 Hz),
4.77 (br d, 1H), 3.88 (br s, 1H), 3.68 (br d, 1H, J=10.8 Hz), 3.56
(dd, 1H, J=10.8, 4.4 Hz), 2.93 (d, 2H, J=6.7 Hz), 2.08 (br s, 1H),
1.40 (s, 9H).
Step 2: Synthesis of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-hydroxypropan-2-yl)carbamate
(A-2e)
##STR00204##
[0469] To a stirred solution of tert-butyl
(S)-(1-(4-cyanophenyl)-3-hydroxypropan-2-yl)carbamate (A-2d) (1.7
g, 6.2 mmol) in methanol (50 mL) was added 6N aq. NaOH (1.03 mL,
6.2 mmol), followed by 27% aq. Solution of hydrogen peroxide (2.71
mL, 21.6 mmol). The reaction mixture was stirred at 50.degree. C.
for 3 h. After cooling, the mixture was neutralized with 1N aq.
HCl. Removal of methanol in vacuo and the residue was triturated
with water. The solids were collected by filtration and dried to
obtain (A-2e) as a white powder (1.5 g, 83%). LC-MS: 317.1
[M+Na].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.89 (s, 1H),
7.77 (d, 2H, J=8.2 Hz), 7.28 (s, 1H), 7.25 (d, 2H, J=8.2 Hz), 6.65
(d, 1H, J=8.6 Hz), 4.75 (t, 1H, J=5.2 Hz), 3.35 (m, 1H), 3.26 (m,
1H), 2.87 (dd, 1H, J=13.6, 5.0 Hz), 2.59 (dd, 1H, J=13.6, 9.0 Hz),
1.30 (s, 9H).
Step 3: Synthesis of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbam-
ate (A-2f)
##STR00205##
[0471] To a stirred solution of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-hydroxypropan-2-yl)carbamate (A-2e)
(1.0 g, 3.4 mmol), phthalimide (0.60 g, 4.1 mmol), and
triphenylphosphine (1.08 g, 4.1 mmol) in anhydrous THE (40 mL) at
0.degree. C. under nitrogen was slowly added diisopropyl
azodicarboxylate (0.81 mL, 4.1 mmol) over 1 h. The reaction mixture
was slowly warmed to rt and stirred overnight. The solids
precipitated out were collected by filtration and washed with THF
and dried to obtain (A-2f) as a white powder (1.33 g, 92%). LC-MS:
446.1 [M+Na].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.90-7.75 (m, 7H), 7.31-7.27 (m, 3H), 6.89 (d, 1H, J=9.2 Hz), 4.03
(m, 1H), 3.66-3.60 (m, 2H), 2.87 (dd, 1H, J=13.8, 5.3 Hz), 2.77
(dd, 1H, J=13.8, 9.8 Hz), 1.09 and 0.96 (s, 9H).
Step 4: Synthesis of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide
hydrochloride (A-4b)
##STR00206##
[0473] To a stirred solution of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbam-
ate (A-2f) (450 mg) in chloroform (20 mL) and methanol (2 mL) was
added 4N HCl solution in 1,4-dioxane (2 mL). The reaction mixture
was stirred at rt overnight, and then concentrated down to dryness
to obtain the crude product (A-4b) as a white powder (460 mg).
LC-MS: 324.1 [M+H].sup.+.
Step 5: Synthesis of
(S)-4-(2-(dimethylamino)-3-(1,3-dioxoisoindolin-2-yl)
propyl)benzamide (A-4c)
##STR00207##
[0475] To a stirred suspension of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide
hydrochloride (A-4b) (180 mg, 0.5 mmol) in acetonitrile (30 mL) and
water (1 mL) at 0.degree. C. was added 37% aqueous solution of
formaldehyde (0.22 mL, 2.5 mmol), followed by sodium
cyanoborohydride (90 mg, 1.5 mmol) in portions. After 10 min,
acetic acid (0.143 mL, 2.5 mmol) was added. The reaction mixture
was slowly warmed to rt and stirred for 3 h. The mixture was
treated with water and adjusted to pH 10 with aq. Na.sub.2CO.sub.3
and extracted with EtOAc. The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate, and concentrated.
The residue was purified by flash column chromatography over silica
gel (0-10% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to afford (A-4c)
as a white solid (125 mg, 71%). LC-MS: 352.2 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 7.89 (br s, 1H), 7.81 (s, 4H), 7.77
(d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=8.2 Hz), 7.28 (br s, 1H), 3.80
(dd, 1H, J=14.0, 9.5 Hz), 3.30 (m, 1H), 3.20 (m, 1H), 2.94 (dd, 1H,
J=13.5, 4.8 Hz), 2.53 (dd, 1H, J=13.5, 9.0 Hz), 2.23 (s, 6H).
Step 6: Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)benzamide (A-4d
##STR00208##
[0477] A mixture of
(S)-4-(2-(dimethylamino)-3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide
(A-4c) (125 mg, 0.36 mmol) in ethanol (10 mL) and hydrazine
monohydrate (90 mg, 1.8 mmol) was stirred at 70.degree. C. for 3 h.
The mixture was concentrated down to 2 mL and triturated with
CH.sub.2Cl.sub.2 and filtered to remove the solids. The filtrate
was concentrated and purified by flash column chromatography over
silica gel (0-20% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to afford
(A-4d) as a white foam (75 mg, 95%). LC-MS: 222.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (d, 2H, J=8.1 Hz),
7.23 (d, 2H, J=8.1 Hz), 6.09 (br s, 1H), 5.65 (br s, 1H), 2.97 (dd,
1H, J=13.0, 3.0 Hz), 2.70-2.50 (m, 3H), 2.35 (s, 7H).
Step 7: Synthesis of
[N,S(R)]--N-(cyclohexylphenylmethylene)-2-methyl-2-propanesulfinamide
(A-4 g)
##STR00209##
[0479] A round bottom flask was charged with titanium(IV)
isopropoxide (35.2 g, 124 mmol) and anhydrous THE (100 mL).
(R)-(+)-tertbutylsulfinamide (A-4e) (5 g, 41 mmol) and cyclopropyl
phenyl ketone (A-4f) (6 g, 41 mmol) were added. After cooling, the
reaction mixture was quenched with brine and filtered through
Celite. The filter cake was washed with EtOAc and the filtrate was
extracted with EtOAc. The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate, and concentrated. The
residue was purified by flash column chromatography over silica gel
(0-60% EtOAc/hexane) to afford (A-4 g) as a yellow oil (4.5 g,
44%). LC-MS: 250.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.50-7.40 (m, 5H), 1.25-1.00 (m, 14H).
Step 8: Synthesis of
N--[(S)-cyclopropylphenylmethyl]-2-methyl-[S(R)]-2-propanesulfinamide
(A-4 h)
##STR00210##
[0481] To a stirred suspension of
[N(R),S(R)]--N-(cyclohexylphenylmethylene)-2-methyl-2-propanesulfinamide
(A-4 g) (4.5 g, 18 mmol) in anhydrous THE (50 mL) at 0.degree. C.
under nitrogen was added 1M L-Selectride solution in THE (25 mL)
over 20 min. The reaction mixture was slowly warmed to rt over 3 h,
and then carefully quenched with methanol. The mixture was filtered
through Celite and the filtrate was concentrated. The residue was
purified by flash column chromatography over silica gel (0-50%
EtOAc/hexane) to isolate both diastereomers.
N--[(R)-cyclopropylphenylmethyl]-2-methyl-[S(R)]-2-propanesulfinamide:
colorless oil (3.0 g), LC-MS: 252.1 [M+H].sup.+; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.40-7.26 (m, 5H), 3.69 (dd, 1H, J=9.2,
2.8 Hz), 3.52 (s, 1H), 1.25 (s, 9H), 1.16 (m, 1H), 0.79 (m, 1H),
0.65 (m, 1H), 0.48 (m, 1H), 0.24 (m, 1H).
N--[(S)-cyclopropylphenylmethyl]-2-methyl-[S(R)]-2-propanesulfinamide
(A-4 h): colorless oil (0.75 g), LC-MS: 252.1 [M+H].sup.+; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.36-7.26 (m, 5H), 3.59 (s, 1H),
3.56 (d, 1H, J=9.2 Hz), 1.22 (s, 9H), 1.20 (m, 1H), 0.68 (m, 1H),
0.54 (m, 1H), 0.48 (m, 1H), 0.40 (m, 1H).
Step 9: Synthesis of (S)-cyclopropyl(phenyl)methanamine
hydrochloride (A-4i
##STR00211##
[0483] To a stirred solution of
N--[(S)-cyclopropylphenylmethyl]-2-methyl-[S(R)]-2-propanesulfinamide
(A-4 h) (1.5 g, 6 mmol) in 1,4-dioxane (25 mL) at 0.degree. C. was
added 4M HCl solution in 1,4-dioxane (6 mL). The reaction mixture
was slowly warmed to rt and stirred for 16 h. The reaction mixture
was diluted with diethyl ether (30 mL) and the solids precipitated
out were collected by filtration to afford (A-4i) as a white powder
(1.05 g, 96%). LC-MS: 131.1 [M+H--NH.sub.3].sup.+; .sup.1H NMR (400
MHz, methanol-d4) .delta. 7.42 (m, 5H), 3.57 (d, 1H, J=10.0 Hz),
1.39 (m, 1H), 0.82 (m, 1H), 0.68-0.55 (m, 2H), 0.41 (m, 1H).
Step 10: Synthesis of 4-nitrophenyl
(S)-(cyclopropyl(phenyl)methyl)carbamate (A-4k)
##STR00212##
[0485] To a stirred suspension of
(S)-cyclopropyl(phenyl)methanamine hydrochloride (A-4i) (1.0 g, 5.4
mmol) in anhydrous THE (30 mL) under nitrogen was added
triethylamine (3 mL, 22 mmol). The solution was cooled to
-40.degree. C. and a solution of p-nitrophenol chloroformate (A-4j)
(1.09 g, 5.4 mmol) in THE (5 mL) was added. The reaction mixture
was slowly warmed to rt and stirred overnight. The reaction mixture
was diluted with water and extracted with EtOAc. The combined
organic layers were washed with 1N aq. HCl and brine, dried over
anhydrous sodium sulfate, and concentrated. The residue was
purified by flash column chromatography over silica gel (30-100%
CH.sub.2Cl.sub.2/hexane) to afford (A-4k) as a white solid (1.1 g,
65%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.23 (d, 2H, J=8.8
Hz), 7.40-7.30 (m, 7H), 5.59 (d, 1H, J=7.0 Hz), 4.19 (t, 1H, J=8.4
Hz), 1.25 (m, 1H), 0.75-0.60 (m, 2H), 0.56 (m, 1H), 0.42 (m,
1H).
Step 11: Synthesis of
4-((S)-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)-2-(dimethylamino)propy-
l)benzamide (Compound A-4)
##STR00213##
[0487] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)benzamide (A-4d) (40 mg) in
anhydrous DMF (4 mL) was added 4-nitrophenyl
(S)-(cyclopropyl(phenyl)methyl)carbamate (A-4k) (55 mg). The
reaction mixture was stirred at rt overnight and then concentrated
in vacuo. The residue was purified by flash column chromatography
over silica gel (0-10% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to
afford Compound A-4 as a white solid (50 mg, 70%). LC-MS: 395.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.90 (s, 1H),
7.76 (d, 2H, J=8.0 Hz), 7.30-7.10 (m, 8H), 6.68 (d, 1H, J=7.8 Hz),
5.73 (br s, 1H), 4.09 (t, 1H, J=8.2 Hz), 3.01 (m, 1H), 2.95-2.75
(m, 2H), 2.66 (m, 1H), 2.35 (m, 1H), 2.26 (s, 6H), 1.02 (m, 1H),
0.50-0.35 (m, 2H), 0.35-0.20 (m, 2H).
Example A5
##STR00214##
[0488] Synthesis of (S)-1-phenylethyl
((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl) propyl)carbamate,
(Compound A-5)
Step 1: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyano-2,6-dimethylphenyl)propanoa-
te (A-5b)
##STR00215##
[0490] To a stirred suspension of zinc powder (2.5 g, 38.5 mmol) in
anhydrous N,N-dimethylacetamide (10 mL) under nitrogen was added
iodine (200 mg). After 5 min, a solution of methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (A-2b) (5.0 g,
15.2 mmol) in N,N-dimethylacetamide (5 mL) was added slowly over 10
min. The mixture was stirred at rt for 30 min and then heated at
70.degree. C. for 1 h. The mixture was cooled to rt and a
suspension of 4-bromo-3,5-dimethylbenzonitrile (A-5a) (2.5 g, 12
mmol), Pd.sub.2(dba).sub.3 (550 mg), and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 492 mg) in
N,N-dimethylacetamide (10 mL) was added into the zinc reagent
mixture. The reaction mixture was heated at 70.degree. C. and
stirred overnight. After cooling, the reaction mixture was quenched
with water, diluted with EtOAc and filtered through Celite. The
filter cake was washed with EtOAc and the filtrate was washed with
1N aq. HCl and brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-50% EtOAc/CH.sub.2Cl.sub.2) to
afford (A-5b) as a white solid (1.5 g, 38%). LC-MS: 355.2 [M+Na];
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (s, 2H), 5.13 (d,
1H, J=8.8 Hz), 4.56 (q, 1H, J=8.0 Hz), 3.67 (s, 3H), 3.15-3.00 (m,
2H), 2.38 (s, 6H), 1.35 (s, 9H).
Step 2: Synthesis of tert-butyl
(S)-(1-(4-cyano-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
(A-5c)
##STR00216##
[0492] To a stirred solution of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyano-2,6-dimethylphenyl)propanoa-
te (A-5b) (1.5 g, 4.5 mmol) in methanol (20 mL) and THE (10 mL) was
added sodium borohydride in small portions with 1 h intervals until
all starting material was consumed (about 800 mg NaBH.sub.4 used).
The reaction mixture was carefully quenched with 1N aq. HCl and
adjusted to pH 5. The volatiles were removed under reduced pressure
and the residue was triturated with water. The white solids
precipitated out were collected by filtration, washed with water
and dried to afford (A-5c) (1.0 g, 73%). LC-MS: 327.2 [M+Na].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (s, 2H), 4.87 (br s,
1H), 3.90 (m, 1H), 3.70 (m, 1H), 3.55 (dt, 1H, J=10.7, 4.4 Hz),
3.05-2.85 (m, 2H), 2.41 (s, 6H), 2.09 (br s, 1H), 1.37 (s, 9H).
Step 3: Synthesis of tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
(A-5d)
##STR00217##
[0494] To a stirred solution of tert-butyl
(S)-(1-(4-cyano-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
(A-5c) (1.0 g, 3.3 mmol) in methanol (30 mL) was added 6N aq. NaOH
(0.55 mL, 3.3 mmol), followed by 27% aq. Solution of hydrogen
peroxide (1.45 mL, 11.5 mmol). The reaction mixture was stirred at
50.degree. C. for 3 h. After cooling, the mixture was neutralized
with 1N aq. HCl. Removal of methanol under reduced pressure and the
residue was triturated with water. The solids were collected by
filtration and dried to obtain (A-5d) a white powder (1.0 g, 94%).
LC-MS: 345.2 [M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.45 (s, 2H), 6.20 (br s, 1H), 5.60 (br s, 1H), 4.87 (d,
1H, J=8.5 Hz), 3.88 (m, 1H), 3.69 (dd, 1H, J=10.5, 3.5 Hz), 3.55
(dd, 1H, J=10.7, 4.6 Hz), 2.95 (m, 1H), 2.43 (s, 7H), 1.38 (s,
9H).
Step 4: Synthesis of tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propa-
n-2-yl)carbamate (A-5e)
##STR00218##
[0496] To a stirred solution of tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
(A-5d) (1.0 g, 3.1 mmol), phthalimide (0.55 g, 3.7 mmol), and
triphenylphosphine (0.98 g, 3.7 mmol) in anhydrous THE (40 mL) at
0.degree. C. under nitrogen was added diisopropyl azodicarboxylate
(0.73 mL, 3.7 mmol) over 20 min. The reaction mixture was slowly
warmed to rt and stirred overnight. The mixture was concentrated
and the residue was purified by flash column chromatography over
silica gel (100% EtOAc) to afford (A-5e) as a white solid (1.2 g,
86%). LC-MS: 474.2 [M+Na].sup.+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.00-7.75 (m, 3H), 7.65-7.50 (m, 2H), 7.50 (s, 2H), 7.21
(s, 1H), 6.94 (d, 1H, J=9.6 Hz), 4.25-4.00 (m, 1H), 3.76 (dd, 1H,
J=13.5, 10.0 Hz), 3.46 (dd, 1H, J=13.5, 3.7 Hz), 2.90-2.80 (m, 2H),
2.35 (s, 6H), 1.08 and 0.88 (s, 9H).
Step 5: Synthesis of tert-butyl
(S)-(1-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propan-2-yl)carbamate
(A-5f)
##STR00219##
[0498] A mixture of tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propa-
n-2-yl)carbamate (A-5e) (600 mg, 1.33 mmol) in ethanol (10 mL) and
hydrazine monohydrate (325 mg, 6.7 mmol) was stirred at 80.degree.
C. for 3 h. After cooling, the mixture was filtered to remove the
solids and the filter cake was washed with ethanol. The filtrate
was concentrated and purified by flash column chromatography over
silica gel to afford (A-5f) a white foam (360 mg, 84%). LC-MS:
322.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45
(s, 2H), 6.07 (br s, 1H), 5.60 (br s, 1H), 4.72 (br s, 1H), 3.82
(br s, 1H), 3.00-2.60 (m, 4H), 1.35 (s, 9H).
Step 6: (S)-1-phenylethyl
((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl) propyl)carbamate
(Compound A-5)
##STR00220##
[0500] (S)-1-phenylethyl
((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl) propyl) carbamate
(Compound A-5) was synthesized according to the procedure for
Example A2 using tert-butyl
(S)-(1-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propan-2-yl)carbamate
(A-5f) as the starting material. LC-MS: 370.2 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 7.80 (s, 1H), 7.53 and 7.48 (s, 2H),
7.40-6.90 (m, 7H), 5.67 (q, 1H, J=6.5 Hz), 3.10-2.80 (m, 3H), 2.66
(dd, 1H, J=13.6, 4.2 Hz), 2.52 (m, 1H), 2.30 (s, 6H), 1.40 (br s,
2H), 1.44 and 1.35 (d, 3H, J=6.5 Hz).
Example A6
##STR00221##
[0501] Synthesis of
4-((S)-2-amino-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)propyl)-3,5-dim-
ethylbenzamide (Compound A-6)
##STR00222##
[0503]
4-((S)-2-amino-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)propyl)-3-
,5-dimethylbenzamide (Compound A-6) was synthesized according to
the procedure for Example A2 using tert-butyl
(S)-(1-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propan-2-yl)carbamate
(A-5f) and 4-nitrophenyl (S)-(cyclopropyl(phenyl)methyl)carbamate
(A-4k) as the starting materials. LC-MS: 395.2 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 7.80 (s, 1H), 7.48 (s, 2H),
7.30-7.25 (m, 4H), 7.22-7.15 (m, 2H), 6.56 (d, 1H, J=8.5 Hz), 5.99
(t, 1H, J=5.6 Hz), 4.14 (t, 1H, J=8.2 Hz), 3.05-2.75 (m, 3H), 2.68
(dd, 1H, J=13.5, 5.0 Hz), 2.55 (dd, 1H, J=13.5, 7.8 Hz), 2.30 (s,
6H), 1.50 (br s, 2H), 1.04 (m, 1H), 0.50-0.38 (m, 2H), 0.35-0.25
(m, 2H).
Example A7
##STR00223##
[0504] Synthesis of (S)-1-phenylethyl
((S)-3-(4-carbamoyl-2,6-dimethylphenyl)-2-(dimethylamino)propyl)carbamate
(Compound A-7)
##STR00224##
[0506] (S)-1-phenylethyl
((S)-3-(4-carbamoyl-2,6-dimethylphenyl)-2-(dimethylamino)propyl)carbamate
(Compound A-7) was synthesized according to the procedure for
Example A3 using (S)-1-phenylethyl
((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propyl)carbamate
(Compound A-5) as the starting material. LC-MS: 398.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.84 and 7.79 (s, 1H), 7.56
and 7.51 (s, 2H), 7.35-7.15 and 7.02 (m, 6H), 6.91 and 6.67 (t, 1H,
J=5.2 Hz), 5.62 (q, 1H, J=6.5 Hz), 3.15 (m, 1H), 2.85-2.65 (m, 3H),
2.29 (s, 12H), 1.41 and 1.29 (d, 3H, J=6.5 Hz).
Example A8
##STR00225##
[0507] Synthesis of
4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutanamido)propyl)-3,5-dimethylbe-
nzamide (Compound A-8)
Step 1: Synthesis of triethyl
(R)-2-phenylpropane-1,1,1-tricarboxylate A-8b)
##STR00226##
[0509] To a solution of 1.48 mL of the alcohol (A-8a) (1.00 equiv.,
12 mmol) and 5.21 mL of triethyl methanetricarboxylate (2.00
equiv., 24.1 mmol) in 45.0 mL of anhydrous toluene at room
temperature, 24.1 mL of 1M trimethyl phosphine solution in toluene
(1M, 2.00 equiv., 24.1 mmol) was added. The resulting solution was
cooled to -78.degree. C. DIAD (4.74 mL, 2.00 equiv., 24.1 mmol) was
added slowly at such a rate to maintain the temperature of the
reaction at -75.degree. C. to -77.degree. C. The reaction was then
stirred at -78.degree. C. for 0.5 hours and warmed to room
temperature for 1-3 hours and was allowed to run overnight. Solvent
was concentrated in vacuo to get crude. The crude was purified by
column chromatography using hexane and ethyl acetate to yield
compound (A-8b) as a clear oil (3.7 g, 91.4%). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.=7.35-7.32 (m, 2H), 7.20-7.12 (m, 3H),
4.13-4.03 (m, 6H), 3.81-3.74 (q, J=7.18, 1H), 1.44-1.41 (d, J=7.23,
3H), 1.13-1.09, (t, J=7.14, 9H).
Step 2: Synthesis of (S)-3-phenylbutanoic acid (A-8d)
##STR00227##
[0511] To triethyl (R)-2-phenylpropane-1,1,1-tricarboxylate (A-8b)
(3.7 g, 1.00 equiv., 11.1 mmol) 11.2 mL of MeOH was added followed
by 20.1 ml of 3.3 N NaOH in water (6.00 equiv., 66.4 mmol). The
resulting mixture was heated to reflux and the reaction was allowed
to continue overnight. Reaction was tracked using HPLC. When no
starting material remained, heating was removed and the reaction
was allowed to reach room temperature. Volatiles were removed in
vacuo and the crude tris acid (A-8c) was taken up in 66.4 mL of
acetic acid (105 equiv., 1.16 mol) and heated to reflux. The reflux
was allowed to continue overnight. The solvent was then
concentrated in vacuo. The resultant crude acid was dissolved in
water, and extracted with ethyl acetate. The combined extracts were
washed with water and then dried using sodium sulfate and
concentrated in vacuo to give product. The product was then
purified via column chromatography, eluting with ethyl
acetate/hexanes yielding compound (A-8d) as a clear oil (1.16 g,
63.9% over 2 steps). .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=7.38-7.31 (m, 2H), 7.29-7.22 (m, 3H), 3.31 (sxt, J=7.2 Hz,
1H), 2.75-2.68 (m, 1H), 2.65-2.57 (m, 1H), 1.36 (d, J=7.1 Hz,
3H)
Step 3: Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylbenzamide
(A-8e)
##STR00228##
[0513]
(S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylbenzamide
(A-8e) was synthesized according to the procedure of Example A4
using tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propa-
n-2-yl)carbamate (A-5e) as the starting material. LC-MS: 250.2
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (s,
2H), 6.00 (br s, 1H), 5.50 (br s, 1H), 2.91 (dd, 1H, J=13.2, 2.5
Hz), 2.78-2.65 (m, 2H), 2.63-2.50 (m, 1H), 2.43 (s, 6H), 2.37 (s,
6H), 2.35 (m, 1H).
Step 4: Synthesis of
4-((S)-2-(dimethylamino)-3-((S)-3-phenylbutanamido)propyl)-3,5-dimethylbe-
nzamide (Compound A-8)
##STR00229##
[0515] To a stirred solution of (S)-3-phenylbutanoic acid (A-8d)
(16 mg, 0.1 mmol), hydroxybenzotriazole (13 mg, 0.1 mmol), and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg,
0.15 mmol) in anhydrous DMF (2 mL) under nitrogen was added
(S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylbenzamide
(A-8e) (25 mg, 0.1 mmol), followed by triethylamine (0.028 mL, 0.2
mmol). The reaction mixture was stirred at rt for 3 h and then
diluted with water and extracted with EtOAc. The combined organic
layers were washed with aq. NaHCO.sub.3 and brine, dried over
anhydrous sodium sulfate, and concentrated. The residue was
purified by flash column chromatography over silica gel (0-5%
MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to afford Compound A-8 as a
white foam (37 mg, 92%). LC-MS: 396.3 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.81 (s, 1H), 7.53 (t, 1H, J=5.3 Hz), 7.48
(s, 2H), 7.30-7.10 (m, 6H), 3.15-3.05 (m, 2H), 2.95-2.65 (m, 3H),
2.35-2.20 (m, 14H), 1.13 (d, 3H, J=7.0 Hz).
Example A9
##STR00230##
[0516] Synthesis of
4-((S)-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)-2-(dimethylamino)
propyl)-3,5-dimethylbenzamide (Compound A-9)
##STR00231##
[0518]
4-((S)-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)-2-(dimethylamino-
)propyl)-3,5-dimethylbenzamide (Compound A-9) was synthesized
according to the procedure for Example A3 using
4-((S)-2-amino-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)propyl)-3,5-dim-
ethylbenzamide (Compound A-6) as the starting material. LC-MS:
423.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.79 (s,
1H), 7.47 (s, 2H), 7.30-7.15 (m, 6H), 6.69 (d, 1H, J=8.4 Hz), 5.72
(m, 1H), 4.06 (t, 1H, J=8.1 Hz), 2.95-2.80 (m, 3H), 2.66 (m, 1H),
2.33 (s, 6H), 2.30 (s, 6H), 0.99 (m, 1H), 0.50-0.35 (m, 2H),
0.31-0.20 (m, 2H).
Example A10
##STR00232##
[0519] Synthesis of
4-((S)-2-(dimethylamino)-3-((R)-3-phenylbutanamido)propyl)benzamide
(Compound A-10)
Step 1: Synthesis of triethyl
(S)-2-phenylpropane-1,1,1-tricarboxylate (A-10b)
##STR00233##
[0521] To a solution of 1.00 mL of the alcohol (A-10a) (1.00
equiv., 7.94 mmol) and 3.44 mL of triethyl methanetricarboxylate
(2.00 equiv., 15.9 mmol) in 30.0 mL of anhydrous toluene at room
temperature, 15.9 mL of 1M trimethyl phosphine solution in toluene
(1M, 2.00 equiv., 15.9 mmol) was added. The resulting solution was
cooled to -78.degree. C. DIAD (3.13 mL, 2.00 equiv., 15.9 mmol) was
added slowly at such a rate to maintain the temperature of the
reaction at -75.degree. C. to -77.degree. C. The reaction was then
stirred at -78.degree. C. for 0.5 hours and warmed to room
temperature for 1-3 hours and was allowed to run overnight. Solvent
was concentrated in vacuo to get crude. The crude was purified by
column chromatography using hexane and ethyl acetate to yield
compound (A-10b) as clear oil (2.46 g, 92.1%). .sup.1H NMR (600
MHz, CHLOROFORM-d) .delta.=4.45-7.43 (d, 2H), 7.30-7.20 (m, 3H),
4.22-4.13 (m, 6H), 1.23-1.19 (t, J=7.2 Hz, 9H).
Step 2: Synthesis of (R)-3-phenylbutanoic acid (A-10d)
##STR00234##
[0523] To triethyl (S)-2-phenylpropane-1,1,1-tricarboxylate (A-10b)
(1.00 equiv., 2.97 mmol) 3.00 mL of MeOH was added followed by 5.41
ml of 3.3 N NaOH in water (6.00 equiv., 17.8 mmol). The resulting
mixture was heated to reflux and the reaction was allowed to
continue overnight. Reaction was tracked using HPLC. When no
starting material remained, heating was removed and the reaction
was allowed to reach room temperature. Volatiles were removed in
vacuo and the crude tris acid (A-10c) was taken up in 17.9 mL of
acetic acid (105 equiv., 312 mmol) and heated to reflux. The reflux
was allowed to continue overnight. The solvent was then
concentrated in vacuo. The resultant crude acid was dissolved in
water, and extracted with ethyl acetate. The combined extracts were
washed with water and then dried using sodium sulfate and
concentrated in vacuo to give product. The product was then
purified via column chromatography, eluting with ethyl
acetate/hexanes yielding compound (A-10d) as clear oil (240 mg,
49.2% over 2 steps). .sup.1H NMR (600 MHz, CHLOROFORM-d)
.delta.=7.34-7.30 (m, 2H), 7.26-7.20 (m, 3H), 3.29 (sxt, J=7.2 Hz,
1H), 2.71-2.66 (m, 1H), 2.62-2.57 (m, 1H), 1.34 (d, J=7.0 Hz,
3H)
Step 3: Synthesis of
(R)--N--((S)-3-(4-cyanophenyl)-2-(dimethylamino)propyl)-3-phenylbutanamid-
e (A-10e)
##STR00235##
[0525] To 160 mg of the amine HCl (A-1i) (1.00 equiv., 579
.mu.mol), 133 mg of HOBT monohydrate (1.50 equiv., 869 .mu.mol) was
added followed by the addition of 800 .mu.L of DMF (5.00
volEquiv.). Next, 349 .mu.L of DIPEA (3.50 equiv., 2.03 mmol) was
added and the reaction mixture was cooled to 0.degree. C. In a
separate vial, 800 .mu.L of DMF (5.00 volEquiv.) was added to 95.4
mg of acid (A-10d) (1.00 equiv 581 .mu.mol) and then transferred to
the reaction mixture at 0.degree. C. Finally, 167 mg of EDC (1.5
equiv., 869 .mu.mol) was added and allowed to stir at 0.degree. C.
for 5 minutes, after which it was allowed to stir at rt. After 3
hours, the reaction was quenched by adding water and stirred for 10
minutes. The white solid was extracted using ethyl acetate. The
combined organic layers were washed with sat. NaHCO.sub.3 twice,
then with water, and brine. The solvent was then evaporated. The
resultant product (A-10e) was flashed in 9:0.5:0.2
DCM/MeOH/NH.sub.3 in MeOH giving 156.5 mg of product (77.3%
yield).
Step 4: Synthesis of
((R)-2-(dimethylamino)-3-((S)-3-phenylbutanamido)propyl) benzamide
(Compound A-10)
##STR00236##
[0527] 54.8 mg of starting material (A-10e) (1.00 equiv., 157
.mu.mol) was added to a vial and dissolved in 165 .mu.L of DMSO
(3.01 volEquiv.). Next, 80.2 mg of potassium carbonate (3.00
equiv., 470 .mu.mol) was added to the reaction mixture. Finally,
28.0 microliters hydrogen peroxide (30% aqueous, 1.75 equiv., 274
.mu.mol) was added dropwise to the reaction mixture. The reaction
was then stirred and monitored via LCMS. After 50 minutes another
1.75 equivalents of hydrogen peroxide were added to push the
reaction forward, and the reaction mixture was monitored via LCMS.
After 20 minutes the reaction was quenched using 0.5 mL of water,
and 0.5 mL of 10% w/w aqueous sodium thiosulfate. The product was
then extracted using ethyl acetate (1 mL.times.3) and the aqueous
layer was tested via LCMS and TLC for presence of product. The
organic layer was then dried using NaSO.sub.4 and concentrated in
vacuo yielding 24.4 mg of product, Compound A-10 (42.3% yield). An
NMR sample was taken in CDCl.sub.3. The CDCl.sub.3 peak covered
part of the spectra so another NMR sample was prepared in
deuterated methanol. (M+H=368.4) H NMR (400 MHz, METHANOL-d4)
.delta.=7.8-7.78 (d, J=8.28 Hz, 2H), 7.26-7.18 (m, 6H), 7.14-7.10
(m, 1H), 2.27 (s, 6H), 1.25-1.24 (d, 3H).
Example A11
##STR00237##
[0528] Synthesis of
4-((S)-2-(dimethylamino)-3-((R)-3-phenylbutanamido)propyl)-3,5-dimethylbe-
nzamide (Compound A-11)
##STR00238##
[0530]
4-((S)-2-(dimethylamino)-3-((R)-3-phenylbutanamido)propyl)-3,5-dime-
thylbenzamide (Compound A-11) was synthesized according to the
procedure for Example A8 using (R)-3-phenylbutanoic acid (A-10d) as
the starting material. LC-MS: 396.3 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.81 (s, 1H), 7.47 (m, 3H), 7.30-7.10 (m,
6H), 3.15-3.05 (m, 2H), 2.90-2.75 (m, 2H), 2.65 (m, 1H), 2.35-2.20
(m, 14H), 1.14 (d, 3H, J=7.0 Hz).
Example A12
##STR00239##
[0531] Synthesis of
(S)-4-(2-(dimethylamino)-3-(2-(isopropyl(phenyl)amino)acetamido)
propyl)-3,5-dimethylbenzamide (Compound A-12)
##STR00240##
[0533]
(S)-4-(2-(dimethylamino)-3-(2-(isopropyl(phenyl)amino)acetamido)
propyl)-3,5-dimethylbenzamide (Compound A-12) was synthesized
according to the procedure for Example A8 using
N-isopropyl-N-phenylglycine (A-12a) (Rheem A. Totah, et al. J. Am.
Chem. Soc. 2001, 123, 10107) as the starting material. LC-MS: 425.3
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.81 (s, 1H),
7.48 (s, 2H), 7.40 (t, 1H, J=5.2 Hz), 7.20 (s, 1H), 7.15 (t, 2H,
J=8.0 Hz), 6.70-6.60 (m, 3H), 4.10 (m, 1H), 3.57 (s, 2H), 3.13 (m,
1H), 2.92-2.75 (m, 2H), 2.68 (m, 1H), 2.28 (s, 6H), 2.22 (s, 6H),
1.08 (t, 6H, J=5.6 Hz).
Example A13
##STR00241##
[0534] Synthesis of
(S)-4-(3-(3-benzyl-3-methylureido)-2-(dimethylamino)propyl)-2-fluoro-N-me-
thylbenzamide (Compound A-13)
[0535] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (50.6 mg, 0.20 mmol, 1 equiv) in dry DMF (2 mL) was added
CDI (35 mg, 0.22 mmol, 1.1 equiv). After stirring at RT for 4 h
under nitrogen, DIPEA (70 .mu.L, 0.4 mmol, 2 equiv) and
N-methyl-1-phenylmethanamine (31 .mu.L, 0.24 mmol, 1.2 equiv) were
added and continued to stir overnight. The solution was
concentrated under vacuum and the residue was purified by flash
column chromatography over silica gel (0-25% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid (47.1
mg, 59% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.06 (t,
J=7.95 Hz, 1H) 7.76 (s, 2H) 7.32-7.52 (m, 6H) 7.14-7.18 (m, 1H)
7.00-7.09 (m, 1H), 5.54 (br d, J=6.60 Hz, 1H), 4.62 (d, J=2.45 Hz,
2H), 3.46 (ddd, J=12.66, 7.40, 4.65 Hz, 1H), 3.19 (d, J=4.65 Hz,
3H), 3.08-3.14 (m, 2H), 3.04-3.08 (m, 3H), 2.89-2.98 (m, 1H),
2.38-2.53 (m, 7H). LCMS: 401.3 [M].sup.+.
Example A14
##STR00242##
[0536] Synthesis of
(S)-4-(3-(3-benzylureido)-2-(dimethylamino)propyl)-2-fluoro-N-methylbenza-
mide (Compound A-14)
[0537] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (50.6 mg, 0.20 mmol, 1 equiv) in dry DMF (2 mL) was added
CDI (35 mg, 0.22 mmol, 1.1 equiv). After stirring at RT for 4 h
under nitrogen, DIPEA (70 .mu.L, 0.4 mmol, 2 equiv) and
N-methyl-1-phenylmethanamine (31 .mu.L, 0.24 mmol, 1.2 equiv) were
added and continued to stir overnight. The solution was
concentrated under vacuum and the residue was purified by flash
column chromatography over silica gel (0-25% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid (47.1
mg, 59% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (t,
J=8.07 Hz, 1H), 7.73-7.83 (m, 3H), 7.36-7.57 (m, 12H), 7.14-7.18
(m, 1H), 7.03-7.10 (m, 1H), 6.24 (br s, 1H), 5.86 (br d, J=5.38 Hz,
1H), 4.50 (d, J=5.62 Hz, 2H), 3.63-3.67 (m, 6H), 3.34-3.48 (m, 1H),
3.03-3.20 (m, 5H), 2.91-3.02 (m, 1H), 2.48-2.58 (m, 1H), 2.45 (s,
5H), 1.39-1.44 (m, 1H). LCMS: 401.3 [M].sup.+.
Example A15
##STR00243##
[0538] Synthesis of
4-((S)-2-(dimethylamino)-3-(3-((S)-1-(pyridin-2-yl)ethyl)ureido)propyl)-2-
-fluoro-N-methylbenzamide (Compound A-15)
[0539] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (50 mg, 0.20 mmol, 1 equiv) in dry DMF (2 mL) was added
CDI (35 mg, 0.22 mmol, 1.1 equiv). After stirring at RT for 4 h
under nitrogen, DIPEA (70 .mu.L, 0.4 mmol, 2 equiv) and
(S)-1-(pyridin-2-yl)ethan-1-amine (29 .mu.L, 0.24 mmol, 1.2 equiv)
were added and continued to stir overnight. The solution was
concentrated under vacuum and the residue was purified by flash
column chromatography over silica gel (0-25% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid (70.7
mg, 88% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.70 (d,
J=4.88 Hz, 1H), 8.02-8.10 (m, 1H), 7.93-8.02 (m, 1H), 7.79-7.87 (m,
1H), 7.74-7.77 (m, 1H), 7.50-7.57 (m, 1H), 7.45-7.49 (m, 1H),
7.33-7.41 (m, 2H), 7.18 (dd, J=8.07, 1.47 Hz, 1H), 7.07 (dd,
J=12.59, 1.10 Hz, 1H), 6.38 (br d, J=6.11 Hz, 1H), 5.78 (br d,
J=5.14 Hz, 1H), 5.13 (quin, J=6.91 Hz, 1H), 3.39 (ddd, J=12.72,
7.34, 4.89 Hz, 1H), 3.08-3.24 (m, 5H), 2.92-3.04 (m, 1H), 2.50-2.61
(m, 2H), 2.43-2.50 (m, 6H), 1.60-1.67 (m, 3H). LCMS: 402.2
[M].sup.+.
Example A16
##STR00244##
[0540] Synthesis of
4-((S)-3-((S)-3-(3,4-dichlorophenoxy)butanamido)-2-(dimethylamino)propyl)-
-2-fluoro-N-methylbenzamide (Compound A-16)
[0541] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (43 mg, 0.17 mmol, 1 equiv) in dry DMF (2 mL) was added
2,5-dioxopyrrolidin-1-yl (S)-3-(3,4-dichlorophenoxy)butanoate (63.7
mg, 0.18 mmol, 1.08 equiv) under nitrogen. After 2 h, the solution
was concentrated under vacuum and the residue was purified by flash
column chromatography over silica gel (0-25% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid (54.8
mg, 66% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98 (t,
J=8.19 Hz, 1H), 7.28 (d, J=8.80 Hz, 1H), 7.01 (s, 1H), 6.98-7.00
(m, 1H), 6.71-6.89 (m, 3H), 6.56 (br d, J=5.62 Hz, 1H), 4.70-4.78
(m, 1H), 3.34 (ddd, J=13.63, 6.91, 4.89 Hz, 1H), 2.98-3.04 (m, 3H),
2.84-2.98 (m, 2H), 2.60-2.72 (m, 1H), 2.49-2.61 (m, 1H), 2.29-2.47
(m, 2H), 2.20-2.29 (m, 7H), 1.32 (d, J=6.11 Hz, 3H). LCMS: 484.2
[M].sup.+.
Example A17
##STR00245##
[0542] Synthesis of
(S)-4-(2-(dimethylamino)-3-(3-methyl-3-(pyridin-2-ylmethyl)ureido)propyl)-
-2-fluoro-N-methylbenzamide (Compound A-17)
[0543] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (42.5 mg, 0.17 mmol, 1 equiv) in dry DMF (2 mL) was added
CDI (30 mg, 0.19 mmol, 1.1 equiv). After stirring at RT for 4 h
under nitrogen, DIPEA (59 .mu.L, 0.34 mmol, 2 equiv) and
N-methyl-1-(pyridin-2-yl)methanamine (25 .mu.L, 0.2 mmol, 1.2
equiv) were added and continued to stir overnight. The solution was
concentrated under vacuum and the residue was purified by flash
column chromatography over silica gel (0-15% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid (18.7
mg, 27% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.52 (d,
J=4.98 Hz, 1H), 8.00 (t, J=8.19 Hz, 1H), 7.66 (td, J=7.64, 1.83 Hz,
1H), 7.24 (d, J=7.83 Hz, 1H), 7.18 (ddd, J=7.58, 4.89, 1.22 Hz,
1H), 7.06 (dd, J=8.07, 1.47 Hz, 1H), 6.94 (dd, J=12.96, 1.47 Hz,
1H), 6.73 (br d, J=7.83 Hz, 1H), 5.72 (br s, 1H), 4.46-4.57 (m,
2H), 3.34 (ddd, J=13.21, 6.85, 4.89 Hz, 1H), 2.84-3.07 (m, 9H),
2.37-2.50 (m, 1H), 2.30-2.36 (m, 6H), 1.87-2.13 (m, 2H). LCMS:
402.2 [M].sup.+.
Example A18
##STR00246##
[0544] Synthesis of
(S)-4-(2-(dimethylamino)-3-(3-(pyridin-2-ylmethyl)ureido)propyl)-2-fluoro-
-N-methylbenzamide (Compound A-18)
[0545] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (42.5 mg, 0.17 mmol, 1 equiv) in dry DMF (2 mL) was added
CDI (30 mg, 0.19 mmol, 1.1 equiv). After stirring at RT for 4 h
under nitrogen, DIPEA (59 .mu.L, 0.34 mmol, 2 equiv) and
pyridin-2-ylmethanamine (21 .mu.L, 0.2 mmol, 1.2 equiv) were added
and continued to stir overnight. The solution was concentrated
under vacuum and the residue was purified by flash column
chromatography over silica gel (0-15% MeOH in CH.sub.2Cl.sub.2 with
1% NH.sub.4OH) to afford a white solid (70.7 mg, 88% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.49 (d, J=5.13 Hz, 1H),
7.97 (t, J=8.19 Hz, 1H), 7.64 (td, J=7.64, 1.83 Hz, 1H), 7.25-7.29
(m, 2H), 7.17 (t, J=6.22 Hz, 1H), 7.04 (d, J=8.14 Hz, 1H), 6.91
(dd, J=12.96, 1.47 Hz, 1H), 6.78 (br dd, J=11.86, 5.26 Hz, 1H),
5.69 (br s, 1H), 5.38 (br d, J=5.62 Hz, 1H), 4.45 (d, J=5.38 Hz,
2H), 3.22-3.30 (m, 1H), 2.92-3.03 (m, 5H), 2.73-2.88 (m, 1H), 2.38
(dd, J=13.33, 9.66 Hz, 1H), 2.28-2.33 (m, 6H), 2.10-2.21 (m, 3H).
LCMS: 388.2 [M].sup.+.
Example A19
##STR00247##
[0546] Synthesis of
(S)-4-(2-(dimethylamino)-3-(3-phenoxypropanamidopropyl)-2-fluoro-N-methyl-
benzamide (Compound A-19)
[0547] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (21 mg, 0.08 mmol, 1 equiv) in dry DMF (1 mL) was added
EDCI (25 mg, 0.13 mmol, 1.5 equiv), HOBt (18 mg, 0.13 mmol, 1.5
equiv), 3-phenoxypropanoic acid (15 mg, 0.9 mmol, 1.1 equiv), and
DIPEA (89 .mu.L, 0.5 mmol, 6 equiv). After 6 h, the solution was
diluted with water and extracted with EtOAc. The combined organic
layers were washed with aq. NaHCO.sub.3 and brine, dried over
anhydrous sodium sulfate, and concentrated. The residue was
purified by flash column chromatography over silica gel (0-15% MeOH
in CH.sub.2Cl.sub.2) to afford a white solid (7.5 mg, 24% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96-8.02 (m, 1H),
7.23-7.28 (m, 5H), 6.84-7.04 (m, 5H), 6.62-6.75 (m, 2H), 4.16-4.23
(m, 2H), 3.33-3.42 (m, 1H), 2.87-3.07 (m, 5H), 2.67-2.82 (m, 1H),
2.61 (t, J=5.87 Hz, 2H), 2.26-2.36 (m, 8H), 1.75-1.93 (m, 5H).
LCMS: 402.2 [M].sup.+.
Example A20
##STR00248##
[0548] Synthesis of
4-((S)-3-(3-((S)-cyclopropyl(phenyl)methyl)ureido)-2-(dimethylamino)propy-
l)-2-fluoro-N-methylbenzamide (Compound A-20)
[0549] To a stirred solution of
4-((S)-2-amino-3-(3-((S)-cyclopropyl(phenyl)
methyl)ureido)propyl)-2-fluoro-N-methylbenzamide (76 mg, 0.19 mmol,
1 equiv) in 9:1 CH.sub.3CN: H.sub.2O at 0.degree. C. was added
NaCNBH.sub.4 (60 mg, 0.95 mmol, 5 equiv) and 37% formaldehyde (21
.mu.L, 0.57 mmol, 3 equiv). After 10 min, HOAc (55 ul, 0.95 mmol, 5
equiv) was added and the solution was allowed to warm to rt for 4
h. Ethyl acetate (10 mL) was added and the solution was washed with
aq. NaHCO.sub.3 and brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-15% MeOH in CH.sub.2Cl.sub.2) to
afford a white solid (45 mg, 58% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.26 (d, J=4.40 Hz, 4H). 6.91-7.01 (m, 1H).
6.79-6.91 (m, 1H). 6.50-6.76 (m, 1H). 3.86-3.98 (m, 1H). 3.08-3.18
(m, 1H). 2.85-3.00 (m, 6H). 2.26-2.34 (m, 5H). 1.11-1.17 (m, 2H).
0.99-1.09 (m, 1H). 0.37-0.56 (m, 2H). 0.21-0.37 (m, 2H). LCMS:
427.2 [M].sup.+.
Example A21
##STR00249##
[0550] Synthesis of
(R)--N--(((S)-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methy-
l)-3-phenylbutanamide (Compound A-21)
[0551] To a stirred solution of
(S)-3-(aminomethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol (50
mg, 0.52 mmol, 1 equiv) in dry DMF (3 mL) was added EDCI (100 mg,
1.04 mmol, 2 equiv), HOBt (70 mg, 1.04 mmol, 2 equiv),
(R)-3-phenylbutanoic acid (47 mg, 0.57 mmol, 1.1 equiv), and DIPEA
(226 .mu.L, 2.6 mmol, 5 equiv). After 3 h, the solution was diluted
with water and extracted with EtOAc. The combined organic layers
were washed with aq. NaHCO.sub.3 and brine, dried over anhydrous
sodium sulfate, and concentrated. The residue was purified by flash
column chromatography over silica gel (0-10% MeOH in
CH.sub.2Cl.sub.2) to afford a white solid (8.1 mg, 5% yield.).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.15-7.30 (m, 6H), 6.86
(d, J=8.31 Hz, 1H), 6.60 (br d, J=7.83 Hz, 1H), 6.40 (s, 1H), 6.03
(br s, 1H), 3.59-3.69 (m, 1H), 3.44-3.57 (m, 2H), 3.19-3.38 (m,
3H), 2.39-2.66 (m, 5H), 2.20 (s, 3H), 1.28 (d, J=6.85 Hz, 3H), 1.21
(t, J=6.97 Hz, 2H). LCMS: 339.2 [M].sup.+.
Example A22
##STR00250##
[0552] Synthesis of
(R)--N--((S)-2-(dimethylamino)-3-(2-oxoindolin-5-yl)propyl)-3-phenylbutan-
amide (Compound A-22)
##STR00251##
[0554]
(R)--N--((S)-2-(dimethylamino)-3-(2-oxoindolin-5-yl)propyl)-3-pheny-
lbutanamide was synthesized according to the general procedure
using (S)-5-(3-amino-2-(dimethylamino)propyl)indolin-2-one and
(R)-3-phenylbutanoic acid as the starting materials. LC-MS: 380.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.25 (s, 1H),
7.44 (m, 1H), 7.30-7.10 (m, 5H), 6.98 (s, 1H), 6.93 (d, 1H, J=7.9
Hz), 6.69 (d, 1H, J=7.9 Hz), 3.42 (s, 2H), 3.15-2.90 (m, 3H), 2.65
(dd, 1H, J=13.4, 5.5 Hz), 2.55 (m, 1H), 2.40-2.20 (m, 3H), 2.20 (s,
6H), 1.15 (d, 3H, J=6.9 Hz).
Example A23
##STR00252##
[0555] Synthesis of
(S)--N--((S)-2-(dimethylamino)-3-(2-oxoindolin-5-yl)propyl)-3-phenylbutan-
amide (Compound A-23)
##STR00253##
[0557]
(S)--N--((S)-2-(dimethylamino)-3-(2-oxoindolin-5-yl)propyl)-3-pheny-
lbutanamide was synthesized according to the general procedure
using (S)-5-(3-amino-2-(dimethylamino)propyl)indolin-2-one and
(S)-3-phenylbutanoic acid as the starting materials. LC-MS: 380.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.25 (s, 1H),
7.46 (br t, 1H), 7.30-7.15 (m, 5H), 6.97 (s, 1H), 6.92 (d, 1H,
J=8.0 Hz), 6.69 (d, 1H, J=7.9 Hz), 3.42 (s, 2H), 3.12 (m, 1H),
3.05-2.90 (m, 2H), 2.70-2.55 (m, 2H), 2.40-2.22 (m, 3H), 2.19 (s,
6H), 1.14 (d, 3H, J=6.9 Hz).
B. Synthesis of Compounds Having the Structure of Formula (I-B)
[0558] Representative Compounds having the structure of Formula
(I-B) can be synthesized by using the general synthetic procedures
set forth in Schemes B1-B3.
##STR00254##
##STR00255##
##STR00256##
Synthesis of Intermediates
Synthesis of
(S)-3-(3-fluorophenyl)-N2,N2-dimethylpropane-1,2-diamine
dihydrochloride (Int-5)
Step 1: Synthesis of
(S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluorophenyl)propanoic acid
(Int-1)
##STR00257##
[0560] 3-Fluoro-L-Phenylalanine (1 g, 5.46 mmol, Combi-blocks, Cat
#SS-0819, Lot #L78093) was dissolved in THE (15 mL) and water (15
mL) and the pH of the solution was adjusted to 9 using saturated
sodium bicarbonate solution. Di-tert-butyl-dicarbonate (1.31 g, 6
mmol) was added to the solution slowly and was stirred overnight.
After completion of the reaction, the pH of the solution was
adjusted to 4 using 0.1 M HCl and the aqueous layer was extracted
with ethyl acetate. Combined organic layers were washed with water
(.times.2) followed by brine, dried using sodium sulfate, filtered
and concentrated under reduced pressure to afford 1.5 g (97% yield)
off-white solid of the title product (Int-1). LCMS (+ESI)
M+H+(-Boc)=184.1.
Step 2: Synthesis of tert-butyl
(S)-(1-amino-3-(3-fluorophenyl)-1-oxopropan-2-yl)carbamate
(Int-2)
##STR00258##
[0562] To a solution of Int-1 (1.5 g, 5.29 mmol) and DMF (15 mL),
DIPEA (2.77 mL, 15.9 mmol), HATU (3.02 g, 7.94 mmol), HOBt
monohydrate (715 mg, 5.29 mmol) and ammonium carbonate (4.19 g,
52.9 mmol) were added and was allowed to stir at room temperature
overnight. After completion of the reaction, the mixture was
diluted with ether and the organic layer was washed with water
(.times.2) followed by brine, dried using sodium sulfate, filtered
and concentrated under reduced pressure to afford 1.1 g (74% yield)
an off-white solid of Int-2. LCMS (+ESI) M+H+(-Boc)=183.1. 1H NMR
(400 MHz, CHLOROFORM-d) .delta.=7.30-7.26 (m, 1H), 7.02 (d, J=7.8
Hz, 1H), 6.98-6.91 (m, 2H), 6.02 (br s, 1H), 5.60 (br s, 1H), 5.11
(br d, J=8.0 Hz, 1H), 4.39 (br d, J=6.0 Hz, 1H), 3.07 (m, 2H), 1.41
(s, 9H).
Step 3: Synthesis of (S)-2-amino-3-(3-fluorophenyl)propenamide
hydrochloride (Int-3)
##STR00259##
[0564] To a solution of tert-butyl
(S)-(1-amino-3-(3-fluorophenyl)-1-oxopropan-2-yl)carbamate (Int-2)
(1.1 g, 3.9 mmol) and THE (5.5 mL), 4 M HCl in dioxane (3.9 mL,
15.6 mmol) was added and was allowed to stir until no starting
material was observed (by TLC). After completion of the reaction,
the solvent was evaporated under reduced pressure. Obtained solid
was re-dissolved in ether and was evaporated under reduced pressure
(this step was repeated two more times). Obtained solid was dried
under high vacuum to afford 710 mg (99% yield) of the title product
(Int-3). LCMS (+ESI) M+H.sup.+=183.1.
Step 4: Synthesis of (S)-2-(dimethylamino)-3-(3-fluorophenyl)
propanamide hydrochloride (Int-4)
##STR00260##
[0566] To a solution of (S)-2-amino-3-(3-fluorophenyl)propenamide
hydrochloride (Int-3) (710 mg, 3.8 mmol) and 9:1 acetonitrile and
water (9.9 mL), formaldehyde (13.3 M, 2.93 mL, 39 mmol) was added
and was cooled to 0.degree. C. Sodium triacetoxyborohydride (2.06
g, 9.74 mmol) was added portion wise and was stirred for 15
minutes. The completion of the reaction was monitored by LCMS.
After completion of the reaction, the mixture was quenched with
saturated sodium bicarbonate solution (11.5 mL) and the pH of the
solution was adjusted to 8 using 5% sodium carbonate solution. The
aqueous layer was extracted with 1:3 isopropanol and ethyl acetate
(.times.4). Combined organic layers were washed with brine, dried
using sodium sulfate, filtered and concentrated under reduced
pressure. The crude material was re-dissolved in isopropanol and
was treated with 37% HCl (12 M, 0.3 mL). The solution was partially
concentrated and was precipitated using ethyl ether. The solid was
filtered and washed with ether, dried under high vacuum to afford
960 mg (99% yield) of the title product (Int-4). LCMS (+ESI)
M+H.sup.+=211.2.
Step 5: Synthesis of
(S)-3-(3-fluorophenyl)-N2,N2-dimethylpropane-1,2-diamine
dihydrochloride (Int-5)
##STR00261##
[0568] (S)-2-(dimethylamino)-3-(3-fluorophenyl)propanamide
hydrochloride (Int-4) (960 mg, 3.89 mmol) was dissolved in THE
(14.4 mL) and was cooled to 0.degree. C. Borane tetrahydrofuran
(0.9 M, 26 mL, 23.3 mmol) was added to the solution slowly
dropwise. After warming to room temperature, the mixture was
refluxed (60.degree. C.) for 20 hours. After completion of the
reaction, the mixture was cooled and quenched using methanol and
the solvent was evaporated under reduced pressure. The residue was
re-dissolved in methanol and was evaporated under reduced pressure
and this step was repeated two more times. Obtained oil was
re-dissolved in isopropanol and 2 N HCl in ether was added followed
by dilution with ether. The slurry was sonicated and was filtered
to afford 530 mg (51% yield) of pale-yellow solid of the title
product (Int-5). LCMS (+ESI) M+H.sup.+=197.2.
Synthesis of (S)-4-(3-amino-2-(dimethylamino)propyl)phenol
dihydrochloride (Int-7)
Step 1: Synthesis of (S)-2-(dimethylamino)-3-(4-hydroxyphenyl)
propanamide hydrochloride (Int-6)
##STR00262##
[0570] (S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propanamide
hydrochloride (Int-6) was prepared by the same procedure as for
Int-4, starting with L-tyrosinamide (Cat #SS-8156, Lot #L79234),
for 95% yield. LCMS (+ESI) M+H.sup.+=209.2. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.=11.02 (br s, 1H), 9.42 (br s, 1H), 7.90 (s,
1H), 7.60 (s, 1H), 7.11-6.93 (m, 2H), 6.78-6.60 (m, 2H), 3.95 (br
d, J=10.2 Hz, 1H), 3.17 (dd, J=4.1, 13.1 Hz, 1H), 2.94 (dd, J=10.8,
12.9 Hz, 1H), 2.79 (s, 6H).
Step 2: Synthesis of (S)-4-(3-amino-2-(dimethylamino)propyl)phenol
dihydrochloride (Int-7)
##STR00263##
[0572] (S)-4-(3-amino-2-(dimethylamino)propyl)phenol
dihydrochloride (Int-7) was prepared by the same procedure as for
Int-5, using Int-6, for 86% yield. LCMS (+ESI) M+H.sup.+=195.2.
.sup.1H NMR (400 MHz, DMSO-d6) .delta.=11.14-10.93 (br s, 1H),
9.62-9.28 (br m, 1H), 8.50 (br s, 2H), 7.18-7.09 (m, 2H), 6.81-6.72
(m, 2H), 3.82-3.73 (m, 1H), 3.47-3.34 (m, 1H), 3.14 (br dd, J=3.3,
13.6 Hz, 1H), 2.96-2.74 (m, 6H), 2.73-2.55 (m, 2H).
Synthesis of (S)-4-(3-amino-2-(dimethylamino)propyl)benzamide
(Int-13)
Step 1: Synthesis of tert-butyl
(S)-(1-(4-cyanophenyl)-3-hydroxypropan-2-yl)carbamate (Int-8)
##STR00264##
[0574] To a stirred solution of the commercially available
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid
(5.0 g, 17.2 mmol) in anhydrous THF (50 mL) at -10.degree. C. under
nitrogen was added N-methylmorpholine (1.89 mL, 17.2 mmol),
followed by slow addition of ethyl chloroformate (1.65 mL, 17.2
mmol). After stirring at -10.degree. C. for 10 min, the reaction
mixture was warmed to rt and stirred for 1 h. The precipitates were
filtered off and the filter cake was washed with THF. The filtrate
was cooled to -10.degree. C. and a solution of sodium borohydride
(0.98 g, 25.9 mmol) in water (3 mL) was slowly added. After 1 h,
the reaction was carefully quenched with 1N aq. HCl. The mixture
was adjusted to pH 8-9 and extracted with EtOAc (3.times.). The
combined organic layers were washed with brine, dried over
anhydrous magnesium sulfate, and concentrated. The residue was
purified by flash column chromatography over silica gel (0-80%
EtOAc/CH.sub.2Cl.sub.2) to afford the title compound (Int-8) as a
white powder (3.25 g, 68%). LC-MS: 299.2 [M+Na].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.60 (d, 2H, J=7.7 Hz), 7.35 (d, 2H,
J=7.7 Hz), 4.77 (br d, 1H), 3.88 (br s, 1H), 3.68 (br d, 1H, J=10.8
Hz), 3.56 (dd, 1H, J=10.8, 4.4 Hz), 2.93 (d, 2H, J=6.7 Hz), 2.08
(br s, 1H), 1.40 (s, 9H).
Step 2: Synthesis of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-hydroxypropan-2-yl)carbamate
(Int-9)
##STR00265##
[0576] To a stirred solution of tert-butyl
(S)-(1-(4-cyanophenyl)-3-hydroxypropan-2-yl)carbamate (Int-8) (1.7
g, 6.2 mmol) in methanol (50 mL) was added 6N aq. NaOH (1.03 mL,
6.2 mmol), followed by 27% aq. Solution of hydrogen peroxide (2.71
mL, 21.6 mmol). The reaction mixture was stirred at 50.degree. C.
for 3 h. After cooling, the mixture was neutralized with 1N aq.
HCl. Removal of methanol in vacuo and the residue was triturated
with water. The solids were collected by filtration and dried to
obtain (Int-9) as a white powder (1.5 g, 83%). LC-MS: 317.1
[M+Na].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.89 (s, 1H),
7.77 (d, 2H, J=8.2 Hz), 7.28 (s, 1H), 7.25 (d, 2H, J=8.2 Hz), 6.65
(d, 1H, J=8.6 Hz), 4.75 (t, 1H, J=5.2 Hz), 3.35 (m, 1H), 3.26 (m,
1H), 2.87 (dd, 1H, J=13.6, 5.0 Hz), 2.59 (dd, 1H, J=13.6, 9.0 Hz),
1.30 (s, 9H).
Step 3: Synthesis of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbam-
ate (Int-10)
##STR00266##
[0578] To a stirred solution of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-hydroxypropan-2-yl)carbamate (Int-9)
(1.0 g, 3.4 mmol), phthalimide (0.60 g, 4.1 mmol), and
triphenylphosphine (1.08 g, 4.1 mmol) in anhydrous THE (40 mL) at
0.degree. C. under nitrogen was slowly added diisopropyl
azodicarboxylate (0.81 mL, 4.1 mmol) over 1 h. The reaction mixture
was slowly warmed to rt and stirred overnight. The solids
precipitated out were collected by filtration and washed with THE
and dried to obtain the title compound (Int-10) as a white powder
(1.33 g, 92%). LC-MS: 446.1 [M+Na]+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.90-7.75 (m, 7H), 7.31-7.27 (m, 3H), 6.89 (d, 1H, J=9.2
Hz), 4.03 (m, 1H), 3.66-3.60 (m, 2H), 2.87 (dd, 1H, J=13.8, 5.3
Hz), 2.77 (dd, 1H, J=13.8, 9.8 Hz), 1.09 and 0.96 (s, 9H).
Step 4: Synthesis of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide
hydrochloride (Int-11)
##STR00267##
[0580] To a stirred solution of tert-butyl
(S)-(1-(4-carbamoylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbam-
ate (Int-10) (450 mg) in chloroform (20 mL) and methanol (2 mL) was
added 4N HCl solution in 1,4-dioxane (2 mL). The reaction mixture
was stirred at rt overnight, and then concentrated down to dryness
to obtain the crude product (Int-11) as a white powder (460 mg).
LC-MS: 324.1 [M+H].sup.+.
Step 5: Synthesis of
(S)-4-(2-(dimethylamino)-3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide
(Int-12)
##STR00268##
[0582] To a stirred suspension of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide
hydrochloride (Int-11) (180 mg, 0.5 mmol) in acetonitrile (30 mL)
and water (1 mL) at 0.degree. C. was added 37% aqueous solution of
formaldehyde (0.22 mL, 2.5 mmol), followed by sodium
cyanoborohydride (90 mg, 1.5 mmol) in portions. After 10 min,
acetic acid (0.143 mL, 2.5 mmol) was added. The reaction mixture
was slowly warmed to rt and stirred for 3 h. The mixture was
treated with water and adjusted to pH 10 with aq. Na.sub.2CO.sub.3
and extracted with EtOAc. The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate, and concentrated.
The residue was purified by flash column chromatography over silica
gel (0-10% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to afford the
title compound (Int-12) as a white solid (125 mg, 71%). LC-MS:
352.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.89 (br
s, 1H), 7.81 (s, 4H), 7.77 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=8.2
Hz), 7.28 (br s, 1H), 3.80 (dd, 1H, J=14.0, 9.5 Hz), 3.30 (m, 1H),
3.20 (m, 1H), 2.94 (dd, 1H, J=13.5, 4.8 Hz), 2.53 (dd, 1H, J=13.5,
9.0 Hz), 2.23 (s, 6H).
Step 6: Synthesis of (S)-4-(3-amino-2-(dimethylamino)propyl)
benzamide (Int-13)
##STR00269##
[0584] A mixture of
(S)-4-(2-(dimethylamino)-3-(1,3-dioxoisoindolin-2-yl)propyl)benzamide
(Int-12) (125 mg, 0.36 mmol) in ethanol (10 mL) and hydrazine
monohydrate (90 mg, 1.8 mmol) was stirred at 70.degree. C. for 3 h.
The mixture was concentrated down to 2 mL and triturated with
CH.sub.2Cl.sub.2 and filtered to remove the solids. The filtrate
was concentrated and purified by flash column chromatography over
silica gel (0-20% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to afford
the title compound (Int-13) as a white foam (75 mg, 95%). LC-MS:
222.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73
(d, 2H, J=8.1 Hz), 7.23 (d, 2H, J=8.1 Hz), 6.09 (br s, 1H), 5.65
(br s, 1H), 2.97 (dd, 1H, J=13.0, 3.0 Hz), 2.70-2.50 (m, 3H), 2.35
(s, 7H).
Synthesis of phenylcyclopropane carboxylic acids
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid
(Int-22)
(1S,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid
(Int-23)
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid
(Int-24)
(1S,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid
(Int-25)
##STR00270## ##STR00271##
[0585] Synthesis of cis-ethyl
2-methyl-2-phenylcyclopropane-1-carboxylate (Int-15) and
trans-ethyl 2-methyl-2-phenylcyclopropane-1-carboxylate
(Int-16)
##STR00272##
[0587] To a stirred mixture of .alpha.-methylstyrene (Int-14) (5 g,
42.4 mmol) and rhodium (II) acetate dimer (56 mg, 0.13 mmol) in dry
CH.sub.2Cl.sub.2 (100 mL) was added ethyl diazoacetate (15% in
toluene) (43.2 mL, 50.8 mmol, 1.0 equiv.) via additional funnel
over 4 h. The resulting mixture was stirred at room temperature for
overnight. Reaction mixture was concentrated under reduced pressure
and purified by column chromatography on silica gel (0-5%
EtOAc/hexane) to afford both the less polar trans-isomer (Int-16)
(2.3 g, 27%) and the cis-isomer (Int-15) (2.2 g, 25%).
Trans-isomer: colorless oil, LC-MS: 205.2 [M+H].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.34-7.28 (m, 4H), 7.21 (m, 1H),
4.23-4.16 (m, 2H), 1.96 (dd, 1H, J=8.3, 6.0 Hz), 1.53 (s, 3H),
1.47-1.39 (m, 2H), 1.30 (t, 3H, J=7.1 Hz). Cis-isomer: colorless
oil, LC-MS: 205.2 [M+H]; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.30-7.15 (m, 5H), 3.90-3.75 (m, 2H), 1.90 (dd, 1H, J=7.7, 5.4 Hz),
1.78 (t, 1H, J=5.0 Hz), 1.46 (s, 3H), 1.14 (dd, 1H, J=7.6, 4.6 Hz),
0.94 (t, 3H, J=7.1 Hz).
Synthesis of cis-2-methyl-2-phenylcyclopropane-1-carboxylic acid
(Int-17)
##STR00273##
[0589] To a solution of cis-ethyl
2-methyl-2-phenylcyclopropane-1-carboxylate (Int-15) (2.5 g, 12.2
mmol, 1 equiv.) in MeOH (30 mL) and water (6 mL) was added LiOH
(820 g, 34.2 mmol, 2.8 equiv.). The resulting mixture was stirred
at rt overnight. Then more LiOH (820 g, 34.2 mmol, 2.8 equiv.) was
added, and the reaction mixture was stirred at 50.degree. C. for
2.5 hours. TLC and LC-MS showed that starting material was
consumed. Then MeOH was carefully evaporated, and the residue was
diluted with water (30 mL), followed by the addition of 1 N HCl (70
mL). Then the aqueous layer was extracted with EtOAc. The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4. After
filtration and concentration, the product was obtained as a
colorless oil (Int-17) (2.15 g), which was used for the next step
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.30-7.15 (m, 5H), 1.88 (dd, 1H, J=7.6, 5.6 Hz), 1.72 (t,
1H, J=5.0 Hz), 1.45 (s, 3H), 1.21 (dd, 1H, J=7.6, 4.6 Hz).
Synthesis of
(S)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-18) and
(S)-3-((1S,2R)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-19)
##STR00274##
[0591] To a stirred solution of
cis-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-17) (2.15
g, 12.2 mmol, 1 equiv.) in dry CH.sub.2Cl.sub.2 (40 mL) at
0.degree. C. under nitrogen were added 5 drops of dry DMF, followed
by oxalyl chloride (2.07 mL, 24.1 mmol, 1.7 equiv.). The resulting
mixture was stirred at 0.degree. C. for 15 min and then stirred at
rt for 2 h. The solvent was carefully evaporated to afford the
desired acid chloride.
[0592] To a stirred solution of (S)-(+)-4-phenyl-2-oxazolidinone
(2.31 g, 14.2 mmol, 1 equiv.) in dry THE (50 mL) at -78.degree. C.
under N.sub.2 was added n-BuLi (2.5 M in hexanes, 5.68 mL, 14.2
mmol, 1 equiv.) dropwise over 10 min. After stirring at -78.degree.
C. for 30 min, a solution of the above prepared acid chloride in
THF (10 mL) was added over 15 min. Then the resulting mixture was
slowly warmed rt and stirred overnight. The reaction was quenched
by addition of water (20 mL) and extracted with EtOAc. The combined
organic layers were dried over anhydrous MgSO.sub.4. After
filtration and concentration, the crude was purified by column
chromatography on silica gel (0-40% EtOAc/hexane) to separate the
diastereomers.
[0593]
(S)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenylox-
azolidin-2-one (more polar): colorless oil (Int-18), 1.8 g (45%).
LC-MS: 322.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.25-7.15 (m, 3H), 7.15-7.07 (m, 2H), 7.06-6.97 (m, 3H), 6.92 (d,
2H, J=7.1 Hz), 5.23 (dd, 1H, J=8.4, 2.8 Hz), 4.64 (t, 1H, J=8.6
Hz), 4.23 (dd, 1H, J=8.8, 3.0 Hz), 3.13 (t, 1H, J=6.6 Hz), 1.60 (s,
3H), 1.19 (dd, 1H, J=7.2, 4.8 Hz).
[0594]
(S)-3-((1S,2R)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenylox-
azolidin-2-one (less polar): white solid (Int-19), 1.8 g (45%).
LC-MS: 322.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.35-7.15 (m, 10H), 5.08 (dd, 1H, J=8.8, 4.6 Hz), 4.56 (t, 1H,
J=8.8 Hz), 4.20 (dd, 1H, J=8.8, 4.6 Hz), 3.13 (t, 1H, J=6.4 Hz),
1.98 (t, 1H, J=5.2 Hz), 1.60 (s, 3H), 1.16 (dd, 1H, J=7.3, 4.8
Hz).
Synthesis of (1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic
acid (Int-22)
##STR00275##
[0596] To a solution of
(S)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-18) (1.8 g, 5.6 mmol, 1 equiv.) in THF (20 mL) and
water (18 mL) was added LiOH (451 mg, 19.6 mmol, 3.5 equiv.) and
17% H.sub.2O.sub.2 in water (2.5 mL, 19.6 mmol, 3.5 equiv.). After
2 h, more LiOH (451 mg) and H.sub.2O.sub.2 (2.5 mL) were added. The
resulting mixture was stirred at rt for another 3 h. The residue
was diluted with water (20 mL), followed by the addition of 1N HCl
until pH 3-4. Then the aqueous layer was extracted with EtOAc. The
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4.
After filtration and concentration, the crude was purified by
column chromatography on silica gel (0-40% eluent EtOAc/hexane) to
give the desired acid (Int-22) as a colorless oil.
Synthesis of (1S,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic
acid (Int-23)
##STR00276##
[0598] To a solution of
(S)-3-((1S,2R)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-19) (1.8 g, 5.6 mmol, 1 equiv.) in THF (20 mL) and
water (18 mL) was added LiOH (451 mg, 19.6 mmol, 3.5 equiv.) and
17% H.sub.2O.sub.2 in water (2.5 mL, 19.6 mmol, 3.5 equiv.). After
20 min, more water (8 mL) was added. The resulting mixture was
stirred at rt for another 2 h (TLC and LC-MS showed that starting
material was consumed). The residue was diluted with water (20 mL),
followed by the addition of 1N HCl (21 mL). Then the aqueous layer
was extracted with EtOAc. The combined organic layers were dried
over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the crude was purified by column chromatography on
silica gel (0-40% eluent EtOAc/hexane) to give the desired acid
(Int-23) (540 mg, 55%) as a colorless oil.
Synthesis of trans-2-methyl-2-phenylcyclopropane-1-carboxylic acid
(Int-17-2)
##STR00277##
[0600] To a solution of trans-ethyl
2-methyl-2-phenylcyclopropane-1-carboxylate (Int-16) (3.5 g, 17.1
mmol, 1 equiv.) in MeOH (40 mL) and water (8 mL) was added LiOH
(1.02 g, 42.8 mmol, 2.5 equiv.). The resulting mixture was stirred
at rt overnight. TLC and LC-MS showed that starting material has
been consumed. Then MeOH was carefully evaporated. The residue was
diluted with water (40 mL), acidified with 2N HCl to pH 3-4, and
extracted with EtOAc. The combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to obtain a yellowish
oil (Int-17-2) (3.2 g), which was used for the next step without
further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.35-7.15 (m, 5H), 1.99 (dd, 1H, J=8.0, 6.2 Hz), 1.59 (s, 3H),
1.55-1.45 (m, 2H).
Synthesis of
(S)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-20) and
(S)-3-((1S,2S)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-21)
##STR00278##
[0602] To a stirred solution of
trans-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-17-2)
(2.5 g, 14.2 mmol, 1 equiv.) in dry CH.sub.2Cl.sub.2 (40 mL) at
0.degree. C. under nitrogen were added 5 drops of dry DMF, followed
by oxalyl chloride (2.07 mL, 24.1 mmol, 1.7 equiv.). The resulting
mixture was stirred at 0.degree. C. for 15 min and then stirred at
rt for 2 h. The solvent was carefully evaporated to afford the
desired acid chloride.
[0603] To a stirred solution of (S)-(+)-4-phenyl-2-oxazolidinone
(2.31 g, 14.2 mmol, 1 equiv.) in dry THE (50 mL) at -78.degree. C.
under N.sub.2 was added n-BuLi (2.5 M in hexanes, 5.68 mL, 14.2
mmol, 1 equiv.) dropwise over 10 min. After stirring at -78.degree.
C. for 30 min, a solution of the above prepared acid chloride in
THF (10 mL) was added over 15 min. Then the resulting mixture was
slowly warmed rt and stirred overnight. The reaction was quenched
by addition of water (20 mL) and extracted with EtOAc. The combined
organic layers were dried over anhydrous MgSO.sub.4. After
filtration and concentration, the crude was purified by column
chromatography on silica gel (0-30% EtOAc/hexane) to separate the
diastereomers.
[0604]
(S)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenylox-
azolidin-2-one (Int-20) (more polar): colorless syrup, 1.7 g (34%).
LC-MS: 322.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.48-7.22 (m, 10H), 5.50 (dd, 1H, J=8.6, 3.4 Hz), 4.73 (t, 1H,
J=8.8 Hz), 4.29 (dd, 1H, J=8.6, 3.4 Hz), 3.47 (t, 1H, J=6.9 Hz),
1.61 (t, 1H, J=5.0 Hz), 1.37 (dd, 1H, J=7.8, 4.4 Hz), 1.17 (s,
3H).
[0605]
(S)-3-((1S,2S)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenylox-
azolidin-2-one (Int-21) (less polar): white solid, 1.7 g (34%).
LC-MS: 322.1 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.47-7.20 (m, 10H), 5.53 (dd, 1H, J=8.8, 4.4 Hz), 4.75 (t, 1H,
J=8.9 Hz), 4.30 (dd, 1H, J=8.8, 4.4 Hz), 3.39 (t, 1H, J=6.9 Hz),
1.59 (t, 1H, J=5.0 Hz), 1.45 (s, 3H), 1.39 (dd, 1H, J=7.9, 4.2
Hz).
Synthesis of (1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic
acid (Int-24)
##STR00279##
[0607] To a solution of
(S)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-20) (1.7 g, 5.3 mmol, 1 equiv.) in THF (20 mL) and
water (8 mL) was added LiOH (426 mg, 18.5 mmol, 3.5 equiv.) and 17%
H.sub.2O.sub.2 in water (2.33 mL, 18.52 mmol, 3.5 equiv.). The
resulting mixture was stirred at rt for 1 h. The residue was
diluted with water (20 mL), followed by the addition of 1N HCl (20
mL). Then the aqueous layer was extracted with EtOAc. The combined
organic layers were dried over anhydrous Na.sub.2SO.sub.4. After
filtration and concentration, the crude was purified by column
chromatography on silica gel (0-40% EtOAc/hexane) to give the
desired acid (Int-24) (770 mg, 83%) as a colorless oil.
Synthesis of (1S,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic
acid (Int-25)
##STR00280##
[0609] To a solution of
(S)-3-((1S,2S)-2-methyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazolid-
in-2-one (Int-21) (1.7 g, 5.3 mmol, 1 equiv.) in THF (25 mL) an
water (10 mL) was added LiOH (476 mg, 20.7 mmol, 3.9 equiv.) and
17% H.sub.2O.sub.2 in water (2.6 mL, 20.7 mmol, 3.9 equiv.). The
resulting mixture was stirred at rt for 80 min and TLC and LC-MS
showed that the reaction was complete. The residue was diluted with
water (20 mL), followed by the addition of 1N HCl (23 mL). Then the
aqueous layer was extracted with EtOAc. The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the crude was purified by column chromatography on
silica gel (0-40% EtOAc/hexane) to give the desired acid (Int-25)
(560 mg, 60%) as a colorless oil.
Synthesis of (1R,2R)-2-isopropyl-2-phenylcyclopropane-1-carboxylic
acid (Int-35) and
(1R,2S)-2-isopropyl-2-phenylcyclopropane-1-carboxylic acid
(Int-36)
##STR00281## ##STR00282##
[0610] Synthesis of 3-methyl-2-phenyl-1-butene (Int-26)
##STR00283##
[0612] To a solution of 16 g (44.7 mmol) of
methyltriphenylphosphonium bromide in 60 mL of dry THF at
-78.degree. C. was added 17.9 mL of a 2.5 M solution of n-BuLi in
hexane (44.7 mmol) and the solution turned brown. After 30 min
stirring at 0.degree. C., 6.31 g (42.5 mmol) of
3-methyl-2-phenylbutanone in 30 mL of THE were added and the
solution was stirred overnight. After 20 mL of water were added and
the solution was extracted with CH.sub.2Cl.sub.2 (3.times.100 mL).
The organic layer was dried over MgSO.sub.4 and the solvent was
evaporated. The crude product was purified by silica-gel flash
chromatography (hexanes as eluent) and 2.7 g (44%) of
(3-methylbut-1-en-2-yl)benzene (Int-26) were obtained as colorless
oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=1.11 (d, J=7.2 Hz,
6H), 2.87 (m, 1H), 5.07 (m, 1H), 5.17 (m, 1H), 7.28-7.39 (m,
5H).
Synthesis of ethyl 2-isopropyl-2-phenylcyclopropane-1-carboxylate
(Int-27) and (Int-28)
##STR00284##
[0614] To a solution (3-methylbut-1-en-2-yl)benzene (Int-26) (6.3
g, 4.3 mmol, 1 equiv.) and rhodium (II) acetate dimer (120 mg) in
dry DCM (100 mL) was added ethyl diazoacetate (15% in toluene) (37
mL, 4.3 mmol, 1 equiv.) via additional funnel over 4 h. The
resulting mixture was stirred at room temperature for overnight.
Reaction mixture was concentrated under reduced pressure. A mixture
of racemic trans- and cis-isomers were obtained and their
separation was done by column chromatography on silica gel (eluent
EtOAc/Hexanes 0-10%). After purification 2.03 g of cis-isomer
(Int-27) (20%) and 3.2 g of trans-isomer (Int-28) (32%) were
obtained. Cis-ethyl 2-isopropyl-2-phenylcyclopropane-1-carboxylate
(Int-27): .sup.1H NMR (400 MHz, CDCl.sub.3, ppm) .delta. 7.28-7.17
(m, 5H), 3.89 (q, J=7.2 Hz, 2H), 1.91 (dd, J=6.8, 4.8 Hz, 1H), 1.63
(t, J=4.8 Hz, 1H), 1.17 (m, 1H), 1.15 (t, J=4.4 Hz, 3H), 1.01 (d,
J=7.2 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H), 0.86 (d, J=7.2 Hz, 3H).
[0615] Trans-ethyl 2-isopropyl-2-phenylcyclopropane-1-carboxylate
(Int-28): .sup.1H NMR (400 MHz, CDCl.sub.3, ppm) .delta. 7.31-7.25
(m, 5H), 4.24 (q, J=7.2 Hz, 2H), 2.01-1.86 (m, 2H), 1.44 (t, J=4.0
Hz, 1H), 1.35 (t, J=7.2 Hz, 3H), 1.30 (t, J=4.0 Hz, 3H), 0.91 (d,
J=7.2 Hz, 3H), 0.81 (d, J=7.2 Hz, 3H).
Synthesis of cis-2-isopropyl-2-phenylcyclopropane-1-carboxylic acid
(Int-29)
##STR00285##
[0617] To a solution of cis-ethyl
2-isopropyl-2-phenylcyclopropane-1-carboxylate (Int-27) (2.0 g, 8.6
mmol, 1 equiv.) in MeOH (25 mL)--water (5 mL) was added LiOH (1.03
g, 43.0 mmol, 5 equiv.). The resulting mixture was stirred at rt
overnight and then stirred at 50.degree. C. for 3 h. TLC and LC-MS
showed that starting material has been consumed. After cooled to
rt, MeOH was carefully evaporated. The residue was diluted with
water (40 mL), followed by the addition of 1 N HCl (50 mL). Then
the aqueous layer was extracted with EtOAc (100 mL.times.4). The
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4.
After filtration and concentration, the product was obtained as a
white solid (1.74 g, 99% g), which was used for the next step
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3,
ppm) .delta. 7.31-7.17 (m, 5H), 1.88 (t, J=4.0 Hz, 1H), 1.60 (t,
J=4.8 Hz, 1H), 1.30-1.22 (m, 2H), 0.99 (t, J=6.8 Hz, 1H), 0.86 (t,
J=6.8 Hz, 1H).
Synthesis of
(R)-3-((1R,2R)-2-isopropyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazo-
lidin-2-one (Int-31) and
(R)-3-((1S,2S)-2-isopropyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazo-
lidin-2-one (Int-32)
##STR00286##
[0619] 1.74 g of cis-2-isopropyl-2-phenylcyclopropane-1-carboxylic
acid (Int-29) (8.5 mmol, 1 equiv.) was dissolved in dry DCM (20
mL). The reaction mixture was cooled to 0.degree. C. with ice-water
bath. Then 5 drops of dry DMF was added, followed by the addition
of (COCl).sub.2 (1.68 mL, 19.6 mmol, 2.3 equiv.). The resulting
mixture was stirred at 0.degree. C. for 15 min and then stirred at
rt for 2 h. The solvent was then evaporated, then dry DCM (20 ml)
was added and evaporated. To a solution of
(R)-4-phenyloxazolidin-2-one (1.39 g, 8.5 mmol, 1 equiv.) in dry
THE (40 ml) at -78.degree. C. under N.sub.2 was added n-BuLi (2.5 M
in hexanes, 3.4 mL, 8.5 mmol, 1 equiv.) dropwise over 10 min. After
stirring at -78.degree. C. for 30 min, a THF solution of the above
prepared acyl chloride (10 mL THF) was added by syringe over 15
min. Then the resulting mixture was stirred from -78.degree. C. to
rt overnight. The reaction was quenched by addition of water (20
mL), followed by extraction with EtOAc (50 mL.times.3). The
combined organic layers were dried over anhydrous MgSO.sub.4. After
filtration and concentration, the crude was purified by column
chromatography on silica gel (eluent EtOAc/Hexanes 0-20%).
[0620]
(R)-3-((1R,2R)-2-isopropyl-2-phenylcyclopropane-1-carbonyl)-4-pheny-
loxazolidin-2-one (Int-31): white solid, 1.3 g (44%). .sup.1H NMR
(400 MHz, CDCl.sub.3, ppm) .delta. 7.36-7.14 (m, 10H), 5.22 (dd,
J=8.8, 4.4 Hz, 1H), 4.68 (t, J=8.8 Hz, 1H), 4.27 (dd, J=8.8, 4.0
Hz, 1H), 3.29 (dd, J=7.2, 5.2 Hz, 1H), 1.79 (t, J=4.8 Hz, 1H), 1.55
(m, 1H), 1.19 (t, J=4.0 Hz, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.88 (d,
J=6.8 Hz, 3H); LC-MS: 350.2 (M+H).sup.+.
[0621]
(R)-3-((1S,2S)-2-isopropyl-2-phenylcyclopropane-1-carbonyl)-4-pheny-
loxazolidin-2-one (Int-32): white solid, 1.43 g (48%). .sup.1H NMR
(400 MHz, CDCl.sub.3, ppm) .delta. 7.36-7.26 (m, 5H), 6.86-6.34 (m,
5H), 5.30 (dd, J=8.0, 2.8 Hz, 1H), 4.68 (t, J=8.8 Hz, 1H), 4.37
(dd, J=9.2, 2.8 Hz, 1H), 3.32 (dd, J=7.6, 5.6 Hz, 1H), 1.77 (t,
J=4.8 Hz, 1H), 1.49 (m, 1H), 1.23 (t, J=4.0 Hz, 1H), 1.01 (d, J=6.8
Hz, 3H), 0.85 (d, J=6.8 Hz, 3H); LC-MS: 350.2 (M+H).sup.+.
Synthesis of (1R,2R)-2-isopropyl-2-phenylcyclopropane-1-carboxylic
acid (Int-35)
##STR00287##
[0623] To a solution of
(R)-3-((1R,2R)-2-isopropyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazo-
lidin-2-one (Int-31) (880 mg, 2.51 mmol, 1 equiv.) in THE (10
mL)--water (4 mL) was added 17% H.sub.2O.sub.2 in water (1.18 mL,
10.3 mmol, 4.1 equiv.) and LiOH (154 mg, 3.77 mmol, 1.5 equiv.).
The resulting mixture was stirred at rt overnight (TLC and LC-MS
showed that starting material has been consumed). The residue was
diluted with water (20 mL), followed by the addition of 1 N NaOH (5
mL). The aqueous layer was extracted with EtOAc (80 mL.times.3),
then treated with 1 N HCl (13 mL). Then the aqueous layer was
extracted with EtOAc (70 mL.times.3). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the product (Int-35) was obtained as a white solid
(450 mg, 88%), which was used in the next step without further
purification.
[0624] .sup.1H NMR (400 MHz, CDCl.sub.3, ppm) .delta. 7.31-7.17 (m,
5H), 1.88 (t, J=4.0 Hz, 1H), 1.60 (t, J=4.8 Hz, 1H), 1.30-1.22 (m,
2H), 0.99 (t, J=6.8 Hz, 1H), 0.86 (t, J=6.8 Hz, 1H).
Synthesis of trans-isopropyl-2-phenylcyclopropane-1-carboxylic acid
(Int-30)
##STR00288##
[0626] To a solution of trans-ethyl
2-isopropyl-2-phenylcyclopropane-1-carboxylate (Int-28) (3.2 g,
13.8 mmol, 1 equiv.) in MeOH (30 mL)--water (6 mL) was added LiOH
(820 mg, 34.4 mmol, 2.5 equiv.). The resulting mixture was stirred
at rt overnight. TLC and LC-MS showed starting material has been
consumed. After cooled to rt, MeOH was carefully evaporated. The
residue was diluted with water (40 mL), followed by the addition of
1 N HCl (40 mL). Then the aqueous layer was extracted with EtOAc
(100 mL.times.3). The combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4. After filtration and concentration, the
product (Int-30) was obtained as a white solid (2.8 g, 99% g),
which was used for the next step without further purification.
.sup.1H NMR (400 MHz, CDCl.sub.3, ppm) .delta. 7.41-7.21 (m, 5H),
2.17-2.00 (m, 2H), 1.49 (t, J=4.4 Hz, 1H), 1.43 (t, J=4.4 Hz, 1H),
0.93 (d, J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H).
Synthesis of
(R)-3-((1R,2S)-2-isopropyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazo-
lidin-2-one (Int-33)
##STR00289##
[0628] 2.8 g of crude acid (Int-30) from above step (13.7 mmol, 1
equiv.) was dissolved in dry DCM (30 mL). The reaction mixture was
cooled to 0.degree. C. with ice-water bath. Then 5 drops of dry DMF
was added, followed by the addition of (COCl).sub.2 (2.7 mL, 31.4
mmol, 2.3 equiv.). The resulting mixture was stirred at 0.degree.
C. for 15 min and then stirred at rt for 2 h. The solvent was then
evaporated, then dry DCM (20 ml) was added and evaporated.
[0629] To a solution of (R)-4-phenyloxazolidin-2-one (2.37 g, 14.5
mmol, 1.06 equiv.) in dry THE (55 ml) at -78.degree. C. under
N.sub.2 was added n-BuLi (2.5 M in hexanes, 5.5 mL, 13.4 mmol)
dropwise over 10 min. After stirring at -78.degree. C. for 30 min,
a TH solution of the above prepared acyl chloride (10 mL THF) was
added by syringe over 15 min. Then the resulting mixture was
stirred from -78.degree. C. to rt overnight. The reaction was
quenched by addition of water (20 mL), followed by extraction with
EtOAc (50 mL.times.3). The combined organic layers were dried over
anhydrous MgSO.sub.4. After filtration and concentration, the crude
was purified by column chromatography on silica gel (Int-33)
(eluent EtOAc/Hexanes 0-20%, less polar product). .sup.1H NMR (400
MHz, CDCl.sub.3, ppm) .delta. 7.49-7.24 (m, 10H), 5.56 (dd, J=8.8,
4.4 Hz, 1H), 4.77 (t, J=8.8 Hz, 1H), 4.34 (dd, J=8.8, 4.4 Hz, 1H),
3.34 (dd, J=7.2, 5.6 Hz, 1H), 1.90 (m, 1H), 1.63 (dd, J=5.6, 4.0
Hz, 1H), 1.36 (dd, J=7.6, 4.0 Hz, 1H), 0.90 (d, J=6.8 Hz, 3H), 0.79
(d, J=6.8 Hz, 3H); LC-MS: 350.2 (M+H).sup.+.
Synthesis of (1R,2S)-2-isopropyl-2-phenylcyclopropane-1-carboxylic
acid (Int-36)
##STR00290##
[0631] To a solution of
(R)-3-((1R,2S)-2-isopropyl-2-phenylcyclopropane-1-carbonyl)-4-phenyloxazo-
lidin-2-one (Int-33) (880 mg, 2.51 mmol, 1 equiv.) in THE (10
mL)--water (4 mL) was added 17% H.sub.2O.sub.2 in water (1.18 mL,
10.3 mmol, 4.1 equiv.) and LiOH (154 mg, 3.77 mmol, 1.5 equiv.).
The resulting mixture was stirred at rt overnight (TLC and LC-MS
showed that starting material has been consumed). The residue was
diluted with water (20 mL), followed by the addition of 1 N NaOH (5
mL). The aqueous layer was extracted with EtOAc (80 mL.times.3),
then treated with 1 N HCl (13 mL). Then the aqueous layer was
extracted with EtOAc (70 mL.times.3). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4. After filtration and
concentration, the product was obtained as a white solid (Int-36)
(390 mg, 76%), which was used in the next step without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3, ppm) .delta.
7.41-7.21 (m, 5H), 2.17-2.00 (m, 2H), 1.49 (t, J=4.4 Hz, 1H), 1.43
(t, J=4.4 Hz, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz,
3H).
Synthesis of 5-Bromo-1-tosyl-1H-indazole (Int-37)
##STR00291##
[0633] To a solution of 5-bromo-1H-indazole (10 g, 50.8 mmol,
Combi-blocks Cat #PY-7893, Lot B16473)) and DMF (50 mL), tosyl
chloride (13.5 g, 71.1 mmol) was added followed by sodium hydride
(2.03 g, 50.8 mmol) and was allowed to stir at 50.degree. C.
overnight. After completion of the reaction, the mixture was poured
into ice cold water and was allowed to stir for 30 minutes. The
creamy white aqueous suspension was extracted with ethyl acetate,
combined organic layers were washed with saturated ammonium
chloride followed by brine, dried using sodium sulfate, filtered
and concentrated under reduced pressure. The crude material was
purified by passing through silica gel and was eluted using 100%
DCM to afford 17.24 g (97%) of the title compound (Int-37) as
creamy white shiny flakes. .sup.1H NMR (600 MHz, CHLOROFORM-d)
.delta.=8.14-8.09 (m, 2H), 7.88-7.83 (m, 3H), 7.65 (dd, J=1.8, 8.8
Hz, 1H), 7.29-7.24 (m, 2H), 2.37 (s, 3H).
Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(1-tosyl-1H-indazol-5-yl)propanoate
(Int-38)
##STR00292##
[0635] Zinc dust (14.4 g, 4.26 mmol) was suspended in anhydrous DMF
(90 mL) under argon atmosphere and trimethylsilyl chloride (4.59
mL, 36.2 mmol) was added slowly and allowed to stir for 30 minutes.
The solution turned yellow orange from colorless precipitate in 30
minutes. The mixture with the precipitate was allowed to settle and
the solution was removed with a syringe under argon atmosphere. The
now activated zinc powder was washed with DMF until no yellow-brown
color was observed in the solution. Methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (Combiblocks,
OR-1812, Batch #18260, 17 g, 51.7 mmol) dissolved in DMF (90 mL)
was then added slowly to the activated zinc. The reaction is
exothermic so the flask is intermittently cooled in an ice water
bath. After the addition is complete the reaction was allowed to
stir at room temperature for 40 minutes. The supernatant of this
reaction was then added to the mixture of Int-37 (18.1 g, 51.7
mmol) in DMF (90 ml) and 2.sup.n Generation Xphos Precatalyst (CAS
#1310584-14-5, 1.22 g, 1.55 mmol,). The reaction is stirred at
50.degree. C. overnight. Reaction was cooled to ambient temperature
followed by the addition of ethyl acetate (2 L). the organic layer
was washed with water (2 L), sat aq NH.sub.4Cl (300 mL), brine (300
mL), dried using Na.sub.2SO.sub.4, filtered, and concentrated to
afford crude product (30 g, caramel amber residue). The crude was
purified on silica gel, eluent hexanes-EtOAc to afford the title
product Int-38 (6.6 g). LCMS (+ESI) M+H+=474.5. .sup.1H NMR (600
MHz, METHANOL-d.sub.4) .delta.=8.27 (s, 1H), 8.10 (d, J=8.6 Hz,
1H), 7.81 (br d, J=8.3 Hz, 2H), 7.61 (s, 1H), 7.50 (br d, J=8.6 Hz,
1H), 7.31 (br d, J=8.2 Hz, 2H), 4.40 (dd, J=5.3, 9.4 Hz, 1H), 3.68
(s, 3H), 3.25 (dd, J=5.2, 13.8 Hz, 1H), 2.99 (br dd, J=9.6, 13.8
Hz, 1H), 2.34 (s, 3H), 1.32-1.22 (m, 9H).
Synthesis of tert-butyl
(S)-(1-amino-1-oxo-3-(1-tosyl-1H-indazol-5-yl)propan-2-yl)carbamate
(Int-39)
##STR00293##
[0637] To a solution of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(1-tosyl-1H-indazol-5-yl)propanoate
(Int-38) (6.6 g, 13.9 mmol) in anhydrous methanol (1.5 mL), 7N
ammonia in methanol (135 mL) was added at 0.degree. C. and was
allowed to stir over the weekend. The solvent was evaporated under
reduced pressure and the crude material was purified by flash
chromatography using 5% methanol/DCM as gradients to obtain 4.32 g
of the title compound (Int-39). .sup.1H NMR (600 MHz,
METHANOL-d.sub.4) .delta.=8.27 (s, 1H), 8.09 (br d, J=8.6 Hz, 1H),
7.81 (br d, J=8.2 Hz, 2H), 7.63 (s, 1H), 7.54 (d, J=8.6 Hz, 1H),
7.30 (d, J=8.2 Hz, 2H), 4.33 (br dd, J=5.2, 9.4 Hz, 1H), 3.25 (br
dd, J=5.2, 13.8 Hz, 1H), 2.91 (br dd, J=9.6, 13.8 Hz, 1H), 2.34 (s,
3H), 1.23 (s, 9H).
Synthesis of (S)-2-amino-3-(1-tosyl-1H-indazol-5-yl)propenamide
(Int-40)
##STR00294##
[0639] To tert-butyl
(S)-(1-amino-1-oxo-3-(1-tosyl-1H-indazol-5-yl)propan-2-yl)carbamate
(Int-39) (4.32 g, 9.42 mmol), formic acid (14.2 mL, 377 mmol) was
added and was allowed to stir at 50.degree. C. until no starting
material was observed. The solvent was evaporated under reduced
pressure and the pH of the residue was adjusted between 9 and 10.
The aqueous layer was extracted with ethyl acetate, washed with
water, followed by brine, dried using sodium sulfate, filtered and
evaporated under reduced pressure to obtain 2.76 g of title
compound (Int-40). LCMS (+ESI) M+H+=359.4. .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta.=8.49 (s, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.80
(d, J=8.4 Hz, 2H), 7.65 (s, 1H), 7.53 (dd, J=1.5, 8.7 Hz, 1H), 7.38
(d, J=8.3 Hz, 2H), 7.31 (br s, 1H), 6.95 (br s, 1H), 3.35 (br d,
J=5.0 Hz, 1H), 3.01 (dd, J=5.0, 13.5 Hz, 1H), 2.71 (dd, J=8.3, 13.5
Hz, 1H), 2.32 (s, 3H), 1.64 (br s, 2H).
Synthesis of
(S)-2-(dimethylamino)-3-(1-tosyl-1H-indazol-5-yl)propanamide
(Int-41)
##STR00295##
[0641] To a solution of
(S)-2-amino-3-(1-tosyl-H-indazol-5-yl)propanamide (Int-40) (2.76 g,
7.70 mmol) and methanol (27.6 mL), formaldehyde (37%, 1.15 mL, 15.4
mmol) and trimethylamine borane (2.25 g, 30.8 mmol) were added at
0.degree. C. and was allowed to stir at room temperature overnight.
After completion of the reaction, 1.25 M HCl in methanol was added
slowly with cooling and was allowed to stir for 15 minutes. The
solvent was evaporated under reduced pressure and the residue was
re-dissolved in methanol (this was repeated three times). To the
obtained crude saturated sodium bicarbonate solution was added and
was allowed to stir and the pH was adjusted to 9 and the aqueous
layer was extracted with ethyl acetate. Combined organic layers
were washed with brine, dried using sodium sulfate, filtered and
concentrated under reduced pressure. The crude material was
purified by flash chromatography using 10% methanol/DCM as
gradients to afford 2 g of title compound (Int-41). LCMS (+ESI)
M+H.sup.+=387.4. .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.=8.47
(s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.63 (s,
1H), 7.51 (dd, J=1.3, 8.6 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.18 (br
s, 1H), 6.87 (br s, 1H), 3.22-3.14 (m, 1H), 3.00 (dd, J=8.8, 13.4
Hz, 1H), 2.88 (dd, J=5.7, 13.5 Hz, 1H), 2.32 (s, 3H), 2.25 (s,
6H).
Synthesis of (S)-3-(1H-indazol-5-yl)-N2,
N2-dimethylpropane-1,2-diamine (Int-42)
##STR00296##
[0643] To the solution of
(S)-2-(dimethylamino)-3-(1-tosyl-1H-indazol-5-yl)propanamide
(Int-41) (1.94 g, 5.02 mmol) and THE (77.6 mL), LAH (1M, 25.1 mL,
25.1 mmol) was added at 0.degree. C. and was warmed to room
temperature and then was allowed to stir at 68.degree. C.
overnight. After completion of the reaction, the mixture was cooled
to 0.degree. C. and water (25 mL), 15% NaOH solution (25 mL) and
water (75 mL) were added and was warmed to room temperature and
later was allowed to stir at room temperature for 1 and a half
hour. The solids were filtered and the cake was washed with more
THE and the solvent was evaporated under reduced pressure. The
crude material was purified by flash chromatography using amino
column using 10% methanol/DCM as gradients to obtain 870 mg of
title compound (Int-42) and 310 mg (26%) of
(S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propanamide at 70% purity
by .sup.1H NMR. LCMS (+ESI) M+H=219.4. .sup.1H NMR (600 MHz,
METHANOL-d.sub.4) .delta.=7.95 (s, 1H), 7.56 (s, 1H), 7.46 (d,
J=8.5 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 3.08-3.04 (m, 1H), 2.78-2.72
(m, 1H), 2.67-2.60 (m, 1H), 2.52 (dd, J=4.2, 13.2 Hz, 1H), 2.45
(dd, J=9.9, 13.4 Hz, 1H), 2.37 (s, 6H).
Example B1
##STR00297##
[0644] Synthesis of
(1R,2R)--N--((S)-3-(2-chloro-4-hydroxyphenyl)-2-(dimethylaminopropyl)-2-m-
ethyl-2-phenylcyclopropane-1-carboxamide (Compound B-1)
Step 1: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-hydroxyphenyl)propanoate
##STR00298##
[0646] To a stirred suspension of zinc powder (2 g, 31 mmol) in
anhydrous N,N-dimethylformamide (10 mL) under nitrogen was added
iodine (250 mg). After 5 min, a solution of methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.0 g, 12
mmol) in N,N-dimethylformamide (10 mL) was slowly added over 10
min. Then additional iodine (250 mg) was added. The mixture was
stirred at rt for 30 min. A suspension of 4-bromo-3-chlorophenol
(2.0 g, 10 mmol), Pd.sub.2(dba).sub.3 (230 mg, 0.25 mmol), and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 210 mg, 0.5
mmol) in N,N-dimethylformamide (10 mL) was added into the zinc
reagent mixture. The reaction mixture was heated at 40.degree. C.
and stirred overnight. After cooling, the reaction mixture was
quenched with water, diluted with EtOAc and filtered through
Celite. The filter cake was washed with EtOAc and the filtrate was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-50% EtOAc/hexane) to afford the
desired product as brown foam (2.7 g, 83%). LC-MS: 352.1
[M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) (rotamers) .delta.
7.04 (d, 1H, J=8.3 Hz), 6.86 (s, 1H), 6.65 (d, 1H, J=7.5 Hz), 5.96
(br s, 0.2H), 5.41 (s, 0.7H), 5.07 (d, 0.8H, J=8.2 Hz), 4.83 (br s,
0.2H), 4.56 (m, 1H), 3.73 (s, 3H), 3.21 (dd, 1H, J=14.0, 6.0 Hz),
3.02 (dd, 0.8H, J=13.6, 7.6 Hz), 2.80 (m, 0.2H), 1.39 and 1.33 (s,
9H).
Step 2: Synthesis of tert-butyl
(S)-(1-amino-3-(2-chloro-4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate
##STR00299##
[0648] A microwave tube was charged with methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-hydroxyphenyl)propanoate
(2.6 g) and 7M ammonia in methanol (20 mL). The reaction was heated
under microwave irradiation at 100.degree. C. for 20 h. LC-MS
indicated the reaction was complete. The reaction was concentrated
down to dryness to afford the desired product as a light yellow
solid (2.6 g). LC-MS: 337.1 [M+Na].sup.+.
Step 3: Synthesis of tert-butyl
(S)-(1-amino-3-(2-chloro-4-hydroxyphenyl)propan-2-yl)carbamate
##STR00300##
[0650] To a stirred solution of tert-butyl
(S)-(1-amino-3-(2-chloro-4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate
(2.0 g, 6.4 mmol) in anhydrous THE (100 mL) under nitrogen was
added borane-DMS complex (6.4 mL, 64 mmol). The reaction mixture
was stirred overnight at room temperature and then at 60.degree. C.
for 1 h. After cooling, the reaction was carefully quenched with
methanol (20 mL) and then heated at 70.degree. C. for 1 h. The
mixture was concentrated and purified by silica gel column (0-20%
MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to recover some starting
material (520 mg) and afford the desired product as a white solid
(500 mg, 26%). LC-MS: 301.1 [M+H]; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.09 (d, 1H, J=8.2 Hz), 6.76 (s, 1H), 6.70-6.55 (m, 2H),
3.53 (m, 1H), 2.78 (dd, 1H, J=13.8, 5.2 Hz), 1.31 and 1.18 (s,
9H).
Step 4: Synthesis of tert-butyl
((S)-1-(2-chloro-4-hydroxyphenyl)-3-((1R,2R)-2-methyl-2-phenylcyclopropan-
e-1-carboxamido)propan-2-yl)carbamate
##STR00301##
[0652] To a stirred solution of
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-24)
(240 mg, 1.36 mmol) and hydroxybenzotriazole (180 mg, 1.3 mmol) in
anhydrous DMF (5 mL) was added
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (400
mg, 2 mmol), followed by triethylamine (0.38 mL, 2.73 mmol). The
mixture was stirred under nitrogen at rt for 3 h and then slowly
added into an ice-cooled solution of tert-butyl
(S)-(1-amino-3-(2-chloro-4-hydroxyphenyl)propan-2-yl)carbamate (400
mg, 1.33 mmol) in anhydrous DMF (5 mL). The reaction mixture was
slowly warmed to rt and stirred overnight. The mixture was diluted
with water and extracted with EtOAc. The combined organic layers
were washed with aq. NaHCO.sub.3 and brine, dried over anhydrous
sodium sulfate, and concentrated. The residue was purified by flash
column chromatography over silica gel (0-80% EtOAc/hexane) to
afford a white solid (420 mg, 69%). LC-MS: 481.2 [M+Na].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.46 (br s, 1H),
7.35-7.15 (m, 5H), 7.06 (br d, 1H, J=8.2 Hz), 6.89 (s, 1H), 6.68
(m, 1H), 6.46 (br s, 1H), 5.10 and 4.95 (d, 1H, J=7.6 Hz), 3.99 (m,
1H), 3.50-3.30 (m, 2H), 2.87 (m, 2H), 1.73 (t, 1H, J=7.2 Hz),
1.55-1.25 (m, 14H).
Step 5: Synthesis of
(1R,2R)--N--((S)-2-amino-3-(2-chloro-4-hydroxyphenyl)propyl)-2-methyl-2-p-
henylcyclopropane-1-carboxamide
##STR00302##
[0654] To a stirred solution of tert-butyl
((S)-1-(2-chloro-4-hydroxyphenyl)-3-((1R,2R)-2-methyl-2-phenylcyclopropan-
e-1-carboxamido)propan-2-yl)carbamate (420 mg) and phenol (400 mg)
in 1,4-dioxane (5 mL) was added 4N HCl solution in 1,4-dioxane (2.5
mL). The reaction mixture was stirred at rt for 8 h and then
concentrated in vacuo. The residue was used for next step reaction
without purification.
Step 6: Synthesis of
(1R,2R)--N--((S)-3-(2-chloro-4-hydroxyphenyl)-2-(dimethylamino)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-1)
##STR00303##
[0656] The crude
(1R,2R)--N--((S)-2-amino-3-(2-chloro-4-hydroxyphenyl)-propyl)-2-methyl-2--
phenylcyclopropane-1-carboxamide from above was dissolved in
acetonitrile (20 mL) and water (2 mL) and cooled at 0.degree. C.
37% aqueous solution of formaldehyde (0.40 mL) was added, followed
by sodium cyanoborohydride (200 mg). After 10 min, acetic acid
(0.30 mL) was added, and the reaction mixture was stirred at
0.degree. C. for 3 h. The reaction solution was adjusted to pH
10-11 with aq. Na.sub.2CO.sub.3 and extracted with EtOAc. The
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, and concentrated. The residue was
purified by flash column chromatography over silica gel (0-5%
MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to afford the desired
product as white foam (325 mg, 92% yield for 2 steps). LC-MS: 387.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.68 (s, 1H),
7.95 (m, 1H), 7.35-7.24 (m, 4H), 7.18 (m, 1H), 7.12 (d, 1H, J=8.4
Hz), 6.77 (s, 1H), 6.67 (d, 1H, J=8.4 Hz), 3.17 (m, 1H), 3.06 (m,
1H), 2.85-2.75 (m, 2H), 2.45 (m, 1H), 2.27 (s, 6H), 1.92 (t, 1H,
J=7.2 Hz), 1.36 (s, 3H), 1.25-1.15 (m, 2H).
Example B2
##STR00304##
[0657] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N-methylbenzamide (Compound B-2)
Step 1: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(methylcarbamoyl)phenyl)-
propanoate
##STR00305##
[0659] To a stirred suspension of zinc powder (2.5 g, 38.5 mmol) in
anhydrous N,N-dimethylformamide (10 mL) under nitrogen was added
iodine (200 mg). After 5 min, a solution of methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (5.0 g, 15.2
mmol) in N,N-dimethylformamide (10 mL) was added slowly over 10
min. The mixture was stirred at rt for 30 min. A suspension of
4-bromo-2-fluoro-N-methylbenzamide (2.8 g, 12 mmol),
Pd.sub.2(dba).sub.3 (280 mg, 0.3 mmol), and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 250 mg, 0.6
mmol) in N,N-dimethylformamide (10 mL) was added into the zinc
reagent mixture. The reaction mixture was heated at 50.degree. C.
and stirred overnight. After cooling, the reaction mixture was
quenched with water, diluted with EtOAc and filtered through
Celite. The filter cake was washed with EtOAc and the filtrate was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-80% EtOAc/hexane) to afford the
desired product as a beige solid (4.0 g, 94%). LC-MS: 377.1
[M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04 (t,
1H, J=8.1 Hz), 7.02 (d, 1H, J=8.0 Hz), 6.91 (d, 1H, J=12.8 Hz),
6.70 (m, 1H), 5.02 (d, 1H, J=8.0 Hz), 4.60 (m, 1H), 3.73 (s, 3H),
3.18 (dd, 1H, J=13.8, 5.4 Hz), 3.07 (m, 1H), 3.03 (d, 3H, J=4.6
Hz), 1.43 (s, 9H).
Step 2: Synthesis of tert-butyl
(S)-(1-(3-fluoro-4-(methylcarbamoyl)phenyl)-3-hydroxypropan-2-yl)carbamat-
e
##STR00306##
[0661] To a stirred solution of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(methylcarbamoyl)phenyl)-
propanoate (4.0 g, 11.3 mmol) in THE (80 mL) was added lithium
borohydride (435 mg, 20 mmol). The reaction mixture was cooled at
0.degree. C. and methanol (4 mL) was slowly added. The reaction
mixture was slowly warmed to rt and stirred for 2 h. LC-MS
indicated the completion of the reaction. The reaction was
carefully quenched with methanol (10 mL) and neutralized with 2N
aq. HCl. The volatiles were removed under reduced pressure and the
residue was extracted with EtOAc. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated to
afford the desired product as a beige solid (3.8 g, 100%). LC-MS:
349.2 [M+Na].sup.+
Step 3: Synthesis of tert-butyl
(S)-(1-amino-3-(3-fluoro-4-(methylcarbamoyl)phenyl)propan-2-yl)carbamate
##STR00307##
[0663] To a stirred solution of tert-butyl
(S)-(1-(3-fluoro-4-(methylcarbamoyl)phenyl)-3-hydroxypropan-2-yl)carbamat-
e (650 mg, 2.0 mmol) and triphenylphosphine (630 mg, 2.4 mmol) in
anhydrous THE (20 mL) at 0.degree. C. under nitrogen was added
diisopropylethylamine (0.35 mL, 2.0 mmol), followed by slow
addition of diisopropyl azodicarboxylate (0.47 mL, 2.4 mmol). The
reaction mixture was slowly warmed to rt and stirred for 5 h. A
second batch of triphenylphosphine (685 mg, 2.6 mmol) was added
slowly over 20 min. The reaction mixture was stirred at rt for 16
h, and then water (0.36 mL, 20 mmol) was added. The reaction
mixture was heated at 50.degree. C. for 18 h and then concentrated.
The residue was purified by flash column chromatography over silica
gel (0-10% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to afford the
desired product as a white solid (270 mg, 42%). LC-MS: 326.2
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.03 (t, 1H,
J=8.2 Hz), 7.09 (d, 1H, J=8.0 Hz), 6.98 (d, 1H, J=12.4 Hz), 6.72
(br s, 1H), 4.72 (br s, 1H), 3.79 (br s, 1H), 3.03 (d, 3H, J=4.5
Hz), 2.95-2.70 (m, 3H), 2.65 (dd, 1H, J=13.0, 6.5 Hz), 1.40 (s,
9H).
Step 4: Synthesis of tert-butyl
((S)-1-(3-fluoro-4-(methylcarbamoyl)phenyl)-3-((1R,2R)-2-methyl-2-phenylc-
yclopropane-1-carboxamido)propan-2-yl)carbamate
##STR00308##
[0665] To a stirred solution of tert-butyl
(S)-(1-amino-3-(3-fluoro-4-(methylcarbamoyl)phenyl)propan-2-yl)carbamate
(70 mg, 0.22 mmol) in anhydrous DMF (2 mL) was added
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (60 mg, 0.22
mmol). The reaction mixture was stirred overnight at rt and then
concentrated in vacuo. The residue was purified by flash column
chromatography over silica gel (0-100% EtOAc/hexane) to afford the
desired product as a white solid (60 mg, 57%). LC-MS: 506.2
[M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05 (t,
1H, J=8.0 Hz), 7.35-7.15 (m, 5H), 7.11 (d, 1H, J=8.0 Hz), 7.00 (d,
1H, J=13.0 Hz), 6.71 (m, 1H), 6.10 (br s, 1H), 4.81 (br d, 1H),
3.96 (br s, 1H), 3.50-3.30 (m, 2H), 3.02 (d, 3H, J=4.8 Hz),
2.95-2.75 (m, 2H), 1.69 (dd, 1H, J=8.2, 6.0 Hz), 1.49 (s, 4H), 1.39
(s, 10H).
Step 5: Synthesis of
4-((S)-2-amino-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxamido)pro-
pyl)-2-fluoro-N-methylbenzamide HCl salt
##STR00309##
[0667] To a stirred solution of tert-butyl
((S)-1-(3-fluoro-4-(methylcarbamoyl)phenyl)-3-((1R,2R)-2-methyl-2-phenylc-
yclopropane-1-carboxamido)propan-2-yl)carbamate (60 mg, 0.12 mmol)
and phenol (60 mg) in 1,4-dioxane (5 mL) was added 4N HCl solution
in 1,4-dioxane (2 mL). The reaction mixture was stirred overnight
and then concentrated in vacuo. The residue was used for next step
reaction without purification.
Step 6: Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N-methylbenzamide (Compound B-2)
##STR00310##
[0669] To a stirred solution of the crude
4-((S)-2-amino-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxamido)pro-
pyl)-2-fluoro-N-methylbenzamide from above in acetonitrile (10 mL)
and water (1 mL) was added 37% aqueous solution of formaldehyde
(0.046 mL, 0.58 mmol), followed by trimethyl orthoformate (0.10 mL,
0.93 mmol). After 15 min, sodium cyanoborohydride (25 mg, 0.35
mmol) was added, and the reaction mixture was stirred at rt for 2
h. The reaction was diluted with EtOAc, washed with aq.
Na.sub.2CO.sub.3 and brine, dried over anhydrous sodium sulfate,
and concentrated. The residue was purified by flash column
chromatography over silica gel (0-10% MeOH/CH.sub.2Cl.sub.2 with 5%
ammonia) to afford the desired product as white foam (38 mg, 74%
yield for 2 steps). LC-MS: 412.2 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 8.16 (br s, 1H), 8.02 (br t, 1H), 7.54 (t, 1H,
J=7.8 Hz), 7.35-7.08 (m, 7H), 3.21 (m, 1H), 3.08 (m, 1H), 2.90-2.75
(m, 2H), 2.75 (d, 3H, J=4.2 Hz), 2.55 (m, 1H), 2.26 (s, 6H), 1.92
(t, 1H, J=7.2 Hz), 1.37 (s, 3H), 1.35-1.18 (m, 2H).
Example B3
##STR00311##
[0670] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)benzamide (Compound B-3)
##STR00312##
[0672]
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-
-carboxamido)propyl)benzamide was synthesized according to the
procedure reported for Example B1 using
(S)-4-(3-amino-2-(dimethylamino)propyl)benzamide and
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-24) as
the starting materials. LC-MS: 380.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.98 (t, 1H, J=5.0 Hz), 7.90 (s, 1H), 7.78
(d, 2H, J=8.0 Hz), 7.33-7.23 (m, 7H), 7.18 (m, 1H), 3.19 (m, 1H),
3.07 (m, 1H), 2.85-2.75 (m, 2H), 2.26 (s, 6H), 1.91 (t, 1H, J=7.2
Hz), 1.36 (s, 3H), 1.28-1.18 (m, 2H).
Example B4
##STR00313##
[0673] Synthesis of
4-((S)-2-(dimethylamino)-3-((1S,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)benzamide (Compound B-4)
##STR00314##
[0675]
4-((S)-2-(dimethylamino)-3-((1S,2R)-2-methyl-2-phenylcyclopropane-1-
-carboxamido)propyl)benzamide was synthesized according to the
procedure reported for Example B1 using
(S)-4-(3-amino-2-(dimethylamino)propyl)benzamide and
(1S,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-23) as
the starting materials. LC-MS: 380.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.89 (s, 1H), 7.80-7.68 (m, 3H), 7.27 (s,
1H), 7.23-7.05 (m, 7H), 3.00 (m, 1H), 2.85-2.70 (m, 2H), 2.61 (m,
1H), 2.42 (dd, 1H, J=13.5, 7.2 Hz), 2.20 (s, 6H), 1.86 (t, 1H,
J=6.6 Hz), 1.47 (t, 1H, J=4.5 Hz), 1.33 (s, 3H), 0.94 (dd, 1H,
J=7.6, 4.0 Hz).
Example B5
##STR00315##
[0676] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)benzamide (Compound B-5)
##STR00316##
[0678]
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-
-carboxamido)propyl)benzamide was synthesized according to Scheme
B2 using (S)-4-(3-amino-2-(dimethylamino) propyl)benzamide and
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-22) as
the starting materials. LC-MS: 380.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.89 (s, 1H), 7.82-7.70 (m, 3H), 7.27 (s,
1H), 7.23-7.05 (m, 7H), 3.00-2.80 (m, 2H), 2.75-2.60 (m, 2H), 2.38
(dd, 1H, J=13.2, 6.6 Hz), 2.21 (s, 6H), 1.87 (t, 1H, J=6.6 Hz),
1.47 (t, 1H, J=4.5 Hz), 1.33 (s, 3H), 0.94 (dd, 1H, J=7.7, 4.0
Hz).
Example B6
##STR00317##
[0679] Synthesis of
3-chloro-4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropan-
e-1-carboxamido)propyl)benzamide (Compound B-6)
##STR00318##
[0681]
3-chloro-4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclo-
propane-1-carboxamido)propyl)benzamide was synthesized according to
the procedure reported for example B1 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-chlorobenzamide and
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-24) as
the starting materials. LC-MS: 414.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 8.04 (s, 2H), 7.88 (s, 1H), 7.75 (d, 1H,
J=8.0 Hz), 7.47 (br s, 1H), 7.44 (d, 1H, J=8.0 Hz), 7.35-7.15 (m,
5H), 3.23 (m, 1H), 3.06 (m, 1H), 3.00-2.85 (m, 2H), 2.68 (m, 1H),
2.28 (s, 6H), 1.90 (t, 1H, J=7.2 Hz), 1.36 (s, 3H), 1.25-1.15 (m,
2H).
Example B7
##STR00319##
[0682] Synthesis of
3-chloro-4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropan-
e-1-carboxamido)propyl)benzamide (Compound B-7)
##STR00320##
[0684]
3-chloro-4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclo-
propane-1-carboxamido)propyl)benzamide was synthesized according to
the procedure reported for example B1 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-chlorobenzamide and
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-22) as
the starting materials. LC-MS: 414.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 8.02 (s, 1H), 7.88-7.75 (m, 2H), 7.71 (d, 1H,
J=7.9 Hz), 7.45 (s, 1H), 7.34 (d, 1H, J=7.9 Hz), 7.20-7.03 (m, 5H),
3.05-2.70 (m, 4H), 2.25 (s, 6H), 1.86 (t, 1H, J=6.5 Hz), 1.45 (t,
1H, J=4.3 Hz), 1.32 (s, 3H), 0.94 (m, 1H).
Example B8
##STR00321##
[0685] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-3,5-dimethylbenzamide (Compound B-8)
Step 1: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyano-2,6-dimethylphenyl)propanoa-
te
##STR00322##
[0687] To a stirred suspension of zinc powder (2.1 g, 32.3 mmol) in
anhydrous N,N-dimethylformamide (10 mL) under nitrogen was added
iodine (170 mg). After 5 min, a solution of methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.2 g, 12.8
mmol) in N,N-dimethylformamide (10 mL) was added slowly over 10
min. The mixture was stirred at rt for 30 min. A suspension of
4-bromo-3,5-dimethylbenzonitrile (2.5 g, 12 mmol),
Pd.sub.2(dba).sub.3 (205 mg, 0.22 mmol), and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 210 mg,
0.51 mmol) in N,N-dimethylformamide (10 mL) was added into the zinc
reagent mixture. The reaction mixture was heated at 50.degree. C.
and stirred overnight. After cooling, the reaction mixture was
quenched with water, diluted with EtOAc and filtered through
Celite. The filter cake was washed with EtOAc and the filtrate was
washed with brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-20% EtOAc/CH.sub.2Cl.sub.2) to
afford the desired product as a white solid (2.0 g, 50%). LC-MS:
355.2 [M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30
(s, 2H), 5.13 (d, 1H, J=8.8 Hz), 4.56 (q, 1H, J=8.0 Hz), 3.67 (s,
3H), 3.15-3.00 (m, 2H), 2.38 (s, 6H), 1.35 (s, 9H).
Step 2: Synthesis of tert-butyl
(S)-(1-(4-cyano-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
##STR00323##
[0689] To a stirred solution of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyano-2,6-dimethylphenyl)propanoa-
te (2.0 g, 6.0 mmol) in ethanol (50 mL) was added sodium
borohydride (0.8 g, 21 mmol). The reaction mixture was heated at
50.degree. C. for 3 h and LC-MS indicated the completion of the
reaction. The reaction was carefully quenched with 2N aq. HCl and
adjusted to pH 5-6. The volatiles were removed under reduced
pressure and the residue was extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous sodium sulfate,
and concentrated. The residue was purified by flash column
chromatography over silica gel (0-100% EtOAc/hexane) to afford the
desired product as a white solid (1.1 g, 60%). LC-MS: 327.2
[M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (s,
2H), 4.87 (br s, 1H), 3.90 (m, 1H), 3.70 (m, 1H), 3.55 (dt, 1H,
J=10.7, 4.4 Hz), 3.05-2.85 (m, 2H), 2.41 (s, 6H), 2.09 (br s, 1H),
1.37 (s, 9H).
Step 3: Synthesis of tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
##STR00324##
[0691] To a stirred solution of tert-butyl
(S)-(1-(4-cyano-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
(1.1 g, 3.6 mmol) in methanol (30 mL) was added 6N aq. NaOH (0.55
mL, 3.3 mmol), followed by 27% aq. Solution of hydrogen peroxide
(1.45 mL, 11.5 mmol). The reaction mixture was stirred at
50.degree. C. for 2 h. After cooling, the mixture was neutralized
with 1N aq. HCl. Removal of methanol under reduced pressure and the
residue was extracted with EtOAc. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated to
afford the desired product as a white solid (0.95 g, 82%). LC-MS:
345.2 [M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45
(s, 2H), 6.20 (br s, 1H), 5.60 (br s, 1H), 4.87 (d, 1H, J=8.5 Hz),
3.88 (m, 1H), 3.69 (dd, 1H, J=10.5, 3.5 Hz), 3.55 (dd, 1H, J=10.7,
4.6 Hz), 2.95 (m, 1H), 2.43 (s, 7H), 1.38 (s, 9H).
Step 4: Synthesis of tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propa-
n-2-yl)carbamate
##STR00325##
[0693] To a stirred solution of tert-butyl
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-hydroxypropan-2-yl)carbamate
(0.95 g, 2.9 mmol), phthalimide (0.50 g, 3.4 mmol), and
triphenylphosphine (0.90 g, 3.4 mmol) in anhydrous THE (50 mL) at
0.degree. C. under nitrogen was added diisopropyl azodicarboxylate
(0.70 mL, 3.4 mmol) over 20 min. The reaction mixture was slowly
warmed to rt and stirred overnight. The mixture was concentrated
and the residue was purified by flash column chromatography over
silica gel (0-100% EtOAc/CH.sub.2Cl.sub.2) to afford the desired
product as a white solid (1.15 g, 86%). LC-MS: 474.2 [M+Na].sup.+;
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.93-7.75 (m, 5H), 7.50 (s,
2H), 7.20 (s, 1H), 6.93 and 6.52 (d, 1H, J=10.0 Hz), 4.07 (m, 1H),
3.76 (t, 1H, J=12.0 Hz), 3.46 (m, 1H), 2.90-2.80 (m, 2H), 2.35 (s,
6H), 1.08 and 0.88 (s, 9H).
Step 5: Synthesis of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)-3,5-dimethylbenzamide
##STR00326##
[0695] To a stirred solution of
(S)-(1-(4-carbamoyl-2,6-dimethylphenyl)-3-(1,3-dioxoisoindolin-2-yl)propa-
n-2-yl)carbamate (0.6 g, 1.3 mmol) in anhydrous CH.sub.2Cl.sub.2
(80 mL) and 2,6-lutidine (0.93 mL, 8.0 mmol) at 0.degree. C. under
nitrogen was slowly added TMSOTf (0.72 mL, 4.0 mmol). The reaction
mixture was slowly warmed to rt and stirred overnight. Additional
TMSOTf (0.3 mL) was added and the reaction was stirred for
additional 3 h. The reaction was quenched with water, adjusted to
pH 9-10 with aq. Sodium bicarbonate, and extracted with
CH.sub.2Cl.sub.2 (2.times.). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-10% MeOH/CH.sub.2Cl.sub.2) to
afford the desired product as a white foam (410 mg, 88%). LC-MS:
352.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86
(d, 2H, J=3.6 Hz), 7.74 (d, 2H, J=3.8 Hz), 7.46 (s, 2H), 6.03 (br
s, 1H), 5.52 (br s, 1H), 3.75 (d, 2H, J=6.5 Hz), 3.47 (m, 1H),
2.90-2.70 (m, 2H), 2.40 (s, 6H).
Step 6: Synthesis of
(S)-4-(2-(dimethylamino)-3-(1,3-dioxoisoindolin-2-yl)propyl)-3,5-dimethyl-
benzamide
##STR00327##
[0697] To a stirred solution of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)-3,5-dimethylbenzamide
(410 mg, 1.2 mmol) in acetonitrile (10 mL) and water (1 mL) was
added 37% aqueous solution of formaldehyde (0.46 mL, 5.8 mmol),
followed by trimethyl orthoformate (1.0 mL, 9.3 mmol). After 15
min, sodium cyanoborohydride (225 mg, 3.5 mmol). The reaction
mixture was stirred at rt for 2 h. The mixture was diluted with
EtOAc, washed with aq. NaHCO.sub.3 and brine, dried over anhydrous
sodium sulfate, and concentrated. The residue was purified by flash
column chromatography over silica gel (0-10% MeOH/CH.sub.2Cl.sub.2)
to afford the desired product as a white solid (300 mg, 68%).
LC-MS: 380.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.78 (dd, 2H, J=5.5, 3.0 Hz), 7.68 (dd, 2H, J=5.5, 3.0 Hz), 7.46
(s, 2H), 6.10 (br s, 1H), 5.55 (br s, 1H), 3.91 (dd, 1H, J=13.6,
10.5 Hz), 3.48 (m, 1H), 3.24 (dd, 1H, J=13.6, 4.5 Hz), 2.99 (dd,
1H, J=13.6, 4.8 Hz), 2.73 (dd, 1H, J=13.6, 10.0 Hz), 2.42 (s, 6H),
2.40 (s 6H).
Step 7: Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylbenzamide
##STR00328##
[0699] A mixture of
(S)-4-(2-(dimethylamino)-3-(1,3-dioxoisoindolin-2-yl)propyl)-3,5-dimethyl-
benzamide (300 mg, 0.79 mmol) in ethanol (10 mL) and hydrazine
monohydrate (0.20 mL, 4 mmol) was stirred at 70.degree. C. for 5 h.
After cooling, the mixture was filtered to remove the solids. The
filtrate was concentrated and purified by flash column
chromatography over silica gel (0-20% MeOH/CH.sub.2Cl.sub.2 with 5%
ammonia) to afford the desired product as a white solid (175 mg,
89%). LC-MS: 250.2 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.43 (s, 2H), 6.00 (br s, 1H), 5.50 (br s, 1H), 2.91 (dd,
1H, J=13.2, 2.5 Hz), 2.78-2.65 (m, 2H), 2.63-2.50 (m, 1H), 2.43 (s,
6H), 2.37 (s, 6H), 2.35 (m, 1H).
Step 8: Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-3,5-dimethylbenzamide (Compound B-8)
##STR00329##
[0701]
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-
-carboxamido)propyl)-3,5-dimethylbenzamide was synthesized
according to the procedure in Example B1 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylbenzamide and
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-24) as
the starting materials. LC-MS: 408.3 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.99 (t, 1H, J=5.0 Hz), 7.81 (s, 1H), 7.49
(s, 2H), 7.35-7.15 (m, 6H), 3.25 (m, 1H), 2.93 (m, 1H), 2.85-2.75
(m, 2H), 2.55 (dd, 1H, J=15.2, 9.8 Hz), 2.33 and 2.32 (s, 12H),
1.89 (t, 1H, J=7.0 Hz), 1.35 (s, 3H), 1.25-1.15 (m, 2H).
Example B9
##STR00330##
[0702] Synthesis of
(R)--N--((S)-3-(4-carbamoylphenyl)-2-(dimethylaminopropyl)-1-phenylpyrrol-
idine-2-carboxamide (Compound B-9)
##STR00331##
[0703] Step 1: Synthesis of phenyl-D-proline
##STR00332##
[0705] A microwave tube was charged under nitrogen with iodobenzene
(810 mg, 4 mmol), D-proline (460 mg, 4 mmol), K.sub.2CO.sub.3 (560
mg), n-Bu.sub.4NI (250 mg), CuI (40 mg), Pd(PPh.sub.3).sub.4 (230
mg), TEA (1.6 mL), DMF (8 mL), and water (0.8 mL). The reaction was
heated under microwave irradiation at 120.degree. C. for 1 h. The
mixture was diluted with water, adjusted to pH 2-3 with 2N aq. HCl,
and extracted with EtOAc. The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate, and concentrated.
The residue was purified by flash column chromatography over silica
gel (0-100% EtOAc/hexane) to afford the desired product as a brown
oil (200 mg). LC-MS: 192.1 [M+H].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.26 (t, 2H, J=7.6 Hz), 6.79 (t, 1H, J=7.5 Hz),
6.61 (d, 2H, J=8.0 Hz), 4.20 (dd, 1H, J=8.8, 2.4 Hz), 3.63 (m, 1H),
3.32 (q, 1H, J=8.0 Hz), 2.40-2.20 (m, 2H), 2.20-1.90 (m, 2H).
Step 2: Synthesis of
(R)--N--((S)-3-(4-carbamoylphenyl)-2-(dimethylamino)propyl)-1-phenlpyrrol-
idine-2-carboxamide (Compound B-9)
##STR00333##
[0707]
(R)--N--((S)-3-(4-carbamoylphenyl)-2-(dimethylamino)propyl)-1-pheny-
lpyrrolidine-2-carboxamide was synthesized according to the
procedure in example B1 using phenyl-D-proline and
(S)-4-(3-amino-2-(dimethylamino)-propyl)benzamide as the starting
materials. LC-MS: 395.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.89 (s, 1H), 7.75 (d, 2H, J=8.0 Hz), 7.63 (t, 1H, J=5.0
Hz), 7.28 (s, 1H), 7.18 (d, 2H, J=8.0 Hz), 7.14 (t, 2H, J=7.8 Hz),
6.63 (t, 1H, J=7.2 Hz), 6.48 (d, 2H, J=8.0 Hz), 3.90 (d, 1H, J=8.8
Hz), 3.53 (m, 1H), 3.20-3.10 (m, 2H), 2.97 (m, 1H), 2.80-2.55 (m,
2H), 2.44 (dd, 1H, J=13.2, 6.8 Hz), 2.16 (s, 7H), 2.00-1.85 (m,
3H).
Example B10
##STR00334##
[0708] Synthesis of
(S)--N--((S)-3-(4-carbamoylphenyl)-2-(dimethylamino)propyl)-1-phenylpyrro-
lidine-2-carboxamide (Compound B-10)
[0709] Compound B-10 was synthesized according to the procedure in
Example B9 using phenyl-L-proline. LC-MS: 395.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.89 (s, 1H), 7.76 (d, 2H,
J=8.0 Hz), 7.68 (br t, 1H), 7.28 (s, 1H), 7.21 (d, 2H, J=8.0 Hz),
7.14 (t, 2H, J=8.0 Hz), 6.62 (t, 1H, J=7.2 Hz), 6.49 (d, 2H, J=8.0
Hz), 3.90 (d, 1H, J=8.5 Hz), 3.51 (m, 1H), 3.20-3.05 (m, 2H), 2.97
(m, 1H), 2.80-2.65 (m, 2H), 2.38 (m, 1H), 2.18 (s, 7H), 1.95-1.85
(m, 3H).
Example B11
##STR00335##
[0710] Synthesis of
(1S,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-methyl-2--
phenylcyclopropane-1-carboxamide (Compound B-11)
##STR00336##
[0712]
(1S,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-met-
hyl-2-phenylcyclopropane-1-carboxamide was synthesized according to
Scheme B2 using (S)-4-(3-amino-2-(dimethylamino)propyl)phenol and
(1S,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-23) as
the starting materials. LC-MS: 353.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.12 (s, 1H), 7.61 (t, 1H, J=5.0 Hz),
7.20-7.05 (m, 5H), 6.91 (d, 2H, J=8.4 Hz), 6.63 (d, 2H, J=8.4 Hz),
2.88 (m, 1H), 2.82 (m, 1H), 2.62 (dd, 1H, J=13.6, 5.2 Hz), 2.22 (m,
1H), 2.20 (s, 6H), 1.87 (dd, 1H, J=7.6, 5.6 Hz), 1.45 (t, 1H, J=4.8
Hz), 1.32 (s, 3H), 0.93 (dd, 1H, J=7.8, 4.0 Hz).
Example B12
##STR00337##
[0713] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-methyl-2--
phenylcyclopropane-1-carboxamide (Compound B-12)
##STR00338##
[0715]
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-met-
hyl-2-phenylcyclopropane-1-carboxamide (Compound B-12) was
synthesized according to the procedure for
(S)-3-(3-fluorophenyl)-N2,N2-dimethylpropane-1,2-diamine
dihydrochloride (Int-5) using
(S)-4-(3-amino-2-(dimethylamino)propyl)phenol and
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (Int-22) as
the starting materials. LC-MS: 353.2 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.12 (s, 1H), 7.67 (t, 1H, J=5.0 Hz),
7.20-7.05 (m, 5H), 6.90 (d, 2H, J=8.2 Hz), 6.62 (d, 2H, J=8.2 Hz),
2.93-2.80 (m, 2H), 2.62-2.50 (m, 2H), 2.20 (s, 7H), 1.87 (dd, 1H,
J=7.6, 5.6 Hz), 1.45 (t, 1H, J=4.8 Hz), 1.32 (s, 3H), 0.94 (dd, 1H,
J=7.8, 4.0 Hz).
Example B13
##STR00339##
[0716] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl-
)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound B-13)
[0717]
(1R,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)-
-propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-13) was synthesized according to the procedure for
(S)-3-(3-fluorophenyl)-N2,N2-dimethylpropane-1,2-diamine
dihydrochloride using 4-iodo-3,5-dimethylphenol as the starting
material. LC-MS: 381.3 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.93 (s, 1H), 7.87 (br t, 1H), 7.33-7.22 (m, 4H), 7.17 (m,
1H), 6.39 (s, 2H), 3.18 (m, 1H), 2.90 (m, 1H), 2.80-2.60 (m, 2H),
2.39 (dd, 1H, J=13.4, 8.5 Hz), 2.31 (s, 6H), 2.19 (s, 6H), 1.90 (t,
1H, J=7.2 Hz), 1.35 (s, 3H), 1.25-1.15 (m, 2H).
Example B14
##STR00340##
[0718] Synthesis of
(1R,2R)--N--((S)-3-(2,6-difluoro-4-hydroxyphenyl)-2-(dimethylamino)propyl-
)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound B-14)
[0719]
(1R,2R)--N--((S)-3-(2,6-difluoro-4-hydroxyphenyl)-2-(dimethylamino)-
-propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was
synthesized according to the procedure for
(S)-3-(3-fluorophenyl)-N2,N2-dimethylpropane-1,2-diamine
dihydrochloride using 4-bromo-3,5-difluorophenol as the starting
material. LC-MS: 389.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 10.15 (s, 1H), 8.02 (br s, 1H), 7.34-7.25 (m, 4H), 7.18 (m,
1H), 6.41 (d, 2H, J=8.9 Hz), 3.15 (m, 1H), 3.05 (m, 1H), 2.80-2.60
(m, 2H), 2.39 (dd, 1H, J=13.5, 7.6 Hz), 2.25 (s, 6H), 1.91 (t, 1H,
J=6.9 Hz), 1.36 (s, 3H), 1.28-1.15 (m, 2H).
Example B15
##STR00341##
[0720] Synthesis of
(1R,2S)--N--((S)-3-(2-chloro-4-hydroxyphenyl)-2-(dimethylaminopropyl)-2-m-
ethyl-2-phenylcyclopropane-1-carboxamide (Compound B-15)
##STR00342##
[0722]
(1R,2S)--N--((S)-3-(2-chloro-4-hydroxyphenyl)-2-(dimethylamino)-pro-
pyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-chlorophenol (Int-2H) and
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid as the
starting materials. LC-MS: 387.1 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 9.65 (s, 1H), 7.72 (t, 1H, J=4.8 Hz), 7.20-7.05
(m, 5H), 7.02 (d, 1H, J=8.4 Hz), 6.74 (s, 1H), 6.62 (d, 1H, J=8.4
Hz), 2.95-2.85 (m, 2H), 2.80-2.60 (m, 2H), 2.32 (dd, 1H, J=13.2,
8.2 Hz), 2.24 (s, 6H), 1.87 (t, 1H, J=6.5 Hz), 1.44 (t, 1H, J=4.5
Hz), 1.31 (s, 3H), 0.93 (dd, 1H, J=7.2, 4.0 Hz).
Example B16
##STR00343##
[0723] Synthesis of
(1R,2R)--N--(((S)-6-hydroxyindolin-2-yl)methyl)-2-methyl-2-phenylcyclopro-
pane-1-carboxamide (Compound B-16)
Step 1: Synthesis of 1-(tert-butyl) 2-methyl
(S)-6-hydroxyindoline-1,2-dicarboxylate
##STR00344##
[0725] To a stirred suspension of zinc powder (3 g, 46 mmol) in
anhydrous N,N-dimethylacetamide (10 mL) under nitrogen was added
iodine (400 mg). After 5 min, a solution of methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (5.0 g, 15.2
mmol) in N,N-dimethylacetamide (10 mL) was added slowly over 10
min. The mixture was heated at 50.degree. C. for 30 min, and then a
suspension of 4-bromo-3-chlorophenol (3.0 g, 15 mmol),
Pd.sub.2(dba).sub.3 (750 mg), and
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos, 675 mg) in
N,N-dimethylacetamide (10 mL) was added into the zinc reagent
mixture. The reaction mixture was heated at 95.degree. C. and
stirred overnight. After cooling, the reaction mixture was quenched
with water, diluted with EtOAc and filtered through Celite. The
filter cake was washed with EtOAc and the filtrate was washed with
1N aq. HCl and brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-50% EtOAc/hexane) to isolate
1-(tert-butyl) 2-methyl (S)-6-hydroxyindoline-1,2-dicarboxylate as
a light brown solid (1.1 g, 25%) and methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-hydroxyphenyl)propanoate
as a light brown foam (2 g, contaminated with some des-chloro side
product). 1-(tert-butyl) 2-methyl
(S)-6-hydroxyindoline-1,2-dicarboxylate: LC-MS: 316.1 [M+Na].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) (rotamers) .delta. 7.47 (s,
0.75H), 7.02 (br s, 0.25H), 6.94 (d, 1H, J=8.8 Hz), 6.45 (m, 1H),
5.14 (s, 0.75H), 5.00-4.80 (m, 1.25H), 3.75 (s, 3H), 3.43 (m, 1H),
3.02 (d, 1H, J=11.6 Hz), 1.61 and 1.49 (s, 9H).
Step 2: Synthesis of tert-butyl
(S)-2-carbamoyl-6-hydroxyindoline-1-carboxylate
##STR00345##
[0727] A microwave tube was charged with 1-(tert-butyl) 2-methyl
(S)-6-hydroxyindoline-1,2-dicarboxylate (500 mg) and 7M ammonia in
methanol (20 mL). The reaction was heated under microwave
irradiation at 100.degree. C. for 24 h. The reaction was
concentrated and purified by silica gel column (0-50%
EtOAc/CH.sub.2Cl.sub.2) to recover some starting material (250 mg)
and afford the desired product as off-white foam (200 mg, 42%).
LC-MS: 301.1 [M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.97 (d, 1H, J=8.0 Hz), 6.48 (d, 1H, J=8.0 Hz), 5.68 (br s,
1H), 5.46 (br s, 1H), 4.84 (br s, 1H), 3.43 (br s, 1H), 3.15 (br s,
1H), 1.55 (s, 9H).
Step 3: Synthesis of (S)-2-(aminomethyl)indolin-6-ol
##STR00346##
[0729] To a stirred solution of tert-butyl
(S)-2-carbamoyl-6-hydroxyindoline-1-carboxylate (230 mg, 0.83 mmol)
in anhydrous THE (10 mL) under nitrogen was added borane-DMS
complex (2M solution in THF, 5 mL, 10 mmol). The reaction mixture
was stirred at 70.degree. C. overnight. After cooling, the reaction
was carefully quenched with methanol (10 mL) and then heated at
70.degree. C. for 2 h. The mixture was concentrated and purified by
silica gel column (0-20% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) to
isolate the products.
Step 4: Synthesis of
(1R,2R)--N--(((S)-6-hydroxyindolin-2-yl)methyl)-2-methyl-2-phenylcyclopro-
pane-1-carboxamide (Compound B-16)
##STR00347##
[0731] To a stirred solution of (S)-2-(aminomethyl)indolin-6-ol (15
mg) in anhydrous DMF (1 mL) was added 2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (20 mg). The
reaction mixture was stirred overnight at rt and then concentrated
in vacuo. The residue was purified by flash column chromatography
over silica gel (0-5% MeOH/CH.sub.2Cl.sub.2 with 5% ammonia) and
further purified by prep HPLC (20-100% MeCN/water-0.1% TFA) to
afford the desired product (Compound B-16) as a light yellow foam
(10 mg). LC-MS: 323.2 [M+H]; .sup.1H NMR (400 MHz,
methanol-d.sub.4) .delta. 7.32-7.22 (m, 4H), 7.17 (m, 1H), 6.84 (d,
1H, J=8.0 Hz), 6.14 (s, 2H), 3.92 (m, 1H), 3.45-3.30 (m, 2H), 3.02
(dd, 1H, J=15.0, 9.1 Hz), 2.69 (dd, 1H, J=15.2, 6.1 Hz), 1.88 (t,
1H, J=6.8 Hz), 1.43 (s, 3H), 1.40-1.30 (m, 2H).
Example B17
##STR00348##
[0732] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-phenylcyc-
lopropane-1-carboxamide (Compound B-17)
##STR00349##
[0734] (S)-4-(3-amino-2-(dimethylamino)propyl)phenol
dihydrochloride salt (30 mg, 0.11 mmol),
(1R,2R)-2-phenylcyclopropane-1-carboxylic acid (AstaTech, W13292,
Lot #P135-06619, 19 mg, 0.11 mmol), and
(benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium
hexafluorophosphate (BOP, 60 mg, 0.13 mmol) were suspended in DCM
(3 mL), DIPEA (78 .mu.L, 0.45 mmol) was added, and the mixture was
stirred in a sealed vial overnight at ambient temperature until
reaction completion (LCMS). The mixture was concentrated, chased
with heptane (.times.3), and the residue purified by silica gel
chromatography, eluent DCM-MeOH 100:0 to 90:10 to afford 34 mg
(90%) of the title product as a clear oil. Analytical sample (5.2
mg) was prepared by additional chromatography, collecting fractions
with >95% HPLC purity. LC-MS (ESI+), m/z 339.5 (M+H).sup.+.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta.=7.26 (t, J=7.5 Hz,
2H), 7.16 (t, J=7.2 Hz, 1H), 7.10 (d, J=7.4 Hz, 2H), 7.04 (d, J=8.5
Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 3.32-3.22 (m, 2H), 2.97-2.85 (m,
2H), 2.46-2.36 (m, 7H), 2.36-2.28 (m, 1H), 1.84 (ddd, J=4.2, 5.2,
8.3 Hz, 1H), 1.45 (ddd, J=4.4, 5.1, 9.3 Hz, 1H), 1.22 (ddd, J=4.7,
6.4, 8.2 Hz, 1H).
Example B18
##STR00350##
[0735] Synthesis of
(1S,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-phenylcyc-
lopropane-1-carboxamide (Compound B-18)
##STR00351##
[0737] Compound B-18 was prepared according to the procedure
described in Example B17, using
(1S,2S)-2-phenylcyclopropane-1-carboxylic acid (AstaTech, F12973,
Lot #P135-06597), in 68% yield. LC-MS (ESI+), m/z 339.5
(M+H).sup.+. .sup.1H NMR (600 MHz, METHANOL-d.sub.4) .delta.=7.24
(t, J=7.6 Hz, 2H), 7.15 (t, J=7.3 Hz, 1H), 7.09 (dd, J=1.2, 8.4 Hz,
2H), 7.02 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 3.28-3.20 (m,
2H), 2.90-2.82 (m, 2H), 2.40-2.34 (m, 7H), 2.34-2.27 (m, 1H), 1.81
(ddd, J=4.3, 5.2, 8.4 Hz, 1H), 1.42 (td, J=4.7, 9.3 Hz, 1H), 1.18
(ddd, J=4.3, 6.3, 8.4 Hz, 1H).
Example B19
##STR00352##
[0738] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-2-methyl-2--
phenylcyclopropane-1-carboxamide (Compound B-19))
##STR00353##
[0740] The compound was prepared by the same procedure above using
(S)-3-(1H-indazol-5-yl)-N.sup.2,N.sup.2-dimethylpropane-1,2-diamine
(nrr-249-1, 140 mg, 513 .mu.mol), and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (PD-14-56, 147
mg, 539 .mu.mol) to afford 138 mg (71%) of title compound. LCMS
(+ESI) M+H.sup.+=377.5. .sup.1H NMR (600 MHz, METHANOL-d.sub.4)
.delta.=7.95 (s, 1H), 7.52 (s, 1H), 7.45 (d, J=8.5 Hz, 1H),
7.22-7.17 (m, 3H), 7.15-7.11 (m, 2H), 7.09-7.05 (m, 1H), 3.11-3.00
(m, 2H), 2.96 (dd, J=5.0, 13.8 Hz, 1H), 2.82 (tt, J=5.4, 8.2 Hz,
1H), 2.48 (dd, J=8.8, 13.9 Hz, 1H), 2.33 (s, 6H), 1.82 (dd, J=5.5,
7.8 Hz, 1H), 1.62 (t, J=5.1 Hz, 1H), 1.40-1.36 (m, 3H), 1.00 (dd,
J=4.6, 7.9 Hz, 1H).
Example B20
##STR00354##
[0741] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)-2-methyl-2--
phenylcyclopropane-1-carboxamide (Compound B-20)
##STR00355##
[0743] The title compound was prepared according to the procedure
as above, starting with
(S)-3-(1H-indazol-5-yl)-N.sup.2,N.sup.2-dimethylpropane-1,2-diamine
(140 mg, 641 .mu.mol) and
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (PD-14-51,
113 mg, 641 .mu.mol) to afford 120 mg (50%) of title compound. LCMS
(+ESI) M+H.sup.+=377.6. .sup.1H NMR (600 MHz, CHLOROFORM-d)
.delta.=10.52 (br s, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.53 (s, 1H),
7.36 (d, J=8.5 Hz, 1H), 7.32-7.28 (m, 2H), 7.24-7.22 (m, 2H),
7.22-7.18 (m, 1H), 7.16 (dd, J=1.5, 8.5 Hz, 1H), 6.42 (br s, 1H),
3.46 (ddd, J=4.8, 6.5, 13.7 Hz, 1H), 3.13-3.05 (m, 2H), 2.89-2.82
(m, 1H), 2.46 (dd, J=10.1, 13.4 Hz, 1H), 2.40-2.37 (m, 6H), 1.68
(dd, J=5.9, 8.4 Hz, 1H), 1.47 (s, 3H), 1.47 (m, 1H), 1.36 (dd,
J=4.8, 8.5 Hz, 1H).
Example B21
##STR00356##
[0744] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-ethyl-2-phenylcyclopropane-1-carbox-
amido)propyl)-2-fluoro-N-methylbenzamide (Compound B-21)
[0745] 2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-ethyl-2-phenylcyclopropane-1-carboxylate was synthesized
by following the procedure used for the synthesis of Int-36 by
substituting propiophenone for 3-methyl-2-phenylbutanone. To a
stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (80 mg, 0.31 mmol) in anhydrous DMF (1 mL) was added
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-ethyl-2-phenylcyclopropane-1-carboxylate (95 mg, 0.33
mmol) and diisopropylethylamine (61 .mu.L, 0.35 mmol). The reaction
mixture was stirred overnight at rt and then quenched by adding
water. The product was extracted into dichloromethane, dried and
then the concentrated. The residue was purified by flash column
chromatography over silica gel (0-10% MeOH/CH.sub.2Cl.sub.2) to
afford the desired product as a white solid (90 mg, 68%). LCMS
(+ESI) m/z 426.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.01 (t, J=8.19 Hz, 1H) 7.16-7.31 (m, 5H) 7.06 (dd,
J=8.07, 1.47 Hz, 1H) 6.93 (dd, J=12.84, 1.34 Hz, 1H) 6.63-6.78 (m,
1H) 6.36 (br d, J=5.38 Hz, 1H) 3.41 (ddd, J=13.51, 6.66, 4.77 Hz,
1H) 2.97-3.06 (m, 5H) 2.81-2.89 (m, 1H) 2.31-2.45 (m, 7H) 1.77-1.90
(m, 2H) 1.68 (dd, J=8.31, 5.87 Hz, 1H) 1.38 (dd, J=5.62, 4.65 Hz,
1H) 1.26 (dd, J=8.31, 4.40 Hz, 1H) 0.75 (t, J=7.46 Hz, 3H).
Example B22
##STR00357##
[0746] Synthesis of
4-((S)-2-(dimethylamino)-3-((1S,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N-methylbenzamide (Compound B-22)
[0747] The title compound was prepared according to Scheme B2,
starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (0.079 g) and
(1S,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid (0.055) to
afford the title compound (0.058 g). LCMS (+ESI) M+H.sup.+=412.2; H
NMR (400 MHz, METHANOL-d4) .delta. ppm 7.69 (t, J=7.83 Hz, 1H),
7.24-7.31 (m, 4H), 7.07-7.19 (m, 3H), 4.53 (br s, 1H), 3.30-3.33
(m, 2H), 2.94-3.04 (m, 2H), 2.91 (s, 3H), 2.54-2.65 (m, 1H), 2.37
(s, 6H), 1.82 (dd, J=8.44, 5.99 Hz, 1H), 1.42 (s, 3H), 1.34 (dd,
J=5.87, 4.89 Hz, 1H), 1.27 (dd, J=8.44, 4.52 Hz, 1H).
Example B23
##STR00358##
[0748] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-N-ethyl-2-fluorobenzamide (Compound B-23)
[0749] The title compound was prepared according to the procedure
of Example B2 above, starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-N-ethyl-2-fluorobenzamide
(40 mg, 0.15 mmol) and 2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (43 mg, 0.16
mmol) to afford the title compound (33 mg, 51%). LCMS (+ESI) m/z
426.3 (M+H).sup.+. .sup.1H NMR (400 MHz CDCl.sub.3) .delta. ppm
7.87-7.96 (m, 2H) 7.13-7.34 (m, 8H) 6.75 (dt, J=10.88, 5.56 Hz, 1H)
3.92 (br s, 1H) 3.76 (dt, J=15.04, 7.40 Hz, 1H) 3.36-3.50 (m, 4H)
2.84-2.94 (m, 7H) 1.86-2.13 (m, 2H) 1.36-1.46 (m, 4H) 1.18-1.31 (m,
5H).
Example B24
##STR00359##
[0750] Synthesis of
(1R,2S)--N--((S)-3-(3-chloro-5-fluoro-4-hydroxyphenyl)-2-(dimethylamino)p-
ropyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
24)
[0751] The title compound was prepared according to the procedure
of Example B1 above, starting with 4-bromo-2-chloro-6-fluorophenol
to afford the title compound (0.079 g). LCMS (+ESI) m/z 405.2
(M+H+). .sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 7.09-7.24
(m, 5H), 6.91 (t, J=1.83 Hz, 1H), 6.82 (dd, J=11.37, 2.08 Hz, 1H),
4.53 (br s, 1H), 2.97-3.06 (m, 2H), 2.66-2.74 (m, 2H), 2.29 (s,
6H), 2.23-2.28 (m, 1H), 1.85 (dd, J=7.83, 5.62 Hz, 1H), 1.67 (t,
J=5.14 Hz, 1H), 1.41 (s, 3H), 1.04 (dd, J=7.83, 4.65 Hz, 1H)
Example B25
##STR00360##
[0752] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-phenylcyc-
lopropane-1-carboxamide (Compound B-25)
[0753] The title compound was prepared according Scheme B2,
starting with (S)-4-(3-amino-2-(dimethylamino)propyl)phenol (0.141
g) and (1R,2S)-2-phenylcyclopropane-1-carboxylic acid (Wuxi AppTec,
LN01817094) (0.086 g) to afford the title compound (0.051 g). LCMS
(+ESI) m/z 339.2 (M+H.sup.+). .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. ppm 7.07-7.21 (m, 5H), 6.88-6.94 (m, 2H), 6.65-6.70 (m,
2H), 2.93-3.06 (m, 2H), 2.69 (dd, J=13.82, 5.01 Hz, 1H), 2.58 (tt,
J=8.22, 5.35 Hz, 1H), 2.34-2.46 (m, 1H), 2.23 (s, 6H), 2.17-2.22
(m, 1H), 1.97-2.07 (m, 1H), 1.57 (dt, J=7.09, 5.38 Hz, 1H),
1.17-1.26 (m, 1H).
Example B26
##STR00361##
[0754] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N,5-dimethylbenzamide (Compound B-26)
[0755] The title compound was prepared according to Scheme B2,
starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N,5-dimethylbenzami-
de (0.0720 g) and 2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.0735 g) to
afford the title compound (0.0980 g). LCMS (+ESI) m/z 426.2 (M+H+).
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 7.55 (br d, J=7.34
Hz, 1H), 7.28 (br s, 4H), 7.16 (br s, 1H), 7.05 (br d, J=12.23 Hz,
1H), 3.36 (br d, J=13.69 Hz, 1H), 3.24 (br dd, J=14.18, 4.65 Hz,
1H), 2.94-3.06 (m, 2H), 2.91 (br s, 3H), 2.61 (br dd, J=12.72, 8.80
Hz, 1H), 2.40 (s, 6H), 2.35 (s, 3H), 1.86 (br t, J=6.73 Hz, 1H),
1.41 (s, 3H), 1.34 (br d, J=4.40 Hz, 1H), 1.29 (br d, J=7.83 Hz,
1H).
Example B27
##STR00362##
[0756] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2,6-difluoro-N-methylbenzamide (Compound B-27)
[0757] The title compound was prepared according to Scheme B2,
starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-2,6-difluoro-N-methylbenzami-
de (0.0812 g) and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.0818 g) to
afford the title compound (0.119 g). LCMS (+ESI) m/z 430.2 (M+H+).
1H NMR (400 MHz, METHANOL-d4) .delta. ppm 7.07-7.27 (m, 5H), 6.83
(d, J=8.56 Hz, 2H), 4.53 (br s, 1H), 2.96-3.07 (m, 2H), 2.89 (s,
3H), 2.68-2.81 (m, 2H), 2.34-2.44 (m, 1H), 2.27 (s, 6H), 1.86 (dd,
J=7.83, 5.62 Hz, 1H), 1.68 (t, J=5.01 Hz, 1H), 1.42 (s, 3H), 1.05
(dd, J=7.95, 4.77 Hz, 1H).
Example B28
##STR00363##
[0758] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2,5-difluoro-N-methylbenzamide (Compound B-28)
[0759] The compound was prepared by the same procedure above using
(S)-4-(3-amino-2-(dimethylamino)propyl)-2,5-difluoro-N-methylbenzamide
and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as starting
materials. LC-MS: 430.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.23 (br s, 1H), 7.84 (m, 1H), 7.34 (m, 1H), 7.16-7.07 (m,
6H), 3.01-2.89 (m, 2H), 2.77 (d, J=4.6 Hz, 3H), 2.68 (m, 2H), 2.52
(m, 1H), 2.21 (s, 6H), 1.87 (dd, J=7.8, 5.4 Hz, 1H), 1.51 (m, 1H),
1.34 (s, 3H), 0.96 (dd, J=7.7, 4.0 Hz, 1H).
Example B29
##STR00364##
[0760] Synthesis of
N-cyclopropyl-2-fluoro-4-((S)-2-(methyl(2,2,2-trifluoroethyl)amino)-3-((1-
R,2S)-2-methyl-2-phenylcyclopropane-1-carboxamido)propyl)benzamide
(Compound B-29)
[0761] The title compound was prepared according to the procedure
of Example B2 above, starting with
(S)-4-(3-amino-2-(methyl(2,2,2-trifluoroethyl)amino)propyl)-N-cyclopropyl-
-2-fluorobenzamide (0.0273 g, 0.0786 mmole) and
2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.024 g,
0.0786 mmole) to afford the title compound (0.0111 g, 28%). LC-MS
(+ESI) M+H.sup.+: 506.2. .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
8.23 (br d, J=3.18 Hz, 1H) 7.75 (t, J=5.38 Hz, 1H) 7.45 (t, J=7.83
Hz, 1H) 7.14-7.22 (m, 4H) 7.02-7.14 (m, 3H) 3.13-3.29 (m, 2H)
2.97-3.05 (m, 1H) 2.87-2.96 (m, 1H) 2.76-2.87 (m, 2H) 2.58-2.66 (m,
1H) 2.32 (s, 3H) 1.84 (dd, J=7.83, 5.62 Hz, 1H) 1.53 (t, J=4.77 Hz,
1H) 1.35 (s, 3H) 0.99 (dd, J=7.95, 4.04 Hz, 1H) 0.64-0.72 (m, 2H)
0.50-0.57 (m, 2H)
Example B30
##STR00365##
[0762] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(3-fluoro-4-hydroxyphenyl)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-30)
[0763]
(1R,2S)--N--((S)-2-(dimethylamino)-3-(3-fluoro-4-hydroxyphenyl)-pro-
pyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluorophenol and
2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 371.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.04-7.21 (m, 5H), 6.47-6.64 (m, 3H), 3.58-3.42
(m, 1H), 3.11-3.18 (m, 1H), 2.56-2.76 (m, 3H), 2.21 (s, 6H),
2.06-2.12 (m, 1H), 1.69-1.73 (m, 1H), 1.56-1.60 (m, 1H), 1.35 (s,
3H), 0.99-1.03 (m, 1H).
Example B31
##STR00366##
[0764] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(2-fluoro-4-hydroxyphenyl)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-31)
[0765]
(1R,2S)--N--((S)-2-(dimethylamino)-3-(2-fluoro-4-hydroxyphenyl)-pro-
pyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-fluorophenol and
2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 371.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.27-7.31 (m, 2H), 7.12-7.24 (m, 3H), 6.76-6.84
(m, 1H), 6.28-6.46 (m, 2H), 3.23-3.40 (m, 1H), 2.98-3.07 (m, 2H),
2.89-2.92 (m, 1H), 2.56 (s, 6H), 2.32-2.41 (bs, 1H), 1.91-1.94 (m,
1H), 1.76-1.81 (m, 1H), 1.46 (s, 3H), 1.08-1.12 (m, 1H).
Example B32
##STR00367##
[0766] Synthesis of
(1R,2S)--N--((S)-2-((cyclopropylmethyl)(methyl)amino)-3-(2-oxo-2,3-dihydr-
obenzo[d]oxazol-6-yl)propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide
(Compound B-32)
[0767] The title compound was prepared according to Scheme B2,
starting with
(S)-6-(3-amino-2-((cyclopropylmethyl)(methyl)amino)propyl)benzo[d]ox-
azol-2(3H)-one and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate to provide the
title compound (0.021 g). LCMS (+ESI) m/z 434.2 (M+H.sup.+).
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 11.65 (d, J=1.47 Hz,
1H), 9.73 (br s, 1H), 8.33-8.43 (m, 1H), 7.05-7.26 (m, 8H) 3.49 (m,
1H), 3.25-3.31 (m, 1H), 3.02-3.21 (m, 3H), 2.69-3.02 (m, 4H),
2.52-2.68 (m, 1H), 2.33 (dt, J=3.73, 1.93 Hz, 1H), 1.85 (td,
J=8.13, 5.50 Hz, 1H), 1.56-1.61 (m, 1H), 1.37 (d, J=3.67 Hz, 3H),
1.00-1.06 (m, 1H), 0.52-0.69 (m, 2H), 0.22-0.51 (m, 2H).
Example B33
##STR00368##
[0768] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-N,3,5-trimethylbenzamide (Compound B-33)
[0769] The title compound was prepared according to the procedure
of Example B2 above, starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-N,3,5-trimethylbenzamide
(0.100 g) and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.104 g) to
afford the title compound (0.081 g). LC-MS (+ESI) M+H. 422.3;
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 8.25 (br d, J=4.16 Hz,
1H) 7.76 (br t, J=4.77 Hz, 1H) 7.39 (s, 2H) 7.07-7.23 (m, 5H)
2.90-2.99 (m, 1H) 2.63-2.81 (m, 6H) 2.32 (s, 6H) 2.25 (s, 6H) 1.86
(t, J=6.48 Hz, 1H) 1.43 (br t, J=3.91 Hz, 1H) 1.32 (s, 3H) 0.94
(dd, J=7.34, 3.42 Hz, 1H)
Example B34
##STR00369##
[0770] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-N-ethyl-2-fluorobenzamide (Compound B-34)
[0771] The title compound was prepared according to the procedure
of Example B2 above, starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-N-ethyl-2-fluorobenzamide
(65 mg, 0.24 mmol) and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (75 mg, 0.27
mmol) to afford the title compound (72 mg, 70%). LCMS (+ESI) m/z
426.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.96 (t, J=8.19 Hz, 1H) 7.15-7.29 (m, 6H) 6.94 (d, J=7.83 Hz, 1H)
6.79 (d, J=12.72 Hz, 1H) 6.57-6.71 (m, 1H) 5.84 (br d, J=6.60 Hz,
1H) 3.46-3.55 (m, 2H) 3.09-3.19 (m, 1H) 2.79-2.87 (m, 1H) 2.53-2.66
(m, 2H) 2.09-2.24 (m, 7H) 1.70-1.78 (m, 1H) 1.54-1.66 (m, 1H) 1.43
(s, 3H) 1.25 (t, J=7.21 Hz, 3H) 1.08 (dd, J=7.95, 5.01 Hz, 1H)
Example B35
##STR00370##
[0772] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N-isopropylbenzamide (Compound B-35)
[0773] The title compound was prepared according to the procedure
of Example B2 above, starting with 75 mg of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-isopropylbenzamide
and 74 mg of 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate to afford the
title compound (90 g). LC-MS: (+ESI) m/z 440.3 (MW+H); .sup.1H NMR
(400 MHz, MeOH-d.sub.4) .delta. 7.56 (t, J=7.70 Hz, 1H), 6.98-7.24
(m, 7H), 4.14-4.22 (m, 1H), 3.04 (d, J=6.11 Hz, 2H), 2.78-2.88 (m,
2H), 2.40-2.50 (m, 1H), 2.32 (s, 6H), 1.83-1.98 (m, 1H), 1.68 (t,
J=5.01 Hz, 1H), 1.41 (s, 3H), 1.24 (d, J=6.60 Hz, 6H), 1.05 (dd,
J=7.70 Hz, J=4.77 Hz, 1H).
Example B36
##STR00371##
[0774] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-3,5-dimethylphenyl)propyl-
)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound B-36)
[0775] The title compound was prepared according to the procedure
of Example B2 above, starting with 75 mg of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2,6-dimethylphenol and 74
mg of 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate to afford the
title compound (46 mg). LC-MS: (+ESI) m/z 381.2 (MW+H); .sup.1H NMR
(400 MHz, MeOH-d.sub.4) .delta. 7.07-7.23 (m, 5H), 6.71 (s, 1H),
3.02 (br, s, 2H), 2.70-2.78 (m, 2H), 2.35 (s, 6H), 2.20-2.30 (m,
1H), 2.17 (s, 6H), 1.80-1.85 (m, 1H), 1.65-1.70 (m, 1H), 1.65-1.70
(m, 1H), 1.40 (s, 3H), 1.02-1.07 (m, 1H).
Example B37
##STR00372##
[0776] Synthesis of
(1R,2S)--N--((S)-3-(4-hydroxyphenyl)-2-(pyrrolidin-1-yl)propyl)-2-methyl--
2-phenylcyclopropane-1-carboxamide (Compound B-37)
[0777]
(1R,2S)--N--((S)-3-(4-hydroxyphenyl)-2-(pyrrolidin-1-yl)propyl)-2-m-
ethyl-2-phenylcyclopropane-1-carboxamide was synthesized according
to Scheme B2 using (S)-4-(3-amino-2-(pyrrolidin-1-yl)propyl)phenol
and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 379.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.24 (d, J=7.8 Hz, 1H), 7.16-7.19 (m, 1H),
7.08-7.12 (m, 1H), 6.71 (d, J=8.1 Hz, 2H), 6.51 (d, J=7.8 Hz, 2H),
2.85-3.0 (m, 1H), 2.45-2.70 (m, 1H), 1.72-1.81 (m, 2H), 1.46-1.62
(m, 5H), 1.57-1.42 (m, 4H), 1.18-1.20 (m, 1H), 1.02-1.06 (m,
1H).
Example B38
##STR00373##
[0778] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N,5-dimethylbenzamide (Compound B-38)
[0779] The title compound was prepared according to Scheme B2,
starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N,5-dimethylbenzami-
de (0.0900 g) and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.0920 g) to
afford the title compound (0.0320 g). LCMS (+ESI) m/z 426.3 (M+H+).
H NMR (400 MHz, METHANOL-d4) .delta. ppm 7.60 (d, J=7.58 Hz, 1H),
7.11-7.28 (m, 6H), 3.43-3.52 (m, 2H), 3.08-3.17 (m, 2H), 2.93 (s,
6H), 2.72-2.89 (m, 4H), 2.33 (s, 3H), 1.89 (dd, J=7.83, 5.38 Hz,
1H), 1.76 (t, J=5.01 Hz, 1H), 1.44 (s, 3H), 1.12 (dd, J=7.83, 4.65
Hz, 1H).
Example B39
##STR00374##
[0780] Synthesis of
N-cyclopropyl-4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclop-
ropane-1-carboxamido)propyl)-2-fluorobenzamide (Compound B-39)
[0781] The title compound was prepared according to the procedure
of Example B2 above, starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (0.07 g) and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.0685 g) to
afford the title compound (0.0652 g). LC-MS (+ESI) M+H. 438.3;
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 8.30 (br d, J=3.67 Hz,
1H) 7.77-7.86 (m, 1H) 7.43 (br t, J=7.83 Hz, 1H) 7.13-7.21 (m, 4H)
7.07-7.12 (m, 1H) 6.99-7.06 (m, 2H) 2.92 (br d, J=4.16 Hz, 2H)
2.78-2.87 (m, 1H) 2.62-2.74 (m, 2H) 2.36-2.44 (m, 1H) 2.21 (br s,
6H) 1.88 (t, J=6.60 Hz, 1H) 1.49 (br t, J=4.04 Hz, 1H) 1.34 (s, 3H)
0.96 (br dd, J=7.70, 3.79 Hz, 1H) 0.68 (q, J=6.03 Hz, 2H) 0.48-0.55
(m, 2H)
Example B40
##STR00375##
[0782] Synthesis of
(1R,2S)--N--((S)-2-((cyclopropylmethyl)(methyl)amino)-3-(4-hydroxy-3-meth-
ylphenyl)propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide
(Compound B-40)
[0783] The title compound was prepared according to the procedure
of Example B1 above, starting with 45 mg of
(1R,2S)--N--((S)-2-amino-3-(4-hydroxy-3-methylphenyl)propyl)-2-methyl-2-p-
henylcyclopropane-1-carboxamide hydrochloride and 8.8 mg of
cyclopropylaldehyde and 37% formaldehyde (20 mg) to afford the
title compound (11 mg). LC-MS: (+ESI) m/z 407.3 (MW+H); .sup.1H NMR
(400 MHz, MeOH-d.sub.4) .delta. 6.94-7.08 (m, 5H), 6.68 (s, 1H),
6.61 (d, J=7.83 Hz, 1H), 6.48 (d, J=8.07 Hz, 1H), 3.16 (s, 3H),
2.82-2.91 (m, 1H), 2.68-2.80 (m, 2H), 2.56 (dd, J=13.45 Hz, 3.91
Hz, 1H), 2.20-2.25 (m, 2H), 2.13 (s, 3H), 2.00-2.12 (m, 1H), 1.99
(s, 3H), 1.68 (dd, J=7.70 Hz, J=5.75 Hz, 1H), 1.38-1.50 (m, 1H),
1.25 (s, 3H), 1.14 (s, 1H), 0.81-0.97 (m, 1H), 0.60-0.78 (m, 2H),
0.34-0.43 (m, 2H), 0.05-0.03 (m, 2H).
Example B41
##STR00376##
[0784] Synthesis of
(1R,2S)--N--((S)-2-(diethylamino)-3-(4-hydroxy-3-methylphenyl)propyl)-2-m-
ethyl-2-phenylcyclopropane-1-carboxamide (Compound B-41)
[0785] The title compound was prepared according to the procedure
of Example B1 above, starting with 45 mg of
(1R,2S)--N--((S)-2-amino-3-(4-hydroxy-3-methylphenyl)propyl)-2-methyl-2-p-
henylcyclopropane-1-carboxamide hydrochloride and acetaldehyde (15
mg) to afford the title compound (25 mg). LC-MS: (+ESI) m/z 395.2
(MW+H); .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. 7.08-7.25 (m,
5H), 6.83 (s, 1H), 6.76 (br d, J=8.07 Hz, 1H), 6.61-6.66 (m, 1H),
2.82-3.07 (m, 3H), 2.56-2.73 (m, 3H) 2.48 (dq, J=13.08 Hz, 6.48 Hz,
2H) 2.20-2.30 (m, 1H), 2.14 (s, 1H), 1.72-1.86 (m, 1 H), 1.52-1.66
(m, 1H), 1.39 (s, 3H), 1.12-1.37 (m, 1H), 0.97-1.07 (m, 7H),
0.74-0.94 (m, 1H).
Example B42
##STR00377##
[0786] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-3-methylphenyl)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-42)
[0787] The title compound was prepared according to the procedure
of Example B1 above, starting with 50 mg of
(1R,2S)--N--((S)-2-amino-3-(4-hydroxy-3-methylphenyl)propyl)-2-methyl-2-p-
henylcyclopropane-1-carboxamide hydrochloride and 37% formaldehyde
(46 mg) to afford the title compound (30 mg). LC-MS: (+ESI) m/z
367.2 (MW+H); .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. 7.09-7.24
(m, 5H), 6.84 (s, 1H), 6.77 (d, J=8.07 Hz, 1H), 6.64 (d, J=8.07 Hz,
1H), 3.63 (s, 1H), 3.01 (d, J=6.36 Hz, 2H), 2.68-2.79 (m, 2H) 2.30
(s, 6H), 2.20-2.30 (m, 1H), 2.15 (s, 3H), 1.83 (dd, J=7.83 Hz,
J=5.62 Hz, 1H), 1.62 (t, J=5.01 Hz, 1H), 1.39 (s, 3H), 1.15-1.34
(m, 1H), 0.96-1.14 (m, 1H), 0.83-0.94 (m, 1H).
Example B43
##STR00378##
[0788] Synthesis of
(1R,2S)--N--((S)-3-(2H-indazol-5-yl)-2-morpholinopropyl)-2-methyl-2-pheny-
lcyclopropane-1-carboxamide (Compound B-43)
##STR00379##
[0789] Step 1: Synthesis of
(S)-2-amino-3-(1-((2-(trimethylsilyl)ethyl)sulfonyl)-1H-indazol-5-yl)prop-
enamide
[0790] A solution of benzyl
(S)-(1-amino-1-oxo-3-(1-((2-(trimethylsilyl)
ethyl)sulfonyl)-1H-indazol-5-yl)propan-2-yl)carbamate (1.48 g, 3.04
mmole) in EtOH (30 mL) was hydrogenated at RT with 10% Pd/C (0.16
g, 0.15 mmole) for 48 h. The catalyst was filtered off through a
pad of Celite. The filtrate was concentrated to dryness to give
(S)-2-amino-3-(1-((2-(trimethylsilyl)ethyl)sulfonyl)-1H-indazol-5-yl)prop-
enamide (1.01 g, 92%). LC-MS (+ESI) M+H: 369.1.
##STR00380##
Step 2: Synthesis of
(S)-2-morpholino-3-(1-((2-(trimethylsilyl)ethyl)
sulfonyl)-1H-indazol-5-yl)propenamide
[0791] A mixture of
(S)-2-amino-3-(1-((2-(trimethylsilyl)ethyl)sulfonyl)-1H-indazol-5-yl)prop-
enamide (1.01 g, 2.74 mmole), NaHCO.sub.3 (1.15 g, 13.7 mmole), and
1-bromo-2-(2-bromoethoxy)ethane (0.96 g, 4.11 mmole) in DMF (12 mL)
was heated at 80.degree. C. in 4 h. The reaction mixture was
cooled, quenched with saturated aqueous NH.sub.4Cl, extracted with
EtOAc (3.times.). The combined extracts were dried over
Na.sub.2SO.sub.4, concentrated, and purified by ISCO (5% MeOH/DCM)
to give
(S)-2-morpholino-3-(1-((2-(trimethylsilyl)ethyl)sulfonyl)-1H-indazol-5-yl-
)propenamide (1.2 g, 86%). LC-MS (+ESI) M+H: 439.1.
##STR00381##
Step 3: Synthesis of
(S)-3-(1H-indazol-5-yl)-2-morpholinopropan-1-amine
[0792] To a stirred solution of
(S)-2-morpholino-3-(1-((2-(trimethylsilyl)ethyl)sulfonyl)-1H-indazol-5-yl-
)propenamide (1.4 g, 3.19 mmole) in THE (30 mL) at 0.degree. C. was
added 1M LAH (9.5 mL, 9.58 mmole) dropwise. The reaction mixture
was heated to 80.degree. C. in 16 h. The reaction mixture was
cooled in an ice bath and slowly added a saturated solution of
Rochelle's salt and stirred for 2 h, extracted with DCM (3.times.).
The combined extracts were dried over Na.sub.2SO.sub.4,
concentrated and purified by ISCO (0-25% MeOH/DCM in 1% NH.sub.4OH)
to give (S)-3-(1H-indazol-5-yl)-2-morpholinopropan-1-amine (0.185
g, 22%). LC-MS (+ESI) M+H: 261.1.
##STR00382##
Step 4: Synthesis of
(1R,2S)--N--((S)-3-(1H-indazol-5-yl)-2-morpholinopropyl)-2-methyl-2-pheny-
lcyclopropane-1-carboxamide
[0793] A mixture of
(S)-3-(1H-indazol-5-yl)-2-morpholinopropan-1-amine (0.0572 g, 0.219
mmole), 2,5-dioxocyclopentyl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.06 g, 0.219
mmole), and DIEA (50 .quadrature.mL, 0.263 mmole) in MeCN/DMF (1:1,
3 mL) was stirred at RT for 16 h. H.sub.2O was added and extracted
with DCM (3.times.). The combined extracts were dried over
Na.sub.2SO.sub.4, concentrated and purified by ISCO (0-15%
MeOH/DCM) to give the title compound (0.0478 g, 52%). LC-MS (+ESI)
M+H: 419.2; H NMR (400 MHz, DMSO-d6) .delta. ppm 12.95 (s, 1H) 7.97
(s, 1H) 7.73 (br t, J=5.14 Hz, 1H) 7.49 (s, 1H) 7.43 (d, J=8.56 Hz,
1H) 7.04-7.21 (m, 6H) 3.54 (br d, J=4.16 Hz, 4H) 2.90-2.99 (m, 2H)
2.83 (br dd, J=13.57, 5.99 Hz, 1H) 2.63-2.70 (m, 1H) 2.43-2.49 (m,
3H) 2.41-2.49 (m, 1H) 1.88 (t, J=6.48 Hz, 1H) 1.47 (br t, J=4.40
Hz, 1H) 1.34 (s, 3H) 0.96 (dd, J=7.58, 3.91 Hz, 1H)
Example B44
##STR00383##
[0794] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(2-fluoro-4-hydroxyphenyl)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-44)
[0795]
(1R,2R)--N--((S)-2-(dimethylamino)-3-(2-fluoro-4-hydroxyphenyl)-pro-
pyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-fluorophenol and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 371.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.17-7.25 (m, 3H), 7.11-7.15 (m, 1H), 6.84-6.95
(m, 2H), 6.49 (d, J=9.8 Hz, 2H), 3.40-3.46 (m, 1H), 3.01-3.10 (m,
1H), 2.83-2.95 (m, 2H), 2.40 (s, 6H), 2.26-2.35 (m, 1H), 1.69-1.73
(m, 1H), 1.38-1.43 (m, 4H), 1.30-1.34 (m, 1H).
Example B45
##STR00384##
[0796] Synthesis of
(1R,2R)--N--((S)-2-((cyclopropylmethyl)(methyl)amino)-3-(4-hydroxyphenyl)-
propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-45)
[0797] The title compound was prepared according to the procedure
of Example B1 above, starting with 31 mg of
(1R,2R)--N--((S)-2-amino-3-(4-hydroxyphenyl)propyl)-2-methyl-2-phenylcycl-
opropane-1-carboxamide hydrochloride and cyclopropaldehyde (6 mg)
and 37% formaldehyde (19 mg) to afford the title compound (16 mg).
LC-MS: (+ESI) m/z 393.3 (MW+H); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.77 (br, s, 1H), 7.25-7.32 (m, 5H), 7.16-7.23 (m, 1H) 6.98
(br d, J=8.07 Hz, 2H), 6.78 (d, J=8.31 Hz, 2H), 3.52 (br d, J=14.43
Hz, 1H), 3.40 (br d, J=9.29 Hz, 1H), 3.26 (br d, J=10.03 Hz, 1H),
2.90-3.12 (m, 1H), 2.60-2.75 (m, 2H), 2.41-2.51 (m, 1H) 2.00 (s,
3H), 1.75-1.85 (m, 1H), 1.44 (s, 3H), 1.32-1.40 (m, 1H), 1.26 (br
s, 1H), 1.00 (br s, 1H), 0.60-0.70 (m, 2H), 0.28 (br d, J=4.40 Hz,
2H)
Example B46
##STR00385##
[0798] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N-methylbenzamide (Compound B-46)
[0799]
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-
-carboxamido)propyl)-2-fluoro-N-methylbenzamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 412.2 [M+1]; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.85 (t, J=8.1 Hz, 1H), 7.06-7.21 (m, 5H), 6.86 (d, J=8.1
Hz, 1H), 6.67-6.74 (m, 2H), 5.90 (bs, 1H), 3.03-3.10 (m, 1H), 2.90
(d, J=5.6 Hz, 3H), 2.76 (dd, J=13.7 Hz, 3.4 Hz, 1H) 2.47-2.60 (m,
2H), 2.08-2.15 (m, 7H), 1.65-1.70 (m, 1H), 1.50-1.54 (m, 1H), 1.35
(s, 3H), 1.00 (dd, J=8.1 Hz, 4.9 Hz, 1H).
Example B47
##STR00386##
[0800] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)
propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-47)
[0801]
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)-
-propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was
synthesized according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylphenol (Int-1G)
and 2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 381.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.06-7.20 (m, 5H), 6.59 (s, 1H), 6.28 (s, 2H),
2.93-2.98 (m, 1H), 2.66-2.80 (m, 2H), 2.35-2.41 (m, 1H), 2.30 (s,
3H), 2.05 (s, 3H), 1.88 (s, 1H), 1.68-1.71 (m, 1H), 1.51-1.53 (m,
1H), 1.33 (s, 3H), 0.97-1.01 (m, 1H).
Example B48
##STR00387##
[0802] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-2-methylphenyl)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-48)
[0803]
(1R,2S)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-2-methylphenyl)-pro-
pyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-methylphenol and
2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 367.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.11-7.26 (m, 5H), 6.70 (d, J=7.8 Hz, 2H), 6.51
(s, 1H), 6.39 (d, J=7.8 Hz, 1H), 3.16-3.21 (m, 1H), 2.73-2.86 (m,
3H), 2.34 (s, 6H), 2.18-2.25 (m, 1H), 2.12 (s, 3H), 1.79-1.83 (m,
1H), 1.62-1.64 (m, 1H), 1.40 (s, 3H), 1.04-1.07 (m, 1H).
Example B49
##STR00388##
[0804] Synthesis of
(1R,2S)--N--((S)-2-(dimethylamino)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-y-
l)propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-49)
[0805] Compound B-49 was prepared by the same procedure above using
(S)-6-(3-amino-2-(dimethylamino)propyl)benzo[d]oxazol-2(3H)-one and
2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as starting
materials. LC-MS: 394.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.5 (s, 1H), 7.95 (m, 1H), 7.30-7.15 (m, 6H), 6.98 (m,
2H), 3.17-3.14 (m, 3H), 2.77 (m, 2H), 2.26 (s, 6H), 1.91 (t, J=6.8
Hz, 1H), 1.36 (s, 3H), 1.22 (m, 2H).
Example B50
##STR00389##
[0806] Synthesis of
(1R,2S)--N--(((S)-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)m-
ethyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-50)
[0807]
(1R,2S)--N--(((S)-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin--
3-yl)methyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was
synthesized according to Scheme B2 using
(S)-3-(aminomethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol and
2,5-dioxopyrrolidin-1-yl
(1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 351.2 [M+1].sup.+; .sup.1H NMR (400 MHz, d6-DMSO)
.delta. 9.12 (s, 1H), 7.99 (s, 1H), 7.20-7.25 (m, 4H), 7.13 (sep,
J=16.4 Hz, 12.7 Hz, 8.3 Hz, 4.4 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H),
6.54 (d, J=7.1 Hz, 1H), 6.42 (s, 1H), 3.57-3.67 (m, 1H), 3.44-3.55
(m, 1H), 3.05-3.14 (m, 1H), 2.90-3.01 (m, 1H), 2.23-2.43 (m, 4H),
1.87-1.91 (m, 1H), 1.51-1.55 (m, 1H), 1.36 (s, 3H), 1.09 (t, J=7.1
Hz, 1H), 0.96-0.99 (m, 1H).
Example B51
##STR00390##
[0808] Synthesis of
(1R,2R)--N--(((S)-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)m-
ethyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-51)
[0809]
(1R,2R)--N--(((S)-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin--
3-yl)methyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was
synthesized according to Scheme B2 using
(S)-3-(aminomethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 351.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.25-7.30 (m, 5H), 7.17-7.22 (m, 1H), 6.86-7.0
(m, 2H), 6.62 (d, J=8.1 Hz, 1H), 6.37 (s, 1H), 3.56-3.77 (m, 4H),
2.95-2.99 (m, 1H), 2.71-2.74 (m, 2H), 2.45 (s, 3H), 2.35 (s, 1H),
1.79-1.84 (m, 1H), 1.49-1.53 (m, 4H), 1.31-1.34 (dd, J=8.3 Hz, 4.6
Hz, 1H).
Example B52
##STR00391##
[0810] Synthesis of
(1R,2R)--N--((S)-3-(6-chloro-2H-indazol-5-yl)-2-(dimethylamino)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-52)
[0811] The title compound was prepared according to the procedure
of Example B2 above, starting with
(1R,2S)--N--((S)-3-(6-chloro-1-((2-(trimethylsilyl)ethoxy)
methyl)-1H-indazol-5-yl)-2-(dimethylamino)propyl)-2-methyl-2-phenylcyclop-
ropane-1-carboxamide (0.175 g, 0.324 mmole) and 1M TBAF (3.2 mL,
3.24 mmole) to afford the title compound (0.0461 g, 35%). LC-MS
(+ESI) M+H.sup.+: 411.2; .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
1.11 (s, 3H) 1.18-1.23 (m, 2H) 1.34 (s, 3H) 1.91 (br t, J=6.97 Hz,
1H) 2.31 (br s, 6H) 2.67-2.73 (m, 1H) 2.87-2.96 (m, 1H) 3.00 (br
dd, J=13.21, 5.62 Hz, 1H) 3.10-3.16 (m, 1H) 3.18-3.28 (m, 1H)
7.14-7.22 (m, 1H) 7.23-7.33 (m, 4H) 7.62 (s, 1H) 7.73 (s, 1H)
7.94-8.03 (m, 1H) 8.05 (s, 1H) 13.09 (s, 1H)
Example B53
##STR00392##
[0812] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-y-
l)propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-53)
[0813] The compound was prepared by the same procedure above using
(S)-6-(3-amino-2-(dimethylamino)propyl)benzo[d]oxazol-2(3H)-one and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as starting
materials. LC-MS: 394.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.5 (s, 1H), 7.74 (m, 1H), 7.15-6.88 (m, 8H), 2.88 (m,
2H), 2.67 (m, 2H), 2.33 (m, 1H), 2.21 (s, 6H), 1.86 (t, J=6.0 Hz,
1H), 1.47 (t, J=4.8 Hz, 1H), 1.33 (s, 3H), 0.94 (m, 1H).
Example B54
##STR00393##
[0814] Synthesis of
(1R,2S)--N--((S)-3-(6-chloro-2H-indazol-5-yl)-2-(dimethylamino)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-54)
[0815] The title compound was prepared according to the procedure
of Example B52 above, starting with
(1R,2S)--N--((S)-3-(6-chloro-1-((2-(trimethylsilyl)ethoxy)
methyl)-1H-indazol-5-yl)-2-(dimethylamino)propyl)-2-methyl-2-phenylcyclop-
ropane-1-carboxamide (0.151 g, 0.279 mmole) and 1M TBAF (1.4 mL,
1.39 mmole) to afford the title compound (0.0389 g, 34%). LC-MS
(+ESI) M+H.sup.+. 411.2; .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
0.93 (br dd, J=6.97, 3.55 Hz, 1H) 1.31 (s, 3H) 1.42 (br t, J=4.04
Hz, 1H) 1.83-1.90 (m, 1H) 2.29 (s, 6H) 2.34 (br s, 1H) 2.57 (br d,
J=4.16 Hz, 1H) 2.68 (br d, J=0.73 Hz, 1H) 2.73-2.82 (m, 1H) 2.95
(br d, J=6.11 Hz, 3H) 7.02-7.10 (m, 1H) 7.10-7.17 (m, 4H) 7.58 (s,
1H) 7.63 (s, 1H) 7.73-7.80 (m, 1H) 8.02 (s, 1H) 13.07 (s, 1H)
Example B55
##STR00394##
[0816] Synthesis of
(1R,2S)--N--((S)-3-(3-chloro-4-hydroxyphenyl)-2-(dimethylaminopropyl)-2-m-
ethyl-2-phenylcyclopropane-1-carboxamide (Compound B-55)
[0817]
(1R,2S)--N--((S)-3-(3-chloro-4-hydroxyphenyl)-2-(dimethylamino)-pro-
pyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-chlorophenol (Int-3H) and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 387.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.11-7.26 (m, 5H), 9.90-6.96 (m, 1H), 6.56-6.72
(m, 3H), 3.10-3.22 (m, 1H), 2.61-2.81 (m, 4H), 2.28 (s, 6H),
2.10-2.16 (m, 1H), 1.78-1.83 (m, 1H), 1.63-1.66 (m, 1H), 142 (s,
3H), 1.06-1.09 (m, 1H).
Example B56
##STR00395##
[0818] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxy-2-methylphenyl)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-56)
[0819] The title compound was prepared according to the procedure
of Example B1 above, starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-methylphenol (229 mg) and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (301 mg) to
afford the title compound (259 mg, 64%). LC-MS: (ESI+) m/z 367.2
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.27-7.32 (m, 2H) 7.17-7.25 (m, 3H) 6.93 (d, J=8.07 Hz, 1H)
6.59-6.64 (m, 2H) 6.40 (m, 1H) 3.42 (m, 1H) 3.03 (m, 1H) 2.95 (dd,
J=13.45, 3.18 Hz, 1H) 2.65-2.75 (m, 1H) 2.36 (s, 6H) 2.32 (m, 1H)
2.27 (s, 3H) 1.68 (dd, J=8.56, 6.11 Hz, 1H) 1.49 (s, 3H) 1.44-1.47
(m, 1H) 1.36 (dd, J=8.31, 4.89 Hz, 1H)
Example B57
##STR00396##
[0820] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)phenyl acetate (Compound B-57)
[0821]
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropane-1-
-carboxamido)propyl)phenyl acetate was synthesized according to
Scheme B2 using (S)-4-(3-amino-2-(dimethylamino)propyl)phenyl
acetate and 2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 395.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.26-7.81 (m, 4H), 7.16-7.21 (m, 4H), 7.02 (d,
J=8.3 Hz, 1H), 3.41-3.49 (m, 1H), 3.21-3.28 (m, 1H), 2.99-3.07 (m,
1H), 2.50-2.53 (m, 1H), 2.45 (s, 6H), 2.29 (s, 3H), 1.73-1.78 (m,
1H), 1.45-1.47 (m, 4H), 1.30-1.33 (m, 1H).
Example B58
##STR00397##
[0822] Synthesis of
(1S,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-methyl-2--
phenylcyclopropane-1-carboxamide (Compound B-58)
[0823]
(1S,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-met-
hyl-2-phenylcyclopropane-1-carboxamide was synthesized according to
Scheme B2 using (S)-4-(3-amino-2-(dimethylamino)propyl)phenol and
2,5-dioxopyrrolidin-1-yl
(1S,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 353.2 [M+1].sup.+; .sup.1H NMR (400 MHz, d6-DMSO)
.delta. 9.12 (s, 1H), 7.60-7.61 (m, 1H), 7.09-7.18 (m, 5H), 6.91
(d, J=Hz, 2H), 6.63 (d, J=Hz, 2H), 2.87-2.94 (m, 1H), 2.77-2.84 (m,
1H), 2.62 (dd, J=13.7 Hz, 5.6 Hz, 1H), 2.19-2.25 (m, 7H), 1.87 (dd,
J=7.8 Hz, 5.6 Hz, 1H), 1.43-1.46 (m, 1H), 1.32 (s, 3H), 0.93 (dd,
J=7.8 Hz, 3.9 Hz, 1H).
Example B59
##STR00398##
[0824] Synthesis of
(1R,2R)--N--((S)-3-(3-chloro-4-hydroxyphenyl)-2-(dimethylamino)propyl)-2--
methyl-2-phenylcyclopropane-1-carboxamide (Compound B-59)
[0825]
(1R,2S)--N--((S)-3-(3-chloro-4-hydroxyphenyl)-2-(dimethylamino)-pro-
pyl)-2-methyl-2-phenylcyclopropane-1-carboxamide was synthesized
according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-chlorophenol (Int-3H) and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 387.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.19-7.30 (m, 5H), 6.84-6.91 (m, 2H), 6.67-6.71
(m, 1H), 3.40-3.57 (m, 1H), 2.73-3.09 (m, 3H), 2.25-2.40 (m, 7H),
1.71-1.74 (m, 1H), 1.46-1.52 (m, 4H), 1.39 (dd, J=8.8 Hz, 5.1 Hz,
1H).
Example B60
##STR00399##
[0826] Synthesis of
3-chloro-4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclopropan-
e-1-carboxamido)propyl)benzamide (Compound B-60)
[0827]
3-chloro-4-((S)-2-(dimethylamino)-3-((1R,2R)-2-methyl-2-phenylcyclo-
propane-1-carboxamido)propyl)benzamide was synthesized according to
Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-chlorobenzamide and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 414.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.17-7.31 (m, 5H), 6.84-6.91 (m, 2H), 6.65-6.61
(m, 1H), 3.40-3.47 (m, 1H), 2.73-3.09 (m, 3H), 2.24-2.40 (m, 7H),
1.70-1.74 (m, 1H), 1.46-1.52 (m, 4H), 1.34-1.39 (m, 1H).
Example B61
##STR00400##
[0828] Synthesis of
4-((2S)-2-(dimethylamino)-3-(2-methyl-2-phenylcyclopropane-1-carboxamido)-
propyl)benzamide (Compound B-61)
[0829]
4-((2S)-2-(dimethylamino)-3-(2-methyl-2-phenylcyclopropane-1-carbox-
amido)propyl)benzamide was synthesized according to Scheme B2 using
(S)-4-(3-amino-2-(dimethylamino)propyl)benzamide and
2,5-dioxopyrrolidin-1-yl
2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 380.2 [M+1].sup.+.
Example B62
##STR00401##
[0830] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-methyl-2--
phenylcyclopropane-1-carboxamide (Compound B-62)
[0831]
(1R,2R)--N--((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-2-met-
hyl-2-phenylcyclopropane-1-carboxamide was synthesized according to
Scheme B2 using (S)-4-(3-amino-2-(dimethylamino)propyl)phenol and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. LC-MS: 353.2 [M+1]+; 1H NMR (400 MHz, d6-DMSO) .delta.
9.15 (s, 1H), 7.89-7.91 (m, 1H), 7.27-7.32 (m, 4H), 7.18-7.21 (m,
1H), 6.92 (d, J=8.3 Hz, 2H), 6.65 (d, J=8.1 Hz, 2H), 3.05-3.13 (m,
2H), 2.65-2.70 (m, 2H), 2.22-2.34 (m, 7H), 1.91-1.95 (m, 1H), 1.36
(s, 3H), 1.19-1.25 (m, 1H).
Example B63
##STR00402##
[0832] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(1H-pyrazolo[3,4-c]pyridin-5-yl)prop-
yl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound B-63)
##STR00403##
[0833] Step 1: Synthesis of
5-bromo-1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridine
[0834] To a stirred mixture of 5-bromo-1H-pyrazolo[3,4 m-c]pyridine
(5 g, 25.51 mmole) and DIEA (5.4 mL, 30.61 mmole) in DCM (50 mL) at
0.degree. C. was added benzenesulfonyl chloride (3.6 mL, 28.06
mmole). After the addition was completed, the reaction mixture was
stirred for 2 h at RT. H.sub.2O was added, and the layers were
separated. The organic layer was dried over Na.sub.2SO.sub.4,
concentrated to give the title compound (7.5 g, 87%). LC-MS (+ESI)
M+H: 338.3.
##STR00404##
Step 2: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4--
c]pyridin-5-yl)propanoate
[0835] To a stirred suspension of Zinc powder (2.3 g, 11.83 mmole)
in DMF (20 mL) was added iodine (0.3 g, 1.18 mmole). After stirring
for 10 minutes, methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.67 g, 14.2
mmole) was added, followed by iodine (0.3 g, 1.18 mmole). The
resulting mixture was stirred for 2 h. The mixture was then added
to the mixture of
5-bromo-1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (4.0 g, 11.83
mmole), S-Phos (0.24 g, 0.6 mmole), and Pd.sub.2(dba).sub.3 (0.21
g, 0.23 mmole) in DMF (10 mL). After the addition was completed,
the reaction mixture was heated to 40.degree. C. in 16 h. The
reaction mixture was cooled, diluted with EtOAc, filtered through
the pad of Celite. The filtrate was concentrated to dryness, and
purified by ISCO (0-50% EtOAc/Hexanes) to give the title compound
(5.14 g, 94%). LC-MS (+ESI) M+H: 461.3.
##STR00405##
Step 3: Synthesis of tert-butyl
(S)-(1-hydroxy-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)propa-
n-2-yl)carbamate
[0836] To a stirred solution of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4--
c]pyridin-5-yl)propanoate (4.5 g, 9.77 mmole) in EtOH (40 mL) at
0.degree. C. was added NaBH.sub.4 (1.1 g, 29.31 mmole) in single
portion. After the reaction was completed, the reaction was
continued to stir for 4 h at 0.degree. C., then slowly quenched
with saturated aqueous NH.sub.4Cl, diluted with H.sub.2O, extracted
with DCM (3.times.). The extracts were dried over Na.sub.2SO.sub.4,
concentrated and purified by ISCO (50% EtOAc/Hexanes) to give the
title compound (1.34 g, 31.7%). LC-MS (+ESI) M+H: 433.2.
##STR00406##
Step 4: Synthesis of tert-butyl
(S)-(1-(1,3-dioxoisoindolin-2-yl)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c-
]pyridin-5-yl)propan-2-yl)carbamate
[0837] To a stirred mixture of tert-butyl
(S)-(1-hydroxy-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)propa-
n-2-yl)carbamate (1.3 g, 3 mmole), triphenylphosphine (0.95 g, 3.6
mmole), and phthamide (0.53 g, 3.6 mmole) in THE (30 mL) at
0.degree. C. was added DIAD (0.73 g, 3.6 mmole) dropwise. After the
addition was completed, the mixture was stirred at RT for 16 h. The
mixture was concentrated, and purified by ISCO (50% EtOAc/Hexanes)
to give the title compound (1.15 g, 68.4%). LC-MS (+ESI) M+H:
562.2.
##STR00407##
Step 5: Synthesis of
(S)-2-(2-amino-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)propy-
l)isoindoline-1,3-dione hydrochloride
[0838] To a stirred solution of tert-butyl
(S)-(1-(1,3-dioxoisoindolin-2-yl)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c-
]pyridin-5-yl)propan-2-yl)carbamate (1.15 g, 2.04 mmole) in MeOH
(20 mL) was added 4M HCl in p-dioxane (4 mL). After the addition,
the reaction mixture was stirred for 4 h at 50.degree. C. The
reaction mixture was cooled, concentrated to dryness to give the
title compound (1.35 g, 100%). LC-MS (+ESI) M+H: 462.2.
##STR00408##
Step 6: Synthesis of
(S)-2-(2-(dimethylamino)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin--
5-yl)propyl)isoindoline-1,3-dione
[0839] To a stirred solution of
(S)-2-(2-amino-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)propy-
l)isoindoline-1,3-dione hydrochloride (1.35 g, 2.52 mmole) in
MeCN/H.sub.2O (10/1, 22 mL) was added 37% CHO (1.02 mL, 12.6
mmole), NaCNBH.sub.3 (0.5 g, 7.6 mmole). After stirring for 10
minutes, HOAc (0.73 mL, 12.6 mmole) was added. The reaction mixture
was stirred for 30 minutes, DCM was added and the layers were
separated. The organic layer was dried over Na.sub.2SO.sub.4,
concentrated to give the title compound (0.95 g, 77%). LC-MS (+ESI)
M+H: 490.2.
##STR00409##
Step 7: Synthesis of
(S)--N2,N2-dimethyl-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-
propane-1,2-diamine
[0840] A mixture of
(S)-2-(2-(dimethylamino)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin--
5-yl)propyl)isoindoline-1,3-dione (0.95 g, 1.94 mmole) and
hydrazine (0.8 mL, 12.6 mmole) in EtOH (30 mL) was heated to
90.degree. C. in 2 h. The reaction mixture was cooled, the solid
was filtered off, washed with EtOH. The filtrate was concentrated,
and purified by ISCO (0-15% MeOH/DCM in 1% NH.sub.4OH) to give the
title compound (0.34 g, 50%). LC-MS (+ESI) M+H: 360.2.
##STR00410##
Step 8: Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4--
c]pyridin-5-yl)propyl)-2-methyl-2-phenylevelopropane-1-carboxamide
[0841] A mixture of
(S)--N2,N2-dimethyl-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-
propane-1,2-diamine (0.07 g, 0.19 mmole) and
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.05 g, 0.19
mmole) in THE (2 mL) was stirred at RT for 16 h. The mixture was
concentrated to dryness and purified by ISCO (0-15% MeOH/DCM) to
give the title compound (0.1 g, 100%). LC-MS (+ESI) M+H: 518.2.
##STR00411##
Step 9: Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(1H-pyrazolo[3,4-c]pyridin-5-yl)prop-
yl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound 63)
[0842] A mixture of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(1-(phenylsulfonyl)-1H-pyrazolo[3,4--
c]pyridin-5-yl)propyl)-2-methyl-2-phenylcyclopropane-1-carboxamide
(0.1 g, 0.19 mmole) and K.sub.2CO.sub.3 in MeOH (3 mL) was heated
to 55.degree. C. in 1 h. The reaction mixture was cooled,
concentrated. H.sub.2O was added, extracted with DCM (3.times.).
The combined extracts were dried over Na.sub.2SO.sub.4,
concentrated, and purified by preparative reverse phase HPLC. The
pure fractions were concentrated to dryness to give the title
compound as mono TFA salt (0.021 g, 23%). LC-MS (+ESI) M+H: 378.2.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 13.58-13.81 (m, 1H)
9.45-9.68 (m, 1H) 9.06 (s, 1H) 8.44 (t, J=5.75 Hz, 1H) 8.25 (s, 1H)
7.79 (d, J=0.73 Hz, 1H) 7.24-7.34 (m, 4H) 7.15-7.23 (m, 1H)
3.84-3.90 (m, 2H) 3.39 (br d, J=5.62 Hz, 1H) 3.27-3.36 (m, 2H) 3.16
(dd, J=14.67, 7.83 Hz, 1H) 2.90 (s, 6H) 1.83 (t, J=7.09 Hz, 1H)
1.36 (s, 3H) 1.27 (d, J=7.09 Hz, 2H).
Example B64
##STR00412##
[0843] Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)prop-
yl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound B-64)
(RM0001450)
##STR00413##
[0844] Step 1: Synthesis of
5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine
[0845] A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (5 g, 25.25
mmole), DHP (4.8 g, 76 mmole), and PPTS (0.5 g, 2.5 mmole) in
DCM/MeCN (1:1, 80 mL) was stirred at RT for 24 h. H.sub.2O was
added, extracted with DCM (3.times.). The combined extracts were
dried over Na.sub.2SO.sub.4, concentrated and purified by ISCO (20%
EtOAc/Hexanes) to give the title compound (7.9 g, 100%). LC-MS
(+ESI) M+H: 282.1.
##STR00414##
Step 2: Synthesis of methyl
(2S)-2-((tert-butoxycarbonyl)amino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-py-
razolo[3,4-b]pyridin-5-yl)propanoate
[0846] To a stirred suspension of Zinc powder (2.1 g, 31.9 mmole)
in DMF (20 mL) was added iodine (0.27 g, 1.06 mmole). After
stirring for 10 minutes, methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.2 g, 12.76
mmole) was added, followed by iodine (0.27 g, 1.06 mmole). The
resulting mixture was stirred for 2 h. The mixture was then added
to the mixture of
5-bromo-1-(phenylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (3.0 g, 10.63
mmole), S-Phos (0.46 g, 1.06 mmole), and Pd.sub.2(dba).sub.3 (0.48
g, 0.53 mmole) in DMF (10 mL). After the addition was completed,
the reaction mixture was heated to 50.degree. C. in 16 h. The
reaction mixture was cooled, diluted with EtOAc, filtered through
the pad of Celite. The filtrate was concentrated to dryness, and
purified by ISCO (0-50% EtOAc/Hexanes) to give the title compound
(1.68 g, 39%). LC-MS (+ESI) M+H: 405.2.
##STR00415##
Step 3: Synthesis of tert-butyl
((2S)-1-hydroxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-
-5-yl)propan-2-yl)carbamate
[0847] To a stirred solution of methyl
(2S)-2-((tert-butoxycarbonyl)amino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-py-
razolo[3,4-b]pyridin-5-yl)propanoate (1.68 g, 4.15 mmole) in THE
(20 mL) was added 4M LiBH.sub.4 in THE (1.5 mL, 6.23 mmole)
dropwise at RT. After the addition was completed, the reaction
mixture was stirred for 2 h. The reaction mixture was cooled in an
ice bath, and slowly quenched with saturated aqueous NH.sub.4Cl,
extracted with EtOAc (3.times.). The combined extracts were dried
over Na.sub.2SO.sub.4, concentrated and purified by ISCO (60%
EtOAc/Hexanes) to give the title compound (0.52 g, 33%). LC-MS
(+ESI) M+H: 377.2.
##STR00416##
Step 4: Synthesis of tert-butyl
((2S)-1-(1,3-dioxoisoindolin-2-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-b]pyridin-5-yl)propan-2-yl)carbamate
[0848] To a stirred mixture of tert-butyl
((2S)-1-hydroxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-
-5-yl)propan-2-yl)carbamate (0.51 g, 1.35 mmole),
triphenylphosphine (0.5 g, 1.9 mmole), and phthamide (0.3 g, 2.03
mmole) in THE (10 mL) at 0.degree. C. was added DIAD (0.38 g, 1.9
mmole) dropwise. After the addition was completed, the mixture was
stirred at RT for 16 h. The mixture was concentrated, and purified
by ISCO (20-70% EtOAc/Hexanes) to give the title compound (0.68 g,
100%). LC-MS (+ESI) M+H: 506.2.
##STR00417##
Step 5: Synthesis of
(S)-2-(2-amino-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)propyl)isoindoline-1,3-d-
ione di-hydrochloride
[0849] To a stirred mixture of tert-butyl
((2S)-1-(1,3-dioxoisoindolin-2-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-b]pyridin-5-yl)propan-2-yl)carbamate (0.68 g, 1.36 mmole)
in MeOH (10 mL) was added 4M HCl in p-dioxane (3.5 mL, 13.6 mmole).
After the addition was completed, the reaction mixture was stirred
at RT for 16 h, concentrated to dryness. EtOAc was added, the
precipitated solid was collected, washed EtOAc, dried to give the
title compound (0.43 g, 80%). LC-MS (+ESI) M+H: 322.1.
##STR00418##
Step 6: Synthesis of
(S)-2-(2-(dimethylamino)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)propyl)isoindo-
line-1,3-dione
[0850] The title compound (0.097 g, 100%) was prepared in the same
method as Step 6 of Example 63. LC-MS (+ESI) M+H: 350.1
##STR00419##
Step 7: Synthesis of
(S)--N2,N2-dimethyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)propane-1,2-diamine
[0851] The title compound (0.029 g, 47%) was prepared in the same
method as Step 7 of Example B63. LC-MS (+ESI) M+H: 220.2
##STR00420##
Step 8: Synthesis of
(1R,2R)--N--((S)-2-(dimethylamino)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)prop-
yl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound B-64)
[0852] A mixture of
(S)--N2,N2-dimethyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)propane-1,2-diamine
(0.029 g, 0.2 mmole) and 2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (0.038 g, 0.2
mmole) in DMF (1 mL) was stirred at RT for 1 h. The reaction
mixture was concentrated to remove the excess DMF, purified by
preparative reverse phase HPLC. The pure fractions were
concentrated to minimal H.sub.2O, neutralized by saturated aqueous
NaHCO.sub.3, extracted with DCM (3.times.). The combined extracts
were dried over Na.sub.2SO.sub.4, concentrated, and co-evaporated
with MTBE to give the title compound (0.015 g, 29%). LC-MS (+ESI)
M+H: 378.2. H NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.42 (d,
J=1.96 Hz, 1H), 8.11 (d, J=1.96 Hz, 1H), 8.04 (s, 1H), 7.21-7.27
(m, 4H), 7.10-7.20 (m, 1H), 3.31-3.41 (m, 2H), 2.99-3.12 (m, 2H),
2.66-2.80 (m, 1H), 2.41 (s, 6H), 1.80 (dd, J=8.31, 5.87 Hz, 1H),
1.38 (s, 3H), 1.29-1.32 (m, 1H), 1.21-1.26 (m, 1H).
Example B65
##STR00421##
[0853] Synthesis of
4-chloro-3-((S)-2-(dimethylamino)-3-((1S,2S)-2-methyl-2-phenylcyclopropan-
e-1-carboxamido)propyl)-N-methylbenzamide (Compound B-65)
[0854]
4-chloro-3-((S)-2-(dimethylamino)-3-((1S,2S)-2-methyl-2-phenylcyclo-
propane-1-carboxamido)propyl)-N-methylbenzamide is synthesized
according to the general procedure using
(S)-3-(3-amino-2-(dimethylamino)propyl)-4-chloro-N-methylbenzamide
and 2,5-dioxopyrrolidin-1-yl
(1S,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate as the starting
materials. 428.2 [M].sup.+.
Example B66
##STR00422##
[0855] Synthesis of
(1R,2R)--N--(((S)-8-chloro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinol-
in-3-yl)methyl)-2-methyl-2-phenylcyclopropane-1-carboxamide
(Compound B-66)
[0856] To a stirred solution of
(S)-3-(aminomethyl)-8-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol
(16.5 mg, 0.07 mmol, 1 equiv) in dry DMF (2 mL) was added
2,5-dioxopyrrolidin-1-yl
(1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylate (24 mg, 0.09
mmol, 1.2 equiv). After 2 h, the solution was concentrated. The
residue was purified by flash column chromatography over silica gel
(0-10% MeOH in CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a
white solid (15.2 mg, 56% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.01 (s, 1H), 7.17-7.36 (m, 6H), 6.82-6.91 (m, 2H),
6.24-6.38 (m, 1H), 3.95 (d, J=16.87 Hz, 1H), 3.60-3.72 (m, 1H),
3.36-3.57 (m, 3H), 2.83-3.05 (m, 11H), 2.65-2.78 (m, 2H), 2.36-2.49
(m, 3H), 1.75-1.78 (m, 1H), 1.34-1.61 (m, 6H). LCMS: 385.2
[M].sup.+.
Example B67
##STR00423##
[0857] Synthesis of
3-chloro-4-((S)-2-(dimethylamino)-3-((1S,2S)-2-methyl-2-phenylcyclopropan-
e-1-carboxamido)propyl)-N-methylbenzamide (Compound B-67)
[0858] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-chloro-N-methylbenzamide
(21.7 mg, 0.08 mmol, 1 equiv) in dry DMF (1 mL) was added
2,5-dioxopyrrolidin-1-yl
(1S,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (24 mg, 0.09
mmol, 1.2 equiv). After 3 h, the solution was concentrated. The
residue was purified by flash column chromatography over silica gel
(0-10% MeOH in CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a
white solid (15.2 mg, 56% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.77 (s, 1H), 7.53 (dd, J=7.95, 1.83 Hz, 1H), 7.18-7.35 (m,
6H), 6.89 (br d, J=4.65 Hz, 1H), 6.51 (br d, J=6.85 Hz, 1H),
3.38-3.39 (m, 1H), 3.34-3.54 (m, 1 H), 3.12-3.27 (m, 1H), 2.88-3.07
(m, 6H), 2.37-2.56 (m, 6H), 1.65-1.77 (m, 1H), 1.51-1.56 (m, 2H),
1.34-1.50 (m, 3H). LCMS: 428.2 [M].sup.+.
Example B68
##STR00424##
[0859] Synthesis of
3-chloro-N-methyl-4-((S)-3-((1S,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)-2-(pyrrolidin-1-yl)propyl)benzamide (Compound B-68)
[0860] To a stirred solution of
(S)-4-(3-amino-2-(pyrrolidin-1-yl)propyl)-3-chloro-N-methylbenzamide
(15 mg, 0.05 mmol, 1 equiv) in dry DMF (1 mL) was added
2,5-dioxopyrrolidin-1-yl
(1S,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (16 mg, 0.06
mmol, 1.2 equiv). After 2 h, the solution was concentrated. The
residue was purified by flash column chromatography over silica gel
(0-10% MeOH in CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a
white solid (15.4 mg, 67% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.77-7.80 (m, 1H), 7.54 (dd, J=7.83, 1.71 Hz, 1H),
7.21-7.37 (m, 8H), 6.54-6.66 (m, 1H), 6.47 (br s, 1H), 3.14-3.38
(m, 3H), 2.90-3.00 (m, 6H), 2.81 (br s, 2H), 2.62-2.78 (m, 4H),
1.84 (br s, 5H), 1.66-1.81 (m, 2H), 1.33-1.55 (m, 4H), 1.23 (t,
J=7.09 Hz, 2H). LCMS: 454.2 [M].sup.+.
Example B69
##STR00425##
[0861] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-phenylcyclopropane-1-carboxamido)pr-
opyl)-2-fluoro-N-methylbenzamide (Compound B-69)
[0862] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (27.5 mg, 0.11 mmol, 1 equiv) in dry DMF (2 mL) was added
EDCI (33 mg, 0.17 mmol, 1.5 equiv), HOBt (23 mg, 0.17 mmol, 1.5
equiv), (1R,2S)-2-phenylcyclopropane-1-carboxylic acid (20 mg, 0.12
mmol, 1.1 equiv), and DIPEA (115 .mu.L, 0.66 mmol, 6 equiv). After
4 h, the solution was diluted with water and extracted with EtOAc.
The combined organic layers were washed with aq. NaHCO.sub.3 and
brine, dried over anhydrous sodium sulfate, and concentrated. The
residue was purified by flash column chromatography over silica gel
(0-15% MeOH in CH.sub.2Cl.sub.2) to afford a white solid (9.9 mg,
23% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84-7.95 (m,
1H), 7.21 (s, 1H), 7.06-7.17 (m, 4H), 6.86 (d, J=7.83 Hz, 1H), 6.72
(br d, J=12.96 Hz, 1H), 3.01-3.17 (m, 1H), 2.88-3.00 (m, 3H),
2.64-2.85 (m, 2H), 2.40-2.48 (m, 1H), 2.32-2.39 (m, 1H), 2.31-2.39
(m, 1H), 2.14-2.25 (m, 5H), 1.84-1.93 (m, 3H), 1.51-1.63 (m, 1H).
LCMS: 398.2 [M].sup.+.
Example B70
##STR00426##
[0863] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2R)-2-phenylcyclopropane-1-carboxamido)pr-
opyl)-2-fluoro-N-methylbenzamide (Compound B-70)
[0864] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F) (57 mg, 0.23 mmol, 1 equiv) in dry DMF (2 mL) was added
EDCI (67 mg, 0.35 mmol, 1.5 equiv), HOBt (47 mg, 0.35 mmol, 1.5
equiv), (1R,2R)-2-phenylcyclopropane-1-carboxylic acid (40 mg, 0.25
mmol, 1.1 equiv), and DIPEA (240 .mu.L, 1.38 mmol, 6 equiv). After
4 h, the solution was diluted with water and extracted with EtOAc.
The combined organic layers were washed with aq. NaHCO.sub.3 and
brine, dried over anhydrous sodium sulfate, and concentrated. The
residue was purified by flash column chromatography over silica gel
(0-15% MeOH in CH.sub.2Cl.sub.2) to afford a white solid (11.7 mg,
13% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.94 (td,
J=8.13, 2.08 Hz, 1H), 7.06-7.21 (m, 4H), 6.93-7.02 (m, 3H), 6.84
(d, J=12.72 Hz, 1H), 6.62 (br d, J=6.36 Hz, 1H), 6.41 (br s, 1H),
3.26-3.43 (m, 1H), 2.73-2.97 (m, 6H), 2.24-2.39 (m, 8H), 1.86-1.90
(m, 1H), 1.45-1.60 (m, 2H), 1.02-1.28 (m, 1H). LCMS: 398.3
[M].sup.+.
Example B71
##STR00427##
[0865] Synthesis of
(1S,2S)--N--(((S)-7-hydroxy-2-methyl-1.2.3.4-tetrahydroisoguinolin-3-yl)m-
ethyl)-2-methyl-2-phenylcyclopropane-1-carboxamide (Compound
B-71)
[0866] To a stirred solution of
(S)-3-(aminomethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol (22
mg, 0.12 mmol, 1 equiv) in dry DMF (1 mL) was added
2,5-dioxopyrrolidin-1-yl
(1S,2S)-2-methyl-2-phenylcyclopropane-1-carboxylate (35 mg, 1.3
mmol, 1.09 equiv). After 2 h, the solution diluted in EtOAc, washed
with water, separated, and dried over MgSO.sub.4. The residue was
purified by flash column chromatography over silica gel (0-100%
EtOAc in hexanes then 0-10% MeOH in CH.sub.2Cl.sub.2 with 1%
NH.sub.4OH) to afford a white solid (28.4 mg, 68% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.07-7.23 (m, 6H), 6.81 (d,
J=8.31 Hz, 2H), 6.57 (dd, J=8.31, 2.45 Hz, 1H), 6.32 (d, J=2.20 Hz,
1H), 3.70 (q, J=15.73 Hz, 2H), 3.56 (dt, J=14.31, 5.07 Hz, 1H),
2.97-3.06 (m, 1H), 2.57-2.74 (m, 2H), 2.40 (s, 3H), 1.68-1.83 (m,
2H), 1.31-1.45 (m, 4H), 1.26 (dd, J=8.31, 4.65 Hz, 1H). LCMS: 351.2
[M].sup.+.
Example B72
##STR00428##
[0867] Synthesis of
4-((S)-2-(dimethylamino)-3-((1R,2S)-2-methyl-2-phenylcyclopropane-1-carbo-
xamido)propyl)-2-fluoro-N-(2,2,2-trifluoroethyl)benzamide (Compound
B-72)
[0868] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-(2,2,2-trifluoroethyl)-
benzamide (117.2 mg, 0.26 mmol, 1 equiv) in 9:1 CH.sub.3CN:
H.sub.2O (2 mL) at 0.degree. C. was added NaCNBH.sub.4 (82 mg, 1.3
mmol, 5 equiv) and 37% formaldehyde (75 .mu.L, 0.78 mmol, 3 equiv).
After 10 min, HOAc (75 ul, 1.3 mmol, 5 equiv) was added and the
solution was allowed to warm to rt for 4 h. Ethyl acetate (10 mL)
was added and the solution was washed with aq. NaHCO.sub.3 and
brine, dried over anhydrous sodium sulfate, and concentrated. The
residue was purified by flash column chromatography over silica gel
(0-15% MeOH in CH.sub.2Cl.sub.2) to afford a white solid (32.3 mg,
56% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.67 (t,
J=7.83 Hz, 1H), 7.02-7.29 (m, 7H), 4.09 (q, J=9.29 Hz, 2H),
3.01-3.13 (m, 2H), 2.86-3.00 (m, 2H), 2.47-2.59 (m, 1H), 2.34-2.47
(m, 6H), 1.78-1.89 (m, 1H), 1.62-1.75 (m, 1H), 1.37-1.46 (m, 3H),
0.99-1.11 (m, 1H). LCMS: 480.2 [M].sup.+.
C. Synthesis of Compounds Having the Structure of Formula (I-C)
[0869] Representative Compounds having the structure of Formula
(I-C) can be synthesized by using the general synthetic procedures
set forth in Schemes C1.
##STR00429## ##STR00430##
Synthesis of Intermediates
Synthesis of (S)-4-(3-amino-2-(dimethylamino)
propyl)-3,5-dimethylphenol (Int-1G)
##STR00431## ##STR00432##
[0870] Step 1: Preparation of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)propan-
oate (Int-1A)
[0871] To a stirred suspension of Zinc powder (7.9 g, 120.92 mmole)
in DMF (40 mL) was added iodine (1.02 g, 4.03 mmole) After stirring
for 10 minutes, methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (19.9 g, 60.46
mmole) was added, followed by another iodine (1.02 g, 4.03 mmole).
The resulting mixture was stirred at RT for 2 h. The mixture was
then added to a stirred mixture of 4-bromo-3,5-dimethylphenol (10
g, 40.31 mmole), S-Phos (1.65 g, 4.03 mmole), and
Pd.sub.2(dba).sub.3 in DMF (20 mL). The reaction mixture was then
heated to 60.degree. C. for 16 h, cooled to RT, diluted with EtOAc,
filtered the a pad of Celite, washed with EtOAc. The filtrate was
concentrated to dryness, and purified by ISCO (0-40% EtOAc/hexanes)
to give Int-1A (11.5 g, 88%). LC-MS (+ESI) M+H: 346.2.
Step 2: Preparation of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-((tert-butyldimethylsilyl)
oxy)-2,6-dimethylphenyl)propanoate (Int-1B)
[0872] To a stirred mixture of Int-1A (11.5 g, 35.58 mmole) and
imidazole (3.9 g, 56.94 mmole) in DCM (100 mL) was added TBS-Cl
(8.1 g, 53.38 mmole). After the addition was completed, the
reaction mixture was stirred for 16 h at RT. H.sub.2O was added and
the layers were separated. The organic layer was dried over
Na.sub.2SO.sub.4, concentrated and purified by ISCO (0-20%
etOAc/hexanes) to give Int-1B (14 g, 89.9%). LC-MS (+ESI) M+H:
438.2.
Step 3: Preparation of tert-butyl
(S)-(1-(4-((tert-butyldimethylsilyl)oxy)-2,6-dimethylphenyl)-3-hydroxypro-
pan-2-yl)carbamate (Int-1C)
[0873] To a stirred solution of Int-1B (14 g, 31.99 mmole) in THE
(100 mL) was added 4M LiBH.sub.4 in THE (12 mL, 47.98 mmole)
dropwise. After the addition was completed, the reaction mixture
was stirred for 16 h. The mixture was cooled in an ice bath and
slowly quenched with saturated aqueous NH.sub.4Cl. The mixture was
diluted with H.sub.2O, extracted with EtOAc (3.times.). The
combined extracts were dried over Na.sub.2SO.sub.4, concentrated to
dryness to give Int-IC (13.2 g, 95.6%). LC-MS (+ESI) M+Na:
432.1.
Step 4: Preparation of tert-butyl
(S)-(1-(4-((tert-butyldimethylsilyl)oxy)-2,6-dimethylphenyl)-3-(1,3-dioxo-
isoindolin-2-yl)propan-2-yl)carbamate (Int-1D)
[0874] To a stirred mixture of Int-1C (13.2 g, 30.55 mmole),
phthalimide (5.4 g, 36.66 mmole), and PPh.sub.3 (9.62 g, 36.66
mmole) in THE at 0.degree. C. was added DIAD (7.41 g, 36.66 mmole)
dropwise. After the addition was completed, the reaction mixture
was a stirred at RT for 16 h. The mixture was concentrated to
dryness, and purified by ISCO (0-40% EtOAc/Hexanes) to give Int-1D
(14.5 g, 88.1%). LC-MS (+ESI) M+Na: 561.2.
Step 5: Preparation of
(S)-2-(2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propyl)isoindoline-1,3-dio-
ne hydrochloride (Int-1E)
[0875] To a stirred solution of Int-1D (14.5 g, 26.91 mmole) in
methanol (150 mL) at 0.degree. C. was added 4M HCl (34 mL 269.1
mmole). The reaction mixture was stirred at 80.degree. C. for 1 h,
cooled to RT, concentrated to dryness, triturated in EtOAc, the
solid (9.3 g, 96%) was collected by filtration, washed with EtOAc,
dried and used in the next step. LC-MS (+ESI) M+H: 325.1.
Step 6: Preparation of
(S)-2-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)
isoindoline-1,3-dione (Int-1F)
[0876] To a stirred solution of Int-1E (9.5 g, 26.33 mmole) in
MeCN/H.sub.2O (10:1, 220 mL) was added 37% formaldehyde (12.6 mL,
157.96 mmole). The mixture was stirred for 30 minutes, then
NaCNBH.sub.3 (4.96 g, 78.98 mmole) was added. The reaction mixture
was stirred for 30 minutes, slowly quenched with saturated aqueous
NH.sub.4Cl, extracted with EtOAc (3.times.). The combined extracts
were dried over Na.sub.2SO.sub.4, concentrated and purified by ISCO
(0-10% MeOH/DCM) to give Int-1F (9.08, 100%). LC-MS (+ESI) M+H:
353.2.
Step 7: Preparation of
(S)-4-(3-amino-2-(dimethylamino)propyl)-3,5-dimethylphenol
(Int-1G)
[0877] To a stirred solution of Int-1F (9.08 g, 25.75 mmole) in
EtOH (100 mL) was added hydrazine (8.3 mL, 128.76 mmole). The
reaction mixture was stirred at 90.degree. C. for 2 h, cooled to
RT, filtered off the solid, washed with EtOH. The filtrate was
concentrated to dryness, and purified by ISCO (15% MeOH/DCM in 1%
NH.sub.4OH) to give Int-1G (3.0 g, 52.2%). LC-MS (+ESI) M+H:
223.1.
Synthesis of(S)-4-(3-Amino-2-(dimethylamino)propyl)-3-chlorophenol
(Int-2H)
##STR00433## ##STR00434##
[0878] Step 1: Synthesis of
4-{[tert-Butyl(dimethyl)silyl]oxy}-2-chlorobenzaldehyde
(Int-2A)
[0879] A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32
mmol), tert-butyl(dimethyl)silyl chloride (5.3 g, 35 mmol),
imidazole (2.9 g, 45 mmol) and N,N-dimethylaminopyridine (10 mg) in
N,N-dimethylformamide (40 mL) was stirred at room temperature for
65 hours. The solvent was removed in vacuo and the residue was
partitioned between ethyl acetate (200 mL) and water (100 mL). The
organic phase was separated, washed with brine (3.times.50 mL),
dried over sodium sulfate and concentrated in vacuo. Purification
by ISCO, eluting with ethyl acetate-Hexanes (0-15%), afforded the
title compound as a colorless oil (3.3 g, 39%), also recovered
starting material (3 g). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.:
0.27 (s, 6H), 1.0 (s, 9H), 6.80 (dd, J=2.0, 8.4 Hz, 1H), 6.87 (d,
J=2.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 10.34 (1H, s).
Step 2: Synthesis of methyl
(Z)-2-((tert-butoxycarbonyl)amino)-3-(4-((tert-butyldimethylsilyl)oxy)-2--
chlorophenyl)acrylate (Int-2B)
[0880] 1.76 ml (14 mmol) of N,N,N,N-tetramethylguanidine was
dropwise added to a solution of 3.3 g (12.2 mmol) of Int-2A and 4 g
(13.4 mmol) of methyl
[(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate in 45 ml
of anhydrous tetrahydrofuran at -78.degree. C. over 20 min. After
stirring for 1 h at -78.degree. C., the reaction mixture was warmed
to RT overnight. The mixture is mixed with 40 ml of water and 200
ml of ethyl acetate. The aqueous layer was further extracted with
ethyl acetate twice (2.times.40 mL). The combined organic phase was
washed with water (30 mL), dried over sodium sulfate and
concentrated. The crude product is purified by ISCO eluting with
ethyl acetate-Hexanes (0-100%) to provide the desired product as a
colorless oil (4.26 g, 79%), LC-MS 464.2 (M+Na). .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta.=0.23 (s, 6H), 0.99 (s, 9H), 1.37 (s, 9H),
3.87 (s, 3H), 6.67-6.76 (m, 1H), 6.91 (m, 1H), 7.41 (s, 1H),
7.55-7.58 m, 1H). By-product (methyl
(Z)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-hydroxyphenyl)acrylate)
(more polar) (0.75 g, 18%): LC-MS 350.1 (M+Na). .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. 1.42 (s, 9H), 3.89 (s, 3H), 6.64-6.66 (m,
1H), 6.84 (brs, 1H), 7.51 (s, 1H), 7.55-7.57 (m, 1H).
Step 3: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-((tert-butyldimethylsilyl)oxy)-2--
chlorophenyl)propanoate (Int-2C)
[0881] A mixture of methyl Int-2B (4.26 g, 9.6 mmol) and
(+)-1,2-bis[(2S,5 S
)-2,5-diethylphospholano]benzene(cyclooctadiene)-rhodium(I)
trifluoromethanesulfonate ([Rh(COD){(S,S)-Et-DuPHOS}] TfO--, 20 mg)
in dry methanol (20 mL) was degassed for 4 times and then placed
under 53 psi of hydrogen and stirred for 4 h at rt. The solution
was concentrated under reduced pressure, and the residue was
purified by ISCO eluting with ethyl acetate-Hexanes (0-100%) to
provide the desired product as a colorless oil (4.27 g, 100%).
LC-MS 466.2 (M+Na). .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.=0.20
(s, 6H), 0.98 (s, 9H), 1.40 (s, 9H), 2.97-3.09 (m, 1H), 3.14-3.25
(m, 1H), 3.71 (s, 3H), 4.53-4.64 (m, 1H), 5.02-5.10 (m, 1H),
6.66-6.69 (m, 1H), 6.87 (m, 1H), 6.97-7.02 (m, 1H).
Step 4: Synthesis of tert-butyl
(S)-(1-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl)-3-hydroxypropan--
2-yl)carbamate (Int-2D)
[0882] To a solution of Int-2C (4.1 g, 9.2 mmol) in dry THE (50 mL)
was added 4 M LiBH.sub.4 in THE solution (4.6 mL, 18.4 mmol) at
0.degree. C. over 10 min, the mixture was then stirred at 0.degree.
C. for 1 h. Then the reaction mixture was stirred at rt overnight
(the reaction progress was monitored by TLC or LC-MS). Then it was
cooled to 0.degree. C., water (5 mL) and then saturated NH.sub.4Cl
sol. (10 mL) were added dropwise (slow addition is necessary). Then
water (50 mL) and ethyl acetate (200 mL) were added, the aqueous
layer was separated and extracted further with ethyl acetate (100
mL). The combined organic layers were washed with water (40 mL),
and then dried over anhydrous Na.sub.2SO.sub.4. After filtration
and concentration, the crude product was put in lyophilization
overnight and used in the next step without further
purification.
Step 5: Synthesis of tert-butyl
(S)-(1-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl)-3-(1,3-dioxoisoi-
ndolin-2-yl)propan-2-yl)carbamate (Int-2E
[0883] To a mixture of Int-2D (crude, 3.84 g, 9.23 mmol),
triphenylphospine (2.54 g, 9.69 mmol, 1.05 eq), and phthalimide
(1.43 g, 9.69 mmol) in anhydrous THE at 0.degree. C. under
nitrogen, was injected DIAD (1.91 mL, 9.69 mmol) dropwise. The
reaction mixture was then stirred from 0.degree. C. to room
temperature overnight. The crude reaction mixture was mixed with
silica gel (40 g), concentrated to dryness on rota vapor, purified
on 120 g silica gel column, eluted with 0-30% EtOAc/hexanes to
provide the desired product. 4.15 g white solid, 82%. LCMS (+ESI)
M+Na+=567.2. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.85
(dd, J=5.26, 3.06 Hz, 2H) 7.68-7.75 (m, 2H) 7.15 (br d, J=8.31 Hz,
1H) 6.87 (d, J=2.45 Hz, 1H) 6.71 (dd, J=8.31, 2.20 Hz, 1H) 4.68 (br
d, J=9.54 Hz, 1H) 4.31 (br d, J=8.07 Hz, 1H) 3.72-3.80 (m, 2H)
2.88-2.99 (m, 2H) 1.20 (s, 9H) 0.98 (s, 9H) 0.20 (s, 6H).
Step 6: Synthesis of
(S)-2-(2-amino-3-(2-chloro-4-hydroxyphenyl)propyl)isoindoline-1,3-dione
hydrochloride (Int-2F)
[0884] To a solution of Int-2E (3.00 g, 5.50 mmol) in MeOH (45 mL),
was added 4N HCl in dioxane (13.8 mL). The mixture was heated at
70.degree. C. for an hour. The solvents were evaporated on rota
vapor. The solid residue was treated with ethyl acetate, filtered,
rinsed with ethyl acetate and dried in vacuo to provide the desired
product. 1.75 g white solid, 87%. LCMS (+ESI) M+H.sup.+=331.1.
.sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm 7.84-7.88 (m, 2H)
7.90-7.93 (m, 2H) 7.25 (d, J=8.56 Hz, 1H) 6.90 (d, J=2.45 Hz, 1H)
6.76 (dd, J=8.44, 2.57 Hz, 1H) 4.93-4.97 (m, 1H) 3.85-4.00 (m, 3H)
3.00-3.15 (m, 2H).
Step 7: Synthesis of
(S)-2-(3-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl)-2-(dimethylami-
no)propyl)isoindoline-1,3-dione (Int-2G)
[0885] To a suspension of Int-2F (1.75 g, 4.80 mmol) in CH.sub.3CN
(30 mL) and water (3 mL), was added 37% formaldehyde (0.98 g, 12.0
mmol), sodium cyanoborohydride (0.90 g, 14.4 mmol) and HOAc (0.86
mL). The mixture was stirred at room temperature for an hour. The
reaction mixture was then partitioned between ethyl acetate (100
mL) and saturated sodium bicarbonate (100 mL). Separated layers,
extracted aqueous was extracted with more ethyl acetate (50 mL).
The combined organic layers were dried over MgSO.sub.4, filtered
and concentrated on rota vapor. The crude material was purified on
80 g silica gel column, eluted with 0-10% MeOH/DCM to provide the
desired product, 1.35 g white solid, 78%. LCMS (+ESI)
M+H.sup.+=359.1. .sup.1H NMR (400 MHz, MeOH-d.sub.4) S ppm
7.72-7.82 (m, 4H) 7.09-7.15 (m, 1H) 6.74-6.79 (m, 1H) 6.59-6.66 (m,
1H) 3.82-3.95 (m, 1H) 3.43-3.51 (m, 2H) 3.32 (s, 1H) 3.02 (br dd,
J=13.57, 4.04 Hz, 1H) 2.56 (br dd, J=13.82, 8.93, 1H) 2.35 (s,
6H).
Step 8: Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-chlorophenol (Int-2H)
[0886] To a solution of Int-2G (1.35 g, 3.76 mmol) in 95% ethanol
(30 mL), was added hydrazine hydrate (80%) (750 mg, 19 mmol). The
mixture was heated at 70.degree. C. for 2 hours. The crude reaction
mixture was diluted with MeOH and mixed with silica gel (.about.20
g), concentrated to dryness on rota vapor, and then purified on 24
g silica gel column, eluted with 0-15% MeOH in DCM with 1%
NH.sub.4OH to provide the desired product, 634 mg white solid, 74%.
LCMS (+ESI) M+H.sup.+=229.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.07 (d, J=8.56 Hz, 1H) 6.77 (d, J=2.45 Hz, 1H) 6.67
(dd, J=8.31, 2.45 Hz, 1H) 2.83 (dd, J=13.33, 3.79 Hz, 1H) 2.52-2.61
(m, 2H) 2.29-2.38 (m, 2H) 2.27 (s, 6H).
Synthesis of (S)-4-(3-amino-2-(dimethylamino)propyl)-2-chlorophenol
(Int-3H)
##STR00435##
[0888] Int-3H was prepared in the same method as that used for
making Int-2H by using appropriate intermediates.
Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F)
##STR00436## ##STR00437##
[0889] Step 1: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(methylcarbamoyl)phenyl)-
propanoate (Int-4A)
[0890] To a suspension of zinc (2.97 g, 45.2 mmol) in DMF (15 mL)
under nitrogen atmosphere, was injected a solution of iodine (230
mg, 0.906 mmol) in DMF (2 mL). The mixture was stirred at room
temperature for 5 minutes. A solution of methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4.46 g, 13.5
mmol) in DMF (10 mL) was injected followed by another portion of
iodine (230 mg, 0.906 mmol) in DMF (2 mL), stirred for 30 minutes.
A mixture of N-methyl 4-bromo-2-fluorobenzamide (3.00 g, 12.9
mmol), Pd.sub.2(dba).sub.3 (591 mg, 0.646 mmol) and Sphos (564 mg,
1.29 mmol) in DMF (15 mL) was injected. The reaction was then
heated at 55.degree. C. overnight. The reaction was cooled down to
room temperature, quenched with water (50 mL), filtered through a
celite pad, rinsed with ethyl acetate (300 mL), extracted with
water (3.times.200 mL) followed by brine (200 mL). The organic
layer was separated, dried over MgSO.sub.4, filtered and
concentrated on rota-vapor. The residue was purified on 220 g
silica gel column eluting with gradient of 0-100% EtOAc/Hexanes to
provide the desired product as a white solid (3.65 g, 80%). LCMS
(+ESI) M+Na+=377.1. .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 8.13
(br s, 1H) 7.55 (t, J=7.83 Hz, 1H) 7.33 (br d, J=8.07 Hz, 1H)
7.11-7.22 (m, 2H) 4.17-4.29 (m, 1H) 3.64 (s, 3H) 3.07 (br dd,
J=13.69, 4.89 Hz, 1H) 2.90 (dd, J=13.69, 10.52 Hz, 1H) 2.77 (d,
J=4.65 Hz, 3H) 1.33 (s, 9H)
Step 2: Synthesis of tert-Butyl
(S)-(1-(3-fluoro-4-(methylcarbamoyl)phenyl)-3-hydroxypropan-2-yl)carbamat-
e (Int-4B)
[0891] To a solution of Int-4A (3.63 g, 10.2 mmol) in THF (100 mL)
at 0.degree. C., lithium boron hydride in THE (4.0 N, 10 mL) was
injected dropwise. The reaction mixture was then stirred from
0.degree. C. to room temperature overnight. The crude reaction
mixture was cooled with ice-water bath, quenched carefully with
saturated NH.sub.4Cl (aq), extracted with ethyl acetate. The
organic layer was separated, dried over MgSO.sub.4, filtered and
concentrated on rota-vapor. The residue was purified on 40 g silica
gel column eluting with gradient of 0-100% EtOAc/Hexanes to provide
the desired product as a white solid (3.10 g, 92%). LCMS (+ESI)
M+Na+=349.1. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.04
(t, J=8.07 Hz, 1H) 7.12 (dd, J=7.95, 1.59 Hz, 1H) 7.01 (d, J=12.96
Hz, 1H) 6.71 (br s, 1H) 4.75 (br s, 1H) 3.81-3.90 (m, 1H) 3.64-3.71
(m, 1H) 3.57 (dt, J=10.58, 5.10 Hz, 1H) 3.03 (dd, J=4.77, 0.86 Hz,
3H) 2.90 (d, J=7.34 Hz, 2H) 2.14 (br s, 1H) 1.41 (s, 9H)
Step 3: Synthesis of tert-Butyl
(S)-(1-(1,3-dioxoisoindolin-2-yl)-3-(3-fluoro-4-(methylcarbamoyl)phenyl)p-
ropan-2-yl)carbamate (Int-4C)
[0892] To a mixture of Int-4B (3.08 g, 9.44 mmol),
triphenylphospine (2.63 g, 9.91 mmol), and phthalimide (1.46 g,
9.91 mmol) in anhydrous THE at 0.degree. C. under nitrogen, was
injected DIAD (1.95 mL, 9.91 mmol) dropwise. The reaction mixture
was then stirred from 0.degree. C. to room temperature overnight.
The precipitate was filtered, rinsed with THE and dried in vacuo to
provide the desired product as a white solid (4.00 g, 93%). LCMS
(+ESI) M+Na+=478.2. .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
8.11-8.19 (m, 1H) 7.79-7.92 (m, 4H) 7.51-7.57 (m, 1H) 7.15 (d,
J=4.65 Hz, 1H) 7.12 (s, 1H) 6.91 (d, J=9.29 Hz, 1H) 4.00 (br d,
J=5.14 Hz, 1H) 3.59-3.69 (m, 2H) 3.32-3.35 (m, 1H) 2.89 (dd,
J=13.94, 4.65 Hz, 1H) 2.75 (d, J=4.65 Hz, 3H) 1.10 (s, 9H)
Step 4: Synthesis of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)-2-fluoro-N-methylbenza-
mide hydrochloride (Int-4D)
[0893] To a suspension of Int-4C (3.99 g, 8.76 mmol) in MeOH (20
mL) and dioxane (20 mL), was added 4N HCl in dioxane (22 mL). The
mixture was stirred at room temperature overnight. The solvents
were evaporated on rota vapor. The solid residue was trituated with
ethyl acetate, filtered, rinsed with ethyl acetate and dried in
vacuo to provide the desired product as a white solid (2.98 g,
87%). LCMS (+ESI) M+H.sup.+=356.1. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 8.27 (br s, 2H) 8.19 (br dd, J=4.16, 2.93 Hz, 1H)
7.83-7.90 (m, 4H) 7.61 (t, J=7.83 Hz, 1H) 7.31 (d, J=11.74 Hz, 1H)
7.25 (dd, J=8.07, 1.22 Hz, 1H) 3.80-3.88 (m, 1H) 3.70-3.80 (m, 1H)
3.65 (dd, J=14.06, 3.79 Hz, 1H) 3.13 (dd, J=14.06, 5.26 Hz, 1H)
2.96 (dd, J=14.18, 8.31 Hz, 1H) 2.77 (d, J=4.65 Hz, 3H)
Step 5: Synthesis of
(S)-4-(2-(dimethylamino)-3-(1,3-dioxoisoindolin-2-yl)propyl)-2-fluoro-N-m-
ethylbenzamide (Int-4E)
[0894] To a suspension of Int-4D (1.62 g, 4.13 mmol) in CH.sub.3CN
(35 mL) and water (3.5 mL), was added 37% formaldehyde (1.99 g,
24.8 mmol), sodium cyanoborohydride (1.05 g, 16.5 mmol). The
mixture was stirred at room temperature for an hour. The reaction
mixture was then partitioned between ethyl acetate (100 mL) and
saturated sodium bicarbonate (100 mL). Separated layers, the
aqueous was extracted with more ethyl acetate (50 mL). The combined
organic layers were dried over MgSO.sub.4, filtered and
concentrated on rota-vapor. The crude material was purified on 40 g
silica gel column eluting with gradient of 0-100% EtOAc/Hexanes to
provide the desired product as a white solid (1.39 g, 88%). LCMS
(+ESI) M+H.sup.+=384.2.
Step 6: Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-fluoro-N-methylbenzamide
(Int-4F)
[0895] To a solution of Int-4E (1.38 g, 3.60 mmol) in 95% ethanol
(30 mL), was added hydrazine hydrate (80%) (1.05 g, 26.6 mmol). The
mixture was heated at 70.degree. C. for 3 hours. The crude reaction
mixture was diluted with MeOH and mixed with silica gel (20 g),
concentrated on rota vapor, and then purified on 24 g silica gel
column eluting with gradient of 0-10% MeOH in DCM with 1%
NH.sub.4OH to provide the desired product as a white solid (0.716
g, 79%). LCMS (+ESI) M+H.sup.+=254.2. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 8.01 (t, J=8.19 Hz, 1H) 7.05 (dd, J=7.95,
1.59 Hz, 1H) 6.91 (dd, J=13.08, 1.35 Hz, 1H) 6.70 (br s, 1H) 3.02
(dd, J=4.77, 0.86 Hz, 3H) 2.93 (dd, J=13.45, 3.42 Hz, 1H) 2.59-2.69
(m, 2H) 2.49-2.57 (m, 1H) 2.30-2.37 (m, 7H).
Synthesis of
(S)-4-(3-amino-2-((cyclopropylmethyl)(methyl)amino)propyl)-2-fluoro-N-met-
hylbenzamide (Int-4H)
##STR00438##
[0896] Step 1:
(S)-4-(2-((cyclopropylmethyl)(methyl)amino)-3-(1,3-dioxoisoindolin-2-yl)p-
ropyl)-2-fluoro-N-methylbenzamide (Int-4G)
[0897] To a suspension of Int-4D (228 mg, 0.582 mmol) in CH.sub.3CN
(5 mL) and water (0.5 mL), was added cyclopropanecarbaldehyde
(0.035 mL, 0.582 mmol). After stirred for 15 minutes at room
temperature, sodium cyanoborohydride (146 mg, 2.33 mmol) was added
and continued to stir for an additional hour. 37% formaldehyde (236
g, 2.91 mmol) was then added and the reaction was stirred at room
temperature for 30 minutes. The reaction mixture was then
partitioned between ethyl acetate (30 mL) and saturated sodium
bicarbonate (30 mL). Separated layers, the aqueous was extracted
with more ethyl acetate (30 mL). The combined organic layers were
dried over MgSO.sub.4, filtered and concentrated on rota-vapor. The
crude material was purified on 12 g silica gel column eluting with
gradient of 0-100% EtOAc/Hexanes to provide the desired product as
a white solid (128 mg, 52%). LCMS (+ESI) M+H.sup.+=424.2,
M+Na.sup.+=446.2.
Step 2:
(S)-4-(3-amino-2-((cyclopropylmethyl)(methyl)aminopropyl)-2-fluoro-
-N-methylbenzamide (Int-4H)
[0898] To a solution of Int-4G (116 mg, 0.274 mmol) in 95% ethanol
(30 mL), was added hydrazine hydrate (80%) (0.080 g, 2.03 mmol).
The mixture was heated at 75.degree. C. for 3 hours. The crude
reaction mixture was diluted with MeOH and mixed with silica gel (4
g), concentrated on rota vapor, and then purified on 4 g silica gel
column eluting with gradient of 0-10% MeOH in DCM with 1%
NH.sub.4OH to provide the desired product as an off-white solid (55
mg, 69%). LCMS (+ESI) M+H.sup.+=294.2.
Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)-N,3,5-trimethylbenzamide
(Int-5H)
##STR00439## ##STR00440##
[0899] Step 1: Synthesis of 4-Bromo-3,5-dimethylbenzoic acid
(Int-5A)
[0900] 4-Bromo-3,5-dimethylbenzonitrile (10 g, 48 mmol) was taken
in ethanol (50 ml) and a solution of potassium hydroxide (13 g in
15 ml water) was added to it. The solution was heated to reflux for
22 hours. After cooling in an ice-bath, it was quenched by slowly
adding 2.5 M sulfuric acid solution. The precipitated solids were
collected by filtration and washed with water. After air-drying,
the solids were taken up in toluene and solvent was removed to get
dry powder. This was dried under vacuum to give the product as a
light brown powder (10.7 g, 98%). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.82 (s, 2H) 2.46-2.52 (m, 6H).
Step 2: Synthesis of 4-Bromo-N,3,5-trimethylbenzamide (Int-5B)
[0901] Int-5A (10.7 g, 46.7 mmol) was taken in dimethylformamide
(150 ml) with methylamine hydrochloride (3.5 g, 51.4 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (9.9
g, 51.4 mmol) and hydroxybenzotriazole (6.9 g, 51.4 mmol). The
solution was cooled in an ice-bath and diisopropylethylamine (18
ml, 100 mmol) was added. After completion of the reaction, it was
diluted with ethyl acetate and washed with dilute sodium
bicarbonate solution. The organic layer was dried and then
concentrated. The residue was purified on Combiflash using
hexanes/ethyl acetate gradient to give the product (8.7 g, 77%) as
a pale white powder. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 7.42-7.48 (m, 2H) 6.37 (br s, 1H) 2.97-3.02 (m, 3H), 2.34-2.48
(m, 6H).
Step 3: Synthesis of Methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(2,6-dimethyl-4-(methylcarbamoyl)phe-
nyl)propanoate (Int-5C)
[0902] To a stirred suspension of Zinc powder (9.4 g, 143 mmol) in
dimethylformamide (50 mL) was added iodine (1.1 g, 4.3 mmol) After
stirring for 10 minutes, methyl
(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (17.1 g, 52
mmol) was added, followed by iodine (1.1 g, 4.3 mmol). The
resulting mixture was stirred at RT for 1 h. The mixture was then
added to a stirred mixture of Int-5B (10.5 g, 43 mmol), S-Phos (1.8
g, 4.3 mmole), and Pd.sub.2(dba).sub.3 (2.0 g, 2.2 mmol) in DMF (20
mL) and then heated to 80.degree. C. for 16 h. After cooling to
room temperature, the suspension was diluted with ethyl acetate and
filtered through packed celite. The filtrate was washed with water
and the organic layer was dried and concentrated to half its
original volume. The precipitated solids were collected by
filtration to give the product as a white powder (6.1 g, 40%). The
filtrate was concentrated, and the residue was purified on
Combiflash using hexanes/ethyl acetate gradient to give additional
product (6.0 g, 38%). Total yield (12.1 g, 78%). .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 7.33 (s, 2H) 6.00-6.16 (m, 1H) 5.05
(br d, J=8.80 Hz, 1H) 4.46 (q, J=8.07 Hz, 1H) 3.56 (s, 3H),
3.02-3.04 (m, 2H), 2.91 (d, J=8.80 Hz, 3H) 2.30 (s, 6H), 1.29 (s,
9H)
Step 4: Synthesis of tert-Butyl
(S)-(1-(2,6-dimethyl-4-(methylcarbamoyl)phenyl)-3-hydroxypropan-2-yl)carb-
amate (Int-5D)
[0903] Int-5C (6.1 g, 16.7 mmol) was taken in tetrahydrofuran (80
ml) and cooled in an ice-bath. A solution of lithium borohydride
(8.4 ml, 4 M in THF, 33.5 mmol) was added slowly to it. The
solution was brought to room temperature and then heated to reflux.
After completion of reaction, it was cooled in an ice-bath and
quenched by adding saturated ammonium chloride solution and then
extracted with ethyl acetate. The organic layer was dried,
concentrated and the residue was purified on Combiflash using
dichloromethane/methanol gradient to give the product (4.6 g, 82%)
as a white powder. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
7.30-7.37 (m, 2H), 6.07 (br s, 1H) 4.83 (br s, 1H) 3.79 (br s, 1H)
3.57-3.62 (m, 1H) 3.42-3.50 (m, 1H) 2.79-2.97 (m, 6H) 2.28-2.35 (m,
6H) 1.31 (br s, 9H).
Step 5: Synthesis of tert-butyl
(S)-(1-(2,6-dimethyl-4-(methylcarbamoyl)phenyl)-3-(1,3-dioxoisoindolin-2--
yl)propan-2-yl)carbamate (Int-5E)
[0904] Int-5D (4.6 g, 13.7 mmol) was dissolved in tetrahydrofuran
(75 ml) and then phthalimide (2.4 g, 16.4 mmol) and
triphenylphosphine (4.3 g, 16.4 mmol) were added. The flask was
flushed with nitrogen and cooled in an ice-bath.
Diisopropylazodicarboxylate (3.3 ml, 17.1 mmol) was added dropwise
and the solution was stirred at room temperature. After completion
of the reaction, the solution was concentrated and the residue was
taken up in ethyl acetate. The precipitated solids were collected
by filtration to give the product as a white powder (5.3 g, 84%).
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 8.29 (br d, J=4.65 Hz,
1H) 7.78-7.90 (m, 4H) 7.43-7.49 (m, 2H) 6.93 (d, J=9.54 Hz, 1H)
3.95-4.19 (m, 1H) 3.76 (dd, J=13.57, 9.90 Hz, 1H) 3.40-3.52 (m, 1H)
2.82-2.90 (m, 2H), 2.75 (d, J=9.54 Hz, 3H), 2.32-2.38 (br, 6H) 1.08
(s, 7H) 0.88 (s, 2H).
Step 6: Synthesis of
(S)-4-(2-amino-3-(1,3-dioxoisoindolin-2-yl)propyl)-N,3.5-trimethylbenzami-
de hydrochloride (Int-5F)
[0905] Int-5E (5.3 g, 11.5 mmol) was taken in ethanol (50 ml) and
solution of HCl in 1,4-dioxane (12 ml, 57 mmol, 4 M solution) was
added to it. After completion of the reaction, the solution was
partially concentrated and then diluted with ethyl acetate. The
precipitated solids were collected by filtration to give the
product as a white powder (5.0 g, 100%). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 8.33-8.51 (m, 4H) 7.80-7.88 (m, 4H) 7.50-7.65
(m, 2H) 3.88-3.96 (m, 1H) 3.21-3.35 (m, 2H) 3.06-3.17 (m, 1H) 2.76
(d, J=4.16 Hz, 3H) 2.30-2.43 (m, 6H). LC-MS (+ESI) M+H: 366
Step 7: Synthesis of
(R)-4-(2-(dimethylamino)-3-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propyl)-N-
,3,5-trimethylbenzamide (Int-5G)
[0906] Int-5F (2.0 g, 4.98 mmol) was taken in acetonitrile (10 ml)
with water (2 ml) and heated to 50 C to get a clear solution. It
was then cooled to room temperature and a solution of formaldehyde
(2.4 ml, 25 mmol) was added to it. After 15 mins, sodium
cyanoborohydride (0.4 g, 12 mmol) was added to it. After a further
15 mins, formaldehyde (0.4 ml, 5 mmol) was added followed by sodium
cyanoborohydride (0.1 g, 3 mmol). After 1 hr the reaction was
complete, and it was quenched by adding saturated ammonium chloride
solution. It was extracted with dichloromethane, dried, and
concentrated. The residue was purified on Combiflash using
dichloromethane/methanol gradient to give the product (1.15 g,
59%). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.71 (dd,
J=5.26, 3.06 Hz, 2H) 7.61 (dd, J=5.50, 3.06 Hz, 2H) 7.33 (s, 2H)
5.91-6.10 (m, 1H) 3.80-3.85 (m, 1H), 3.30-3.41 (m, 1H), 3.20-3.30
(m, 1H) 2.80-2.90 (m, 4H overlap) 2.60-2.75 (m, 1H) 2.28-2.36 (m,
12H). LC-MS (+ESI) M+H: 394
Step 8: Synthesis of
(S)-4-(3-amino-2-(dimethylamino)propyl)-N,3,5-trimethylbenzamide
(Int-5H)
[0907] Int-5G (1.6 g, 4.1 mmol) was taken in ethanol (40 ml) and
then hydrazine solution (1.3 ml, 20 mmol, 50% solution) was added
to it. The solution was heated to reflux for 3 hours during which
time a thick white precipitate formed. After cooling to room
temperature, the solution was diluted with ethyl acetate and the
precipitated solids were removed by filtration. The filtrate was
concentrated and then purified on Combiflash using
dichloromethane/methanol/ammonium hydroxide gradient to give the
product as a white powder (0.75 g, 70%). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.35-7.42 (m, 2H) 6.30-6.45 (br 1H)
2.99-3.05 (m, 3H), 2.88-2.96 (m, 2H) 2.85 (br, 2H) 2.67-2.70 (m,
1H) 2.54-2.60 (m, 1H) 2.43 (br, 6H), 2.35 (br, 6H). LC-MS (+ESI)
M+H: 264
Synthesis of
(S)--N2,N2-dimethyl-3-(1-tosyl-1H-indazol-5-yl)propane-1,2-diamine
(Int-6G)
##STR00441## ##STR00442##
[0908] Step 1: Synthesis of 5-bromo-1-tosyl-1H-indazole
(Int-6A)
[0909] To a stirred mixture of 5-bromo-1H-indazole (6.75 g, 34.25
mmole) and DIEA (7.3 mL, 41.11 mmole) in DCM (80 mL) at 0.degree.
C. was added Ts-Cl (6.85 g, 35.97 mmole). After the addition was
completed, the reaction mixture was stirred for 16 h at RT.
H.sub.2O was added, layers were separated. The aqueous layer was
extracted with DCM (2.times.). The combined extracts were dried
over Na.sub.2SO.sub.4, concentrated and purified by ISCO (0-30%
EtOAc/Hexanes) to give Int-6A (10.35 g, 76%). LC-MS (+ESI) M+H:
399.1.
Step 2: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(1-tosyl-1H-indazol-5-yl)propanoate
(Int-6B)
[0910] To a stirred suspension of zinc powder (0.94 g, 14.31 mmole)
in DMF (10 mL) was added iodine (0.12 g, 0.48 mmole). After
stirring for 10 minutes, methyl (R)-2-((tert-butoxycarbonyl)
amino)-3-iodopropanoate (1.88 g, 5.72 mmole), followed by iodine
(0.12 g, 0.48 mmole). The resulting mixture was stirred for 2 h.
The mixture was then added to a stirred mixture of Int-6A (1.9 g,
4.77 mmole), S-Phos (0.10 g, 0.24 mmole), and Pd.sub.2(dba).sub.3
in DMF (10 mL). The reaction mixture was heated to 60.degree. C. in
16 h, cooled to RT, diluted with EtOAc, filtered through a pad of
Celite. The filtrate was concentrated and purified by ISCO (0-60%
EtOAc/Hexanes) to give Int-6B (1.21 g, 53.5%). LC-MS (+ESI) M+H:
399.1.
Step 3: Synthesis of tert-butyl
(S)-(1-hydroxy-3-(1-tosyl-1H-indazol-5-yl)propan-2-yl)carbamate
(Int-6C)
[0911] To a stirred solution of Int-6B (6.6 g, 14.04 mmole) in THF
(60 mL) at 0.degree. C. was added 4M LiBH.sub.4 (5.3 mL, 21.06
mmole) dropwise. After the addition was completed, the reaction
mixture was stirred at RT for 16 h at RT, cooled in an ice bath,
slowly quenched by saturated aqueous NH.sub.4Cl, stirred for 15
minutes, extracted with EtOAc (3.times.). The combined extracts
were dried over Na2SO4, concentrated and purified by ISCO (45%
EtOAc/Hexanes) to give Int-6C (2.6 g, 42%). LC-MS (+ESI) M+H:
446.2.
Step 4: Synthesis of tert-butyl
(S)-(1-(1,3-dioxoisoindolin-2-yl)-3-(1-tosyl-1H-indazol-5-yl)propan-2-yl)-
carbamate (Int-6D)
[0912] To a stirred mixture of Int-6C (2.6 g, 5.84 mmole),
PPh.sub.3 (1.84 g, 7.01 mmole), and phthalimide (1.03 g, 7.01
mmole) in THE (40 mL) at 0.degree. C. was added DIAD (1.42 g, 7.01
mmole) dropwise. After the addition was completed, the reaction
mixture was stirred for 16 h at RT. The mixture was concentrated to
dryness and purifier by ISCO (0-50% EtOAC/Hexanes) to give Int-6D
(3.1 g, 92.5%). LC-MS (+ESI) M+H: 575.2.
Step 5: Synthesis of
(S)-2-(2-amino-3-(1-tosyl-1H-indazol-5-yl)propyl)isoindoline-1,3-dione
hydrochloride (Int-6E)
[0913] To a stirred solution of Int-6D (2.1 g, 3.65 mmole) in MeOH
(30 mL) at 0.degree. C. was added 4M HCl (9.6 mL, 18.28 mmole) in
p-dioxane. The mixture was stirred at RT for 3 h, concentrated to
dryness, triturated in EtOAc. The solid was collected, washed with
EtOAc, dried to give Int-6E (1.95 g, 100%). LC-MS (+ESI) M+H:
475.2.
Step 6: Synthesis of
(S)-2-(2-(dimethylamino)-3-(1-tosyl-1H-indazol-5-yl)propyl)isoindoline-1,-
3-dione (Int-6F)
[0914] To a stirred solution of Int-6E (1.95 g, 3.82 mmole) in
MeCN/H.sub.2O (10:1, 44 mL) was added 37% formaldehyde (1.55 g,
19.09 mmole). After stirring for 30 minutes, NaCNBH.sub.3 (0.72 g,
11.45 mmole). The reaction mixture was stirred for 30 minutes,
quenched by saturated aqueous NH.sub.4Cl, stirred for 10 minutes,
extracted with DCM (3.times.). The combined extracts were dried
over Na.sub.2SO.sub.4, concentrated to give Int-6F (2.0 g, 100%).
LC-MS (+ESI) M+H: 503.2.
Step 7: Synthesis of
(S)--N2,N2-dimethyl-3-(1-tosyl-1H-indazol-5-yl)propane-1,2-diamine
(Int-6G)
[0915] A mixture of Int-6F (2.0 g, 3.98 mmole) and hydrazine (1.3
mL, 19.89 mmole) in EtOH (40 mL) was heated to 90.degree. C. in 2
h. The reaction mixture was cooled, and the solid was filtered off,
washed with EtOAc (3.times.). The filtrate was concentrated and
purified by ISCO (0-25% MeOH/DCM in 1% NH.sub.4OH) to give Int-6G
(0.4 g, 27%). LC-MS (+ESI) M+H: 373.2.
Synthesis of
(S)-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-N2,N2,2-trimethylpropane-1-
,2-diamine(Int-7H)
##STR00443## ##STR00444##
[0916] Step 1: Synthesis of methyl
(S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoate (Int-7A)
[0917] To a dry 100 mL round-bottom flask purged with N.sub.2 is
added methanol (20 mL) followed by thionyl chloride (1.45 mL, 20
mmol) dropwise at room temperature over 5 minutes. The solution is
allowed to stir at room temperature for 10 additional minutes,
after which time solid .alpha.-methyl-L-tyrosine (1.03 g, 5.27
mmol) is added. The mixture is heated to reflux for 24 hours, after
which time LC-MS analysis indicates greater than 90% conversion to
the methyl ester. The homogeneous orange reaction mixture is cooled
to room temperature and the methanol is removed by rotary
evaporation. Diethyl ether (5 mL) is added, causing a precipitate
to form. The solid is collected by filtration, washed with ether
and pump-dried to provide the product HCl salt as a beige solid,
1.48 g, which is carried forward without further purification.
LC-MS: 210.1 m/z [M+H].sup.+; .sup.1H NMR (400 MHz, d6-DMSO)
.delta. ppm 8.53 (br s, 3H) 6.94-6.98 (m, 2H) 6.71-6.75 (m, 2H)
3.73 (s, 3H) 3.02 (s, 2H) 1.48 (s, 3H);
Step 2: Synthesis of methyl
(S)-2-amino-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-methylpropanoate
(Int-7B)
[0918] To a scintillation vial containing crude Int-7A (1.48 g,
assumed 5.1 mmol) is added dimethylformamide (5 mL) followed by
imidazole (1.2 g, 17.5 mmol), triethylamine (1.4 mL, 10 mmol), and
lastly tert-butyldimethylsilyl chloride (900 mg, 6 mmol). The brown
heterogeneous mixture is left to stir at room temperature and
monitored by LC-MS. Additional portions of imidazole, triethylamine
and tert-butyldimethylsilyl chloride are added as necessary until
complete conversion to the TBS protected phenol is observed by
LC-MS. After 4 hours, the reaction is worked up by addition of
saturated aqueous NaHCO.sub.3 (50 mL) and extracted 3 times with
10% methanol in ethyl acetate. The combined organic layers are
washed with brine, dried over MgSO.sub.4, filtered and concentrated
by rotary evaporation to provide the crude desired product as a tan
oil, 3.94 g. The crude product is contaminated with DMF, TBSOH and
imidazole, and is carried forward without purification. LC-MS:
324.2 m/z [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 6.98-7.02 (m, 2H) 6.73-6.77 (m, 2H) 3.69 (s, 3H) 3.06 (d,
J=13.21 Hz, 1H) 2.73 (d, J=13.45 Hz, 1H) 1.38 (s, 3H) 0.98 (s, 9H)
0.19 (s, 6H).
Step 3: Synthesis of methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-((tert-butyldimethylsilyl)oxy)phe-
nyl)-2-methylpropanoate (Int-7C)
[0919] To a 100 mL round-bottom flask is added di-tert-butyl
dicarbonate (1.5 g, 7 mmol) followed by dichloromethane (10 mL).
The crude Int-7B (3.94 g, assume 5.1 mmol) is added as a solution
in 15 mL dichloromethane. The reaction is stirred at room
temperature for 5 days, with additional portions of di-tert-butyl
dicarbonate added as necessary to push the reaction to completion.
After 5 days LC-MS analysis indicates complete conversion of the
starting material to the desired product. The reaction mixture is
worked up by the addition of water (50 mL) and is extracted 3 times
with ethyl acetate. The combined organic layers are washed with
brine, dried over MgSO.sub.4, filtered and concentrated by rotary
evaporation to provide the desired crude product as a pale orange
oil, 5.19 g. The crude product is contaminated with imidazole and
TBSOH, and is carried forward without further purification. LC-MS:
324.2 m/z [M-Boc+H].sup.+, 446.2 m/z [M+Na].sup.+; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 6.93 (d, J=8.31 Hz, 2H) 6.74 (d,
J=8.31 Hz, 2H) 5.1 (br s, 1H) 3.74 (s, 3H) 3.3 (br s, 1H) 3.08-3.15
(m, 1H) 1.63 (s, 9H) 1.56 (s, 3H) 0.98 (s, 9H) 0.19 (s, 6H).
Step 4: Synthesis of tert-butyl
(S)-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-hydroxy-2-methylpropan--
2-yl)carbamate (Int-7D)
[0920] To a 250 mL round-bottom flask containing substrate Int-7C
(5.19 g, assume 5.1 mmol) is added THE (25 mL). The solution is
brought to 0.degree. C. using an ice bath, and a solution of
LiBH.sub.4 (4N in THF, 4 mL, 16 mmol) is added dropwise over 5
minutes. The reaction is allowed to warm to room temperature with
stirring over 4 hours. Additional LiBH.sub.4 (1.5 mL, 6 mmol) is
added and the reaction is stirred at room temperature for an
additional 16 hours, after which time LC-MS analysis indicates
complete conversion to the desired alcohol product. The reaction is
worked up by slowly, carefully pouring into 30 mL saturated aqueous
NH.sub.4Cl, and is extracted 3 times with ethyl acetate. The
combined organic layers are washed with brine, dried over
MgSO.sub.4, filtered and concentrated by rotary evaporation to
provide a pale yellow oil. The product is purified by column
chromatography (0 to 50% ethyl acetate in hexanes) to provide the
product as a colorless oil which solidifies into a white solid at
room temperature, 1.74 g (4.4 mmol, 86% yield over 4 steps from
.alpha.-methyl-L-tyrosine). LC-MS: 296.2 m/z [M-Boc+H]+, 418.2 m/z
[M+Na].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.04
(d, J=8.31 Hz, 2H) 6.78 (d, J=8.31 Hz, 2H) 4.48 (br s, 1H) 4.24 (br
s, 1H) 3.61-3.72 (m, 2H) 3.08 (br d, J=13.94 Hz, 1H) 2.75 (d,
J=13.69 Hz, 1H) 1.47 (s, 9H) 1.06 (s, 3H) 0.99 (s, 9H) 0.20 (s,
6H).
Step 5: Synthesis of
(S)-2-amino-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-methylpropan-1-o-
l (Int-7E)
[0921] To a 100 mL round-bottom flask, open to air, is added
substrate Int-7D (1.04 g, 2.6 mmol). Then, dichloromethane (15 mL)
is added and the colorless homogeneous solution is brought to
0.degree. C. using an ice bath. Trifluoroacetic acid (1.4 mL, 5
mmol) is added dropwise over 5 minutes. The ice bath is removed and
the solution is allowed to warm to room temperature overnight with
stirring (16 hours), after which time LC-MS analysis indicates
complete conversion of starting material to a mixture of the
desired product and its trifluoroacetate ester (LC-MS: 392.2 m/z
[M+H]+) with no concomitant loss of the TBS group and only trace
(<2%) isobutylene incorporation. The reaction is worked up by
rotary evaporation and pump-dried to remove all volatiles to afford
the product as a pale pink oil, 1.63 g. The crude product is
contaminated with trifluoroacetic acid, as well as its labile
trifluoroacetate ester, but is carried forward without further
purification. Characterization of desired free alcohol product:
LC-MS: 296.2 m/z [M+H]+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 7.04 (d, J=8.31 Hz, 2H) 6.78 (d, J=8.31 Hz, 2H) 4.34-4.43 (m,
2H) 3.64-3.76 (m, 1H) 2.96-3.08 (m, 1H) 2.92 (s, 1H) 0.99
(overlapping s, 12H) 0.20 (s, 6H).
Step 6: Synthesis of
(S)-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-(dimethylamino)-2-methyl-
propan-1-ol (Int-7F)
[0922] To a 100 mL round-bottom flask is added the crude primary
amine substrate Int-7E (1.63 g, assume 2.5 mmol), followed by
acetonitrile (15 mL) and water (1.5 mL). The colorless homogeneous
solution is cooled to 0.degree. C. in an ice bath. To the reaction
mixture is added 37% aqueous formaldehyde (0.60 mL, 8 mmol)
followed by sodium cyanoborohydride (943 mg, 15 mmol), and the
reaction is stirred at 0.degree. C. for 10 minutes. Then, acetic
acid (0.86 mL, 15 mmol) is added. Additional portions of
formaldehyde and sodium cyanoborohydride are added to push the
reaction to completion, and additional water is added to maintain a
homogeneous solution. The reaction is stirred for 2 hours after
which time LC-MS analysis indicates complete conversion to the
desired product, along with trace undesired TBS deprotection. The
reaction is worked up by addition of 50 mL saturated aqueous
NaHCO.sub.3, and extracted 3 times with 10% methanol in ethyl
acetate. The combined organic layers are washed with brine, dried
over MgSO.sub.4, filtered and concentrated by rotary evaporation.
The residue obtained is purified by column chromatography (0 to 15%
methanol with 1% NH.sub.4OH in DCM) using an Evaporative Light
Scattering Detector (ELSD) for peak visualization to afford the
desired compound as a colorless oil (715 mg, 88% yield over 2 steps
from Boc-protected amine). LC-MS: 324.3 m/z [M+H]+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 7.07-7.12 (m, 2H) 6.80-6.84 (m,
2H) 4.39 (s, 1H) 3.63-3.67 (m, 1H) 3.52-3.59 (m, 1H) 3.12 (d,
J=12.96 Hz, 1H) 2.94 (s, 6H) 2.83 (d, J=12.96 Hz, 1H) 1.25 (s, 3H)
0.99 (s, 9H) 0.21 (s, 6H).
Step 7: Synthesis of
(S)-1-azido-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-N,N,2-trimethylpro-
pan-2-amine (Int-7G)
[0923] To a scintillation vial containing amino alcohol substrate
Int-7F (559 mg, 1.73 mmol) is added THE (10 mL), followed by
triethylamine (1.4 mL, 10 mmol). The homogeneous mixture is cooled
to 0.degree. C. using an ice bath. Methanesulfonyl chloride (0.31
mL, 4 mmol) is added dropwise over 5 minutes, resulting in a yellow
heterogeneous suspension. The intermediate mesylate formed (LC-MS
496.2 m/z [M+Na].sup.+) is highly reactive and can easily hydrolyze
back to the starting alcohol or undergo substitution to form a
vicinal aminochloride (LC-MS 342.2, 344.2 m/z [M+H].sup.+) if
allowed to warm to room temperature. After 10 minutes of stirring
at 0.degree. C., an aqueous solution of sodium azide (650 mg, 10
mmol/5 mL water) is added portionwise over 30 seconds, and the
biphasic clear yellow mixture is allowed to warm to room
temperature with vigorous stirring for 15 minutes. The reaction is
quickly worked up by pouring into 20 mL saturated aqueous
NaHCO.sub.3 and extracted 3 times with ethyl acetate. The combined
organic layers are washed with brine, dried over MgSO.sub.4,
filtered and concentrated by rotary evaporation to provide the
crude product as a pale yellow oil (650 mg), which is taken forward
without further purification. LC-MS: 349.3 m/z [M+H]; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 7.05-7.13 (m, 2H) 6.79-6.88 (m,
2H) 2.80-3.02 (m, 4H) 2.72 (br s, 6H) 1.41 (s, 3H) 0.98 (s, 9H)
0.20 (s, 6H).
Step 8. Synthesis of
(S)-3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-N.sup.2,N.sup.2,2-trimethy-
lpropane-1,2-diamine (Int-7H)
[0924] To the crude amino azide substrate Int-7G (650 mg, assume
1.73 mmol) in a 250 mL round-bottom flask is added THE (10 mL), and
the solution is cooled to 0.degree. C. in an ice bath. Lithium
aluminum hydride (1M/THF, 4 mL, 4 mmol) is added dropwise over 5
minutes, the ice bath is removed and the pale yellow homogeneous
solution is allowed to warm to room temperature with stirring.
Additional lithium aluminum hydride is added as necessary to push
the reaction to completion. After 2 hours, LC-MS analysis indicates
complete conversion of the azide. The reaction is worked up by
addition of 50 mL 1M potassium sodium tartrate and 50 mL ethyl
acetate. A 1-inch bar-shaped stirbar is used to vigorously stir the
biphasic mixture for 24 hours at room temperature until both the
organic and aqueous layers are clear. 50 mL saturated aqueous
NaHCO.sub.3 is added, and the aqueous layer is extracted 3 times
with ethyl acetate. The combined organic layers are washed with
brine, dried over MgSO.sub.4, filtered and concentrated by rotary
evaporation. The residue obtained is purified by column
chromatography (0 to 10% methanol in DCM) using an Evaporative
Light Scattering Detector (ELSD) for peak visualization to afford
the desired vicinal diamine as a colorless oil (331 mg, 1.02 mmol,
59% yield over 2 steps from the amino alcohol). LC-MS: 323.3 m/z
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
6.98-7.11 (m, 2H) 6.78-6.90 (m, 2H) 3.97 (br s, 2H) 2.89 (s, 6H)
2.77-2.83 (m, 1H) 2.69-2.75 (m, 1H) 1.28 (s, 3H) 0.99 (s, 9H) 0.22
(s, 6H).
Example C1
##STR00445##
[0925] Synthesis of
(S)-4-chloro-N-(3-(2-chloro-4-hydroxyphenyl)-2-(dimethylaminopropyl)-3,5--
difluorobenzamide (Compound C-1)
[0926] The title compound was prepared according to Scheme C1,
starting with Int-2H (intermediate 2H, 30.9 mg, 0.135 mmol),
4-chloro-3,5-difluorobenzoic acid (31.2 mg, 0.162 mmol) to afford
33.0 mg (61%) of title compound. LCMS (+ESI) M+H.sup.+=403.1,
405.1. .sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 7.52 (d,
J=8.30 Hz, 2H) 7.14 (d, J=8.31 Hz, 1H) 6.80 (d, J=2.45 Hz, 1H) 6.67
(dd, J=8.31, 2.69 Hz, 1H) 3.46-3.56 (m, 1H) 3.36-3.42 (m, 1H)
3.15-3.23 (m, 1H) 3.07 (dd, J=13.57, 4.28 Hz, 1H) 2.61 (dd,
J=13.69, 9.54 Hz, 1H) 2.44 (s, 6H).
Example C2
##STR00446##
[0927] Synthesis of
(S)--N-(3-(2-Chloro-4-hydroxyphenyl)-2-(dimethylamino)propyl)-3,4-dimethy-
lbenzenamide (Compound C-2)
[0928] Int-2H (intermediate 2H, 30 mg, 0.13 mmol) in DMF (1 mL) was
added 3,4-dimethyl benzoic acid (22 mg, 0.14 mmol), EDC (28 mg,
0.14 mmol), HOBT (9 mg, 0.07 mmol) and IPEA (50 mg, 0.39 mmol). The
mixture was stirred at ambient temperature for 2 hours. Water and
EtOAc were added. The organic layer was washed with water
(.times.3) and concentrated. The residue was chromatographed
(Silica gel, DCM/10% MeOH in DCM=9:1 to 0:1) to afford the title
compound as a white solid, 27 mg (58%). LCMS (+ESI) M+H.sup.+=361.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.50 (d, J=1.96 Hz,
1H), 7.46 (dd, J=7.83, 1.96 Hz, 1H), 7.19 (d, J=8.07, 1 Hz), 7.15
(d, J=8.31 Hz, 1H), 6.81 (d, J=2.45 Hz, 1H), 6.69 (dd, J=8.44 2.57
Hz, 1H), 3.50-3.40 (m, 2H), 3.21-3.13 (m, 1H), 3.07 (d, J=13.69,
4.65 Hz, 1H), 2.64 (dd, J=13.57, 9.42 Hz, 1H), 2.45 (s, 6H), 2.31
(s, 6H).
Example C3
##STR00447##
[0929] Synthesis of
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(4-hydroxyphenyl)-2-methylpropyl)-
benzamide (Compound C-3)
[0930] To a 1-dram vial is added Int-7H (31.7 mg, 0.098 mmol),
followed by DMF (0.5 mL) and DIEA (0.07 mL, 0.4 mmol). To this
solution is added 3,4-dichlorobenzoic acid (26.7 mg, 0.14 mmol) as
a solution in DMF (0.5 mL), and the colorless homogeneous solution
is cooled to 0.degree. C. in an ice bath. Lastly, solid HATU (76
mg, 0.2 mmol) is added to the solution all at once. The ice bath is
removed and the yellow homogeneous solution is allowed to warm to
room temperature over the course of 2 hours, after which time LC-MS
analysis indicates complete amide-bond formation to form the
intermediate
(S)--N-(3-(4-((tert-butyldimethylsilyl)oxy)phenyl)-2-(dimethylamino)-2-me-
thylpropyl)-3,4-dichlorobenzamide, which is not directly isolated
(LC-MS: 495.2, 497.2, 499.2 m/z [M+H].sup.+). To the reaction
mixture is added 2 mL 1M NaOH and 2 mL methanol, and the reaction
is stirred vigorously for 48 hours at room temperature, after which
time LC-MS analysis indicates complete phenolic TBS deprotection to
the desired final product. The reaction is worked up by addition of
50 mL saturated aqueous NaHCO.sub.3. The aqueous layers are
extracted 3 times with ethyl acetate, the combined organic layers
washed once with brine, then dried over MgSO.sub.4, filtered, and
the solvent removed by rotary evaporation. The oily residue
obtained is purified by column chromatography (0 to 15% methanol
with 1% NH.sub.4OH in DCM) using an Evaporative Light Scattering
Detector (ELSD) for peak visualization to afford the desired
compound as a colorless oil, 20.7 mg (0.054 mmol, 55% yield over 2
steps from primary amine). LC-MS: 381.1, 383.1, 385.1 m/z
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.79 (t,
J=1.22 Hz, 1H) 7.48 (d, J=0.98 Hz, 2H) 6.99-7.04 (m, 2H) 6.71-6.75
(m, 2H) 6.66 (s, 1H) 3.21 (d, J=13.45 Hz, 1H) 3.03-3.09 (m, 1H)
3.00 (d, J=13.94 Hz, 1H) 2.54 (br d, J=12.72 Hz, 1H) 2.45 (s, 6H)
1.44 (s, 3H).
Example C4
##STR00448##
[0931] Synthesis of
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)benzamide
(Compound C-4)
Step 1: Preparation of
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(1-tosyl-1H-indazol-5-yl)propyl)b-
enzamide
[0932] A mixture of Int-6G (0.13 g, 0.35 mmole),
3,4-dichlorobenzoic acid 0.067 g, 0.35 mmole), HOBT (0.03 g, 0.18
mmole), EDC (0.08 g, 0.42 mmole), and DIEA (0.12 g, 0.87 mmole) in
DMF (2 mL) was stirred at RT for 16 h. H.sub.2O was added, and the
solid was collected, washed with H.sub.2O, dried and purified by
ISCO (0-10% MeOH/DCM) to give
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(1-tosyl-1H-indazol-5-yl)propyl)b-
enzamide (0.08 g, 42%). LC-MS (+ESI) M+H: 545.1.
Step 2: Preparation of
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)benzamide
(Compound C-4)
[0933] A mixture of
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(1-tosyl-1H-indazol-5-yl)propyl)b-
enzamide (0.08 g, 0.14 mmole) and K.sub.2CO.sub.3 (0.1 g, 0.71
mmole) in MeOH (5 mL) was stirred at 70.degree. C. in 2 h. The
reaction mixture was cooled, concentrated, taken up in H.sub.2O,
the solid was collected, dried and purified by ISCO (0-10%
MeOH/DCM) to give
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)benzamide
(0.01 g, 20%). .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 12.93
(s, 1H), 8.38 (t, J=5.38 Hz, 1H), 7.91-8.00 (m, 2H), 7.68-7.79 (m,
2H), 7.56 (s, 1H), 7.44 (d, J=8.56 Hz, 1H), 7.14-7.25 (m, 1H), 3.44
(ddd, J=13.57, 7.83, 5.75 Hz, 1H), 3.19 (dt, J=13.63, 5.53 Hz, 1H),
2.97-3.03 (m, 1H), 2.89-2.96 (m, 1H), 2.57 (dd, J=13.82, 7.95 Hz,
1H), 2.30 (s, 6H). LC-MS (+ESI) M+H: 391.1.
Example C5
##STR00449##
[0934] Synthesis of
(S)-3-chloro-N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-
-4-methoxybenzamide (Compound C-5)
[0935]
(S)-3-Chloro-N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)p-
ropyl)-4-methoxybenzamide was synthesized according to Scheme C1
using Int-1G and 3-chloro-4-methoxybenzoic acid as the starting
materials (68% yield). LC-MS: 391.2 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.86 (s, 1H), 8.05 (m, 1H), 7.78-7.75
(m, 1H), 7.78-7.75 (m, 2H), 7.21-7.19 (m, 1H), 6.40 (s, 2H), 3.900
(s, 3H), 3.49-3.39 (m, 1H), 3.02-2.93 (m, 2H), 2.71-2.61 (m, 1H),
2.48-2.39 (m, 1H), 2.33 (s, 6H), 2.20 (s, 6H).
Example C6
##STR00450##
[0936] Synthesis of
(S)-4-chloro-N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-
-3-fluorobenzamide (Compound C-6)
[0937]
(S)-4-Chloro-N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)p-
ropyl)-3-fluorobenzamide was synthesized according to Scheme C1
using Int-1G and 4-chloro-3-fluorobenzoic acid as the starting
materials (68% yield). LC-MS: 379.2 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.88 (s, 1H), 8.23 (m, 1H), 7.78-7.75
(m, 1H), 7.71-7.64 (m, 2H), 6.40 (s, 2H), 3.47-3.38 (m, 1H),
3.01-2.90 (m, 2H), 2.72-2.63 (m, 1H), 2.48-2.39 (m, 1H), 2.33 (s,
6H), 2.20 (s, 6H).
Example C7
##STR00451##
[0938] Synthesis of
(S)-3,4-Dichloro-N-(3-(2-chloro-4-hydroxyphenyl)-2-(dimethylamino)propyl)-
benzamide (Compound C-7)
[0939] Int-2H (intermediate 2H, 30 mg, 0.13 mmol) in DMF (1 mL) was
added 3,4-dichlorobenzoic acid (25 mg, 0.13 mmol), EDC (27 mg, 0.14
mmol), HOBT (8 mg, 0.06 mmol) and IPEA (42 mg, 0.33 mmol). The
mixture was stirred at ambient temperature for 2 hours. Water and
EtOAc were added. The organic layer was washed with water
(.times.3) and concentrated. The residue was chromatographed
(Silica gel, DCM/10% MeOH in DCM=5:1 to 0:1) to afford the title
compound as a white solid, 28 mg (54%). LCMS (+ESI) M+H.sup.+=402.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.91 (d, J=1.71 Hz,
1H), 7.67-7.58 (m, 2H), 7.14 (d, J=8.31 Hz, 1H), 6.81 (d, J=2.45
Hz, 1H), 6.68 (dd, J=8.31, 2.45 Hz, 1H), 3.54-3.47 (m, 1H),
3.42-3.37 (m, 1H), 3.23-3.15 (m, 1H), 3.07 (dd, J=13.69, 4.40 Hz,
1H), 2.62 (dd, J=13.69, 9.54 Hz, 1H), 2.44 (s, 6H).
Example C8
##STR00452##
[0940] Synthesis of
(S)-4-bromo-3-chloro-N-(3-(2-chloro-4-hydroxyphenyl)-2-(dimethylamino)pro-
pyl)benzamide (Compound C-8)
[0941] The title compound was prepared according to Scheme C1,
starting with Int-2H (intermediate 2H, 136 mg, 0.595 mmol) and
4-bromo-3-chlorobenzoic acid (154 mg, 0.655 mmol) to afford 110 mg
(42%) of title compound. LCMS (+ESI) M+H+=445.0, 447.0, 449.0.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.55 (br s, 1H) 8.29 (t,
J=5.38 Hz, 1H) 7.92 (d, J=1.96 Hz, 1H) 7.80 (d, J=8.31 Hz, 1H) 7.60
(dd, J=8.31, 1.96 Hz, 1H) 7.07 (d, J=8.31 Hz, 1H) 6.70 (d, J=2.45
Hz, 1H) 6.60 (dd, J=8.31, 2.45 Hz, 1H) 3.37 (ddd, J=13.63, 8.13,
5.87 Hz, 1H) 3.04 (dt, J=13.57, 5.44 Hz, 1H) 2.87-2.96 (m, 1H) 2.76
(dd, J=13.82, 5.75 Hz, 1H) 2.41-2.48 (m, 1H) 2.22 (s, 6H).
Examples C10-C18
##STR00453##
[0942] Synthesis of
(S)-4-(3-(2-Chlorobenzamido)-2-(dimethylaminopropyl)-N,3,5-trimethylbenza-
mide (Compound C-10)
[0943] Int-5H (60 mg, 0.23 mmol) was dissolved in DMF (1 ml) with
2-chlorobenzoic acid (30 mg, 0.27 mmol) and HATU (105 mg, 0.27
mmol) was added. Diisopropylethylamine (48 mL, 0.30 mmol) was then
added and the solution was stirred at room temperature. After
completion of the reaction, the reaction mixture was concentrated
and purified by reverse phase chromatography using a gradient of
water/acetonitrile in 0.1% TFA. The solution of the product was
neutralized by adding aqueous NaOH solution. The product was
extracted into dichloromethane, filtered through magnesium sulfate
and then concentrated to give the product as a white powder (33
mg). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.87 (br s,
1H) 7.31-7.44 (m, 5H) 7.23-7.29 (m, 2H) 6.47 (br s, 1H) 5.41 (br s,
2H) 3.89-3.96 (m, 1H) 3.79-3.87 (m, 1H) 3.42 (ddd, J=14.80, 4.89,
3.30 Hz, 1H) 3.14-3.20 (m, 1H) 2.96-3.09 (m, 10H) 2.37-2.41 (m,
6H). MS: ESI 402 [M+H].sup.+.
[0944] The Compounds of Table 4 were prepared in the same method as
described in Example C10 by using appropriate reagents.
TABLE-US-00004 TABLE 4 Comp. No. Yield/Analytical Data C-11 0.113
g, 18.5%; .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 8.28 (br dd,
J = 8.31, 3.67 Hz, 2H), 7.79 (d, J = 8.56 Hz, 2H), 7.53 (d, J =
8.80 Hz, 2H), 7.45 (s, 2H), 3.52 (br dd, J = 4.77, 1.59 Hz, 1H),
3.01 (dt, J = 14.12, 5.04 Hz, 2H), 2.81-2.91 (m, 1H), 2.75 (d, J =
4.40 Hz, 3H), 2.57-2.66 (m, 1H), 2.33 (s, 12H). LC-MS (+ESI) M + H:
402.2. C-12 0.008 g, 12.1%; .sup.1H NMR (400 MHz, DMSO-d6): .delta.
ppm 8.47 (t, J = 5.01 Hz, 1H), 8.22-8.33 (m, 1H), 7.73-7.82 (m,
3H), 7.45 (s, 2H), 3.46-3.58 (m, 1H), 2.96-3.05 (m, 2H), 2.83-2.92
(m, 1H), 2.75 (d, J = 4.65 Hz, 3H), 2.56-2.66 (m, 1H), 2.34 (s,
6H), 2.33 (s, 6H). LC-MS (+ESI) M + H: 436.1. C-13 17 mg, 33%);
LCMS (+ESI) M + H.sup.+ = 420.2. .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. ppm 7.51-7.66 (m, 5 H) 3.89-4.07 (m, 2 H) 3.75 (d, J = 4.89
Hz, 1 H) 3.16- 3.28 (m, 5 H) 3.12 (s, 3 H) 2.92 (s, 3 H) 2.51 (s, 6
H) C-14 7 mg, 13%; LCMS (+ESI) M + H.sup.+ = 420.2. .sup.1H NMR
(400 MHz, METHANOL-d4) .delta. ppm 7.79 (dd, J = 7.09, 2.20 Hz, 1
H) 7.63 (ddd, J = 8.68, 4.52, 2.20 Hz, 1 H) 7.45 (s, 2 H) 7.21 (t,
J = 8.80 Hz, 1 H) 3.80-3.91 (m, 2 H) 3.22-3.26 (m, 1 H) 3.08- 3.18
(m, 2 H) 3.07 (s, 3 H) 3.00 (s, 3 H) 2.80 (s, 3 H) 2.39 (s, 6 H)
1.19 (s, 1 H). C-15 0.009 g, 21.5%; .sup.1H NMR (400 MHz, MeOH-d4):
.delta. ppm 7.46 (s, 2H), 7.23 (s, 1H), 7.16 (d, J = 0.98 Hz, 2H),
3.46-3.58 (m, 1H), 3.11-3.24 (m, 2H), 3.04 (dd, J = 13.69, 4.16 Hz,
1H), 2.89 (s, 3H), 2.78-2.86 (m, 1H), 2.49 (s, 6H), 2.43 (s, 6H),
2.33 (s, 3H). LC-MS (+ESI) M + H: 416.2. C-16 0.005 g, 8.5%;
.sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 9.80-9.94 (m, 1H),
8.49-8.62 (m, 1H), 8.26-8.39 (m, 1H), 7.67 (d, J = 1.71 Hz, 1H),
7.54 (s, 2H), 7.42-7.50 (m, 2H), 4.02-4.16 (m, 1H), 3.67-3.81 (m,
2H), 3.21 (br d, J = 1.22 Hz, 1H), 3.03- 3.07 (m, 1H), 3.01 (br d,
J = 4.65 Hz, 3H), 2.94 (br d, J = 4.65 Hz, 3H), 2.76 (d, J = 4.65
Hz, 3H), 2.41 (s, 6H). LC-MS (+ESI) M + H: 436.1. C-17 0.005 g,
12.6%; .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 8.16-8.29 (m,
1H), 7.95-8.05 (m, 1H), 7.75 (d, J = 8.80 Hz, 2H), 7.44 (s, 2H),
6.97 (d, J = 8.80 Hz, 2H), 3.80 (s, 3H), 3.43-3.55 (m, 1H),
2.95-3.06 (m, 2H), 2.81-2.90 (m, 1H), 2.61-2.69 (m, 1H), 2.35 (br
s, 6H), 2.33 (s, 6H). LC-MS (+ESI) M + H: 398.3. C-18 0.0173 g,
38.4%; .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 8.16-8.31 (m,
1H), 7.74 (br t, J = 5.14 Hz, 1H), 7.46 (s, 2H), 7.15 (d, J = 7.58
Hz, 1H), 6.95-7.06 (m, 2H), 3.36-3.46 (m, 1H), 2.94-3.02 (m, 2H),
2.86 (dd, J = 13.57, 5.26 Hz, 1H), 2.76 (d, J = 4.65 Hz, 3H), 2.63
(dd, J = 13.69, 7.83 Hz, 1H), 2.35 (s, 12H), 2.28 (d, J = 5.38 Hz,
6H). LC-MS (+ESI) M + H: 396.2.
Example C19
##STR00454##
[0945] Synthesis of
(S)-4-chloro-N-(3-(2-chloro-4-hydroxyphenyl)-2-(dimethylaminopropyl)-3-fl-
uorobenzamide (Compound C-19)
[0946] The title compound was prepared according to Scheme C1,
starting with Int-2H (intermediate 2H, 102 mg, 0.445 mmol) and
4-chloro-3-fluorobenzoic acid (85.5 mg, 0.490 mmol) to afford 115
mg (67%) of title compound. LCMS (+ESI) M+H+=385.1, 387.1. .sup.1H
NMR (400 MHz, METHANOL-d4) .delta. ppm 7.63 (d, J=9.97 Hz, 1H)
7.53-7.58 (m, 2H) 7.14 (d, J=8.56 Hz, 1H) 6.80 (d, J=2.45 Hz, 1H)
6.68 (dd, J=8.44, 2.57 Hz, 1H) 3.47-3.54 (m, 1H) 3.36-3.43 (m, 1H)
3.18 (tt, J=9.08, 4.86 Hz, 1H) 3.07 (dd, J=13.69, 4.40 Hz, 1H) 2.62
(dd, J=13.69, 9.29 Hz, 1H) 2.44 (s, 6H).
Examples C.sub.20-C.sub.22
##STR00455##
[0947] Synthesis of
(S)--N-(3-(2-Chloro-4-hydroxyphenyl)-2-(di-methylaminopropyl)-4-cycloprop-
ylbenzamide (Compound C-20)
[0948] Int-2H (intermediate 2H, 25 mg, 0.11 mmol) in DMF (1 mL) was
added 4-cyclopropylbenzoic acid (18 mg, 0.11 mmol), EDC (23 mg,
0.12 mmol), HOBT (8 mg, 0.06 mmol) and IPEA (36 mg, 0.28 mmol). The
mixture was stirred at ambient temperature for 2 hours. Water and
EtOAc were added. The organic layer was washed with water
(.times.3) and concentrated. The residue was chromatographed
(Silica gel, DCM/10% MeOH in DCM=5:1 to 0:1) to afford the title
compound as a white solid, 16 mg (39%). LCMS (+ESI) M+H.sup.+=373.
.sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.65-7.63 (m, 2H),
7.16-7.11 (m, 3H), 6.81 (d, J=2.69 Hz, 1H), 6.69 (dd, J=13.69, 2.69
Hz, 1H), 3.52-3.35 (m, 2H), 3.20-3.16 (m, 1H), 3.07 (dd, J=13.57,
4.52 Hz, 1H), 2.63 (dd, J=13.69, 9.29 Hz, 1H), 2.45 (s, 6H),
2.00-1.92 (m, 1H), 1.09-0.99 (m, 2H), 0.78-0.73 (m, 2H).
[0949] The Compounds of Table 5 were prepared in the same method as
described in Example C20 by using appropriate reagents.
TABLE-US-00005 TABLE 5 Comp. No. Yield/Analytical Data C-21 White
solid, 15 mg (40%). LCMS (+ESI) M + H+ = 368. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 7.75-7.71 (m, 2 H), 7.47-7.43 (m, 2 H)
7.15 (d, J = 8.31 Hz, 1 H), 6.81 (d, J = 2.45 Hz, 1 H), 6.68 (dd, J
= 8.44, 2.57 Hz, 1 H), 3.53 (dd, J = 13.94, 8.56 Hz, 1 H), 3.39
(dd, J = 13.94, 5.38 Hz, 1 H), 3.20 (dt, J = 8.4, 4.55 Hz, 1 H),
3.08 (dd, J = 13.57, 4.52 Hz, 1 H), 2.63 (dd, J = 13.57, 9.42 Hz, 1
H), 2.46 (s, 6 H). C-22 white solid (22.5 mg, 54%). LCMS (+ESI) M +
H.sup.+ = 367.1, 369.1. .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
ppm 7.77 (t, J = 1.83 Hz, 1 H) 7.66 (dt, J = 7.76, 1.38 Hz, 1 H)
7.53 (ddd, J = 8.07, 2.08, 1.10 Hz, 1 H) 7.43 (t, J = 7.95 Hz, 1 H)
7.15 (d, J = 8.31 Hz, 1 H) 6.81 (d, J = 2.45 Hz, 1 H) 6.68 (dd, J =
8.31, 2.45 Hz, 1 H) 3.46-3.54 (m, 1 H) 3.37-3.44 (m, 1 H) 3.15-3.23
(m, 1 H) 3.07 (dd, J = 13.69, 4.65 Hz, 1 H) 2.63 (dd, J = 13.57,
9.42 Hz, 1 H) 2.45 (s, 6 H)
Example C23
##STR00456##
[0950]
(S)-3-chloro-N-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)benzami-
de (Compound C-23)
[0951] To a stirred solution of
(S)-4-(3-amino-2-(dimethylamino)propyl)phenol (21 mg, 0.08 mmol, 1
equiv) in dry DMF (3 mL) was added EDCI (92 mg, 0.48 mmol, 1.5
equiv), HOBt (65 mg, 0.48 mmol, 1.5 equiv), 3-chlorobenzoic acid
(55 mg, 0.35 mmol, 1.1 equiv), and DIPEA (340 .mu.L, 1.92 mmol, 6
equiv). After 2 h, the solution was diluted with water and
extracted with EtOAc. The combined organic layers were washed with
aq. NaHCO.sub.3 and brine, dried over anhydrous sodium sulfate, and
concentrated. The residue was purified by flash column
chromatography over silica gel (0-15% MeOH in CH.sub.2Cl.sub.2) to
afford a white solid (26 mg, 26% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.70-7.74 (m, 1H), 7.56-7.62 (m, 1H), 7.40-7.47
(m, 2H), 6.97 (d, J=8.31 Hz, 2H), 6.68-6.78 (m, 3H), 3.52-3.63 (m,
1H), 3.15-3.30 (m, 1H), 2.85-3.03 (m, 3H), 2.45 (s, 5H), 2.27-2.40
(m, 3H), 1.96 (s, 2H). LCMS: 332.2 [M].sup.+.
Examples C24-C31
##STR00457##
[0952] Synthesis of
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)pro-
pyl)benzamide (Compound C-24
[0953] Compound C-16 was synthesized according to Scheme C1 using
Int-1G and 3,4-dichlorobenzoic acid as the starting materials (78%
yield). LC-MS: 395.2 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.92 (s, 1H), 8.32 (m, 1H), 8.01 (m, 1H),
7.74-7.72 (m, 2H), 6.39 (s, 2H), 3.40-3.55 (m, 1H), 3.02-2.85 (m,
2H), 2.75-2.63 (m, 1H), 2.47-2.37 (m, 1H), 2.32 (s, 6H), 2.18 (s,
6H). The Compounds of Table 6 were prepared in the same method as
described in Example C24 by using appropriate reagents.
TABLE-US-00006 TABLE 6 Comp. No. Yield/Analytical Data C-25 89%
yield; LC-MS: 361.2 [M + 1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.92 (s, 1H), 8.24 (m, 1H), 7.82 (s, 1H),
7.78-7.73 (m, 1H), 7.57-7.46 (m, 2H), 6.40 (s, 2H), 3.52-3.47 (m,
1H), 3.01-2.88 (m, 2H), 2.73-2.64 (m, 1H), 2.47- 2.37 (m, 1H), 2.33
(s, 6H), 2.20 (s, 6H) C-26 56% yield; LC-MS: 429.2 [M + 1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.93 (s, 1H), 8.48 (m,
1H), 8.05(s, 1H), 7.96-7.90 (m, 2H), 6.40 (s, 2H), 3.51-3.39 (m,
1H), 3.02-2.91 (m, 2H), 2.76-2.68 (m, 1H), 2.49-2.38 (m, 1H), 2.34
(s, 6H), 2.20 (s, 6H) C-27 0.019 g, 19.6%; .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 8.89 (br s, 1H), 8.08 (dd, J = 9.66, 1.83 Hz,
2H), 7.98-8.05 (m, 1H), 7.76 (dd, J = 8.56, 1.71 Hz, 1H), 7.64 (d,
J = 8.80 Hz, 1H), 7.05 (dd, J = 2.20, 0.73 Hz, 1H), 6.42 (s, 2H),
3.39- 3.56 (m, 1 H), 3.28 (br s, 1H), 3.00-3.10 (m, 1H), 2.86-2.99
(m, 1H), 2.66- 2.80 (m, 1H), 2.28-2.46 (m, 6H), 2.22 (s, 6H). LC-MS
(+ESI) M + H: 429.2. C-28 white solid, 29 mg (70%). LCMS (+ESI) M +
H+ = 355. .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. 7.45 (d,
J = 1.96 Hz, 1 H), 7.41 (dd, J = 7.70, 2.08 Hz, 1 H), 7.18 (d, J =
7.58 Hz, 1 H), 6.49 (s, 2 H), 3.55 (dd, J = 13.69, 8.56 Hz, 1 H),
3.25 (dd, J = 13.57, 5.26 Hz, 1 H), 3.16-3.07 (m, 1 H), 2.93 (dd, J
= 13.94, 4.40 Hz, 1 H), 2.73 (dd, J = 13.94, 10.52, 1 H), 2.50 (s,
6H), 2.31-2.30 (m, 12 H) C-29 7 mg (13%) of title compound. LCMS
(+ESI) M + H.sup.+ = 397.2, 399.2. .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. ppm 7.48 (d, J = 8.46 Hz, 2 H) 6.47 (s, 2 H)
4.84-4.89 (m, 1 H) 3.56 (dd, J = 13.69, 9.05 Hz, 1 H) 3.20-3.26 (m,
1 H) 3.15 (ddt, J = 10.58, 9.23, 4.52, 4.52 Hz, 1 H) 2.93 (dd, J =
14.06, 4.03 Hz, 1 H) 2.65-2.74 (m, 1 H) 2.49 (s, 6 H) 2.31 (s, 6 H)
C-30 white powder (55 mg, 60%). 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 7.53-7.70 (m, 3 H) 7.19 (br s, 1 H) 6.53 (s, 2 H)
3.43-3.52 (m, 1 H) 3.22 (br t, J = 11.74 Hz, 1 H) 2.85-3.05 (m, 2
H) 2.56-2.74 (m, 1 H) 2.50 (br s, 6H) 2.23 (br s, 6H) MS: ESI 413
[M + H]+ C-31 (0.062 g, 74.5%); .sup.1H NMR (400 MHz, DMSO-d6):
.delta. ppm 8.89 (br s, 1H), 8.08 (dd, J = 9.66, 1.83 Hz, 2H),
7.98-8.05 (m, 1H), 7.76 (dd, J = 8.56, 1.71 Hz, 1H), 7.64 (d, J =
8.80 Hz, 1H), 7.05 (dd, J = 2.20, 0.73 Hz, 1H), 6.42 (s, 2H),
3.39-3.56 (m, 1H), 3.28 (br s, 1H), 3.00-3.10 (m, 1H), 2.86-2.99
(m, 1H), 2.66-2.80 (m, 1H), 2.28-2.46 (m, 6H), 2.22 (s, 6H). LC-MS
(+ESI) M + H: 367.1.
Examples C32-C35
##STR00458##
[0954] Synthesis of
(S)--N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-4-(trif-
luoromethyl)benzamide (Compound C-32)
[0955] To a 1-dram vial is added amine substrate Int-1G (36.2 mg,
0.16 mmol), DMF (0.5 mL) and DIEA (0.1 mL, 0.57 mmol). To the amine
solution is added 4-trifluoromethylbenzoic acid (34.1 mg, 0.18
mmol) as a solution in DMF (0.5 mL). The homogeneous solution is
cooled to 0.degree. C. using an ice bath. Lastly, HATU (114 mg, 0.3
mmol) is added as a solid all at once. The ice bath is removed and
the solution is allowed to warm to room temperature with stirring
for 1 hour, after which time LC-MS analysis indicates complete
conversion to the desired product. The reaction is worked up by
addition of saturated aqueous NaHCO.sub.3 (20 mL) and is extracted
3 times with ethyl acetate. The combined organic layers are washed
with brine, dried over MgSO.sub.4, filtered and concentrated by
rotary evaporation. The obtained residue is purified by column
chromatography (0 to 15% methanol with 1% NH.sub.4OH in DCM) using
an Evaporative Light Scattering Detector (ELSD) for peak
visualization to afford the desired compound as a colorless oil
(15.1 mg, 24% yield). LC-MS: 395.2 m/z [M+H]+; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.85 (br d, J=8.31 Hz, 2H) 7.66 (d,
J=8.31 Hz, 2H) 6.52 (s, 2H) 3.44-3.56 (m, 1H) 3.23-3.35 (m, 1H)
3.00-3.15 (br s, 1H) 2.94 (dd, J=13.69, 3.42 Hz, 1H) 2.67 (br dd,
J=13.45, 11.49 Hz, 1H) 2.55 (s, 6H) 2.29 (s, 6H).
[0956] The Compounds of Table 7 were prepared in the same method as
described in Example C32 by using appropriate reagents.
TABLE-US-00007 TABLE 7 Comp. No. Yield/Analytical Data C-33 white
solid (55.0 mg, 97% yield). LC-MS: 377.3 m/z [M + H]+; .sup.1H NMR
(400 MHz, d6-DMSO) .delta. ppm 9.08 (br s, 1 H) 8.37 (s, 1 H)
7.96-8.03 (m, 3 H) 7.86-7.90 (m, 1 H) 7.58-7.65 (m, 3 H) 6.48 (s, 2
H) 3.44-3.95 (br m, 2 H) 3.08-3.15 (m, 1 H) 2.82-2.91 (m, 1 H) 2.41
(br s, 6H) 2.27 (s, 6 H) C-34 colorless oil (52.4 mg, 93% yield).
LC-MS: 378.3 m/z [M + H]+; .sup.1H NMR (400 MHz, d6-DMSO) .delta.
ppm 9.15 (br s, 2 H) 8.55 (d, J = 5.38 Hz, 2 H) 8.05 (br d, J =
8.31 Hz, 2 H) 7.82 (t, J = 7.34 Hz, 1 H) 7.73 (br d, J = 7.09 Hz, 1
H) 6.46 (br s, 2 H) 3.71-4.02 (m, 1 H) 3.17-3.27 (m, 1 H) 2.70-3.10
(br m, 2 H) 2.40 (br s, 6 H) 2.26 (s, 6 H) C-35 colorless oil (46.0
mg, 81% yield). LC-MS: 378.2 m/z [M + H]+; .sup.1H NMR (400 MHz,
d6-DMSO) .delta. ppm 9.37 (s, 1 H) 8.93 (br s, 1 H) 8.65 (br s, 1
H) 8.51 (s, 1 H) 8.20 (dd, J = 18.10, 8.31 Hz, 2 H) 7.76-7.91 (m, 2
H) 6.44 (s, 2 H) 3.18-3.36 (m, 2 H) 2.86-3.00 (m, 1 H) 2.72-2.86
(m, 1 H) 2.43 (br s, 6 H) 2.24 (s, 6 H)
Example C36
##STR00459##
[0957]
(S)-3-chloro-N-((7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-
-yl)methyl)benzamide (Compound C-36)
[0958] To a stirred solution of
(S)-3-(aminomethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol (21
mg, 0.11 mmol, 1 equiv) in dry DMF (1 mL) was added EDCI (32 mg,
0.17 mmol, 1.5 equiv), HOBt (23 mg, 0.17 mmol, 1.5 equiv),
3-chlorobenzoic acid (19 mg, 0.12 mmol, 1.1 equiv), and DIPEA (115
.mu.L, 0.66 mmol, 6 equiv). After 4 h, the solution was diluted
with water and extracted with EtOAc. The combined organic layers
were washed with aq. NaHCO.sub.3 and brine, dried over anhydrous
sodium sulfate, and concentrated. The residue was purified by flash
column chromatography over silica gel (0-15% MeOH in
CH.sub.2Cl.sub.2) to afford a white solid (21.5 mg, 59% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (s, 1H), 7.62 (d,
J=7.58 Hz, 1H), 7.25-7.44 (m, 2H), 7.17-7.24 (m, 3H), 6.86 (d,
J=8.31 Hz, 1H), 6.64 (dd, J=8.19, 1.83 Hz, 1H), 6.30 (br s, 1H),
3.63-3.85 (m, 3H), 3.48-3.63 (m, 1H), 3.11 (br s, 2H), 2.61-2.85
(m, 3H), 2.47 (s, 3H). LCMS: 331.1 [M].sup.+.
Examples C37-C40
##STR00460##
[0959]
(S)-2,4-dichloro-N-(2-(dimethylamino)-3-(3-fluoro-4-(methylcarbamoy-
l)phenyl) propyl) benzamide (Compound C-37)
[0960] To a stirred mixture Int-4F (0.09 g, 0.36 mmole) and DIEA
(0.055 g, 0.43 mmole) in DCM at 0.degree. C. was added
2,4-dichlorobenzoyl chloride (0.082 g, 0.39 mmole). After the
addition was completed, the reaction mixture was stirred at
0.degree. C. for 2 h. H.sub.2O was added, extracted with DCM
(3.times.). The combined extracts were dried over Na.sub.2SO.sub.4,
concentrated and purified by ISCO (0-10% MeOH/DCM in 1% NH.sub.4OH)
to give
(S)-2,4-dichloro-N-(2-(dimethylamino)-3-(3-fluoro-4-(methylcarbamoyl)phen-
yl) propyl) benzamide (0.133 g, 88.5%). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. ppm 8.31 (t, J=5.50 Hz, 1H), 8.06-8.19 (m, 1H),
7.67 (d, J=1.96 Hz, 1H), 7.55 (t, J=7.95 Hz, 1H), 7.46-7.50 (m,
1H), 7.39 (d, J=8.31 Hz, 1H), 7.11-7.19 (m, 2H), 3.32-3.41 (m, 1H),
3.14-3.23 (m, 1H), 2.95 (quin, J=6.79 Hz, 1H), 2.79-2.88 (m, 1H),
2.77 (d, J=4.65 Hz, 3H), 2.61-2.69 (m, 1H), 2.28 (s, 6H). LC-MS
(+ESI) M+H: 426.1.
[0961] The Compounds of Table 8 were prepared in the same method as
described in Example C37 by using appropriate reagents.
TABLE-US-00008 TABLE 8 Comp. No. Yield/Analytical Data C-38 58.0 mg
(73%); LCMS (+ESI) M + H.sup.+ = 466.2, M + Na.sup.+ = 488.2.
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 7.68 (s, 1 H) 7.51
(t, J = 7.95 Hz, 1 H) 7.41-7.47 (m, 2 H) 7.01 (dd, J = 7.95, 1.34
Hz, 1 H) 6.92-6.98 (m, 1 H) 3.18-3.37 (m, 3 H) 2.87 (dd, J = 13.82,
4.77 Hz, 1 H) 2.76 (s, 3 H) 2.49 (dd, J = 13.69, 8.56 Hz, 1 H)
2.23-2.41 (m, 5 H) 0.71 (dt, J = 12.11, 5.93 Hz, 1 H) 0.30-0.40 (m,
2 H) -0.01 (br d, J = 4.89 Hz, 2 H) C-39 white solid, 78 mg (76%).
LCMS (+ESI) M + H+ = 426. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 8.04 (t, J = 8.07 Hz, 1 H), 7.80 (d, J = 1.96 Hz, 1 H),
7.55-7.47 (m, 2 H), 7.08 (dd, J = 7.95, 1.59 Hz, 1 H), 6.94 (dd, J
= 12.72, 1.47 Hz, 1 H), 6.84 (br, s, 1 H), 6.65 (br, s, 1 H), 3.56
(ddd, J = 13.69, 6.85, 4.65 Hz, 1 H), 3.12-3.02 (m, 2 H), 3.02-3.00
(m, 3 H), 2.95-2.85 (m, 1 H), 2.48-2.40 (m, 1 H), 2.38 (s, 6 H)
C-40 .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 8.05-8.18 (m, 1H),
7.87 (br t, J = 5.50 Hz, 1H), 7.55 (t, J = 7.95 Hz, 1H), 7.09-7.22
(m, 3H), 6.98-7.07 (m, 2H), 3.33- 3.40 (m, 1H) 3.10-3.19 (m, 1H),
2.93-3.01 (m, 1H), 2.81-2.88 (m, 1H), 2.77 (d, J = 4.65 Hz, 3H),
2.61 (dd, J = 13.82, 6.97 Hz, 1H), 2.29 (s, 3H) 2.28 (s, 9H). LC-MS
(+ESI) M + H: 386.2.
Example C41
##STR00461##
[0962] Synthesis of
(S)-3-chloro-4-(3-(3-chlorobenzamido)-2-(dimethylaminopropyl)-N-methylben-
zamide (Compound C-41)
[0963] The title compound was prepared according to the procedure
as Example C17 starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-3-chloro-N-methylbenzamide
(42.3 mg, 0.157 mmol), 3-chlorobenzoic acid (29.5 mg, 0.188 mmol)
to afford 46.0 mg (72%) of title compound. LCMS (+ESI)
M+H.sup.+=408.1, 410.1. .sup.1H NMR (400 MHz, METHANOL-d4) .delta.
ppm 7.84 (d, J=1.71 Hz, 1H) 7.73 (t, J=1.83 Hz, 1H) 7.68 (dd,
J=7.95, 1.83 Hz, 1H) 7.65 (dt, J=7.83, 1.34 Hz, 1H) 7.50-7.55 (m,
1H) 7.39-7.48 (m, 2H) 3.50-3.57 (m, 1H) 3.38-3.45 (m, 1H) 3.25-3.31
(m, 1H) 3.19 (dd, J=13.45, 4.89 Hz, 1H) 2.91 (s, 3H) 2.82 (dd,
J=13.45, 8.80 Hz, 1H) 2.46 (s, 6H).
Examples C42-C46
##STR00462##
[0964] Synthesis of
(S)-4-(3-(3,4-Dichlorobenzamido)-2-(dimethylamino)propyl)-N,3,5-trimethyl-
benzamide Hydrochloride (Compound C-42)
[0965] Int-5H (crude, 25 mg, 0.095 mmol) in DMF (1 mL) was added 3,
4-dichlorobenzoic acid (22 mg, 0.11 mmol), HATU (43 mg, 0.11 mmol)
and IPEA (25 mg, 0.19 mmol). The mixture was stirred at ambient
temperature for 3 hours. Water and EtOAc were added. The organic
layer was washed with water (.times.3) and concentrated. The
residue was chromatographed (Silica gel, DCM/10% MeOH in DCM=9:1 to
0:1). The oil was added 2 N HCl (0.1 mL) in diethyl ether to afford
the title compound as a salt, 2.8 mg (76%). LCMS (+ESI)
M+H.sup.+=436. .sup.1H NMR (400 MHz, methanol-d4) .delta. 7.96 (d,
J=1.96 Hz, 1H), 7.73-7.60 (m, 4H), 4.08-3.96 (m, 2H), 3.40-3.23 (m,
3H), 3.22 (s, 3H), 3.16 (s, 3H), 2.96 (s, 3H), 2.55 (s, 6H).
[0966] The Compounds of Table 9 were prepared in the same method as
described in Example C42 by using appropriate reagents.
TABLE-US-00009 TABLE 9 Comp. No. Yield/Analytical Data C-43 white
solid, 2.1 mg (76%). LCMS (+ESI) M + H+ = 408. .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.41-7.26 (m, 4 H), 7.21-7.13 (m, 1 H),
6.92 (d, J = 7.83 Hz, 1 H), 6.70 (br, d, J = 6.11 Hz, 1 H), 6.12
(br, s, 1 H), 3.43 (ddd, J = 13.45, 6.97, 4.52 Hz, 1 H), 3.24-3.14
(m, 1 H), 3.03-2.90 (m, 5 H), 2.70 (dd, J = 13.08, 10.88 Hz, 1 H),
2.41 (s, 6 H), 2.39 (s, 6 H), 2.22-2.12 (m, 1 H), 1.03-0.81 (m, 4
H) C-44 LC-MS: 402.2 [M + 1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.58 (m, 1H), 7.49 (m, 1H), 7.34-7.25 (m,
4H), 3.49-3.43 (m, 1H), 3.18-3.11 (m, 2H), 2.95-2.83 (m, 1H), 2.77
(s, 3H), 2.74-2.69 (m, 1H), 2.56 (s, 6H), 2.44 (s, 6H) C-45 (0.017
g, 41.4%). .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 8.21-8.28
(m, 1H), 8.12-8.21 (m, 1H), 7.75-7.80 (m, 2H), 7.49-7.54 (m, 1H),
7.41-7.47 (m, 4H), 3.62 (m, 1H) 3.31 (s, 6H), 2.99-3.08 (m, 1H),
2.84-2.94 (m, 1H), 2.76 (d, J = 4.65 Hz, 3H), 2.61-2.72 (m, 1 H),
2.53 (br d, J = 1.71 Hz, 1H), 2.35 (s, 6H). LC-MS (+ESI) M + H:
368.2 C-46 LC-MS: 369.2 [M + 1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.58 (m, 1H), 8.03-8.00 (m, 1H), 7.96-7.91
(m, 2H), 7.52-7.47 (m, 3H), 3.55-3.31 (m, 3H), 3.26-2.21 (m, 1H),
3.18-3.09 (m, 1H), 2.90 (s, 3H), 2.88-2.87 (m, 1H), 2.56 (s, 6H),
2.44 (s, 6H)
Examples C47-C49
##STR00463##
[0967] Synthesis of
(S)--N-(3-(2,6-dimethyl-4-(methylcarbamoyl)phenyl)-2-(dimethylamino)
propyl)pyrazine-2-carboxamide (Compound C-47)
[0968] Int-5H (40 mg, 0.15 mmol) was taken in dimethylformamide
(0.6 ml) with pyrazine-2-carboxylic acid (22 mg, 0.18 mmol) and
HATU (70 mg, 0.18 mmol) was added. Diisopropylethylamine (32 mL,
0.19 mmol) was then added and the solution was stirred at room
temperature. After completion of the reaction, the reaction mixture
was concentrated and the residue was purified by reverse phase
chromatography using a gradient of water/acetonitrile in 0.1% TFA.
The solution of the product was neutralized by adding aqueous NaOH
solution. The product was extracted into dichloromethane, filtered
through magnesium sulfate and then concentrated to give the product
as a white powder (12 mg). .sup.1H NMR (400 MHz, METHANOL-d4)
.delta. ppm 9.05 (s, 1H) 8.59-8.71 (m, 1H) 8.43-8.53 (m, 1H)
7.74-8.11 (m, 1H) 7.36-7.46 (m, 2H) 3.83-4.01 (m, 2H) 3.44-3.69 (m,
1H) 3.21-3.35 (m, 1H) 2.90-3.19 (m, 6H), 2.76 (br s, 3H) 2.28-2.40
(m, 6H). MS ESI 370 [M+H].
[0969] The Compounds of Table 10 were prepared in the same method
as described in Example C47 by using appropriate reagents.
TABLE-US-00010 TABLE 10 Comp. No. Yield/Analytical Data C-48 (0.003
g, 6.8%). .sup.1H NMR (400 MHz, MeOH-d4): .delta. ppm 8.47 (d, J =
1.96 Hz, 1H), 8.06 (d, J = 1.96 Hz, 1H), 7.46 (s, 2H), 3.50-3.65
(m, 1H), 3.23-3.27 (m, 1H,) 3.25 (br d, J = 5.14 Hz, 1H), 3.05-3.14
(m, 1H), 2.89-2.95 (m, 1H), 2.88 (s, 3H), 2.59 (br s, 6H), 2.43 (s,
6H). LC-MS (+ESI) M + H: 438.3 C-49 white powder (12 mg). .sup.1H
NMR (400 MHz, DMSO-d6).delta. ppm 8.65-8.74 (br s, 1H) 8.24-8.32
(m, 2 H) 7.50-7.56 (m, 3 H) 3.62-3.70 (br s, 1 H) 3.10- 3.20 (m, 2
H) 2.82-3.30 (m 3 H), 2.76-2.78 (s, 6 H) 2.52-2.54 (m, 3 H) 2.40
(s, 6 H) 2.27-2.37 (m, 3 H)
Examples C50-C52
Synthesis of
(S)-2,4-dichloro-N-(2-(dimethylamino)-3-(1H-indazol-5-yl)propyl)
benzamide (Compound C-50)
##STR00464##
[0971] To a solution of Int-6G (200 mg, 0.54 mmol) in dry DCM (4
mL) was added DIPEA (0.32 mL, 1.88 mmol). The mixture was cooled to
0.degree. C. and a solution of 2,4-dichlorobenzoyl chloride (16 mg,
0.69 mmol) in dry DCM (2 mL) was added dropwise over 5 min. The
mixture was stirred from 0.degree. C. to room temperature
overnight. The crude mixture was diluted with ethyl acetate and
washed with sat. NaHCO.sub.3 solution and water. The organic layer
was dried over anhydrous MgSO.sub.4. After filtration and
concentration, the crude material was purified on 12 g silica gel
column, eluted with 10% MeOH in DCM: DCM (0-25%) to provide the
desired intermediate (about 193 mg), which was not pure and used
directly in the next step. LC-MS: 545.1 [M+1].sup.+.
[0972] The above intermediate was dissolved in methanol (7 mL),
then potassium carbonate (400 mg, 2.89 mmol) was added. The
resulting mixture was stirred at 55.degree. C. for 2 h. The mixture
was cooled to room temperature and diluted with ethyl acetate and
water, the aqueous later was extracted with ethyl acetate twice.
The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The crude material was
purified on 80 g silica gel column, eluted with 10% MeOH in DCM:
DCM (0-40%) to provide the desired product as a white solid. (42
mg, 20% for two steps). LC-MS: 391.1 [M+1].sup.+; .sup.1H NMR (400
MHz, MeOD-d.sub.6) .delta. 7.98 (s, 1H), 7.66 (s, 1H), 7.51-7.32
(m, 2H), 7.30-7.24 (m, 2H), 7.22 (m, 1H), 3.53-3.41 (m, 2H),
3.16-3.13 (m, 2H), 2.75-2.68 (m, 1H), 2.46 (s, 6H).
[0973] The Compounds of Table 11 were prepared in the same method
as described in Example C50 by using appropriate reagents.
TABLE-US-00011 TABLE 11 Comp. No. Yield/Analytical Data C-51 (0.025
g, 42.2%); 1H NMR (400 MHz, DMSO-d6): .delta. ppm 12.92 (s, 1H),
7.98 (s, 1H), 7.75 (t, J = 5.38 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J =
8.56 Hz, 1H), 7.22 (dd, J = 8.56, 1.47 Hz, 1H), 7.13 (d, J = 7.83
Hz, 1H), 6.92-7.04 (m, 2H), 3.32-3.39 (m, 1H), 3.13-3.22 (m, 1H),
2.87-3.00 (m, 2H), 2.56-2.65 (m, 1H), 2.30 (s, 6 H), 2.28 (d, J =
3.42 Hz, 6H). LC-MS (+ESI) M + H: 351.2. C-52 (0.011 g, 30%); 1H
NMR (400 MHz, DMSO-d6): .delta. ppm 12.92 (s, 1H), 8.32 (br dd, J =
6.85, 3.67 Hz, 1H), 8.23 (d, J = 1.71 Hz, 1H), 7.96 (s, 1H), 7.56
(s, 1H), 7.47-7.52 (m, 1H), 7.44 (d, J = 8.56 Hz, 1H), 7.20 (dd, J
= 8.56, 1.47 Hz, 1H), 3.27 (br s, 1H), 3.11-3.20 (m, 1H), 2.99 (dt,
J = 8.80, 4.40 Hz, 1H), 2.85-2.94 (m, 1H), 2.51-2.55 (m, 1H), 2.47
(s, 3H), 2.33 (s, 6H), 2.28 (s, 3H). LC-MS (+ESI) M + H: 352.2.
Examples C53-C54
##STR00465##
[0974] Synthesis of
(S)--N-((7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)-3,-
4-dihydroisoquinoline-2(1H)-carboxamide (Compound C-53)
[0975] To a stirred solution of
(S)-3-(aminomethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ol (75
mg, 0.39 mmol, 1 equiv) in dry DMF (2 mL) was added CDI (70 mg,
0.43 mmol, 1.1 equiv) under nitrogen. After 3.5 h, DIPEA (136 uL,
0.78 mmol, 2 equiv) and 1,2,3,4-tetrahydroisoquinoline (59 uL, 0.47
mmol, 1.2 equiv) were added and allowed to stir overnight. The
solution was then concentrated under vacuum and the residue was
purified by flash column chromatography over silica gel (0-15% MeOH
in CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid
(78.8 mg, 57% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.17 (br s, 2H), 7.65 (s, 1H), 7.01-7.19 (m, 5H), 6.87 (d, J=8.31
Hz, 1H), 6.68 (dd, J=8.19, 2.57 Hz, 1H), 6.51 (d, J=2.45 Hz, 1H),
5.51 (t, J=4.65 Hz, 1H), 4.45-4.54 (m, 1H), 3.37-3.77 (m, 5H),
2.91-3.00 (m, 1H), 2.81 (t, J=5.87 Hz, 2H), 2.66-2.74 (m, 1H), 2.41
(s, 2H). LCMS: 352.2 [M].sup.+.
[0976] The Compounds of Table 12 were prepared in the same method
as described in Example C53 by using appropriate reagents.
TABLE-US-00012 TABLE 12 Comp. No. Yield/Analytical Data C-54 white
solid (19.9 mg, 50% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.85 (d, J = 2.20 Hz, 1 H), 7.59 (dd, J = 8.31, 1.96 Hz, 1
H), 7.47 (d, J = 8.31 Hz, 1 H), 6.87-6.95 (m, 2 H), 6.59 (dd, J =
8.19, 2.57 Hz, 1 H), 6.45 (d, J = 2.45 Hz, 1 H), 3.65-3.80 (m, 3
H), 3.46-3.54 (m, 3 H), 2.96-3.03 (m, 1 H), 2.67- 2.81 (m, 2 H),
2.43 (s, 3 H). LCMS: 365.1 [M]
Example C55
##STR00466##
[0977] Synthesis of
(S)--N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethyphenyl)propyl)-3,4-dihy-
droisoquinoline-2(1H)-carboxamide (Compound C-55)
[0978] To a stirred solution of Int-1G (62.7 mg, 0.28 mmol, 1
equiv) in dry DMF (4 mL) was added CDI (47 mg, 0.29 mmol, 1.04
equiv) under nitrogen. After 3.5 h, DIPEA (100 uL, 0.56 mmol, 2
equiv) and 1,2,3,4-tetrahydroisoquinoline (42 uL, 0.34 mmol, 1.2
equiv) were added and allowed to stir overnight. The solution was
then concentrated under vacuum and the residue was purified by
flash column chromatography over silica gel (0-15% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a light yellow solid
(53.0 mg, 50% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.66-7.85 (m, 1H), 7.26-7.39 (m, 4H), 6.75 (s, 2H), 5.58 (dd,
J=5.62, 2.69 Hz, 1H), 4.57-4.67 (m, 2H), 3.67-3.74 (m, 2H),
3.33-3.47 (m, 2H), 2.97-3.11 (m, 4H), 2.71-2.86 (m, 1H), 2.55-2.67
(m, 6H), 2.35-2.49 (m, 6H). LCMS: 382.3 [M].sup.+.
Example C56
##STR00467##
[0979]
(S)-4-(3-(3,4-dichlorobenzamido)-2-(dimethylamino)propyl)-3,5-dimet-
hylphenyl acetate (Compound C-56)
[0980] To a stirred solution of
(S)-3,4-dichloro-N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)pro-
pyl)benzamide (Compound C-24) (200 mg, 0.46 mmol, 1 equiv) in dry
THE (10 mL) was added NAHCO.sub.3 (80 mg, 0.92 mmol, 2 equiv) and
acetic anhydride (219 .mu.L, 2.32 mmol, 5 equiv). After 18 h, the
solution was filtered, rinsed with ethyl acetate, and concentrated.
The residue was purified by flash column chromatography over silica
gel (0-10% MeOH in CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a
white solid (178 mg, 89% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 10.13 (br s, 1H), 7.85 (d, J=2.20 Hz, 1H), 7.66 (br t,
J=4.40 Hz, 1H), 7.55 (dd, J=8.31, 2.20 Hz, 1H), 7.44 (d, J=8.31 Hz,
1H), 6.77 (s, 2H), 3.26-3.51 (m, 4H), 2.91-3.03 (m, 1H), 2.76 (dd,
J=13.69, 11.49 Hz, 1H), 2.60 (s, 6H), 2.22-2.45 (m, 9H), 1.87-2.04
(m, 3H). LCMS: 437.1 [M].
Example C57
##STR00468##
[0981]
(S)-4,5-dichloro-N-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphen-
yl)propyl)-2-fluorobenzamide (Compound C-57)
[0982] To a stirred solution of (Int-1G) (26 mg, 0.12 mmol, 1
equiv) in dry DMF (2 mL) was added EDCI (35 mg, 0.18 mmol, 1.5
equiv), HOBt (24 mg, 0.18 mmol, 1.5 equiv),
4,5-dichloro-2-fluorobenzoic acid (27 mg, 0.13 mmol, 1.1 equiv),
and DIPEA (126 .mu.L, 0.72 mmol, 6 equiv). After 4 h, the solution
was diluted with water and extracted with EtOAc. The combined
organic layers were washed with aq. NaHCO.sub.3 and brine, dried
over anhydrous sodium sulfate, and concentrated. The residue was
purified by flash column chromatography over silica gel (0-15% MeOH
in CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid
(22.5 mg, 45% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.08 (d, J=7.34 Hz, 1H), 7.45-7.62 (m, 1H), 7.21-7.27 (m, 1H), 6.48
(s, 2H), 3.42-3.50 (m, 1H), 3.12-3.24 (m, 1H), 2.83-2.96 (m, 2H),
2.53-2.65 (m, 1H), 2.35-2.47 (m, 6H), 2.22-2.30 (m, 6H). LCMS:
413.1 [M].
Example C58
##STR00469##
[0983]
(S)--N-(2-(dimethylamino)-3-(3-fluoro-4-(methylcarbamoyl)phenyl)pro-
pyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound C-58)
[0984] To a stirred solution of Int-4F (50 mg, 0.2 mmol, 1 equiv)
in dry DMF (2 mL) was added CDI (33 mg, 0.2 mmol, 1.1 equiv). After
stirring at RT for 4 h under nitrogen, DIPEA (70 .mu.L, 0.4 mmol, 2
equiv) and 1,2,3,4-tetrahydroisoquinoline (30 .mu.L, 0.24 mmol, 1.2
equiv) were added and continued to stir overnight. The solution was
concentrated under vacuum and the residue was purified by flash
column chromatography over silica gel (0-15% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford a white solid (26.1
mg, 32% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.99 (t,
J=8.19 Hz, 1H), 6.99-7.20 (m, 6H), 6.93 (dd, J=12.84, 1.59 Hz, 1H),
6.69 (br dd, J=11.49, 4.65 Hz, 1H), 5.30 (br d, J=6.11 Hz, 1H),
4.47 (s, 2H), 3.47-3.60 (m, 2H), 3.37 (ddd, J=13.14, 7.03, 4.77 Hz,
1H), 2.81-3.06 (m, 9H), 2.39-2.47 (m, 1H), 2.32-2.39 (m, 6H). LCMS:
413.3 [M].sup.+.
Example C59
##STR00470##
[0985]
(S)--N-(3-(1H-indazol-5-yl)-2-(pyrrolidin-1-yl)propyl)-3,4-dichloro-
benzamide (Compound C-59)
[0986] To a stirring solution of
(S)-3,4-dichloro-N-(2-(pyrrolidin-1-yl)-3-(1-tosyl-1H-indazol-5-yl)propyl-
)benzamide (74.4 mg, 0.13 mmol, 1 equiv) in dry MeOH (3 mL) was
added K.sub.2CO.sub.3 (90 mg, 0.65 mmol, 5 equiv) and heated to
70.degree. C. After 3 h, the solution was filtered, washed with
MeOH, and concentrated. The residue was purified by flash column
chromatography over silica gel (0-15% MeOH in CH.sub.2Cl.sub.2 with
1% NH.sub.4OH) to afford a white solid (46 mg, 85% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 10.76 (br s, 1H), 7.99 (d, J=0.98
Hz, 1H), 7.76 (d, J=1.47 Hz, 1H), 7.54 (s, 1H), 7.35-7.49 (m, 3H),
7.17 (dd, J=8.56, 1.47 Hz, 1H), 6.85-6.97 (m, 1H), 3.41-3.47 (m,
2H), 3.18 (dd, J=13.45, 3.42 Hz, 1H), 2.86-2.96 (m, 1H), 2.67-2.85
(m, 5H), 1.86 (br s, 5H). LCMS: 417.1 [M].
Example C60
##STR00471##
[0987]
(S)-3,4-dichloro-N-((7-hydroxy-1,2,3,4-tetrahydroisoquinolin-3-yl)m-
ethyl)benzamide (Compound C-60)
[0988] To a stirring solution of tert-butyl
(S)-3-((3,4-dichlorobenzamido)methyl)-7-hydroxy-3,4-dihydroisoquinoline-2-
(1H)-carboxylate (1.106 g, 2.45 mmol, 1 equiv) in dry dioxane (5
mL) was added 4M HCl in dioxanes (3 mL, 12.3 mmol, 5 equiv). After
4 h, the solution was filtered, washed with MeOH, and dried under
vacuum. A small aliquot of the precipitate was purified by flash
column chromatography over silica gel (0-25% MeOH in
CH.sub.2Cl.sub.2 with 1% NH.sub.4OH) to afford 15 mg of a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11 (d, J=2.20
Hz, 1H), 7.85 (dd, J=8.44, 2.08 Hz, 1H), 7.68 (d, J=8.31 Hz, 1H)
7.47-7.55 (m, 1H), 7.07 (d, J=8.31 Hz, 1H), 6.73 (dd, J=8.56, 2.45
Hz, 1H), 6.62 (d, J=2.45 Hz, 1H), 4.24-4.34 (m, 2H), 3.63-3.83 (m,
3H), 3.34-3.37 (m, 1H), 2.99-3.07 (m, 1H), 2.86-2.96 (m, 1H). LCMS:
351.1 [M].
Example C61
##STR00472##
[0989] Synthesis of
(S)-3,4-dichloro-N-(3-(3-chloro-4-hydroxyphenyl)-2-(dimethylamino)propyl)-
benzamide (Compound C-61)
[0990] The title compound was prepared in a manner similar to
Example C8, starting with
(S)-4-(3-amino-2-(dimethylamino)propyl)-2-chlorophenol (Int-3H,
53.8 mg, 0.235 mmol), 3,4-dichlorobenzoic acid (44.9 mg, 0.235
mmol) to afford 51.3 mg (55%) of title compound. LCMS (+ESI)
M+H.sup.+=401.1, 403.1. .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
9.82 (s, 1H) 8.35 (t, J=5.50 Hz, 1H) 8.01 (d, J=1.71 Hz, 1H)
7.71-7.78 (m, 2H) 7.17 (d, J=1.96 Hz, 1H) 6.97 (dd, J=8.31, 1.96
Hz, 1H) 6.85 (d, J=8.07 Hz, 1H) 3.39 (ddd, J=13.45, 7.83, 5.62 Hz,
1H) 3.12-3.20 (m, 1H) 2.84-2.97 (m, 1H) 2.69-2.75 (m, 1H) 2.39 (dd,
J=13.94, 7.83 Hz, 1H) 2.27 (s, 6H).
Examples C62-C.sub.64
Synthesis of
(S)-3,4-dichloro-N-(2-((cyclopropylmethyl)(methyl)amino)-3-(1H-indazol-5--
yl)propyl)benzamide (Compound C-62)
##STR00473##
[0991] Step 1: Preparation of
(S)-2-(2-((cyclopropylmethyl)(methyl)amino)-3-(1-tosyl-1H-indazol-5-yl)pr-
opyl)isoindoline-1,3-dione (Int-6H)
[0992] To a stirred mixture of Int-6E (0.3 g, 0.59 mmole), in
MeCN/H2O (4:1, 10 mL) was added cyclopropanecarbaldehyde (0.045 g,
0.65 mmole). The stirring was continued for 30 minutes, NaCNBH3
(0.055 g, 0.88 mmole) was added and stirred for 30 minutes. 37%
formaldehyde (0.14 g, 1.76 mmole) and continued to stir for 15
minutes, NaCNBH.sub.3 (0.055 g, 0.88 mmole) was finally added. The
reaction mixture was stirred for 1 h, saturated aqueous NH.sub.4Cl
was added, extracted with DCM (3.times.). The combined extracts
were dried over Na.sub.2SO.sub.4, concentrated and purified by ISCO
(0-10% MeOH/DCM) to give (S)-2-(2-((cyclopropylmethyl)
(methyl)amino)-3-(1-tosyl-1H-indazol-5-yl)propyl)isoindoline-1,3-dione
(0.26 g, 80.2%). LC-MS (+ESI) M+H: 543.2.
Step 2: Preparation of
(S)--N2-(cyclopropylmethyl)-N2-methyl-3-(1-tosyl-1H-indazol-5-yl)propane--
1,2-diamine (Int-6I)
[0993] To a stirred mixture of Int-6H (0.25 g, 0.46 mmole) in EtOH
(5 mL) was added hydrazine (0.074 g, 2.31 mmole). The reaction
mixture was heated to 90.degree. C. for 2 h, cooled to RT, and the
solid was filtered off, washed with EtOAc. The filtrate was
concentrated and purified by ISCO (0-15% MeOH/DCM in 1% NH.sub.4OH)
to give Int-6I (0.16 g, 83.7%). LC-MS (+ESI) M+H: 413.2.
Step 3: Preparation of (S)-3,4-dichloro-N-(2-((cyclopropylmethyl)
(methyl)amino)-3-(1-tosyl-1H-indazol-5-yl)propyl)benzamide
(Int-6J)
[0994] A mixture of Int-6I (0.16 g, 0.38 mmole),
3,4-dichlorobenzoic acid (0.09 g, 0.38 mmole), HOBT (0.03 g, 0.2
mmole), EDC (0.08 g, 0.46 mmole), and DIEA (0.13 g, 0.96 mmole) in
DMF (3 mL) was stirred for 16 h. H.sub.2O was added and the solid
was collected, washed with H.sub.2O, dried and purified by ISCO
(50% EtOAc/DCM) to give Int-6J (0.18 g, 81.1%). LC-MS (+ESI) M+H:
585.2.
Step 4: Synthesis of
(S)-3,4-dichloro-N-(2-((cyclopropylmethyl)(methyl)amino)-3-(1H-indazol-5--
yl)propyl) benzamide (Compound C-62)
[0995] A mixture of Int-6J (0.18 g, 0.31 mmole) and K.sub.2CO.sub.3
(0.22 g, 1.56 mmole) in MeOH (5 mL) was heated to 70.degree. C. in
2 h. The mixture was cooled to RT, H.sub.2O was added, adjusted
pH=6-7 with 5N HCl, extracted with DCM (3.times.). The extracts
were dried over Na.sub.2SO.sub.4, concentrated, and purified by
ISCO (0-15% MeOH/DCM in 1% NH.sub.4OH) to give Compound C-65 (0.054
g, 39.7%). .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 12.92 (s,
1H), 8.32 (t, J=5.14 Hz, 1H), 7.95 (dt, J=5.01, 1.04 Hz, 2H), 7.72
(d, J=1.22 Hz, 2H), 7.55 (s, 1H), 7.43 (d, J=8.56 Hz, 1H), 7.21
(dd, J=8.56, 1.47 Hz, 1H), 3.37-3.46 (m, 1H), 3.12-3.22 (m, 2H),
2.90 (dd, J=13.94, 4.89 Hz, 1H), 2.58 (dd, J=13.57, 7.46 Hz, 1H),
2.39 (t, J=6.60 Hz, 2H), 2.35 (s, 3H), 0.68-0.79 (m, 1H), 0.38 (dd,
J=7.70, 5.75 Hz, 2H), 0.04 (br d, J=1.96 Hz, 2H). LC-MS (+ESI) M+H:
431.2.
[0996] The Compounds of Table 13 were prepared in the same method
as described in Example C62 by using appropriate reagents.
TABLE-US-00013 TABLE 13 Comp. No. Yield/Analytical Data C-63 (0.034
g, 71%); .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 12.95 (s, 1
H), 8.44 (t, J = 5.26 Hz, 1H), 7.92-8.00 (m, 2H), 7.73 (s, 2H),
7.61 (s, 1H), 7.45 (d, J = 8.31 Hz, 1H,) 7.25 (d, J = 8.56 Hz, 1H),
3.39-3.48 (m, 1H), 3.23-3.32 (m, 2H), 3.19 (dt, J = 14.73, 5.35 Hz,
2H), 2.86-2.94 (m, 1H), 2.73 (dd, J = 13.82, 7.46 Hz, 1H), 2.47 (s,
3H). LC-MS (+ESI) M + H: 459.1. C-64 (60 mg, 48%). 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 10.78 (br s, 1 H) 8.02 (s, 1 H) 7.85 (br
s, 1 H) 7.44-7.60 (m, 3 H) 7.29-7.43 (m, 1 H) 7.11- 7.28 (m, 2 H)
3.62 (br s, 1 H) 3.16 (br d, J = 13.45 Hz, 3 H) 2.81 (br s, 2 H)
2.58 (br s, 3H) 1.17 (br s, 6 H) LC-MS (+ESI) M + H: 420.
Example C65
Synthesis of
(S)-4-chloro-N-(2-(dimethylamino)-3-(2H-indazol-5-yl)propyl)-3-fluorobenz-
amide (Compound C-65)
##STR00474##
[0998] The title compound was prepared in the same method as
described in previous examples. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 10.5 (br s, 1H) 7.99 (d, J=0.98 Hz, 1H) 7.54 (s, 1H)
7.49 (dd, J=10.03, 1.22 Hz, 1H) 7.37-7.42 (m, 3H) 7.17 (dd, J=8.56,
1.71 Hz, 1H) 6.98 (br d, J=5.62 Hz, 1H) 3.59 (ddd, J=13.69, 6.73,
4.77 Hz, 1H) 3.12-3.20 (m, 2H) 2.90-2.98 (m, 1H) 2.38-2.54 (m,
7H)
Example C66
Synthesis of
(S)--N-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-[1,1'-biphenyl]-2-ca-
rboxamide (Compound C-66)
##STR00475##
[1000] The title compound was prepared in the same method as
described in previous examples. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 7.70 (d, J=8.0 Hz, 1H) 7.46-7.50 (m, 1H) 7.35-7.45 (m,
7H), 6.89 (d, J=8.0 Hz, 2H) 6.79 (d, J=8.0 Hz, 2H) 6.20 (d, J=6.0
Hz, 1H) 3.38-3.44 (m, 1H) 2.70-2.76 (m, 1H) 2.03-2.14 (m, 2H) 1.97
(s, 6H)
Example C67
Synthesis of
(S)--N-(3-(4-carbamoylphenyl)-2-(dimethylamino)propyl)-2,4-dimethylbenzam-
ide (Compound C-67)
##STR00476##
[1002]
(S)--N-(3-(4-carbamoylphenyl)-2-(dimethylamino)propyl)-2,4-dimethyl-
benzamide was synthesized according to the general procedure using
(S)-4-(3-amino-2-(dimethylamino)propyl)benzamide and
2,4-dimethylbenzoic acid as the starting materials. LC-MS: 354.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.91 (br s,
1H), 7.87 (brt, 1H, J=4.8 Hz), 7.79 (d, 2H, J=7.8 Hz), 7.30 (d, 3H,
J=7.8 Hz), 7.14 (d, 1H, J=7.6 Hz), 7.06-6.97 (m, 2H), 3.13 (m, 1H),
2.95 (m, 1H), 2.85 (dd, 1H, J=13.6, 6.4 Hz), 2.58 (dd, 1H, J=13.6,
7.2 Hz), 2.28 (s, 12H).
Example C68
Synthesis of
(S)-4-(2-(dimethylamino)-3-(2-methoxybenzamido)propyl)-N,3,5-trimethylben-
zamide (Compound C-68)
##STR00477##
[1004] The title compound was prepared in the same method as
described in previous examples. .sup.1H NMR (400 MHz, DMSO-d6):
.delta. ppm 8.33 (br t, J=4.52 Hz, 1H), 8.17 (q, J=4.48 Hz, 1H),
7.73 (dd, J=7.83, 1.71 Hz, 1H), 7.35-7.43 (m, 3H), 7.06 (d, J=7.83
Hz, 1H), 6.94 (td, J=7.46, 0.98 Hz, 1H), 3.82 (s, 3H), 3.08-3.15
(m, 2H), 2.78-2.88 (m, 2H), 2.67 (d, J=4.40 Hz, 3H), 2.54-2.61 (m,
1H), 2.34 (s, 6H), 2.28 (s, 6H). LC-MS (+ESI) M+H: 398.2.
Example D1
In Vitro Activity
MOR Agonist and Antagonist Assays
[1005] MOR cAMP Agonist Assay
[1006] The ability of test compounds to activate the mu opioid
receptor (MOR) assay was evaluated at Multispan Inc. (26219 Eden
Landing Road, Hayward, Calif. 94545) in stably transfected cell CHO
cell expressing the mOR receptor (CHO-K1 Multispan Inc., Cat
#C1350-1a) by measuring cAMP levels in cells treated with the test
compounds using a commercial kit (cAMP Hi-Range Kit; Cisbio, Cat
#62AM6PEC). The activity of test compounds is recorded in Table 14,
below, as their EC.sub.50, the concentration the test compound,
which induces a response halfway between the baseline and its
maximal response. With respect to MOR activity, "+++" denotes an
EC.sub.50 less than 100 nM; "++" denotes an EC.sub.50 from 100 nM
to 1,000 nM; and "+" denotes an EC.sub.50 greater than 1,000
nM.
MOR cAMP Antagonist Assay
[1007] The ability of test compounds to antagonize or inhibit the
mu opioid receptor (MOR) assay was evaluated at Multispan Inc.
(26219 Eden Landing Road, Hayward, Calif. 94545) in stably
transfected cell CHO cell expressing the mOR receptor (CHO-K1
Multispan Inc., Cat #C1350-1a) by measuring cAMP levels in cells
treated with the test compounds using a commercial kit (cAMP
Hi-Range Kit; Cisbio, Cat #62AM6PEC) after activation of the
receptor with the mOR agonist DAMGO at the EC.sub.80. The activity
of test compounds is recorded in Table 14, below, as their
IC.sub.50, the concentration the test compound, which induces a
response halfway between the baseline and its maximal response.
With respect to MOR activity, "+++" denotes an IC.sub.50 less than
100 nM; "++" denotes an IC.sub.50 from 100 nM to 1,000 nM; and "+"
denotes an IC.sub.50 greater than 1,000 nM.
MOR GTP.gamma.S Agonist Assay
[1008] The ability of test compounds to activate the mu opioid
receptor (MOR) assay was evaluated at Multispan Inc. (26219 Eden
Landing Road, Hayward, Calif. 94545) in stably transfected cell CHO
cell expressing the MOR receptor (CHO-K1 Multispan Inc., Cat
#C1350-1a). Membranes obtained from the stable cell lines
over-expressing MOR were subjected to GTP.gamma.S assay using SPA
beads (Perkin Elmer, Cat #RPNQ0001). The activity of test compounds
is recorded in Table 14, below, as their EC.sub.50, the
concentration the test compound, which induces a response halfway
between the baseline and its maximal response. With respect to MOR
activity, "+++" denotes an EC.sub.50 less than 100 nM; "++" denotes
an EC.sub.50 from 100 nM to 1,000 nM; and "+" denotes an EC.sub.50
greater than 1,000 nM.
KOR cAMP Antagonist Assay
[1009] The ability of compounds to inhibit the kappa opioid
receptor (KOR) was evaluated at Multispan Inc. (26219 Eden Landing
Road, Hayward, Calif. 94545) in stably transfected cell CHO cell
expressing the kOR receptor (CHO-K1 Multispan Inc., Cat #C1352-1a)
by measuring cAMVP levels after activation of the kOR receptor with
dynorphin B in cells treated with the compound. cAMP levels were
measured with a commercial kit (cAMP Hi-Range Kit; Cisbio, Cat
#62AM6PEC). The activity of test compounds is recorded in Table 14,
below, as the IC.sub.50, the concentration at which test compounds
inhibit 5000 of the activation induced by dynorphin B. With respect
to KOR activity, "+++" denotes an IC.sub.50 less than 100 nM; "++"
denotes an IC.sub.50 from 100 nM to 1,000 nM; and "+" denotes an
IC.sub.50 greater than 1,000 nM.
TABLE-US-00014 TABLE 14 Activity of Representative Compounds
Compound mOR cAMP MOR GTP.gamma.S MOR cAMP kOR cAMP No. EC.sub.50
EC.sub.50 IC.sub.50 IC.sub.50 A-1 + --- --- ++ A-2 + --- --- + A-3
+++ --- --- + A-4 +++ --- --- +++ A-5 ++ --- --- +++ A-6 ++ --- ---
++ A-7 + --- --- ++ A-8 + --- --- + A-9 + --- --- + A-10 + --- ---
++ A-11 + --- --- ++ A-22 --- +++ +++ --- A-23 --- +++ +++ --- B-1
+++ --- --- +++ B-2 +++ --- --- + B-3 +++ --- --- + B-4 +++ --- ---
++ B-5 +++ --- --- +++ B-6 +++ --- --- ++ B-7 +++ --- --- +++ B-8
+++ --- --- ++ B-9 ++ --- --- + B-10 ++ --- --- ++ B-11 ++ --- ---
+ B-12 + --- --- +++ B-13 +++ --- --- +++ B-14 +++ --- --- + B-15 +
--- --- + B-16 + --- --- + B-17 +++ --- --- ++ B-18 --- --- --- ++
B-19 +++ --- --- + B-20 +++ --- --- + B-21 +++ --- --- --- B-22 +++
--- --- --- B-23 +++ --- --- --- B-24 --- --- --- ++ B-25 ++ ---
--- --- B-26 +++ --- --- --- B-27 +++ --- --- --- B-28 +++ --- ---
--- B-29 +++ --- --- --- B-30 --- --- +++ +++ B-31 +++ --- +++ +++
B-32 ++ --- --- --- B-33 --- --- --- --- B-34 +++ --- --- --- B-35
--- --- --- --- B-36 --- --- +++ +++ B-37 --- --- --- --- B-38 ---
--- --- --- B-39 +++ --- --- + B-40 +++ --- --- + B-41 +++ --- ++
++ B-42 +++ --- +++ ++ B-43 + --- --- + B-44 --- --- --- + B-45 ---
--- --- --- B-46 +++ --- --- + B-47 +++ --- +++ --- B-48 + --- +++
+++ B-49 +++ --- --- + B-50 +++ --- --- --- B-51 +++ --- --- ---
B-52 +++ --- --- --- B-53 +++ --- --- --- B-54 +++ --- --- ++ B-55
--- --- +++ +++ B-56 +++ --- --- +++ B-57 --- --- --- --- B-58 ++
--- --- + B-59 +++ --- --- --- B-60 +++ --- --- +++ B-61 +++ ---
--- + B-62 +++ --- --- ++ C-1 --- --- +++ --- C-2 --- --- +++ ---
C-3 --- + --- --- C-4 --- +++ --- --- C-5 --- +++ --- --- C-6 ---
+++ --- --- C-7 --- --- +++ --- C-8 --- --- +++ --- C-9 --- C-10
--- ++ --- --- C-11 --- +++ --- --- C-12 --- +++ --- --- C-13 ---
+++ --- --- C-14 --- +++ --- --- C-15 --- +++ --- --- C-16 --- +++
--- --- C-17 --- +++ --- --- C-18 --- +++ --- --- C-19 --- ++ ---
--- C-20 --- + --- --- C-21 --- + --- --- C-22 --- +++ + ++ C-23
--- ++ --- --- C-24 --- +++ +++ +++ C-25 --- +++ --- --- C-26 ---
+++ +++ --- C-27 --- +++ +++ --- C-28 --- +++ +++ --- C-29 --- +++
--- --- C-30 --- +++ +++ --- C-31 --- +++ +++ --- C-32 --- +++ ++
--- C-33 --- +++ +++ --- C-34 --- +++ +++ --- C-35 --- +++ +++ ---
C-36 --- +++ --- --- C-35 --- +++ --- --- C-38 --- +++ --- --- C-39
--- +++ +++ --- C-40 --- +++ +++ + C-41 --- +++ --- --- C-42 ---
+++ --- --- C-43 --- +++ --- --- C-44 --- +++ --- --- C-45 --- +++
--- + C-46 --- + --- --- C-47 --- + --- --- C-48 --- ++ --- ---
C-49 --- ++ --- --- C-50 --- ++ --- --- C-51 --- ++ --- --- C-52
--- + --- --- C-53 --- +++ --- --- C-54 --- +++ +++ --- C-55 --- +
--- --- C-56 --- --- +++ --- C-57 --- +++ +++ --- C-58 --- +++ ---
--- C-59 --- ++ +++ --- C-60 --- +++ +++ --- C-61 --- +++ +++ ---
C-62 --- ++ --- --- C-63 --- + --- --- C-64 --- +++ +++ --- C-65
--- +++ --- --- C-66 --- + + ++ C-67 --- +++ --- + C-68 --- +++ ---
---
Example D2
In Vivo Activity
Hot Plate Assay
[1010] Male Sprague-Dawley rats weighing 275-300 grams were used in
the study, n=8-10 per group. Animals are injected SC with 0.9%
normal saline solution. At 15, 45, and 80 min after the injection,
animals were placed onto a hotplate set to 52 degrees centigrade,
and baseline latency is recorded (baseline latency=average time to
2.sup.nd withdrawal response consisting of either a lick of a rear
paw, shaking a rear paw, backwards walking or jumping). A day later
animals were injected SC with test compounds either in vehicle
solution, or with a mix of compounds in solution. Next the test
latency was recorded (test latency=time to withdrawal on the
hotplate measured at 15, 45, 80, 120, 180 and 240 min using the
procedure described). Times were then converted to % maximum
possible effect (% MPE)=(test_latecy-baseline_latency)/(30
sec-baseline_latency); where 30 sec is the cutoff where the animal
is removed if no response ifs observed as it is the time point at
which injury is expected to occur.
[1011] FIG. 1 shows that MOR agonist Compound B-56 is analgesic in
the hotplate test as it increased the time to exhibit a withdrawal
response in the hotplate test. This is indicative of central
activation of MORs as peripheral MOR agonists have been shown to
have limited efficacy in this test (Emerich, D. F., et al., Brain
Research, 1998, 801(1-2):259-266). Further, MOR antagonists
Compound B-15 blocks in vivo the analgesic activity of the agonist
Compound B-56, when co-dosed, but has no effect on its own (see
FIG. 1).
Respiratory Depression Assay
[1012] Male Sprague-Dawley rats weighing 275-300 grams were used in
this strudy, n=4-6 per group. The animals were placed into a whole
body unrestrained plethysmograph, and baseline breathing was
recorded for 15 minutes. Next, animals were injected SC with
fentanyl (3 mg/kg SC), and breathing was monitored for 10-12 min.
Next animals were injected with test compound, either naloxone (0.1
mg/kg SC) or Compound B-15 (30 mg/kg SC), and breathing was
recorded for up to 4 hrs. Post-hoc an experimenter blinded to the
treatment conditions analyzed the trace as previously described
(Laferriere, A., et al., Developmental Brain Research, 2005,
156(2):210-217) and minute volume (MV=tidal volume.times.breaths
per minute) was calculated for each animal. Data is presented in
FIG. 2 as a % of the average of the baseline period (post drug
MV/average baseline MV).
[1013] The various embodiments described above can be combined to
provide further embodiments. All of the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet are incorporated herein by reference, in their entirety.
Aspects of the embodiments can be modified, if necessary to employ
concepts of the various patents, applications and publications to
provide yet further embodiments.
[1014] This application claims the benefit of priority to U.S.
Provisional Application No. 62/652,819, filed Apr. 4, 2018, and
U.S. Provisional Application No. 62/792,754, filed Jan. 15, 2019,
which applications are hereby incorporated by reference in their
entirety.
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