Note: Descriptions are shown in the official language in which they were submitted.
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BETA ADRENERGIC AGONIST AND METHODS OF USING THE SAME
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional App. No.
62/869,448, filed
July 1,2019, U.S. Provisional App. No. 62/934,482, filed November 12,2019,
U.S. Provisional
App. No. 63/018,431, filed April 30, 2020, U.S. Serial No. 16/831,285, filed
March 26, 2020
and U.S. Serial No. 16/831,370, filed March 26, 2020, the contents of each of
which is hereby
incorporated by reference in their entirety.
FIELD
[0002] The present disclosure relates generally to chemical compounds and,
in some
embodiments, to beta adrenergic agonists and uses in the treatment of diseases
associated
with an adrenergic receptor.
BACKGROUND
[0003] PCT Application Publication Number W02017197324 discloses
laldrenergic
receptor modulating compounds and methods of treating a subject for a disease
or condition
associated with an adrenergic receptor including administering a
therapeutically effective
amount of the subject compound."
[0004] United States Patent Application Publication Number 20130096126
discloses "a
method for enhancing learning or memory of both in a mammal having impaired
learning or
memory or both from a neuro-degenerative disorder, which entails the step of
administering at
least one compound or a salt thereof which is a (31-adrenergic receptor
agonist, partial agonist
or receptor ligand in an amount effective to improve the learning or memory or
both of said
mammal."
[0005] United States Patent Application Publication Number 20140235726
discloses "a
method of improving cognition in a patient with Down syndrome, which entails
administering
one or more 132 adrenergic receptor agonists to the patient in an amount and
with a frequency
effective to improve cognition of the patient as measured by contextual
learning tests."
[0006] United States Patent Application Publication Number 20160184241
discloses "a
method of improving cognition in a patient with Down syndrome, which entails
intranasally
administering one or more 132-ADR agonists or pharmaceutically-acceptable
salts of either or
both to the patient in an amount and with a frequency effective to improve
cognition of the
patient as measured contextual learning tests."
1
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SUMMARY
[0007] The present disclosure is based at least in part on the
identification of compounds
that modulate adrenergic receptor and methods of using the same to treat
diseases associated
with an adrenergic receptor. Disclosed herein is a compound according to
Formula (I) or an
optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or
prodrug thereof
OH
A N R5
I I
(R1 )rn
X
:1
G
Formula (I)
[0008] In some embodiments of Formula (I), each Ri is independently
selected from the
group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or
substituted amino,
pentafluorosulfanyl, unsubstituted or substituted sulfonyl, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted
alkenyl,
unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted ¨(C=0)-alkyl, unsubstituted or substituted ¨(C=0)-cycloalkyl,
unsubstituted or substituted ¨(C=0)-aryl, unsubstituted or substituted ¨(C=0)-
heteroaryl,
unsubstituted or substituted aryl, and unsubstituted or substituted
heteroaryl.
[0009] In some embodiments of Formula (I), m is an integer selected from 0
to 3.
[0010] In some embodiments of Formula (I), each A, B, and X is
independently a nitrogen
or carbon.
[0011] In some embodiments of Formula (I), P is N, 0, or CR2; Q is N, 0, or
CR2; G is
NR5 or 0; and/or Z is NR5, 0, S, or CR3R4. In some embodiments, R2 is selected
from the
group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted
or substituted
amino, unsubstituted or substituted alkyl, and unsubstituted or substituted
alkoxy. In certain
embodiments, each R3 and R4 is selected from the group consisting of hydrogen,
halogen,
cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or
substituted alkyl,
and unsubstituted or substituted alkoxy.
2
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[0012] In some embodiments of Formula (I), Rs is one or more selected from the
group
consisting of H, unsubstituted or substituted alkyl, unsubstituted or
substituted alkoxy,
unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl,
unsubstituted or
substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or
substituted
heteroaryl,
4 Riu
1-
,,R6 1_¨>q¨"X2
1_114.:(R9)ri
(RO o-N
11)--
n
-\(R,J), 1_L
, fl
L is a C1-05 alkyl linker optionally substituted; each Xi, X2, X3, and X4 is
independently
a covalent bond, a carbon, an oxygen, or a nitrogen, optionally substituted
with hydrogen,
unsubstituted or substituted alkyl, or unsubstituted or substituted
cycloalkyl; Y is 0 or S;
R6 and R7 are independently selected from hydrogen, unsubstituted or
substituted alkyl, or
R6 and R7 are cyclically linked and together with X2 to form an optionally
substituted
cycloalkyl or heterocycle; each Rs is independently selected from the group
consisting of
hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino,
unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy,
unsubstituted or
substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or
substituted heteroaryl;
n is an integer selected from 0 to 4; R9 is selected from the group consisting
of hydrogen,
halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or
substituted alkoxy, and
unsubstituted or substituted amino; and Rio is selected from the group
consisting of
hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or
substituted
alkoxy.
[0013] Also
disclosed herein is a compound according to Formula (II) or an optically pure
stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof
3
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OH
A ,<R7
(R1)rn R6
X R5
G
Formula (II)
[0014] In some embodiments of Formula (II), each Ri is independently
selected from
the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or
substituted
amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl,
unsubstituted or
substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or
substituted alkenyl,
unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted ¨(C=0)-alkyl, unsubstituted or substituted ¨(C=0)-cycloalkyl,
unsubstituted or substituted ¨(C=0)-aryl, unsubstituted or substituted ¨(C=0)-
heteroaryl,
unsubstituted or substituted aryl, and unsubstituted or substituted
heteroaryl.
[0015] In some embodiments of Formula (II), m is an integer selected from 0
to 3.
[0016] In some embodiments of Formula (II), each A, B, and X is
independently a
nitrogen or carbon.
[0017] In some embodiments of Formula (II), P is N, 0, or CR2; Q is N, 0,
or CR2; G
is NRs or 0; and/or Z is NRs, 0, S, or CR3R4.
[0018] In some embodiments of Formula (ID, R2 is selected from the group
consisting of
hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino,
unsubstituted
or substituted alkyl, and unsubstituted or substituted alkoxy.
[0019] In some embodiments of Formula (II), each R3 and R4 is selected from
the group
consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or
substituted amino,
unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
[0020] In some embodiments of Formula (II), Rs, R6, and R7 are
independently selected
from the group consisting of H, unsubstituted or substituted alkyl,
unsubstituted or
substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or
substituted
alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted
aryl,
unsubstituted or substituted heteroaryl,
4
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rX4 ,R12
A /R8 X3 X3 so FL-Xi X2 * kig>
(R10)n (R10) N-Nn
Frr µ(R11)n
R9 X4
N-(R11)
0¨N
0¨k(Rii)n 10 ¨(R11) ¨(Ri
1)n
0n N
hi2 1-LN? 1-LN
(R11)n FL
* (R11)n N (R11)n
FL, and IN
or R5 and R6 together with the carbon form an unsubstituted or substituted 3-7
membered
cycloalkyl or heterocycle ring; L is a C1-05 alkyl linker optionally
substituted; each Xi, X2,
X3, and X4 is independently a covalent bond, a carbon, an oxygen, or a
nitrogen, optionally
substituted with hydrogen, unsubstituted or substituted alkyl, or
unsubstituted or
substituted cycloalkyl; Y is 0 or S; Rs and R9 are independently selected from
hydrogen,
unsubstituted or substituted alkyl, or Rs and R9 are cyclically linked and
together with X2
to form an optionally substituted cycloalkyl or heterocycle; each Rio is
independently
selected from the group consisting of hydrogen, halogen, cyano, nitro,
hydroxyl,
unsubstituted or substituted amino, unsubstituted or substituted alkyl,
unsubstituted or
substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or
substituted
alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted
aryl, and
unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4;
Rii is selected
from the group consisting of hydrogen, halogen, cyano, unsubstituted or
substituted alkyl,
unsubstituted or substituted alkoxy, and unsubstituted or substituted amino;
and R12 is
selected from the group consisting of hydrogen, cyano, unsubstituted or
substituted alkyl,
and unsubstituted or substituted alkoxy.
[0021] Also disclosed herein is a compound according to Formula (I'):
OH
,131( N
DI Ai I
(R =')m, _X' R10' R11'
W'
Formula (I')
or a pharmaceutically acceptable salt, wherein:
A', B', W', and X' are each independently a nitrogen atom or carbon atom;
Ring D' is a fused ring selected from benzo, 5-9 membered monocyclic or
bicyclic
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heteroaryl containing 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur,
and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or
heterocyclyl having 1-
3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -0-, -OR', -
NR'2, -SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated
heterocyclic ring having
1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
a 5-6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur, or:
two RA groups on the same carbon or are optionally taken together with their
intervening atoms to form an optionally substituted 3-6 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
from which the two RA groups are attached, independently selected from
nitrogen, oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with
their intervening atoms to form an optionally substituted 4-10 membered
saturated or partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
6
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Y'
'
R2' is selected from hydrogen, RA, -OR', R9
rX4' R12'
x3' 1110 (Rit)n, x3' 1110 (Rii.)n,
3'
NCX4' )(R11'1
in ,
N¨ (R13')
0¨N IN __ (R13')n'
A/
R12' N HL'( 11, R¨)n' EL'
11 _____ (R13), I ,....¨(R13')FL n'
NA
, and N =
L' is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent
bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and Rth' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2, to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RH' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN;
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2; and
R7' and le are each independently hydrogen or optionally substituted C1-2
aliphatic.
7
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D'
.)m.
[0022] As described herein, a structure depicted as (R1 , includes for
________________________________________________________ D'
(R1 ,)m, ________________________________________ (R )m.
example, structures , and
[0023] Also disclosed herein is a compound according to Formula (II'):
OH
H R6'
D' 11
(Rt)m. ,x, R10. R11. R4.
W'
Formula (II')
or a pharmaceutically acceptable salt, wherein:
A', B', W', and X' are each independently a nitrogen atom or carbon atom;
Ring D' is a fused ring selected from benzo, 5-9 membered monocyclic or
bicyclic
heteroaryl containing 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur,
and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or
heterocyclyl having 1-
3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -0-, -OR', -
NR'2, -SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur, or:
two RA groups on the same carbon or are optionally taken together with their
intervening atoms to form an optionally substituted 3-6 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
from which the two RA groups are attached, independently selected from
nitrogen, oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
8
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having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
CN, -NO2,
(X4'
Y'
0
II IRio' X3' X3'
HU¨Xi' 2. (R11')n, (16 (R1")
9'
-OR', -NR'2, R
R12'
N---N N---- (R13),,,
I ( __ \
X3'
k(R13')n, .,_.
FL' N
1 ,,,
)/ (R1 1' )n, I-L' R ,,' FL' N
,
r N ,N
(R13
FL' (Ria) .)n, ri __ (R13.)n,
,... .../....;......-
n, FL'
, and
/
hL'.--g -
N , or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from 3-7 membered saturated
carbocyclic
ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having
1-4
heteroatoms independently selected from nitrogen, oxygen, and sulfur; an
optionally
substituted 3-7 membered saturated or a partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, and
sulfur;
L' is an optionally substituted C1-5 alkylene;
9
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X", X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and RH' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2, to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RIP is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN;
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2; and
R7' and le are each independently hydrogen or optionally substituted C1-2
aliphatic.
[0024] Also disclosed herein is a compound according to Formula
OH
H
6' N
(R1 )m
R4'
P'
I
Z'
Formula (III')
or a pharmaceutically acceptable salt thereof, wherein:
A', B', and X' are each independently a nitrogen atom or carbon atom;
P' and Q' are each independently ¨N=, -NR'-, -CR'=, or -CR'2-;
G' is -NR'- or -0-;
Z' is =NR% =0, =S, or =CR'2;
¨ is a single bond or double bond;
each RP is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -OR', -NR'2,
-C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
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each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m is an integer selected from 0 to 3;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
Y'
H ,,Rio'
L'¨X1 X2 ( R11' )n,
R9' NCX4'
=
CN, -NO2, -OR', -NR'2,
X4' R12'
(R13'),.
_______________________ )
x3' le (R11.)n, ___ ( X3'
,,, (Rit)n, FL' Riz
0¨N N __ (R13') n'
FFL' =><(Ri 3')n, L' L'
11
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I (R1 3')n'
L'
, and , or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from a 3-7 membered saturated
carbocyclic
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a
partially unsaturated
monocyclic heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, and sulfur;
L' is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and Rth' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2', to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RH' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN; and
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2.
12
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[0025] Further disclosed herein is a compound with the following structure:
OH
Pi .....
. I
!AN, 1
=.:),=-
.....-- Ne...õ...,
1 i
O
Compound 04-1
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug
thereof
[0026] Further disclosed herein is a compound with the following structure:
L- ,OH
e--- , -=,-.
i,......,----
N '0
Ã
Me
Compound 04-2
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug
thereof
[0027] Further disclosed herein is a compound with the following structure.
N-"),.....,
.''' NH
OH
mil' -0 0
Compound 04-3
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug
thereof
13
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[0028] Further disclosed herein is a compound with the following structure:
'NH
41111IP
F
Compound 04-4
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug
thereof
[0029] Further disclosed herein is a compound with the following structure:
OH
N
HNJ.õ
If
Compound 04-5
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug
thereof
[0030] Also disclosed herein is a compound according to Formula (IV'):
OH
H R6'
N
R3a' XI R7 R8' R4'
B
R3b' (R
Formula (IV')
or a pharmaceutically acceptable salt thereof, wherein:
A', B', and X' are each independently a nitrogen atom or carbon atom;
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -0-, -OR', -
NR'2, -SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
14
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heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
R3" and R3b' are independently hydrogen, RA, -OR', -C(0)R', -C(0)NR'2, or -
CO2R', or:
R3' and R31' are optionally taken together with their intervening atoms to
form an
optionally substituted 4-10 membered saturated or partially unsaturated
carbocyclic or
heterocyclic ring having 1-3 heteroatoms, in addition to the nitrogen from
which R3" and R31'
are attached, independently selected from nitrogen, oxygen, and sulfur;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
Y' x3,
I- LI_X1X2H ,Rio'
1110 (R11')n,
' X4'
CN, -NO2, -OR', -NR'2, R9
X4' R12'
N-14 (R13'),.
2
x3' = (Ri ')n, ____ ( X3'
N
,,
''(Rh 1), FL' FL' Ri 2'
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=
0¨N ft __ (R13.)n, (R13')õ,
hNuAs/-
FL'
HL(R13)n'
I _õ.¨(R13')n'
FL'
FL'
,and N ,or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from a 3-7 membered saturated
carbocyclic
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a
partially unsaturated
monocyclic heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, and sulfur;
L' is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and Rth' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2', to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RH' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN;
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2; and
R7' and le are each independently hydrogen or optionally substituted C1-2
aliphatic.
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[0031] Also disclosed herein
is a compound according to Formula (V'):
OH
H R6'
NN
R4'
H2N
(R1'),,
Formula (V')
or a pharmaceutically acceptable salt thereof, wherein:
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -OR', -NR'2,
-SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
R10' X3'
FL-X1JLX2'- (R11)
' X4'
CN, -NO2, -OR', -NR'2, R9
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R12'
N-14
)(3' (R11')n, _______ ( X3' YN 2
N (Rit) F
n, L' Ri2'
r0-N (R3) ii __
FL'
(R13')n'
-HR13')n'
I ,.....¨(R13')n'
FL'
FL'
,and N ,or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from a 3-7 membered saturated
carbocyclic
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a
partially unsaturated
monocyclic heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, and sulfur;
L is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y1' is 0 or S;
R9' and R1 ' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2', to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RH' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12 is hydrogen, RA, or -CN; and
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each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2.
[0032] Further disclosed herein is a compound with the following structure:
OH H
H2N
CI
or a pharmaceutically acceptable salt thereof
[0033] Further disclosed herein is a compound with the following structure:
N
H2N
CI
or a pharmaceutically acceptable salt thereof
[0034] Further disclosed herein is a compound according to Formula (VI'):
R3a' OH H
R6'
R3b .,N N N R5
\\X' R4'
B'
(R1'),,
Formula (VI'),
or a pharmaceutically acceptable salt thereof,
wherein each of A', B', X', R3a', R31', R4', R5', R6', and m' is as
defined above
and as described in embodiments provided herein, both singly and in
combination.
[0035] Further disclosed herein is a compound according to Formula (VIP):
OH H
R6'
HON N R5'
A'B \X R4'
(RI)m,
Formula (VII'),
or a pharmaceutically acceptable salt thereof,
wherein each of A', B', X', R4', R5', R6', and m' is as defined above and
as
described in embodiments provided herein, both singly and in combination.
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[0036] Also
disclosed herein is a pharmaceutical composition including a compound as
disclosed herein, i.e., a compound with a structure of Formula (I), Formula
(I'), Formula (II),
Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'),
Formula (VII'), or a
pharmaceutically acceptable excipient.
[0037] In
certain embodiments a compound as disclosed herein is an agonist, partial
agonist
or antagonist of an adrenergic receptor; in some embodiments the compound is a
01-adrenergic
receptor agonist, 02-adrenertic receptor agonist or non-selective 01/02-
adrenergic receptor
agonist; in some embodiments the compound is a 01-adrenergic receptor agonist;
in some
embodiments the compound is a 02-adrenergic receptor agonist; in some
embodiments the
compound is a compound is a non-selective 01/02-adrenergic agonist.
[0038] Further
disclosed is a method of treating a subject with a disease, the method
including administering to the subject a therapeutically effective amount of a
compound as
disclosed herein, i.e., a compound with a structure of Formula (I), Formula
(I'), Formula (II),
Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), or
Formula (VII').
In some embodiments, the disease is a disease associated with an adrenergic or
receptor.
In some embodiments, the disease is a neurodegenerative disease. In some
embodiments, the
subject is a human.
[0039] In some
embodiments, the disease is selected from myocardial infarction, stroke,
ischemia, Alzheimer's disease, Parkinson's disease, Gehrig's disease
(Amyotrophic Lateral
Sclerosis), Huntington's disease, Multiple Sclerosis, senile dementia,
subcortical dementia,
arteriosclerotic dementia, AIDS-associated dementia, other dementias, cerebral
vasculitis,
epilepsy, Tourette's syndrome, Wilson's disease, Pick's disease, encephalitis,
encephalomyelitis, meningitis, prion diseases, cerebellar ataxias, cerebellar
degeneration,
spinocerebellar degeneration syndromes, Friedrich's ataxia, ataxia
telangiectasia, spinal
dysmyotrophy, progressive supranuclear palsy, dystonia, muscle spasticity,
tremor, retinitis
pigmentosa, striatonigral degeneration, mitochondrial encephalomyopathies, and
neuronal
ceroid lipofuscinosis. In some embodiments, the compound is administered to
the subject
through oral, enteral, topical, inhalation, transmucosal, intravenous,
intramuscular,
intraperitoneal, subcutaneous, intranasal, epidural, intracerebral,
intracerebroventricular,
epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac,
intracavernous,
intradermal, intralesional, intraocular, intraosseous infusion,
intraperitoneal, intrathecal,
intrauterine, intravaginal, intravesical, intravitreal, transdermal,
perivascular, buccal, vaginal,
sublingual, or rectal route.
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[0040] In some
embodiments, the disease is a neurodegenerative disease that is one or more
selected from the group consisting of MCI (mild cognitive impairment), aMCI
(amnestic MCI),
Vascular Dementia, Mixed Dementia, FTD (fronto-temporal dementia; Pick's
disease), HD
(Huntington disease), Rett Syndrome, PSP (progressive supranuclear palsy), CBD
(corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (Multiple
system atrophy),
SDS (Shy¨Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain
injury), CTE
(chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome;
alcoholic
dementia & thiamine deficiency), normal pressure hydrocephalus,
hypersomnia/narcolepsy,
ASD (autistic spectrum disorders), FXS (fragile X syndrome), TSC (tuberous
sclerosis
complex), prion-related diseases (CJD etc.), depressive disorders, DLB
(dementia with Lewy
bodies), PD (Parkinson's disease), PDD (PD dementia), ADHD (attention deficit
hyperactivity
disorder), Alzheimer's disease (AD), early AD, and Down Syndrome (DS). In some
embodiments the disease is a neurodegenerative disease that is one or more
selected from the
group consisting of MCI, aMCI, Vascular Dementia, Mixed Dementia, FTD (fronto-
temporal
dementia; Pick's disease), HD (Huntington disease), Rett Syndrome, PSP
(progressive
supranuclear palsy), CBD (corticobasal degeneration), SCA (spinocerebellar
ataxia), MSA
(Multiple system atrophy), SDS (Shy¨Drager syndrome), olivopontocerebellar
atrophy, TBI
(traumatic brain injury), CTE (chronic traumatic encephalopathy), stroke, WKS
(Wernicke-
Korsakoff syndrome; alcoholic dementia & thiamine deficiency), normal pressure
hydrocephalus, hypersomnia/narcolepsy, ASD (autistic spectrum disorders), FXS
(fragile X
syndrome), TSC (tuberous sclerosis complex), prion-related diseases (CJD
etc.), depressive
disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD
dementia),
and ADHD (attention deficit hyperactivity disorder). In some embodiments the
subject does
not have Alzheimer's disease (AD). In some embodiments the subject does not
have Down
Syndrome.
[0041] In
certain embodiments of the methods disclosed herein, the methods include
administering to the subject a compound as disclosed herein and a peripherally
acting 13-blocker
(PABRA).
[0042] As used
herein, the term "peripherally acting 13-blocker (PABRA)" means a (3
adrenergic receptor antagonist or simply a 131-, 132- or non-selective 13-
blocker. Examples of
selective peripherally acting 13-blockers (PABRA) that may in certain
embodiments be used in
the methods disclosed herein include nadolol, atenolol, sotalol and labetalol.
In certain
embodiments a 13-blocker that can be used in the methods herein is one or more
selected from
the group consisting of acebutolol, betaxolol, bisoprolol, celiprolol,
esmolol, metaprolol ad
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nevivolol; in other embodiments the methods do not use acebutolol, betaxolol,
bisoprolol,
celiprolol, esmolol, metaprolol or nevivolol as a 13-blocker.
[0043] In
certain embodiments a peripherally acting 13-blocker (PABRA) is administered
to
the subject prior to administration of a compound of the disclosure; in other
embodiments a
peripherally acting 13-blocker (PABRA) is administered to the subject
concurrently with the
administration of a compound of the disclosure.
[0044] In
certain embodiments of the compositions and methods provided herein, one or
more peripherally acting 13-blockers (PABRA) are administered prior to or
concurrently with a
compound of the disclosure in order to inhibit or preclude agonism of
peripheral 131 and/or 132
adrenergic receptors by a compound of the disclosure. In various embodiments
it is preferred
to block peripheral 131 and/or 132 adrenergic receptors in accordance with the
compositions and
methods of the present disclosure in order to preclude, or at least minimize,
any adverse
peripheral cardiac, metabolic or muscular effects on humans being treated.
[0045] In some
embodiments of the methods provided herein, a 131 agonist, a 132 agonist, or
a non-selective 131 / 132 agonist is administered to the patient in addition
to a compound as
disclosed herein.
[0046] As used
herein, the term 131 agonist" is used to mean 131-adrenergic receptor agonist
or 131-ADR agonist. In certain embodiments the term 131 agonist is understood
to include
compounds that are primarily 131 agonists, but which may also exhibit some
peripheral agonism
for other adrenergic receptors, such as 132-adrenergic receptors. In this
application, the terms
"131-adrenergic receptor agonist", "131-ADR agonist", "131AR agonist" and 131
agonist" may
be used interchangeably. In certain embodiments, the term 131-ADR agonist
expressly includes
both selective and partial agonists, as well as biased and non-biased
agonists. Examples of
131 adrenergic agonists include, for example, xamoterol, noradrenalin,
isoprenaline, dopamine,
pindolol and dobutamine and the pharmaceutically-acceptable salts of any of
the above. Partial
agonists and ligands of the 131-ADR are known. Further, using the methodology
of Kolb et al,
but for 131-ADR instead, one skilled in the art could determine new ligands by
structure-based
discovery. See Proc. Natl. Acad. Sci. USA 2009, 106, 6843-648.
[0047] As used
herein, the term 132 agonist is used to mean 132-adrenergic receptor agonist
or 132-ADR agonist. In certain embodiments, the term 132 agonist is understood
to include
compounds that are primarily 132 agonists, but which may also exhibit some
peripheral agonism
for other adrenergic receptors, such as 131-adrenergic receptors. In this
application the terms
"132-adrenergic receptor agonist", "132-ADR agonist", "132AR agonist" and 132
agonist" may
be used interchangeably. In some embodiments the term 132-ADR agonist
expressly includes
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both selective and partial agonists. 132 agonists that may be used in
accordance with various
aspects and embodiments of the present disclosure may be short-acting, long-
acting or ultra
long-acting. Examples of short-acting 132 agonists that may be used are
salbutamol,
levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol,
bitolterol mesylate,
oritodrine, isoprenaline, salmefamol, fenoterol, terbutaline, albuterol, and
isoetharine.
Examples of long-acting 132 agonists that may be used are salmeterol,
bambuterol, formoterol
and clenbuterol. Examples of ultra long-acting 132 agonists include
indacaterol, vilanterol and
olodaterol.
[0048] It was
surprisingly found that compounds of the present disclosure exhibit
unexpectedly beneficial properties, as demonstrated in the Examples section
herein. For
instance, it was surprisingly found that compounds of the present disclosure
act as low nM (<
nM) partial agonists of the 132 adrenergic receptor.
DETAILED DESCRIPTION
[0049] In the
following detailed description of the embodiments of the instant disclosure,
numerous specific details are set forth in order to provide a thorough
understanding of the
disclosed embodiments. However, it will be obvious to one skilled in the art
that the
embodiments of this disclosure may be practiced without these specific
details. In other
instances, well known methods, procedures, components, and circuits have not
been described
in detail so as not to unnecessarily obscure aspects of the embodiments of the
instant
disclosure.
[0050] The
following explanations of terms and methods are provided to better describe
the
present disclosure and to guide those of ordinary skill in the art in the
practice of the present
disclosure. 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. The term "comprises" means "includes."
Thus, "comprising
A or B," means "including A, B, or A and B," without excluding additional
elements. The term
"about" will be understood by persons of ordinary skill in the art. Whether
the term "about" is
used explicitly or not, every quantity given herein refers to the actual given
value, and it is also
meant to refer to the approximation to such given value that would be
reasonably inferred based
on the ordinary skill in the art.
[0051] It is
further to be understood that all base sizes or amino acid sizes, and all
molecular
weight or molecular mass values, given for nucleic acids or polypeptides are
approximate, and
are provided for description. Although methods and materials similar or
equivalent to those
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described herein can be used in the practice or testing of this disclosure,
suitable methods and
materials are described below.
[0052] Unless
otherwise explained, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the art to
which this
disclosure belongs. Definitions of common terms in molecular biology may be
found in
Benjamin Lewin, Genes V, published by Oxford University Press, 1994 (ISBN 0-19-
854287-
9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by
Blackwell
Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular
Biology
and Biotechnology: a Comprehensive Desk Reference, published by VCH
Publishers, Inc.,
1995 (ISBN 1-56081-569-8).
[0053] Unless
indicated otherwise, the nomenclature of substituents that are not explicitly
defined herein are arrived at by naming the terminal portion of the
functionality followed by
the adjacent functionality toward the point of attachment. A person of
ordinary skill in the art
would recognize that the above definitions are not intended to include
impermissible
substitution patterns (e.g., methyl substituted with 5 different groups,
pentavalent carbon, and
the like). Such impermissible substitution patterns are easily recognized by a
person of ordinary
skill in the art. All publications, patent applications, patents, and other
references mentioned
herein are incorporated by reference in their entirety. All sequences provided
in the disclosed
Genbank Accession numbers are incorporated herein by reference as available on
Aug. 11,
2011. In case of conflict, the present specification, including explanations
of terms, will
control. In addition, the materials, methods, and examples are illustrative
only and not intended
to be limiting.
[0054] Alkyl
groups refer to univalent groups derived from alkanes by removal of a
hydrogen atom from any carbon atom, which include straight chain and branched
chain with
from 1 to 12 carbon atoms, and typically from 1 to about 10 carbons or in some
embodiments,
from 1 to about 6 carbon atoms, or in other embodiments having 1, 2, 3 or 4
carbon atoms.
Examples of straight chain alkyl groups include, but are not limited to,
methyl, ethyl, n-propyl,
n-butyl, n-pentyl, and n-hexyl groups. Examples of branched chain alkyl groups
include, but
are not limited to isopropyl, isobutyl, sec-butyl and tert-butyl groups. Alkyl
groups may be
substituted or unsubstituted. Representative substituted alkyl groups may be
mono-substituted
or substituted more than once, such as, but not limited to, mono-, di-, or tri-
substituted. As used
herein, the term alkyl, unless otherwise stated, refers to both cyclic and
noncyclic groups.
[0055] The
terms "cyclic alkyl" or "cycloalkyl" refer to univalent groups derived from
cycloalkanes by removal of a hydrogen atom from a ring carbon atom. Cycloalkyl
groups are
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saturated or partially saturated non-aromatic structures with a single ring or
multiple rings
including isolated, fused, bridged, and spiro ring systems, having 3 to 14
carbon atoms, or in
some embodiments, from 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6 or 7
carbon atoms. Cycloalkyl
groups may be substituted or unsubstituted. Representative substituted
cycloalkyl groups may
be mono-substituted or substituted more than once, such as, but not limited
to, mono-, di-, or
tri-substituted. Examples of monocyclic cycloalkyl groups include, but are not
limited to
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of multi-
cyclic ring
systems include, but are not limited to, bicycle[4.4.0]decane,
bicycle[2.2.11heptane,
spiro[2.2]pentane, and the like. (Cycloalkyl)oxy refers to -0-cycloalkyl.
(Cycloalkyl)thio
refers to -S-cycloalkyl. This term also encompasses oxidized forms of sulfur,
such as -S(0)-
cycloalkyl, or --S(0)2-cycloalkyl.
[0056] Alkenyl
groups refer to straight and branched chain and cycloalkyl groups as defined
above, with one or more double bonds between two carbon atoms. Alkenyl groups
may have 2
to about 12 carbon atoms, or in some embodiment from 1 to about 10 carbons or
in other
embodiments, from 1 to about 6 carbon atoms, or 1, 2, 3 or 4 carbon atoms in
other
embodiments. Alkenyl groups may be substituted or unsubstituted.
Representative substituted
alkenyl groups may be mono-substituted or substituted more than once, such as,
but not limited
to, mono-, di-, or tri-substituted. Examples of alkenyl groups include, but
are not limited to,
vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl,
cyclohexenyl,
butadienyl, pentadienyl, and hexadienyl, among others.
[0057] Alkynyl
groups refer to straight and branched chain and cycloalkyl groups as defined
above, with one or more triple bonds between two carbon atoms. Alkynyl groups
may have 2
to about 12 carbon atoms, or in some embodiment from 1 to about 10 carbons or
in other
embodiments, from 1 to about 6 carbon atoms, or 1, 2, 3 or 4 carbon atoms in
other
embodiments. Alkynyl groups may be substituted or unsubstituted.
Representative substituted
alkynyl groups may be mono-substituted or substituted more than once, such as,
but not limited
to, mono-, di-, or tri-substituted. Exemplary alkynyl groups include, but are
not limited to,
ethynyl, propargyl, and -CC(CH3), among others.
[0058] Aryl
groups are cyclic aromatic hydrocarbons that include single and multiple ring
compounds, including multiple ring compounds that contain separate and/or
fused aryl groups.
Aryl groups may contain from 6 to about 18 ring carbons, or in some
embodiments from 6 to
14 ring carbons or even 6 to 10 ring carbons in other embodiments. Aryl group
also includes
heteroaryl groups, which are aromatic ring compounds containing 5 or more ring
members,
one or more ring carbon atoms of which are replaced with heteroatom such as,
but not limited
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to, N, 0, and S. Aryl groups may be substituted or unsubstituted.
Representative substituted
aryl groups may be mono-substituted or substituted more than once, such as,
but not limited to,
mono-, di-, or tri-substituted. Aryl groups include, but are not limited to,
phenyl, biphenylenyl,
triphenylenyl, naphthyl, anthryl, and pyrenyl groups. Aryloxy refers to -0-
aryl. Arylthio refers
to -S-aryl, wherein aryl is as defined herein. This term also encompasses
oxidized forms of
sulfur, such as -S(0)-aryl, or -S(0)2-aryl. Heteroaryloxy refers to -0-
heteroaryl. Heteroarylthio
refers to -S-heteroaryl. This term also encompasses oxidized forms of sulfur,
such as -S(0)-
heteroaryl, or -S(0)2-heteoaryl. N-oxides are also contemplated. In some
embodiments, a
compound of the present disclosure is in the form of an N-oxide.
[0059] Suitable
heterocyclyl groups include cyclic groups with atoms of at least two
different elements as members of its rings, of which one or more is a
heteroatom such as, but
not limited to, N, 0, or S. Heterocyclyl groups may include 3 to about 20 ring
members, or 3
to 18 in some embodiments, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring
members. The ring
systems in heterocyclyl groups may be unsaturated, partially saturated, and/or
saturated.
Heterocyclyl groups may be substituted or unsubstituted. Representative
substituted
heterocyclyl groups may be mono-substituted or substituted more than once,
such as, but not
limited to, mono-, di-, or tri-substituted. Exemplary heterocyclyl groups
include, but are not
limited to, pyrrolidinyl, tetrahydrofuryl,
dihydrofuryl, tetrahydrothienyl,
tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl,
piperazinyl,
azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,
tetrahydrothiophenyl,
tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl,
pyrazolyl, pyrazolinyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl,
thietanyl,
homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-
tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl,
purinyl,
quinolizinyl, cinnolinyl, phthalazinyl, pteridinyl, and benzothiazolyl groups.
Heterocyclyloxy
refers to -0-heterocycyl. Heterocyclylthio refers to -S-heterocycyl. This term
also encompasses
oxidized forms of sulfur, such as -5(0)-heterocyclyl, or -5(0)2-heterocyclyl.
[0060]
Polycyclic or polycyclyl groups refer to two or more rings in which two or
more
carbons are common to the two adjoining rings, wherein the rings are "fused
rings"; if the rings
are joined by one common carbon atom, these are "spiro" ring systems. Rings
that are joined
through non-adjacent atoms are "bridged" rings. Polycyclic groups may be
substituted or
unsubstituted. Representative polycyclic groups may be substituted one or more
times.
[0061] Halogen
groups include F, Cl, Br, and I; nitro group refers to ¨NO2; cyano group
refers to ¨CN; isocyano group refers to -NEC; epoxy groups encompass
structures in which an
26
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oxygen atom is directly attached to two adjacent or non-adjacent carbon atoms
of a carbon
chain or ring system, which is essentially a cyclic ether structure. An
epoxide is a cyclic ether
with a three-atom ring.
[0062] An
alkoxy group is a substituted or unsubstituted alkyl group, as defined above,
singular bonded to oxygen. Alkoxy groups may be substituted or unsubstituted.
Representative
substituted alkoxy groups may be substituted one or more times. Exemplary
alkoxy groups
include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy,
hexoxy,
isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, and
cyclohexyloxy groups.
[0063] Thiol
refers to ¨SH. Thiocarbonyl refers to (=S). Sulfonyl refers to -S02-alkyl, -
S02-
substituted alkyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -
S02-substituted
aryl, -S02-heteroaryl, -S 02-substituted heteroaryl, -S02-heterocyclyl, and -
S02-substituted
heterocyclyl. Sulfonylamino refers to -NRaS02alkyl, -NRaS02-substituted alkyl,
-
NRaS02cycloalkyl, --NRaS 025ub5tituted cycloalkyl, -NRaS02a1yl, -NRaS
025ub5tituted aryl, -
-NRaS 02heter0 aryl, -NRaS 02 substituted heteroaryl, -NRaS02heterocyclyl, -
NRaS 02
substituted heterocyclyl, wherein each Ra independently is as defined herein.
[0064] Carboxyl
refers to -COOH or salts thereof Carboxyester refers to -C(0)0-alkyl, -
C(0)0- substituted alkyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)(3-
cycloalkyl, -C(0)0-
substituted cycloalkyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -
C(0)0-
heterocyclyl, and -C(0)0-substituted heterocyclyl. (Carboxyester)amino refers
to -NRa-
C(0)0-alkyl, -NRa-C(0)0-substituted alkyl, -NRa-C(0)0-a1yl, -NRa-C(0)0-
substituted aryl,
-NRa-C(0)(3-cycloalkyl, --NRa-C(0)0-substituted cycloalkyl, -NRa-C(0)0-
heteroaryl, --NRa-
C(0)0-substituted heteroaryl, -NRa-C(0)0-heterocyclyl, and -NRa-C(0)0-
substituted
heterocyclyl, wherein Ra is as recited herein. (Carboxyester)oxy refers to -0-
C(0)0-alkyl, -0-
C(0)0- substituted alkyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl, -0-C(0)(3-
cycloalkyl, -
0-C(0)0-substituted cycloalkyl, -0-C(0)0-heteroaryl, -0-C(0)0-substituted
heteroaryl, -0-
C(0)0-heterocyclyl, and -0-C(0)0-substituted heterocyclyl. Oxo refers to (=0).
[0065] The
terms "amine" and "amino" refer to derivatives of ammonia, wherein one of
more hydrogen atoms have been replaced by a substituent which include, but are
not limited to
alkyl, alkenyl, aryl, and heterocyclyl groups. In some embodiments,
substituted amino can
include -NH-CO-R. Carbamate groups refers to ¨0(C=0)NR1R2, where Ri and R2 are
independently hydrogen, aliphatic groups, aryl groups, or heterocyclyl groups.
[0066]
Aminocarbonyl refers to -C(0)N(R1)2, wherein each Rb independently is selected
from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,
substituted
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cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted
heterocyclyl. Also, each
Rb may optionally be joined together with the nitrogen bound thereto to form a
heterocyclyl or
substituted heterocyclyl group, provided that both Rb are not both hydrogen.
Aminocarbonylalkyl refers to -alkylC(0)N(Rb)2, wherein each Rb independently
is selected
from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,
substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted
heterocyclyl. Also, each
Rb may optionally be joined together with the nitrogen bound thereto to form a
heterocyclyl or
substituted heterocyclyl group, provided that both Rb are not both hydrogen.
Aminocarbonylamino refes to -NRaC(0)N(Rb)2, wherein Ra and each Rb are as
defined herein.
Aminodicarbonylamino refers to -NRaC(0)C(0)N(Rb)2, wherein Ra and each Rb are
as defined
herein. Aminocarbonyloxy refers to -0-C(0)N(R1)2, wherein each Rb
independently is as
defined herein. Aminosulfonyl refers to -SO2N(R1)2, wherein each Rb
independently is as
defined herein.
[0067] Imino refers to -N=Rc wherein RC may be selected from hydrogen,
aminocarbonylalkyloxy, substituted aminocarbonylalkyloxy,
aminocarbonylalkylamino, and
substituted aminocarbonylalkylamino.
[0068] As
described herein, compounds of the present disclosure may contain "optionally
substituted" moieties. In general, the term "substituted," whether preceded by
the term
"optionally" or not, means that one or more hydrogens of the designated moiety
are replaced
with a suitable substituent. Unless otherwise indicated, an "optionally
substituted" group may
have a suitable substituent at each substitutable position of the group, and
when more than one
position in any given structure may be substituted with more than one
substituent selected from
a specified group, the substituent may be either the same or different at
every position.
Combinations of substituents envisioned by this disclosure are preferably
those that result in
the formation of stable or chemically feasible compounds. The term "stable,"
as used herein,
refers to compounds that are not substantially altered when subjected to
conditions to allow for
their production, detection, and, in certain embodiments, their recovery,
purification, and use
for one or more of the purposes disclosed herein.
[0069] Suitable
monovalent substituents on a substitutable carbon atom of an "optionally
substituted" group are independently halogen; -(CH2)0_4R ; -(CH2)0_40R ; -
0(CH2)0-4R , -0-
(CH2)0_4C(0)0W); -(CH2)o_4CH(OR )2; -(CH2)o_45R ; -(CH2)0_4Ph, which may be
substituted
with R ; -(CH2)0_40(CH2)0_113h which may be substituted with R ; -CH=CHPh,
which may be
substituted with R ; -(CH2)0_40(CH2)0_1-pyridyl which may be substituted with
R ; -NO2; -
CN; -N3; -(CH2)0_4N(R )2; -(CH2)0_4N(R )C(0)R ; -N(R )C(S)R ; -(CH2)0-
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4N(R )C(0)NR 2; -N(R )C(S)NR 2; -(CH2)0_4N(R )C(0)0R ;
N(R )N(R )C(0)R ; -N(R )N(R )C(0)NR 2; -N(R )N(R )C(0)0R ; -(CH2)0_4C(0)R ; -
C(S)R ; -(CH2)o_4C(0)0R ; -(CH2)0_4C(0)SR ; -(CH2)0_4C(0)0SiR 3; -
(CH2)0_40C(0)R ; -
0C(0)(CH2)o_4SR); SC(S)SR ; -(CH2)o_4SC(0)R ; -(CH2)o_4C(0)NR 2; -C(S)NR 2; ¨
C(S)SR ; -S C(S)SR ; -(CH2)o_40C(0)NR 2; -C(0)N(OR )R ; -C(0)C(0)R ; -
C(0)CH2C(0)R ; -C(NOR )R ; -(CH2)0_4S SR ; -(CH2)0_4S (0)2R ; -(CH2)0_4S
(0)20R ; -
(CH2)o_40 S (0)2R ; -S (0)2NR 2; -S(0)(NR )R ; -
S(0)2N=C(NR 2)2; -(CH2)o-
4S (0)R ; -N(R )S(0)2NR 2; -N(R )S (0)2R ; -N(OR )R
; -C(NH)NR 2; -
P (0)2R ; -P(0)R 2; -0P(0)R 2; -0P(0)(OR )2; -SiR 3; -(Ci_4 straight or
branched
alkylene)O¨N(R )2; or -(Ci_4 straight or branched alkylene)C(0)0¨N(R )2,
wherein each R
may be substituted as defined below and is independently hydrogen, C1-6
aliphatic, -CH2Ph, -
0(CH2)0_11311, -CH2-(5-6 membered heteroaryl ring), or a 5-6¨membered
saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or, notwithstanding the definition above, two independent
occurrences of
R , taken together with their intervening atom(s), form a 3-12¨membered
saturated, partially
unsaturated, or aryl mono¨ or bicyclic ring having 0-4 heteroatoms
independently selected
from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
[0070] Suitable
monovalent substituents on R (or the ring formed by taking two
independent occurrences of R together with their intervening atoms), are
independently
halogen, -(CH2)0_2R*; -(haloR'); -(CH2)0_20H; -
(CH2)0_20R*; -(CH2)o-
2CH(OR')2; -0(haloR'); -CN; -N3; -(CH2)0_2C(0)R.; -(CH2)0_2C(0)0H; -
(CH2)0_2C(0)0R.;
-(CH2)0_25R*; -(CH2)o_25H; -(CH2)0_2NH2; -(CH2)0_2NHR.; -(CH2)o_2NR*2; -NO2, -
SiRs3; -
0SiRs3; -C(0)SR., -(C1_4 straight or branched alkylene)C(0)0R*; or -SSR*
wherein each R*
is unsubstituted or where preceded by "halo" is substituted only with one or
more halogens,
and is independently selected from C1-4 aliphatic, -CH2Ph, ¨0(CH2)o-1Ph, or a
5-6 membered
saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms
independently selected
from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a
saturated carbon atom of
R include =0 and S.
[0071] Suitable
divalent substituents on a saturated carbon atom of an "optionally
substituted" group include the following: =0; =S; =NNR*2; =NNHC(0)R*;
=NNHC(0)0R*;
=NNHS(0)2R*; =NR*; =NOR*; -0(C(R*2))2_30-; or -S(C(R*2))2_3S-; wherein each
independent
occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be
substituted as defined
below, or an unsubstituted 5-6¨membered saturated, partially unsaturated, or
aryl ring having
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0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Suitable divalent
substituents that are bound to vicinal substitutable carbons of an "optionally
substituted" group
include: -0(CR*2)2_30-, wherein each independent occurrence of R* is selected
from hydrogen,
C1-6 aliphatic which may be substituted as defined below, or an unsubstituted
5-6¨membered
saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms
independently selected
from nitrogen, oxygen, or sulfur.
[0072] Suitable
substituents on the aliphatic group of R* include halogen, -
R*; -(haloR'); -OH, -OR'; -0(haloRs); -CN; -C(0)0H; -C(0)OR'; -NH2; -NHR*; -
NR*2; or
-NO2; wherein each R* is unsubstituted or where preceded by "halo" is
substituted only with
one or more halogens, and is independently C1-4 aliphatic, -CH2Ph; -
0(CH2)0_11311; or a 5-6¨
membered saturated; partially unsaturated; or aryl ring having 0-4 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur.
[0073] Suitable
substituents on a substitutable nitrogen of an "optionally substituted" group
include -Rt; -NR12; -C(0)R1; -C(0)0R1; -C(0)C(0)R1;
C(0)CH2C(0)Rt; -S(0)2R; -S(0)2NRt2; -C(S)NR"r2; -C(NH)NR"r2; or -N(R)S(0)2R;
wherein
each Rt is independently hydrogen, C1-6 aliphatic which may be substituted as
defined below,
unsubstituted ¨0Ph, or an unsubstituted 5-6¨membered saturated, partially
unsaturated, or aryl
ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or,
notwithstanding the definition above, two independent occurrences of Rt, taken
together with
their intervening atom(s) form an unsubstituted 3-12¨membered saturated,
partially
unsaturated, or aryl mono¨ or bicyclic ring having 0-4 heteroatoms
independently selected
from nitrogen, oxygen, or sulfur.
[0074] Suitable
substituents on the aliphatic group of Rt are independently halogen, -
R*; -(haloRs); -OH; -0R*; -0(haloRs); -CN; -C(0)0H; -C(0)OR'; -NH2; -NHR*; -
NR*2;
or -NO2; wherein each R* is unsubstituted or where preceded by "halo" is
substituted only with
one or more halogens, and is independently C1-4 aliphatic, -CH2Ph; -0(CH2)o-
1Ph; or a 5-6¨
membered saturated; partially unsaturated; or aryl ring having 0-4 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur.
[0075]
Additionally, unless otherwise stated, structures depicted herein are also
meant to
include compounds that differ only in the presence of one or more isotopically
enriched atoms.
For example, compounds having the present structures including the replacement
of hydrogen
by deuterium (e.g., D or H2) or tritium (e.g., T or H3), or the replacement of
a carbon by a 13C-
or "C-enriched carbon are included and are within the scope of this
disclosure. Such
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compounds are useful, for example, as analytical tools, as probes in
biological assays, or as
therapeutic agents in accordance with the present disclosure
[0076]
Pharmaceutically acceptable salts of compounds described herein include
conventional nontoxic salts or quaternary ammonium salts of a compound, e.g.,
from non-toxic
organic or inorganic acids. For example, such conventional nontoxic salts
include those derived
from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic,
phosphoric,
nitric, and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic,
maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic,
fumaric,
toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and
the like. In other
cases, described compounds may contain one or more acidic functional groups
and, thus, are
capable of forming pharmaceutically acceptable salts with pharmaceutically
acceptable bases.
These salts can likewise be prepared in situ in the administration vehicle or
the dosage form
manufacturing process, or by separately reacting the purified compound in its
free acid form
with a suitable base, such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically
acceptable metal cation, with ammonia, or with a pharmaceutically acceptable
organic primary,
secondary or tertiary amine. Representative alkali or alkaline earth salts
include the lithium,
sodium, potassium, calcium, magnesium, and aluminum salts and the like.
Representative
organic amines useful for the formation of base addition salts include
ethylamine,
diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and
the like.
[0077]
"Prodrug" refers to a derivative of an active agent that requires a
transformation
within the body to release the active agent. In certain embodiments, the
transformation is an
enzymatic transformation. Prodrugs are frequently, although not necessarily,
pharmacologically inactive until converted to the active agent. "Promoiety"
refers to a form of
protecting group that, when used to mask a functional group within an active
agent, converts
the active agent into a prodrug. In some cases, the promoiety will be attached
to the drug via
bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo. Any
convenient
prodrug forms of the subject compounds can be prepared, e.g., according to the
strategies and
methods described by Rautio et al. ("Prodrugs: design and clinical
applications", Nature
Reviews Drug Discovery 7, 255-270 (February 2008)).
[0078]
Disclosed herein is a compound according to Formula (I) or an optically pure
stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof
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OH
B/ A N R5
II
(R1 )rn
X
:1
G
Formula (I)
[0079] In some embodiments of Formula (I), each Ri is independently
selected from the
group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or
substituted amino,
pentafluorosulfanyl, unsubstituted or substituted sulfonyl, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted
alkenyl,
unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted ¨(C=0)-alkyl, unsubstituted or substituted ¨(C=0)-cycloalkyl,
unsubstituted or substituted ¨(C=0)-aryl, unsubstituted or substituted ¨(C=0)-
heteroaryl,
unsubstituted or substituted aryl, and unsubstituted or substituted
heteroaryl.
[0080] In some embodiments of Formula (I), m is an integer selected from 0
to 3.
[0081] In some embodiments of Formula (I), each A, B, and X is
independently a nitrogen
or carbon.
[0082] In some embodiments of Formula (I), P is N, 0, or CR2; Q is N, 0, or
CR2; G is
NR5 or 0; and/or Z is NR5, 0, S, or CR3R4. In some embodiments, R2 is selected
from the
group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted
or substituted
amino, unsubstituted or substituted alkyl, and unsubstituted or substituted
alkoxy. In certain
embodiments, each R3 and R4 is selected from the group consisting of hydrogen,
halogen,
cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or
substituted alkyl,
and unsubstituted or substituted alkoxy.
[0083] In some embodiments of Formula (I), R5 is one or more selected from the
group
consisting of H, unsubstituted or substituted alkyl, unsubstituted or
substituted alkoxy,
unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl,
unsubstituted or
substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or
substituted
heteroaryl,
32
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Y rx4 Rio
,.......L . RI, .n
3 , = 3 =
e.N.,.,s õ.,..N,,,_,
11 -1-(R9) t N111)-(.R.9)11
1---V--"-N#
FL'
FL
,.and. N 4!7
L is a C1-05 alkyl linker optionally substituted; each Xi, X2, X3, and X4 is
independently
a covalent bond, a carbon, an oxygen, or a nitrogen, optionally substituted
with hydrogen,
unsubstituted or substituted alkyl, or unsubstituted or substituted
cycloalkyl; Y is 0 or S;
R6 and R7 are independently selected from hydrogen, unsubstituted or
substituted alkyl, or
R6 and R7 are cyclically linked and together with X2 to form an optionally
substituted
cycloalkyl or heterocycle; each Rs is independently selected from the group
consisting of
hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino,
unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy,
unsubstituted or
substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or
substituted
cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or
substituted heteroaryl;
n is an integer selected from 0 to 4; R9 is selected from the group consisting
of hydrogen,
halogen, cyano, unsubstituted or substituted alkyl, unsubstituted or
substituted alkoxy, and
unsubstituted or substituted amino; and Rio is selected from the group
consisting of
hydrogen, cyano, unsubstituted or substituted alkyl, and unsubstituted or
substituted
alkoxy.
[0084] Also disclosed herein is a compound according to Formula (II) or an
optically pure
stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof
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OH
A ,<R7
(R1)rn R6
X R5
G
Formula (II)
[0085] In some embodiments of Formula (II), each Ri is independently
selected from
the group consisting of hydrogen, halogen, cyano, nitro, unsubstituted or
substituted
amino, pentafluorosulfanyl, unsubstituted or substituted sulfonyl,
unsubstituted or
substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or
substituted alkenyl,
unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted ¨(C=0)-alkyl, unsubstituted or substituted ¨(C=0)-cycloalkyl,
unsubstituted or substituted ¨(C=0)-aryl, unsubstituted or substituted ¨(C=0)-
heteroaryl,
unsubstituted or substituted aryl, and unsubstituted or substituted
heteroaryl.
[0086] In some embodiments of Formula (II), m is an integer selected from 0
to 3.
[0087] In some embodiments of Formula (II), each A, B, and X is
independently a
nitrogen or carbon.
[0088] In some embodiments of Formula (II), P is N, 0, or CR2; Q is N, 0,
or CR2; G
is NRs or 0; and/or Z is NRs, 0, S, or CR3R4.
[0089] In some embodiments of Formula (ID, R2 is selected from the group
consisting of
hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or substituted amino,
unsubstituted
or substituted alkyl, and unsubstituted or substituted alkoxy.
[0090] In some embodiments of Formula (II), each R3 and R4 is selected from
the group
consisting of hydrogen, halogen, cyano, nitro, hydroxyl, unsubstituted or
substituted amino,
unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy.
[0091] In some embodiments of Formula (II), Rs, R6, and R7 are
independently selected
from the group consisting of H, unsubstituted or substituted alkyl,
unsubstituted or
substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or
substituted
alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted
aryl,
unsubstituted or substituted heteroaryl,
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rX4 ,R12
A /R8 X3 X3 so FL-Xi X2 * kig>
(R10)n (R10) N-Nn
Frr µ(R11)n
R9 X4
N-(R11)
0¨N
0¨k(Rii)n 10 ¨(R11) ¨(Ri
1)n
0n N
hi2 1-LN? 1-LN
(R11)n FL
* (R11)n N (R11)n
FL, and IN
or R5 and R6 together with the carbon form an unsubstituted or substituted 3-7
membered
cycloalkyl or heterocycle ring; L is a C1-05 alkyl linker optionally
substituted; each Xi, X2,
X3, and X4 is independently a covalent bond, a carbon, an oxygen, or a
nitrogen, optionally
substituted with hydrogen, unsubstituted or substituted alkyl, or
unsubstituted or
substituted cycloalkyl; Y is 0 or S; Rs and R9 are independently selected from
hydrogen,
unsubstituted or substituted alkyl, or Rs and R9 are cyclically linked and
together with X2
to form an optionally substituted cycloalkyl or heterocycle; each Rio is
independently
selected from the group consisting of hydrogen, halogen, cyano, nitro,
hydroxyl,
unsubstituted or substituted amino, unsubstituted or substituted alkyl,
unsubstituted or
substituted alkoxy, unsubstituted or substituted alkenyl, unsubstituted or
substituted
alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted
aryl, and
unsubstituted or substituted heteroaryl; n is an integer selected from 0 to 4;
Rii is selected
from the group consisting of hydrogen, halogen, cyano, unsubstituted or
substituted alkyl,
unsubstituted or substituted alkoxy, and unsubstituted or substituted amino;
and R12 is
selected from the group consisting of hydrogen, cyano, unsubstituted or
substituted alkyl,
and unsubstituted or substituted alkoxy.
[0092] Also disclosed herein is a compound according to Formula (I'):
OH
,131( N
DI Ai I
(R =')m, _X' R10' R11'
W'
Formula (I')
or a pharmaceutically acceptable salt, wherein:
A', B', W', and X' are each independently a nitrogen atom or carbon atom;
Ring D' is a fused ring selected from benzo, 5-9 membered monocyclic or
bicyclic
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heteroaryl containing 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur,
and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or
heterocyclyl having 1-
3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -0-, -OR', -
NR'2, -SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur, or:
two RA groups on the same carbon or are optionally taken together with their
intervening atoms to form an optionally substituted 3-6 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
from which the two RA groups are attached, independently selected from
nitrogen, oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
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Y'
'
R2' is selected from hydrogen, RA, -OR', R9
rX4' R12'
x3' =INC 1110 (Rit)n, 3x ' 1110 (Rii.)n,
X4' '
(R11 )n,
N¨ (R13')
0¨N ft __ (R13')n'
(')n, 11-L/
R12 R13 ' FL' N
11 _____ (R13')n, I ,....¨(R13')FL n'
NA
, and N =
L' is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and Rth' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2, to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RH' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN;
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2; and
R7' and le are each independently hydrogen or optionally substituted C1-2
aliphatic.
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[0093] Also disclosed herein is a compound according to Formula (II'):
OH
H R6'
ccAIEVN R5'
D' 11
(Rt)m. ,x, Rio. R11. R4.
W'
Formula (II')
or a pharmaceutically acceptable salt, wherein:
A', B', W', and X' are each independently a nitrogen atom or carbon atom;
Ring D' is a fused ring selected from benzo, 5-9 membered monocyclic or
bicyclic
heteroaryl containing 1-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur,
and a 5 to 7-membered saturated or partially unsaturated carbocyclyl or
heterocyclyl having 1-
3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -0-, -OR', -
NR'2, -SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur, or:
two RA groups on the same carbon or are optionally taken together with their
intervening atoms to form an optionally substituted 3-6 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
from which the two RA groups are attached, independently selected from
nitrogen, oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
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intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
x3'
L' ¨XI' j( X2' 1110 (R1t)n,
'
CN, -NO2, -OR', -NR'2, R9
('X4' Ri2'
N-41
x3 I. (R11')n,
J/
R'), 3'
FL (R1 )11'
R12'
(R13')n, \¨N El __ (R13) ii __
HuFL
(R13 )n'
¨(R13'),.
,and N ,or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from 3-7 membered saturated
carbocyclic
ring; an optionally substituted 5-6 membered monocyclic heteroaryl ring having
1-4
heteroatoms independently selected from nitrogen, oxygen, and sulfur; an
optionally
substituted 3-7 membered saturated or a partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, and
sulfur;
L' is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and RH' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and Rm' are cyclically linked and, together with X2, to form an optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
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membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RI' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN;
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2; and
Ir and le are each independently hydrogen or optionally substituted C1-2
aliphatic.
[0094] Also disclosed herein is a compound according to Formula (III'):
OH
H R6'
'
B' *Au N R5
(R1 )m'
R4'
P'
:1
Q'
Z'
Formula (III')
or a pharmaceutically acceptable salt thereof, wherein:
A', B', and X' are each independently a nitrogen atom or carbon atom;
P' and Q' are each independently ¨N=, -NR'-, -CR'=, or -CR'2-;
G' is -NR'- or -0-;
Z' is =NR', =0, =S, or =CR'2;
= is a single bond or double bond;
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -OR', -NR'2,
-C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
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carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
Y'
X3'
u Ri 0'
1-12¨Xt X2 (R1")
R9' X4'
=
CN, -NO2, -OR', -NR'2,
(=_====_ x4' R12'
N
x3' le (R11'), ____ ( X3'
)
FL' N
,,, (Ri t)n, FL' Ri
\---N N __ (R3) ii __
FL' <(1Ri 3')n, FL'
FL'
n 13
(R')n,
_õ..(R13')n'
,and ,or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from a 3-7 membered saturated
carbocyclic
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a
partially unsaturated
monocyclic heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, and sulfur;
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L' is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and Rth' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2', to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RH' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN; and
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2.
[0095] Also disclosed herein is a compound according to Formula (IV'):
OH
H R8'
R3a' \X' R7' R8' R4'
B'
R3b' (R1')õ,
Formula (IV')
or a pharmaceutically acceptable salt thereof, wherein:
A', B', and X' are each independently a nitrogen atom or carbon atom;
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -0-, -OR', -
NR'2, -SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur;
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each R' is independently hydrogen or an optionally substituted group selected
from C1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
R3a' and R31' are independently hydrogen, RA, -OR', -C(0)R', -C(0)NR'2, or -
CO2R', or:
R3a' and R31' are optionally taken together with their intervening atoms to
form an
optionally substituted 4-10 membered saturated or partially unsaturated
carbocyclic or
heterocyclic ring having 1-3 heteroatoms, in addition to the nitrogen from
which R3a' and R3b'
are attached, independently selected from nitrogen, oxygen, and sulfur;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
Y'
u ,Rio' X3'
L' ¨ X1 X2 (R11)n,
' X4'
CN, -NO2, -OR', -NR'2, R9
(__'= x4' R12'
N-N N-
VR13'),.
x3' le (R11.)n, I __ ( X3'
N
'Rh 1), H LIn, Ri
\-N _______________________________________ (R13.)n' ______________ (R13')õ,
FL' )<(Ri 3')n, FL' FL' hL'
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I õ.¨(R13')n'
1-L
,and N ,or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from a 3-7 membered saturated
carbocyclic
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a
partially unsaturated
monocyclic heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, and sulfur;
L' is an optionally substituted C1-5 alkylene;
Xr, X3', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y' is 0 or S;
R9' and Rth' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2', to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each RH' is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12' is hydrogen, RA, or -CN;
each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2; and
R7' and le are each independently hydrogen or optionally substituted C1-2
aliphatic.
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[0096] Also disclosed herein
is a compound according to Formula (V'):
OH
H R6'
NN
R4'
H2N
(R1'),,
Formula (V')
or a pharmaceutically acceptable salt thereof, wherein:
each R1' is independently hydrogen, halogen, RA, -CN, -NO2, -SF5, -OR', -NR'2,
-SO2R', -C(0)R', -C(0)NR'2, -NR'C(0)R', -NR'CO2R', or -CO2R';
each RA is independently an optionally substituted group selected from C1-6
aliphatic,
phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-
6 membered
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur;
each R' is independently hydrogen or an optionally substituted group selected
from C1_6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated
monocyclic
carbocyclic ring, an 8-10 membered bicyclic partially unsaturated or aromatic
carbocyclic
ring, a 4-8 membered saturated or partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a 5-6
membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, and an 8-10 membered bicyclic partially
unsaturated or
heteroaromatic ring having 1-5 heteroatoms independently selected from
nitrogen,
oxygen, or sulfur, or:
two R' groups on the same carbon or nitrogen are optionally taken together
with their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur;
m' is an integer selected from 0 to 3;
R4', R5', and R6' are each independently selected from hydrogen, halogen, RA, -
YI R10' X3'
FL-X1JLX2'- (R11)
' X4'
CN, -NO2, -OR', -NR'2, R9
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R12'
N-14 13')n.
YN
)(3' (R11')n, 2
N (Rit) F
n, L' Riz
r0¨N (R3) ii __
FL'
(R13')n'
-HR13')n'
I ,.....¨(R13')n.
FL'
FL'
,and N ,or:
R4' and R5' are optionally taken together with the carbon to which they are
attached
to form an optionally substituted ring selected from a 3-7 membered saturated
carbocyclic
ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or a
partially unsaturated
monocyclic heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, and sulfur;
L' is an optionally substituted C1-5 alkylene;
XP, X'', and X4' are each independently a bivalent group selected from a
covalent bond, -CR'2-, -0-, and -NR'-;
X2' is a carbon atom or nitrogen atom;
Y1' is 0 or S;
R9' and R1 ' are each independently hydrogen or optionally substituted alkyl,
or:
R9' and R1 ' are cyclically linked and, together with X2', to form an
optionally
substituted 3-7 membered saturated carbocyclic ring; an optionally substituted
5-6
membered monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur; or an optionally substituted 7-12 membered
saturated or partially
unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently
selected from
nitrogen, oxygen, and sulfur;
each R1P is independently RA, halogen, -CN, -NO2, -NR'2, or -OR';
n' is an integer selected from 0 to 4;
R12 is hydrogen, RA, or -CN; and
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each R13' is independently hydrogen, halogen, RA, -CN, -OR', or -NR'2.
[0097] As defined above and described herein, A' is a nitrogen atom or a
carbon atom.
[0098] In some embodiments A' is a nitrogen atom. In some embodiments, A'
is a carbon
atom.
[0099] In some embodiments A' is selected from those depicted in Table 1,
below.
[00100] As defined above and described herein, B' is a nitrogen atom or a
carbon atom.
[00101] In some embodiments B' is a nitrogen atom. In some embodiments, B' is
a carbon
atom.
[00102] In some embodiments B' is selected from those depicted in Table 1,
below.
[00103] As defined above and described herein, X' is a nitrogen atom or a
carbon atom.
[00104] In some embodiments X' is a nitrogen atom. In some embodiments, X' is
a carbon
atom.
[00105] In some embodiments X' is selected from those depicted in Table 1,
below.
[00106] As defined above and described herein, W' is a nitrogen atom or a
carbon atom.
[00107] In some embodiments W' is a nitrogen atom. In some embodiments, W' is
a carbon
atom.
[00108] In some embodiments W' is selected from those depicted in Table 1,
below.
[00109] In some embodiments, any of the nitrogen atoms mentioned above is
optionally in
the form of an N-oxide.
[00110] As defined above and described herein, P' and Q' are each
independently ¨N=, -NR'-
-CR'=, or -CR'2-.
[00111] In some embodiments, P' is ¨N=. In some embodiments, P' is -NR'-. In
some
embodiments, P' is -CR'=. In some embodiments, P' is -CR'2-. In some
embodiments, P' is -
CH=. In some embodiments, Q' is ¨N=. In some embodiments, Q' is -NR'-. In some
embodiments, Q' is -CR'=. In some embodiments, Q is -CR'2-. In some
embodiments, Q' is -
CH=.
[00112] In some embodiments P' and Q' are selected from those depicted in
Table 1,
below.
[00113] As defined above and described herein, G' is -NR'- or -0-.
[00114] In some embodiments, G' is -NR'-. In some embodiments, G' is -0-. In
some
embodiments, G' is -NH-. In some embodiments, G' is -NMe-.
[00115] In some embodiments G' is selected from those depicted in Table 1,
below.
[00116] As defined above and described herein, Z' is =NR', =0, =S, or =CR'2.
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[00117] In some embodiments, Z is =NR'. In some embodiments, Z' is =0. In some
embodiments, Z' is =S. In some embodiments, Z' is =CR'2.
[00118] In some embodiments Z' is selected from those depicted in Table 1,
below.
[00119] As defined above and described herein, = is a single bond or double
bond.
[00120] In some embodiment, ¨ is a single bond. In some embodiment, ¨ is
double
bond.
[00121] In some embodiments ¨ is selected from those depicted in Table 1,
below.
[00122] As defined above and described herein, Ring D' is a fused ring
selected from benzo,
5-9 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur, and a 5 to 7-membered saturated or
partially
unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently
selected from
nitrogen, oxygen, or sulfur.
[00123] In some embodiments, Ring D' is benzo. In some embodiments, Ring D' is
a 5-9
membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms
independently
selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring D' is a 5
to 7-membered
saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3
heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In some embodiments,
Ring D' is
(RI),. ______________________________ (R1'),. __
. In some embodiments, Ring D' is N . In
some embodiments,
(R1 )m )rnX/ )rni
N r\k
Ring D' is . In some embodiments, Ring D' is . In
some
embodiments, Ring D' is N . In some embodiments, Ring D' is N'
1,
In some embodiments, Ring D' is (R)m N¨jd . In some embodiments, Ring D' is
OZ-11
(R )m, N . In some embodiments, Ring D' is (R1 )m In some
embodiments, Ring
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1,
(R1),,,A7 i, (R1')õ,, __,...
D' is N ¨ 1. In some embodiments, Ring D' is N ¨ ; .
In some embodiments,
, _____________ N-...1 S-...4
(Rt)m (R1'),,, I
A
Ring D' is NA. In some embodiments, Ring D' is N . In
some
/...1 /S---
____Aembodiments, Ring D' is . In some
embodiments, Ring D' is . In
0-.....õ1
(R1')m. I
A
some embodiments, Ring D' is N . In
some embodiments, Ring D' is
Olf
0¨(
11. (R1')m.Nd
R . In some embodiments, Ring D' is . In
some embodiments, Ring
01 0
1
(RI)m, ( N (Rt)m, __
A 0 N
A
D' is H . In some embodiments, Ring D' is H. In
some
----1
(R1 )m _______________________
embodiments, Ring D' is 0 N
A. In some
embodiments, Ring D' is
0
----1
(R1),,, ______________________________ (RI)m' I
0 A. In some embodiments, Ring D' is A . In
some embodiments,
1 , ( 1
(R 'Thi. µ
.."-N--1
)\-
Ring D' is 0 . In some embodiments, Ring D'
is N . In
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(R1')m,
`1/4
some embodiments, Ring D is N . In
some embodiments, Ring D' is
(R1')m,
N . In some embodiments, Ring D' is
[00124] In some embodiments Ring D' is selected from those depicted in Table
1, below.
[00125] As defined above and described herein, each R1' is independently
halogen, RA,
-CN, -NO2, -SF5, -0-, -OR', -NR'2, -SO2R', -C(0)R', -C(0)NR'2, -NR1C(0)R', -
NR'CO2R',
or -CO2R'.
[00126] In some embodiments, R1' is hydrogen. In some embodiments, R1' is
halogen.
In some embodiments, R1' is RA. In some embodiments, Ry is -CN. In some
embodiments,
R1' is -NO2. In some embodiments, Ry is -SF5. In some embodiments, R1' is -0-.
In some
embodiments, R1' is -OR'. In some embodiments, R1' is -NR'2. In some
embodiments, R1'
is -SO2R'. In some embodiments, R1' is -C(0)R'. In some embodiments, R1' is -
C(0)NR'2.
In some embodiments, R1' is -NR1C(0)R'. In some embodiments, R1 is -NR'CO2R'.
In
some embodiments, R1' is -CO2R'. In some embodiments, R1' is -Br. In some
embodiments, R1' is -Cl. In some embodiments, R1' is -F. In some embodiments,
R1' is -
CH3. In some embodiments, R1' is -CH2CH3. In some embodiments, R1' is -
CH(CH3)2. In
some embodiments, R1' is -CF3. In some embodiments, R1' is -CF2H. In some
embodiments, R1' is -CFH2. In some embodiments, R1' is -CF2CH3. In some
embodiments,
R1' is -CH2CF3. In some embodiments, R1' is -CCCH. In some embodiments, R1' is
vinyl.
In some embodiments, R1' is -CCCF3. In some embodiments, R1' is -CO2H. In some
embodiments, R1' is -OH. In some embodiments, R1' is -OCH3. In some
embodiments, R1'
is -OCH2CH3. In some embodiments, R1' is -OCH(CH3)2. In some embodiments, R1'
is -
OCF3. In some embodiments, Ry is -NHCH3. In some embodiments, R1' is -NHCD3.
In
some embodiments, R1' is -N(CD3)CO2tBu. In some embodiments, R1' is -NHCH2CH3.
In
some embodiments, R1' is -NHCH2(CH3)2. In some embodiments, R1' is -NHCH2CF3.
In
some embodiments, R1' is -NHPh. In some embodiments, R1' is -NHAc. In some
0
H2N)ccs
embodiments, R1' is -N(CH3)2. In some embodiments, R1' is rr . In
some
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0
).
N /
embodiments, R1' is I . In
some embodiments, R1' is I>1.. In some embodiments,
R1' is 0-1. In some embodiments, R1' is 0-1. In some embodiments, R1' is 111
.<( q
. In some embodiments, R1' is -1. In some
embodiments, R1' is OA. In some
N
CNA sN-1
embodiments, R1' is C . In some embodiments, R1' is N . In
some
N=N\ ___________________ k HN-"N
1
i I Nz--
embodiments, R1' s HN& . In some embodiments, R1' is N . In
some
F
embodiments, R1' is = . In some embodiments, R1' is . In
some
N/7 k NO
N /
embodiments, R1' is ¨ . In some embodiments,
R1' is / . In some
"Li CNA
embodiments, R1' is' y . In some embodiments, R1' is N . In
some
N
embodiments, R1' is Nz:-il . In
some embodiments, R1' is H . In some
0-1
embodiments, R1' is -N . In some embodiments, R1' is H .
In some
0
HO'ILC
,
embodiments, R1' is S . In
some embodiments, R1' is HN---1. In some
F>
F0...._ >.
H N
embodiments, R1' is ----1\k----µ . In some embodiments, R1' is H . In
some
N H2N--)e2-
embodiments, R1' is H . In some embodiments, R1' is
[00127] In some embodiments, R1' is selected from those depicted in Table 1,
below.
[00128] As defined above and described herein, each R' is independently
hydrogen or an
optionally substituted group selected from C1-6 aliphatic, a 3-8 membered
saturated or
partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered
bicyclic
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partially unsaturated or aromatic carbocyclic ring, a 4-8 membered saturated
or partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic
ring having
1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an
8-10
membered bicyclic partially unsaturated or heteroaromatic ring having 1-5
heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two R' groups on
the same
carbon or nitrogen are optionally taken together with their intervening atoms
to form an
optionally substituted 4-10 membered saturated or partially unsaturated
carbocyclic or
heterocyclic ring having 1-3 heteroatoms, in addition to the carbon or
nitrogen from which the
two R' groups are attached, independently selected from nitrogen, oxygen, and
sulfur.
[00129] In some embodiments, R' is hydrogen. In some embodiments, R' is an
optionally
substituted C1-6 aliphatic. For instance, in some embodiments, R' is -CF3, -
CF2H, or -
CFH2. In some embodiments, R' is an optionally substituted 3-8 membered
saturated
monocyclic carbocyclic ring. In some embodiments, R' is an optionally
substituted 3-8
membered partially unsaturated monocyclic carbocyclic ring. In some
embodiments, R' is
an optionally substituted phenyl. In some embodiments, R' is an optionally
substituted 8-
membered bicyclic partially unsaturated carbocyclic ring. In some embodiments,
R' is
an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In
some
embodiments, R' is an optionally substituted 4-8 membered saturated monocyclic
heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,
oxygen,
or sulfur. In some embodiments, R' is an optionally substituted 4-8 membered
partially
unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently
selected
from nitrogen, oxygen, or sulfur. In some embodiments, R' is an optionally
substituted 5-
6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. In some embodiments, R' is an
optionally
substituted 8-10 membered bicyclic partially unsaturated ring having 1-5
heteroatoms
independently selected from nitrogen, oxygen, or sulfur. In some embodiments,
R' is an
optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5
heteroatoms independently selected from nitrogen, oxygen, or sulfur. In
some
embodiments, two R' groups on the same carbon or nitrogen are optionally taken
together with
their intervening atoms to form an optionally substituted 4-10 membered
saturated or partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
or nitrogen from which the two R' groups are attached, independently selected
from nitrogen,
oxygen, and sulfur.
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[00130] In some embodiments, R' is selected from those depicted in Table 1,
below.
[00131] As defined above and described herein, m' is an integer selected from
0 to 4.
[00132] In some embodiments, m' is 0. In some embodiments, m' is 1. In some
embodiments, m' is 2. In some embodiments, m' is 3. In some embodiments, m' is
4.
[00133] In some embodiments, m is selected from those depicted in Table 1,
below.
[00134] As defined above and described herein, each RA is independently an
optionally
substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered
saturated or partially
unsaturated heterocyclic ring having 1-2 heteroatoms independently selected
from nitrogen,
oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur, or two RA groups on the same
carbon or are
optionally taken together with their intervening atoms to form an optionally
substituted 3-6
membered saturated or partially unsaturated carbocyclic or heterocyclic ring
having 1-3
heteroatoms, in addition to the carbon from which the two RA groups are
attached,
independently selected from nitrogen, oxygen, and sulfur.
[00135] In some embodiments, RA is an optionally substituted C1-6 aliphatic.
In some
embodiments, RA is an optionally substituted 3-7 membered saturated monocyclic
carbocyclic ring. In some embodiments, RA is an optionally substituted 3-7
membered
partially unsaturated monocyclic carbocyclic ring. In some embodiments, RA is
an
optionally substituted phenyl. In some embodiments, RA is a 5-6 membered
heteroaryl ring
having 1-4 heteroatoms independently selected from nitrogen, oxygen, and
sulfur. In some
embodiments, two RA groups on the same carbon or are optionally taken together
with their
intervening atoms to form an optionally substituted 3-6 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the carbon
from which the two RA groups are attached, independently selected from
nitrogen, oxygen, and
sulfur.
Y'
,R10.
'
[00136] As defined above, R2' is hydrogen, RA, -OR', R9
rX4'R12'
AN¨N
x3' 116 (Ri i')n, x3' (R1 i')n, I ( )Z3'
IlleC X4' (R11')n,
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N
N¨yR13'),,,
__V n, O¨N
ft __________________________________________________________ (R13')n.
1-1-1- N / ..A F /./
1412' ru N L (R13')n' EL
N
II _____ (R13.), I ,.....(R13)n. N n'
NA. .../....,,,....
1¨L FL'
, and N
[00137] In some embodiments, R2' is hydrogen. In some embodiments, R2' is RA.
In some
YI
II
FL,-)(1---)(2'
I
9 '
embodiments, R2' is -OR'. In some embodiments, R2' is R . In
some
---x3 . (Rit)n,
\CX4'
embodiments, R2' is . In
some embodiments, R2' is
rX4'
1 ___
X340 / \
(R11.) \
n, X3'
YN R i ,, i'i Nn,.
. In some embodiments, R2' is ( In some
R12'
N¨Ni N.-----
(R13')n,
k/c ,
FL' (R13 )11' FL' 1\,/
embodiments, R2' is . In some embodiments,
R2' is R12'
R13') ,
O¨- (R n
1 .A L. N -2
. In some embodiments, R2' is 1- . In
some embodiments, R2' is
N
0¨N _________________________________________________ (R13')n.
1 ,... /.%
1-1-'
In some embodiments, R2' is FL . In
some
N
II __________________________ (R13')n,
NA
1-12
embodiments, R2' is . In
some embodiments, R2' is
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I ,.¨(R13')n' N
-,A.::õ.........-
ty
. In some embodiments, R2' is N . In
some
embodiments, R2' is -CH3. In some embodiments, R2' is -CD3. In some
embodiments, R2' is
-C(CH3)3. In some embodiments, R2' is -C(CD3)3. In some embodiments, R2' is -
C(CH3)2CH2OR'. In some embodiments, R2' is -C(CH3)2CH2OH. In some embodiments,
R2' is -iPr. In some embodiments, R2' is -CH2iPr. In some embodiments, R2' is
110 /
0 . In some embodiments, R2' is . In
some embodiments, R2' is
In some embodiments, R2' is . In some embodiments, R2' is . In
F
jf--F
some embodiments, R2' is . In some embodiments, R2'
is .
[00138] In some embodiments R2' is selected from those depicted in Table 1,
below.
[00139] As defined above and described herein, R3a' and R31' are independently
hydrogen,
RA, -OR', -C(0)R', -C(0)NR'2, or -CO2R', or R3a' and R31' are optionally taken
together with
their intervening atoms to form an optionally substituted 4-10 membered
saturated or partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the nitrogen
from which R3a' and R3b' are attached, independently selected from nitrogen,
oxygen, and
sulfur.
[00140] In some embodiments, R3a' is hydrogen. In some embodiments, R3a' is
RA. In some
embodiments, R3a' is -OR'. In some embodiments, R3a' is -C(0)R'. In some
embodiments, R3a'
is -C(0)NR'2. In some embodiments, R3a' is -CO2R'. In some embodiments, R3b'
is hydrogen.
In some embodiments, R31' is RA. In some embodiments, R31' is -OR'. In some
embodiments,
R31' is -C(0)R'. In some embodiments, R31' is -C(0)NR'2. In some embodiments,
R31' is -
CO2R'. In some embodiments, R3a' and R3b' are optionally taken together with
their
intervening atoms to form an optionally substituted 4-10 membered saturated or
partially
unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms, in
addition to the nitrogen
from which R3a' and R31' are attached, independently selected from nitrogen,
oxygen, and
sulfur.
[00141] In some embodiments R3a' and R31' are selected from those depicted in
Table 1,
below.
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[00142] As defined above, R4', R5', and R6' are each independently hydrogen,
halogen,
Ne
Rio' x3'
1 ____________________________________ L' ¨X1' jL VC X2' (10 (R11.)
R9 ' x
n,
1
4'
RA, -CN, -NO2, -OR', -NR'2,
rX4' R12'
\ N-N Nil----(R13'),,
k/,, 1 ---L 2
x3' . (Rit)n, I ____ ( X3' 1-L. N
(R13.)n, i
_______________________ )(Rit)n, FL'
N N
0¨(R13')n, 0-N El(R13')n' II (R13')n,
F1-1-1(R13')n, 1 L' 1¨L',
I ,¨(R13')n.
N, n
-./..õ.........-
1¨LI 1-L'.--."
, and \ N , or R4'
and R5' are optionally taken
together with the carbon to which they are attached to form an optionally
substituted ring
selected from a 3-7 membered saturated carbocyclic ring, a 5-6 membered
monocyclic
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur, and a 3-7 membered saturated or a partially unsaturated monocyclic
heterocyclic ring
having 1-2 heteroatoms independently selected from nitrogen, oxygen, and
sulfur.
[00143] In some embodiments, R2' is hydrogen. In some embodiments, R2' is RA.
In some
embodiments, R2' is -OR'. In some embodiments, R2' is -NR'2. In some
embodiments, R2'
Y'
H .....R10' )(3'
I- L' -X1' X2 0 (R11)
R9' µ11C X4'
is . In some embodiments, R2' is . In
)C4'
X3'
110 (Rii.)n,
some embodiments, R2' is . In
some embodiments, R2' is
R12'
I ( __ \x3'
(R ,
i i'Nn.
/ In some embodiments, R2' is FL'
. In some
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fi
HU- N
12 '
embodiments, R2' is R . In
some embodiments, R2' is
O-N
I L'
. In some embodiments, R2' is (R13')n' . In some
_____________________________ (R13')n.
L'
embodiments, R2' is F . In
some embodiments, R2' is
/*
ii __
(R13.)n,
1-12
. In some embodiments, R2' is . In some
embodiments, R2' is N . In
some embodiments, R2' is -CH3. In some
embodiments, R2' is -CD3. In some embodiments, R2' is -C(CH3)3. In some
embodiments, R2'
is -C(CD3)3. In some embodiments, R2' is I*1 O.
[00144] In some embodiments, R4' is hydrogen. In some embodiments, R4' is
halogen. In
some embodiments, R4' is RA. In some embodiments, R4' is -CN. In some
embodiments,
R4' is -NO2. In some embodiments, R4' is -OR'. In some embodiments, R4' is -
CH2OR'. In
some embodiments, R4' is -CH2iPr. In some embodiments, R4' is -NR'2. In some
Y'
,Ricy
L'-Xt
9'
embodiments, R4' is R . In
some embodiments, R4' is
rX4'
X3'
(Ri i')n, 1110 (Rit)n,
. In some embodiments, R4' is . In
some
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Riz
YN (R13'),-,,
embodiments, R4' is (R \
)n'= In some embodiments, R4' is FL
N¨VR13')n,
FL' N
12'
In some embodiments, R4' is R . In
some embodiments, R4' is
(R13')n, 0¨N
FL' FL'
. In some embodiments, R4' is (R13'). In some
_____________________________ (R13')n.
embodiments, R4' is . In
some embodiments, R4' is
,N
ii _____
(R13')n, I ,.....(R13')n,
. In some embodiments, R4' is . In some
embodiments, R4' is N . In
some embodiments, R4' and R5' are
optionally taken together with the carbon to which they are attached to form
an optionally
substituted 3-7 membered saturated carbocyclic ring. In some embodiments, R4'
and R5'
are optionally taken together with the carbon to which they are attached to
form an optionally
substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms
independently
selected from nitrogen, oxygen, and sulfur. In some embodiments, R4' and R5'
are optionally
taken together with the carbon to which they are attached to form an
optionally substituted 3-
7 membered saturated or a partially unsaturated monocyclic heterocyclic ring
having 1-2
heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some
embodiments,
R4' is -CH3. In some
embodiments, R4' is -CD3. In some embodiments, R4' is
1.1
[00145] In some embodiments, R5' is hydrogen. In some embodiments, R5' is
halogen. In
some embodiments, R5' is RA. In some embodiments, R5' is -CN. In some
embodiments,
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R5' is -NO2. In some embodiments, R5' is -OR'. In some embodiments, R5' is -
NR'2. In
Y'
1-¨X XIR'113' 12t j( 2'
1
9'
some embodiments, R5' is R . In
some embodiments, R5' is
rX4'
X3' X3'
0 (R1 t)n, 1110 (Ri i')n,
VCX4'
. In some embodiments, R5' is . In
some
I Y\
N--14
( \
i 4 x3'
(R13')
(R . i'
Nri, .
embodiments, R5' is ) In some embodiments, R5' is FL'
=
N¨(R13).
1
12'
In some embodiments, R5' is R . In
some embodiments, R5' is
(:)---k
\
1-1213
i FL' *)<ID, 'N
. In some embodiments, R5' is k ' µn'
. In some
N
0 _____ 13'
(R )n.
/./
L'
embodiments, R5' is F . In
some embodiments, R5' is
/..
rN _______ 1'
(R3 )n, I ,....(R13)n,
NA. .../...............¨
hL' FL'
. In some embodiments, R5' is . In
some
NJ_
FL--t.y
embodiments, R5' is ' N . In
some embodiments, R5' is -CH3. In some
1101
embodiments, R5' is -CD3. In some embodiments, R5' is 0 ..
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VA [00146] In some embodiments, R4' and R5' are . In some embodiments, R4'
and R5'
\\>A
are . In some embodiments, R4' and R5' are . In
some embodiments, R4' and
F
\\>C17
R5' are . In
some embodiments, R4' and R5' are F . In some embodiments,
VIllIfr R4' and R5' are .
[00147] In some embodiments, R6' is hydrogen. In some embodiments, R6' is
halogen. In
some embodiments, R6' is RA. In some embodiments, R6' is -CN. In some
embodiments,
R6' is -NO2. In some embodiments, R6' is -OR'. In some embodiments, R6' is -
NR'2. In
Y'
H , Ri 0'
I¨ L' ¨X1' X2'
1
9'
some embodiments, R6' is R . In
some embodiments, R6' is
X4'
X3' X3'
010 (R11')n, up (Rit)n,
VCX4'
. In some embodiments, R6' is . In
some
R12'
I ( ___________________ \
X3'
YNi i
(R . i' N¨NI
N FL'
embodiments, R6' is m,. In some
embodiments, R6' is .
N----- (R13),
FL' N
1
12'
In some embodiments, R6' is R . In
some embodiments, R6' is
0----- (R13')n, 0¨N
..A -2 ,)\
FL' N FL' 13
. In some embodiments, R6' is (R )n.
In some
N
1 (R13')n.
/.%
L'
embodiments, R6' is F . In
some embodiments, R6' is
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ii _____ (R13) I _...(R13')/-1'
. In some embodiments, R6' is . In
some
embodiments, R6' is N . In
some embodiments, R6' is -CH3. In some
1101
embodiments, R6' is -CD3. In some embodiments, R6' is 0
[00148] In some embodiments, R2', R4', R5', and R6' are each selected from
those depicted
in Table 1, below.
[00149] As defined above and described herein, L' is an optionally substituted
C1-5
alkylene.
[00150] In some embodiments, L' is an optionally substituted C1-5 alkylene. In
some
embodiments, L' is -CH2-.
[00151] In some embodiments, L' is selected from those depicted in Table 1,
below.
[00152] As defined above and described herein, Xr, X3', and X4' are each
independently
a bivalent group selected from a covalent bond, -CR'2-, -0-, and -NR'-.
[00153] In some embodiments, Xr is a covalent bond. In some embodiments, Xr is
-
CR'2-. In some embodiments, X1' is -0-. In some embodiments, Xr is -NR'-. In
some
embodiments, X3' is a covalent bond. In some embodiments, X3' is -CR'2-. In
some
embodiments, X3' is -0-. In some embodiments, X3 is -NR'-. In some
embodiments, X4'
is a covalent bond. In some embodiments, X4' is -CR'2-. In some embodiments,
X4' is -
0-. In some embodiments, X4' is -NR'-.
[00154] In some embodiments, Xr, X3', and X4' are selected from those depicted
in
Table 1, below.
[00155] As defined above and described herein, X2' is a carbon atom or a
nitrogen atom.
[00156] In some embodiments, X2' is a carbon atom. In some embodiments, X2' is
nitrogen
atom.
[00157] In some embodiments, X2' is selected from those depicted in Table 1,
below.
[00158] As defined above and described herein, Y' is =0 or =S.
[00159] In some embodiments, Y' is =0. In some embodiments, Y' is S.
[00160] In some embodiments, Y' is selected from those depicted in Table 1,
below.
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[00161] As defined above and described herein, R9' and Rm' are each
independently
hydrogen or an optionally substituted alkyl, or R9' and Rm' are cyclically
linked and
together with X2', to form an optionally substituted ring selected from a 3-7
membered
saturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-
4
heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7
membered
saturated or partially unsaturated monocyclic heterocyclic ring having 1-2
heteroatoms
independently selected from nitrogen, oxygen, and sulfur, and a 7-12 membered
saturated or
partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms
independently selected
from nitrogen, oxygen, and sulfur.
[00162] In some embodiments, R9' is hydrogen. In some embodiments, R9' is an
optionally substituted C1-6 alkyl. In some embodiments, Rth' is hydrogen. In
some
embodiments, Rm' is an optionally substituted C1-6 alkyl. In some embodiments,
R9' and
RI are cyclically linked and together with X2' to form an optionally
substituted 3-7
membered saturated carbocyclic ring. In some embodiments, R9' and Rm' are
cyclically
linked and together with X2' to form an optionally substituted 5-6 membered
monocyclic
heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur. In some embodiments, R9' and RH' are cyclically linked and together
with X2' to
form an optionally substituted 3-7 membered saturated or partially unsaturated
monocyclic
heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur. In some embodiments, R9' and RH' are cyclically linked and together
with X2' to
form an optionally substituted 7-12 membered saturated or partially
unsaturated bicyclic
heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen,
oxygen, and
sulfur.
[00163] In some embodiments, R9' and Rm' are each selected from those depicted
in
Table 1, below.
[00164] As defined above and described herein, each RH' is independently RA,
halogen,
-CN, -NO2, -NR'2, or -OR'.
[00165] In some embodiments, RH' is hydrogen. In some embodiments, Rll' is
halogen.
In some embodiments, RH' is -CN. In some embodiments, RH' is -NO2. some
embodiments, Rll' is -NR'2. In some embodiments, RH' is -OR'.
[00166] In some embodiments, each Rll' is independently selected from those
depicted
in Table 1, below.
[00167] As defined above, n' is an integer selected from 0 to 4.
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[00168] In some embodiments, n' is 0. In some embodiments, n' is 1. In some
embodiments, n' is 2. In some embodiments, n' is 3. In some embodiments, n' is
4.
[00169] As defined above and described herein, R12' is hydrogen, RA, or -CN.
[00170] In some embodiments, R12' is hydrogen. In some embodiments, R12' is
RA. In some
embodiments, R12' is -CN.
[00171] In some embodiments, R12' is selected from those depicted in Table 1,
below.
[00172] As defined above and described herein, each R13' is independently
hydrogen,
halogen, RA, -CN, -OR', -NR'2.
[00173] In some embodiments, R13' is hydrogen. In some embodiments, R13' is
halogen.
In some embodiments, R13' is -CN. In some embodiments, R13' is -OR'. In some
embodiments,
R13' is -NR'2.
[00174] In some embodiments, R13' is selected from those depicted in Table 1,
below.
[00175] As defined above and described herein, R7' and le are each
independently
hydrogen or optionally substituted C1-2 aliphatic.
[00176] In some embodiments, R7' is hydrogen. In some embodiment, R7' is an
optionally substituted Ci aliphatic. In some embodiment, R7' is methyl. In
some
embodiment, R7' is an optionally substituted C2 aliphatic. In some embodiment,
R7' is
ethyl. In some embodiments, R8' is hydrogen. In some embodiment, R8' is an
optionally
substituted Ci aliphatic. In some embodiment, le is methyl. In some
embodiment, R8' is
an optionally substituted C2 aliphatic. In some embodiment, R8' is ethyl.
[00177] In some embodiments, R7' and le are selected from those depicted in
Table 1,
below.
[00178] In some embodiments, the present disclosure provides a compound of
Formula (I'),
wherein Ring D' is benzo, A' is a carbon atom, and Rio' and R11' are hydrogen
as shown, to
provide a compound of Formula (I'-a):
OH
R2'
,
W'
Formula (r-a)
or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', RP,
R2', and m' is as
defined above and described in embodiments herein, both singly and in
combination.
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[00179] In some embodiments, the present disclosure provides a compound of
Formula (I'),
(R1')õ
wherein Ring D' is N¨ 1, A'
is a carbon atom, and R1 ' and R1P are hydrogen as
shown, to provide a compound of Formula (I'-b):
OH
I NR2'
(R1'),, ___________________ \ .X'
NW'
Formula (I'-b)
or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', RP,
R2', and m' is as
defined above and described in embodiments herein, both singly and in
combination.
[00180] In some embodiments, the present disclosure provides a compound of
Formula (I'),
wherein Ring D' is NA A' is
a carbon atom, and R1 ' and R11' are hydrogen as
shown, to provide a compound of Formula (I'-c):
OH
Rz
im
Igp
W'
Formula (I'-c)
or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', RP,
R2', and m' is as
defined above and described in embodiments herein, both singly and in
combination.
[00181] In some embodiments, the present disclosure provides a compound of
Formula (I'),
>1/4
wherein Ring D is N , A' is
a carbon atom, and R1 ' and R11' are hydrogen
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as shown, to provide a compound of Formula (I'-d):
HO
N
'R2
(R1')m, ______________________________ X'
W'
Formula (I'-d)
or a pharmaceutically acceptable salt thereof, wherein each of B', W', X', RP,
R2', and m' is as
defined above and described in embodiments herein, both singly and in
combination.
[00182] In some embodiments, the present disclosure provides a compound of
Formula (I'),
(R1),
wherein Ring D' is N¨ , A'
B', W', and X' are a carbon atoms, and R1 ' and Rll' are
hydrogen as shown, to provide a compound of Formula (I'-e):
HO
N R2'
(R1'),, \N
Formula (I'-e)
or a pharmaceutically acceptable salt thereof, wherein each of RP, R2', and m'
is as defined
above and described in embodiments herein, both singly and in combination.
[00183] The term "treatment" is used interchangeably herein with the term
"therapeutic
method" and refers to both 1) therapeutic treatments or measures that cure,
slow down, lessen
symptoms of, and/or halt progression of a diagnosed pathologic conditions,
disease or disorder,
and 2) and prophylactic/ preventative measures. Those in need of treatment may
include
individuals already having a particular medical disease or disorder as well as
those who may
ultimately acquire the disorder (i.e., those at risk or needing preventive
measures).
[00184] The term "subject" as used herein refers to any individual or patient
to which the
subject methods are performed. Generally, the subject is human, although as
will be
appreciated by those in the art, the subject may be an animal.
[00185] The terms "therapeutically effective amount", "effective dose",
"therapeutically
effective dose", "effective amount," or the like refer to the amount of a
subject compound that
will elicit the biological or medical response in a tissue, system, animal or
human that is being
sought by administering said compound. Generally, the response is either
amelioration of
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symptoms in a patient or a desired biological outcome. In some embodiments,
such amount
should be sufficient to modulate an adrenergic receptor.
[00186] In some embodiments, an effective amount of an adrenergic receptor
modulating
compound is an amount that ranges from about 50 ng/ml to 50 pg/ml (e.g., from
about 50 ng/ml
to 40 pg/ml, from about 30 ng/ml to 20 pg/ml, from about 50 ng/ml to 10 pg/ml,
from about 50
ng/ml to 1 pg/ml, from about 50 ng/ml to 800 ng/ml, from about 50 ng/ml to 700
ng/ml, from
about 50 ng/ml to 600 ng/ml, from about 50 ng/ml to 500 ng/ml, from about 50
ng/ml to 400
ng/ml, from about 60 ng/ml to 400 ng/ml, from about 70 ng/ml to 300 ng/ml,
from about 60
ng/ml to 100 ng/ml, from about 65 ng/ml to 85 ng/ml, from about 70 ng/ml to 90
ng/ml, from
about 200 ng/ml to 900 ng/ml, from about 200 ng/ml to 800 ng/ml, from about
200 ng/ml to
700 ng/ml, from about 200 ng/ml to 600 ng/ml, from about 200 ng/ml to 500
ng/ml, from about
200 ng/ml to 400 ng/ml, or from about 200 ng/ml to about ng/ml).
[00187] In some embodiments, an effective amount of an adrenergic receptor
modulating
compound is an amount that ranges from about 10 pg to 100 mg, e.g., from about
10 pg to 50
pg, from about 50 pg to 150 pg, from about 150 pg to 250 pg, from about 250 pg
to 500 pg,
from about 500 pg to 750 pg, from about 750 pg to 1 ng, from about 1 ng to 10
ng, from about
ng to 50 ng, from about 50 ng to 150 ng, from about 150 ng to 250 ng, from
about 250 ng
to 500 ng, from about 500 ng to 750 ng, from about 750 ng to 1 mg, from about
1 pg to 10 pg,
from about 10 pg to 50 pg, from about 50 pg to 150 pg, from about 150 pg to
250 pg, from
about 250 pg to 500 pg, from about 500 pg to 750 pg, from about 750 pg to 1
mg, from about
1 mg to 50 mg, from about 1 mg to 100 mg, or from about 50 mg to 100 mg. The
amount can
be a single dose amount or can be a total daily amount. The total daily amount
can range from
about 10 pg to 100 mg, or can range from about 100 mg to 500 mg, or can range
from about
500 mg to 1000 mg.
[00188] Also disclosed herein are pharmaceutical compositions including
compounds as
disclosed herein e.g., with the structures of Formula (I), Formula (I'),
Formula (II), Formula
(II'), Formula (III), Formula (IV) Formula (I), Formula (I'), Formula (II),
Formula (II'),
Formula (III), Formula (IV), Formula (VI'), and Formula (VII'). The term
"pharmaceutically
acceptable carrier" refers to a non-toxic carrier that may be administered to
a patient, together
with a compound of this disclosure, and which does not destroy the
pharmacological activity
thereof Pharmaceutically acceptable carriers that may be used in these
compositions include,
but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin,
serum proteins
such as human serum albumin, buffer substances such as phosphates, glycine,
sorbic acid,
potassium sorbate, partial glyceride mixtures of saturated vegetable fatty
acids, water, salts or
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electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol
and wool fat.
[00189] In pharmaceutical composition comprising only the compounds described
herein as
the active component, methods for administering these compositions may
additionally
comprise the step of administering to the subject an additional agent or
therapy. Such therapies
include, but are not limited to, an anemia therapy, a diabetes therapy, a
hypertension therapy,
a cholesterol therapy, neuropharmacologic drugs, drugs modulating
cardiovascular function,
drugs modulating inflammation, immune function, production of blood cells;
hormones and
antagonists, drugs affecting gastrointestinal function, chemotherapeutics of
microbial diseases,
and/or chemotherapeutics of neoplastic disease. Other pharmacological
therapies can include
any other drug or biologic found in any drug class. For example, other drug
classes can
comprise allergy/cold/ENT therapies, analgesics, anesthetics, anti-infl
ammatori es,
antimicrobials, antivirals, asthma/pulmonary therapies, cardiovascular
therapies, dermatology
therapies, endocrine/metabolic therapies, gastrointestinal therapies, cancer
therapies,
immunology therapies, neurologic therapies, ophthalmic therapies, psychiatric
therapies or
rheumatologic therapies. Other examples of agents or therapies that can be
administered with
the compounds described herein include a matrix metalloprotease inhibitor, a
lipoxygenase
inhibitor, a cytokine antagonist, an immunosuppressant, a cytokine, a growth
factor, an
immunomodulator, a prostaglandin or an anti-vascular hyperproliferation
compound.
[00190] The term "therapeutically effective amount" as used herein refers to
the amount of
active compound or pharmaceutical agent that elicits the biological or
medicinal response in a
tissue, system, animal, individual or human that is being sought by a
researcher, veterinarian,
medical doctor or other clinician, which includes one or more of the
following: (1) Preventing
the disease; for example, preventing a disease, condition or disorder in an
individual that may
be predisposed to the disease, condition or disorder but does not yet
experience or display the
pathology or symptomatology of the disease, (2) Inhibiting the disease; for
example, inhibiting
a disease, condition or disorder in an individual that is experiencing or
displaying the pathology
or symptomatology of the disease, condition or disorder (i.e., arresting
further development of
the pathology and/or symptomatology), and (3) Ameliorating the disease; for
example,
ameliorating a disease, condition or disorder in an individual that is
experiencing or displaying
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the pathology or symptomatology of the disease, condition or disorder (i.e.,
reversing the
pathology and/or symptomatology).
[00191] In some embodiments, a compound as disclosed herein may be an
adrenergic
receptor modulating compound (e.g., an agonist, partial agonist or antagonist
of an adrenergic
receptor). The adrenergic receptor modulating compounds of the present
disclosure can in
some embodiments find use in modulating the activity of a target adrenergic
receptor in vitro
or in vivo. Aspects of the subject methods include contacting a sample with an
effective amount
of an adrenergic receptor modulating compound (e.g., as described herein) to
determine
whether the activity desired exists.
[00192] Adrenergic receptors (ADRs) are G-protein coupled receptors (GPCR)
that are
widely expressed throughout the body and play an important role in regulating
multiple
physiological processes including cognition, stress-related behavior,
inflammation, and smooth
muscle contraction/dilation, cardiac muscle contraction, airway reactivity and
cognition.
Adrenergic receptors mediate the central and peripheral effects of
noradrenaline (NA) and
adrenaline. Multiple subtypes of ADRs exist, including a-adrenergic receptors
and 13-
adrenergic receptors. Each subtype is expressed in distinct patterns and
involved in different
physiological processes. Therefore, ligands that selectively target one
subtype are valuable both
as research tools to identify the roles of different ADR subtypes and as
therapeutic agents for
multiple diseases related to dysfunction of the NA and adrenaline systems.
[00193] 0-adrenergic receptors further include three sub-types: 01-adrenergic
receptor (131-
ADR), 02-adrenergic receptor (r32-ADR), and 03-adrenergic receptor (03-ADR).
Because
these subtypes are expressed in distinct patterns and involved in different
physiological
processes, ligands that can selectively target one subtype have therapeutic
potential for multiple
diseases. However, discovery of subtype-selective ligands has been challenging
due to a high
level of sequence homology shared by these subtypes. A lot of existing
agonists for 13-
adrenergic receptors also exhibit inferior blood-brain-barrier (BBB)
penetration, which is
required in an effort for drug discovery for central nervous system (CNS)
indications.
[00194] As a class of G-protein coupled receptor, adrenergic receptors signal
via G protein-
and 13 -arrestin-dependent pathways. G protein- or 13 -arrestin signaling can
mediate different
physiological responses. Recently, it has become clear that agonists can show
biased activation
of signaling pathways. The ability of ligands to activate the receptor and
produce responses in
a pathway-dependent manner has been termed "signaling bias" or "functional
selectivity". As
G proteins and 13-arrestins mediate distinct physiological processes, biased
agonists can provide
improved therapeutic selectivity with reduced adverse effects. Thus, the
present disclosure is
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directed to 0-adrenergic receptor subtype-selective agonists with improved
blood-brain-barrier
(BBB) penetration.
[00195] An adrenergic receptor modulating compound can be an agonist of the
target
adrenergic receptor. In some cases, an effective amount of an adrenergic
receptor modulating
compound is an amount sufficient to activate an activity related to the
adrenergic receptor in a
cell by 10% or more, such as 20% or more, 30% or more, 40% or more, 50% or
more, 60% or
more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or or even
more relative
to a control, e.g., a control cell exhibiting a known activity level of the
receptor.
[00196] The adrenergic receptor modulating compound can be a partial agonist
of the target
adrenergic receptor. In some cases, an effective amount of an adrenergic
receptor modulating
compound is an amount sufficient to achieve partially agonism of the
adrenergic receptor in a
cell, e.g., where the subject compound achieves 10% activation or more of the
receptor, such
as 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or
more, 80%
or more, or 90% or more, relative to a control, e.g., a receptor that is fully
activated. Partial
agonism may be assessed using any convenient methods, such as a cell based
assay using a
known full agonist as a 100% activation control, where the relative maximum
activation of the
receptor can be measured relative to the full agonist.
[00197] The adrenergic receptor modulating compound can be an antagonist of
the target
adrenergic receptor. In some cases, an effective amount of an adrenergic
receptor modulating
compound is an amount sufficient to inhibit or decrease the activity of the
target adrenergic
receptor in a sample by 10% or more, such as 20% or more, 30% or more, 40% or
more, 50%
or more, 60% or more, 70% or more, 80% or more, 90% or more, or even more
relative to a
control, e.g., a sample not contacted with the compound of interest.
[00198] In some embodiments of the method, the target adrenergic receptor is a
01-
adrenergic receptor. In some embodiments of the method, the target adrenergic
receptor is a
132-adrenergic receptor. In some embodiments of the method, the target
adrenergic receptor is
a 03-adrenergic receptor. In some embodiments, the compound is an agonist for
both 01-
adrenergic receptor and 02-adrenergic receptor. In certain cases, the compound
is selective for
the 02-adrenergic receptor over a131-adrenergic receptor.
[00199] The target adrenergic receptor may be one that is responsible for a
mediating an
intracellular signal or pathway in a cell. In some embodiments, the sample
includes a cell and
modulating the adrenergic receptor modulates a physiological process in the
cell. Any
convenient physiological processes can be targeted for modulation in a cell
using the subject
methods. In some embodiments, the physiological process is one that is
implicated in cardiac
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function, in certain instances, the physiological process is one that is
implicated in cognitive
function. In certain instances, the physiological process is one that is
implicated in an
inflammatory pathway or condition. The subject methods can provide for
mediation of the
intracellular concentration of a signaling molecule in a cell, such as cAMP.
The subject
methods can provide for partial or full blockage of the target adrenergic
receptor to result in
modulation (e.g., activation) of cAMP in a sample. In some embodiments, the
method does not
modulate 0-arrestin pathways of the cell. In some cases, the cells are
inflammatory cells and
the function of the cells is regulated. The subject methods can provide for
inhibition of an
inflammatory pathway in a cell. In some cases, TNF-alpha is inhibited in the
cell, e.g., the
concentration or production of TNF-alpha is reduced by practicing the subject
method. In
certain embodiments of the method, the cell is a neuron. In some embodiments,
modulating the
adrenergic receptor enhances neurogenesis.
[00200] The compounds of this disclosure may be employed in a conventional
manner for
controlling, preventing, treating a disease described herein, including, but
not limited to,
myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's
disease, Gehrig's
disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple
Sclerosis, senile
dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated
dementia, other
dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's
disease, Pick's disease,
encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar
ataxias, cerebellar
degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia,
ataxia telangiectasia,
spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle
spasticity, tremor,
retinitis pigmentosa, striatonigral degeneration, mitochondrial
encephalomyopathies, neuronal
ceroid lipofuscinosis, cerebral autosomal dominant arteriopathy with
subcortical infarcts
(CADASIL) and diabetic retinopathy. Such methods of treatment, their dosage
levels and
requirements may be selected by those of ordinary skill in the art from
available methods and
techniques.
[00201] As used herein, the terms "combination," "combined," and related terms
refer to the
simultaneous or sequential administration of therapeutic agents in accordance
with this
disclosure. For example, a described compound may be administered with another
therapeutic
agent simultaneously or sequentially in separate unit dosage forms or together
in a single unit
dosage form. Accordingly, the present disclosure provides a single unit dosage
form
comprising a described compound, an additional therapeutic agent, and a
pharmaceutically
acceptable carrier, adjuvant, or vehicle. Two or more agents are typically
considered to be
administered "in combination" when a patient or individual is simultaneously
exposed to both
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agents. In many embodiments, two or more agents are considered to be
administered "in
combination" when a patient or individual simultaneously shows therapeutically
relevant levels
of the agents in a particular target tissue or sample (e.g., in brain, in
serum, etc.).
[00202] When the compounds of this disclosure are administered in combination
therapies
with other agents, they may be administered sequentially or concurrently to
the patient.
Alternatively, pharmaceutical or prophylactic compositions according to this
disclosure
comprise a combination of ivermectin, or any other compound described herein,
and another
therapeutic or prophylactic agent. Additional therapeutic agents that are
normally administered
to treat a particular disease or condition may be referred to as "agents
appropriate for the
disease, or condition, being treated."
[00203] In some embodiments, the subject method includes administering a
therapeutically
effective amount of one or more additional active agents. By combination
therapy is meant that
an adrenergic receptor modulating compound can be used in a combination with
another
therapeutic agent to treat a single disease or condition. In particular
embodiments, a compound
of the present disclosure is administered concurrently with the administration
of another
therapeutic agent, which can be administered as a component of a composition
including the
compound of the present disclosure or as a component of a different
composition.
[00204] The subject compounds can be administered in combination with other
therapeutic
agents in a variety of therapeutic applications. Therapeutic applications of
interest for
combination therapy include those applications in which activity of a target
adrenergic receptor
is the cause or a compounding factor in disease progression. As such, the
subject compounds
find use in combination therapies in which the inhibition of a target
adrenergic receptor in the
subject is desired. Examples of disease conditions which may be treated by a
combination
therapy including a subject compound include, but are not limited to, cardiac
conditions or
diseases, neurodegenerative or neurodevelopmental disease, respiratory
disorders, asthma,
memory impairment, depression, inflammatory diseases, stroke, ischemic brain
or tissue injury
and cancer. Agents of interest which can be used in jointly with the subject
adrenergic receptor
modulating compounds include, but are not limited to, antidepressants,
antipsychotics, beta-
blockers, vasoconstrictors, antihypotensives, decongestants, chemotherapeutic
agents, agents
used in Alzheimer's disease, and anti-inflammatory agents.
[00205] The subject adrenergic receptor modulating compounds can be used
jointly with any
agent useful in the treatment of a cardiac condition, such as cardiogenic
shock, hypertension,
congestive heart failure, coronary heart disease, arrhythmias, myocardial
infarction or ischemic
heart diseases. Agents of interest which can be used in jointly with the
subject adrenergic
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receptor modulating compounds include, but are not limited to, denopamine,
dobutamine,
xamoterol, acebutolol, atenolol, betaxolol, bisoprolol, pindolol, esmolol,
metoprolol,
nebivolol, vortioxetine, Carvedilol, Labetalol, Phentolamine, Prazosin,
Cirazoline,
Methoxamine, Synephrine, Etilefrine, Metaraminol, Midodrine, and cumarin.
[00206] The subject adrenergic receptor modulating compounds can be used
jointly with any
agent useful in the treatment of a neurodegenerative or neurodevelopmental
disease, such as
such as Alzheimer's Disease, memory impairment, cognitive impairment,
depression, stroke
and ischemic brain or tissue injury, Down's syndrome or Autism. Agents of
interest which can
be used in jointly with the subject adrenergic receptor modulating compounds
include, but are
not limited to, acepromazine. In some embodiments, the subject adrenergic
receptor
modulating compounds can be used in the treatment of a disease, such as a
neurodegenerative
or neurodevelopmental disease, in combination with a cholinesterase inhibitor
or a NMDA
receptor modulators. Agents of interest include, but are not limited to,
Donepezil, Aricept,
Galantamine, Razadyne, Memantine, Namenda, Rivastigmine, Exelon, Tacrine and
Cognex.
Other agents of interest which can be used in jointly with the subject
adrenergic receptor
modulating compounds include, but are not limited to, 4-NEMD, 7-Me-
marsanidine,
Agmatine, Apraclonidine, Brimonidine, Cannabigerol, Clonidine, Detomidine,
Dexmedetomidine, Fadolmidine, Guanabenz, Guanfacine, Lofexidine, Marsanidine,
Medetomidine, Methamphetamine, Mivazerol, Rilmenidine, Romifidine, Talipexole,
Tiamenidine, Tizanidine, Tolonidine, Xylazine, Xylometazoline, Aripiprazole,
Asenapine,
Atipamezole, Cirazoline, Clozapine, Efaroxan, Idazoxan, Lurasidone, Melperone,
Mianserin,
Mirtazapine, Napitane, Olanzapine, Paliperidone, Phenoxybenzamine,
Phentolamine,
Piribedil, Rauwolscine, Risperidone, Rotigotine, Quetiapine, Norquetiapine,
Setiptiline,
Tolazoline, Yohimbine, Ziprasidone and Zotepine. Other agents of interest
which can be used
in jointly with the subject adrenergic receptor modulating compounds include,
but are not
limited to, bitolterol, fenoterol, hexoprenaline, isoprenaline or
isoproterenol, levosalbutamol or
levalbuterol, orciprenaline or metaproterenol, pirbuterol, procaterol,
salbutamol or albuterol,
terbutaline, bambuterol, clenbuterol, formoterol, salmeterol, carmoterol,
indacaterol,
milveterol, olodaterol, vilanterol, fenoterol, hexoprenaline, isoxsuprine,
ritodrine, salbutamol
or albuterol, terbutaline, zilpaterol, ICI-118,551 and butoxamine.
[00207] The compounds utilized in the compositions and methods of this
disclosure may also
be modified by appending appropriate functionalities to enhance selective
biological
properties. Such modifications are known in the art and include those, which
increase
biological penetration into a given biological system (e.g., blood, lymphatic
system, or central
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nervous system), increase oral availability, increase solubility to allow
administration by
injection, alter metabolism and/or alter rate of excretion.
[00208] According to a preferred embodiment, the compositions of this
disclosure are
formulated for pharmaceutical administration to a subject or patient, e.g., a
mammal, preferably
a human being. Such pharmaceutical compositions are used to ameliorate, treat
or prevent any
of the diseases described herein in a subject.
[00209] Agents of the disclosure are often administered as pharmaceutical
compositions
comprising an active therapeutic agent, i.e., and a variety of other
pharmaceutically acceptable
components. See Remington's Pharmaceutical Science (15th ed., Mack Publishing
Company,
Easton, Pa., 1980). The preferred form depends on the intended mode of
administration and
therapeutic application. The compositions can also include, depending on the
formulation
desired, pharmaceutically acceptable, non-toxic carriers or diluents, which
are defined as
vehicles commonly used to formulate pharmaceutical compositions for animal or
human
administration. The diluent is selected so as not to affect the biological
activity of the
combination. Examples of such diluents are distilled water, physiological
phosphate-buffered
saline, Ringer's solutions, dextrose solution, and Hank's solution. In
addition, the
pharmaceutical composition or formulation may also include other carriers,
adjuvants, or
nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
[00210] In some embodiments, the present disclosure provides pharmaceutically
acceptable
compositions comprising a therapeutically effective amount of one or more of a
described
compound, formulated together with one or more pharmaceutically acceptable
carriers
(additives) and/or diluents for use in treating the diseases described herein,
including, but not
limited to stroke, ischemia, Alzheimer's, ankylosing spondylitis, arthritis,
osteoarthritis,
rheumatoid arthritis, psoriatic arthritis, asthma atherosclerosis, Crohn's
disease, colitis,
dermatitis diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome,
systemic lupus
erythematous, nephritis, ulcerative colitis and Parkinson's disease. While it
is possible for a
described compound to be administered alone, it is preferable to administer a
described
compound as a pharmaceutical formulation (composition) as described herein.
Described
compounds may be formulated for administration in any convenient way for use
in human or
veterinary medicine, by analogy with other pharmaceuticals.
[00211] As described in detail, pharmaceutical compositions of the present
disclosure may
be specially formulated for administration in solid or liquid form, including
those adapted for
the following: oral administration, for example, drenches (aqueous or non-
aqueous solutions
or suspensions), tablets, e.g., those targeted for buccal, sublingual, and
systemic absorption,
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boluses, powders, granules, pastes for application to the tongue; parenteral
administration, for
example, by subcutaneous, intramuscular, intravenous or epidural injection as,
for example, a
sterile solution or suspension, or sustained-release formulation; topical
application, for
example, as a cream, ointment, or a controlled-release patch or spray applied
to the skin, lungs,
or oral cavity; intravaginally or intrarectally, for example, as a pessary,
cream or foam;
sublingually; ocularly; transdermally; or nasally, pulmonary and to other
mucosal surfaces.
[00212] Wetting agents, emulsifiers and lubricants, such as sodium lauryl
sulfate and
magnesium stearate, as well as coloring agents, release agents, coating
agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can also be
present in the
compositions.
[00213] Examples of pharmaceutically acceptable antioxidants include: water
soluble
antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate,
sodium
metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as
ascorbyl palmitate,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin,
propyl gallate,
alpha-tocopherol, and the like; and metal chelating agents, such as citric
acid, ethylenediamine
tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the
like.
[00214] Formulations for use in accordance with the present disclosure include
those suitable
for oral, nasal, topical (including buccal and sublingual), rectal, vaginal
and/or parenteral
administration. The formulations may conveniently be presented in unit dosage
form and may
be prepared by any methods well known in the art of pharmacy. The amount of
active
ingredient, which can be combined with a carrier material, to produce a single
dosage form will
vary depending upon the host being treated, and the particular mode of
administration. The
amount of active ingredient that can be combined with a carrier material to
produce a single
dosage form will generally be that amount of the compound, which produces a
therapeutic
effect. Generally, this amount will range from about 1% to about 99% of active
ingredient. In
some embodiments, this amount will range from about 5% to about 70%, from
about 10% to
about 50%, or from about 20% to about 40%.
[00215] In certain embodiments, a formulation as described herein comprises an
excipient
selected from the group consisting of cyclodextrins, liposomes, micelle
forming agents, e.g.,
bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a
compound of the
present disclosure. In certain embodiments, an aforementioned formulation
renders orally
bioavailable a described compound of the present disclosure.
[00216] Methods of preparing formulations or compositions comprising described
compounds include a step of bringing into association a compound of the
present disclosure
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with the carrier and, optionally, one or more accessory ingredients. In
general, formulations
may be prepared by uniformly and intimately bringing into association a
compound of the
present disclosure with liquid carriers, or finely divided solid carriers, or
both, and then, if
necessary, shaping the product.
[00217] The pharmaceutical compositions may be in the form of a sterile
injectable
preparation, for example, as a sterile injectable aqueous or oleaginous
suspension. This
suspension may be formulated according to techniques known in the art using
suitable
dispersing or wetting agents (such as, for example, Tween 80) and suspending
agents. The
sterile injectable preparation may also be a sterile injectable solution or
suspension in a non-
toxic parenterally acceptable diluent or solvent, for example, as a solution
in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are mannitol,
water,
Ringer's solution and isotonic sodium chloride solution. In addition, sterile,
fixed oils are
conventionally employed as a solvent or suspending medium. For this purpose,
any bland fixed
oil may be employed including synthetic mono- or diglycerides. Fatty acids,
such as oleic acid
and its glyceride derivatives are useful in the preparation of injectables, as
are natural
pharmaceutically acceptable oils, such as olive oil or castor oil, especially
in their
polyoxyethylated versions. These oil solutions or suspensions may also contain
a long-chain
alcohol diluent or dispersant, such as those described in Pharmacopeia
Helvetica, or a similar
alcohol. Other commonly used surfactants, such as Tweens, Spans and other
emulsifying
agents or bioavailability enhancers which are commonly used in the manufacture
of
pharmaceutically acceptable solid, liquid, or other dosage forms may also be
used for the
purposes of formulation.
[00218] In some cases, in order to prolong the effect of a drug, it may be
desirable to slow
the absorption of the drug from subcutaneous or intramuscular injection. This
may be
accomplished by the use of a liquid suspension of crystalline or amorphous
material having
poor water solubility. The rate of absorption of the drug then depends upon
its rate of
dissolution, which in turn, may depend upon crystal size and crystalline form.
Alternatively,
delayed absorption of a parenterally administered drug form is accomplished by
dissolving or
suspending the drug in an oil vehicle.
[00219] Injectable depot forms are made by forming microencapsule matrices of
the
described compounds in biodegradable polymers such as polylactide-
polyglycolide.
Depending on the ratio of drug to polymer, and the nature of the particular
polymer employed,
the rate of drug release can be controlled. Examples of other biodegradable
polymers include
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poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also
prepared by
entrapping the drug in liposomes or microemulsions, which are compatible with
body tissue.
[00220] The pharmaceutical compositions of this disclosure may be orally
administered in
any orally acceptable dosage form including, but not limited to, capsules,
tablets, and aqueous
suspensions and solutions. In the case of tablets for oral use, carriers,
which are commonly
used include lactose and corn starch. Lubricating agents, such as magnesium
stearate, are also
typically added. For oral administration in a capsule form, useful diluents
include lactose and
dried cornstarch. When aqueous suspensions and solutions and propylene glycol
are
administered orally, the active ingredient is combined with emulsifying and
suspending agents.
If desired, certain sweetening and/or flavoring and/or coloring agents may be
added.
[00221] Formulations described herein suitable for oral administration may be
in the form of
capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually
sucrose and acacia or
tragacanth), powders, granules, or as a solution or a suspension in an aqueous
or non-aqueous
liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir
or syrup, or as
pastilles (using an inert base, such as gelatin and glycerin, or sucrose and
acacia) and/or as
mouth washes and the like, each containing a predetermined amount of a
compound of the
present disclosure as an active ingredient. Compounds described herein may
also be
administered as a bolus, electuary or paste.
[00222] In solid dosage forms for oral administration (capsules, tablets,
pills, dragees,
powders, granules and the like), an active ingredient is mixed with one or
more
pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium
phosphate, and/or
any of the following: fillers or extenders, such as starches, lactose,
sucrose, glucose, mannitol,
and/or silicic acid; binders, such as, for example, carboxymethylcellulose,
alginates, gelatin,
polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol;
disintegrating
agents, such as agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain
silicates, and sodium carbonate; solution retarding agents, such as paraffin;
absorption
accelerators, such as quaternary ammonium compounds; wetting agents, such as,
for example,
cetyl alcohol, glycerol monostearate, and non-ionic surfactants; absorbents,
such as kaolin and
bentonite clay; lubricants, such as talc, calcium stearate, magnesium
stearate, solid
polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and
coloring agents. In the
case of capsules, tablets and pills, the pharmaceutical compositions may also
comprise
buffering agents. Solid compositions of a similar type may also be employed as
fillers in soft
and hard-shelled gelatin capsules using such excipients as lactose or milk
sugars, as well as
high molecular weight polyethylene glycols and the like.
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[00223] Tablets may be made by compression or molding, optionally with one or
more
accessory ingredients. Compressed tablets may be prepared using binder (for
example, gelatin
or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,
disintegrant (for
example, sodium starch glycolate or cross-linked sodium carboxymethyl
cellulose), surface-
active or dispersing agent. Molded tablets may be made in a suitable machine
in which a
mixture of the powdered compound is moistened with an inert liquid diluent. If
a solid carrier
is used, the preparation can be in tablet form, placed in a hard gelatin
capsule in powder or
pellet form, or in the form of a troche or lozenge. The amount of solid
carrier will vary, e.g.,
from about 25 to 800 mg, preferably about 25 mg to 400 mg. When a liquid
carrier is used, the
preparation can be, e.g., in the form of a syrup, emulsion, soft gelatin
capsule, sterile injectable
liquid such as an ampule or nonaqueous liquid suspension. Where the
composition is in the
form of a capsule, any routine encapsulation is suitable, for example, using
the aforementioned
carriers in a hard gelatin capsule shell.
[00224] Tablets and other solid dosage forms, such as dragees, capsules, pills
and granules,
may optionally be scored or prepared with coatings and shells, such as enteric
coatings and
other coatings well known in the pharmaceutical-formulating art. They may
alternatively or
additionally be formulated so as to provide slow or controlled release of the
active ingredient
therein using, for example, hydroxypropylmethyl cellulose in varying
proportions to provide
the desired release profile, other polymer matrices, liposomes and/or
microspheres. They may
be formulated for rapid release, e.g., freeze- dried. They may be sterilized
by, for example,
filtration through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form
of sterile solid compositions that can be dissolved in sterile water, or some
other sterile
injectable medium immediately before use. These compositions may also
optionally contain
opacifying agents and may be of a composition that they release the active
ingredient(s) only,
or preferentially, in a certain portion of the gastrointestinal tract,
optionally, in a delayed
manner. Examples of embedding compositions that can be used include polymeric
substances
and waxes. The active ingredient can also be in micro-encapsulated form, if
appropriate, with
one or more of the above-described excipients.
[00225] Liquid dosage forms for oral administration of compounds of the
disclosure include
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions,
syrups and
elixirs. In addition to the active ingredient, the liquid dosage forms may
contain inert diluents
commonly used in the art, such as, for example, water or other solvents,
solubilizing agents
and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,
ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in
particular, cottonseed,
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groundnut, corn, germ, olive, castor and sesame oils), glycerol,
tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof
[00226] Besides inert diluents, oral compositions can also include adjuvants
such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring, coloring,
perfuming and
preservative agents.
[00227] Suspensions, in addition to active compounds, may contain suspending
agents as,
for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, and
mixtures thereof
[00228] The pharmaceutical compositions of this disclosure may also be
administered in the
form of suppositories for rectal administration. These compositions can be
prepared by mixing
a compound of this disclosure with a suitable non-irritating excipient, which
is solid at room
temperature but liquid at the rectal temperature and therefore will melt in
the rectum to release
the active components. Such materials include, but are not limited to, cocoa
butter, beeswax
and polyethylene glycols.
[00229] Topical administration of the pharmaceutical compositions of this
disclosure is
especially useful when the desired treatment involves areas or organs readily
accessible by
topical application. For application topically to the skin, the pharmaceutical
composition
should be formulated with a suitable ointment containing the active components
suspended or
dissolved in a carrier. Carriers for topical administration of the compounds
of this disclosure
include, but are not limited to, mineral oil, liquid petroleum, white
petroleum, propylene glycol,
polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
Alternatively, the
pharmaceutical composition can be formulated with a suitable lotion or cream
containing the
active compound suspended or dissolved in a carrier. Suitable carriers
include, but are not
limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl
alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical
compositions of this
disclosure may also be topically applied to the lower intestinal tract by
rectal suppository
formulation or in a suitable enema formulation. Topically-administered
transdermal patches
are also included in this disclosure.
[00230] The pharmaceutical compositions of this disclosure may be administered
by nasal
aerosol or inhalation. Such compositions are prepared according to techniques
well-known in
the art of pharmaceutical formulation and may be prepared as solutions in
saline, employing
benzyl alcohol or other suitable preservatives, absorption promoters to
enhance bioavailability,
fluorocarbons, and/or other solubilizing or dispersing agents known in the
art.
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[00231] For ophthalmic use, the pharmaceutical compositions may be formulated
as
micronized suspensions in isotonic, pH adjusted sterile saline, or,
preferably, as solutions in
isotonic, pH adjusted sterile saline, either with or without a preservative
such as
benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutical compositions
may be formulated in an ointment such as petrolatum.
[00232] Transdermal patches have the added advantage of providing controlled
delivery of
a compound of the present disclosure to the body. Dissolving or dispersing the
compound in
the proper medium can make such dosage forms. Absorption enhancers can also be
used to
increase the flux of the compound across the skin. Either providing a rate
controlling membrane
or dispersing the compound in a polymer matrix or gel can control the rate of
such flux.
[00233] Examples of suitable aqueous and nonaqueous carriers, which may be
employed in
the pharmaceutical compositions of the disclosure, include water, ethanol,
polyols (such as
glycerol, propylene glycol, polyethylene glycol, and the like), and suitable
mixtures thereof,
vegetable oils, such as olive oil, and injectable organic esters, such as
ethyl oleate. Proper
fluidity can be maintained, for example, by the use of coating materials, such
as lecithin, by
the maintenance of the required particle size in the case of dispersions, and
by the use of
surfactants.
[00234] Such compositions may also contain adjuvants such as preservatives,
wetting agents,
emulsifying agents and dispersing agents. Inclusion of one or more
antibacterial
and/orantifungal agents, for example, paraben, chlorobutanol, phenol sorbic
acid, and the like,
may be desirable in certain embodiments. It may alternatively or additionally
be desirable to
include isotonic agents, such as sugars, sodium chloride, and the like into
the compositions. In
addition, prolonged absorption of the injectable pharmaceutical form may be
brought about by
the inclusion of agents, which delay absorption such as aluminum monostearate
and gelatin.
[00235] In certain embodiments, a described compound or pharmaceutical
preparation is
administered orally. In other embodiments, a described compound or
pharmaceutical
preparation is administered intravenously. Alternative routes of
administration include
sublingual, intramuscular, and transdermal administrations.
[00236] When compounds described herein are administered as pharmaceuticals,
to humans
and animals, they can be given per se or as a pharmaceutical composition
containing, for
example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in
combination
with a pharmaceutically acceptable carrier.
[00237] Preparations described herein may be given orally, parenterally,
topically, or
rectally. They are of course given in forms suitable for the relevant
administration route. For
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example, they are administered in tablets or capsule form, by injection,
inhalation, eye lotion,
ointment, suppository, etc. administration by injection, infusion or
inhalation; topical by lotion
or ointment; and rectal by suppositories. Oral administrations are preferred.
[00238] Such compounds may be administered to humans and other animals for
therapy by
any suitable route of administration, including orally, nasally, as by, for
example, a spray,
rectally, intravaginally, parenterally, intracisternally and topically, as by
powders, ointments
or drops, including buccally and sublingually.
[00239] Regardless of the route of administration selected, compounds
described herein
which may be used in a suitable hydrated form, and/or the pharmaceutical
compositions of the
present disclosure, are formulated into pharmaceutically-acceptable dosage
forms by
conventional methods known to those of skill in the art.
[00240] Actual dosage levels of the active ingredients in the pharmaceutical
compositions of
the disclosure may be varied so as to obtain an amount of the active
ingredient that is effective
to achieve the desired therapeutic response for a particular patient,
composition, and mode of
administration, without being toxic to the patient.
[00241] Also provided are kits that include the disclosed adrenergic receptor
modulating
compounds. Systems of the present disclosure include collections of active
agents brought
together, e.g., by a health care practitioner, for administration to a
subject, such as a patient.
Such systems may include an adrenergic receptor modulating compound and one or
more
additional active agents disclosed herein. Kits that include adrenergic
receptor modulating
compounds which are provided that may include one or more dosages of an
adrenergic receptor
modulating compound, and optionally one or more dosages of one or more
additional active
agents. Conveniently, the formulations may be provided in a unit dosage
format. In such kits,
in addition to the containers containing the formulation(s), e.g. unit doses,
is an informational
package insert describing the use of the subject formulations in the methods
of the as disclosed
herein, e.g., instructions for using the subject unit doses to treat cellular
proliferative disease
conditions. These instructions may be present in the subject systems and kits
in a variety of
forms, one or more of which may be present in the kit. One form in which these
instructions
may be present is as printed information on a suitable medium or substrate,
e.g., a piece or
pieces of paper on which the information is printed, in the packaging of the
kit, in a package
insert, etc. Yet another means would be a computer readable medium, e.g.,
diskette, CD, etc.,
on which the information has been recorded. Yet another means that may be
present is a website
address which may be used via the intern& to access the information at a
removed site. Any
convenient means may be present in the kits.
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[00242] Table 1 below illustrates exemplary compounds of the instant
disclosure.
Table 1. The compounds in the instant disclosure.
Compound
Chemical Structure MS (M+H)
No.
OH
H
5Ny...._
02-1 1 244.2
H2N
CI
OH
Li)H
02-2 I 278.2
H2N
CF3
OH
H
N
02-3 I 225.2
/
H2N
OH
H
02-4
225.2
H2N N
OH
H
CII\l<
i
02-5 I N
H2NN--..
)NH
()::
(R)
02-6 210.1
I INI
/
NH2
)NH
OH
02-7 (S) 211.2
I INI
/
OH
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Compound
Chemical Structure MS (M+H)
No.
)NH
OH
02-8 211.2
I
OH
NH
02-9 258.8
N OH
H2N
CI
NH
,fR)
02-10 N 10H 249.3
H2N
I I
NH
47(S)
02-11 N OH 249.3
H2N
I I
)NH
OH
(R
02-12 224.3
I
NH2
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Compound
Chemical Structure MS (M+H)
No.
NH
OH
02-13 fs,) 224.3
- NH2
NH
02-14 ,(iR) 258.8
'OH
H 2N
CI
NH
(s)OH
02-15 244.3
N
CI
NH 2
I OH H
N
02-16 ji..S
244.1
t'12.11'
'CI
1
02-17
¨ ,
"
ci
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OH:
02-18 I 274.1
Hz =
,
N
02-19
C,1
H H
N
N '
02-20 256.1
C I
02-21
CI
.7H
N F
02-22
H4N
02-23
=
OH Fi
,
02-24
,141
F
02-25
tki-kr
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OH
I H
04-1 261.22
Ht4)
0
1
0H
04-2 275.26
NN 0
NINIH
04-3 262.24
CY'eN
>'
'NH
H
04-4 279.25
r Nµ
N
F H
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OH
N HN
04-5 262.22
HN,
0
04-6 RJ 345.4
OH H
0
04-7 ) 253.2 N (s) N I 0)
OH
04-8 0( R) = 327.4
N (s) N
OH H
04-9 235.2
OH
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OH
H - H
04-10 252.3
I
0
Cr
04-11 HN 236.3
N_ N(
OH H
(0 1 s (30
04-12 R) 344.4
N N -(S) N
H _
OH H
H
N N 0
04-13 262.2
(R)
OH
)c NH
)NH
OH
04-14 (s) 262.28
\
0 0
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1
0 N
\
04-15 275.3
(s)
HO
HN(
F
H
SNO
04-16 279.25
(s)
'OH
)cNH
H
0 N
\
04-17 275.26
(s)
HO
HNi(
H
0 N
\ 101
04-18 275.26
s (R)
HO'
HNi(
>NH
04-19 265.3
0
lei
NO
H
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>NH
04-20
0
0 )
N
H
>NH
04-21
S
1F
F
>NH
.00H
04-22 (:)
S NZ
IF
F
YNH
' ,OH
0:0
04-23 252.35
NI., .
HN
F
)4NH
,,OH
04-24 n 234.25
N sHN
F.IN 0
N
04-25 HOµ , (R)
234.35
HN7(
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. / 0
N
HN
04-26 s OR)
234.25
HOs
HN7&
\
N
04-27 (s) 248.3
s
HO 248.3
HN
\
N\
04-28 248.3
(s)
HO
HN
)4NH
,OH
04-29 iw 249.21
s/ .
N
0
)4NH
OH
04-30 (s) 249.21
s/ .
N
0
H
Ns
N
/
F
04-31 252.35
OH
NH
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H
F N,N
/
04-32 252.33
OH
NH
>NH
.,,OH
04-33
ei.--!---\
-...(/N
N H
qi)N
N
04-34 235.3
rCOH
NH
H
N,
N
i
04-35 248.3
OH
NH
/ 1
I F
04-36 313.23
)N (8) N
H F
OH F
/ 1
I F
04-37 313.18
)N _ (R) N
H F
OH F
91
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N
HO,, ISI
/
(R)
04-38 245.2
HN
/ .
1
04-39 279
)N (s) -N
H
OH CI
/ 1
I
04-40 279
)N _ (IR) -N
H ¨
OH CI
I
04-41 263.29
YN (s) N
H
OH F
/ 1
1
04-42 263.33
N _ (R) - N
H ¨
OH F
I
04-43 )N (s) N 313.26
H
OH
F F
F
92
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1
04-44 )N (R) N 313.26
H -
OH
F F
04-45
245.1
)N (s) N
OH
04-46 245.1
)N R N
H -
OH
OH 11
H -
04-47 N N 270.3
NH
04-48 234.2
(R)
N' 10H
HN
93
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¨1¨
NH
04-49
JR) 248.31
N' 0 'OH
N
i
¨1¨
NH
04-50 (s) 248.31
/ 0 OH
N
N
i
P 0
04-51 N 249.3
0- H H
0 0
04-52 N 249.3
(s) N
H
OH
0,
N
04-53 /
>N
H
OH
.......k¨NH 9H
. 0?)
04-54 283.1
N
H
94
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OH
H _
N -
04-55 389.35
0
NH
OH H
I. (R) N..1,_-04-56
269.1
HN .
HNX
HO (,)
04-57 283.1
N
H
H
N
04-58
OH
H
N
04-59
0
HN
H F
N
04-60 301.35
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H
N
/ \
04-61 N¨ 284.4
H0µ.
HN--..6
H
N N
/ \
04-62
OH
N
N
04-63
OH
H
N
N
/ \
04-64 284.4
HOµs
HN--E
H F
N
04-65
HOµs
HN-....6
OH
H
N
04-66 40/ 375.5
0
HN
96
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F)
NH
F F 00H
04-67 n 297.24
0 N
F)
NH
F F OH
04-68 (s) 297.24
0 N
)4NH
,%OH
(R)
04-69 0 N
313.27
F F
F
)4NH
OH
(S)
04-70 0 N
313.28
F F
F
)<NH
OH
04-71 (s) 270.31
N
N /
/
97
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)NH
04-72 iR.) 270.27
N
N /
/
)4NH
L.s.OH
04-73 T 246.2
N
I
N
)4NH
OH
04-74 (s)
246.27
0 NL)
N
)NH
.0H
04-75 4(R)
246.27
s )
N
F 0
I
N
04-76 , (R) 263.2
HO'
HN?(
98
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)4NH
OH
(s)
04-77 0 N
270.27
II
N
YNN
00H
ff
04-78 0 N
270.27
II
N
HN
HO,,
(s)
04-79 263.1
0 N
F
HN
HO
(R)
04-80 263.1
0 N
F
99
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)4NH
OH
(s)
04-81 s N
313
F F
F
)4NH
00H
(R)
04-82 s N
313.1
F F
F
)NH
OH
P
04-83 259.16
)%1 0
)NH
00H
(R)
04-84 259.19
N 0
)NH
00H
04-85 (R) F 313.1
F
N
F
/
100
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)4NH
OH
04-86 (s) F 313.1
F
N
F
/
)4NH
OH
04-87 (s) 259.43
N 0
yNH
00H
04-88 (R) 259.43
N s
)NH
OH
04-89 (s) 263.24
F$ N
/
)4NH
00H
04-90 (R) 263.29
F$ N
/
101
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)NH
00H
(s)
04-91 313.32
N 1 0
F
F
F
)NH
OH
(R)
04-92 313.28
N 1 0F I
F
F
)NH
OH
04-93 (s) 245.28
s N
)NH
%0H
04-94 rw 245.1
s N
)NH
00H
04-95 (s) 245.1
N I.I
102
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NH
OH
04-96 245.2
I
FIN1(
HO
(s)
04-97 261.26
OH
OH
NNe
04-98 I 244.2
,N
H CH N I
04-99 >vN
04-100 >N,
OH N-
N
04-101
- N<
- N OH H
HN
HO
04-102 (R) 277.4
0
HN
103
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HN
04-103 HO (R) 275.4
A #
0 NH
NH
, OH
ss
04-104 (R) 259.3
N' .HN
N
NH
, OH
..
04-105 (R) 233.4
/ 101
HN
NH
, OH
04-106 *(s) 251.3
oE
re"
N I I
HN
NH
OH
04-107 (R)
251.3
(:J
N/ iNe"
, I
HN
104
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NH
00H
(R)
04-108 268.8
N/
HN
CI
NH
,OH
04-109 (R) 248.3
N
HN
HN
HO
04-110 (R) 249.3
HN (101
NH
,OH
04-111 (R) 247.4
1.1
HN
NH
, OH
04-112 F (R) 251.2
1101
HN
105
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NH
, OH
04-113 F(R) 252.3
N 1.1
HN
NH
, OH
04-114 = *(R) 248.3
I
HN N
NH
04-115 235.3
.(R)
e'OH
HN
HO
04-116 (R) 251.3
=<S
NH
04-117 .0R) 268.8
OH
HN
CI
106
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NH
04-118 248.3
, fR)
OH
HN
HNX
HO (R)
04-119 284.4
\
NH pH
(R)
04-120 261.4
NH
OH
(R)
04-121 249.3
0
HN
HNX
HO (R)
04-122 301.4
*
107
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HN
04-123 HO (R) 261.4
HN
NH
04-124 234.3
, (R)
OH
HN
(R)
04-125 N (R).
NH 375.5
OH
NH
(s)OH
235.3 04-126
N/ I
HN
NH
, OH
04-127 =*(R) 235.3
N/IrI
HN
108
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H
04-128 N NH N 284.4
OH
NH
,OH
s(R)
04-129 277.4
N
H 0
)NH
.0H
(R)
04-130 248.3
N1/ 1101
HN
HNX
HO (R)
04-131 284.4
N
N
H
)NH
,OH
**
04-133 (R) 293.4
s0q......
NO
H
109
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N
OH I I
H
04-134 k N R) N 270.3
N
OH I I
H :
04-135 )cN = P N 270.3
/ 1
I F
04-136 313.3
-N
H - F
OH F
/
F
04-137 329.3
H I F
OH 0 F
HN .N\
04-138 s (R) 248.2
HO'
HN
110
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NH
, OH
04-139 (R) 268.4
CI
HN
OH
N
04-140 (R) HN 234.4
OH
NH
,OH
04-141 (IR) 277.4
N 0
CL NH
,OH
04-142 (R)259.4
\
N 0
04-143 HN (R) N 261.4
- H
OH
0
111
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NH
,OH
..
04-144 (s) 235.3
N
N(DO/
HN
NH
OH
04-145 (R)
235.3
N' N I
HN -
HN ¨N
\
04-146
. 252.2
F :(R) ki -
- H H
0
NH
, OH
04-147 ' (IR) 250.4
N' ISI
HN F
04 NH
, OH
04-148 ' (IR) 264.4
N' .HN F
112
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OH
H -
N : (R) F
04-149 I
0 238.2
\
N¨ NH
o
HN sN'\
04-150 264.3
. R)
Hoµ
HN
HN
N HO
04-151 \ \ (R) 259.4
N' I.1
HN
04-152 N (R) NH 247.4
H
OH
0
NH
.00H
04-153 (R) 235.4
\
N' I
HN --...%N
113
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NH
,OH
04-154 *(R) 264.2
N/
HN 0
NH
04-155 ,(R) 248.5
i'OH
HN
NH
04-156 , (R) 252.4
"OH
HN
NH
04-157 235.5
(R)
OH
HN N
HN
HO
04-158 F (R) 285.4
0
HN 1101
114
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0/
H
N 0
1.1 /
04-159 291.3
s (R)
HO'
HN
NH
00H
04-160 * (R) 268.3
N' 101
IN-IN CI
NH
, OH
..
04-161 (R) 235.2
N s
*
N.
HN
OH
NH
04-162 0 OH 250.2
. (R)
N' $1
HN
115
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NH
. , OH
s(R)
04-163 236.5
N/ 101
HN
F
HN¨N
\
04-164
01 rti 220.2
'&) NH
, OH
..
04-165 (R) 260.2
N' 1.HN
V. NH
, OH
..
04-166 g 246.2
N/ I.HN
'c?' NH
, OH
**(R)
04-167 250.1
N/ .HN
F
116
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HN ¨ N
\
F
04-168
401 N 252.1
¨ H
OH
HN ¨ N
\
04-169 F
. N) 238.1
: (R)
¨ H
OH
NH
s OH
04-170 * (IR) 236.3
N' 40HN F
'Cill NH
, OH
04-171 ' (IR) 250.2
N,/ 1101
HN F
04 NH
,OH
' (IR)
04-172 264.1
N/ .HN
F
117
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NH
,OH
04-173 F(R) 250.1
N
HN
OH
H -
N (R)
04-174 234.5
N- NH
OH
H
(R).04-175 248.5
N- NH
NH
04-176 F 251.2
,fR)
/ 'OH
HN
OH
NH
04-177 250.3
=
,fR)
HN
'OH
118
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NH
04-178 232.3
.fR)
HN
OH
N 0
04-179 259.4
(R)
OH
,NH
NH
,OH
*(R)
04-180 1 259.3
N.
HN
I I
NH
,01-1
.(R)
04-181 N 302.3
./ 1101
HN
F F
119
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NH
, OH
'(R)
04-182 302.3
N 1101
HN
r NH
04-183
m 220.3
(R)
- H
OH
N 0
04-184 273.3
R)
OH
OcNH
OH
N
04-185
HN
ON
04-186 /-N-;=:`
120
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ON
H
-
04-187 r4N-
OH
04-188 )7-
y
=
OH H
N
----
04-189
HN
OH
I
04-190
111,4'
04-191
OH.
t,
04-193
e
121
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OH
N ,
04-194
HN
(f.
OH H
N =
04-195
H N -N
ON H
04-196
= -CF3
HN -N
OH 9
04-197
-Th
HN-N'
H H
HiF2=C = . N
04-198 ,
=
N-141
OH H
F
04-199
N
OH H
04-200 = N =
1(
=
H N
122
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HO
H
04-201
14 "ee'
Ft
11 i
,
04-203
H
1,1 0 , _.,,,,,..Thi ,.....-4,õ,,,
04-204 H
1.-- I
N 1
H
...,.....,
HO 04-205 H
H
7
H o
04-206
N 1 .=1
'2:1:'=;.\''1:6'
H
,,,.....
NO _,,, (,./s)
04-207 I-I
N
N's . ,
H
04-208
N" 1
H
123
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HO
04-209
N
14.
Ho.
= = 'hey-- =
HFs, H
04-210
N
A =
u
- N =
"
04-211 OH 268.3
14 =
H:0
04-212 H
,
HO
04-213 238.1
124
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HO
ri
04-214 252.2
F .
H .
11
04-215 232.1
N
ONA.
4
04-215 264.1
rii16' ,)
H.
HO
04-216 236.1
4,
HO
04-217 246.1
=
HO
H
04-218 232.2
N,
HO
04-219 234.2
et's'y
N
125
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HO ,.õ,,,,,
04-220 H
lift
H
HO ...-. Q'
'
04-221 . H
/=.. ...,,,
4 1 -
14 ' = fr."''.
H
04-222 oq----- -,.. 218.2
W' I
H
140 ., õk. =
'µk-----11-
1-1
04-223 ..A: .40
N .. = . =
H
HO
*4=.(" N11 .
H
04-224
¨q i
14 ---- -7"
H
CI 04-225
1
. ,
'µ - l'''..6-
HN ¨ . ''.
El
126
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)NH
OH
04-226 (R) 245.1
Id-
[00243] Also disclosed herein is a pharmaceutical composition including a
compound with
a structure of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula
Formula
(IV'), Formula (V'), Formula (VI'), Formula (VII'), and a pharmaceutically
acceptable
excipient. Further disclosed is a method of treating a subject with a disease
associated with an
adrenergic receptor, the method comprising or administering to the subject a
therapeutically
effective amount of a compound with a structure of Formula (I), Formula (I'),
Formula (II),
Formula (II'), Formula (III'), Formula (IV'), Formula (V'), Formula (VI'), or
Formula (VII'),
thereby treating the subject. In some embodiments, the disease is a
neurodegenerative disease,
the subject is a human.
[00244] In some embodiments, the disease is selected from the group consisting
of
myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's
disease, Gehrig's
disease (Amyotrophic Lateral Sclerosis), Huntington's disease, Multiple
Sclerosis, senile
dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated
dementia, other
dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's
disease, Pick's disease,
encephalitis, encephalomyelitis, meningitis, prion diseases, cerebellar
ataxias, cerebellar
degeneration, spinocerebellar degeneration syndromes, Friedrich's ataxia,
ataxia telangiectasia,
spinal dysmyotrophy, progressive supranuclear palsy, dystonia, muscle
spasticity, tremor,
retinitis pigmentosa, striatonigral degeneration, mitochondrial
encephalomyopathies, and
neuronal ceroid lipofuscinosis. In some embodiments, the compound is
administered to the
subject through oral, enteral, topical, inhalation, transmucosal, intravenous,
intramuscular,
intraperitoneal, subcutaneous, intranasal, epidural, intracerebral,
intracerebroventricular,
epicutaneous, extra-amniotic, intra-arterial, intra-articular, intracardiac,
intracavernous,
intradermal, intralesional, intraocular, intraosseous infusion,
intraperitoneal, intrathecal,
intrauterine, intravaginal, intravesical, intravitreal, transdermal,
perivascular, buccal, vaginal,
sublingual, or rectal route. In one embodiment, the compound is selected from
those
compounds set forth in Table 1.
[00245] The following examples are provided to further illustrate the
advantages and features
of the present disclosure, but they are not intended to limit the scope of the
disclosure. While
127
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the examples is typical of those that might be used, other procedures,
methodologies, or
techniques known to those skilled in the art may alternatively be used.
EXAMPLES
EXAMPLE I
COMPOUND SYNTHESIS
BF3K
--_,.. CI
CI Br I Boc20, DMAP, Et3N CI, NBS,
tBuOH/H20
I __________________________________________ ..- I
H2N N Pd(dppf)Cl2, IPA H2N N
CH3CN, rt, 16 h (Boc)2N N 50 C to
rt, 2 h
TEA, 80 C
OHH OH
CI H2N (
CI N 1. 4N HCI in dioxane
H
0
CINI
I
(Boc)2N N Et0H, 65 C (Boc)2N N 2. SFC chiral
column seperation H2N N
seal tube, 2 h
compound 02-1
Scheme 1. Synthesis of compound 02-1.
[00246] Scheme 1 illustrates the synthesis of compound 02-1. 1-1-1NMR (400
MHz, DMSO-
d6) 6 7.86 (d, J= 1.6 Hz, 1H), 7.52 (d, J= 1.6 Hz, 1H), 6.12 (s, 2H), 5.16
(bs, 1H), 4.40 (m,
1H), 2.62 (m, 2H), 1.29 (bs, 1H), 1.00 (s, 9H); LC-MS: m/z 244.2 (M+1)+.
0
HCI
Sn(nBu)3,. 1.5N .
Pd(PPh04 I / 0
dioxane 120 C H2N
Al:lip 1
NBS ...21... N__ Br ,
CF3
,tc)
F
====-= MeCN H2N H2N
H2N
F-B
CF3 CF3 e 1
F Ke . ) , pd(OAc)2 CF3
N ,
K2CO3 I ,..= 02, DMF, H20
Pd(dPM2C14 H2N Wacker oxidation
dioxane/H20 CF3
0 ti
J
' r:c)N CBS selective
H2N I reduction
0 Me0H, rt H2N
CF3 OH
(1) NBS, THF, H20
__________________________________________________________________ ;y='N
(2) Br2, HBr, AcOH, 70 C H2N
rq.,,, Br j<
CF3 (R)-2-Methyl-CBS-
OH H2N H2N
oxazaborolidine CF3
_________________________________ . _________________ .
I compound 02-2
BH3.THF, PhMe H2N MeCN, 40 C
-35 C - -15 C CF3
Scheme 2. Synthesis of compound 02-2.
[00247] Scheme 2 illustrates the synthesis of compound 02-2. 1-1-1NMR (400
MHz, DMSO-
d6) 6 8.37 (d, J= 2.3 Hz, 1H), 8.08 (d, J= 2.2 Hz, 1H), 6.77 (s, 2H), 4.48 (d,
J= 4.9 Hz, 1H),
3.86¨ 3.79 (m, 1H), 3.69 (dd, J = 11.5, 5.1 Hz, 1H), 1.25 (s, 9H); LC-MS: m/z
278.2 (M+1)+.
128
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NNCI 0 F Ke K20s04.2H20
Boc20, Et3N
N
H K2CO3 DMAP, DCM Boc,N Na104, acetone, H20
2N
Pd(dPPf)2C14 H2N
Boc
dioxane/H20
OH H OH
N 0 N,N1 HCl/dioxane
Boc,N)L.7'
SiCI4, EIMPA, EA Boc,N DCM
H2N
Boc BHINH3, Na2CO3, DCM
Boc
compound 02-3
Scheme 3. Synthesis of compound 02-3.
[00248] Scheme 3 illustrates the synthesis of compound 02-3.
[00249] Step 1: Synthesis of 4-methyl-6-vinylpyridazin-3-amine. To a stirred
solution of 6-
chloro-4-methylpyridazin-3-amine (0.72 g, 5.01 mmol), potassium
vinyltrifluoroborate (0.87
g, 6.51 mmol) and K2CO3 (2.07 g, 15.03 mmol) in dioxane/H20 (16 mL/4 mL) was
added
Pd(dppf)2C12 (0.367 g, 0.501 mmol). The resulting mixture was purged with N2
before heating
to 85 C for 12 hrs. After cooled down, the reaction mixture was diluted with
Et0Ac. The
organic layer was separated and washed with brine (30 mL). The aqueous layer
was extracted
with Et0Ac (30 mLx3). The combined organic layers were dried over Na2SO4,
filtered, and
concentrated under reduced pressure. The residue was purified via flash
chromatography
eluting with DCM/CH3OH (30/1 to 10/1) to provide 4-methyl-6-vinylpyridazin-3-
amine as a
yellow solid (0.55 g, 82%). LC-MS: m/z 136.1 (M+1)+.
[00250] Step 2: Synthesis of 4-methyl-6-vinylpyridazin-3-N(Boc)2. To a stirred
solution of
4-methyl-6-vinylpyridazin-3-amine (0.55 g, 4.1 mmol), di-tert-butyl
dicarbonate (1.8 g, 8.2
mmol), and trietitylamine (1.8 mL, 12.3 mmoL) in dichloromethane (16 mL) was
added DMAP
(0.025 g, 0.21 mmol). The resulting mixture was stirred at room temperature
for 4 hrs. The
reaction mixture was concentrated under reduced pressure. The residue was
purified via flash
chromatography eluting with DCM/CH3OH (40/1 to 15/1) to provide 4-methy1-6-
vinylpyridazin-3-N(Boc)2 as a white solid (1 g, 73%). LC-MS: m/z 336.1 (M+1)+.
[00251] Step 3: Synthesis of 6-N(Boc)2-5-methylpyridazine-3-carbaldehyde. To a
stirred
solution of 4-methyl-6-vinylpyridazin-3-N(Boc)2 (0.5 g, 1.49 mmol) in
acetone/H20 (16 mL/4
mL) were added NaI04 (0.96 g, 4.47 mmol) and K20s04.H20 (0.03 g, 0.075 mmol).
The
resulting mixture was stirred at room temperature for 24 hrs. The reaction
mixture was
partitioned between Et0Ac (30 mL) and brine (30 mL). The organic layer was
dried over
Na2SO4, filtered, and concentrated under reduce pressure. The residue was
purified via flash
chromatography eluting with PE/Et0Ac (30/1 to 2/1) to provide 6-N(Boc)2-5-
methylpyridazine-3-carbaldehyde (0.3 g, 59.7%). LC-MS: m/z 337.2 (M+1)+.
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[00252] Step 4:
Synthesis of 1-(6- N(Boc)2-5 -methy 1py ri dazin-3 -y1)-2-(tert-
butyl amino)ethan-1-ol. tert-Butyl isocyanide (0.06 g, 0.70 mmol) was added to
a stirred
solution of 6-N(Boc)2-5-methyl py ri dazine-3 -carbal dehy de (0.2 g, 0.58
mmol),
hexamethylphosphoramide (0.012 g, 0.058 mmol) and SiC14 (0.125 g, 0.66 mmol)
in
dichloromethane (4 mL) at -20 C. After stirring at -20 C for 4 hrs, BH3NH3
(0.026 g, 0.88
mmol) was added. The mixture was stirred at room temperature for 3 hrs and
then diluted with
dichloromethane (10 mL). The organic solution was added to an aqueous solution
of Na2CO3
(10 wt. %, 20 mL). The resulting mixture was stirred at room temperature for
30 minutes. The
reaction mixture was filtered and washed with DCM (10 mL). The aqueous layer
was separated
and extracted with DCM (10 mL x 2). The combined organic layers were dried
over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified
via flash
chromatography eluting with DCM/CH3OH (30/1 to 10/1) to provide 1-(6-N(Boc)2-5-
methylpyridazin-3-y1)-2-(tert-butylamino)ethan-1-ol (0.025 g, 10 %). LC-MS:
m/z 425.3
(M+1)+.
[00253] Step 5: Synthesis of 1-(6-amino-5-methylpyridazin-3-y1)-2-(tert-
butylamino)ethan-
1-ol. To a stirred solution of 1-(6-N(Boc)2-5-methylpyridazin-3-y1)-2-(tert-
butylamino)ethan-
1-ol (0.025 g, 0.058 mmol) in dichloromethane (3 mL) was added 4N HC1 in
dioxane (3 mL,
12 mmol). The reaction mixture was stirred at room temperature for 24 hrs. The
mixture was
concentrated under reduced pressure to provide 1-(6-amino-5-methylpyridazin-3-
y1)-2-(tert-
butylamino)ethan-1-ol (0.012 g, 59.7%). 11-1NMR (400 MHz, DMSO-d6) 6 9.29 (s,
1H), 8.65
(s, 1H),8.47 (s, 2H), 7.90 (d, J= 1.3 Hz, 1H), 6.74 (s, 1H), 5.06 - 4.96 (m,
1H), 3.21 - 3.13
(m, 2H), 2.31 (d, J= 1.2 Hz, 3H), 1.32 (s, 9H). LC-MS: m/z 225.23(M+1)+.
Sn(nBu)3
NBS (BrN(O'
1.5N HCI
N
H2N N meCn di Pd(PP11132)400c
0 (R)-2-Methyl-CBS- OH OH
PyHBr3, HBr NBr oxazaborolidine
Br H2N
Aõnu I -
1-ts-,..r H2N BH3.THF, PhMe H2N)\.N MeCN, 40 C- H2N-
"L'A
-35 C - -15 C
compound 02-4
Scheme 4. Synthesis of compound 02-4.
[00254] Scheme 4 illustrates the synthesis of compound 02-4. 11-1 NMR (400
MHz,
Chloroform-d) 6 7.83 (s, 1H), 4.45 (s, 2H), 3.88 (dd, J= 9.0, 4.9 Hz, 1H),
3.55 (dd, J= 10.4,
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4.9 Hz, 1H), 3.32 (t, J= 9.7 Hz, 1H), 2.39 (d, J= 0.7 Hz, 3H), 1.06 (s, 9H);
LC-MS: m/z 225.2
(M+1)+.
set %--A.sonsuh
mICPSA, OCM
Ik Py It
b. TPA*MF. e .C,AT 101-y-= (i)PdMPts, difintarte,izec t:
MN, AWN
NN
a (2) 1 N
Stss.pi Steti2
Su,
0 00MtyCB
OH
. -ks; ..N
õ N20 "
'
mi; SHAM*, f'We f44õ,_ ago'cNt40"C 41, j
4.vc- -16"C
Stiz,o4 Sto0
Scheme 5. Synthesis of compound 04-1.
[00255] Scheme 5 illustrates the synthesis of compound 04-1.
[00256] Step 1: Synthesis of 5-bromoquinolin-2(1H)-one. (a) To a
solution of 5-
bromoquinoline (7.6 g, 36.5 mmol) in DCM (100 mL) was added m-CPBA (8.1g, 47
mmol) in
three portions at room temperature. Upon completion of addition, the reaction
mixture was
stirred at room temperature for 3 hrs. After this time, 1N NaOH aqueous
solution (120 ml)
was added to the reaction and the resulting mixture was extracted with DCM
(100 mL x3).
The combined organic layers were washed with brine, dried over anhydrous
MgSO4, filtered
and concentrated to afford 5-Bromoquinoline 1-oxide (5.1g, 63%) as alight-
yellow solid. LC-
MS: m/z 223.9 (M+1)+. (b) To a solution of 5-bromoquinoline 1-oxide (5.1 g, 23
mmol) in
DMF (50 mL) at 0 C was added trifluoroacetic anhydride (24 g, 115 mmol) in
three portions.
The reaction was then stirred at room temperature overnight. The reaction
mixture was
quenched by a saturated aq. NaHCO3 solution (300 mL) and extracted with DCM
(100 mLx
3). The combined organic layers were washed with brine, dried over anhydrous
MgSO4,
filtered and concentrated to afford 5-bromoquinolin-2(1H)-one (4 g, 78%) as a
yellow solid.
LC-MS: m/z 223.9 (M+1)+.
[00257] Step 2: Synthesis of 5-acetylquinolin-2(1H)-one. To a
stirred solution of 5-
bromoquinolin-2(1H)-one and 1-ethoxyvinyltri-n-butyltin (1.1 eq.) in dioxane
was added
Pd(PPh3)4 (0.05 eq). The resulting mixture was purged with N2 (3x) before
heating to 120 C
for 6 hrs. After cooled down, 1.5N HC1 (2 eq.) was introduced to the flask and
stirring was
continued at rt overnight. The reaction solution was then quenched with
saturated NaHCO3
aqueous solution and extracted with Et0Ac. The combined organic layers were
washed with
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brine, dried over Na2SO4 and concentrated. The crude product was purified via
flash
chromatography to afford 5-acetylquinolin-2(1H)-one. LC-MS: m/z 188.1(M+1)+.
[00258] Step 3: Synthesis of 5-(2-bromoacetyl)quinolin-2(1H)-one. To a stirred
solution
of 5-acetylquinolin-2(1H)-one and HBr (40%) in AcOH was added pyridinium
tribromide (1.2
eq.). The resulting mixture was stirred at 40 C overnight. After cooling to
rt the mixture was
quenched with saturated NaHCO3 aqueous solution. The reaction mixture was
subsequently
extracted with Et0Ac. The combined organic layers were washed with brine,
dried over
Na2SO4 and concentrated. The crude product was purified via flash
chromatography to afford
5-(2-bromoacetyl)quinolin-2(1H)-one. LC-MS: m/z 267.1 (M+1)+.
[00259] Step 4: Synthesis of (R)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one.
To a
stirred solution of 5-(2-bromoacetyl)quinolin-2(1H)-one in toluene was added
(R)-2-methyl-
CBS-oxazaborolidine (0.2 eq.) at -35 C. The resulting mixture was stirred at -
35 C for 30
minutes. BH3.THF (1N in THF, 1 eq.) was then introduced dropwise via syringe.
After
addition, the reaction was warmed up to -15 C. After 2 hrs the reaction
mixture was quenched
with saturated NaHCO3 aqueous solution (10 mL) and extracted with Et0Ac. The
combined
organic layers were washed with brine, dried over Na2SO4 and concentrated. The
crude
product was purified via flash chromatography to afford (R)-5-(2-bromo-l-
hydroxyethyl)quinolin-2(1H)-one. LC-MS: m/z 269.1 (M+1)+.
[00260] Step 5: Synthesis of (R)-5-(2-(tert-butylamino)-1-
hydroxyethyl)quinolin-2(1H)-one
(Compound 04-1). To a stirred solution of (R)-5-(2-bromo-1-
hydroxyethyl)quinolin-2(1H)-
one in MeCN was added tert-butylamine (60 eq.). The resulting mixture was
stirred at 40 C
for 48 hrs. The reaction was concentrated, and the residue was re-dissolved
with Et0Ac. The
organic layer was washed with saturated NaHCO3 aqueous solution and brine,
dried over
Na2SO4 and concentrated. The crude product was purified via HPLC (C18,
MeCN/H20 (0.1%
formic acid), (1% - 100%)) to afford (R)-5-(2-(tert-butylamino)-1-
hydroxyethyl)quinolin-
2(1H)-one (04-1) as a white solid (5-step yield: 12%). 11-1NMR (400 MHz, DMSO-
d6) 6 11.82
(br,1H), 8.21 (d, J = 9.9 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.36 (dd, J= 7.6,
1.1 Hz, 1H), 7.28
(d, J = 8.5 Hz, 1H), 6.57 (d, J = 9.9 Hz, 1H), 5.38 (dd, J= 9.6, 2.8 Hz, 1H),
3.00 - 2.85 (m,
2H), 1.24 (s, 9H). LC-MS: m/z 261.2 (M+1)+ .
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o N CI C)
N IC N IC
NBS CITx% DBU
y- y: _____________________________ -
MeCN ---- Br Et3N, Pd(Ac0)2 DIPEA, 120 C HN (1)
Pd(PPh3)4, dioxane, 120 C
NH2 NH2 Tricyclohexyl phosphine NH2 0 (2) 1.5N
HCI
0
DMF 100 C
Step 1 Step 3 Step 4
Step 2
0 0 OH OH
CXII
Br (R)-2-Methyl-CBS Br H2N.J
pyHBr3 HBr I -oxazaborolidine
AcOH BH3.THF, PhMe HN I MeCN
HL? HN HN
0 0 0 0
Step 5 Step 6 Step 7
Scheme 6. Synthesis of compound 04-5.
[00261] Scheme 6 illustrates the synthesis of compound 04-5.
[00262] Step 1: Synthesis of 3-bromo-2-chloropyridin-4-amine. To a stirred
solution of 2-
chloropyridin-4-amine (10 g, 77.78 mmoL) in MeCN (250 mL) was added N-
Bromosuccinimide (13.8 g, 77.78 mmoL). The resulting mixture was stirred at
room
temperature for 12 hrs. The reaction was concentrated. The crude product was
purified by
purified via flash chromatography (silica, pet ether/Et0Ac: 20/1 to 3/1) to
afford 3-bromo-2-
chloropyridin-4-amine as a yellow solid (7.1 g, 43.9%). LC-MS: m/z 206.94,
208.97 (M+1,
M+2)+.
[00263] Step 2: Synthesis of ethyl (E)-3-(4-amino-2-chloropyridin-3-
yOacrylate. To a
stirred solution of 3-bromo-2-chloropyridin-4-amine (2 g, 9.6 mmoL), ethyl
acrylate (1.9 g,
19.3 mmoL), Et3N (2.91 g, 28.8 mmoL) and tricyclohexyl phosphine (1.3 g, 4.8
mmol) in DMF
(100 mL) was added Pd(OAc2) (431 mg, 1.9 mmoL, 0.2 eq). The resulting mixture
was purged
with N2 (3x) before heating to 100 C for 24 hrs. After cooled down, the
reaction mixture was
diluted with Et0Ac (50 mL). The organic layer was washed with brine (30 mL x
3) and dried
over Na2SO4, filtered, and concentrated. The residue was purified by flash
chromatography
(silica, pet ether/Et0Ac: 30/1 to 1/1) to afford ethyl (E)-3-(4-amino-2-
chloropyridin-3-
yl)acrylate as a yellow solid (1.2 g, 55.3%). LC-MS: m/z 227.1, 229.1 (M+1,
M+2)+.
[00264] Step 3: Synthesis of Synthesis of 5-chloro-1,6-naphthyridin-2(11-1)-
one. To a stirred
solution of ethyl (E)-3-(4-amino-2-chloropyridin-3-yl)acrylate (2.5 g, 11.01
mmoL) in DIPEA
(20 mL) was added DBU (3.3 g, 22.02 mmoL). The resulting mixture was stirred
at 120 C
for 8 hrs. The reaction mixture was concentrated. The residue was purified by
flash
chromatography (silica, DCM/CH3OH: 40/1 to 15/1) to give 5-chloro-1,6-
naphthyridin-2(111)-
one (1 g, 50.2%). LC-MS: m/z 181.0, 183.0 (M+1, M+2)+.
[00265] Step 4-7: Synthesis of (5)-5-(2-(tert-butylamino)-1-hydroxy ethyl)-1,6-
naphthyri din-
2(1H)-one (Compound 04-5). Procedures similar to the synthesis of Compound 04-
1 were
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employed using 5-chloro-1,6-naphthyridin-2(111)-one instead of 5-bromoquinolin-
2(1H)-one
as starting material to obtain (S)-5-(2-(tert-butylamino)-1-hydroxyethyl)-1,6-
naphthyridin-
2(1H)-one (04-5) as a white solid, 12 mg, 4-step yield: 9.2%). NMR (400
MHz, DMSO-
d6) 6 12.03 (br,1H), 8.42 (d, J= 5.7 Hz, 1H), 8.34 (d, J= 9.9 Hz, 1H), 7.21
(d, J= 5.7 Hz, 1H),
6.63 (d, J = 9.9 Hz, 1H), 5.25 (t, J = 6.3 Hz, 1H), 3.16 (d, J = 6.7 Hz, 2H),
1.22 (d, J = 12.6
Hz, 9H). LC-MS: m/z 262.2. (M+1)+.
OH
An Br fa" Br OH
NaH, SEMCI Pd(dppf)C12, Cs2CO3 11 AD-mix-13
F "PP F 411" _______________________ F __________________ F
/ DMF, 0 C rt, 2h
HN-N ,NN dioxane/H20, 90 C, 5h ,N-N t-Bu0H-
H20 (1:1), 0 C ,N-N
SEM SEM SEM
Step 1 Step 2 Step 3
0 OH
OH
i. nBu2SnO, TsCI, Et3N
CH2Cl2, rt, 18h F tBuNH2 CF3COOH
411111"
K2CO3, CH3OH. Et0H/H20, 60 C, 16h F N- N / THF F
4111"
,
SEM SEM HN-N HCI
Step 4 Step 5 Step 6
Scheme 7. Synthesis of compound 04-23.
[00266] Scheme 7 illustrates the synthesis of compound 04-23.
[00267] Step 1: Synthesis of 4-bromo-7-fluoro-1-42-
(trimethylsilypethoxy)methyl)-1H-
indazole. To a stirred solution of 4-bromo-7-fluoro-1H-indazolel (2.5 g, 11.62
mmol) in DMF
(20 mL) at 0 C was added NaH (60%, 0.79 g, 19.75 mmol) portion-wise. The
resulting
mixture was stirred for 1 h, then 2-(trimethylsilyl)ethoxymethyl chloride (3.1
mL, 2.92 g, 17.44
mmol) was added. The mixture was stirred at room temperature for 6 hrs. The
reaction was
quenched with saturated ammonium chloride solution (20 mL). The mixture was
extracted
with ethyl acetate (50 mL x 3). The combined organic layers were washed with
H20 (100 mL
x 3), brine, dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The
residue was purified via column chromatography eluting with 20 % Et0Ac in
Petroleum ether
to provide 4-bromo-7-fluoro-1-42-(trimethylsilypethoxy)methyl)-1H-indazole as
a yellow oil
(1.9 g, 48%). LC-MS: m/z 346.3 M+1)+.
[00268] Step 2: Synthesis of 7-fluoro-1-42-(trimethylsilypethoxy)methyl)-4-
viny1-1H-
indazole. To a stirred solution of 4-bromo-7-fluoro-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-
indazole (1.9 g, 5.51 mmol) in dioxane/H20 (20 mL/2 mL) was added potassium
vinyltrifluoroborate (1.47 g, 11.01 mmol), Pd(dppf)C12.CH2C12 (0.45 g, 0.55
mmol), Cs2CO3
(5.38 g, 16.5 mmol) under N2. The mixture was stirred at 100 C for 16 hrs.
The reaction
mixture was filtered through a pad of celite and washed with Et0Ac (100 mL).
The filtrate
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was washed with H20, brine, dried over Na2SO4, filtered, and concentrated
under reduced
pressure. The residue was purified via column chromatography eluting with 10%
Et0Ac in
petroleum ether to provide 7-fluoro-1-42-(trimethylsilypethoxy)methyl)-4-viny1-
1H-indazole
as an oil (1.6 g, 99%). LCMS: m/z 293.3 (M+1)+.
[00269] Step 3: Synthesis of (R)-1-(7-fluoro-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-
indazol-4-ypethane-1,2-diol. To a
stirred solution of 7-fluoro-1-42-
(trimethylsilypethoxy)methyl)-4-viny1-1H-indazole (1.6 g, 5.47 mmol) in tert-
BuOH/H20 (20
mL/20 mL) at 0 C was added AD-mix-beta (8.25 g), and then stirred at room
temperature for
16 hrs. After the completion of the reaction, the mixture was quenched with
saturated Na2S03
solution (20 mL) and extracted with Et0Ac (100 mL). The organic layer was
concentrated
under reduced pressure. The residue was purified via column chromatography
eluting with
50% Et0Ac in petroleum ether to provide (R)-1-(7-
fluoro-1
(trimethylsilypethoxy)methyl)-1H-indazol-4-ypethane-1,2-diol as a yellow oil
(2.1 g, 99%).
LCMS: m/z 327.3 (M+1)+.
[00270] Step 4: Synthesis of (R)-7-
fluoro-4-(oxiran-2-y1)-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-indazole. (i) To a stirred solution of (R)-1-
(7-fluoro-1-42-
(trimethylsilypethoxy)methyl)-1H-indazol-4-ypethane-1,2-diol (2.1 g, 6.4 mmol)
in CH2C12
(20 mL) was added n-Bu2SnO (0.16 g, 0.64 mmol), p-TsC1 (1.4 g, 7.1 mmol), and
Et3N (776
mg, 7.6 mmol). The reaction mixture was then stirred at room temperature for
16 hrs. The
reaction was quenched with water. The mixture was extracted with CH2C12 (50 mL
x 3). The
combined organic layers were washed with water, brine, dried over sodium
sulfate, filtered,
and concentrated under reduced pressure. The
residue was purified via column
chromatography eluting with 30 % Et0Ac in petroleum ether to provide (R)-2-(7-
fluoro-1-42-
(trimethylsilypethoxy)methyl)-1H-indazol-4-y1)-2-hydroxyethy14-
methylbenzenesulfonate as
a yellow oil (2.76 g, 90%). LCMS: m/z 481.3 (M+1)+. (ii) To a stirred solution
of (R)-2-(7-
fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-y1)-2-hydroxy ethyl
4-
methylbenzenesulfonate (2.76 g, 5.76 mmol) in Me0H (10 mL) was added K2CO3
(3.97 g,
28.8 mmol). The resulting mixture was stirred at room temperature for 2 hrs.
The reaction
mixture was concentrated in vacuo to provide a residue, which was re-dissolved
in CH2C12.
Organic layer was then washed with H20, dried over Na2SO4, filtered, and
concentrated in
vacuo to provide (R)-7-fluoro-4-(oxiran-2-y1)-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-
indazole as an oil (2.1 g), which was used for next step without further
purifications.
[00271] Step 5: Synthesis of (R)-2-
(tert-butylamino)-1-(7-fluoro-1-42-
(trimethylsilypethoxy)methyl)-1H-indazol-4-ypethan-1-ol. To a stirred solution
of (R)-7 -
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fluoro-4-(oxiran-2-y1)-1-42-(trimethylsilypethoxy)methyl)-1H-indazole (2.1 g,
6.48 mmol) in
Et0H/H20 (4 mL/8 mL) was added tert-BuNH2 (2.37 g, 32.42 mmol). The reaction
mixture
was stirred at 60 C for 18 hrs. The reaction mixture was concentrated in
vacuo. The residue
was purified by column chromatography eluting with 5% Me0H in dichloromethane
to provide
(R)-2-(tert-butylamino)-1-(7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
indazol-4-
ypethan-1-ol as a yellow oil (2 g, 81%). LCMS: m/z 382.3 (M+1)+.
[00272] Step 6: Synthesis of (R)-2-(tert-butylamino)-1-(7-fluoro-1H-indazol-4-
ypethan-1-
ol. To a stirred solution of
(R)-2-(tert-butylamino)-1-(7-fluoro-1-42-
(trimethylsilypethoxy)methyl)-1H-indazol-4-ypethan-1-ol (2 g, 5.24 mmol) in
CH2C12 (8 mL)
at 0 C was added CF3COOH (10 mL). The reaction mixture was stirred at room
temperature
for 2 hrs and then concentrated in vacuo. The residue was purified by column
chromatography
eluting with 10% Me0H in CH2C12 (containing 1% NH4OH) to provide (R)-2-(tert-
butylamino)-1-(7-fluoro-1H-indazol-4-ypethan-1-ol (0.7 g, 90% pure by HPLC).
This
compound was further purified by reversed-phase HPLC (0.1% TFA in CH3CN/H20)
and
lyophilized with 1 N aqueous HC1 (1 mL) to provide (R)-2-(tert-butylamino)-1-
(7-fluoro-1H-
indazol-4-ypethan-1-ol HC1 salt as a white solid (0.37 g, 25%). 1FINMR (400
MHz, CD30D)
6 8.39 - 9.33 (m, 1H), 7.22 - 7.17 (m, 1H), 7.12 (dd, J= 10.3, 8.0 Hz, 1H),
5.31 - 5.25 (m,
1H), 3.22 (d, J = 9.1 Hz, 2H), 1.39 (s, 9H); HPLC: 99.2 % @254 nM; LCMS: m/z
252.3
(M+1)+; SFC: 99% ee [AD-H column, mobile phase: HEP: IPA (0.1% DEA) = 95:51.
CI
CI BF3K, Cs2CO3 1. mCPBA, NaHCO3
NTJN NaH, SEMCI r.u=-=
= =-=..2.2 Ns I
CH2Cl2, rt,
CH2Cl2, 0 C rt, 2 h sEnii dioxane/H20, 90 C, 5 h =
SEM 2. tBuNH2
Et0H/H20, 60 C, 16 h
Step 1 Step 2 Step 3
HN1< HN< HN
HON<
HO.) HO.,) HO,,.)
H
Pd/C, H2 1. TBAF, THF
___________________ 11. N1,1N N/ _ 1PN
CH3OH, rt, 18 h 2. SFC chiral
SEIVI JJ column seperation
SEIVI
Step 4 Step 5
Scheme 8. Synthesis of compounds 04-144 and compound 04-145.
[00273] Scheme 8 illustrates the synthesis of compound 04-144 and compound 04-
145.
[00274] Step 1: Synthesis of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
pyrazolo[4,3-c]pyridine. To a stirred solution of 4-chloro-1H-pyrazolo [4,3-
c]pyridine (4 g,
27.35 mmol) in DMF (25 mL) at 0 C was added NaH (60%, 1.64 g, 41 mmol). The
resulting
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mixture was stirred for 0.5 h, then SEMC1 (5.93 g, 35.55 mmol) was added. The
mixture was
stirred at room temperature for 2 hrs. The reaction was quenched with
saturated ammonium
chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL
x 3). The
combined organic layers were washed with H20 (100 mL x 3), brine, dried over
sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was purified
via column
chromatography eluting with 30 % Et0Ac in petroleum ether to provide 4-chloro-
1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-clpyridine as a yellow oil (3
g, 39%). LC-MS:
m/z 284.2 M+1)+.
[00275] Step 2 - Synthesis of 1-42-(trimethylsilypethoxy)methyl)-4-viny1-1H-
pyrazolo[4,3-
clpyridine. To a stirred solution of 4-chloro-1-42-
(trimethylsilypethoxy)methyl)-1H-
pyrazolo[4,3-clpyridine (3 g, 10.57 mmol) in dioxane/H20 (20 mL/2 ml) was
added potassium
vinyltrifluoroborate (2.83 g, 21.14 mmol), Pd(dppf)C12.CH2C12 (856 mg, 1.05
mmol), and
Cs2CO3 (10.33 g, 31.71 mmol) under N2. The mixture was stirred at 100 C for 16
hrs. The
reaction mixture was filtered through a pad of celite and washed with Et0Ac
(100 mL). The
filtrate was washed with H20 (20 mL x 2), brine (30 mL), dried over Na2SO4,
filtered, and
concentrated under reduced pressure. The residue was purified via column
chromatography
eluting with 10% Et0Ac in petroleum ether to provide 1-42-
(trimethylsilypethoxy)methyl)-4-
viny1-1H-pyrazolo[4,3-clpyridine as an oil (2.5 g, 81%). LC-MS: m/z 293.3
M+1)+.
[00276] Step 3: Synthesis of 4-
(2-(tert-butylamino)-1-hy droxy ethyl)-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-clpyridine 5-oxide. To a
stirred solution of 1-
((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-pyrazolo[4,3-clpyridine (2.0 g,
7.26 mmol) in
CH2C12 (10 mL) at room temperature was added saturated NaHCO3 solution (10 mL)
and
mCPBA (3.76 g, 21.78 mmol) portion-wise. The resulting mixture was stirred for
10 min
before addition of t-BuNH2 (2.5 g, 34.31 mmol) and Et0H (5 mL). The resulting
mixture was
stirred at 60 C for 16 hrs. The mixture was concentrated in vacuo. The
residue was purified
via column chromatography eluting with 10% CH3OH in CH2C12 to provide 4-(2-
(tert-
butylamino)-1-hy droxy ethyl)-1-42-(trimethylsilypethoxy)methyl)-1H-pyrazolo
[4,3 -
c]pyridine 5-oxide (1.2 g, 76% HPLC purity), which was used in the next step
without further
purifications. LC-MS: m/z 381.2 M+1)+.
[00277] Step 4: Synthesis of 2-(tert-butylamino)-1-(1-42-
(trimethylsilypethoxy)methyl)-
1H-pyrazolo[4,3-c]pyridin-4-ypethan-1-ol. A
mixture of 4-(2-(tert-butylamino)-1-
hy droxy ethyl)-1-42-(trimethyls ilypethoxy)methyl)-1H-pyrazol o [4,3 -c]
pyridine 5-oxide (0.6
g, 1.58 mmol) and Pd/C (10% on carbon, 0.06 g) under a balloon of hydrogen in
Et0H (6 mL)
was stirred at room temperature for 24 hrs and then stirred at 60 C for 48
hrs. The mixture
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was filtered through a pad of celite and the filtrate was concentrated in
vacuo to provide 2-(tert-
butylamino)-1 -(1 -((2-(trimethyls ilypethoxy)methyl)-1H-py razolo [4,3 -c]
pyri din-4-yl)ethan-1 -
ol (0.3 g), which was used directly in the next step without further
purification. LC-MS: m/z
365.2 M+1)+.
[00278] Step 5: Synthesis of (S)-2-(tert-butylamino)-1-(1H-pyrazolo[4,3-
clpyridin-4-
ypethan-1-ol and (R)-2-
(tert-butylamino)-1 -(1H-pyrazolo [4,3-c] pyri din-4-ypethan-1 -ol.
TBAF (1M in THF, 4 ml, 4 mmol) was added to 2-(tert-butylamino)-1-(1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-clpyridin-4-ypethan-1-ol (0.3
g, 0.82 mmol)
and the mixture was stirred at 50 C for 48 hrs. The mixture was purified by
preparative TLC
(10% CH3OH in CH2C12) and further purified via reverse phase chromatography to
provide 2-
(tert-butylamino)-1-(1H-pyrazolo[4,3-clpyridin-4-ypethan-1-ol as a colorless
oil (0.11 g,
57%). LC-MS: m/z 235.2 M+1)+. Racemic 2-(tert-butylamino)-1-(1H-pyrazolo[4,3-
clpyridin-
4-ypethan-1-ol (0.11 g, 0.47 mmol) was separated via SFC (column: IG-H; mobile
phase:
HEP/Et0H (0.1% DEA) = 70/30) to provide (R)-2-(tert-butylamino)-1-(1H-
pyrazolo[4,3-
clpyridin-4-yl)ethan-1-ol (0.02 g, 36%) and (S)-2-(tert-butylamino)-1-(1H-
pyrazolo[4,3-
clpyridin-4-yl)ethan-1-ol (0.02 g, 36%) as a white solid. (R)-2-(tert-
butylamino)-1-(1H-
pyrazolo[4,3-clpyridin-4-ypethan-1-ol: 1-1-1NMR (400 MHz, CD30D) 6 9.03 (s,
1H), 8.45 (d,
J= 6.9 Hz, 1H), 8.08 (d, J= 6.4 Hz, 1H), 5.95 (d, J = 9.4 Hz, 1H), 3.58 (d, J
= 12.9 Hz, 1H),
3.39 (t, J= 11.5 Hz, 1H), 1.43 (s, 9H); LC-MS: m/z 235.3 (M+1)+; SFC: 98.7%
ee. (S)-2-(tert-
butylamino)-1-(1H-pyrazolo[4,3-clpyridin-4-ypethan-1-ol: 11-1 NMR (400 MHz,
CD30D) 6
9.03 (s, 1H), 8.45 (d, J = 6.9 Hz, 1H), 8.08 (d, J= 6.4 Hz, 1H), 5.95 (d, J=
9.4 Hz, 1H), 3.58
(d, J = 12.9 Hz, 1H), 3.39 (t, J = 11.5 Hz, 1H), 1.43 (s, 9H); LC-MS: m/z
235.3 (M+1)+; SFC:
98.3% ee.
EXAMPLE 2
EVALUATION OF SYNTHESIZED ADRENERGIC RECEPTOR AGONISTS
[00279] cAMP homogeneous time-resolved fluorescence (HTRF): experimental
methods.
Compound efficacy is determined using the cAMP Gs dynamic HTRF assay (Cisbio,
catalog
# 62AM4PEC) largely following the manufacturer's instructions, also detailed
below.
[00280] Compound preparation: Candidate beta-adrenergic compounds, dissolved
to 10 mM
in DMSO, are diluted in lx stimulation buffer 1 (Cisbio Part# 64SB1FDD)
containing 1 mM
3-Isobuty1-1-methylxanthene (IBMX; Cayman Chemical Company, catalog # 13347).
Serial
dilutions are made in a 96 well V-bottom polypropylene compound microplate
(Corning,
catalog # 3363) in stimulation buffer containing 1 mM IBMX, to 2X of the final
desired
concentration. Standard serial dilution curves are 10-point, 5-fold dilutions
starting from a
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highest concentration of 10 p.M. Controls present on every assay plate are
0.1% DMSO
(vehicle control), 1 p.M isoproterenol (full beta-adrenergic agonist control)
and 15 p.M
xamoterol (partial beta-adrenergic agonist control). 5 pL from the 2X compound
plate is
stamped into a white 384 round well small volume HiBase assay plate (Greiner
Bio-One;
catalog # 784075) to provide 4 technical replicates per concentration, per
compound. Assay
plates are centrifuged at 500 x g for 10 seconds. Compounds and IBMX are
prepared at 2X
final dose to compensate for addition of cells.
[00281] Cell preparation: lx stimulation buffer, washing PBS (Dulbecco's
phosphate-
buffered saline, -Mg -Ca; Caisson Labs, catalog # PBL01), assay PBS
(Dulbecco's phosphate-
buffered saline, + Mg, + Ca; Caisson Labs, catalog # PBL02) and Versene (0.02%
EDTA
disodium salt solution in PBS without calcium or magnesium; Caisson Labs,
catalog # EDL01)
are pre-warmed to 37 C. Cells expressing beta-adrenergic receptor were washed
in washing
PBS to remove growth medium and then released from the surface by incubating
with Versene
for 5-10 minutes at 37 C. Cells are harvested using assay PBS, counted
manually by
hemocytometer or by an automated cell counter, pelleted by centrifugation (200
x g, 5 minutes)
and resuspended in 37 C 1X stimulation buffer to a final density of 1.5 x 10^6
cells/mL. 5 pL
of the suspended cell solution (7500 cell total) are added to all wells of the
384 well assay plate,
the assay plate was covered with an Axygen0 plate seal (Corning PCR-SP) and
incubated in a
humidified 37 C environment supplemented with 5% CO2 for 30 minutes.
[00282] HTRF reagent addition, reading and data analysis: After 30 minutes of
cell
stimulation with test compound, the assay plates are centrifuged at 500 x g
for 10 seconds, and
incubation was stopped with the addition of 5 pL cAMP-D2 acceptor, diluted
1:21 in detection
and lysis buffer 2 (Cisbio 62CL2FDF) was added to all cells. Subsequently, 5
pL Anti-cAMP-
Eu Donor, diluted 1:21 in detection and lysis buffer 2, was added to cells.
Plates were sealed
and reactions gently `vortexed' at 900 rpm on a Heidolph Titramax 1000 for at
least 30 minutes
at room temperature. Plates are centrifuged again at 500 x g for 10 seconds,
and HTRF was
measured using a Tecan Spark plate reader at 50 flashes per well. HTRF ratios
(665 nm / 620
nm x 10,000) are determined and plotted in GraphPad Prism to generate a
concentration-effect
curve. Potency estimates (EC50 and pEC50) are derived from the four-parameter
nonlinear
regression of the concentration-effect curve and an estimate of relative
efficacy is determined
by comparing the magnitude of the test compound HTRF signal window (min ¨ max
dose)
with the signal window of the full agonist control, isoproterenol. The potency
data are shown
in Table 2 and Table 3 below.
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Table 2. The pharmacological data of the chemical compounds disclosed herein.
Iii 02
Compound EC-
EGO (nM)
(nM)
02-1 C B
02-2 D D
EC50 (nM): A < 10 nM ; B = 10-100 nM; C = 100 nM4 p,M; D > 1 laM
Table 3. The pharmacological data of the chemical compounds disclosed herein.
Average pECso Average pECso Average pECso
[Receptor [Receptor [Receptor
Compound subtype: Bl-AR; subtype: B2-AR; subtype:
Cell type: CHO- Cell type: CHO- Endogenous; Cell
K1 (HitHunter)] K1 (HitHunter)] type: 1321N1]
02-1 C B C
02-2 D D -
02-3 D C -
02-4 C D -
02-6 C B C
02-7 D D D
02-8 D D D
02-9 C B -
02-10 D C -
02-11 D D -
02-12 D D -
02-13 B B -
02-14 B A -
04-1 A A -
04-2 B A -
04-3 D C -
04-4 A A -
04-5 D D -
04-6 B A -
04-7 B B -
04-8 B A -
04-9 C B -
04-10 B B -
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04-11 B B -
04-12 C B -
04-13 B A -
04-14 C A -
04-15 D C -
04-16 C B -
04-17 C D -
04-18 A B -
04-19 A A -
04-24 B B -
04-25 A A -
04-26 B B -
04-27 A B -
04-28 C D -
04-29 C D -
04-30 D - -
04-36 A A -
04-38 C A -
04-39 A A -
04-40 B B -
04-41 A A -
04-42 C C -
04-43 A A -
04-44 C A -
04-45 A A -
04-46 C C -
04-48 D D -
04-49 D D -
04-50 C B -
04-51 D D -
04-52 C B -
04-54 D C -
04-55 B A -
04-56 A A -
04-57 A A -
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04-67 D D -
04-68 D D -
04-69 B C -
04-70 - A -
04-71 C C -
04-72 A A -
04-73 B B -
04-74 D D -
04-75 A A -
04-76 A A -
04-77 - D -
04-78 C - -
04-79 C C -
04-80 A A -
04-81 C C -
04-82 A A -
04-83 C C -
04-84 A B -
04-85 A A -
04-86 C C -
04-87 C C -
04-88 A A -
04-89 D - -
04-90 C D -
04-91 D - -
04-92 D D -
04-93 C C -
04-94 A A -
04-96 B B -
04-97 D D -
04-98 A B -
04-102 C C -
04-103 C C -
04-104 C A -
04-105 D D -
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04-106 C C -
04-107 D C -
04-108 A A -
04-109 B A -
04-110 D D -
04-111 D D -
04-112 A A -
04-113 A A -
04-114 D D -
04-115 C B -
04-116 A A -
04-117 C A -
04-118 D D -
04-119 A A -
04-120 D C -
04-121 - D -
04-122 A A -
04-123 D C -
04-124 B A -
04-125 B A -
04-126 D D -
04-127 B A -
04-128 D C -
04-129 D B -
04-130 A A -
04-131 A A -
04-133 A A -
04-134 B C -
04-135 A A -
04-136 D C -
04-137 C B -
04-138 D C -
04-139 D D -
04-140 D C -
04-141 B A -
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04-142 A A -
04-143 B B -
04-144 D D -
04-145 D D -
04-146 A A -
04-147 A A -
04-148 A A -
04-149 A A -
04-150 B A -
04-151 A B -
04-152 A A -
04-153 D B -
04-154 C A -
04-155 D C -
04-156 B A -
04-157 C B -
04-158 B A -
pEC50: A> 8 ; B = 8-7; C = <7-6; D <6
[00283] Those skilled in the art will recognize, or be able to ascertain,
using no more than
routine experimentation, numerous equivalents to the specific composition and
procedures
described herein. Such equivalents are considered to be within the scope of
this disclosure, and
are covered by the following claims.
[00284] In addition to the various embodiments described in the specification
above, the
following additional embodiments are contemplated herein.
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Embodment 1. A compound according to Formula (I) or an optically pure
stereoisomer,
pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
OH
H
A N
B R5
II
(Ri)rn
X
IP
:I
GIQ
Z
Formula (I)
each Ri is independently selected from the group consisting of hydrogen,
halogen,
cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl,
unsubstituted or
substituted sulfonyl, unsubstituted or substituted alkyl, unsubstituted or
substituted
alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted
alkynyl,
unsubstituted or substituted cycloalkyl, unsubstituted or substituted ¨(C=0)-
alkyl,
unsubstituted or substituted ¨(C=0)-cycloalkyl, unsubstituted or substituted
¨(C=0)-aryl,
unsubstituted or substituted ¨(C=0)-heteroaryl, unsubstituted or substituted
aryl, and
unsubstituted or substituted heteroaryl,
m is an integer selected from 0 to 3,
each A, B, and X is independently a nitrogen or carbon,
P is N, 0, or CR2, Q is N, 0, or CR2, G is NRs or 0, and/or Z is NRs, 0, S, or
CR3R4,
R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro,
hydroxyl,
unsubstituted or substituted amino, unsubstituted or substituted alkyl, and
unsubstituted or
substituted alkoxy,
each R3 and R4 is selected from the group consisting of hydrogen, halogen,
cyano, nitro,
hydroxyl, unsubstituted or substituted amino, unsubstituted or substituted
alkyl, and
unsubstituted or substituted alkoxy,
Rs is one or more selected from the group consisting of H, unsubstituted or
substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or
substituted alkenyl,
unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted aryl, unsubstituted or substituted heteroaryl,
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rX4 Rio
R6 x N-r4
1/4"\\=
x, L tRon
-1'(R
..!, " NiLi)
¨(R9)
N-9 "
Ett
L is a C1-05 alkyl linker optionally substituted,
each Xi, X2, X3, and X4 is independently a covalent bond, a carbon, an oxygen,
or
a nitrogen, optionally substituted with hydrogen, unsubstituted or substituted
alkyl, or
unsubstituted or substituted cycloalkyl,
Y is 0 or S,
R6 and R7 are independently selected from hydrogen, unsubstituted or
substituted
alkyl, or R6 and R7 are cyclically linked and together with X2 to form an
optionally
substituted cycloalkyl or heterocycle,
each Rs is independently selected from the group consisting of hydrogen,
halogen,
cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted
alkenyl,
unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted aryl, and unsubstituted or substituted heteroaryl,
n is an integer selected from 0 to 4, and
R9 is selected from the group consisting of hydrogen, halogen, cyano,
unsubstituted
or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted
or substituted
amino; and Rio is selected from the group consisting of hydrogen, cyano,
unsubstituted or
substituted alkyl, and unsubstituted or substituted alkoxy.
Embodiment 2. A compound according to Formula (II) or an optically pure
stereoisomer,
pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
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OH
H
A. N x R7
B
(R1)ni R6
X R5
IP
LI
G...,/
z
Formula (II)
each Ri is independently selected from the group consisting of hydrogen,
halogen,
cyano, nitro, unsubstituted or substituted amino, pentafluorosulfanyl,
unsubstituted or
substituted sulfonyl, unsubstituted or substituted alkyl, unsubstituted or
substituted
alkoxy, unsubstituted or substituted alkenyl, unsubstituted or substituted
alkynyl,
unsubstituted or substituted cycloalkyl, unsubstituted or substituted ¨(C=0)-
alkyl,
unsubstituted or substituted ¨(C=0)-cycloalkyl, unsubstituted or substituted
¨(C=0)-aryl,
unsubstituted or substituted ¨(C=0)-heteroaryl, unsubstituted or substituted
aryl, and
unsubstituted or substituted heteroaryl,
m is an integer selected from 0 to 3,
each A, B, and X is independently a nitrogen or carbon,
P is N, 0, or CR2, Q is N, 0, or CR2, G is NR5 or 0, and/or Z is NR5, 0, S, or
CR3R4,
R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro,
hydroxyl,
unsubstituted or substituted amino, unsubstituted or substituted alkyl, and
unsubstituted or
substituted alkoxy,
each R3 and R4 is selected from the group consisting of hydrogen, halogen,
cyano,
nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or
substituted alkyl, and
unsubstituted or substituted alkoxy,
Rs, R6, and R7 are independently selected from the group consisting of H,
unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy,
unsubstituted or
substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or
substituted
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cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted
heteroaryl,
rX4 ,R12
R8 X3 X3 so *
FL-Xi X2 (R10)n (R10) N-Nn
Frrµ(R11)n
R9 X4
N15 (R11)nN N
0¨(R11)
ili3¨(R11)n
1-1-1\1 n N
Ri 12 L)<N
(R11)n FL
110 (R11)n m (R11)n
, and
or R5 and R6 together with the carbon form an unsubstituted or substituted 3-7
membered
cycloalkyl or heterocycle ring; L is a Cl-05 alkyl linker optionally
substituted,
each Xi, X2, X3, and X4 is independently a covalent bond, a carbon, an oxygen,
or
a nitrogen, optionally substituted with hydrogen, unsubstituted or substituted
alkyl, or
unsubstituted or substituted cycloalkyl,
Y is 0 or S,
Rs and R9 are independently selected from hydrogen, unsubstituted or
substituted
alkyl, or Rs and R9 are cyclically linked and together with X2 to form an
optionally
substituted cycloalkyl or heterocycle,
each Rio is independently selected from the group consisting of hydrogen,
halogen,
cyano, nitro, hydroxyl, unsubstituted or substituted amino, unsubstituted or
substituted
alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted
alkenyl,
unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl,
unsubstituted
or substituted aryl, and unsubstituted or substituted heteroaryl,
n is an integer selected from 0 to 4,
Rii is selected from the group consisting of hydrogen, halogen, cyano,
unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and
unsubstituted
or substituted amino, and
R12 is selected from the group consisting of hydrogen, cyano, unsubstituted or
substituted alkyl, and unsubstituted or substituted alkoxy.
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Embodiment 3. A compound with the following structure:
OH
1
HN,{
0
Compound 04-1
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug thereof
Embodiment4. A compound with the following structure:
-"*. 'NH
sc,OH
I
N 0
fcle
Compound 04-2
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug
thereof
Embodiment 5. A compound with the following structure:
NH
LOH
0' .0
Compound 04-3
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug
thereof
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Embodiment 6. A compound with the following structure:
1,1,1.
OH
cy....., ......., is A
F A
Compound 04-4
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug thereof
Embodiment 7. A compound with the following structure:
OH
H
, N,:, ,,. N I
HiN
j
I
I
NN,,^'
0
Compound 04-5
or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate,
or prodrug thereof
Embodiment 8. A pharmaceutical composition including the compound of any one
of
embodiments 1-2 and a pharmaceutically acceptable excipient.
Embodiment 9. The compound of any one of embodiments 1-7, wherein the compound
is an
agonist, partial agonist or antagonist of an adrenergic receptor;
Embodiment 10. The compound of any one of embodiments 1-7, wherein the
compound is a
131-adrenergic receptor agonist, 02-adrenertic receptor agonist or non-
selective 131/132-
adrenergic receptor agonist.
Embodiment 11. The compound of any one of embodiments 1-7, wherein the
compound is a
131-adrenergic receptor agonist.
Embodiment 12. The compound of any one of embodiments 1-7, wherein the
compound is a
02-adrenergic receptor agonist.
Embodiment 13. The compound of any one of embodiments 1-7, wherein the
compound is a
non-selective 131/02-adrenergic agonist.
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Embodiment 14. A method of treating a subject with a disease, the method
including
administering to the subject a therapeutically effective amount of a compound
of any one of
claims 1-2.
Embodiment 15. The method according to embodiment 14, wherein the disease is a
disease associated with an adrenergic receptor.
Embodiment 16.The method according to embodiment 14, wherein the disease is a
neurodegenerative disease.
Embodiment 17. The method according to embodiment 14, wherein the subject is a
human.
Embodiment 18. The method according to embodiment 14, wherein the disease is
selected
from myocardial infarction, stroke, ischemia, Alzheimer's disease, Parkinson's
disease,
Gehrig's disease (Amyotrophic Lateral Sclerosis), Huntington's disease,
Multiple Sclerosis,
senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-
associated dementia,
other dementias, cerebral vasculitis, epilepsy, Tourette's syndrome, Wilson's
disease, Pick's
disease, encephalitis, encephalomyelitis, meningitis, prion diseases,
cerebellar ataxias,
cerebellar degeneration, spinocerebellar degeneration syndromes, Friedrich's
ataxia, ataxia
telangiectasia, spinal dysmyotrophy, progressive supranuclear palsy, dystonia,
muscle
spasticity, tremor, retinitis pigmentosa, striatonigral degeneration,
mitochondrial
encephalomyopathies, and neuronal ceroid lipofuscinosis.
Embodiment 19. The method according to embodiment 14, wherein the compound is
administered to the subject through oral, enteral, topical, inhalation,
transmucosal, intravenous,
intramuscular, intraperitoneal, subcutaneous, intranasal, epidural,
intracerebral,
intracerebroventricular, epicutaneous, extra-amniotic, intra-arterial, intra-
articular,
intracardiac, intracavernous, intradermal, intralesional, intraocular,
intraosseous infusion,
intraperitoneal, intrathecal, intrauterine, intravaginal, intravesical,
intravitreal, transdermal,
perivascular, buccal, vaginal, sublingual, or rectal route.
Embodiment 20. The method according to embodiment 14, wherein the disease is a
neurodegenerative disease that is one or more selected from the group
consisting of MCI (mild
cognitive impairment), aMCI (amnestic MCI), Vascular Dementia, Mixed Dementia,
FTD
(fronto-temporal dementia; Pick's disease), HD (Huntington disease), Rett
Syndrome, PSP
(progressive supranuclear palsy), CBD (corticobasal degeneration), SCA
(spinocerebellar
ataxia), MSA (Multiple system atrophy), SDS (Shy¨Drager syndrome),
olivopontocerebellar
atrophy, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy),
stroke, WKS
(Wernicke-Korsakoff syndrome; alcoholic dementia & thiamine deficiency),
normal pressure
hydrocephalus, hypersomnia/narcolepsy, ASD (autistic spectrum disorders), FXS
(fragile X
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CA 03144093 2021-12-16
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PCT/US2020/040308
syndrome), TSC (tuberous sclerosis complex), prion-related diseases (CJD
etc.), depressive
disorders, DLB (dementia with Lewy bodies), PD (Parkinson's disease), PDD (PD
dementia),
ADHD (attention deficit hyperactivity disorder), Alzheimer's disease (AD),
early AD, and
Down Syndrome (DS).
Embodiment 21. The method according to embodiment 14, wherein the disease is a
neurodegenerative disease that is one or more selected from the group
consisting of MCI,
aMCI, Vascular Dementia, Mixed Dementia, FTD (fronto-temporal dementia; Pick's
disease),
HD (Huntington disease), Rett Syndrome, PSP (progressive supranuclear palsy),
CBD
(corticobasal degeneration), SCA (spinocerebellar ataxia), MSA (Multiple
system atrophy),
SDS (Shy¨Drager syndrome), olivopontocerebellar atrophy, TBI (traumatic brain
injury), CTE
(chronic traumatic encephalopathy), stroke, WKS (Wernicke-Korsakoff syndrome;
alcoholic
dementia & thiamine deficiency), normal pressure hydrocephalus,
hypersomnia/narcolepsy,
ASD (autistic spectrum disorders), FXS (fragile X syndrome), TSC (tuberous
sclerosis
complex), prion-related diseases (CJD etc.), depressive disorders, DLB
(dementia with Lewy
bodies), PD (Parkinson's disease), PDD (PD dementia), and ADHD (attention
deficit
hyperactivity disorder). In some embodiments the subject does not have
Alzheimer's disease
(AD)
Embodiment 22. The method according to any one of embodiments 14-21, wherein
the
subject does not have Down Syndrome
Embodiment 23. The method of any one of embodiments 14-22, wherein
administering to
the subject further includes a peripherally acting 13-blocker (PABRA) along
with the
compound.
Embodiment 24. The method of embodiment 23, wherein a peripherally acting 13-
blocker
(PABRA) is administered to the subject prior to administration of the
compound.
Embodiment 25. The method of embodiment 23, wherein a peripherally acting 13-
blocker
(PABRA) is administered to the subject concurrently with the administration of
the compound.
Embodiment 26. The method of any one of embodiments 14-22, wherein a131
agonist, a132
agonist, or a non-selective 131 / 132 agonist is administered to the patient
in addition to the
compound.
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