Note: Descriptions are shown in the official language in which they were submitted.
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COMPOUNDS AND METHODS FOR THE TREATMENT OF OCULAR DISORDERS
CROSS-REFERENCE TO RELATED APPLICATIONS
100011 This application claims the benefit of U.S. Provisional Application No.
63/094,793, filed
October 21, 2020, and U.S. Provisional Application No. 63/170,988, filed April
5, 2021, the
content of each of which is incorporated by reference herein in its entirety.
BACKGROUND OF THE DISCLOSURE
100021 Restasis (0.05% cyclosporine A, Allergan) was approved by the Food and
Drug
Administration (FDA) to increase tear production in patients whose tear
production is presumed
to be suppressed due to ocular inflammation associated with
keratoconjunctivitis sicca. Xiidra
(lifitegrast ophthalmic solution) 5% is indicated for the treatment of signs
and symptoms of dry
eye disease (DED).
SUMMARY OF THE DISCLOSURE
100031 Provided in certain embodiments herein are compounds, pharmaceutical
(e.g., ophthalmic)
compositions, and methods of treatment. In specific embodiments, methods of
treatment provided
herein include the treatment of ocular and/or periocular indications or
abnormalities. In some
embodiments, the ocular and/or periocular indications or abnormalities treated
by or with a
composition or compound provided herein are indications or abnormalities that
have
m ultifactori al etiologies and/or interactions. In certain embodiments
provided herein are
compounds (and compositions comprising such compounds) that have
multifunctional efficacies,
such as when administered in or around the eye (e.g., to the ocular surface,
the eyelid, such as the
eyelid margin or the inner surface of the eyelid, or the like).
100041 In some embodiments, provided herein is a method of treating
inflammation or
hyperkeratosis (e.g., of the eye or skin).
100051 In certain embodiments, methods provided herein involve the method of
treating
meibomian gland dysfunction (MGD).
100061 Currently there are no approved pharmacological agents useful for the
treatment of MGD.
The recognition that terminal duct obstruction from hyperkeratinization of the
ductal epithelium
on meibomian glands is a core mechanism behind meibomian gland dysfunction
(MGD) is
consistent with clinical experience demonstrating that effective treatments
for MGD require
resolution of ductal obstruction and evacuation of glandular contents (Nichols
et al, 2011; Lane et
al, 2012; Blackie et al, 2015). Warm compresses and thermal/mechanical devises
(e.g., LipiFlow)
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are used in an attempt to raise the internal temperature of the meibomian
glands over the normal
melting point for meibum (i.e., 32 C to 40 C) in an attempt to resolve
terminal duct obstruction
(Lane et al, 2012). Unfortunately, warm compresses are unable to achieve this
benefit for severely
obstructed glands which can having a melting point > 40 C. Current technology
for removing
keratinized obstruction of the meibomian gland also includes physical removal
methods (e.g.,
debridement and gland probing), which are quite painful to patients.
100071 Subsequent to a period of MGD, various stages of inflammatory or
bacterial disease at the
ocular surface are frequently observed because meibomian gland obstniction can
cause a cascade
of events that include further deterioration of the glands (Knop, IOVS, 2011)
from stasis of the
meibum in the secretory glands, mechanical pressure and stress from glandular
obstruction, and
increased bacterial growth that is associated with the downstream release of
bacterial lipases, toxic
mediators, and/or inflammatory mediators. All these factors reduce the quality
and/or quantity of
meibum the glands can release which in turn can cause chronic mechanical
traumatization of the
conjunctival, corneal and eyelid tissues which will lead to further tissue
damage and the release
of inflammatory mediators. Thus, many patients suffering from MGD also have
inflammatory
disease affecting their conjunctiva, cornea, larcrimal gland, lids or goblet
cells causing comorbid
conditions such as dry eye syndrome or blepharitis for which there is an unmet
medical need.
100081 For example, literature has used the terms posterior blepharitis and
MGD as if they were
synonymous, but these terms are not interchangeable. Posterior blepharitis
describes inflammatory
conditions of the posterior lid margin, of which MGD can be one possible
cause. In its earliest
stages, MGD may not be associated with clinical signs characteristic of
posterior blepharitis At
this stage, affected individuals may be symptomatic, but alternatively, they
may be asymptomatic
and the condition regarded as subclinical. As MGD progresses, symptoms develop
and lid margin
signs, such as changes in meibum expressibility and quality and lid margin
redness, may become
more visible. At this point, an MGD-related posterior blepharitis is said to
be present.
100091 In certain embodiments, provided herein are methods of treating ocular
(or dermatological)
disorders associated with keratosis (e.g., lid keratosis, surface ocular
keratosis, and/or gland
blockage ¨ such as in MGD), microbial infiltration/infection (e.g., bacterial
infiltration/infection),
and/or inflammation (such as inflammation associated keratosis or not
associated with keratosis).
In certain instances, disorders of the skin and/or eye (and/or surround
tissue/skin) are difficult to
differentially diagnose and/or have multiple etiologies. For example, in some
instances, it can be
difficult to distinguish between ocular disorders that involve (1)
inflammation only, (2)
inflammation associated with keratolytic activity, (3) inflammation associated
with both
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keratolytic activity (e.g., inducing keratosis) and microbial infiltration,
(4) keratolytic activity, but
not inflammation and/or microbial infiltration, or various other combinations.
In some instances,
compounds and compositions provided herein can be used in such ocular and/or
dermatological
indications without the need for differential diagnosis (which can be
difficult, e.g., because of
similar symptom scores, etc.). Further, many ocular and/or dermatological
disorders involve
multiple etiologies, such inflammation, microbial infiltration, keratolytic
activity, or various
combinations thereof As a result, therapeutic agents, such as those described
herein, that target
multiple etiologies are beneficial in providing therapeutic efficacy, such as
by targeting both an
underlying condition (e.g., keratolytic activity and/or microbial
infiltration) and a symptom, such
as inflammation or dry eye.
100101 As such, provided herein are compounds, compositions, methods, and
formulations for the
treatment of ocular (e.g., periocular) or dermatological disorders, such as
those having
abnormalities having multifactorial etiologies. In specific embodiments,
ocular disorders include,
by way of non-limiting example, surface disorders, such as MGD, dry eye and
associated
inflammatory and bacterial disease.
100111 Provided in some embodiments herein is a compound, or a
pharmaceutically acceptable
salt or solvate thereof, having the structure of Formula (I):
N R02
RQO 0
ORQ
Q ORQ
OR
Formula (I).
100121 In some embodiments, each RQ is independently H, RN, substituted or
unsubstituted alkyl,
or substituted or unsubstituted heteroalkyl, wherein at least one RQ is RN. In
some embodiments,
RN is D-La-. In some embodiments, D is a keratolytic agent. In some
embodiments, La is a linker.
100131 In some embodiments, each RQ is independently H, RN, substituted or
unsubstituted alkyl,
or substituted or unsubstituted heteroalkyl, wherein one RQ is RN. In some
embodiments, each RQ
is independently H, 10, substituted alkyl, or unsubstituted alkyl. In specific
embodiments, at least
one RQ is RN. In some embodiments, each RQ is independently H, RN, or
unsubstituted alkyl,
wherein one RQ is RN. In some embodiments, the unsubstituted alkyl is methyl,
ethyl, or propyl.
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In some embodiments, each RQ is independently H, RN, or unsubstituted
heteroalkyl, wherein one
RQ is RN. In some embodiments, each RQ is independently H, methyl, or RN,
wherein one RQ is
RN.
100141 In some embodiments, alkyl is optionally substituted with one or more
selected from the
group consisting of -OH, -SH, substituted or unsubstituted alkyl (alkylene),
unsubstituted or
substituted aryl, substituted or unsubstituted heteroalkyl, -NI ICOMe, -
0(C=0)CI I20I I, -
0(C=0)CH(CH3)0H, -0(C=0)alkyl, and -(C=0)0alkyl (e.g., where alkyl is methyl,
ethyl,
propyl, isopropyl, or t-butyl) In some embodiments, the alkyl is substituted
with one or more
selected from the group consisting of alkyl, heterocycloalkyl, -NHCOMe, -
0(C=0)alkyl, and -
(C=0)0alkyl (e.g., where alkyl is methyl, ethyl, propyl, isopropyl, or t-
butyl). In some
embodiments, the heterocycloalkyl is dithiolane oxide.
100151 In some embodiments, provided herein is a compound, or a
pharmaceutically acceptable
salt thereof, having the structure of Formula (I-A):
o>r,
çDj
OR'
= 0
HO =
OH
0
z
OH
Formula (I-A).
100161 In some embodiments, R' is D-La-. In some embodiments, D is a
keratolytic agent. In some
embodiments, La is a linker.
100171 In some embodiments, La comprises one or more linker groups, each
linker group being
selected from the group consisting of a bond, -0-, -S-, halo, alkyl
(alkylenyl), heteroalkyl
(heteroalkylenyl), disulfide, ester, and carbonyl (>C=0). In some embodiments,
each linker group
is selected from the group consisting of a bond, -0-, -S-, halo, alkyl
(alkylenyl), heteroalkyl
(heteroalkylenyl), and ester. In some embodiments, La comprises one or more
linker groups, each
linker group being selected from the group consisting of a bond, alkyl
(alkylenyl), heteroalkyl
(heteroalkylenyl), ester, and carbonyl (>C=0). In some embodiments, each
linker group is
selected from the group consisting of a bond, halo, alkyl (alkylenyl),
heteroalkyl (heteroalkylenyl),
and ester. In some embodiments, each linker group is selected from alkyl
(alkylene) and
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heteroalkyl (heteroalkylene), the alkyl (alkylene) or heteroalkyl
(heteroalkylene) being optionally
substituted.
100181 In some embodiments, La is alkyl (alkylene) substituted with oxo and
one or more of alkyl
and heteroalkyl. In some embodiments, the alkyl or heteroalkyl is substituted
with one or more
halo, alkyl, or haloalkyl. In some embodiments, the alkyl or heteroalkyl is
substituted with one or
more alkyl or hal oalkyl . In some embodiments, La comprises one or more
linker group, each linker
group being independently selected from a bond, -0-, -S-, halo, (C=0), -
(C=0)alkyl-, -
(C=0)heteroalkyl-, -(C=0)0-, -(C=0)0alkyl-, -(C=0)0heteroalkyl-, -(C=0)S-, -
(C=0)Salkyl-, -
(C=0)Sheteroalkyl-, alkylene, or heteroalkylene, where each alkyl,
heteroalkyl, alkylene, or
heteroalkyl is independently optionally substituted. In some embodiments, La
comprises (C=0), -
(C=0)alkyl-, -(C=0)heteroalkyl -, -(C=0)0-, -(C=0)0a1ky1
-(C=0)0h eteroalkyl -
(C=0)0 alky10-, -(C=0)0heteroalky10-, -(C=0)S-, -(C=0)Salkyl-, -
(C=0)Sheteroalkyl-,
alkylene, and heteroalkylene. In some embodiments, La comprises one or more
linker group, each
linker group being independently selected from a bond, (C=0), -(C=0)alkyl-, -
(C=0)heteroalkyl-
, -(C=0)0-, -(C=0)0alkyl-, -(C=0)0heteroalkyl-, -(C=0)S-, -(C=0)Salkyl-, -
(C=0)Sheteroalkyl-, alkylene, or heteroalkylene, where each alkyl,
heteroalkyl, alkylene, or
heteroalkyl is independently optionally substituted. In some embodiments, La
comprises (C=0), -
(C=0)alkyl-, -(C=0)heteroalkyl-, -(C=0)0-, -(C=0)0alkyl-, -(C=0)0heteroalkyl-,
-
(C=0)0alky10-, -(C=0)0heteroalky10-, -(C=0)S-, -(C=0)Salkyl-, -
(C=0)Sheteroalkyl-,
alkylene, and heteroalkylene. In some embodiments, L' comprises -0-, (C=0), -
(C=0)alkyl-,-
(C=0)0-, -(C=0)0alkyl-, and/or-(C=0)0alky10-. In some embodiments, L' is a
bond.
100191 In some embodiments, the linker comprises the structure of Formula (A):
_Kfx
G2):1
Formula (A)
wherein:
Q is a bond, -0-, -S-, or optionally substituted amino;
each Gl and G2 is independently hydrogen, halo, alkyl, heteroalkyl, or
cycloalkyl,
wherein the alkyl or cycloalkyl is optionally substituted; and
g is 1-20.
100201 In some embodiments, the compound comprises more than one linker of
Formula (A). In
some embodiments, Q is a bond or -0-. In some embodiments, Q is a bond and
each G1 and G2 is
independently hydrogen, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl
are each optionally
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substituted. In some embodiments, Q is -0- and each GI and G2 is independently
hydrogen, alkyl,
or cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted. In
some embodiments, Q
is a bond or -0- and each G1 is hydrogen and each G2 is independently alkyl or
haloalkyl. In some
embodiments, Q is a bond or -0- and each GI is hydrogen and each G2 is methyl.
In some
embodiments, Q is a bond or -0- and each GI- and G2 is hydrogen. In some
embodiments, Q is a
bond and each GI- is hydrogen and each G2 is methyl. In some embodiments, Q is
a bond and each
Gl and G2 is hydrogen. In some embodiments, Q is -0-, each GI- is hydrogen,
and each G2 is
methyl. In some embodiments, Q is -0- and each GI and G2 is hydrogen.
100211 In some embodiments, g is 1-20. In some embodiments, g is 1-10. In some
embodiments,
g is 1-5. In some embodiments, g is 2. In some embodiments, g is 1.
100221 In some embodiments, g is 1 or 2, Q is a bond and each GI is hydrogen,
and each G2 is
methyl. In some embodiments, g is 1 or 2, Q is a bond, and each GI and G2 is
hydrogen. In some
embodiments, g is 1 or 2, Q is -0-, each GI is hydrogen, and each G2 is
methyl. In some
embodiments, g is 1 or 2, Q is -0-, and each G-1- and G2 is hydrogen.
100231 In some embodiments, the linker comprises one or more bond, oxo, -0-,
methylene,
, or
100241 In some embodiments, g is 1-20. In some embodiments, g is 1-10. In some
embodiments,
g is 1-8. In some embodiments, g is 1, 2, 3, 4, 5, 6, 7, or 8.
100251 In some embodiments, the linker comprises one or more of:
-5? and/or -5" .
100261 In some embodiments, the linker comprises one or more -0-, oxo,
methylene,
s<Y)4, or
100271 In some embodiments, the linker comprises one or more oxo, one or more -
0-, and.
100281 In some embodiments, the linker comprises one or more oxo, one or more -
0-, and:
sY
-6-
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[0029] In some embodiments, L is a bond.
[0030] In some embodiments, any linker or L provided herein is attached to the
rest of a molecule
provided herein to form a ketal. In some embodiments, any linker or L provided
herein is attached
to the rest of a molecule provided herein to form an ester.
[0031] In some embodiments, D comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
[0032] In some embodiments, D comprises a radical of one or more keratolytic
group, each radical
of the one or more keratolytic group being independently selected from the
group consisting of a
radical of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical
of lactic acid (Lac),
a radical of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical
of lipoic acid sulfoxide
(Lipox), a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl
cysteine (NAC), a radical
of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril
(Cap), and a radical of
bucillamine (Buc).
[0033] In some embodiments, D comprises a thiol radical of one or more
keratolytic group, each
thiol radical of the one or more keratolytic group being independently
selected from the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diLltip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
100341 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]., [Lac-
NAC]., [Cy s-Cy s]. , [diHLip-NAC -NAC]-,
[diHLip-Cap-Cap]., [diHLip-Cap],
[diHLip-Cys-Cys]., [diHLip-Cys]., [diHLip-Lipox-Lipox]., and [diHLip-Lipox]..
100351 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, substituted (e.g.,
straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., (N-)
substituted with alkyl
(e.g., further substituted with oxo and thiol)). In some embodiments, the
substituted alkyl is
substituted with one or more (alkyl) substituent, at least one (alkyl)
substituent being
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independently selected from the group consisting of -OH, -SH, -COOH,
substituted unsaturated
cycloalkyl (e.g., being substituted with one or more C1-C4 alkyl), and
substituted or unsubstituted
(disulfide containing) heterocycloalkyl (e.g., dithiolanyl, dithiolanyl
sulfone, and dithiolanyl
oxide). In some embodiments, the substituted alkyl is substituted with one or
more (alkyl)
substituent, at least one (alkyl) substituent being independently selected
from the group consisting
of -SIT, substituted unsaturated cycloalkyl (e.g., being substituted with one
or more C1-C4 alkyl),
and substituted or unsubstituted disulfide containing heterocycloalkyl (e.g.,
di thi ol an e oxide). In
some embodiments, the substituted alkyl being substituted with one or more
(alkyl) substituent,
at least one (alkyl) substituent being independently selected from the group
consisting of -SH,
substituted unsaturated cycloalkyl (e.g., being substituted with one or more
Ci-C4 alkyl), and
dithiolanyl oxide. In some embodiments, the substituted heteroalkyl being
substituted with one or
more (heteroalkyl) substituent, at least one (heteroalkyl) substituent being
independently selected
from the group consisting of -SH, -COOH, and thioalkyl. In some embodiments,
the substituted
alkyl, substituted heteroalkyl, or substituted heterocycloalkyl are further
optionally substituted.
100361 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, substituted (e.g.,
straight or branched) heteroalkyl, or substituted heterocycloalkyl (e.g., (N-)
substituted with alkyl
(e.g., further substituted with oxo and thiol)). In some embodiments, the
substituted alkyl being
substituted with one or more (alkyl) substituent, at least one (alkyl)
substituent being
independently selected from the group consisting of -SH and dithiolanyl oxide.
In some
embodiments, the substituted heteroalkyl being substituted with one or more
(heteroalkyl)
substituent, at least one (heteroalkyl) substituent being independently
selected from the group
consisting of -SH, -COOH, and thioalkyl. In some embodiments, the substituted
alkyl, substituted
heteroalkyl, or substituted heterocycloalkyl are further optionally
substituted.
100371 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of hydroxyl, thiol,
amino, acetamide, -
COOH, substituted unsaturated cycloalkyl (e.g., being substituted with one or
more C1-C4 alkyl),
unsubstituted (saturated) heterocycloalkyl (e.g., dithiolanyl),
and substituted (saturated)
heterocycloalkyl (e.g., dithiolanyl oxide or dithiolanyl sulfone).
100381 In some embodiments, D is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more substituent, each
substituent being
independently selected from the group consisting of thiol, amino, acetamide,
substituted
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unsaturated cycloalkyl (e.g., being substituted with one or more Ci -C4
alkyl), and substituted (e.g.,
saturated) heterocycloalkyl (e.g., dithiolanyl oxide).
100391 In some embodiments, the substituted heterocycloalkyl is saturated
(e.g., dithiolanyl,
dithiolanyl sulfone, or dithiolanyl oxide).
100401 In some embodiments, D is substituted alkyl, the alkyl being
substituted with substituted
heterocycloalkyl (e.g., dithiolanyl oxide). In some embodiments, the
substituted heterocycloalkyl
is substituted with one or more substituent, each substituent being
independently selected from
the group consisting of C1-C3 alkyl, oxo (e.g., or -0), and -COOH.
100411 In some embodiments, D comprises:
0
00
SH NH2 NH Sis
H
"5) , or
100421 In some embodiments, D comprises:
=
100431 In some embodiments, D comprises:
SH
.1)sse
100441 In some embodiments, D comprises:
NH2
H S
100451 In some embodiments, D comprises:
0
--)L NH
=
100461 In some embodiments, D comprises:
oe
-9-
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100471 In some embodiments, D comprises:
HOj
SN
100481 In some embodiments, D comprises:
0 HN
HO'
100491 In some embodiments, D-La- is:
0
SH NH2 NH
H S r'N
0
or
0
Sis
0
-10-
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100501 In some embodiments, D-La- is:
HO
S s
0 HN
HO) c
S-s
0 or 0
100511 In some embodiments, D is substituted heterocycloalkyl (e.g., N-
substituted with alkyl
(e.g., further substituted with oxo and thiol)).
100521 In some embodiments, D comprises:
N
HS 0 , or
100531 In some embodiments, D comprises:
N
HS
100541 In some embodiments, D comprises:
N _se
0
100551 In some embodiments, D comprises:
N
0
100561 In some embodiments, D comprises:
-11 -
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100571 In some embodiments, D-12- is:
cy\
NDY\
0
0 HS 0 00 , or 0
100581 In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl comprising
one or more ester, one or more amide, and/or one or more disulfide (e.g.,
within the (e.g., linear
or branched) heteroalkyl chain).
100591 In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted (saturated)
heterocycloalkyl (e.g., dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide,
or N-attached
heterocycl oal kyl substituted with carboxyli c acid).
100601 In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl comprising
one ester (e.g., within the (e.g., linear or branched) heteroalkyl chain).
100611 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two amide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
100621 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
100631 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
100641 In some embodiments, D is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one or two disulfide and one amide (e.g., within the
(e.g., linear or
branched) heteroalkyl chain).
100651 In some embodiments, D is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
substituent, each substituent
being independently selected from the group consisting of thioalkyl, amino,
carboxylic acid, C1-
C6 alkyl, acetamide, thiol, oxo, and optionally substituted (e.g., N-attached)
heterocycloalkyl (e.g.,
optionally substituted with carboxylic acid).
100661 In some embodiments, D is substituted branched heteroalkyl.
-12-
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100671 In some embodiments, D comprises:
OH
0 P 0
H N "j.- 0,N1 D
HOyLl
-y0 0 S,s HO 0o S,s
HN y---õsõ.S.,,...)sss
-b)-.õ..s-S-.,õ..F,
HOO or
.
100681 In some embodiments, D is:
OH
0 0
,x11 D
HN- 0
jC
HairLI
0 S,
S HO--..A) 0 S,
S
HN ..--,.S..,),....-----,1(\,,
bl *S-S
HO 0 or 0
.
100691 In some embodiments, D comprises:
HSv
07 (:)..,,OH
0 NH
NH 0
HO
S, ,s ,..,._.(SH
S 0 HN) St-'-
S
}L
0 HOy-H
0 NH -S
OH or
,
OH
0
O. .\IN\c--D
0 0 s,
s
HO
S
-13-
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100701 In some embodiments, D is:
HSv
0/ 01_,OH
0 NH
HO, ________________________________ NH 0
S, ,s ,.._...(
S 0 1L-
0 H0
SH HN-
,1r-H
0 S
N H -S
---,/OH or
,
OH
0
0 N\\D
...----,i
0 0 S,\ / S
Ha--ii
N \---S's-,---S
100711 In some embodiments, D is:
0 0 LISF;Ei 0 0 0SHH 0 0SH
õKiss NN
OH N
N --)(OH FISLHNy\z-
H H
NH2 0 NH2 0
0
OH
0 0
HN 0.x.11\--D
)*("-
HOy-1-õI
0 S,s 0 S
0,
HO 0 S
HN y,', s , S =...,.......,.(1ZZ, .'j
N)LCSS-r:µ
HO "--0 0 ,
,
0 0
"ANN
}L-N1H
H0 SS '242. NN..,....s,S..,..,.)-..e
n HS,,,,I.,
Eõ,
Hr
NH2 0 , H 0 0 0,or 0
.
-14-
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100721 In some embodiments, D comprises:
0 0
\
HO N N
N H2 0
100731 In some embodiments, D comprises:
SH
0
N H2 0
100741 In some embodiments, D comprises:
0 (SH
HS**Ns,
100751 In some embodiments, D comprises:
0
HN-j-
H0,1(H
-y0 0 S,
HOO
100761 In some embodiments, D comprises:
o OH
0 NH NH
HO
0
-15-
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100771 In some embodiments, D is:
0 OH
0 HO, NH
z S 0
100781 In some embodiments, D comprises:
0
NOH
,sC IP 0 OH
S
100791 In some embodiments, D is:
0
0H
rThrN
,s 0 0 OH
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100801 In some embodiments, D comprises:
HS \/
0/ 0 OH
0 NH
, _________________________________________________ /-NH
HO
S,
S 0
100811 In some embodiments, D is:
HS \/
_____________________________________________________ 0 OH
0 NH
c_
HO SNs sJSH
100821 In some embodiments, D comprises:
OH
0
0
/Th
HO
0 S,s 0
[0083] In some embodiments, D comprises:
0 NH2
NH2
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100841 In some embodiments, D comprises:
Oy-
HS
0 0
100851 In some embodiments, D comprises:
0
-)L NH
HN
HO 0
100861 In some embodiments, D comprises:
0
--A NH
100871 In some embodiments, D comprises: HOCH2-, HOCH(CH3)-, HO(CH2CH20)4CH2-,
HO(CH2CH20)4CH2CH2-, HOCH2(C=0)-, HOCH(CH3)(C=0)-, HO(CH2CH20)4CH2(C=0)-,
HO(CH2CH20)4CH2CH2(C-0)-, CH30(C-0)-, CH3CH20(C-0)-, (CH3)2C0(C-0)-,
(CH3)3 CO(C=0)-, CH3 (C=0)-, CH3CH2(C=0)-, (CH3)2C(C=0)-,
(CH3)3C(C=0)-,
HOCH2(C=0)-, HO(CH3)CH(C=0)-,
HO(CH3)CH(C=0)0(CH3)CH(C=0)-,
CH3(C=0)0(CH3)CH(C=0)-, CH30(C=0)0(CH3)CH(C=0)-, CH30(C=0)(CH3)CHO(C=0)-,
CH3 CH20(C=0)(CH3)CHO(C=0)-,
HOCH2(HOCH2)CHCH20(C=0)-,
CH3 (C=0)0CH2(CH3(C=0)0CH2)CHCH20 (C=0)-,
(CH3)3 C(C-0)0CH2((CH3)3C(C-0)0CH2)CHCH2 0(C-0)-,
HO(CH3)CH(C=0)0CH2(HO(CH3)CH(C=0)0CH2)CHCH20(C=0)-,
HSCH2(C=0)-,
HS(CH3)CH(C=0)-, HSCH2(NH2)CH(C=0)-,
HS CH2(CH3 (C=0)NH)CH(C=0)-,
HOOC(NH2)CHCH2CH2(C=0)NH(HSCH2)CH(C=0)NHCH2(C=0)-,
(C=0)CH(NH2)CH2CH2(C=0)NHCH(CH2 SH)(C=0)NHCH2C 00H,
HS(CH3)2C(C=0)NH(SHCH2)CH(C=0)-,
HO 0 C (NH2)CHCH2 S SCH2CH(NH2)(C=0)-,
HSCH2(CH3(C=0)NH)CH(C=0)0CH(CH3)(C=0)-,
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A
o o HS
0
H N )1.`
0
0 S...s
NH
H N H N
H 0 0 0 HO 0 0, or
OH
0
Oxl\sHO
,s
HO 00 S
S S
0
100881 In some embodiments, D comprises: HSCH2(C=0)-, HS(CH3)CH(C=0)-,
HSCH2(NH2)CH(C=0)-,
HS CH2(CH3(C =0)NH)CH(C=0)-,
HO OC(NH2)CHCH2CH2(C=0)NH(HS CH2)CH(C=0)NHCH2 (C=0)-,
(C=0)CH(NH2)CH2CH2(C=0)NHCH(CH2SH)(C=0)NHCH2COOH,
HS (CH3)2 C(C=0)NH(SHCH2)CH(C=0)-,
HO OC (NH2)CHCH2 S SCH2CH(NH2)(C=0)-,
HSCH2(CH3(C=0)NH)CH(C=0)0CH(CH3)(C=0)-,
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0
H N
0 HOyLi
o
,y0 0 s
sl 's
\ )----µb o HNy--,,s,S \
0
0 HS , HO-.0
,
OH
0
0
0
0
}(NH HO 0 S,
_jct
ji
HN ,,,--õs,S,.õ,ly'lli,
HO 0 0,or 0 .
100891 In some embodiments, D-L' is:
O o
0
SH Si NH NH2
HS-r\ H-r\z. \ HS ,µ\ HS -Ir\z
0 0 , 0 , 0 ,
0 ,
NC111-r\ 0 0 -'. SH 0 0 0 ..c., SH
Flitl,
H
0
HON'--A-15 't1'iN N OH
H H
NH2
0 NH2 0 HS
,
,
0
H N
HOy-1.1
SH -,y0 0 S,
S
0
\ HNy.--,, ,S \
HS7\AN S
H 0
0 HOO ,
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OH
0
)
0 S --yL
HO 0 O NH -S
-&.1,,,..,,,s,s,yµ
0 , HOO 0, or
0 NH2
HOAr'SSjYµ
NH2 0 .
100901 In some embodiments, D-La is:
O o
0
SH SI -)LNH NH2
HS'y\- --H-r\e- \ HS\ HS ,ITA
0 , 0 , 0 , 0 , 0 ,
oCN --'SH rSH
Ilir\ 0 0 0 0 H
0
H
HO)L-r-t'NMIN-)1Y ''12ey---1\N--)LOH
H NH2 0 NH2 H0 ,HS
,
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H2\y
0 0y0H
0 NH
0 NH
HO) c __________________________________ S\ HO,
..s1N1H
,S
S s's S s 0
õSH
0
*,=,õ/
0 0
,
0
0-1(N OH
Sµ s 0 0 OH
S
0
-yO }L-NH 0 NH2
0
HO)'Y
0 , or NH2
0
100911 In some embodiments, D is a "keratolytic agent" radical that, upon
release, hydrolysis, or
other mechanism metabolizes or otherwise produces (e.g., when administered to
an individual or
patient, such as in or around the eye, such as the eyelid margin) an active
keratolytic agent (e.g.,
a carboxylic acid and/or a thiol). In some instances, upon release (e.g., by
hydrolysis or other
mechanism), D produces a plurality of active keratolytic agents. In some
instances, the active
keratolytic agent comprises one or more of -SH, -OH, COOH (or C00-), or
disulfide. In some
embodiments, the active keratolytic agent is a carboxylic acid. In some
embodiments, the active
keratolytic agent is selected from the group consisting of acetic acid,
glycolic acid, lactic acid,
lipoic acid, pivalic acid, isobutryic acid, butyric acid, propionic acid,
formic acid, and carbonic
acid. In some embodiments, the active keratolytic agent is a thiol. In some
embodiments, the active
keratolytic agent is a carboxylic acid.
100921 In some embodiments, one or more group of the keratolytic agent (e.g.,
thiol, hydroxy,
carboxylic acid, amide, or amine) is protected or masked (e.g., with
optionally substituted Ci-C6
alkyl (e.g., being optionally substituted with oxo)). In some embodiments, one
or more thiol of
the keratolytic agent is protected or masked with acetyl. In some embodiments,
one or more amine
of the keratolytic agent is protected or masked with acetyl. In some
embodiments, one or more
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carboxylic acid of the keratolytic agent is protected or masked with methyl,
ethyl, propyl,
isopropyl, or t-butyl. In some embodiments, one or more carboxylic acid of the
keratolytic agent
is protected or masked with ethyl.
[0093] In some embodiments, La is attached to D by a bond.
[0094] In some embodiments, any L or linker provided herein comprises one or
more substituted
or un sub stituted al koxy (e.g., polyethylene glycol (PEG)).
[0095] In some embodiments, any L or linker provided herein comprises a
compound having a
structure of Formula (B).
[0096] In some embodiments, X is a bond or 0. In some embodiments, X is a
bond. In some
embodiments, X is 0.
[0097] In some embodiments, any L or linker provided herein is attached to the
compound having
a structure of Formula (B). In some embodiments, the linker is -(C=0)(OCR8R9),-
.
100981 In some embodiments, the linker is -(C=0)0CH(CH.3)-. In some
embodiments, the linker
is -(C=0)(OCH2CH2), and attached to the compound having a structure of Formula
(B).
[0099] In some embodiments, z is an integer from 1-20. In some embodiments, z
is an integer
from 1-10. In some embodiments, z is an integer from 1-5. In some embodiments,
z is 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10. In some embodiments, z is 4. In some embodiments, z is
8.
[0100] In some embodiments, the linker is -(C=0)(OCH2CH2)z and attached to -
0(C=0)-. In
some embodiments, the linker is -(C=0)(OCH2CH2)4 and attached to -0(C=0)-. In
some
embodiments, the linker is -(C=0)(OCH2CH2)8 and attached to -0(C=0)-.
[0101] In some embodiments, the compound having the structure of Formula (B)
is attached to a
keratolytic agent provided herein (e.g., as described elsewhere herein). In
some embodiments, the
compound having the structure of Formula (B) is attached to and includes at
least a portion of a
keratolytic agent provided herein (e.g., as described elsewhere herein).
[0102] In some embodiments, the compound having the structure of Formula (B)
is attached to
any R or R' provided herein (e.g., as described elsewhere herein).
101031 In certain instances, provided herein is a combination of an anti-
inflammatory and/or anti-
microbial moiety (e.g., having a structure of any formula provided herein,
minus the R') with a
keratolytic moiety (e.g., being represented by and/or having a structure of
D). In certain
embodiments, such moieties are radicals connected by a linker that is a bond,
with the keratolytic
moiety being hydrolyzable to produce both (1) an anti-inflammatory and/or anti-
microbial agent
and (2) one or more active keratolytic agent. In some embodiments, such
moieties are radicals
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connected by a hydrolyzable linker, with the hydrolyzable linker being
hydrolyzable, such that
both (1) an anti-inflammatory and/or anti-microbial agent and (2) one or more
active keratolytic
agent are released (e.g., in vivo, such as after therapeutic (e.g., topical)
delivery to the eye and/or
skin).
101041 In some embodiments, a compound provided herein comprises a first
radical (e.g., a first
radical of Formul a I (or any other formula provided herein)) that is dim eri
zed with a second radical
(e.g., a second radical of Formula I (or any other formula provided herein)).
In some embodiments,
each radical of Formula I (or any other formula provided herein) is dimerized
through an -SH
group thereof (e.g., forming an S-S linkage).
101051 In some embodiments, provided herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (Ia):
-,,...
OH
_
OH N
A0 H
ds .
d=
RXL O<
-- y
0 ...--,..)..,õ
Me2N-
Formula (Ia).
[0106] In some embodiments, L is bond, -(C=0)(OCR8R9)2-, or -(C=0)(OCR8R9)z0-.
In some
embodiments, L is bond, -(C=0)0(CR8R9)z-, or -(C=0)0(CR8R9)z0-. In some
embodiments, each
R8 and R9 is independently H, halogen, Ci-C3-alkyl, CI-C3-haloalkyl, Ci-C3-
alkoxy, C3-05-
cycloalkyl, or R8 and R9 are taken together with the atoms to which they are
attached to form a
C3-05-cycloalkyl. In some embodiments, z is 1-6. In some embodiments, X is
absent or -0-. In
some embodiments, R is substituted (e.g., straight or branched) alkyl,
substituted (e.g., straight or
branched) heteroalkyl, or substituted heterocycloalkyl (e.g., (N-) substituted
with alkyl (e.g.,
further substituted with oxo and thiol)). In some embodiments, the substituted
alkyl is substituted
with one or more (alkyl) substituent, at least one (alkyl) substituent being
independently selected
from the group consisting of -SH, substituted or unsubstituted (e.g.,
unsaturated) cycloalkyl, and
substituted heteroalkyl (e.g., dithiolanyl oxide). In some embodiments, the
substituted alkyl is
substituted with one or more (alkyl) substituent, at least one (alkyl)
substituent being
independently selected from the group consisting of -SH, substituted or
unsubstituted (e.g.,
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unsaturated) cycloalkyl, and dithiolanyl oxide. In some embodiments, the
substituted alkyl is
substituted with one or more (alkyl) substituent, at least one (alkyl)
substituent being
independently selected from the group consisting of -SH and dithiolanyl oxide.
In some
embodiments, the substituted heteroalkyl is substituted with one or more
(heteroalkyl) substituent,
at least one (heteroalkyl) substituent being independently selected from the
group consisting of -
SIT, -COOTT, and thioalkyl. In some embodiments, the substituted alkyl,
substituted heteroalkyl,
or substituted heterocycl oalkyl are further optionally substituted.
101071 In some embodiments, L is bond In some embodiments, L is -
(C=0)(0Clele)z- or -
(C=0)(OCIVIV),0-. In some embodiments, L is -(C=0)(OCIeR9),-. In some
embodiments, L is
-(C=0)(OCR8R9)z0-. In some embodiments z is 1-3. In some embodiments, z is 1.
In some
embodiments, each R8 and R9 is independently H or C1-C3-alkyl. In some
embodiments, each R8
is H and each R9 is C1-C3-alkyl. In some embodiments, each R.8 is H and each
R9 is CH3. In some
embodiments, le and R9 are H. In some embodiments, L is -(C=0)0CH(CH3)-. In
some
embodiments, L is -(C=0)0CH(CH3)0-.
101081 In some embodiments, X is absent. In some embodiments, X is -0-.
101091 In some embodiments, L is -(C=0)0CH(CH3)- or -(C=0) OCH(CH3)0- and X is
absent
or -0-.
101101 In some embodiments, L is -(C=0)0CH(CH3)- and X is absent. In some
embodiments, L
is -(C=0)0CH(CH3)0- and X is absent.
101111 In some embodiments, L is -(C=0)0CH(CH3)- and X is -0-. In some
embodiments, L is
-(C=0)0CH(CH3)0- and X is -0-.
101121 In some embodiments, L is bond and X is absent.
101131 In some embodiments, R is substituted alkyl, substituted heteroalkyl,
or substituted
heterocycloalkyl.
101141 In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of hydroxyl, thiol,
amino, acetamide, -
COOH, substituted unsaturated cycloalkyl (e.g., being substituted with one or
more C1-C4 alkyl),
unsubstituted (saturated) heterocycloalkyl (e.g., dithiolanyl),
and substituted (saturated)
heterocycloalkyl (e.g., dithiolanyl oxide or dithiolanyl sulfone). In some
embodiments, R is
substituted (e.g., straight or branched) alkyl, the (e.g., straight or
branched) alkyl being substituted
with one or more (alkyl) substituent, each (alkyl) substituent being
independently selected from
the group consisting of thiol, amino, acetamide, substituted unsaturated
cycloalkyl (e.g., being
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substituted with one or more Ci-C4 alkyl), and substituted (saturated)
heterocycloalkyl (e.g.,
dithiolanyl oxide). In some embodiments, R is substituted (e.g., straight or
branched) alkyl, the
(e.g., straight or branched) alkyl being substituted with thiol. In some
embodiments, R is
substituted (e.g., straight or branched) alkyl, the (e.g., straight or
branched) alkyl being substituted
with thiol and amide. In some embodiments, R is substituted (e.g., straight or
branched) alkyl, the
(e.g., straight or branched) alkyl being substituted with thiol and acetami de
(e.g., -N(C=0)CII3).
In some embodiments, R is substituted (e.g., straight or branched) alkyl, the
(e.g., straight or
branched) alkyl being substituted with 1,2-dithiolanyl oxide In some
embodiments, R is
substituted (e.g., straight or branched) alkyl, the (e.g., straight or
branched) alkyl being substituted
with substituted unsaturated cycloalkyl (e.g., being substituted with one or
more Cl-C4 alkyl).
101151 In some embodiments, R is substituted alkyl. In some embodiments, R is
substituted alkyl,
wherein the substituted alkyl is substituted with one or more alkyl sub
stituent, at least one alkyl
substituent being independently selected from the group consisting of
substituted or unsubstituted
cycloalkyl and substituted heterocycloalkyl. In some embodiments, R is
substituted alkyl, the
alkyl being substituted with substituted (saturated) heterocycloalkyl. In some
embodiments, R is
substituted alkyl, the alkyl being substituted with 1,2-dithiolanyl oxide. In
some embodiments, R
is substituted alkyl, the alkyl being substituted with substituted
heterocycloalkyl (e.g., C5-C15
heterocycloalkyl (e.g., C12 heterocycloalkyl with one or more disulfide and
one or more amide
within the heterocycloalkyl ring)) being substituted with one or more
substituent, at least one
substituent being independently selected from the group consisting of Ci-C3
alkyl, oxo, and -
COON. In some embodiments, the substituted alkyl is further optionally
substituted.
101161 In some embodiments, L is bond, X is absent, and R is substituted
(e.g., straight or
branched) alkyl, the (e.g., straight or branched) alkyl being substituted with
one or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
thiol, amino, acetamide, substituted unsaturated cycloalkyl (e.g., being
substituted with one or
more C i-C4 alkyl), and substituted (saturated) heterocycloalkyl (e.g.,
dithiolanyl oxide).
101171 In some embodiments, L is bond, X is absent, and R is substituted
alkyl, wherein the
substituted alkyl is substituted with one or more alkyl substituent, at least
one alkyl substituent
being independently selected from the group consisting of substituted or
unsubstituted cycloalkyl
and substituted heterocycloalkyl. In some embodiments, the substituted alkyl
is further optionally
substituted.
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10H81 In some embodiments, R is:
R4a R4b
'T p
wherein:
each R4a and R4b is independently H, halogen, or substituted or unsubstituted
alkyl;
p is an integer from 1-10; and
q is an integer from 1-3.
101191 In some embodiments, q is 1 and p is an integer from 3-5.
101201 In some embodiments, each R4a and R4b is H.
101211 In some embodiments, R is.
NR6R7
.S
R5 'ksjY
R10 R11
wherein:
R5 is -SR;
Rh: is:
substituted alkyl or substituted heteroalkyl,
wherein the alkyl is substituted with one or more alkyl substituent, each
alkyl substituent being independently selected from the group
consisting of carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo,
and optionally substituted heterocycloalkyl, and the heteroalkyl is
substituted with one or more heteroalkyl substituent, each heteroalkyl
substituent being independently selected from the group consisting of
oxo, carboxylic acid, amino, thioalkyl, thiol, acetamide, and C1-C3
alkyl;
R6 and R7 are each independently H, substituted or unsubstituted alkyl, or
substituted
or unsubstituted heteroalkyl;
each RI- and R" is independently H, halogen, C1-C3-alkyl, C1-C3-haloalkyl, Ci-
C3-
alkoxy, C3-05-cycloalkyl, or two of Itl and R11 are taken together with the
atoms
to which they are attached to form a C3-05-cycloalkyl; and
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s is an integer from 1-10.
[0122] In some embodiments, R6,
R7, le and RH are each H, and s is 1-3.
[0123] In some embodiments, Ric is heteroalkyl substituted with carboxylic
acid. In some
embodiments, Ric is alkyl substituted with one or more alkyl substituent, each
alkyl substituent
being independently selected from the group consisting of carboxylic acid and
acetamide.
[0124] In some embodiments, R5 is:
/
HS SA
scsr...s.r0H õ..,L.I...OH A
s OH HS
OH
0
1
ciii-OH
.).L NH NH2 0 0 rS
0
0
\c_
H _.)----µ0 S0 H,
,vS.,,../y N (
0H ,...õ)
H0)(1N *1.1-1" OH S
H /
Oy'
1
0
SH S ...-..
0 0
.224..S.N.f,r0H HS*Ct N..-1.,--- OH 0 or ,....H.r.OH
0 .
,
[0125] In some embodiments, R is:
0
SH NH2 NH
I
,..-- ,--- ...,-- i
HS" ----'11 HS,....,,-1-,/ HS..,J,s
, or
0 6
S Is
Ø.
ss- .
[0126] In some embodiments, R is:
HS"" .....-.'
55. .
101271 In some embodiments, R is:
SH
./L1
.
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[0128] In some embodiments, R is:
NH2
HS
,sr
[0129] In some embodiments, R is:
0
--A NH
HSLj
[0130] In some embodiments, R is:
[0131] In some embodiments, R is:
Oe
sis
.0- .
[0132] In some embodiments, R is:
0
Sµ
[0133] In some embodiments, R is:
S\S
0 HN
HO (\s_
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101341 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl comprising
one or more ester, one or more amide, and/or one or more disulfide (e.g.,
within the (e.g., linear
or branched) heteroalkyl chain).
101351 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl comprising
one ester (e.g., within the (e.g., linear or branched) heteroalkyl chain).
101361 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two amide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain)
101371 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
101381 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
101391 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one or two disulfide and one amide (e.g., within the
(e.g., linear or
branched) heteroalkyl chain).
101401 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted
heterocycloalkyl (e.g., dithiolanyl, dithiolanyl sulfone, dithiolanyl oxide,
or N-attached
heterocycloalkyl substituted with carboxylic acid). In some embodiments, R is
substituted (e.g.,
linear or branched) heteroalkyl, the (e.g., linear or branched) heteroalkyl
being substituted with
one or more (heteroalkyl) substituent, each (heteroalkyl) substituent being
independently selected
from the group consisting of thioalkyl, amino, carboxylic acid, C1-C6 alkyl,
thiol, oxo, and
optionally substituted (e.g., N-attached) heterocycloalkyl (e.g., optionally
substituted with
carboxylic acid). In some embodiments, R is substituted linear heteroalkyl,
the linear heteroalkyl
being substituted with thioalkyl, amino, and carboxylic acid. In some
embodiments, R is
substituted linear heteroalkyl, the linear heteroalkyl being substituted with
thioalkyl, thiol, and Ci-
C4 alkyl. In some embodiments, R is substituted branched heteroalkyl, the
branched heteroalkyl
being substituted with one or more carboxylic acid. In some embodiments, R is
substituted
branched heteroalkyl, the branched heteroalkyl being substituted with one or
more Ci-C4 alkyl,
one or more oxo, and one or more N-attached pyrrolidine substituted with
carboxylic acid. In some
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embodiments, R is substituted linear heteroalkyl, the linear heteroalkyl being
substituted with
amino and carboxylic acid. In some embodiments, R is substituted linear
heteroalkyl, the linear
heteroalkyl being substituted with thioalkyl. In some embodiments, R is
substituted linear
heteroalkyl, the linear heteroalkyl being substituted with acetamide and
carboxylic acid.
101411 In some embodiments, R is substituted heteroalkyl, wherein the
substituted heteroalkyl is
substituted with one or more heteroalkyl substituent, each heteroalkyl
substituent being
independently selected from the group consisting of -COOH, substituted
heterocycloalkyl,
acetamide, alkoxy, oxo, thiol, C1-C3 alkyl, and thioalkyl In some embodiments,
R is substituted
heteroalkyl, the heteroalkyl being substituted with -COOH, -CH2SH, and/or
optionally substituted
N-attached heterocycloalkyl. In some embodiments, the substituted heteroalkyl
is further
optionally substituted. In some embodiments, the substituted heteroalkyl is
further substituted
with one or more other substituent, each substituent being independently
selected from the group
consisting of acetamide, amino, Ci-C6 alkyl, thiol, and oxo.
101421 In some embodiments, R is substituted heteroalkyl, the heteroalkyl
being substituted with
one or more substituent, each substituent being independently selected from
the group consisting
of -COOH and acetamide.
101431 In some embodiments, R is substituted heteroalkyl, the heteroalkyl
being substituted with
one or more substituent, each substituent being independently selected from
the group consisting
of oxo and acetamide (e.g., wherein the heteroalkyl chain comprises a
disulfide bond and -0-).
101441 In some embodiments, R is substituted heteroalkyl, the heteroalkyl
being substituted with
one or more substituent, each substituent being independently selected from
the group consisting
of C1-C3 alkyl, oxo, and substituted N-attached heterocycloalkyl (e.g.,
optionally substituted with
-COOH).
101451 In some embodiments, R is substituted heteroalkyl, the heteroalkyl
being substituted with
one or more substituent, each substituent being independently selected from
the group consisting
of Ci-C3 alkyl, oxo, -COOH, and thiol (e.g., wherein the branched heteroalkyl
chain comprises
two disulfide bonds and two -NH-).
101461 In some embodiments, R is substituted heteroalkyl comprising one or
more ester, amide,
or disulfide bond within the heteroalkyl chain.
101471 In some embodiments, R is substituted heteroalkyl, the heteroalkyl
being substituted with
-COOH, -CH2SH, and/or optionally substituted N-attached heterocycloalkyl, and
being further
substituted with one or more other substituent, each substituent being
independently selected from
the group consisting of acetamide, amino, C1-C6 alkyl, thiol, and oxo.
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101481 In some embodiments, R is substituted heteroalkyl comprising two
disulfide bonds within
the heteroalkyl chain, the heteroalkyl being substituted with -COOH or
substituted N-attached
heterocycloalkyl. In some embodiments, the heteroalkyl is further substituted
with one or more
other substituent, each substituent being independently selected from the
group consisting of
acetamide and CI-C6 alkyl.
101491 In some embodiments, R is substituted heteroalkyl comprising one
disulfide bond within
the heteroalkyl chain, the heteroalkyl being substituted with acetamide, -
COOH, and -SH.
101501 In some embodiments, R is heterocycloalkyl N-substituted with alkyl,
the alkyl being
further substituted with oxo and/or thiol.
101511 In some embodiments, L is bond, X is absent, and R is substituted
(e.g., linear or branched)
heteroalkyl, the (e.g., linear or branched) heteroalkyl being substituted with
one or more
(heteroalkyl) substituent, each (heteroalkyl) substituent being independently
selected from the
group consisting of thioalkyl, amino, carboxylic acid, Cl-Co alkyl, acetamide,
thiol, oxo, and
optionally substituted (e.g., N-attached) heterocycloalkyl (e.g., optionally
substituted with
carboxylic acid).
101521 In some embodiments, L is bond, X is absent, and R is substituted
heteroalkyl, wherein
the substituted heteroalkyl is substituted with one or more heteroalkyl
substituent, at least one
heteroalkyl substituent being independently selected from the group consisting
of -COOH,
substituted heterocycloalkyl, and thioalkyl. In some embodiments, the
substituted heteroalkyl is
further optionally substituted.
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101531 In some embodiments, R is:
SH SH
(SH
0 0
HO N
N ,,..--\4 ssse,T.--,,,)1.. NH0 H HS H
NH2 0 , NH2 0
H ,
OH
0 HN 0)L-
HO(-H
0 S,s
HN
HO 0
y^.,s,S,õ)\õ./.\õ./y
&-L,..,/,.., S....S1
HO---0
0
0 NH2
}LNH 0
s...s,,,..),,õ HN .-..,s,S..,..,,--1-..,/ -)L NH
HO H S -,,..--1-,:sssi
NH2 , HO---0 ,or
=
101541 In some embodiments, R is:
SH r SH
) N
C. Li
0
HO 0 0
,SH
\'' si' N
LHNOH
H
i
NH2 0 , NH2 0 H ,
HSv
0¨< (:),,OH
0 NH
HO, ___ (NH 0
S, ,s ..).,ISH
S 0 HN)L-
õI, 0 HOyi.,1
0 S
--., ---it-NH 'S
..,,./
OH
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OH
0
ON---D
0
S,
--A 0 0\ 0
NH2 NH
s,
N S ,ss" HOSS
N H2
0
)LNH
HSõ.õ.,-cs
or .
101551 In some embodiments, R is:
SH
0 0
N H2 0
101561 In some embodiments, R is:
SH
0 0
sfsN-1[\1')LOH
NH2 0
=
101571 In some embodiments, R is:
rSH
0
HS
101581 In some embodiments, R is:
0
HN--k
HOyi.õ1
--y0 0 S,s
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[0159] In some embodiments, R is:
HN
0 Hay.1.1
}LNH 0 SS
OH
[0160] In some embodiments, R is:
OH
0
O. N-\FID
0 ,
HO 0 S
[0161] In some embodiments, R is:
OH
0
O.
/Th
0 S,s
HO-lb
[0162] In some embodiments, R is.
0 N H2
HOS'Scse
NH2
[0163] In some embodiments, R is:
Oy=
NH
0 0
s.
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[0164] In some embodiments, R is:
0
-)L NH
H 00
[0165] In some embodiments, R is:
0
HSJy
101661 In some embodiments, R is:
HS \/
C)
0 NH
HO' _________________________________________________ rsc-- NH
SH
s
NS s'
101671 In some embodiments, R is substituted branched heteroalkyl.
[0168] In some embodiments, R is:
OH
0
0
H N 0.x.1\10
HO'
0 S,
0 S,
HN H 0 0
HO 0 or
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101691 In some embodiments, R is:
HS\/
0/o OH
0 NH
HO,NH0
S 0
0 HO,r-H
0 )1-NH S -S
0y,S,sse
OH , or
OH
0
0 I\\\D
_vO 0, cs S,s
HO
=
101701 In some embodiments, R-X-L is:
OH
0 0
HNA-=
HOy--H
sy0 0 S,
HO 00 S
0
HO 0 Of
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101711 In some embodiments, R-X-L is:
HS \/
0 NH
HO, (1.---NH 0
S, .,.
,s ,..(SH
S 0 HN-IL-
0 HOõr-H
0 S
.., )1.-.NH -S
)\-S=-s-"
OH or
,
OH
0
0 N\\D
S,
0 0\ / S
H 0 ¨V;
N \S,sr,
101721 In some embodiments, R-X-L is:
OH
0 0
HN)L-
HOy-1-1
..----")
S HO 0
0 S,
S
0
HOO or 0
.
101731 In some embodiments, R is substituted heterocycloalkyl (e.g., N-
substituted with alkyl
(e.g., further substituted with oxo and/or thiol)).
101741 In some embodiments, R is:
NC11.
N'Y
HS 0 , 0 , or H
, .
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101751 In some embodiments, R is:
HS
101761 In some embodiments, R is:
0
101771 In some embodiments, R is:
N
0
101781 In some embodiments, R is:
101791 In some embodiments, R-X-L is
clys' _Ks-1
)555 N-
N
HS 0 0 , or
101801 In some embodiments, R comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
lipoic acid sulfonyl
(Lipsulf), a radical of N-acetyl cysteine (NAC), a radical of cysteine (Cys),
a radical of glutathione
(GSH), a radical of captopril (Cap), and a radical of bucillamine (Buc)).
101811 In some embodiments, R comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
N-acetyl cysteine
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(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
101821 In some embodiments, R comprises a radical of one or more keratolytic
group, each radical
of the one or more keratolytic group being independently selected from the
group consisting of a
radical of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical
of lactic acid (Lac),
a radical of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical
of lipoic acid sulfoxide
(Lipox), a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl
cysteine (NAC), a radical
of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril
(Cap), and a radical of
bucillamine (Buc).
101831 In some embodiments, R comprises a thiol radical of one or more
keratolytic group, each
thiol radical of the one or more keratolytic group being independently
selected from the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
101841 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]., [Cys-
Cys]-, [diHLip-NAC-NAC]-, [difiLip-NAC]-, [diHLip-Cap-Cap]-, [difiLip-Cap].,
[difiLip-Cys-
Cys]-, [diHLip-Cys]=, [diHLip-Lipox-Lipox]-, and [diHLip-Lipox]-.
101851 In some embodiments, R is:
SH
0 0
SH NH2
HS HO))-(NXir
HS/ /Lcsf
SH OG
0 0SH
N 0
NH2 0 ss" HS
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OH
0 0
HN)L- 0,,INI
HOIr-H
0 S,
HO
0 S
HN,
HO 0
0
0 NH2 `y0
-)LNH
STh
HO)YS"-SS I HN y---õ.sS,
i ><
N
----µ.
NH2 , HOO
0 ,
, ,
S 0
--- -D, rcs S }L NH
N
0 , N---,/ HS ,,sss
H ,or -sF .
101861 In some embodiments, R-X-L- is:
SH
SH NH2
HS
)(t.r.., jt X1rH
HO N
HS õ-If
"..--si --).-si H
NH2 0
,
SH 00
0 0
o ='SH
ssest, H Sls
N,_,IL,
N OH c.).,, )---µ0 HSN
H S353',.--../
NH2 0 HS
H
OH
0 H N 0 )I-- 0,,ININO
H0,1(1-,1
0 S,
S HO 0 S,s
-b 0
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0
0 NH2
--)L'NH
S --,
HO)YSss, I H N r,
SS ssssc
>KNJy
----"µ
NH2 , HO 0
0 ,
,
7
0
--i.. II
NH
----.µ
N
N...---1 HS ,..,..i
0 , H ,or 2- .
101871 In some embodiments, R-X-L- is:
SH
H S HON)
SH
HS NH2
scf õ...,...1,,,
/ N
NH2 " 0
/ /
SH 00
NCI 11
0
SH
H SA
ssssYN -11\1 )LOH )---"k0 HS
N
NH2 HS
H
0 H 0
HN
HAN )(
0 0 S HOy-H
'ANH 0 S,
S
/
, H OH
,
OH
0
Ox..1 D
0 0\\ / S,
S 0 NH2
H 01V
N \''S'Ssi- HOA'rS--S
NH2
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0
)NH >(S D S D
I HNS .J.,./ N i.sss N is zr
e ---1
-----µo , --µ
N ="ys ,--=_,
HO 0
S \ 0
H HOLY -,,,, N
_
0 H N S
HO) ____,.. Sµ S
1
S
S -S s __, ,
c
0
.,,
--j-L NH
HS....,1-..4 -....s
2 or
101881 In some embodiments, the compound is other than a compound having the
structure:
= OH _
_
O'''-'7,
OH N
HO,=. \ .õ
d H =
0
HS :.
= --...-- ''==,
SIHCOMe
Me2N .
101891 Provided in some embodiments herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (lb):
-'"- OH
= _
0-----ssiCsr.
OH N
A0 H
O's
d i OH==,
-,
R): -L
X y
0
Me2N'
Formula (lb)
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101901 In some embodiments, L is bond, -(C=0)(OCR8R9)7-, or -(C=0)(OCR8R9)70-.
In some
embodiments, each R8 and R9 is independently H, halogen, Ci-C3-alkyl,
Ci-C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are
attached to form a C3-05-cycloalkyl. In some embodiments, z is 1-6. In some
embodiments, X is
absent or -0-.
101911 In some embodiments, IV is:
2b
R2c R2d
R
R2a
R1 as m
eDi2
0
R1 bs
R2f
101921 In some embodiments, Rla and Rib are each independently -H or -SRI'. In
some
embodiments, each Ric is independently substituted or unsubstituted (e.g.,
straight or branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being
independently selected from the group consisting of carboxylic acid, -SH,
thioalkyl, acetamide,
amino, oxo, optionally substituted heterocycloalkyl (e.g., N-attached
pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted
with one or more (heteroalkyl) substituent, each (heteroalkyl) substituent
being independently
selected from the group consisting of carboxylic acid, amino, thioalkyl,
thiol, acetamide, and CI-
-2e,
C3 alkyl). In some embodiments, each R2 R2b R2c Rat tc
a , , , , and R2f is independently H,
halogen,
Ci-C3-alkyl, Ci-C3-alkoxy, C3-05-cycloalkyl, or two of R2a
and 2b
tc, R2' and R2d,
or R2e and R2f are taken together with the atoms to which they are attached to
form a C3-05-
cycloalkyl. In some embodiments, m is an integer from 1-10. In some
embodiments, n and o are
each independently an integer from 0-3. In some embodiments, n and o are each
independently an
integer from 1-3.
101931 In some embodiments, L, Rg, R9, X, and z are each described elsewhere
herein.
101941 In some embodiments, n and o are each independently 0, 1, or 2. In some
embodiments, n
is 1 or 1. In some embodiments, n is 2. In some embodiments, o is 0 or 1. In
some embodiments,
o is 0. In some embodiments, o is 0 and n is 2.
101951 In some embodiments, n and o are each independently 0 or 1. In some
embodiments, n is
0 or 1. In some embodiments, n is 1. In some embodiments, o is 0 or 1. In some
embodiments, o
is 0. In some embodiments, o is 0 and n is 1.
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101961 In some embodiments, m is 3-5. In some embodiments, m is 4. In some
embodiments, o
is 0 and m is 4. In some embodiments, n is 2 and m is 4. In some embodiments,
o is 0, n is 2, and
m is 4.
101971 In some embodiments, m is 3-5. In some embodiments, m is 4. In some
embodiments, n
is 0 and m is 4. In some embodiments, n is 1 and m is 4. In some embodiments,
o is 0, n is 1, and
m is 4.
101981 In some embodiments, each R2a, R2b, R2c, R2d, R2c, and R' is
independently H, halogen,
C1-C3alkyl, or C1-C3haloalkyl In some embodiments, each R2, R2b, R2c, R2d,
R2e7 and R' is
independently H, halogen, Ci-C3alkyl, or Ci-C3haloalkyl, at least one of lea,
R2b, R2c, R2d, R2e,
and R' being halogen, Ci-C3alkyl, or Ci-C3haloa1kyl. In some embodiments, each
R2', R2b, Tee,
R2d, K-rs2e,
and R' is H.
101991 In some embodiments, IV is:
sRib
R1 aS/
102001 In some embodiments, IV is:
SRlb
R1 as
102011 In some embodiments, Rh and Rib are each independently -H or -SR', In
some
embodiments, each Ric is independently substituted or unsubstituted (e.g.,
straight or branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being
independently selected from the group consisting of carboxylic acid, -SH,
thioalkyl, acetamide,
amino, oxo, optionally substituted heterocycloalkyl (e.g., N-attached
pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted
with one or more (heteroalkyl) substituent, each (heteroalkyl) substituent
being independently
selected from the group consisting of carboxylic acid, amino, thioalkyl,
thiol, acetamide, and Ci-
C3 alkyl).
102021 In some embodiments, RI-a is -H or -SRI' and Rib is -SRI', or Rh is -
SRI and Rib is -H or
-SRI'. In some embodiments, Rla is -H or -SRI' and Rib is -SRI'. In some
embodiments, Rh is -H
and Rib is -SRI'. In some embodiments, Rla is -SRI' and Rib is -H or -SRI'. In
some embodiments,
Rla is -SRI' and Rib is -SRI'. In some embodiments, Rla and Rib are each -SR'.
102031 In some embodiments, Rla and Rib each independently comprise a radical
of one or more
keratolytic group (e.g., each radical of the one or more keratolytic group
being independently
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selected from the group consisting of a radical of glycolic acid (GA), a
radical of thioglycolic acid
(TGA), a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a
radical of lipoic acid
(Lip), a radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic
acid (diHLip), a radical
of N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of
glutathione (GSH), a radical
of captopril (Cap), and a radical of bucillamine (Buc)).
[0204] In some embodiments, Rh and Rib are each independently a radical of one
or more
keratolytic group, each radical of the one or more keratolytic group being
independently selected
from the group consisting of a radical of glycolic acid (GA), a radical of
thioglycolic acid (TGA),
a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a radical
of lipoic acid (Lip), a
radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic acid
(diHLip), a radical of N-
acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of glutathione
(GSH), a radical of
captopril (Cap), and a radical of bucillamine (Buc).
[0205] In some embodiments, Rla and Itlb each independently comprise a (thiol)
radical of one or
more keratolytic group, each (thiol) radical of the one or more keratolytic
group being
independently selected from the group consisting of a (thiol) radical of
thioglycolic acid (TGA),
a (thiol) radical of thiolactic acid (TLac), a (thiol) radical of
dihydrolipoic acid (diHLip), a (thiol)
radical of N-acetyl cysteine (NAC), a (thiol) radical of cysteine (Cys), a
(thiol) radical of
glutathione (GSH), a (thiol) radical of captopril (Cap), and a (thiol) radical
of bucillamine (Buc).
[0206] In some embodiments, RI-a and Rib are each independently a thiol
radical of one or more
keratolytic group, each thiol radical of the one or more keratolytic group
being independently
selected from the group consisting of a thiol radical of thioglycolic acid
(TGA), a thiol radical of
thiolactic acid (TLac), a thiol radical of dihydrolipoic acid (diHLip), a
thiol radical of N-acetyl
cysteine (NAC), a thiol radical of cysteine (Cys), a thiol radical of
glutathione (GSH), a thiol
radical of captopril (Cap), and a thiol radical of bucillamine (Buc).
[0207] In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]., [Lac-
NAC [Cy s-Cy s] = , -NAC]-, kliElLip-NAC].,
ap-Cap], RlifILip-Cap].,
[diHLip-Cys-Cys]., [diHLip-Cys]., [diHLip-Lipox-Lipox]., and [diHLip-Lipox]..
[0208] In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
of Rla and/or Rib to the rest of the molecule. In some embodiments, (the thiol
radical of) Rla and/or
Rib each independently attach to the rest of the molecule to form a disulfide
bond.
[0209] In some embodiments, Rla and Rib are each independently -H or:
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s&s HS SA
X.._ OH õ,--L.I.r.OH ise's OH HS
OH
0
cay0H
1
SOH SOH
)LNH N H2 0 0 H 0
0
:Yµb
HON"--Cir N S
0y,
sc(..NH
1
SH
SNOH 0 0 0 0
HS.KLLN,-.T.OH H
0 0 ,or 0 .
102101 In some embodiments, Ria and Rib are the same. In some embodiments, Ria
and Rib are
each -SR and the same. In some embodiments, Ria and Rib are different. In some
embodiments,
Ria and Rib are each SR' and different.
102111 In some embodiments, L is bond, X is absent, and IV is:
RS...
R1 C
c') .
102121 In some embodiments, L is -(C=0)0CH(CH3)-, X is absent, and Rx is:
RIcSR1 C
,s
s
102131 In some embodiments, L is -(C=0)0CH(CH3)-, X is absent, and Rx is:
RIcS,
sR
102141 In some embodiments, each Ric is independently substituted or
unsubstituted (e.g., straight
or branched) alkyl or substituted or unsubstituted (e.g., straight or
branched) heteroalkyl. In some
embodiments, each Ric is independently substituted (e.g., straight or
branched) alkyl or substituted
(e.g., straight or branched) heteroalkyl. In some embodiments, each Ric is
independently
substituted (e.g., straight or branched) alkyl. In some embodiments, each Ric
is (the same)
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substituted (e.g., straight or branched) alkyl. In some embodiments, each RI
is (a different)
substituted (e.g., straight or branched) alkyl.
102151 In some embodiments, each 11.1c is independently substituted (e.g.,
straight or branched)
heteroalkyl. In some embodiments, each Itic is (the same) substituted (e.g.,
straight or branched)
heteroalkyl. In some embodiments, each lee is (a different) substituted (e.g.,
straight or branched)
heteroalkyl.
102161 In some embodiments, one of Ric is substituted (e.g., straight or
branched) alkyl and the
other is substituted (e g , straight or branched) heteroalkyl
102171 In some embodiments, each It1c is the same. In some embodiments, each
It1c is different.
102181 In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
alkyl, the substituted alkyl being substituted with one or more (alkyl) sub
stituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH,
thioalkyl (e.g., -CH2SH), acetamide (e.g., -NH(C=0)CH3), amino, oxo, and
optionally substituted
heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with -COOH).
102191 In some embodiments, the optionally substituted heterocycloalkyl is:
OH
\..õN
102201 In some embodiments, each R1 is independently substituted (e.g.,
straight or branched)
heteroalkyl, the substituted heteroalkyl being substituted with one or more
(heteroalkyl)
sub stituent, each (heteroalkyl) sub stituent being independently selected
from the group consisting
of carboxylic acid, amino, thioalkyl (e.g., -CH2SH), thiol, acetamide (e.g., -
NH(C=0)CH3), and
Ci-C3 alkyl.
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102211 In some embodiments, R1c is:
HS JUNAJN,
OH Hs
OH
0
NH NH2 0 0 0
HO)Ly-)LN-ThrN.'-)LOH 0
0 0 NH2 0
oY-
µ2'
SH
0 0 0 0
1)(11,,N,--y0H HS,c1LN,-(trOHOH
0 0 , or 0
102221 In some embodiments, RIO, Rib, and each Itic each independently
comprise one or more
substituent that is a carboxylic acid or an ester. In some embodiments, Rla,
Rib, and each Ric each
independently comprise one or more substituent that is a carboxylic acid
(e.g., -(C=0)0H). In
some embodiments, Rla comprises one or more substituent that is a carboxylic
acid (e.g., -
(C=0)0H). In some embodiments, Itlb comprises one or more substituent that is
a carboxylic acid
(e.g., -(C=0)0H). In some embodiments, each It' independently comprises one or
more
substituent that is a carboxylic acid (e.g., -(C=0)0H). In some embodiments,
Rla, Itlb, and each
Ric each independently comprise one or more substituent that is an ester
(e.g., -(C=0)0-Ci-
C4alkyl) In some embodiments, R1a comprises one or more substituent that is an
ester (e g , -
(C=0)0-Ci-C4alkyl). In some embodiments, Rth comprises one or more substituent
that is an ester
(e.g., -(C=0)0-Ct-C4alkyl). In some embodiments, each Ric independently
comprises one or more
substituent that is an ester (e.g., -(C=0)0-Ci-C4alkyl).
102231 In some embodiments, the -(C=0)0H of Rh, Rib, and/or Ric is optionally
esterified (e.g.,
-(C=0)0H or -(C=0)0-Ci-C4alkyl). In some embodiments, the Ci-C4alkyl is
methyl, ethyl,
propyl, isopropyl, butyl, or t-butyl.
102241 Provided in some embodiments herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (Ic):
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OH
7
OH N
HO,,.
Oss
0 H HO
d H
RY
y
0
Me2N
Formula (Ic)
102251 In some embodiments, L is bond, -(C=0)(OCR8R9),-, or -(C=0)(OCR8R9)z0-.
In some
embodiments, each R8 and R9 is independently H, halogen, C1-C3-alkyl, C1-C3-
haloalkyl, Ci-C3-
alkoxy, C3-05-cycloalkyl, or 12_8 and R9 are taken together with the atoms to
which they are
attached to form a C3-05-cycloalkyl. In some embodiments, z is 1-6. In some
embodiments, X is
absent or -0-.
102261 In some embodiments, RY is:
Raa R4b
e s
P
102271 In some embodiments, each lea and Wth is independently H, halogen, or
substituted or
unsubstituted alkyl_ In some embodiments, p is an integer from 1-10 In some
embodiments, q is
an integer from 1-3.
102281 In some embodiments, L, R8, R9, z, and X are each described elsewhere
herein.
102291 In some embodiments, RY is:
R4a R4b
e s
P
102301 In some embodiments, each R4a and R4b is independently H, halogen, or
substituted or
unsubstituted alkyl. In some embodiments, p is an integer from 1-10. In some
embodiments, q is
an integer from 1-3.
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102311 In some embodiments, q is 1 or 2. In some embodiments, q is 1. In some
embodiments, p
is an integer from 3-5. In some embodiments, p is 4. In some embodiments, q is
1 and p is 4.
102321 In some embodiments, each R4a and R" is independently H or substituted
or unsubstituted
alkyl. In some embodiments, each R4a and R" is independently H, halogen, C1-
C3alkyl, or C1-
C3haloalkyl. In some embodiments, each R" and R" is H.
102331 In some embodiments, q is 1, p is an integer from 3-5, and each R4a and
R" is
independently H, halogen, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments,
q is 1, p is 4, and
each R" and R' is ft
102341 In some embodiments, L is -(C=0)0CH(CH3)-, X is absent, and R31 is:
oe
s -is
/ .
102351 In some embodiments, provided herein is a compound, or a
pharmaceutically acceptable
salt or solvate (e.g., or a stereoisomer) thereof, having the structure of
Formula (Id):
=,...,
OH
7
(:)...7.
HOh.
0 H
/......_)v
0 ' 1
d =
RzõL y 0 -1"H
X ==?
0 _
.--....--.",,
Me2Nr
Formula (Id)
102361 In some embodiments, L is bond, -(C=0)(OCR8R9)7-, or -(C=0)(OCR8R9)70-.
In some
embodiments, each R8 and R9 is independently H, halogen, C1-C3-alkyl, Ci-C3-
haloalkyl, C1-C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are
attached to form a C3-Cs-cycloalkyl. In some embodiments, z is 1-6. In some
embodiments, X is
absent or -0-.
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102371 In some embodiments, Rz is:
NR6R7
R5/
R1 R11
102381 In some embodiments, R5 is -SRI'. In some embodiments, Ric is
substituted or
unsubstituted (e.g., straight or branched) alkyl (e.g., substituted with one
or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally substituted
heterocycloalkyl
(e.g., N-attached pyrrolidinyl substituted with -COOH)) or substituted or
unsubstituted (e.g.,
straight or branched) heteroalkyl (e.g., substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of carboxylic
acid, amino, thioalkyl, thiol, acetamide, and Ci-C3 alkyl). In some
embodiments, R6 and 117 are
each independently H, substituted or unsubstituted alkyl, or substituted or
unsubstituted
heteroalkyl. In some embodiments, each Rth and R" is independently H, halogen,
CI-C3-alkyl,
C1-C3-haloalkyl, C1-C3-alkoxy, C3-05-cycloalkyl, or two of RI and are
taken together with
the atoms to which they are attached to form a C3-05-cycloalkyl. In some
embodiments, s is an
integer from 1-10.
102391 In some embodiments, L, Rg, R9, X, and z are each described elsewhere
herein.
102401 In some embodiments, R5 is -SRI'. In some embodiments, Ric is
substituted or
unsubstituted (e.g., straight or branched) alkyl (e.g., substituted with one
or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally substituted
heterocycloalkyl
(e.g., N-attached pyrrolidinyl substituted with -COOH)) or substituted or
unsubstituted (e.g.,
straight or branched) heteroalkyl (e.g., substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of carboxylic
acid, amino, thioalkyl, thiol, acetamide, and Ci-C3 alkyl). In some
embodiments, R6 and IC are
each independently H, substituted or unsubstituted alkyl, or substituted or
unsubstituted
heteroalkyl. In some embodiments, each Itm and R" is independently H, halogen,
CI-C3-alkyl,
Ci-C3-haloalkyl, Ci-C3-alkoxy, C3-05-cycloalkyl, or two or more of Rl and R11
are taken together
with the atoms to which they are attached to form a C3-05-cycloalkyl. In some
embodiments, s is
an integer from 1-10.
102411 In some embodiments Ric is substituted alkyl or substituted
heteroalkyl.
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102421 In some embodiments R' is substituted alkyl, the alkyl being
substituted with one or more
alkyl substituent, each alkyl substituent being independently selected from
the group consisting
of carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, and optionally
substituted
heterocycloalkyl. In some embodiments, R1` is alkyl substituted with one or
more alkyl
substituent, each alkyl substituent being independently selected from the
group consisting of
carboxylic acid and acetamide.
102431 In some embodiments Ric is substituted heteroalkyl, the heteroalkyl
being substituted with
one or more heteroalkyl substituent, each heteroalkyl substituent being
independently selected
from the group consisting of oxo, carboxylic acid, amino, thioalkyl, thiol,
acetamide, and C1-C3
alkyl. In some embodiments, Ric is heteroalkyl substituted with carboxylic
acid.
102441 In some embodiments, Ric is substituted heteroalkyl, the heteroalkyl
being substituted with
-COOH and oxo. In some embodiments, R1c is substituted heteroalkyl, the
heteroalkyl being
substituted with oxo and acetamide. In some embodiments, Ric is substituted
heteroalkyl, the
heteroalkyl being substituted with Ci-C3 alkyl, oxo, and substituted N-
attached heterocycloalkyl.
In some embodiments, Ric is substituted heteroalkyl, the heteroalkyl being
substituted with -
COOH, C i-C3 alkyl, oxo, and thiol.
102451 In some embodiments, R6 and R7 are each independently H or substituted
or unsubstituted
alkyl (e.g., C1-C3 alkyl optionally substituted with oxo). In some
embodiments, R6 and R7 are each
independently H or Ci-C3 alkyl optionally substituted with oxo. In some
embodiments, R6 and R7
are each independently H or -(C=0)CH3. In some embodiments, R6 is H and R7 is
H or -
(C=0)CH3. In some embodiments, R6 is H and R7 is -(C=0)CH3. In some
embodiments, R6 and
R7 are H.
102461 In some embodiments, each Itm and R" is independently H, halogen, Ci-
C3alkyl, or Ci-
C3haloalkyl. In some embodiments, each RI' and R'' is H.
102471 In some embodiments, s is 1-3. In some embodiments, s is 1. In some
embodiments, s is 1
and RI and R" are H.
102481 In some embodiments, R6, R7, le and R11 are each H, and s is 1-3.
102491 In some embodiments, R5 comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diHLip), a radical of
N-acetyl cysteine
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(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
102501 In some embodiments, R5 is a radical of one or more keratolytic group,
each radical of the
one or more keratolytic group being independently selected from the group
consisting of a radical
of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical of
lactic acid (Lac), a radical
of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical of lipoic
acid sulfoxide (Lipox),
a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine
(NAC), a radical of cysteine
(Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a
radical of bucillamine
(Buc).
102511 In some embodiments, R5 comprises a (thiol) radical of one or more
keratolytic group,
each (thiol) radical of the one or more keratolytic group being independently
selected from the
group consisting of a (thiol) radical of thioglycolic acid (TGA), a (thiol)
radical of thiolactic acid
(TLac), a (thiol) radical of dihydrolipoic acid (diHLip), a (thiol) radical of
N-acetyl cysteine
(NAC), a (thiol) radical of cysteine (Cys), a (thiol) radical of glutathione
(GSH), a (thiol) radical
of captopril (Cap), and a (thiol) radical of bucillamine (Buc).
102521 In some embodiments Rs is a thiol radical of one or more keratolytic
group, each thiol
radical of the one or more keratolytic group being independently selected from
the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
102531 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]-, [Lac-
NAC]-, [Cys-Cys]-, [diHLip-NAC-NAC]., [diHLip-NAC]., [diHLip-Cap-Cap].,
[difiLip-Cap].,
[difiLip-Cys-Cys]., [difiLip-Cys]., [difiLip-Lipox-Lipox]=, and [diHLip-
Lipox]..
102541 In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
of R5 to the rest of the molecule. In some embodiments, R5 attaches to the
rest of the molecule to
form a disulfide bond.
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102551 In some embodiments, R5 is:
sos-,s
HS
sc"-=,s-rOH ,,-y0H -4s OH HS
OH
0
cly.OH
1
kS(OH SOH
}LNH NH2 0 0 0
0
HON"--Ctr- OH S
0 0 NH2 0
N H
SH
0 o ,,S 0 0
OH
0 , or 0
102561 In some embodiments, R5 comprises one or more substituent that is a
carboxylic acid or
an ester. In some embodiments, R5 comprises one or more substituent that is a
carboxylic acid
(e.g., -(C=0)0H). In some embodiments, R5 comprises one or more substituent
that is an ester
(e.g., -(C=0)0-C 1-C4alkyl).
102571 In some embodiments, the -(C=0)OH of R5 is optionally esterified (e.g.,
-(C0)OH or -
(C=0)0-Ci-C4alkyl). In some embodiments, the Ci-C4alky1 is methyl, ethyl,
propyl, isopropyl,
butyl, or t-butyl.
102581 In some embodiments, R' is:
NNW
ssa
102591 In some embodiments, R7 is H or -(C=0)CH3. In some embodiments, R7 is
H. In some
embodiments, R7 is -(C=0)CH3.
102601 In some embodiments, Ric is described elsewhere herein.
102611 In some embodiments, provided herein is a pharmaceutical composition
comprising any
compound provided herein, such as a compound represented by any one of Formula
(I), Formula
(I-A), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id),
Table 1, or a
pharmaceutically acceptable salt thereof, and at least one pharmaceutically
acceptable excipient.
In some embodiments, the pharmaceutical composition is suitable for ophthalmic
administration.
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In some embodiments, the pharmaceutical composition is suitable for topical
ophthalmic
administration. In some embodiments, topical ophthalmic administration is
administration in
and/or around the eye, such as to the eyelid margin. In some embodiments,
topical ophthalmic
administration is administration to the ocular surface and the inner surface
to the eyelid.
102621 In some embodiments, a compound or a pharmaceutical composition
comprising any
compound provided herein, such as a compound of any one of Formula (I),
Formula (I-A),
Formula (Ia), Formula (Ia'), Formula (lb), Formula (Ic), Formula (Id), Table
1, or a
pharmaceutically acceptable salt thereof, is substantially hydrolytically
stable (e g , stable in an
aqueous composition (e.g., solution), such as a buffer solution or
ophthalmically acceptable
aqueous composition). In some embodiments, the compound or the pharmaceutical
composition
is formulated in an aqueous vehicle. In some embodiments, the compound or the
pharmaceutical
composition is formulated and stored in an aqueous vehicle. In some instances,
compositions or
formulations provided herein are chemically and/or physically stable in an
aqueous composition.
102631 In some embodiments, a compound provided herein, such as a compound of
any one of
Formula (I), Formula (I-A), Formula (Ia), Formula (Ia'), Formula (lb), Formula
(Ic), Formula (Id),
Table 1, or a pharmaceutically acceptable salt thereof, is reduced to one or
more keratolytic agent
(e.g., a free form of a radical of Formula (I), Formula (I-A), Formula (Ia),
Formula (Ia'), Formula
(lb), Formula (Ic), Formula (Id), or Table 1, such as wherein R is a negative
charge or H) and/or
hydrolyzed to an active pharmaceutical agent(e.g., a free form of a radical of
Formula (I), Formula
(I-A), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Id),
or Table 1, such as
wherein R is a negative charge or H) In some embodiments, the compound or
pharmaceutical
composition is reduced to one or more keratolytic agent in an ocular space. In
some embodiments,
the compound or pharmaceutical composition is reduced to one or more
keratolytic agent by a
reductase in an ocular space.
102641 In some embodiments, a compound provided herein, such as a compound of
any one of
Formula (I), Formula (I-A), Formula (Ia), Formula (Ia'), Formula (lb), Formula
(Ic), Formula (Id),
Table 1, or a pharmaceutically acceptable salt thereof, is hydrolyzed to an
active pharmaceutical
agent (e.g., a free form of a radical of Formula (I), Formula (I-A), Formula
(Ia), Formula (Ia'),
Formula (lb), Formula (Ic), Formula (Id), or Table 1, such as wherein R is a
negative charge or
H) and a keratolytic agent. In some embodiments, the compound or
pharmaceutical composition
is hydrolyzed to an active pharmaceutical agent and a keratolytic agent in an
ocular space. In some
embodiments, the compound or pharmaceutical composition is hydrolyzed to an
active
pharmaceutical agent and a keratolytic agent by an esterase in an ocular
space. In some
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embodiments, the active pharmaceutical agent is an anti-bacterial agent. In
some embodiments
the anti-bacterial agent is azithromycin. In some embodiments, the keratolytic
agent is a
carboxylic acid. In some embodiments, the carboxylic acid is selected from the
group consisting
of acetic acid, glycolic acid, lactic acid, lipoic acid, pivalic acid,
isobutryic acid, butyric acid,
propionic acid, formic acid, and carbonic acid. In some embodiments, the
active keratolytic agent
is a thiol.
102651 In some embodiments, a compound or a pharmaceutical composition
comprising any
compound provided herein, such as a compound of any one of Formula (I),
Formula (I-A),
Formula (Ia), Formula (Ia'), Formula (lb), Formula (Ic), Formula (Id), Table
1, or a
pharmaceutically acceptable salt thereof. In certain embodiments, the
composition further
comprises an amount of a free form of a radical of any of Formula (I), Formula
(I-A), Formula
(Ia), Formula (Ia'), Formula (lb), Formula (Ic), Formula (Id), Table 1, or the
like (such as wherein
the free form is the radical, wherein R is a negative charge or an H). In some
embodiments, a
composition provided herein comprises a (e.g., weight or molar) ratio of a
compound provided
herein to a free form of a radical of Formula (I), Formula (I-A), Formula
(Ia), Formula (Ia'),
Formula (lb), Formula (Ic), Formula (Id), Table 1, or a pharmaceutically
acceptable salt thereof
(e.g., wherein R is a negative charge or an H) is about 1:99 to about 100:0
(e.g., the amount of the
free form of the radical relative to the overall amount of free form of the
radical plus the conjugate
is between 0% (weight or molar) and 99%). In some embodiments, the relative
amount of the free
form of the radical is 0% to about 50%, such 0% to about 20%, 0% to about 10%,
about 0.1% to
about 10%, about 0.1 % to about 5%, less than 5%, less than 2.5%, less than
2%, or the like
(percentages being weight/weight or mole/mole percentages). In some instances,
such aqueous
compositions are pre-manufactured or are manufactured at the time of
application in order to
maintain high concentrations of the compound relative to the free form of a
radical thereof In
some embodiments, such concentrations of the compound are present in the
composition for at
least 45 minutes in an aqueous composition (such as in an aqueous composition,
e.g., a HEPES
buffer, such as under the conditions described herein, such as in Table 2).
Table 2 of the Examples
illustrate good stability of the compositions provided herein and such
recitations are incorporated
in the disclosure hereof. Further, in some instances, compounds provided
herein release free form
of a radical of a compound of Formula (I), Formula (I-A), Formula (Ia),
Formula (Ia'), Formula
(lb), Formula (Ic), Formula (Id), or Table 1, (e.g., wherein R is a negative
charge or H), such as
when administered to an individual (e.g., ocular (e.g., pert-ocular) or
dermatological
administration). In more specific instances, when administered to an
individual at a location with
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esterases and/or reductases present, rapid release of active (free) forms of a
radical of Formula (I),
Formula (I-A), Formula (Ia), Formula (Ia'), Formula (lb), Formula (Ic),
Formula (Id), or Table 1,
(e.g., wherein R is a negative charge or H) (and, a keratolytic agent and/or
agent that further
produces active keratolytic agent(s) (e.g., by further hydrolysis and/or
reduction thereof)).
102661 In some embodiments, provided herein a compound or a pharmaceutical
composition
comprising any compound provided herein, such as a compound of any one of
Formula (I),
Formula (I-A), Formula (Ia), Formula (Ia'), Formula (lb), Formula (Ic),
Formula (Id), Table 1, or
a pharmaceutically acceptable salt thereof, has keratolytic effects (e g ,
reduces disulfide (S-S)
bonds) (e.g., in any environment provided herein).
102671 Provided in some embodiments herein is a method of treating
inflammation and/or
hyperkeratosis, the method comprising administering to an individual (e.g., in
need thereof) any
compound provided herein (e.g., of any Formula or Table provided herein)
(e.g., in a
therapeutically effective amount). In specific embodiments, the inflammation
and/or
hyperkeratosis is inflammation and/or hyperkeratosis of the eye, periocular
structures (e.g.,
eyelid), and/or skin.
102681 Provided in some embodiments herein is a method of treating a dermal or
an ocular disease
or disorder in an individual, comprising administering to the individual in
need thereof a
composition comprising any compound provided herein, such as a compound
represented by any
one of Formula (I), Formula (I-A), Formula (Ia), Formula (Ia'), Formula (Ib),
Formula (Ic),
Formula (Id), Table 1, or a pharmaceutically acceptable salt thereof. In some
embodiments, the
dermal or the ocular disease or disorder is associated with keratosis,
microbial infiltration,
microbial infection, inflammation, or any combination thereof.
102691 Provided in some embodiments herein is a method of treating a
dermatological or an
ophthalmic disease or disorder in an individual in need of thereof, comprising
administering to
the individual in need thereof a composition comprising any compound provided
herein, such as
a compound represented by any one of Formula (I), Formula (I-A), Formula (Ia),
Formula (Ia'),
Formula (lb), Formula (Ic), Formula (Id), Table 1, or a pharmaceutically
acceptable salt thereof
In some embodiments, the dermatological or ophthalmic disease or disorder is
inflammation or
hyperkeratosis of the eyes or skin (e.g., the ocular surface). In some
embodiments, the
dermatological or ophthalmic dermatological disease or disorder is selected
from the group
consisting of meibomian gland dysfunction (MGD), dry eye disease (DED), ocular
manifestations
of graft versus host disease, vernal keratoconjunctivitis, atopic
keratoconjunctivitis, Cornelia de
Lange Syndrome, evaporative eye disease, aqueous deficiency dry eye,
blepharitis, and seborrheic
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blepharitis. In some embodiments, the dermatological or ophthalmic disease or
disorder is
inflammation or hyperkeratosis (e.g., of the eyes or skin), such as, for
example, meibomian gland
dysfunction (MGD), dry eye disease (DED), ocular manifestations of graft
versus host disease,
vernal keratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de Lange
Syndrome, evaporative
eye disease, aqueous deficiency dry eye, blepharitis, seborrheic blepharitis,
or any combination
thereof.
102701 In some embodiments, the ophthalmic disease or disorder is selected
from dry eye, lid
wiper epitheliopathy (LWE), contact lens discomfort (CLD), contact lens
discomfort, dry eye
syndrome, evaporative dry eye syndrome, aqueous deficiency dry eye syndrome,
blepharitis,
keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland
disorder, inflammation of
the anterior surface of the eye, infection of the anterior surface of the eye,
infection of the lid,
demodex lid infestation, lid wiper epitheliopathy and autoimmune disorder of
the anterior surface
of the eye.
102711 In some embodiments, provided herein is a method of treating an ocular
(e.g., pen-ocular)
or dermatological indication (e.g., associated with keratolytic activity,
inflammation, and/or
microbial infiltration), the method comprising administering a therapeutically
effective amount of
a compound or composition provided herein. In some embodiments, a composition
provided
herein (e.g., used in a method provided herein) comprises a compound provided
herein in a
therapeutically effective amount (e.g., at a concentration effective to treat
keratosis/keratolytic
activity, inflammation, and/or microbial infiltration), in the eye,
surrounding tissue, or skin. In
some embodiments, a (e.g., pharmaceutical and/or ophthalmic) composition
provided herein
comprises about 0.1 wt. % to about 10 wt % of a compound provided herein.
102721 In some embodiments, ocular and/or dermatological disorders include,
for example,
inflammatory conditions of the eyelids (e.g., hordeolum (stye), blepharitis,
and chalazion), ocular
surface (e.g., dry eye disease and anterior uveitis) and posterior eye (e.g.,
posterior and pan-
uveitis), abnormalities of the pen-ocular glands (e.g., meibomian gland
dysfunction (MGD)),
allergic-type conditions, (e.g., eczema, atopic dermatitis, atopic
keratoconjunctivitis refractory to
topical steroid treatment, and vernal keratoconjunctivitis), surgical
complications (e.g., corneal
transplant rejection, post-corneal transplant glaucoma, cataracts secondary to
phakic corneal
transplant, fungal infections in keratoplasty patients, and post-LASIK dry eye
and/or poor
refractive outcomes), corneal abnormalities (e.g., inflammatory corneal
ulceration, rheumatoid
corneal ulcers, and Thygeson's superficial punctate keratitis), conjunctival
abnormalities (e.g.,
iridocyclitis, ligneous conjunctivitis), ocular complications from systemic
treatments and/or
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autoimmune diseases (e.g., pauciarticular juvenile rheumatoid arthritis, graft
versus host disease,
and sjogren's syndrome) and/or infectious disease of the anterior surface of
the eye. In some
embodiments, provided herein are compositions and methods for the treatment of
ocular and
peri ocular abnormalities that have multifactorial etiologies and
interactions.
INCORPORATION BY REFERENCE
102731 All publications, patents, and patent applications mentioned in this
specification are herein
incorporated by reference for the specific purpose identified herein.
DETAILED DESCRIPTION
Certain Definitions
102741 As used herein and in the appended claims, the singular forms "a,"
"and," and "the" include
plural referents unless the context clearly dictates otherwise. Thus, for
example, reference to "an
agent" includes a plurality of such agents, and reference to the cell"
includes reference to one or
more cells (or to a plurality of cells) and equivalents thereof, and so forth.
When ranges are used
herein for physical properties, such as molecular weight, or chemical
properties, such as chemical
formulae, all combinations and subcombinations of ranges and specific
embodiments therein are
intended to be included. The term "about" when referring to a number or a
numerical range means
that the number or numerical range referred to is an approximation within
experimental variability
(or within statistical experimental error), and thus the number or numerical
range may vary
between 1% and 15% of the stated number or numerical range. The term
"comprising" (and related
terms such as "comprise" or "comprises" or "having" or "including") is not
intended to exclude
that in other certain embodiments, for example, an embodiment of any
composition of matter,
composition, method, or process, or the like, described herein, may "consist
of" or "consist
essentially of' the described features.
102751 The terms "treat," "treating," or "treatment" as used herein, include
reducing, alleviating,
abating, ameliorating, relieving, or lessening the symptoms associated with a
disease, disease sate,
or indication (e.g., addiction, such as opioid addiction, or pain) in either a
chronic or acute
therapeutic scenario. Also, treatment of a disease or disease state described
herein includes the
disclosure of use of such compound or composition for the treatment of such
disease, disease state,
or indication.
102761 "Amino" refers to the ¨NH2 radical.
102771 "Cyano" refers to the -CN radical.
102781 "Nitro" refers to the -NO2 radical.
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102791 "Oxo" refers to the =0 radical.
102801 "Alkyl" generally refers to a straight or branched hydrocarbon chain
radical consisting
solely of carbon and hydrogen atoms, such as having from one to fifteen carbon
atoms (e.g., Ci-
C15 alkyl). Unless otherwise state, alkyl is saturated or unsaturated (e.g.,
an alkenyl, which
comprises at least one carbon-carbon double bond). Disclosures provided herein
of an "alkyl" are
intended to include independent recitations of a saturated "alkyl," unless
otherwise stated. Alkyl
groups described herein are generally monovalent, but may also be divalent
(which may also be
described herein as "alkylene" or "alkylenyl" groups) In certain embodiments,
an alkyl
comprises one to thirteen carbon atoms (e.g., Ci-C13 alkyl). In certain
embodiments, an alkyl
comprises one to eight carbon atoms (e.g., Ci-C8 alkyl). In other embodiments,
an alkyl comprises
one to five carbon atoms (e.g., C1-05 alkyl). In other embodiments, an alkyl
comprises one to four
carbon atoms (e.g., CI-CI alkyl). In other embodiments, an alkyl comprises one
to three carbon
atoms (e.g., Ci-C3 alkyl). In other embodiments, an alkyl comprises one to two
carbon atoms (e.g.,
Cl-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g.,
Ci alkyl). In other
embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15
alkyl). In other
embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8
alkyl). In other
embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-05 alkyl).
In other
embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-05
alkyl). In other
embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-
propyl), 1-methylethyl
(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl
(iso-butyl),
1,1-di m ethyl ethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached
to the rest of the molecule
by a single bond. In general, alkyl groups are each independently substituted
or unsubstituted.
Each recitation of "alkyl" provided herein, unless otherwise stated, includes
a specific and explicit
recitation of an unsaturated "alkyl" group. Similarly, unless stated otherwise
specifically in the
specification, an alkyl group is optionally substituted by one or more of the
following substituents:
halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -0Ra,
-0C(0)-Ra, -N(Ra)2, -
C (0)Ra, -C (0)0Ra, - C (0)N(Ra)2, -N(Ra) C (0)0Ra, - OC (0)-N(Ra)2, -N(R') C
(0)Ra, -
N(Ra)S (0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2), -S(0)tRa
(where t is 1 or 2) and -
S(0)tN(Ra)2 (where t is 1 or 2) where each IV is independently hydrogen, alkyl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl,
carbocyclyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl
(optionally substituted
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with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally
substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally
substituted with halogen,
hydroxy, methoxy, or trifluoromethyl).
102811 "Alkoxy" refers to a radical bonded through an oxygen atom of the
formula ¨0-alkyl,
where alkyl is an alkyl chain as defined above.
102821 "Alkenyl" refers to a straight or branched hydrocarbon chain radical
group consisting
solely of carbon and hydrogen atoms, containing at least one carbon-carbon
double bond, and
having from two to twelve carbon atoms. In certain embodiments, an alkenyl
comprises two to
eight carbon atoms. In other embodiments, an alkenyl comprises two to four
carbon atoms. The
alkenyl is optionally substituted as described for "alkyl- groups.
102831 "Alkylene- or "alkylene chain- generally refers to a straight or
branched divalent alkyl
group linking the rest of the molecule to a radical group, such as having from
one to twelve carbon
atoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene,
and the like. Unless
stated otherwise specifically in the specification, an alkylene chain is
optionally substituted as
described for alkyl groups herein.
102841 "Aryl" refers to a radical derived from an aromatic monocyclic or
multicyclic hydrocarbon
ring system by removing a hydrogen atom from a ring carbon atom. The aromatic
monocyclic or
multicyclic hydrocarbon ring system can contain hydrogen and carbon from five
to eighteen
carbon atoms, where at least one of the rings in the ring system is fully
unsaturated, i.e., it contains
a cyclic, delocalized (4n+2) 7c¨electron system in accordance with the Mickel
theory. The ring
system from which aryl groups are derived include, but are not limited to,
groups such as benzene,
fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise
specifically in the
specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is
meant to include aryl
radicals optionally substituted by one or more substituents independently
selected from alkyl,
alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted
aryl, optionally substituted
aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted
carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl,
optionally substituted heterocyclyl alkyl, optionally substituted heteroaryl,
optionally substituted
heteroaryl alkyl, -R'-OR', -Rb-OC(0)-Ra, -Rb-OC(0)-0Ra, -Rb-OC(0)-N(Ra)2, -R
b_N(Ra)27 _Rb_
C(0)Ra, -Rb-C (0)0Ra, -Rb-C(0)N(Ra)2, -Rb-O-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -
Rb-
N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1
or 2), -Rb-S(0)tORa
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(where t is 1 or 2) and -Rb-S(0)tN(R1)2 (where t is 1 or 2), where each Ra is
independently
hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy,
methoxy, or
trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,
hydroxy, methoxy, or
trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl),
aralkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), h eterocyclyl
(optionally substituted with halogen, hydroxy, m ethoxy, or trifluorom ethyl),
heterocycl yl al kyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
or heteroarylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
each Rb is
independently a direct bond or a straight or branched alkylene or alkenylene
chain, and Re is a
straight or branched alkylene or alkenylene chain, and where each of the above
substituents is
unsubstituted unless otherwise indicated.
102851 "Aralkyl" or "aryl-alkyl" refers to a radical of the formula -Re-aryl
where Re is an alkylene
chain as defined above, for example, methylene, ethylene, and the like. The
alkylene chain part
of the aralkyl radical is optionally substituted as described above for an
alkylene chain. The aryl
part of the aralkyl radical is optionally substituted as described above for
an aryl group.
102861 "Carbocycly1" or "cycloalkyl" refers to a stable non-aromatic
monocyclic or polycyclic
hydrocarbon radical consisting solely of carbon and hydrogen atoms, which
includes fused or
bridged ring systems, having from three to fifteen carbon atoms. In certain
embodiments, a
carbocyclyl comprises three to ten carbon atoms. In other embodiments, a
carbocyclyl comprises
five to seven carbon atoms. The carbocyclyl is attached to the rest of the
molecule by a single
bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C
bonds, no double or triple
bonds between two carbons) or unsaturated (i.e., containing one or more double
bonds or triple
bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also
referred to as
"cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g.,
cyclopentenyl,
cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals
include, for
example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,
decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated
specifically in the
specification, the term "carbocyclyl" is meant to include carbocyclyl radicals
that are optionally
substituted by one or more substituents independently selected from alkyl,
alkenyl, alkynyl, halo,
fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,
optionally substituted aralkyl,
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optionally substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted
carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted
heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-10, -Rb-OC(0)-010, -Rb-OC(0)-N(Ra)2, -
Rb_N(Ra)2, _Rb _
C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-O-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -
Rb-
N(Ra)C (0)Ra, -Rb -N(R S (0)tRa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1
or 2), -Rb-S(0)tORa
(where t is 1 or 2) and -R'-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is
independently
hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy,
methoxy, or
trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,
hydroxy, methoxy, or
trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluorom ethyl),
aralkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), heterocyclyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
or heteroarylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
each Rb is
independently a direct bond or a straight or branched alkylene or alkenylene
chain, and R. is a
straight or branched alkylene or alkenylene chain, and where each of the above
substituents is
unsubstituted unless otherwise indicated.
102871 -Carboxylic acid," -COOH," or -(C=0)0H" refers to a radical of the
formula ¨COOH.
Each recitation of "carboxylic acid," "COOH," or "(C=0)0H" provided herein,
unless otherwise
stated, includes a specific and explicit recitation of an esterified
"carboxylic acid," "COOH," or
"(C=0)0H" group (e.g., or radical thereof). In some embodiments, the
esterified carboxylic acid
group (or radical thereof) is (C=0)0-Ci-C4alkyl, wherein alkyl is as defined
hereinabove. In some
embodiments, "carboxylic acid," "COOH," or "(C=0)0H" is COOH. In some
embodiments,
"carboxylic acid,- -COOH,- or "(C=0)0H- is (C=0)0-Ci-C4alkyl.
102881 "Carbocyclylalkyl" refers to a radical of the formula ¨Rc-carbocycly1
where RC is an
alkylene chain as defined above. The alkylene chain and the carbocyclyl
radical is optionally
substituted as defined above.
102891 "Carbocyclylalkenyl" refers to a radical of the formula ¨Rc-carbocycly1
where RC is an
alkenylene chain as defined above. The alkenylene chain and the carbocyclyl
radical is optionally
substituted as defined above.
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102901 "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom
of the formula ¨
0-Rc-carbocyclyl where RC is an alkylene chain as defined above. The alkylene
chain and the
carbocyclyl radical is optionally substituted as defined above.
102911 -Halo" or -halogen" refers to fluoro, bromo, chloro, or iodo
substituents.
102921 "Haloalkyl" refers to an alkyl radical, as defined above, that is
substituted by one or more
halogen radicals, as defined above, for example, trihalomethyl, dihalomethyl,
halomethyl, and the
like. In some embodiments, the haloalkyl is a fluoroalkyl, such as, for
example, trifluoromethyl,
diflu orom ethyl, flu orom ethyl, 2,2,2-trifluoroethyl, 1-flu orom ethy1-2-flu
oroethyl, and the like. In
some embodiments, the alkyl part of the fluoroalkyl radical is optionally
substituted as defined
above for an alkyl group.
102931 The term "heteroalkyl" refers to an alkyl group as defined above in
which one or more
skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the
appropriate number
of substituents or valencies ¨ for example, -CH2- may be replaced with -NH- or
-0-). For example,
each substituted carbon atom is independently substituted with a heteroatom,
such as wherein the
carbon is substituted with a nitrogen, oxygen, sulfur, or other suitable
heteroatom. In some
instances, each substituted carbon atom is independently substituted for an
oxygen, nitrogen (e.g.
-NH-, -N(alkyl)-, or -N(ary1)- or having another substituent contemplated
herein), or sulfur (e.g. -
S-, -S(=0)-, or -S(=0)2-). In some embodiments, a heteroalkyl is attached to
the rest of the
molecule at a carbon atom of the heteroalkyl. In some embodiments, a
heteroalkyl is attached to
the rest of the molecule at a heteroatom of the heteroalkyl. In some
embodiments, a heteroalkyl is
a C1-C18 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12
heteroalkyl. In some
embodiments, a heteroalkyl is a CI-C6 heteroalkyl. In some embodiments, a
heteroalkyl is a CI-
C4 heteroalkyl. Representative heteroalkyl groups include, but are not limited
to -OCH20Me, or -
CH2CH20Me. In some embodiments, heteroalkyl includes alkoxy, alkoxyalkyl,
alkylamino,
alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and
heterocycloalkylalkyl, as
defined herein. Unless stated otherwise specifically in the specification, a
heteroalkyl group is
optionally substituted as defined above for an alkyl group.
102941 "Heteroalkylene" refers to a divalent heteroalkyl group defined above
which links one part
of the molecule to another part of the molecule. Unless stated specifically
otherwise, a
heteroalkylene is optionally substituted, as defined above for an alkyl group.
102951 "Heterocycly1" refers to a stable 3- to 18-membered non-aromatic ring
radical that
comprises two to twelve carbon atoms and from one to six heteroatoms selected
from nitrogen,
oxygen and sulfur. Unless stated otherwise specifically in the specification,
"heterocycly1" and
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"heterocycloalkyl" are used interchangeably herein. Unless stated otherwise
specifically in the
specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic
or tetracyclic ring
system, which optionally includes fused or bridged ring systems. The
heteroatoms in the
heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if
present, are optionally
quaternized. The heterocyclyl radical is partially or fully saturated. The
heterocyclyl radical is
saturated (i.e., containing single C-C bonds only) or unsaturated (e.g.,
containing one or more
double bonds or triple bonds in the ring system). In some instances, the
heterocyclyl radical is
saturated (e g , dithiolanyl or dithiolanyl oxide) In some instances, the
heterocyclyl radical is
saturated and substituted (e.g., dithiolanyl oxide). In some instances, the
heterocyclyl radical is
unsaturated. The heterocyclyl is attached to the rest of the molecule through
any atom of the
ring(s). Examples of such heterocyclyl radicals include, but are not limited
to, dithiolanyl,
dioxolanyl, thienyl [1,3 ]dithianyl,
decahydroisoquinolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,
piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
tetrahydrofuryl, trithianyl,
tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the
specification, the term
"heterocyclyl" is meant to include heterocyclyl radicals as defined above that
are optionally
substituted by one or more substituents selected from alkyl, alkenyl, alkynyl,
halo, fluoroalkyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally
substituted aral kenyl optionally substituted aral kynyl optionally
substituted carb ocy cl yl
optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl,
optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, -R"-
oRa, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2 _Rb_N(Ra)2 7 _Rb _ (
0 ) Ra b_
C (0)0Ra,
-Rb-C (0)N(Ra)2, -Rb C (0)N(Ra)2, -Rb-N(Ra)C (0)0Ra,
-Rb -N(Ra) C (0)Ra, -Rb-
N(Ra)S (0)tRa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2), -Rb-
S(0)tOlta (where t is 1 or 2)
and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently
hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl,
cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally
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substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each RI" is
independently a direct
bond or a straight or branched alkylene or alkenylene chain, and W is a
straight or branched
alkylene or alkenylene chain, and where each of the above substituents is
unsubstituted unless
otherwise indicated.
[0296] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl
radical as defined
above containing at least one nitrogen and where the point of attachment of
the heterocyclyl
radical to the rest of the molecule is through a nitrogen atom in the
heterocyclyl radical. An
N-heterocyclyl radical is optionally substituted as described above for
heterocyclyl radicals.
Examples of such AT-heterocyclyl radicals include, but are not limited to, 1-
morpholinyl, 1-
piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and
imidazolidinyl.
[0297] "C-heterocyclyl- or "C-attached heterocyclyl" refers to a heterocyclyl
radical as defined
above containing at least one heteroatom and where the point of attachment of
the heterocyclyl
radical to the rest of the molecule is through a carbon atom in the
heterocyclyl radical. A
C-heterocyclyl radical is optionally substituted as described above for
heterocyclyl radicals.
Examples of such C-heterocyclyl radicals include, but are not limited to, 2-
morpholinyl, 2- or 3-
or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
[0298] "Heterocyclylalkyl" refers to a radical of the formula ¨W-heterocycly1
where R' is an
alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing
heterocyclyl, the
heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
The alkylene chain of
the heterocyclylalkyl radical is optionally substituted as defined above for
an alkylene chain. The
heterocyclyl part of the heterocyclylalkyl radical is optionally substituted
as defined above for a
heterocyclyl group.
[0299] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom
of the formula ¨
0-W-heterocyclyl where RC is an alkylene chain as defined above. If the
heterocyclyl is a
nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to
the alkyl radical at the
nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is
optionally substituted as
defined above for an alkylene chain. The heterocyclyl part of the
heterocyclylalkoxy radical is
optionally substituted as defined above for a heterocyclyl group.
[0300] "Heteroaryl" refers to a radical derived from a 3- to 18-membered
aromatic ring radical
that comprises two to seventeen carbon atoms and from one to six heteroatoms
selected from
nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a
monocyclic, bicyclic,
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tricyclic or tetracyclic ring system, wherein at least one of the rings in the
ring system is fully
unsaturated, i.e., it contains a cyclic, delocalized (4n+2) 7c¨electron system
in accordance with the
Htickel theory. Heteroaryl includes fused or bridged ring systems. The
heteroatom(s) in the
heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if
present, are optionally
quaternized. The heteroaryl is attached to the rest of the molecule through
any atom of the ring(s).
Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl,
benzindolyl, 1,3 -benzodioxolyl, b enzofuranyl,
benzooxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-
benzodioxanyl,
benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,
benzopyranonyl, benzofuranyl, benzofuranonyl,
benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-
a]pyridinyl, carbazolyl,
cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-
d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-
benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl,
furanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,1 0-hexahydrocycl oocta[d]pyri dazinyl ,
5,6,7, 8,9, 1 0-hexahydrocycl oocta[d]pyri di nyl ,
isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl,
indolinyl,
isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-
tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl,
5,6,6a,7,8,9, 1 0, 1 0a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-
pyrrolyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl,
pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-
d]pyrimidinyl,
pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,
quinolinyl,
isoquinolinyl, tetrahydroquinolinyl,
5,6,7, 8-tetrahy droquinazolinyl,
5,6,7, 8-tetrahydrob enzo[4, 5 ]thieno[2,3 -d]pyrimidinyl,
6,7,8,9-tetrahy dro-5H-cy cl ohepta [4,5 ]thi eno [2,3 -d] pyrimi dinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and
thiophenyl (i.e.
thienyl). Unless stated otherwise specifically in the specification, the term
"heteroaryl" is meant
to include heteroaryl radicals as defined above which are optionally
substituted by one or more
substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,
haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally substituted
aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted carbocyclyl,
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optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl,
optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl,
-R"-OC(0)-R, -R"-OC(0)-OW', -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-
C(0)0Ra,
-Rb-C(0)N(Ra)2, -Rb-O-W-C(0)N(Ra )2 , -Rb-N(Ra)C (0)0Ra, -Rb -N(Ra) C
(0)Ra, -Rb-
N(Ra)S (0)tRa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2), -Rb-
S(0)tORa (where t is 1 or 2)
and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently
hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroal kyl ,
cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), h eterocy cl
yl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is
independently a direct
bond or a straight or branched alkylene or alkenylene chain, and RC is a
straight or branched
alkylene or alkenylene chain, and where each of the above substituents is
unsubstituted unless
otherwise indicated.
[0301] "N-heteroaryl" refers to a heteroaryl radical as defined above
containing at least one
nitrogen and where the point of attachment of the heteroaryl radical to the
rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is
optionally substituted
as described above for heteroaryl radicals
103021 "C-heteroaryl" refers to a heteroaryl radical as defined above and
where the point of
attachment of the heteroaryl radical to the rest of the molecule is through a
carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally substituted as
described above for
heteroaryl radicals.
[0303] "Heteroarylalkyl" refers to a radical of the formula ¨Rc-heteroaryl,
where RC is an alkylene
chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl,
the heteroaryl is
optionally attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the
heteroarylalkyl radical is optionally substituted as defined above for an
alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally substituted as
defined above for a
heteroaryl group.
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103041 "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of
the formula ¨0-
Rc-heteroaryl, where RC is an alkylene chain as defined above. If the
heteroaryl is a
nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the
alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is
optionally substituted as
defined above for an alkylene chain. The heteroaryl part of the
heteroarylalkoxy radical is
optionally substituted as defined above for a heteroaryl group.
103051 The compounds disclosed herein, in some embodiments, contain one or
more asymmetric
centers and thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that are
defined, in terms of absolute stereochemistry, as (R)- or (5)-. Unless stated
otherwise, it is intended
that all stereoisomeric forms of the compounds disclosed herein are
contemplated by this
disclosure. When the compounds described herein contain alkene double bonds,
and unless
specified otherwise, it is intended that this disclosure includes both E and Z
geometric isomers
(e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic
and optically pure
forms, and all tautomeric forms are also intended to be included. The term
"geometric isomer"
refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double
bond. The term
"positional isomer" refers to structural isomers around a central ring, such
as ortho-, meta-, and
para- isomers around a benzene ring.
103061 In general, optionally substituted groups are each independently
substituted or
unsubstituted. Each recitation of an optionally substituted group provided
herein, unless otherwise
stated, includes an independent and explicit recitation of both an
unsubstituted group and a
substituted group (e.g., substituted in certain embodiments, and unsubstituted
in certain other
embodiments). Unless otherwise stated, substituted groups may be substituted
by one or more of
the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, -0Ra, -
SRa, -0C(0)-R, -N(Ra)2, -C(0)Ra, -C(0)0Ra, -C(0)N(Ra)2, -N(Ra)C(0)0Ra, -0C(0)-
N(Ra)2, -
N(Ra)C(0)Ra, -N(Ra)S(0)1Ra (where t is 1 or 2), -S(0)10R0 (where t is 1 or 2),
-S(0)1R0 (where t
is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently
hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl,
carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aryl
(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl
(optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl
(optionally
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substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
103071 "Pharmaceutically acceptable salt" includes both acid and base addition
salts. A
pharmaceutically acceptable salt of any one of the pharmacological agents
described herein is
intended to encompass any and all pharmaceutically suitable salt forms.
Exemplary
pharmaceutically acceptable salts of the compounds described herein are
pharmaceutically
acceptable acid addition salts and pharmaceutically acceptable base addition
salts.
103081 "Pharmaceutically acceptable acid addition salt" refers to those salts
which retain the
biological effectiveness and properties of the free bases, which are not
biologically or otherwise
undesirable, and which are formed with inorganic acids such as hydrochloric
acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,
hydrofluoric acid, phosphorous
acid, and the like. Also included are salts that are formed with organic acids
such as aliphatic
mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy
alkanoic acids, alkanedioic
acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and
include, for example, acetic acid,
trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, maleic acid, malonic
acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the
like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates,
sulfites, bisulfites, nitrates,
phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates,
pyrophosphates,
chlorides, bromides, iodides, acetates, trifluoroacetates, propionates,
caprylates, isobutyrates, oxalates,
m al on ates, succi n ate sub erates, sebacates, fumarates, m al eates, m an
del ate s, b en zoates,
chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates,
benzenesulfonates,
toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like.
Also contemplated are salts of amino acids, such as arginates, gluconates, and
galacturonates (see, for
example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical
Science, 66:1-19
(1997)). Acid addition salts of basic compounds are, in some embodiments,
prepared by contacting the
free base forms with a sufficient amount of the desired acid to produce the
salt according to methods and
techniques with which a skilled artisan is familiar.
103091 "Pharmaceutically acceptable base addition salt- refers to those salts
that retain the
biological effectiveness and properties of the free acids, which are not
biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic base or an
organic base to the
free acid. Pharmaceutically acceptable base addition salts are, in some
embodiments, formed with
metals or amines, such as alkali and alkaline earth metals or organic amines.
Salts derived from
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inorganic bases include, but are not limited to, sodium, potassium, lithium,
ammonium, calcium,
magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts
derived from
organic bases include, but are not limited to, salts of primary, secondary,
and tertiary amines,
substituted amines including naturally occurring substituted amines, cyclic
amines and basic ion
exchange resins, for example, isopropylamine, trimethylamine, diethylamine,
triethylamine,
tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-
diethylaminoethanol,
di cycl oh exyl amine, 1 y si ne, arginine, hi sti dine, caffeine, procaine,
N,N-dib enzyl ethyl en edi am i n e,
chloroprocaine, hydrabamine, choline, betaine, ethylenedi amine, ethylenedi
aniline, N-
methylglucamine, glucosamine, methylglucamine, theobromine, purines,
piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.
Compositions
103101 The meibomian glands are large sebaceous glands located in the eyelids,
and unlike skin,
are unassociated with hair. The meibomian glands produce the lipid layer of
the tear film that
protects it against evaporation of the aqueous phase. The meibomian gland
orifice is located on
the epithelial side of the lid margin, and can be a few hundred microns from
the mucosal side. The
glands are located on both upper and lower eyelids, with higher amounts of the
glands on the
upper eyelid. A single meibomian gland is composed of clusters of secretory
acini that are
arranged circularly around a long central duct and connected to it by short
ductules. The terminal
part of the central duct is lined by an ingrowth of the epidermis that covers
the free lid margin and
forms a short excretory duct that opens as an orifice at the posterior part of
the lid margin just
anterior to the mucocutaneous junction near the inner lid border. The oily
secretion composed of
lipids is synthesized within the secretory acini. The lipid secretion is a
liquid at near body
temperature and is delivered to the skin of the lid margin as a clear fluid,
called "meibum." It
forms shallow reservoirs on the upper and lower lid margins, and consists of a
complex mixture
of cholesterol, wax, cholesteryl esters, phospholipids, with small amounts of
triglycerides,
triacylglycerols, and hydrocarbons. The separate meibomian glands are arranged
in parallel, and
in a single row throughout the length of the tarsal plates in the upper and
lower lids. The extent of
the glands corresponds roughly to the dimensions of the tarsal plates.
103111 The term "keratinized obstruction- as used herein refers to a blockage
of the meibomian
gland, regardless of the location of the blockage. In some embodiments, the
blockage is complete,
whereas in other embodiments, the blockage is partial. Regardless of the
degree of blockage, such
keratinized obstruction leads to meibomian gland dysfunction. In some
embodiments, the
keratinized obstruction is composed of keratinized material and lipids. In
some embodiments, the
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keratinized obstruction is a blockage at the meibomian gland orifice and
excretory duct. In some
embodiments, the keratinized obstruction is caused by keratinization of the
epithelium at the lid
margin and meibomian gland. In certain instances, the keratin obstruction is
influenced by the
migration or aberrant differentiation of stem cells. In some embodiments, the
keratinized
obstruction results in reduced delivery of oil to the lid margin and tear
film, and stasis inside the
meibomian gland that causes increased pressure, resultant dilation, acinar
atrophy, and low
secretion. In certain instances, keratinization of the meibomian gland causes
degenerative gland
dilation and atrophy.
[0312] Ocular surface diseases is a group of diseases including, but not
limited to, dry eye
syndrome (including evaporative DES and/or aqueous deficiency DES),
blepharitis, keratitis,
meibomian gland dysfunction, conjunctivitis, lacrimal gland disorder, contact
lens related
conditions and inflammatory, infectious, or autoimmune diseases or disorders
of the anterior
surface of the eye. The term, "meibomian gland dysfunction,- as used herein,
refers to chronic,
diffuse abnormality of the meibomian glands, that is characterized by terminal
duct obstruction or
qualitative or quantitative changes in the glandular secretion, or both. MGD
may result in
alteration of the tear film, eye irritation symptoms, inflammation, or ocular
surface disease. The
most prominent aspects of MGD are obstruction of the meibomian gland orifices
and terminal
ducts and changes in the meibomian gland secretions.
[0313] In some instances, meibomian gland dysfunction (MGD) is a chronic,
diffuse abnormality
of the meibomian glands, which can be characterized by terminal duct
obstruction and/or
qualitative/quantitative changes in the glandular secretion. Terminal duct
obstruction is caused
by hyperkeratinization of the ductal epithelium (Nichols et al, Inv. Oph. &
Vis. Sci (2011);
52(4):1922-1929). These alterations in both meibum quality and expression may
result in
alteration of the tear film, symptoms of eye irritation, and ocular surface
disease such as
evaporative dry eye. The principal clinical consequence of MGD is evaporative
dry eye syndrome
and large population based studies (i.e., Bankok Study and the Shihpai Eye
Study) estimate that
over 60% of patients with dry eye symptoms also have MGD (Schaumberg et al,
Investigative
Ophthalmology and Visual Science. (2011); 52(4):1994-2005).
[0314] MGD is a leading contributor of dry eye syndrome. The occurrence of dry
eye syndrome
is widespread and affects about 20 million patients in the United States
alone. Dry eye syndrome
is a disorder of the ocular surface resulting from either inadequate tear
production or excessive
evaporation of moisture from the surface of the eye. Tears are important to
corneal health because
the cornea does not contain blood vessels, and relies on tears to supply
oxygen and nutrients. Tears
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and the tear film are composed of lipids, water, and mucus, and disruption of
any of these can
cause dry eye. An inadequate amount of lipids flowing from the meibomian
glands as caused by
a keratinized obstruction, may cause excessive evaporation, thereby causing
dry eye syndrome.
103151 In some embodiments, altered meibomian gland secretion is detected by
physically
expressing the meibomian glands by applying digital pressure to the tarsal
plates. In subjects
without MGD, the meibum is a pool of clear oil. In MGD, both the quality and
expressibility of
the expressed material is altered. The altered meibum is also known as
meibomian excreta and is
made up of a mixture of altered secretions and keratinized epithelial material
In MGD, the quality
of expressed lipid varies in appearance from a clear fluid, to a viscous fluid
containing particulate
matter and densely opaque, toothpaste-like material. The meibomian orifices
may exhibit
elevations above surface level of the lid, which is referred to as plugging or
pouting, and is due to
obstruction of the terminal ducts and extrusion of a mixture of meibomian
lipid and keratinized
material.
103161 Obstructive MGD is characterized by all or some of the following: 1)
chronic ocular
discomfort, 2) anatomic abnormalities around the meibomian gland orifice
(which is one or more
of the following: vascular engorgement, anterior or posterior displacement of
the mucocutaneous
junction, irregularity of the lid margin) and 3) obstruction of the meibomian
glands (obstructive
findings of the gland orifices by slit lamp biomicroscopy (pouting, plugging
or ridge), decreased
meibum expression by moderate digital pressure).
103171 Current methods for assessing and monitoring MGD symptoms include, but
are not limited
to patient questionnaires, meibomian gland expression, tear stability break up
time, and
determining the number of patent glands as seen by digital expression.
103181 In some embodiments, the symptoms of a patient are assessed by asking
the patient a series
of questions. Questionnaires allow the assessment of a range of symptoms
associated with ocular
discomfort. In some embodiments, the questionnaire is the SPEED questionnaire.
The SPEED
questionnaire assesses frequency and severity of a patient's dry eye symptoms.
It examines the
occurrence of symptoms on the current day, past 72 hours and past three
months. A SPEED score
is tallied based on the patient's answers to the questions, to give a range of
severity of the patient's
symptoms. The SPEED questionnaire includes questions such as the following: 1)
what dry eye
symptoms are you experiencing, and when do they occur? 2) how frequently do
you experience
dryness, grittiness, or scratchiness in your eyes? 3) how often do you
experience soreness or
irritation of the eyes? 4) how often do you experience burning or watering of
the eyes? 5) how
often do you experience eye fatigue? and 6) how severe are the symptoms?
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10M91 Meibomian gland expressibility is optionally determined to assess the
meibomian gland
function. In normal patients, meibum is a clear to light yellow oil. Meibum is
excreted from the
glands when digital pressure is placed on the glands. Changes in meibomian
gland expressibility
are one potential indicator of MGD. In some embodiments, during expression,
quantifying the
amount of physical force applied during expression is monitored in addition to
assessing lipid
volume and lipid quantity.
103201 Tear stability break up time (TBUT) is a surrogate marker for tear
stability. Tear film
instability is a core mechanism in dry eye and MGD Low TBUT implies a
possibility of lipid
layer compromise and MGD. TBUT is optionally measured by examining fluorescein
breakup
time, as defined as the time to initial breakup of the tear film after a
blink. Fluorescein is optionally
applied by wetting a commercially available fluorescein-impregnated strip with
saline, and
applied to the inferior fornix or bulbar conjuctiva. The patient is then asked
to blink several times
and move the eyes. The break up is then analyzed with a slit lamp, a cobalt
blue filter, and a beam
width of 4 mm. The patient is instructed to blink, and the time from upstroke
of the last blink to
the first tear film break or dry spot formation is recorded as a measurement.
103211 Other methods for assessing MGD symptoms, include but are not limited
to, Schirmer test,
ocular surface staining, lid morphology analysis, meibography, meibometry,
interferometry,
evaporimetry, tear lipid composition analysis, fluorophotometry, meiscometry,
osmolarity
analysis, indices of tear film dynamics, evaporation and tear turnover.
103221 Current treatments for MGD include lid warming, lid massage, lid
hygiene, lid expression
and meibomian gland probing. Pharmacological methods, prior to those described
herein, have
not been used.
103231 Lid hygiene is considered the primary treatment for MGD and consists of
three
components: 1) application of heat, 2) mechanical massage of eyelids and 3)
cleansing the eyelid.
Eyelid warming procedures improve meibomian gland secretion by melting the
pathologically
altered meibomian lipids. Warming is achieved by warm compresses or devices.
Mechanical lid
hygiene includes the use of scrubs, mechanical expression and cleansing with
various solutions of
the eyelashes and lid margins. Lid margins are optionally also cleansed with
hypoallergenic bar
soap, dilute infant shampoo or commercial lid scrubs. Physical expression of
meibomian glands
is performed in a physician's office or is performed by the patient at home.
The technique varies
from gentle massage of the lids against the eyeball to forceful squeezing of
the lids either against
each other or between a rigid object on the inner lid surface and a finger,
thumb, or rigid object
(such as a glass rod, cotton swab, or metal paddle) on the outer lid surface.
The rigid object on the
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inner lid surface protects the eyeball from forces transferred through the
eyelid during expression
and to offer a stable resistance, to increase the amount of force that is
applied to the glands.
103241 Eyelid warming is limited because the warming melts the lipids, but
does not address
movement of the keratinized material. Further, eyelid warming induces
transient visual
degradation due to corneal distortion. Mechanical lid hygiene is also limited
because the force
needed to remove an obstruction can be significant, resulting in significant
pain to the patient. The
effectiveness of mechanical lid hygiene is limited by the patient's ability to
tolerate the associated
pain during the procedure Other treatments for MGD are limited
103251 Physical opening of meibomian glands obstruction by meibomian gland
expression is an
acceptable method to improve meibomian gland secretion and dry eye symptoms.
In addition
probing of the meibomian gland canal has been used to open the obstructed
canal Both methods,
expression and probing, are limited, however, by the pain induced by the
procedure, the possible
physical insult to the gland and canal structures and their short lived effect
estimated at days and
weeks. Therefore, methods are needed to improve patient comfort, which will
not cause harm to
the meibomian glands and canals, that will reduce the dependency on frequent
office visits and
improve secretion of meibum.
103261 Patent US 9,463,201 entitled, "Compositions and methods for the
treatment of meibomian
gland dysfunction" describes a method for treating meibomian gland dysfunction
involving the
topical administration of a therapeutically-effective amount of at least one
keratolytic agent in an
ophthalmically-acceptable carrier. The patent includes keratolytic agents that
are inorganic
selenium (Se) compounds such as selenium disulfide (SeS2) or organoselenium
compounds such
as Ebselen (2-Phenyl-1,2-benzoselenazol-3-one). This agent would treat the
underlying cause of
MGD, but not a "plus" inflammatory disease as described by the DEWS report on
MGD.
103271 The role of inflammation in the etiology of MGD is controversial. The
terms posterior
blepharitis and MGD are not synonymous. Posterior blepharitis describes
inflammatory conditions
of the posterior lid margin and has various causes, of which MGD can be one
possible cause
(Nichols et al 2011). In its earliest stages, MGD is not associated with
clinical signs characteristic
of posterior blepharitis. As MGD progresses, an MGD-related posterior
blepharitis is said to be
present. MGD-related posterior blepharitis affects the meibomian glands and
meibomian gland
orifices. MGD-related posterior blepharitis is characterized by flora changes,
esterase and lipase
release, lipid changes, and eyelid inflammation. Hyperkeratinization of the
meibomian gland
epithelium (thickening of the lining of the glands) may lead to obstruction
and a decrease in the
quantity of meibomian gland secretions and may be responsible for MGD-related
posterior
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blepharitis. Diagnosis of MGD-related posterior blepharitis includes meibomian
gland expression
with demonstration of an altered quality of expressed secretions, and/or by a
loss of gland
functionality (decreased or absent expressibility). The TFOS report on
Meibomian Gland Disease
specifically notes that anterior blepharitis and exacerbated inflammatory
ocular surface disease
are "plus" diseases to MGD which are managed by topical, ocular steroids
(Nichols et al 2011).
Since these "plus" conditions can be present in various levels of severity
from early to late MGD
there is a need for treatments and/or combinations of treatments that can
target both the underlying
non-inflammatory pathophysiology of MGD and inflammation associated with these
comorbid
conditions.
103281 MGD-related inflammatory eye disease may comprise a different mechanism
than
blepharitis-related MGD. MGD-related inflammatory eye disease is characterized
by an
inflammatory cascade involving activation and migration of T lymphocytes to
the inflamed tissue.
T lymphocyte infiltration may result in lacrimal gland stimulation and
upregulation of cytokines.
Exemplary cytokines that may be involved in MGD-related inflammatory eye
disease include, but
are not limited to, interleukin-1, interleukin-4, interleukin-6, inteleukin-8,
interferon gamma,
macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha.
Kinase pathways
including the mitogen activated protein kinase (MAPK) pathway are also
activated in the
inflammatory cascade. The inflammatory process results in loss of mucin-
producing goblet cells
and destruction of the ocular surface that can lead to further damage.
103291 Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), is
considered a self-
sustaining disease that is progressively disconnected from its initial cause.
Dry eye syndrome is
associated with inflammation at the ocular surface and periocular tissue.
Inflammation is
characterized by the activation and migration of T lymphocytes to the inflamed
tissue including
in the conjunctiva and lacrimal glands. Inflammatory cytokines, chemokines,
and matrix
metalloproteinase have also been identified as being increased.
103301 Animal models of dry eye disease have been established and reviewed
(Barabino, et al,
(Invest. Ophthalmol. Vis. Sci. 2004, 45:1641-1646)). Barabino, et al, (Invest.
Ophthalmol. Vis.
Sci. 2005, 46:2766-2771) described a model wherein exposure of normal mice to
a low-humidity
environment in a controlled-environment chamber leads to significant
alterations in tear secretion,
goblet cell density, and acquisition of dry eye-related ocular surface signs.
However, no single
animal model adequately accounts for the immune, endocrine, neuronal and
environmental factors
which contribute to dry eye pathogenesis.
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103311 Anti-inflammatory agents may be used to treat ocular surface diseases
or disorders
including dry eye syndrome. Corticosteroids are an effective anti-inflammatory
therapy in dry eye
disease. For example, in a 4-week, double-masked, randomized study in 64
patients with dry eye
and delayed tear clearance, loteprednol etabonate 0.5% ophthalmic suspension
(Lotemax [Bausch
and Lomb, Rochester, NY]), QID, was found to be more effective than its
vehicle in improving
some signs and symptoms (Pflugfelder et al, Am J Ophthalmol (2004); 138:444-
57). The TFOS
2007 report on dry eye disease went so far as to conclude that, "In the US
Federal Regulations,
ocular corticosteroids receiving "class labeling" are indicated for the
treatment " of steroid
responsive inflammatory conditions of the palpebral and bulbar conjunctiva,
cornea and anterior
segment of the globe such as allergic conjunctivitis, acne rosacea,
superficial punctate keratitis,
herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis,
when the inherent hazard
of steroid use is accepted to obtain an advisable diminution in edema and
inflammation.- KCS, in
some instances, is included in this list of steroid-responsive inflammatory
conditions (Therapy
Subcommittee of the International Dry Eye WorkShop, 2007. Management and
Therapy of Dry
Eye Disease: Report of the Management and Therapy Subcommittee of the
International Dry Eye
WorkShop (2007). 2007;5: 163-178)." While the US FDA does not agree with this
conclusion,
short courses of steroids, especially Lotemax, can be used to treat
inflammation associated with
dry eye disease.
[0332] Other anti-inflammatory agents include nonsteroidal anti-inflammatory
drugs (NSAlDs).
NSA1Ds inhibit the activity of cyclooxygenases including cyclooxygenase-1 (COX-
1) and
cyclooxygenase-2 (COX-2), which are enzymes involved in the synthesis of
prostaglandins and
thromboxanes from arachidonic acid. Prostaglandin and thromboxane signaling
are involved in
inflammation and immune modulation. In some cases, NSAIDs are used for
treating dry eye
disease by treating the inflammation at the ocular surface.
103331 Treatment of dry eye is also accomplished through agents that enhance
tear fluid and
mucin production. For example, agonists of the P2Y2 receptor have been shown
to increase tear
fluid and mucin secretion. The mechanism is thought to involve P2Y2 signaling
to raise
intracellular calcium and open chloride channels in the apical membrane. The
P2Y2 receptor
belongs to the family of purinergic receptors, which have been classified into
P1 receptors and P2
receptors on the basis of their native agonism by purine nucleosides and
purine and pyrimidine
nucleotides, respectively. P2 receptors are further distinguished
physiologically into two types:
P2X receptors and P2Y receptors. The P2Y receptors are involved in diver
signaling including
platelet aggregation, immunity, lipid metabolism, and bone activity. Several
studies have also
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demonstrated the presence of P2X and P2Y receptors in ocular tissues,
including the retina, ciliary
body, and lens. These studies indicate that P2Y2 receptors appear to be the
main subtype of
purinergic receptor located at the ocular surface. P2Y2 receptors have also
been demonstrated to
be localized in ocular tissues in the conjunctival epithelial goblet and
serous cells and meibomian
gland acinus and ductal epithelial cells of the rhesus macaque.
Azithromycin
103341 Azithromycin is a macrolide antibiotic with a 15-membered ring. Its
chemical name is
(2R,3 S,4R,5R,M,10R,11R,12S,13 S,14R)-13-[(2,6-dideoxy-3-C-methy1-3-0-methyla-
L-ribo-
hexopyranosyl)oxy]-2-ethy1-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl 1
14[3 ,4,6-trideoxy-
3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-
one having a
molecular weight of 749, and an empirical formula is C381472N2012. The
structural formula is:
J\IMe2
= 0
HO = H 0
.= =
/ 0
bme
0
OH
103351 Azithromycin acts by binding to the 50S ribosomal subunit of
susceptible microorganisms
and interfering with microbial protein synthesis. In the topical ophthalmic
setting, Azithromycin
is formulated as a 1% solution of pH 6.3 comprising benzalkonium chloride.
Azithromycin is
indicated for the treatment of bacterial conjunctivitis caused by susceptible
isolates of the
following microorganisms: Haemophilus influenzae, Staphylococcus aureus,
Streptococcus mitis
group, or Streptococcus pneumoniae. Further information about azithromycin
ophthalmic
solution can be found in, for example, US 6,239,113, 6,569,443, or 7,056,893
103361 Described herein are compounds (e.g., keratolytic conjugates and/or
dual acting-agents)
which address simultaneously the non-inflammatory keratolytic blockage
component of
meibomian gland dysfunction and the inflammation associated dry eye disease
including aqueous
deficiency. In some embodiments, a compound provided herein is useful as
either an acute therapy
(e.g., by a trained specialist or physician) or as a chronic therapy (e.g., in
the hands of a patient,
or alternatively, by a trained specialist or physician). A compound provided
herein is tested, in
some embodiments, using the assays and methods described herein (e.g., as
described in the
examples). In some embodiments, a compound provided herein represents a
significant advance
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in the art as the first-order metabolites obtained from metabolism of the
agents are operative
against both the keratolytic and the inflammatory component of dry eye
disease.
103371 Provided in some embodiments herein is a compound, having the structure
of Formula
(I):
NR02
00R0
0
0
(NRQ ORQ
ORQ
0
OR
Formula (I),
wherein,
each RQ is independently H, RN, substituted or unsubstituted alkyl, or
substituted or
unsubstituted heteroalkyl, wherein at least one RQ is RN;
RN is D- La-;
is a keratolytic agent; and
La is a linker,
or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate
thereof.
103381 In some embodiments, the compound has a structure represented by.
//õ.r=-=,õ..õNRQ2
0>r,
ORQ
= 0
RQO 7
OR
0 Q
OR
NRQ ORQ
RQ0, 0
z
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103391 In some embodiments, provided herein is a compound, having the
structure of Formula (I-
A):
OR'
7 0
HO
,0
0 ''0Me
N 0
OH
Formula (I-A)
wherein,
R' is D- La-;
is a keratolytic agent; and
La is a linker,
or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate
thereof.
103401 In some embodiments, La comprises one or more linker group, each linker
group being
independently selected from the group consisting of a bond, -0-, -S-, alkyl
(alkylenyl), heteroalkyl
(heteroalkylenyl), disulfide, ester, and carbonyl (>C=0). In some embodiments,
the keratolytic
agent comprises one or more groups of the group (e.g., keratolytic group, such
as a group
conferring keratolytic activity), each group (e.g., keratolytic group) being
independently selected
from the group consisting of thiol, disulfide, selenium (e.g., selenide,
diselenide), carboxylic acid
or a group which can be metabolized to a carboxylic acid.
103411 In some embodiments, R' is alkyl or heteroalkyl substituted with at
least one oxo, and
further optionally substituted.
103421 In some embodiments, R' is:
0
(222.
R8 R9
wherein:
is 1-6;
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each le and R9 is independently H, halogen, CI-C3-alkyl,
C1-C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl; and
Ri2 is H, alkyl, aryl or heteroalkyl, the alkyl, aryl, or heteroalkyl
being
optionally substituted,
or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate
thereof.
103431 In some embodiments, the alkyl or heteroalkyl of R12 is substituted
with one or more
substituent, each substituent being independently selected from the group
consisting of alkyl,
heteroalkyl, hydroxyl, thiol, thioether, disulfide, seleno, selenol, sulfone,
amide, halo, oxo,
heterocyclyl, and cycloalkyl, wherein the heterocyclyl and cycloalkyl is
optionally substituted
(e.g., with one or more substituent selected from the group consisting of
alkyl, heteroalkyl,
hydroxyl, thiol, thioether, disulfide, selenol, sulfone, amide, halo, and
oxo).
103441 In some embodiments, z is described elsewhere herein.
103451 In some embodiments, each le and R9 is described elsewhere herein.
103461 In some embodiments, provided herein is a compound having the structure
of Formula
(Ia'):
OH
M e F/11:1)
HO,
=
0 H H
0 -
Rx õ L 0
y
0
Me2N
Formula (Ia')
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
wherein,
L is bond, -(C=0)(OCR8R9)z-, or -(C=0)(OCIVR9)z0-;
each le and R9 is independently H, halogen, Ci-C3-alkyl, C1-C3-haloalkyl, Ci-
C3-
alkoxy, C3-05-cycloalkyl, or le and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6;
X is absent or -0-; and
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R is substituted alkyl, substituted heteroalkyl, or substituted
heterocycloalkyl,
wherein the substituted alkyl is substituted with one or more alkyl
substituent, at least
one alkyl substituent being independently selected from the group consisting
of
substituted or unsubstituted cycloalkyl and substituted heterocycloalkyl, and
the
substituted heteroalkyl is substituted with one or more heteroalkyl sub
stituent, at
least one heteroalkyl substituent being independently selected from the group
consisting of -COON, substituted heterocycloalkyl, and thioalkyl, the
substituted
alkyl or substituted heteroalkyl being further optionally substituted
103471 In some embodiments, provided herein is a compound having the structure
of Formula
(Ia):
OH
_
OH N
A0 H
=== = 0 H''''
d=
X y =----(?
0 ..,...õ9.,,õ ,
Me2N1
Formula (Ia)
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
wherein,
L is bond, -(C=0)(OCIeR9)z-, or -(C=0)(0CleR9)z0-;
each le and R9 is independently H, halogen, CI-C3-alkyl, CI-C3-haloalkyl, CI-
C3-
alkoxy, C3-05-cycloalkyl, or 11_8 and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6;
X is absent or -0-; and
R is substituted (e.g., straight or branched) alkyl, substituted (e.g.,
straight or branched)
heteroalkyl, or substituted heterocycloalkyl (e.g., (N-) substituted with
alkyl (e.g.,
further substituted with oxo and thiol)), the substituted alkyl being
substituted with
one or more (alkyl) substituent, at least one (alkyl) substituent being
independently
selected from the group consisting of -SH, substituted or unsubstituted (e.g.,
unsaturated) cycloalkyl, and dithiolanyl oxide, or the substituted heteroalkyl
being
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substituted with one or more (heteroalkyl) substituent, at least one
(heteroalkyl)
substituent being independently selected from the group consisting of -SH, -
COOH, and thioalkyl, the substituted alkyl, substituted heteroalkyl, or
substituted
heterocycloalkyl being further optionally substituted.
103481 In some embodiments, L is bond. In some embodiments, L is -
(C=0)(OCR8R9)z- or -
(C=0)(OCR8R9)z0-. In some embodiments, L is -(C=0)(OCR8R9)z-. In some
embodiments, L is
-(C=0)(OCR8R9)z0- In some embodiments z is 1-3. In some embodiments, z is 1.
In some
embodiments, each R8 and R9 is independently H or Ci-C3-alkyL In some
embodiments, each R8
is H and each R9 is C1-C3-alkyl. In some embodiments, each 11.8 is H and each
R9 is CH3. In some
embodiments, le and R9 are H. In some embodiments, L is -(C=0)0CH(CH3)-. In
some
embodiments, L is -(C=0)0CH(CH3)0-.
103491 In some embodiments, X is absent. In some embodiments, X is -0-.
103501 In some embodiments, L is -(C=0)0CH(CH3)- or -(C=0) OCH(CH3)0- and X is
absent
or -0-.
103511 In some embodiments, L is -(C=0)0CH(CH3)- and X is absent.
103521 In some embodiments, L is -(C=0)0CH(CH3)- and X is -0-.
103531 In some embodiments, L is bond and X is absent.
103541 In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of hydroxy, optionally
substituted alkoxy
(e.g., optionally substituted with oxo and hydroxy or oxo and C1-C3 alkoxy)),
oxo, optionally
substituted alkyl (e.g., optionally substituted with alkoxy further optionally
substituted with oxo,
Ci-C4 alkyl, and/or hydroxy), optionally substituted heterocycloalkyl (e.g.,
optionally substituted
dioxane (e.g., 1,3 dioxanyl optionally substituted with methyl), dithiolanyl,
or dithiolanyl oxide),
hydroxyalkyl, thiol, acetamide, substituted unsaturated cycloalkyl (e.g.,
being substituted with one
or more Ci-C4 alkyl), and amino.
103551 In some embodiments, R is substituted (e.g., straight or branched)
alkyl, the (e.g., straight
or branched) alkyl being substituted with one or more (alkyl) substituent,
each (alkyl) substituent
being independently selected from the group consisting of thiol, amino,
acetamide, substituted
unsaturated cycloalkyl (e.g., being substituted with one or more Ci-C4 alkyl),
and substituted
heterocycloalkyl (e.g., dithiolanyl oxide).
103561 In some embodiments, R is substituted alkyl, the alkyl being
substituted with substituted
heterocycloalkyl.
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103571 In some embodiments, R is substituted alkyl. In some embodiments, R is
substituted alkyl,
wherein the substituted alkyl is substituted with one or more alkyl
substituent, at least one alkyl
substituent being independently selected from the group consisting of
substituted or unsubstituted
cycloalkyl and substituted heterocycloalkyl. In some embodiments, R is
substituted alkyl, the
alkyl being substituted with substituted heterocycloalkyl. In some
embodiments, R is substituted
alkyl, the alkyl being substituted with 1,2-dithiolanyl oxide. In some
embodiments, R is
substituted alkyl, the alkyl being substituted with substituted C5-C15
heterocycloalkyl (e.g., C12
heterocycloalkyl with one or more disulfide and one or more amide within the
heterocycloalkyl
ring) being substituted with one or more substituent, at least one substituent
being independently
selected from the group consisting of Ci-C3 alkyl, oxo, and -COOH. In some
embodiments, the
substituted alkyl is further optionally substituted
103581 In some embodiments, L is bond, X is absent, and R is substituted
(e.g., straight or
branched) alkyl, the (e.g., straight or branched) alkyl being substituted with
one or more (alkyl)
substituent, each (alkyl) substituent being independently selected from the
group consisting of
thiol, amino, acetamide, substituted unsaturated cycloalkyl (e.g., being
substituted with one or
more CI-CI alkyl), and substituted heterocycloalkyl (e.g., dithiolanyl oxide).
103591 In some embodiments, R is:
0
--)L
SH NH2 NH
HS-sse
, or
06
S s
\.sr,
s' =
103601 In some embodiments, R is:
0
S.
0 HN
HO'¨*
S-
-s5- or
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103611 In some embodiments, R is:
R4a R4b
'T p
wherein:
each R4a and R4b is independently H, halogen, or substituted or unsubstituted
alkyl;
p is an integer from 1-10; and
q is an integer from 1-3.
103621 In some embodiments, q is 1 and p is an integer from 3-5.
103631 In some embodiments, each R4a and R4b is H.
103641 In some embodiments, R is:
o
scrr'
103651 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or more -C-O-C- (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103661 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or more ester, one or more carbonate, one or more
amide, and/or one
or more disulfide (e.g., within the (e.g., linear or branched) heteroalkyl
chain).
103671 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl comprising
one or more ester, one or more amide, and/or one or more disulfide (e.g.,
within the (e.g., linear
or branched) heteroalkyl chain).
103681 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one carbonate (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
103691 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two ester (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103701 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester (e.g., within the (e.g., linear or branched)
heteroalkyl chain).
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103711 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester and one carbonate (e.g., within the (e.g.,
linear or branched)
heteroalkyl chain).
103721 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two ester and one amide (e.g., within the (e.g.,
linear or branched)
heteroalkyl chain).
103731 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one ester and one amide (e.g., within the (e.g., linear
or branched)
heteroalkyl chain).
103741 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two amide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103751 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl
chain).
103761 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one disulfide (e.g., within the (e.g., linear or
branched) heteroalkyl chain).
103771 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl comprising one or two disulfide and one ester (e.g., within the
(e.g., linear or branched)
heteroalkyl chain).
103781 In some embodiments, R is substituted or unsubstituted (e.g., linear or
branched)
heteroalkyl containing one or two disulfide and one amide (e.g., within the
(e.g., linear or
branched) heteroalkyl chain).
103791 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of optionally
substituted C1-C6 alkyl, acetamide, hydroxy, heterocycloalkyl, thiol,
thioalkyl, amino, and
carboxylic acid.
103801 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with one or more
(heteroalkyl) substituent, each
(heteroalkyl) substituent being independently selected from the group
consisting of thioalkyl,
amino, carboxylic acid, Ci-C6 alkyl, acetamide, thiol, oxo, and optionally
substituted (e.g., N-
attached) heterocycloalkyl (e.g., optionally substituted with carboxylic
acid).
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[0381] In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with substituted C1-C6
alkyl, the C1-C6 alkyl
being substituted with heteroalkyl being further optionally substituted with
one or more additional
substituent, each additional substituent being independently selected from the
group consisting of
hydroxy, carboxylic acid, optionally substituted N-substituted pyrrolidinyl
(e.g., optionally
substituted with carboxylic acid)).
103821 In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with heterocycloalkyl In
some embodiments, R
is substituted (e.g., linear or branched) heteroalkyl, the (e.g., linear or
branched) heteroalkyl being
substituted with 1,2-dithiolane, 1,2-dithiolane oxide, optionally substituted
dioxane (e.g.,
optionally substituted with one or more
C1-
C6 alkyl), (e.g., N-substituted) pyrrolidine (e.g., substituted with alkyl
(e.g., further substituted
with oxo, thiol, and Ci-C3 alkyl)), or substituted (e.g., N-attached)
pyrrolidine (e.g., substituted
with carboxylic acid).
[0383] In some embodiments, R is substituted (e.g., linear or branched)
heteroalkyl, the (e.g.,
linear or branched) heteroalkyl being substituted with acetamide and
carboxylic acid.
[0384] In some embodiments, R is substituted heteroalkyl, the heteroalkyl
being substituted with
-COOH, -CH2SH, and/or optionally substituted N-attached heterocycloalkyl, and
being further
substituted with one or more other sub stituent, each sub stituent being
independently selected from
the group consisting of acetamide, amino, Ci-C6 alkyl, thiol, and oxo.
[0385] In some embodiments, R is substituted heteroalkyl comprising two
disulfide bonds within
the heteroalkyl chain, the heteroalkyl being substituted with -COOH or
substituted N-attached
heterocycloalkyl, and being further substituted with one or more other sub
stituent, each substituent
being independently selected from the group consisting of acetamide and C1-C6
alkyl.
[0386] In some embodiments, R is substituted heteroalkyl comprising one
disulfide bond within
the heteroalkyl chain, the heteroalkyl being substituted with acetamide, -
COOH, and -SH.
[0387] In some embodiments, L is bond, X is absent, and R is substituted
(e.g., linear or branched)
heteroalkyl, the (e.g., linear or branched) heteroalkyl being substituted with
one or more
(heteroalkyl) substituent, each (heteroalkyl) substituent being independently
selected from the
group consisting of thioalkyl, amino, carboxylic acid, Ci-C6 alkyl, acetamide,
thiol, oxo, and
optionally substituted (e.g., N-attached) heterocycloalkyl (e.g., optionally
substituted with
carboxylic acid).
-88-
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103881 In some embodiments, R is:
NR6R7
42SeY
Rio R11
wherein:
R5 is -SItic;
Ric is:
substituted alkyl or substituted heteroalkyl,
wherein the alkyl is substituted with one or more alkyl substituent, each
alkyl substituent being independently selected from the group
consisting of carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo,
and optionally substituted heterocycloalkyl, and the heteroalkyl is
substituted with one or more heteroalkyl substituent, each heteroalkyl
substituent being independently selected from the group consisting of
oxo, carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3
alkyl;
R6 and R7 are each independently H, substituted or unsubstituted alkyl, or
substituted
or unsubstituted heteroalkyl;
each Rm and le is independently H, halogen, C1-C3-alkyl, C1-C3-haloalkyl, Ci-
C3-
alkoxy, C3-05-cycloalkyl, or two of Rm and RH are taken together with the
atoms
to which they are attached to form a C3-05-cycloalkyl; and
s is an integer from 1-10.
103891 In some embodiments, R6, R7, Rm and RH are each H, and s is 1-3.
103901 In some embodiments, RC is heteroalkyl substituted with carboxylic
acid.
103911 In some embodiments, Ric is alkyl substituted with one or more alkyl
substituent, each
alkyl substituent being independently selected from the group consisting of
carboxylic acid and
acetamide.
-89-
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[0392] In some embodiments, R5 is:
/ \
''S HS Sr
35sr-s,,--y0H ,..-1-,OH As OH HS OH
0 , 0 , 0 ,
0 ,
0
I
clirOH
S
-)LNH NH2 0 0 '' H ?i
0
)---µ0
\,..SOH .,z(-S.....-HrOH H0)-11,,N,----y.Ni-L,
OH S
H /
0 , 0 , NH2
,
1
I
0
.,,SH
0 00
HS7c-110H
H H
0 0 ,or 0 .
[0393] In some embodiments, R is:
SH SH
0 0 0 0
SH
0
HO)XlrõN skKNõCyH
OH HSx.A.N
H H
NH2 0 NH2 0 H
,
OH
0 0
HN-k-
HO,IrLi
0 S,s 0 S,S
HN
HO
0 :cs,Scssi
HO 0
0
-)
0 NH2 -y0 1.-NH 0
y,--õs_Ss.õ,õõõ1õi )1'. NH
HO) HN
YS-S'")), HS.,._)--_,,s
NH2 , HOO ,or
[0394] In some embodiments, R is substituted branched heteroalkyl.
-90-
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103951 In some embodiments, R is:
HS\/
0/o OH
0 NH
HO,NH0
S 0
0 HO,r-H
0 )1-NH S -S
0y,S,sse
OH , or
OH
0
0 I\\\D
0 0 S,s\ /
=
103961 In some embodiments, R is:
OH
0 0
HN)Ls=
HOy--H
sy0 0 S,
HO 00 S
0
HO 0 Of
-91-
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103971 In some embodiments, R-X-L is:
HS\/
0 (:).,,OH
0 NH
HO, NH 0
Sµ ,s SH
S 0 HN)L'-
0 HO,r-H
0 S
)1-NH -S
-S--s-
-.,./OH , or
'
OH
0
0 I\\\D
-----,1
0 0 S,\ / S
HO ¨IV)
103981 In some embodiments, R-X-L is:
OH
0 0
H N)Ls= 0,.11NO
HOy--H
sy0 0 S,s HO 0 S
0 -S
HN,õ----õs_Sy
.....,
HO 0 Of .
103991 In some embodiments, R-X-L is:
OH
0 0
0 tO
HN)-L"
HO..1(L1
--"-1
0 S,s HO 0
0 SS
HN,..--õsõ.S.õ....,.-1,õ,..,,--..--y0,TA
...N.A...
S
HO 0 '..- or 0
0
-92-
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104001 In some embodiments, R is substituted heterocycloalkyl (e.g., N-
substituted with alkyl
(e.g., further substituted with oxo and thiol)).
104011 In some embodiments, R is heterocycloalkyl N-substituted with alkyl,
the alkyl being
further substituted with oxo and/or thiol.
104021 In some embodiments, R is:
sof ><N/
N
o ,o N
HS , or 1.
104031 In some embodiments, R comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sulfoxide (Lipox), a radical of dihydrolipoic acid (diffLip), a radical
of N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
104041 In some embodiments, R comprises a radical of one or more keratolytic
group, each radical
of the one or more keratolytic group being independently selected from the
group consisting of a
radical of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical
of lactic acid (Lac),
a radical of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical
of lipoic acid sulfoxide
(Lipox), a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl
cysteine (NAC), a radical
of cysteine (Cys), a radical of glutathione (GSH), a radical of captopril
(Cap), and a radical of
bucillamine (Buc).
104051 In some embodiments, R comprises a thiol radical of one or more
keratolytic group, each
thiol radical of the one or more keratolytic group being independently
selected from the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diFILip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
104061 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]., [Lac-
NAC]., [Cys-Cys]., [diHLip-NAC-NAC]., [diHLip-NAC]., [diHLip-Cap-Cap].,
[diHLip-Cap].,
[diHLip-Cys-Cys]., [diHLip-Cys]., [diHLip-Lipox-Lipox]., and [diHLip-Lipox]..
-93 -
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104071 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]-, [Cys-
Cys]=, [diHLip-NAC-NAC]=, [difiLip-NAC]=, [diHLip-Cap-Cap]., [difiLip-Cap].,
[difiLip-Cys-
Cys]-, [diHLip-Cys]-, [dinLip-Lipox-Lipox]-, and [dinLip-Lipox]-.
104081 Unless stated otherwise, a radical (or.) is molecule having unpaired
electrons. In some
embodiments, the radical is a radical of a heteroatom (e.g., -0-, -1\1--, or-
S.). In some embodiments,
the radical (e g , the molecule having unpaired electron) is paired with
another unpaired electron
of another molecule to form paired electrons. In some embodiments, a radical
of a keratolytic
agent provided herein is paired with any compound provided herein. In some
embodiments, a first
radical of a keratolytic agent provided herein is paired with a second radical
of a keratolytic
provided herein.
104091 In some embodiments, the radical of the keratolytic group is the point
of attachment of R
to the rest of the molecule. In some embodiments, (the thiol radical of) R
each independently
attach to the rest of the molecule to form a disulfide bond.
104101 In some embodiments, R is:
SH NH2 Nzz,
HO N
NH2 0
SH 0
0 0
SH
Sis N 0
ssKr-)LN-IN-)(OH HS
NH2 0 / HS
OH
LN
0 H N 0
00HO S,s
HO 0
-94-
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0
0 NH2
NH
S--1
HO)YSS 1 HN
,,s,S..1õ/ ><N,..1.),
---µ
NH2 HOO
0 ,
,
0
S
S --i.. II
''''' NH
/
..--µ
N _ ---,
N----1 HS --)-.=-sss
0 , H
104111 In some embodiments, R is:
SH
SH NH2
)0t,
N
HO N
H,...,...1,/
HHS/-j'yS H
NH2 0
SH 08
NCIII
SH
0 -'- 0
---
H S Is 0
sssss N Thr NJ )LOH )---"µO HS
H
'A-IL N - ----7
NH2 0 _Fs' HS
H
HSv
0-< __ 01,,OH
0 NH
HO, __________________________ (-----NH 0
S, ,s ...,(SH
S 0 H N A-
0 HOy1,1
NH 0 S,
--õ, }L S
0y1õ,....õ..S,s.-----õõ---1--ys
\is
OH
OH
0
Ox.1\1.
0 0,_<,.. S,
S 0 NH2
HO-lb Ss/ ,
HO)Sie
NH2
-95-
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0
H S
HNS -><N N _KS
N
HO 0 0 0
0
0
HOLY
HN
HO
6 S
0
NH
or .
104121 In some embodiments, R is the radical recited in Compound 1.
104131 In some embodiments, R is the radical recited in Compound 2.
104141 In some embodiments, R is the radical recited in Compound 3
104151 In some embodiments, R is the radical recited in Compound 4.
104161 In some embodiments, R is the radical recited in Compound 5.
104171 In some embodiments, R is the radical recited in Compound 6
104181 In some embodiments, R is the radical recited in Compound 7.
104191 In some embodiments, R is the radical recited in Compound 8.
104201 In some embodiments, R is the radical recited in Compound 9.
104211 In some embodiments, R is the radical recited in Compound 10.
104221 In some embodiments, R is the radical recited in Compound 11.
104231 In some embodiments, R is the radical recited in Compound 12.
104241 In some embodiments, R is the radical recited in Compound 13.
104251 In some embodiments, R is the radical recited in Compound 14.
104261 In some embodiments, R is the radical recited in Compound 15.
104271 In some embodiments, R is the radical recited in Compound 16.
104281 In some embodiments, R is the radical recited in Compound 17.
104291 In some embodiments, R is the radical recited in Compound 18
104301 In some embodiments, R is the radical recited in Compound 19
104311 In some embodiments, R is the radical recited in Compound 20.
104321 In some embodiments, R is the radical recited in Compound 24.
104331 In some embodiments, R is the radical recited in Compound 25
-96-
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[0434] In some embodiments, R is the radical recited in Compound 26.
[0435] In some embodiments, R is the radical recited in Compound 28.
[0436] In some embodiments, R is the radical recited in Compound 29.
[0437] In some embodiments, R is the radical recited in Compound 31.
[0438] In some embodiments, R is the radical recited in Compound 32.
[0439] In some embodiments, R is the radical recited in Compound 33.
[0440] In some embodiments, R is the radical recited in Compound 34.
[0441] In some embodiments, R is the radical recited in Compound 35
[0442] In some embodiments, R is the radical recited in Compound 36.
[0443] In some embodiments, R is the radical recited in Compound 37.
[0444] In some embodiments, R is the radical recited in Compound 38.
[0445] In some embodiments, R is the radical recited in Compound 40.
[0446] In some embodiments, R is the radical recited in Compound 41.
104471 In some embodiments, R is the radical recited in Compound 42.
[0448] In some embodiments, R is the radical recited in Compound 43.
[0449] In some embodiments, R is the radical recited in Compound 44.
[0450] In some embodiments, R is the radical recited in Compound 45.
[0451] In some embodiments, R is the radical recited in Compound 46.
[0452] In some embodiments, R is the radical recited in Compound 47.
[0453] In some embodiments, R is the radical recited in Compound 48.
[0454] In some embodiments, R is the radical recited in Compound 49.
[0455] In some embodiments, R is the radical recited in Compound 50.
104561 In some embodiments, R is the radical recited in Compound 51.
[0457] In some embodiments, the compound is other than a compound having the
structure
OH_
- 7
CY.7.,.
OH N
A
H =,,
Oh.
0 H
.-
0 ' ....:==
0
0
HS/)=LOI'r v): j
NHCOMe
MeAr =
-97-
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104581 Provided in some embodiments herein is a compound having the structure
of Formula (lb):
OH
bHN
Me0......)v.T.C)
HOh. \
'-õ
0
0 H HO
d
Rx
'x'Ly
0
Me2N1'
Formula (lb)
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
wherein:
L is bond, -(C=0)(OCIVR9)z-, or -(C=0)(OCIVR9)z0-;
each le and R9 is independently H, halogen, Ci-C3-alkyl,
Ci-C3-
alkoxy, C3-05-cycloalkyl, or le and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6;
X is absent or -0-; and
Rx is:
R2b R2d
R2a
R1 as R2c m ssi
2m= e
0 rµ
R1 bs
R2f
Rla and Rib are each independently -H or -SR';
each lec is independently substituted or unsubstituted (e.g., straight or
branched) alkyl (e.g., substituted with one or more (alkyl) substituent, each
(alkyl) substituent being independently selected from the group consisting
of carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally
substituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituent,
each (heteroalkyl) substituent being independently selected from the group
-98-
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consisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Cl-C3
alkyl);
each R2', R2b, R2c, R2d, R2e, and R2f is independently H, halogen, CI-C3-
alkyl,
Cl-C3-alkoxy, C3-05-cycloalkyl, or two of R2a and R2b, R2' and
R2d, or R2 and R2f are taken together with the atoms to which they are
attached
to form a C3-05-cycloalkyl;
m is an integer from 1-10; and
n and o are each independently an integer from 0-3.
104591 Provided in some embodiments herein is a compound having the structure
of Formula (lb):
OH
0 /
0
0 H OH
d=
Rx
0
Me2N1
Formula (lb)
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
wherein:
L is bond, -(C=0)(OCR8R9),-, or -(C=0)(OCR8R9),0-;
each R8 and R9 is independently H, halogen, C1-C3-alkyl,
Ci-C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6;
X is absent or -0-; and
Rx is:
R2b R2G R2d
R2a
R1as m
e2
0
R1 bs
R2f
Ria and Rib are each independently -H or
-99-
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each RI is independently substituted or unsubstituted (e.g., straight or
branched) alkyl (e.g., substituted with one or more (alkyl) substituent, each
(alkyl) substituent being independently selected from the group consisting
of carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally
substituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with
-COOTI)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituent,
each (heteroalkyl) substituent being independently selected from the group
consisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, and C1-C3
alkyl);
each R2a, R2b, R2c, R2d, R2e, and R21 is independently H, halogen, C1-C3-
alkyl,
C1-C3-alkoxy, C3-05-cycloalkyl, or two of R2a and R21, R2' and
R2d, or R2' and R2f are taken together with the atoms to which they are
attached
to form a C3-05-cycloalkyl;
m is an integer from 1-10; and
n and o are each independently an integer from 1-3.
[0460] In some embodiments, o is 0.
[0461] In some embodiments, o is 0, and Rx is:
010 002c Dad
R".2).9.1
R1as mi
R1bs
[0462] In some embodiments, o is 0 and n is 2.
[0463] In some embodiments, o is 0, n is 2, and IV is:
R2c R2d
R2a
R1as
mi
R2a R2b
SRlb
[0464] In some embodiments, o is 0 and n is 1.
[0465] In some embodiments, o is 0, n is 1, and IV is:
02c1
nc. 02c ).µ
õ 2,
as
Ribs
400_
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104661 In some embodiments, m is an integer from 3-5.
104671 In some embodiments, each R2a, R2b, R2c, Rat, R2e, and R21- is
independently H, halogen,
CI-C3alkyl, or CI-C3haloalkyl. In some embodiments, each R2a, R2b, R2c, R2d,
lc ¨ 2e,
and R21- is H.
104681 In some embodiments, IV is:
sRlb
wherein:
Rla and Rib are each independently -H or -SR', and
each R1' is independently substituted or unsubstituted (e.g., straight or
branched) alkyl (e.g., substituted with one or more (alkyl) substituent, each
(alkyl) substituent being independently selected from the group consisting
of carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally
substituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituent,
each (heteroalkyl) substituent being independently selected from the group
consisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3
alkyl).
104691 In some embodiments, IV is:
SR 1 b
R1 as
syv ,
wherein:
Rla and Rth are each independently -H or -SR"; and
each Ric is independently substituted or unsubstituted (e.g., straight or
branched) alkyl (e.g., substituted with one or more (alkyl) substituent, each
(alkyl) substituent being independently selected from the group consisting
of carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally
substituted heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with
-COOH)) or substituted or unsubstituted (e.g., straight or branched)
heteroalkyl (e.g., substituted with one or more (heteroalkyl) substituent,
each (heteroalkyl) substituent being independently selected from the group
-101-
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consisting of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3
alkyl).
104701 In some embodiments, Rh is -H or -SR" and Rib is -SR", or Rla is -SR"
and Rib is -H or
-SRI'. In some embodiments, Ria and Rib are each -SR'.
104711 In some embodiments, Ria and Rib each independently comprise a radical
of one or more
keratolytic group (e.g., each radical of the one or more keratolytic group
being independently
selected from the group consisting of a radical of glycolic acid (GA), a
radical of thioglycolic acid
(TGA), a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a
radical of lipoic acid
(Lip), a radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic
acid (diHLip), a radical
of N-acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of
glutathione (GSH), a radical
of captopril (Cap), and a radical of bucillamine (Buc)).
104721 In some embodiments, RI-a and Rib are each independently a radical of
one or more
keratolytic group, each radical of the one or more keratolytic group being
independently selected
from the group consisting of a radical of glycolic acid (GA), a radical of
thioglycolic acid (TGA),
a radical of lactic acid (Lac), a radical of thiolactic acid (TLac), a radical
of lipoic acid (Lip), a
radical of lipoic acid sulfoxide (Lipox), a radical of dihydrolipoic acid
(diHLip), a radical of N-
acetyl cysteine (NAC), a radical of cysteine (Cys), a radical of glutathione
(GSH), a radical of
captopril (Cap), and a radical of bucillamine (Buc).
[0473] In some embodiments, RI-a and Rib each independently comprise a (thiol)
radical of one or
more keratolytic group, each (thiol) radical of the one or more keratolytic
group being
independently selected from the group consisting of a (thiol) radical of
thioglycolic acid (TGA),
a (thiol) radical of thiolactic acid (TLac), a (thiol) radical of
dihydrolipoic acid (diHLip), a (thiol)
radical of N-acetyl cysteine (NAC), a (thiol) radical of cysteine (Cys), a
(thiol) radical of
glutathione (GSH), a (thiol) radical of captopril (Cap), and a (thiol) radical
of bucillamine (Buc).
[0474] In some embodiments, RI-a and Rib are each independently a thiol
radical of one or more
keratolytic group, each thiol radical of the one or more keratolytic group
being independently
selected from the group consisting of a thiol radical of thioglycolic acid
(TGA), a thiol radical of
thiolactic acid (TLac), a thiol radical of dihydrolipoic acid (diHLip), a
thiol radical of N-acetyl
cysteine (NAC), a thiol radical of cysteine (Cys), a thiol radical of
glutathione (GSH), a thiol
radical of captopril (Cap), and a thiol radical of bucillamine (Buc).
104751 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Laci-, [Lac-
-102-
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NAC]-, [Cys-Cys]-, [diHLip-NAC-NAC]., [diHLip-NAC]=, [diHLip-Cap-Cap].,
[diHLip-Cap]=,
[diHLip-Cys-Cys]=, [diHLip-Cys]=, [diHLip-Lipox-Lipox]=, and [diElLip-Lipox]=.
104761 Unless stated otherwise, a radical (or.) is molecule having unpaired
electrons. In some
embodiments, the radical is a radical of a heteroatom (e.g., -0-, -N-, or -S-
). In some embodiments,
the radical (e.g., the molecule having unpaired electron) is paired with
another unpaired electron
of another molecule to form paired electrons. In some embodiments, a radical
of a keratolytic
agent provided herein is paired with any compound provided herein. In some
embodiments, a first
radical of a keratolytic agent provided herein is paired with a second radical
of a keratolytic
provided herein.
104771 In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
of RI' and/or Rib to the rest of the molecule. In some embodiments, Ria and/or
Rib attach to the
rest of the molecule to form a disulfide bond.
104781 In some embodiments, lea and Rib are each independently -H or:
"5-.3 HS SA
As.s'yoH OH s<l's OH Hs
OH
0
cy0H
1
kSOH SOH
)LNH NH2 0 0 0
0
N
OH S
1
0 '.-SH
0 0 0
HS7c1t.w.---y0HOH
0 0 , or 0
104791 In some embodiments, RI a and Rib are the same. In some embodiments, RI-
a and Rib are
different.
-103 -
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[0480] In some embodiments, IV is:
Rics,
R1cs.,
wherein:
each Ric is independently substituted or unsubstituted (e.g., straight or
branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally substituted
heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with -COOH)) or
substituted or unsubstituted (e.g., straight or branched) heteroalkyl (e.g.,
substituted with one or more (heteroalkyl) substituent, each (heteroalkyl)
substituent being independently selected from the group consisting of
carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3 alkyl).
[0481] In some embodiments, Rx is:
R1 Cs,
wherein:
each Rle is independently substituted or unsubstituted (e.g., straight or
branched)
alkyl (e.g., substituted with one or more (alkyl) substituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH, thioalkyl, acetamide, amino, oxo, optionally substituted
heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with -COOH)) or
substituted or unsubstituted (e.g., straight or branched) heteroalkyl (e.g.,
substituted with one or more (heteroalkyl) substituent, each (heteroalkyl)
substituent being independently selected from the group consisting of
carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3 alkyl).
[0482] In some embodiments, each Ric is independently substituted or
unsubstituted (e.g., straight
or branched) alkyl or substituted or unsubstituted (e.g., straight or
branched) heteroalkyl. In some
embodiments, each Ric is independently substituted (e.g., straight or
branched) alkyl or substituted
(e.g., straight or branched) heteroalkyl.
[0483] In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
alkyl, the substituted alkyl being substituted with one or more (alkyl)
substituent, each (alkyl)
-104-
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substituent being independently selected from the group consisting of
carboxylic acid, -SH,
thioalkyl, acetamide, amino, oxo, and optionally substituted heterocycloalkyl
(e.g., N-attached
pyrrolidinyl substituted with -COOH).
104841 In some embodiments, each Ric is independently substituted (e.g.,
straight or branched)
heteroalkyl, the substituted heteroalkyl being substituted with one or more
(heteroalkyl)
substituent, each (heteroalkyl) substituent being independently selected from
the group consisting
of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Cl-C3 alkyl.
104851 In some embodiments, R Rib, and each Ric each independently comprise
one or more
substituent that is a carboxylic acid or an ester. In some embodiments, Ria,
Rib, and each Ric each
independently comprise one or more substituent that is a carboxylic acid
(e.g., -(C=0)0H). In
some embodiments, Ria comprises one or more substituent that is a carboxylic
acid (e.g., -
(C=0)0H). In some embodiments, Rib comprises one or more substituent that is a
carboxylic acid
(e.g., -(C=0)0H). In some embodiments, each Ric independently comprises one or
more
substituent that is a carboxylic acid (e.g., -(C=0)0H). In some embodiments,
Ria, Rib, and each
Ric each independently comprise one or more substituent that is an ester
(e.g., -(C=0)0-Ci-
C4alkyl). In some embodiments, Ria comprises one or more substituent that is
an ester (e.g., -
(C=0)0-CI-C4alkyl). In some embodiments, Rib comprises one or more substituent
that is an ester
(e.g., -(C=0)0-Cl-C4alkyl). In some embodiments, each Ric independently
comprises one or more
substituent that is an ester (e.g., -(C=0)0-Ci-C4alkyl).
104861 In some embodiments, the -(C=0)0H of Ria, Rib, and/or Ric is optionally
esterified (e.g.,
-(C=0)0H or -(C=0)0-Ci-C4alkyl). In some embodiments, the Ci-C4alkyl is
methyl, ethyl,
propyl, isopropyl, butyl, or t-butyl.
104871 Provided in some embodiments herein is a compound having the structure
of Formula (Ic):
OH
7
HO1
N
0 /
1
0
0 H = OH
d H
,L
x y
o =
Me2Nr
Formula (Ic)
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
-105-
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wherein:
L is bond, -(C=0)(OCR8R9)z-, or -(C=0)(OCR8R9)z0-;
each R8 and R9 is independently H, halogen, CI-CI-alkyl,
C1-C3-
alkoxy, C3-05-cycloalkyl, or R8 and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6;
Xis absent or -0-; and
RY is:
R4a R4b
I P
0 e
ic
each R4a and R4b is independently H, halogen, or substituted or unsubstituted
alkyl;
p is an integer from 1-10; and
q is an integer from 1-3.
[0488] In some embodiments, q is 1.
[0489] In some embodiments, p is an integer from 3-5. In some embodiments, p
is 4. In some
embodiments, q is 1 and p is 4.
[0490] In some embodiments, q is 1 and p is an integer from 3-5.
[0491] In some embodiments, each R4a and R4b is independently H or substituted
or unsubstituted
alkyl. In some embodiments, each R4a and R4b is independently H, halogen, C1-
C3alkyl, or Ci-
C3haloalkyl. In some embodiments, each R4a and R41) is H.
[0492] In some embodiments, RY is:
0
S
SCS*54
[0493] In some embodiments, the sulfoxide of any compound provided herein is
racemic. In some
embodiments, the sulfoxide of any compound provided herein is an enantiomer.
In some
embodiments, the sulfoxide of any compound provided herein is has a
stereochemistry that is (R)
or (S).
-106-
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104941 In some embodiments, provided herein is a compound having the structure
of Formula
(Id):
OH
= _
"
dz
Rz, -L 0 1"6H
X y =,---?
0 .:-........õ.õ,-
,.,,õ
Me2N1-
Formula (Id)
or a pharmaceutically acceptable salt or solvate (e.g., or a stereoisomer)
thereof,
wherein:
L is bond, -(C=0)(OCR8R9)z-, or -(C=0)(OCR8R9)z0-;
each R8 and R9 is independently H, halogen, Ci-C3-alkyl, C1-C3-haloalkyl, Ci-
C3-
alkoxy, C3-05-cycloalkyl, or Rg and R9 are taken together with the atoms to
which they are attached to form a C3-05-cycloalkyl;
z is 1-6;
X is absent or -0-; and
Rz is:
N R6R7
R5-s-W---/
R10 R11
,
R5 is -SR';
Ric is substituted or unsubstituted (e.g., straight or branched) alkyl (e.g.,
substituted with one or more (alkyl) substituent, each (alkyl) substituent
being independently selected from the group consisting of carboxylic acid,
-SH, thioalkyl, acetamide, amino, oxo, optionally substituted
heterocycloalkyl (e.g., N-attached pyrrolidinyl substituted with -COOH))
or substituted or unsubstituted (e.g., straight or branched) heteroalkyl
(e.g.,
substituted with one or more (heteroalkyl) substituent, each (heteroalkyl)
-107-
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substituent being independently selected from the group consisting of
carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3 alkyl);
R6 and R7 are each independently H, substituted or unsubstituted alkyl, or
substituted or unsubstituted heteroalkyl;
each R1 and R" is independently H, halogen, CI-C3-alkyl, CI-C3-haloalkyl,
Ci-
C3-alkoxy, C3-05-cycloalkyl, or two of R1 and R" are taken together with the
atoms to which they are attached to form a C3-05-cycl alkyl ; and
s is an integer from 1-10
[0495] In some embodiments, R6 and R7 are each independently H or substituted
or unsubstituted
alkyl (e.g., Cl-C3 alkyl optionally substituted with oxo). In some
embodiments, R6 and R7 are each
independently H or Ci-C3 alkyl optionally substituted with oxo. In some
embodiments, R6 and R7
are each independently H or -(C=0)CH3. In some embodiments, R.6 is H and R7 is
H or -
(C=0)CH3. In some embodiments, R6 is H and R7 is -(C=0)CH3. In some
embodiments, R6 and
R7 are H.
[0496] In some embodiments, each R1 and R" is independently H, halogen, Ci-
C3alkyl, or Ci-
C3haloalkyl. In some embodiments, each R1 and R11 is H.
[0497] In some embodiments, s is 1-3. In some embodiments, s is 1. In some
embodiments, s is 1
and R1 and R" are H.
[0498] In some embodiments, R6, R7, R1 and R" are each H, and s is 1-3.
[0499] In some embodiments Ric is substituted alkyl or substituted
heteroalkyl.
[0500] In some embodiments, Ric is heteroalkyl substituted with carboxylic
acid.
[0501] In some embodiments, Ric is alkyl substituted with one or more alkyl
substituent, each
alkyl substituent being independently selected from the group consisting of
carboxylic acid and
acetamide.
[0502] In some embodiments R1' is substituted heteroalkyl, the heteroalkyl
being substituted with
one or more heteroalkyl substituent, each heteroalkyl substituent being
independently selected
from the group consisting of oxo, carboxylic acid, amino, thioalkyl, thiol,
acetamide, and C1-C3
alkyl. In some embodiments, Ric is heteroalkyl substituted with carboxylic
acid.
[0503] In some embodiments, Ric is substituted heteroalkyl, the heteroalkyl
being substituted with
-COOH and oxo. In some embodiments, Ric is substituted heteroalkyl, the
heteroalkyl being
substituted with oxo and acetamide. In some embodiments, Ric is substituted
heteroalkyl, the
heteroalkyl being substituted with Cl-C3 alkyl, oxo, and substituted N-
attached heterocycloalkyl.
-108-
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In some embodiments, R' is substituted heteroalkyl, the heteroalkyl being
substituted with -
COOH, C1-C3 alkyl, oxo, and thiol.
105041 In some embodiments, R5 comprises a radical of one or more keratolytic
group (e.g., each
radical of the one or more keratolytic group being independently selected from
the group
consisting of a radical of glycolic acid (GA), a radical of thioglycolic acid
(TGA), a radical of
lactic acid (Lac), a radical of thiolactic acid (TLac), a radical of lipoic
acid (Lip), a radical of lipoic
acid sul foxi de (Li pox), a radical of dihydrolipoic acid (di HLi p), a
radical of N-acetyl cysteine
(NAC), a radical of cysteine (Cys), a radical of glutathione (GSH), a radical
of captopril (Cap),
and a radical of bucillamine (Buc)).
105051 In some embodiments, R5 is a radical of one or more keratolytic group,
each radical of the
one or more keratolytic group being independently selected from the group
consisting of a radical
of glycolic acid (GA), a radical of thioglycolic acid (TGA), a radical of
lactic acid (Lac), a radical
of thiolactic acid (TLac), a radical of lipoic acid (Lip), a radical of lipoic
acid sulfoxide (Lipox),
a radical of dihydrolipoic acid (diHLip), a radical of N-acetyl cysteine
(NAC), a radical of cysteine
(Cys), a radical of glutathione (GSH), a radical of captopril (Cap), and a
radical of bucillamine
(Buc).
105061 In some embodiments, R5 comprises a (thiol) radical of one or more
keratolytic group,
each (thiol) radical of the one or more keratolytic group being independently
selected from the
group consisting of a (thiol) radical of thioglycolic acid (TGA), a (thiol)
radical of thiolactic acid
(TLac), a (thiol) radical of dihydrolipoic acid (diHLip), a (thiol) radical of
N-acetyl cysteine
(NAC), a (thiol) radical of cysteine (Cys), a (thiol) radical of glutathione
(GSH), a (thiol) radical
of captopril (Cap), and a (thiol) radical of bucillamine (Buc).
105071 In some embodiments R5 is a thiol radical of one or more keratolytic
group, each thiol
radical of the one or more keratolytic group being independently selected from
the group
consisting of a thiol radical of thioglycolic acid (TGA), a thiol radical of
thiolactic acid (TLac), a
thiol radical of dihydrolipoic acid (diHLip), a thiol radical of N-acetyl
cysteine (NAC), a thiol
radical of cysteine (Cys), a thiol radical of glutathione (GSH), a thiol
radical of captopril (Cap),
and a thiol radical of bucillamine (Buc).
105081 In some embodiments, the (e.g., thiol) radical of the keratolytic agent
comprises a (e.g.,
thiol) radical of one or more keratolytic group, each (e.g., thiol) radical of
the one or more
keratolytic group being independently selected from the group consisting of
[Lac-Lac]., [Lac-
NAC]-, [Cys-Cys]-, [diHLip-NAC-NAC]., [difiLip-NAC]., [diHLip-Cap-Cap].,
[diHLip-Cap]..,
[difThip-Cys-Cys]=, [diffLip-Cys]=, [diffLip-Lipox-LipoxP, and [diHLip-
Lipox]...
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105091 In some embodiments, the thiol radical of the keratolytic group is the
point of attachment
of le to the rest of the molecule. In some embodiments, R5 attaches to the
rest of the molecule to
form a disulfide bond.
105101 In some embodiments, le is:
HS S)211
H (OH
's OH HS
OH
0 0 0
0
0
cly.OH
S1oH SOH HON N
OH S
1
ss(s N H
0 -"-SH
0 0 0
SNOH0 H H S N H H
0 , or 0
105111 In some embodiments, It' is :
NHR7
Rics
e .
105121 In some embodiments, R7 is H or -(C=0)CE13. In some embodiments, R7 is
H. In some
embodiments, R7 is -(C=0)CH3.
105131 In some embodiments, each Rk is independently substituted or
unsubstituted (e.g., straight
or branched) alkyl or substituted or un sub stituted (e.g., straight or
branched) h eteroal kyl . In some
embodiments, each Ric is independently substituted (e.g straight or branched)
alkyl or substituted
(e.g., straight or branched) heteroalkyl.
105141 In some embodiments, each R1c is independently substituted (e.g.,
straight or branched)
alkyl, the substituted alkyl being substituted with one or more (alkyl) sub
stituent, each (alkyl)
substituent being independently selected from the group consisting of
carboxylic acid, -SH,
thioalkyl, acetamide, amino, oxo, and optionally substituted heterocycloalkyl
(e.g., N-attached
pyrrolidinyl substituted with -COOH).
- 1 10-
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105151 In some embodiments, each RI is independently substituted (e.g.,
straight or branched)
heteroalkyl, the substituted heteroalkyl being substituted with one or more
(heteroalkyl)
sub stituent, each (heteroalkyl) sub stituent being independently selected
from the group consisting
of carboxylic acid, amino, thioalkyl, thiol, acetamide, and Ci-C3 alkyl.
105161 In some embodiments, R5 and each Rk each independently comprise one or
more
substituent that is a carboxylic acid or an ester. In some embodiments, R5 and
each Rlc each
independently comprise one or more substituent that is a carboxylic acid
(e.g., -(C=0)0H). In
some embodiments, R5 and each Ric each independently comprise one or more
substituent that is
an ester (e.g., -(C=0)0-Ci-C4alkyl).
105171 In some embodiments, the -(C=0)0H of R5 and/or Ric is optionally
esterified (e.g., -
(C=0)0H or -(C=0)0-Ci-C4alkyl) In some embodiments, the C1-C4alky1 is methyl,
ethyl,
propyl, isopropyl, butyl, or t-butyl.
105181 Provided in some embodiments herein is a compound, a stereoisomer
thereof, or a
pharmaceutically acceptable salt of the compound or the stereoisomer, having a
structure provided
in Table 1.
Table 1
OH
JHN
M e )
HO,,. \
Os'
0 H
d
x y
0 õ,.,9.=,õ
Me2N1'
Compound R X
1 absent bond
sH
2 absent bond
sH
3 absent bond
NH2
4 HS absent bond
-1 1 1-
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OH
ey'".a.
-0H N
.....C.\) ?
HO,,.
= "'-,
Os
d7
RXL .....,=-k 0E1
0 .....).",,
Me2Nf
Compound R X L
0
NH
- absent bond
e
,o
6 1S¨Se absent bond
\---"==,,,-^,^,sss,-,
0
,o
7 1S¨S'e absent bond
e
CI
C)7-31
8 absent bond
8
0
Cl/ ilS¨S
9 absent bond
0 0 SH
HO-.1.
H
N µ2\ absent bond
- L.NX11
H
Fl H2 0
r s H
0 0
11 sss()L N -cii- N
OH absent bond
H
NH2 0
r s H
0
12 HS N absent bond
sis
H
-112-
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-.=- OH
0---')Crifi
OH N
.....C.\ ) 1)
Ha,.
Os'
POH
o -
RXLy
..)<0E1
'-
Me2Nf
Compound R X L
0 SH
,
--
13 HS xelL----,/ absent bond
14 : NQS
absent bond
\JHD
H S
0
HN-j.
H 0 yi...1
15 absent bond
-r0 0 s,
s
HNx--,s.Scsse
HO 0
0
HNA"
HOyLi
16 -0 0 s absent bond
-S
HN.,,s--S-.....--^,ses
HO"---0
OH
--
O&.
0 KI-,1
--=
17 se--I absent bond
HO 00 S.s
-- j
N s
-113-
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--. OH
Or.a.
a OH N
......C.\) ?
HO,,.
Os
u 7
RXL 0
s - y
0 .....).",,
Me2Nf
Compound R X L
OH
--/
0 N.,/)
18 ve=Th absent bond
HO 00 S
'S
--....1.1\1,r, ,S....:wf
S
0 NH2
19 HO ,K.....---=, ,S,./ S absent bond
R1H2
20 HS"--.
/
absent -
(C=0)0CH(CH3)0-
21 HS...--
/
absent -
(C=0)0CH20-
NH2
22 HS...._.j../ absent -
(C=0)0CH(CH3)0-
e
,o
23 S¨Se absent -
(C=0)0CH(CH3)0-
,
se-
e
,o
24 S¨se
absent C -
(C=0)0CH20-
-1---------_-.4-,
sr
e
,o
25 S--se
absent
(C=0)0CH(CH2CH3)0-
se
G
,0
S--s
26 absent -
(C=0)0C(CH3)20-
sr's'
-114-
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--.'` OH
ey''..1.
-0H N
HOMeOf____)v__õ,.....Ø\ ?
,,.
= "'-,
Os
OH
d 7
sX-Ly
0 .....).",,
Me2Nf
Compound R X L
27
CI) rS absent bond
H
-'('-'-
rS
28 absent bond
H2N)-Y
? 29 S
absent bond
----fr-N---r-/
H
02N 0
Y
30 S absent bond
? r
H
31
1 absent bond
..õ..-- ,...- ,...... /
0
NH
32 absent bond
_.---..
HO 0
-115-
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--. OH
0/"..
a OH N
......C.\) 1.)
H 0,
-
Os
u 7
0
RX1- ....)<E1
0 ...\/1",,
Me2Nf
Compound R X L
33
N absent bond
-----µ
0
34 N----V absent bond
--
0
-j
N iss
H absent bond
iss EN1
36 1
0 absent -
(C=0)(0(CH2)2)40-
HS
i H
37 1
0 absent -
(C=0)(0(CH2)2)s0-
HS
38 Ø4,,,S y
absent bond
0
39 HO/ J1---s absent bond
.s
0
Q.
0 s
absent bond
oe
cfs ¨s
41 absent bond
-116-
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--'- OH
ey'".a.
-0H N
.....C.\) ?
HO,,.
= "'-,
Os
d7
RXL .....õ-koH
0 .....).",,
Me2Nf
Compound R x L
0
,o
42 S¨s6
absent bond
C----C..------.---->s
e
,o
S¨s
43 ce)Z. absent bond
0 H
HO)LICI\i y
0
44 S
absent bond
(I) L,
H
0 H
CD-j=Lt.i\i,i(
0
45 S
absent bond
H
0 0 OH
0 NH
>(¨ t:"NH
HO
Sµ ,S L.
IS s 0
46
absent bond
-..,
--...../
-117-
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--'- OH
ey.a.
OH N
M e Of.._ . . __.. . . C. \) /.
. )
HO,,.
=
Os
0 H - OH
d7
RXLy
.....õ-koH
s -
0 .....).",,
Me2Nf
Compound R X L
0
CI(OH
N
0
PH..
ni: 1{13-0H S
% ,S 0
47 / IS S absent bond
\--)=,,,
HS
0¨ 01,,OH
0 NH
HO, c_ NH
S%
48 / IS S 0
absent bond
0
HO -
_ H 0
I/ õ.
( S
S I\ S
49 SN/ absent bond
-..,_
-118-
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OH
-oH N
HO,,.
0 H Os'
HO
d
R
y
0
Me2N'
Compound R X
S.
0 HN
HO
50 s_ J
s ..õ absent bond
S¨s
51 absent bond
0
0
stS
c)y105191 Each recitation of" "provided herein, unless otherwise
stated, includes a specific
and explicit recitation of:
e o 8 0 0
0 0 0
CfS¨S S S¨s (*-S
c)irse /1'(\rõ.s'
5- 5" 5" 3- , and
105201 The compounds used in the reactions described herein are made according
to organic
synthesis techniques starting from commercially available chemicals and/or
from compounds
described in the chemical literature or the present disclosure. "Commercially
available chemicals"
are obtained from standard commercial sources including Acros Organics
(Pittsburgh, PA),
Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin
Chemicals Ltd.
(Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto,
Canada), Bionet
(Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co.
(Hauppauge,
-119-
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NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher
Scientific
Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier
Scientific (Logan, UT),
ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.),
Lancaster Synthesis
(Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical
Co. (Orem,
UT), Pfaltz 8z Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce
Chemical Co.
(Rockford, IL), Riedel de IIaen AG (Hanover, Germany), Spectrum Quality
Product, Inc. (New
Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc.
(Rockville, MD), and
Wako Chemicals USA, Inc (Richmond, VA)
105211 Suitable reference books and treatise that detail the synthesis of
reactants useful in the
preparation of compounds described herein, or provide references to articles
that describe the
preparation, include for example, "Synthetic Organic Chemistry", John Wiley &
Sons, Inc., New
York; S. R. Sandler et al., "Organic Functional Group Preparations,- 2' Ed.,
Academic Press,
New York, 1983; H. 0. House, "Modern Synthetic Reactions-, 2nd Ed., W. A.
Benjamin, Inc.
Menlo Park, Calif 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed.,
John Wiley & Sons,
New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms
and
Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable
reference books and
treatise that detail the synthesis of reactants useful in the preparation of
compounds described
herein, or provide references to articles that describe the preparation,
include for example,
Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting
Materials", Second,
Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5;
Hoffman, R.V.
"Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN
0-19-509618-
5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional
Group
Preparations" 2hd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.
"Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992)
John Wiley &
Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry"
(2000) Wiley-VCH,
ISBN: 3-527-2987 1 -1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups"
(1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic
Chemistry" 7th Edition
(2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate
Organic
Chemistry- 2" Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;
"Industrial Organic
Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia"
(1999) John
Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-
2000) John
Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John
Wiley & Sons,
in 73 volumes.
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[0522] Specific and analogous reactants are optionally identified through the
indices of chemicals
prepared by the Chemical Abstract Service of the American Chemical Society,
which are available
in most public and university libraries, as well as through on-line databases
(contact the American
Chemical Society, Washington, D.C. for more details). Chemicals not
commercially available in
catalogs are optionally prepared by custom chemical synthesis houses, where
many of the standard
chemical supply houses (e.g., those listed above) provide custom synthesis
services. A reference
for the preparation and selection of pharmaceutical salts of the keratolytic
conjugate described
herein is P. Ft Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts",
Verlag Helvetica
Chimica Acta, Zurich, 2002.
[0523] In some embodiments, a compound provided herein is a compound
represented by any one
of Formula (I), Formula (I-A), Formula (Ia), Formula (Ia'), Formula (lb),
Formula (Ic), Formula
(Id), or Table 1. In some embodiments, a compound provided herein is
administered as a pure
chemical. In other embodiments, a compound provided herein is combined with a
pharmaceutically suitable or acceptable carrier (also referred to herein as a
pharmaceutically
suitable (or acceptable) excipient, physiologically suitable (or acceptable)
excipient, or
physiologically suitable (or acceptable) carrier) selected on the basis of a
chosen route of
administration and standard pharmaceutical practice as described, for example,
in Remington: The
Science and Practice of Pharmacy (Gennaro, 21' Ed. Mack Pub. Co., Easton, PA
(2005)).
[0524] Provided in some embodiments herein is a pharmaceutical composition
comprising at least
one keratolytic conjugate together with one or more pharmaceutically
acceptable carriers. The
carrier(s) (or excipi ent(s)) is acceptable or suitable if the carrier is
compatible with the other
ingredients of the composition and not deleterious to the recipient (i.e., the
subject) of the
composition.
[0525] In some embodiments, a compound provided herein (e.g., such as a
compound represented
by any one of Formula (I), Formula (I-A), Formula (Ia), Formula (Ia'), Formula
(lb), Formula
(Ic), Formula (Id), or Table 1) is substantially pure, in that it contains
less than, for example, about
5%, or less than about 1%, or less than about 0.1%, of other organic small
molecules, such as
unreacted intermediates or synthesis by-products that are created, for
example, in one or more of
the steps of a synthesis method.
[0526] Suitable oral dosage forms include, for example, tablets, pills,
sachets, or capsules of hard
or soft gelatin, methylcellulose or of another suitable material easily
dissolved in the digestive
tract. In some embodiments, suitable nontoxic solid carriers are used which
include, for example,
pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium
saccharin, talcum,
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cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,
Remington: lhe Science
and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA
105271 (2005)).
105281 In some embodiments provided herein is a pharmaceutical composition
comprising a
compound provided herein (e.g., such as a compound represented by any one of
Formula (I),
Formula (I-A), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic),
Formula (Id), or Table 1)
and at least one pharmaceutically acceptable excipient. In some embodiments,
the pharmaceutical
composition is suitable for ophthalmic administration. In some embodiments,
the pharmaceutical
composition is suitable for topical ophthalmic administration. In some
embodiments, topical
ophthalmic administration is administration in and/or around the eye, such as
to the eyelid margin.
In some embodiments, topical ophthalmic administration is administration to
the ocular surface
and the inner surface to the eyelid.
105291 In some embodiments, a keratolytic conjugate provided herein (such as a
compound
represented by any one of Formula (I), Formula (I-A), Formula (Ia), Formula
(Ia'), Formula (Ib),
Formula (Ic), Formula (Id), or Table 1) is formulated as a solution or
suspension for topical
administration to the eye.
105301 In some embodiments, a keratolytic conjugate provided herein (such as a
compound
represented by any one of Formula (I), Formula (I-A), Formula (Ia), Formula
(Ia'), Formula (Ib),
Formula (Ic), Formula (Id), or Table 1) is formulated for administration by
injection. In some
instances, the injection formulation is an aqueous formulation. In some
instances, the injection
formulation is a non-aqueous formulation. In some instances, the injection
formulation is an oil-
based formulation, such as sesame oil, or the like.
105311 In some embodiments, the dose of the composition comprising at least
one keratolytic
conjugate as provided herein differ, depending upon the patient's (e.g.,
human) condition, that is,
general health status, age, and other factors.
105321 Pharmaceutical compositions provided in some embodiments herein are
administered in a
manner appropriate to the disease to be treated (or prevented). An appropriate
dose and a suitable
duration and frequency of administration will be determined by such factors as
the condition of
the patient, the type and severity of the patient's disease, the particular
form of the active
ingredient, and the method of administration. In general, an appropriate dose
and treatment
regimen provides the composition(s) in an amount sufficient to provide
therapeutic and/or
prophylactic benefit (e.g., an improved clinical outcome, such as more
frequent complete or partial
remissions, or longer disease-free and/or overall survival, or a lessening of
symptom severity).
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Optimal doses are generally determined using experimental models and/or
clinical trials. The
optimal dose depends upon the body mass, weight, or blood volume of the
patient.
105331 In other embodiments, the topical compositions described herein are
combined with a
pharmaceutically suitable or acceptable carrier (e.g., a pharmaceutically
suitable (or acceptable)
excipient, physiologically suitable (or acceptable) excipient, or
physiologically suitable (or
acceptable) carrier). Exemplary ex ci pi ents are described, for example, in
Remington: The Science
and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
Methods of Treatment Utilizing Keratolytic Conjugates
105341 In some embodiments provided herein is a method of treating a
dermatological or
ophthalmic disease or disorder in a patient in need of thereof, comprising
administering to the
patient any compound provided herein, or a pharmaceutically acceptable salt
thereof, or a (e.g.,
pharmaceutical) composition comprising any compound provided herein, or a
pharmaceutically
acceptable salt thereof, such as a compound represented by any one of Formula
(I), Formula (I-
A), Formula (Ia), Formula (Ia'), Formula (lb), Formula (Ic), Formula (Id), or
Table 1. In some
embodiments provided herein the pharmaceutical composition is in the form of a
solution or
suspension suitable for topical ophthalmic administration. In some
embodiments, topical
ophthalmic administration is administration in and/or around the eye, such as
to the eyelid margin.
In some embodiments, topical ophthalmic administration is administration to
the ocular surface
and the inner surface to the eyelid.
105351 In some embodiments, the dermatological or ophthalmic disease or
disorder is
inflammation or hyperkeratosis (e.g., of the eyes or skin). In some
embodiments, the
dermatological or ophthalmic disease or disorder is inflammation or
hyperkeratosis of the eyes or
skin (e.g., the ocular surface). In some embodiments, the dermatological or
ophthalmic
dermatological disease or disorder is selected from the group consisting of
meibomian gland
dysfunction (MGD), dry eye disease (DED), ocular manifestations of graft
versus host disease,
vernal keratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de Lange
Syndrome, evaporative
eye disease, aqueous deficiency dry eye, blepharitis, and seborrheic
blepharitis. In some
embodiments, the dermatological or ophthalmic disease or disorder is
inflammation or
hyperkeratosis (e.g., of the eyes or skin), such as, for example, meibomian
gland dysfunction
(MGD), dry eye disease (DED), ocular manifestations of graft versus host
disease, vernal
keratoconjunctivitis, atopic keratoconjunctivitis, Cornelia de Lange Syndrome,
evaporative eye
disease, aqueous deficiency dry eye, blepharitis, seborrheic blepharitis, or
any combination
thereof.
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105361 In some embodiments, the ophthalmic disease or disorder is selected
from the group
consisting of dry eye, lid wiper epitheliopathy (LWE), contact lens discomfort
(CLD), dry eye
syndrome, evaporative dry eye syndrome, aqueous deficiency dry eye syndrome,
blepharitis,
keratitis, meibomian gland dysfunction, conjunctivitis, lacrimal gland
disorder, contact lens
related conditions and inflammation of the anterior surface of the eye,
infection of the anterior
surface of the eye, and autoimmune disorder of the anterior surface of the
eye.
105371 Provided herein is a method for treating an ocular surface disorder in
an individual in need
thereof comprising topical administration of a keratolytic conjugate to the
individual in need
thereof. In some embodiments, administration occurs with the assistance of a
health-care provider
(e.g., this category includes both acute and maintenance uses of the
keratolytic conjugate). An
acute use, in some embodiments, requires a stronger keratolytic conjugate
(either in terms of
concentration of the agent or the inherent activity of the agent). A
maintenance use, in some
embodiments, allows for the use of lower concentrations of the agent, or
agents with lower
inherent activity. A maintenance use, in some embodiments, involves a patient
at a routine visit
to the health care provider. Both acute uses and maintenance uses optionally
involve use of an
eye-protecting device or apparatus. In some embodiments, the acute use is
performed by the health
care provider, and the maintenance use is performed by the patient or non-
health care provider. In
some embodiments, administration does not occur with the active assistance of
a health care
provider (e.g., but rather involves the patient applying the keratolytic
conjugate to his/her own
eyelid margin). In some embodiments, such administration occurs over an
extended period of time
(e.g., one way of describing this patient-administered multi-administration
mode is as a chronic
use). In some embodiments, different or second formulations of the keratolytic
conjugate are used
for chronic or patient-administered uses. In some embodiments the different or
second formulation
utilizes a lower concentration of the keratolytic conjugate. In some
embodiments, the second or
different formulation utilizes a keratolytic conjugate that has a lower
activity than the first
formulation.
105381 It should be understood that the present methods also include the
physical removal of an
obstruction in an meibomian gland (e.g., followed by chronic and/or
maintenance administration
of a keratolytic conjugate provided herein).
105391 In some embodiments provided herein is a method for treating meibomian
gland
dysfunction in a patient in need thereof, comprising topically administering
to the patient a
composition comprising a therapeutically-effective amount of at least one
keratolytic conjugate
in an ophthalmically-acceptable carrier. In some embodiments, the topical
administration of the
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composition comprising a therapeutically-effective amount of at least one
keratolytic conjugate
in an ophthalmically-acceptable carrier results in enhanced meibum production.
105401 In some embodiments, the topical administration of the composition
comprising a
therapeutically-effective amount of at least one keratolytic conjugate in an
ophthalmically-
acceptable carrier occurs until the keratinized obstruction is relieved. In
some embodiments, the
topical administration of the composition comprising a therapeutically-
effective amount of at least
one keratolytic conjugate in an ophthalmically-acceptable carrier occurs
periodically after
relieving of the keratinized obstruction In some embodiments, the topical
administration of the
composition comprising a therapeutically-effective amount of at least one
keratolytic conjugate
in an ophthalmically-acceptable carrier is a single administration. In some
embodiments, the
topical administration of the composition comprising a therapeutically-
effective amount of at least
one keratolytic conjugate in an ophthalmically-acceptable carrier is a
periodic administration. In
some embodiments, the topical administration of the composition comprising a
therapeutically-
effective amount of at least one keratolytic conjugate in an ophthalmically-
acceptable carrier
occurs once a day. In some embodiments, the topical administration of the
composition
comprising a therapeutically-effective amount of at least one keratolytic
conjugate in an
ophthalmically-acceptable carrier occurs twice a day. In some embodiments, the
topical
administration of the composition comprising a therapeutically-effective
amount of at least one
keratolytic conjugate in an ophthalmically-acceptable carrier occurs more than
twice a day.
105411 In some embodiments, the composition for topical administration
comprises a
therapeutically-effective amount of at least one keratolytic conjugate in an
ophthalmi cally-
acceptable carrier is a solution. In some embodiments, the composition for
topical administration
comprises a therapeutically-effective amount of at least one keratolytic
conjugate in an
ophthalmically-acceptable carrier is a solution suitable for topical
administration as eye drops. In
some embodiments, the composition for topical administration comprises a
therapeutically-
effective amount of at least one keratolytic conjugate in an ophthalmically-
acceptable carrier is a
gel, ocular insert, spray, or other topical ocular delivery method. In some
embodiments, the
composition for topical administration comprises a therapeutically-effective
amount of at least
one keratolytic conjugate in an ophthalmically-acceptable carrier is a semi-
solid. In some
embodiments, the composition for topical administration comprises a
therapeutically-effective
amount of at least one keratolytic conjugate in an ophthalmically-acceptable
carrier is
homogenous. In some embodiments, the composition for topical administration
comprises a
therapeutically-effective amount of at least one keratolytic conjugate in an
ophthalmically-
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acceptable carrier is a dispersion. In some embodiments, the composition for
topical
administration comprises a therapeutically-effective amount of at least one
keratolytic conjugate
in an ophthalmically-acceptable carrier is hydrophilic. In some embodiments,
the composition for
topical administration comprises a therapeutically-effective amount of at
least one keratolytic
conjugate in an ophthalmically-acceptable carrier and an oleaginous base. In
some embodiments,
the composition for topical administration comprises a therapeutically-
effective amount of at least
one keratolytic conjugate in an ophthalmically-acceptable carrier and at least
one ophthalmically-
acceptable excipient
105421 In some embodiments provided herein is a method for treating MGD in a
patient in need
thereof comprising topical administration of a composition comprising a
keratolytic conjugate. In
some embodiments, the topical administration of the composition comprising a
keratolytic
conjugate occurs once a week. In some embodiments, the topical administration
of the
composition comprising a keratolytic conjugate occurs twice a week. In some
embodiments, the
topical administration of the composition comprising a keratolytic conjugate
occurs every other
day. In some embodiments, the topical administration of the composition
comprises a keratolytic
conjugate occurs every day. In some embodiments, the topical administration of
the composition
comprises a keratolytic conjugate occurs several times a day.
105431 In some embodiments, the method comprises administering a compound or
formulation
provided herein in an acute treatment scenario. In some embodiments, the
method comprises
treatment of a patient naïve to treatment. In some embodiments, the method
comprises
administering a compound or formulation provided herein in a chronic treatment
scenario In some
embodiments, the method comprises administering a compound or formulation
provided herein
in a maintenance therapy scenario. In an acute treatment scenario, the
administered dosage of
keratolytic conjugate may be higher than the administered dosage of
keratolytic conjugate
employed in a chronic treatment scenario or a maintenance therapy scenario. In
an acute treatment
scenario, the keratolytic conjugate may be different from the keratolytic
conjugate employed in a
chronic treatment scenario. In some embodiments, the course of therapy begins
in the initial phase
of therapy as an acute treatment scenario and later transitions into a chronic
treatment scenario or
a maintenance therapy scenario. In some embodiments, the meibomian gland
opening
pharmacological agent administered in the acute treatment scenario is a
keratolytic agent and/or
keratoplastic agent, and the pharmacological agent administered in the chronic
treatment scenario
or a maintenance therapy scenario is a keratolytic conjugate.
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105441 In some embodiments, an initial treatment is administered (e.g., by a
physician or
healthcare professional) to an individual to initially open a blockage of the
meibomian gland, such
as by placing a more highly concentrated formulation of one of the keratolytic
conjugate provided
herein. In the event the higher concentration formulations are required, the
application thereof
may require ocular shielding or other activity to minimize the impact of
irritation or disruption of
the ocular surface or surrounding tissues. Following such a procedure, a
patient may be given a
different formulation of keratolytic conjugate to take home to apply
periodically to the lid margin
to maintain the patency of the meibomian gland Such application may occur
twice daily, once a
day, weekly or monthly, depending on the formulation activity and the
therapeutic product profile
of the formulation.
105451 Provided in some embodiments of the methods of treatment described
herein is the
location of the topical administration of the composition. In some
embodiments, the composition
comprising a keratolytic conjugate is administered such that no irritation to
eye occurs. In some
embodiments, the composition comprising a keratolytic conjugate is
administered to the eye lid
margin.
105461 In some embodiments of the methods of treatment provided herein is the
use of a protective
element provided to the eye to avoid irritation to the eye. Although the
formulations described
herein are generally non-irritating, in some embodiments (e.g., high
concentration of agent or
when used on a sensitive eye) a protective element provides an additional
layer of safety and
comfort for the patient. In some embodiments, the composition comprising a
keratolytic conjugate
is administered while an eye shield is placed on the eye to reduce contact of
the pharmacological
agent with the cornea and/or conjunctiva such that reduced irritation to eye
occurs. In some
embodiments, the eye shield is a contact lens or an eye covering. In some
embodiments, the eye
covering comprises a self-adhesive. In some embodiments, the composition
comprising a
keratolytic conjugate is administered while the lid is pulled away from the
globe to reduce contact
of the pharmacological agent with the cornea and/or conjunctiva such that
reduced irritation to
eye occurs.
105471 While exemplary embodiments of the present invention have been shown
and described
herein, it will be obvious to those skilled in the art that such embodiments
are provided by way of
example only. Numerous variations, changes, and substitutions will now occur
to those skilled in
the art without departing from the invention. It should be understood that
various alternatives to
the embodiments of the invention described herein may be employed in
practicing the invention.
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It is intended that the following claims define the scope of the invention and
that methods and
structures within the scope of these claims and their equivalents be covered
thereby.
EXAMPLES
I. Chemical Synthesis
105481 Solvents, reagents and starting materials were purchased from
commercial vendors and
used as received unless otherwise described. All reactions were performed at
room temperature
unless otherwise stated. Starting materials were purchased from commercial
sources or
synthesized according to the methods described herein or using literature
procedures or the present
disclosure.
Abbreviations
105491 The following abbreviations are used in the Examples and other parts of
the description:
AcOH: Acetic acid
CDC13: Deuterochloroform
COMU: (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-
carbenium
hexafluorophosphate
CV: Column Volume
DBU: 1,8-Diazabicyclo[5,4,0]undec-7-ene
DCM: Dichloromethane
DIPEA: NN- Diisopropylethylamine
D20: Deuterium oxide
DMF: N, N-Dim ethylformami de
DMSO-D6: Deuterated dimethyl sulfoxide
DPBS: Dulbecco's phosphate-buffered saline
Et0Ac: Ethyl acetate
h: Hour(s)
HC1: Hydrochloric acid
LCMS: Liquid chromatography-mass spectrometry
M: Molar
MeCN; Acetonitrile
MeOH: Methanol
MgS 04 : Magnesium sulfate
mins: Minute(s)
N2: Nitrogen
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Na2SO4: Sodium sulfate
NH4C1: ammonium chloride
r.t.: Room tempearture
Rt: Retention time
s: Second
sat.: Saturated
TEA: Tri ethyl amine
THF: Tetrahydrofuran
vac: Vacuum
Analytical Methods:
[0550] Method A: Waters Sunfire C18 3.5 pm, 50 x 4.6 mm; A = water + 0.1%
formic acid; B =
MeCN; 45 C; %B: 0.0 min 5% 2.25 mL/min, 1.0 min 37.5% 2.2 mL/min, 3.0 min 95%
2.2
mL/min, 3.5 min 95% 2.3 mL/min, 3.51 min 0% 2.3 mL/min, 4.0 min 0% 2.25
mL/min.
[0551] Method B: Waters Sunfire C18 5 pm, 100 x 4.6 mm; A = water + 0.1%
formic acid; B =
MeCN + 0.1% formic acid; 45 C; %B: 0.0 min 5%, 0.50 min 5%, 7.5 min 95%, 10.0
min 95%,
10.1 min 5%, 13.0 min 5%; 1.5 mL/min.
[0552] Method C: Phenomenex Luna C18 (2) 3 pm, 50 x 4.6 mm; A = water + 0.1%
formic acid;
B = Me0H + 0.1% formic acid; 45 C; %B: 0.0 min 5% 2.25 mL/min, 1.0 min 37.5%
2.2 mL/min,
3.0 min 95% 2.2 mL/min, 3.5 min 95% 2.3 mL/min, 3.51 min 5% 2.3 mL/min, 4.0
min 5% 2.25
mL/min.
[0553] Method D: Waters Sunfire C18 3.5 pm, 50 x 4.6 mm; A = water + 0.1%
formic acid; B =
MeCN; 45 C; %B: 0.0 min 5% 2.25 mL/min, 1.0 min 20% 2.2 mL/min, 3.0 min 50%
2.2 mL/min,
3.25 min 95% 2.2 mL/min, 3.50 min 95% 2.3 mL/min, 3.51 min 100% 2.30 mL/min,
4.0 min
100% 2.25mL/min.
[0554] Method E: Phenomenex Gemini NX C18 5 pm, 150 x 4.6 mm; A = water + 0.1%
formic
acid; B = Me0H; 40 C; %B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min 95%,
10.1 min
5%, 13.0 min 5%; 1.5 mL/min.
105551 Method F: Waters CSH C18 1.7 pm, 100 x 2.1 mm; A = water + 0.1% formic
acid; B =
MeCN, 45 C; %B: 0.05 min 5% 0.35 mL/min, 5.00 min 95% 0.35 mL/min, 6.60 min
5% 0.35
mL/min. 8.00 min end.
Chemical Synthesis Example 1:
Method 1:
[0556] Step I. Methyl 2-((tert-butyldiphenylsilyl)oxy)acetate
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0 0
____________________________________________________ -.,0)-0TBDPS
105571 To a stirred solution of methyl glycolate (0.77 mL, 10.0 mmol) in
anhydrous DMF (14
mL) were added imidazole (803 mg, 11.8 mmol) and tert-
butylchlorodiphenylsilane (3.12 mL,
12.0 mmol) and the mixture stirred at room temperature for 3 hours. The
solvent was evaporated
in vacuo and the residue diluted with DCM and washed with ice-cold water. The
organic layer
was dried (MgSO4) and the solvent evaporated in vacuo to give the crude
product which was
purified by flash chromatography (Biotage SP1; 100 g SNAP cartridge) eluting
with isohexane
10% Et0Ac-isohexane to yield the title compound as a colourless oil (3.26 g,
99%). LCMS
(Method A): Rt = 3.50 min; [M+Na] = 351.2. I-H-NMR (400 MHz, CDC13) 6 7.67-
7.69 (m, 4H),
7.37-7.43 (m, 6H), 4.24 (s, 2H), 3.68 (s, 3H), 1.09 (t, J= 3.0 Hz, 9H)
105581 Step 2: 2-((tert-Butyldiphenylsilyl)oxy)acetic acid
0 0
HOAõ..-OTBDPS
105591 To a stirred solution of methyl 2-((tert-butyldiphenylsilyl)oxy) (1.00
g, 3.04
mmol) in THE (2.75 mL) and water (0.92 mL) was added 0.75 M lithium
hydroxideoo (4.06 mL,
3.05 mmol) and the mixture stirred at room temperature for 20 hours. The
reaction mixture was
diluted with water (10 mL) and extracted with Et20 (3 x 20 mL). The aqueous
phase was acidified
to pH3 with 5 M HC1(aco and the solution extracted with Et0Ac (3 x 20 mL). The
combined
organics were dried (MgSO4), filtered and the solvent evaporated in vacuo. The
crude product was
purified by flash chromatography (Biotage SP1; 25 g SNAP cartridge) eluting
with isohexane
Et0Ac to yield the title compound as a colourless oil (0.65 g, 68%). LCMS
(Method A): Rt = 2.77
min; EM-Hr = 313.3. 'H-NM. (400 MHz, CDC13) 6 7.61-7.66 (m, 4H), 7.39-7.47 (m,
6H), 4.22
(s, 2H), 1.08-1.12 (m, 9H).
105601 Step 3: (25,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,35,4R,5R,8R,10R,1
IR,12S,13S,14R)-
2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-
11-yl)oxy)-
-130-
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6-methyltetrahydro-2H-pyran-3-yl 2-((tert-
butyldiphenylsilyl)oxy)acetate
OTBDPS
HO HO
=
N
HO
7
0
titio"= OH 0
0\__(\< mt,¶"
..s..=041)
0
'S
0 0
\ 0
E OH \
\ 0
OH C)\
105611 To a solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (97 mg,
0.308 mmol) and
azithromycin dihydrate (291 mg, 0.370 mmol) in toluene (15 mL) at room
temperature was added
TEA (155 pL, 1.11 mmol), 4-(dimethylamino)pyridine (286 mg, 2.34 mmol) and
2,4,6-
trichlorobenzoyl chloride (162 pL, 1.05 mmol). The mixture was stirred at room
temperature for
121 hours. The resulting mixture was diluted with DCM (10 mL), sat. NaHCO3(aq)
(10 mL) and
H20 (10 mL) and the layers separated. The aqueous phase was extracted with DCM
(3 x 10 mL).
The combined organics were dried (MgSO4), filtered, and the solvent evaporated
in vacuo. The
crude product was purified by flash chromatography (Biotage SP1; 10 g SNAP
cartridge) eluting
with 4:1 isohexane-acetone (1% TEA) ¨> acetone (1% TEA) and further purified
by flash
chromatography (Biotage SP1; 10 g SNAP cartridge) eluting with isohexane ¨>
acetone (1%
TEA). The crude product was then purified by reversed-phase preparative HPLC.
Fractions
containing desired product were combined, diluted with DCM and neutralised
with sat.
NaHCO3(Ø The organic layer was separated, and the aqueous phase extracted
with DCM. The
combined organics were washed with sat. brine solution, dried (MgSO4) and
evaporated in vacuo
to yield the title compound as a colourless gum (40 mg, 12%). LCMS (Method A):
Rt = 1.72 min;
[M+H]P = 1046.0
105621 Step 4: (25',3R,45',6R)-4-(Dimethylamino)-2-(((2R, 35',
4R,5R,8R,10R,11R,I2S,135',14R)-
2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pymn-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxci-6-azacyclopentadecan-
11-yl)oxy)-
6-methyltetrahydro-2H-pyran-3-yl 2-hydroxyacetate
-13 1 ¨
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OTBDPS OH
'.\.,.
..............0
\ E O N ------. CI \\N---.---'
g HO N
g HO
N
_____________________________________________________________________________
--____N 's . \ 0 =====<
_________________________________________________ )II. N 0
.s' N 1"n=¨
o 0 ...........,....."0H
....................,H
Ittiw" s \044) ittim"
....0
..
HON7\0 __ '''''''µ 41=.,
01
.i... :3 --7,-.- 2
\ 0 -
... OH
105631 To a stirred solution
of (2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3,4,10-trihydroxy-13-
0(2R,4R,5S,6S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-
heptamethyl-
15-oxo-1-oxa-6-azacyclopentadecan-11-y1)oxy)-6-methyltetrahydro-2H-pyran-3-y1
2-((tert-
butyldiphenylsilyl)oxy)acetate (40 mg, 0.0383 mmol) in anhydrous THF (1.0 mL)
under N2 was
added 1M tetrabutylammonium fluoride hydrate (115 uL, 0.115 mmol) in THF. The
reaction was
stirred at room temperature for 2 hours then quenched with sat. NaHCO3(aco and
extracted with
Et0Ac. The organic layer was washed with sat. brine solution and the layers
separated. The
organic phase was dried (MgSO4), filtered and the solvent evaporated in vacua
The crude product
was purified by flash chromatography (Biotage SP1; 10 g SNAP cartridge)
eluting with isohexane
(2% TEA) ¨> acetone (2% TEA) to yield the title compound as a white solid (12
mg, 39%). LCMS
(Method B): Rt = 3.04 min; [M-41] = 807.9.
Method 2:
105641 (2S, 3R,4S,6R)-4-(Dimethylamino)-2-(((2R, 3S, 4R, 5R, 8R, 10R, I IR,
12S, 13S, 14R)-2-ethyl-
3, 4, 10-trihydroxy-13-(((2R, 4R, 5 S,6S)-5-hydroxy-4-methoxy-4, 6-dime
thyltetrahydro-21-1-pyran-
2-yl)oxy)-3, 5 , 6, 8, 10, 12, 14-heptamethyl-15-oxo- 1 -oxa-6-
azacyclopentadecan- 11-yl)oxy)-6-
methyltetrahydro-2H-pyran-3-y1 (S)-2-hydroxypropanoate
OH
7
HO HO HN ¨
'.
=
_______________________________________________________________________________
____ µ
;
i HO
\ __
õ............N.,,OH ______________________________ A.
HO in.."A 0 02 S µ Ho . ItIto."
.4,-4734.4?
=
\ 0
\ 0 = 0 H \
-132-
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105651 This reaction was performed using a flow setup: A solution of L-(+)-
lactic acid (0.24 mL,
3.18 mmol) and DIPEA (0.67 mL, 3.82 mmol) in DCM (10 mL) (flow rate: 2.0
mL/min) and a
solution of triphosgene (OAS g, 0.510 mmol) in DCM (6 mL) (flow rate: L2
mL/min) were
introduced to a T-shape mixer 1 at r.t. with syringe pumps. The resultant
mixture was passed
through reaction tube 1 (inner diameter: 0.8 mm, length: 54 mm, volume: 27 mL,
reaction time:
0.5 s) at r.t. The resultant mixture and a solution of azithromycin dihydrate
(1.00 g, 1.27 mmol)
in DCM (10 mL) (flow rate: 2.0 mL/min) were introduced to T- shape mixer 2 at
r.t. The resultant
mixture was passed through reaction tube 2 (inner diameter: 0.8 mm, length:
742 mm, volume:
373 tL, reaction time: 4.3 s) at r.t. After 55 s the resultant mixture was
collected, diluted with
DCM (25 mL), and washed with sat. NH4C1(aq) (8 x 30 mL). The combined organics
were washed
with sat. brine solution (20 mL), dried (MgSO4), filtered and the solvent
evaporated in vaello. The
crude product was purified by flash chromatography (Biotage SP1; 25g Sfar
cartridge) eluting
with 8:2 isohexane-acetone (1% TEA) -> acetone (1% TEA) to yield (2S,3R,4S,6R)-
4-
(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3,4,10-
trihydroxy-13-
(((2R,4R,5 S, 6 S)-5 -hy droxy-4 -m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-
yl)oxy)-
3,5,6,8,10,12,14-heptamethy1-15-oxo-l-oxa-6-azacyclopentadecan-11-y1)oxy)-6-
methyltetrahydro-2H-pyran-3-y1 (S)-2-hydroxypropanoate (227 mg, 22%) as a
white solid. LCMS
(Method D): Rt = L73 min; [M+H] = 82L6.
Chemical Synthesis Example 2:
Method A.
105661 (25, 3R, 45, 6R)-4-(Dimethylamino)-2-(((212, 3S, 412, 5R, 8R, I OR, I
1R, 12S, 135, 14R)-2-ethyl-
3, 4, 10-trihydroxy-13-(((2R, 4R, 5 S,63)-5-hydroxy-4-methoxy-4, 6-dime
thyltetrahydro-2H-pyran-
2-yl)oxy)-3, 5 , 6, 8, 10, 12, 14-heptamethy1-15-oxo-1-oxa-6-
azacyclopentadecan-11-yl)oxy)-6-
methyltetrahydro-2H-pyran-3-y1 5-((3R)-2-oxido-1, 2-di thiolan-3-
yl)pentanoate and
(2S, 3R, 4S, 6R)-4-(Dimethylamino)-2-(((2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S,
13S, 14R) -2-ethyl-3, 4, 10-
trihydroxy-13-(((2R, 4R, 5 S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-
pyran-2 -
yl)oxy)-3, 5, 6,8, 10, 12, 14-heptamethy1-15-oxo-1-oxa-6-azacyclopentadecan-11-
yl)oxy)-6-
methyltetrahydro-2H-pyran-3-y15-((3R)-1-oxido-1, 2-dithiolan-3-yl)pentanoate
-133 -
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S-- -o\
1 I ,(o-
St...,
\.....,-3N
-.......",0
7 HO
HO
0 N
------N '''s \ ..010="---A
:3 0
l---\\---i
1111:1H0 i 0 "" µsP94111h:
c..5. 0
0 =ssµ
.r..,' ...3.
105671 (2 S,3R,4 S,6R)-4-(Dimethylamino)-2-(((2R,3 S,4R, 5R, 8R, 10R, 11R,
12S,13 S,14R)-2-
ethyl -3 ,4,10-tri hy droxy-13 -(((2R,4R, 55,6 S)-5 -hy droxy-4-m eth oxy-4,6-
dim ethyl tetrahy dro-2H-
pyran-2-yl)oxy)-3 ,5,6,8,10,12, 14-heptamethy1-15 -oxo-1 -oxa-6-azacy
clopentadecan-11 -yl)oxy)-
6-methyltetrahydro-2H-pyran-3-y1 5-((R)-1,2-dithiolan-3-yl)pentanoate (1.50 g,
1.60 mmol) had
been stored in vacllo at 30 C in the dark (vac oven) for a period of 2 weeks.
Over this time
approximately 10% of the various sulfoxide isomers had formed. The crude
material was purified
by flash chromatography (Biotage SP1; 25g SNAP cartridge) eluting with
isohexane -> 3:1
isohexane-acetone (1% TEA) -) acetone to yield (2S,3R,4S,6R)-4-(dimethylamino)-
2-
(((2R,3 S,4R, 5R, 8R, 10R,11R,12 S, 13 S,14R)-2-ethy1-3 ,4, 10-trihydroxy -13 -
(((2R, 4R, 5 S,6S)-5-
hy droxy-4 -m ethoxy-4,6 -dim ethyltetrahy dro-2H-py ran-2-yl)oxy)-3 ,5,6,8,
10,12,14-heptam ethyl-
15 -oxo-1-oxa-6-azacy cl op entadec an-11 -yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 5 -((3R)-2 -
oxi do-1,2-dithi olan-3 -yl)pentanoate and
(2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R, 5R, 8R, 10R,11R,12 S, 13 S,14R)-2-ethy1-3 ,4, 10-trihydroxy -13 -
(((2R, 4R, 5 S,65)-5-
hy droxy-4 -m ethoxy-4,6 -dim ethyltetrahy dro-2H-py ran-2-yl)oxy)-3 ,5,6,8,
10,12,14-heptam ethyl-
15 -ox o-1-ox a-6-azacy cl op entadec an-11 -yl )oxy)-6-m ethyl tetrahy dro-2H-
py ran-3 -yl 5 -((3R)-1 -
oxido-1,2-dithiolan-3 -yl)pentanoate (103 mg, 3%) as a white solid. LCMS
(Method A): Rt = 1.60
min; [M+11]-' = 953.7.
Method B.
105681 (2S, 3R, 4S, 6R)-4-(Diniethylamino)-2-(((2R, 3S, 4R, 5R, 8R, 10R, 11R,
12S, 13S, 14R.)-2-ethyl-
3,4, 10-tr ihydroxy-13-(((2R,4R, 5S, 6S)-5 -hydroxy-4-me thoxy-4,6-dimethylte
trahydro-2H-pyran-
2-yl)oxy)-3, 5,6, 8, 10, 12, 14-heptamethy1-15-oxo- 1 -oxa-6-
azacyclopentadecan-11-yboxy)-6-
inethyhetrahydro-2H-pyran-3-y1 5 -((3R)-2-oxido-1, 2-dithiolan-3-
yl)pentanoate and
(2 S, 3R, 4S, 6R)-4-(Dimethylamino)-2-(((2R, 35, 4R, 5R,8R, 10R, 11R, 125,
135, 14R)-2-ethyl-3, 4, 10-
trihydroxy-13-(((2R, 4R, 5 ,S', 65)-5-hydroxy-4-methoxy-4 , 6-
dimethyltetrahydro-2H-pyran-2-
-134-
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yl)oxy)-3,5,6,8,10, 12,14-heptamethy1-15-oxo-1-oxa-6-azacyclopentadecan-11-
yl)oxy)-6-
methyltetrahydro-2H-pyran-3-y15-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoate
-o
,o- \
(...--1=,,,, \---
J.,Q,
\ --
f HO HO,,. N L.
$ -
/-\----
H 0 ==
7 ===.... 0
ON N
-----. T HO
--,.0
r
\ ..----
0....
N
''. "" '3s a OH \ 1111.= ,.,*0
\ 0 0
0
105691 A mixture of 5-((3R)-1-oxido-1,2-dithiolan-3-yl)pentanoic acid and 5-
((3R)-2-oxido-1,2-
dithiolan-3-yl)pentanoic acid (0.73 g, 3.27 mmol), azithromycin (1.87 g, 2.50
mmol), and 1-
cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carb enium
hexafluorophosphate (3.74 g, 8.74 mmol) were dissolved in anhydrous DCM (25
mL). DIPEA
(2.5 mL, 14.3 mmol) was added, and the mixture stirred at 30 C for 20 h. The
mixture was diluted
with DCM (40 mL) and the solution washed successively with sat. NH4C1(ao (2 x
60 mL) and sat.
brine solution (50 mL). The organic phase was dried (MgSO4), filtered and the
solvent evaporated
in vacuo. The crude product was purified by flash chromatography eluting with
isohexane (1%
TEA) ¨> 3:1 isohexane-acetone (1% TEA) to yield the title product (1.45 g,
58%) as a viscous
orange oil. LCMS (Method A): Rt = 2.14 min; [M+H] = 953.6.
Chemical Synthesis Example 3:
105701 Step 1: (R)-2,2-Dimethylthiazolidine-4-carboxylic acid
0
0 H
HO)I....(N H 2
_________________________________________________ 10.-
H0)--
SH S
105711 A suspension of L-cysteine (2.00 g, 16.0 mmol) in anhydrous acetone (50
mL) was stirred
at reflux under an atmosphere of nitrogen for 18 hours. 'the reaction mixture
was cooled to r.t.,
filtered through a celite cartridge, concentrated to ¨ 50% of its original
volume then left to stand
at r.t. After 4 hours the mother liquor was decanted. The solid was further
washed with acetone
(10 mL) then dried in vacuo to yield (R)-2,2-dimethylthiazolidine-4-carboxylic
acid (2.29 g, 89%)
as a white solid. LCMS (Method A): Rt = 0.53 mins; [M+H] = 162.1. 1H-NMR (400
MHz, D20)
-135-
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6 4.47 (dd, J = 8.0, 7.3 Hz, 1H), 3.50 (dd, J = 12.1, 8.0 Hz, 1H), 3.35 (dd, J
= 12.4, 7.3 Hz, 1H),
1.70 (s, 3H), 1.69 (3s, 3H).
105721 Step 2: (R)-3-Acetyl-2,2-dimethylthiazolidine-4-carboxylic acid
0 H 0 Y
HO
105731 (R)-2,2-Dimethylthiazolidine-4-carboxylic acid (500mg, 3.10 mmol) was
dissolved in
acetone (30mL). Acetic anhydride (0.60 mL, 6.20 mmol) was added in one portion
and the
mixture stirred at r.t. for 10 minutes. DBU (0.93 mL, 6.20 mmol) was added in
one portion. The
reaction mixture was stirred at r.t. for 16 hours. The mixture was diluted
with sat. NRIC1(ao (50
mL) and Et0Ac (30 mL) and the layers separated. The aqueous phase was
extracted with Et0Ac
(2 x 30 mL) and the combined organics dried (MgSO4), filtered and the solvent
evaporated in
vacuo. The aqueous phase was acidified with 2M HC1 and the solution extracted
with Et0Ac (3
x 30 mL). The combined organics were dried (MgSO4), filtered and the solvent
evaporated in
(R)-3-Acetyl-2,2-dimethylthiazolidine-4-carboxylic acid (350mg, 56%) was
obtained as a
white solid. LCMS (Method E): Rt = 5.70 min; [M-Hr = 204.3. 11-1-NMR (400 MHz,
acetone-D6)
6 11.52 (br s, 1H), 5.09 (dd, J= 6.0, 0.9 Hz, 1H), 3.41 (dd, J= 11.9, 6.0 Hz,
1H), 3.30 (dd, J =
11.9, 1.4 Hz, 1H), 2.02 (s, 3H), 1.83 (s, 3H), 1.79 (s, 3H).
[0574] Step 3: (2S, 3R,4S,6R)-4-(D i me thylamino)-2-(((2R, 3S, 4R, 5R, 8R,
10R, 11R, 12S, 13S, 14R)-2-
ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyhetrahydro-211-
pyran-2-y1)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-
11-y1)oxy)-
6-methyltetrahydro-2H-pyran-3-y1 (R)-3-acetyl-2,2-dimethylthiazolidine-4-
carboxylate
0
0
HO
--e\
o
,
HO s,
OH 0 __
11µttkµ"
.$N
0
_______________________________________________________________________________
___
HO
õ
Illtto"
\ 0
[05751 (R)-3-Acetyl-2,2-dimethylthiazolidine-4-carboxylic acid (100 mg, 0.490
mmol),
azithromycin (380 mg, 0.490 mmol) and COMU (737 mg, 1.72 mmol) were dissolved
in
-136-
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anhydrous THE (10 mL). DIPEA (0.50 mL, 2.95 mmol) was added, and the mixture
stirred at r.t.
under N2 for 18 hours. The mixture was diluted with Et0Ac (50mL) and the
solution washed with
sat NH4C100 (3 x 20mL), dried (MgSO4), filtered and the solvent evaporated in
vacuo. The crude
product was purified by flash chromatography (Biotage SP1; 25g Sfar cartridge)
eluting with
isohexane 3:1 isohexane-acetone (1% TEA). (2S,3R,4S,6R)-4-
(Dimethylamino)-2-
(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3,4,10-tri hydroxy-13 -
(((2R,4R,5 S,6 S)-5-
hydroxy-4-m eth oxy-4,6-di m ethyl tetrahydro-2H-pyran-2-yl)oxy)-
3,5,6,8,10,12,14-h eptam ethyl -
15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-y1
(R)-3-acety1-
2,2-dimethylthiazolidine-4-carboxylate (250 mg, 54%) was obtained as a white
solid. LCMS
(Method E): Rt = 5.43 min; [M-Ffi] = 934.9. 1-H-NMIR (400 MHz, CDC13) 6 5.07
(d, J = 4.8 Hz,
1H), 4.74 (dd, J= 10.5, 7.3 Hz, 1H), 4.68 (td, J= 6.2, 2.4 Hz, 1H), 4.58 (d,
J= 7.3 Hz, 1H), 4.26
(q, J= 2.3 Hz, 1H), 4.11-4.21 (m, 1H), 4.00-4.07 (m, 1H), 3.63-3.70 (m, 2H),
3.49-3.54 (m, 1H),
3.30-3.38 (m, 3H), 3.22-3.26 (m, 1H), 3.05 (t, J= 9.8 Hz, 1H), 2.84 (s, 1H),
2.62-2.79 (m, 2H),
2.48-2.57 (m, 1H), 2.33 (d, J= 15.6 Hz, 3H), 2.23-2.29 (m, 1H), 2.20 (d, J=
10.1 Hz, 4H), 2.12
(d, J = 10.1 Hz, 1H), 1.87-2.06 (m, 6H), 1.85 (d, J= 6.9 Hz, 2H), 1.35-1.75
(m, 4H), 1.29-1.34
(m, 4H), 1.25 (t, J= 5.7 Hz, 4H), 1.21 (d, J= 6.9 Hz, 3H), 1.13-1.16 (m, 1H),
1.06-1.10 (m, 4H),
0.85-0.94 (m, 6H).
Chemical Synthesis Example 4:
[0576] Step I: 3-Acetyl-2-methylthiazolidine-4-carboxylic acid
0 H 0 Y
HO
HO
[0577] To a solution of 2-methyl-1,3-thiazolidine-4-carboxylic acid (300 mg,
2.04 mmol) in
anhydrous acetone (30 mL) under an atmosphere of N2, was added acetic
anhydride (0.39 mL,
4.08 mmol) followed by DBU (0.61 mL, 4.08 mmol). The reaction mixture was
stirred at r.t. for
17 hours. Water (30 mL) was added, and the mixture stirred for 10 minutes. The
mixture was
extracted with Et0Ac (2 x 30 mL) and the combined organics washed with sat.
brine solution (30
mL), dried (MgSO4), filtered and the solvent evaporated in vacuo to yield 3-
acety1-2-
methylthiazolidine-4-carboxylic acid (212 mg, 55%) as a yellow oil. LCMS
(Method C): Rt =
1.27, 1.31 min; [M+H]P = no obvious mass ion. III-NMR (400 MHz, CDC13) 6 8.48
(br s, 2H),
5.08-5.41 (m, 1H), 4.70-4.90 (m, 1H), 3.02-3.49 (m, 2H), 2.00-2.18 (m, 3H),
1.48-1.69 (m, 3H).
105781 Step 2: (25, 3R, 4S, 6R)-4-(Dim ethylamino)-2-(((2R, 3S, 4R, 5R, 8R,
10R, I IR, 12,13S, 14R)-2-
ethyl-3, 4,10-trihydroxy-13-(((2R,4R,5S, 6S)-5-hydroxy-4-methory-4,6-
dirnethyltetrahydro-2H-
-137-
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pyran-2-yl)oxy)-3,5, 6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-
azacyclopentadecan-11-yl)oxy)-
6-methyltetrahydro-2H-pyran-3-y1 3-acety1-2-methylthiazolidine-4-carboxylate
0 HN
- HO
=
`µµ HO
N
OH 0
__________________________________________________ )1m.
HO 0 "I" S 5
= , OM.<
OH
0
0 0
\ 0 OH \ HO = """."
4 - o
OH \
105791 3-Acety1-2-methyl-thiazolidine-4-carboxylic acid (50 mg, 0.264 mmol),
azithromycin
(204 mg, 0.264 mmol) and COMU (396 mg, 0.925 mmol) were dissolved in anhydrous
THF (20
mL). DIPEA (0.28mL, 1.59 mmol) was added and the mixture stirred at r.t. under
N2 for 18 hours.
The mixture was diluted with Et0Ac (50 mL), washed with sat. NH4C1(aco (3 x
20mL), dried
(MgSO4), and the crude product purified by flash chromatography (Biotage SP1;
25g Sfar
cartridge) eluting with isohexane 3:1 isohexane-acetone (1%
TEA) to yield (2S,3R,4S,6R)-4-
(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3,4,10-
trihydroxy-13-
(((2R,4R,5 S, 6 S)-5-hy droxy-4-m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-
yl)oxy)-
3,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacycl opentadecan-1 1-y1 )oxy )-
6-
methyltetrahydro-2H-pyran-3-y1 3 -acetyl-2-m ethylthi azoli di ne-4-
carboxylate (104 mg, 43%) as
an off-white solid. LCMS (Method C): Rt = 1.96 min; [M+1-1]+= 920.7.
Chemical Synthesis Example 5:
105801 Step 1: (25,3R,4S,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R,5R,8RJOR,11R,125,13S,14R)-2-
ethy1-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pyran-2-y1)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-
11-y1)oxy)-
6-methyltetrahydro-2H-pyran-3-y1
N-(((9117fhtoren-9-yl)methoxy)carbony1)-S-(tert-buty1)-L-
cysteinate
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\ s
HO N--*..---
,
OH 0
___________________________________________________
H0 tt ttttt .. /46..
1
z.- 0
11.."........_ NI*
s, =
"%.
g.._, ,===
S.' OH .........L.,OH
0
HO
0
\ 0 i
_
OH
[0581] Azithromycin (1.88 g, 2.50 mmol), COMU (3.75 g, 8.76 mmol) and D1PEA
(2.60 mL,
15.0 mmol) were dissolved in anhydrous DCM (50 mL). AT-Fmoc-(R)-2-amino-3-(S-
tert-
butyl)propanoic acid (1.00 g, 2.50 mmol) was added and the mixture stirred at
30
C for 20 hours. The solution was diluted with DCM (10 mL) and the solution
washed with sat.
NH4C1(ao (2 x 30 mL). The organic phase was dried (MgSO4), filtered and the
solvent
evaporated in vacua The crude product was purified by flash chromatography
(Biotage Isolera
four; 50g Sfar cartridge), eluting with 95:5 isohexane-acetone (1% TEA) ¨>
65:35 isohexane-
acetone (1% TEA) to yield (2S,3R,4S,6R)-4-
(dimethylamino)-2-
(42R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R,5 S,6 S)-5-
hy droxy-4-m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 N-4(9H-
fluoren-9-yl)methoxy)carbony1)-S-(tert-buty1)-L-cysteinate (1.35 g, 45 %) as a
yellow oil. LCMS
(Method A): Rt = 2.02 min; [M+Hr = 1131.3.
[0582] Step 2: (2S,3R,4S,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R,5R,8R,I0R,IIR,12S,13S,14R)-2-
ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,65)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pyran-2-ypoxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-
11-ypoxy)-
6-methyhetrahydro-211-pyran-3-yl S-(tert-buty1)-L-cysteinate
-139-
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0 N
S
H2N
N
S HO
HO
0 gm..--
N
0
0 oH
Illtit". .0041k
HO HO41
W. õo=
s.,o44>
a
===
o
\ 0
105831 (2 S,3R,4 S,6R)-4-(Dimethylamino)-2-(((2R,3 S,4R,5R, 8R, 10R,
11R,12S,13 S,14R)-2-
ethyl-3,4, 10-tri hydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-m eth oxy-4,6-di m
ethyl tetrahy dro-2H-
pyran-2-yl)oxy)-3 ,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacy
clopentadecan-11-yl)oxy)-
6-methyltetrahy dro-2H-pyran-3 -y1
N-0(9H-fluoren-9-yl)methoxy)carbony1)-S-(tert-buty1)-L-
cysteinate (1.35 g, 1.19 mmol) was dissolved in DMF (20 mL). Piperidine (5.00
mL, 50.6 mmol)
was added, and the mixture stirred at r.t. for 90 minutes. The solvent was
evaporated in VaC1,10 and
then dried in a vac. oven at 40 C for 16 hours. Crude (2S,3R,4S,6R)-4-
(Dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3,4, 10-trihy droxy-13 -
(((2R,4R,5 S,6 S)-5-
hy droxy-4-methoxy-4,6-dimethyltetrahy dro-2H-pyran-2-yl)oxy)-3,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 S-(tert-
buty1)-L-cysteinate (3.14 g) was obtained as a yellow solid which was purified
no further. LCMS
(Method A): Rt = 1.57 min; [M+Hr = 909Ø
105841 Step 3: (2S,3R,4S,6R)-4-(Dimethylamino)-2-(((2R,3S,4R,5R,8R,I0R,1
1R,12S, I3S, 14R)-2-
ethyl-3,4,10-trihydroxy-1 3-(((2R, 4R, 5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pyran-2-yl)oxy)-3,5,6,8, 10,12, 14-heptamethy1-15-oxo- 1-oxa-6-
azacyclopentadecan-11-yl)oxy)-
6-methyhetrahydro-2H-pyran-3-y1 N-acetyl-S-(tert-butyl)-L-cysteinate
-140-
CA 03196145 2023- 4- 18
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rs
H2N
N
= HO = HO \ N
sõ
0 __________________________________________________________________________
0 __
isz,0,411)
HO HO
==1.
\ 0 C)\
105851 Crude (2 S,3R,4 S,6R)-4-(di m ethyl am i no)-2-(((2R,3
S,4R,5R,8R,10R,11R,12 S,13 S,14R)-
2-ethy1-3 ,4, 10-tri hy droxy -13 -(((2R,4R, 5 S,6 S)-5-hy droxy -4-m ethoxy-
4, 6-dim ethyltetrahy dro-
2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,12, 14-heptam ethyl-15 -oxo-1-oxa-6-azacy cl
op entad ecan-11-
yl)oxy)-6-methyltetrahydro-2H-pyran-3-y1 S-(tert-butyl)-L-cysteinate (1.00 g)
was dissolved in
anhydrous acetone (18 mL). DBU (0.160 mL, 1.10 mmol) was added in one portion
and the
mixture stirred at r.t. for 10 mins. Acetic anhydride (0.100 mL, 1.10 mmol)
was added dropwise
over 2 mins. The mixture was stirred at r.t. for 18 h. The solvent was
evaporated in vacuo and the
residue diluted with Et0Ac (25 mL) and sat. NH4C1(aq) (25 mL). The mixture was
stirred at r.t.
for 10 minutes and the layers separated. The organic phase was dried (MgSO4),
filtered and the
solvent evaporated in vacuo. The crude product was purified by flash
chromatography (Biotage
Isolera four; 50g Sfar cartridge), eluting with 9:1 isohexane-acetone (1% TEA)
¨> 6:4 isohexane-
acetone (1% TEA) to yield
2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R, 5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R, 5 S,6 S)-5-
hy droxy-4-m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12, 14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 N-ac etyl- S-
(tert-buty1)-L-cy stei n ate (650 mg, 56%) as a white solid. LCMS (Method A):
Rt = 1.60min;
11\4+H1 = 950.8.
105861 Step 4: (2S,3R,4S,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R,5R,8R,10R,11R,12S,13S, 14R)-2-
ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-
11-y1)oxy)-
6-methyltetrahydro-21-1-pyran-3-y1 AT-acetyl-S-((2-nitrophenyl)thio)-L-
cysteinate
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02N 0
ir..S
0
0
H
\ ...------
OH 0
Wm". µ1.04414,
= Moo"
iso,
7
H01770
OH \....,\
z.,.... ,
..õ .
.._ .
HO
a .:.-
105871 2-Nitrobenzenesulfenyl chloride (40.5 mg, 0.210 mmol) was suspended in
anhydrous acetic acid (4.20 mL)
and (2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3,4,10-trihydroxy-13 -
(((2R,4R,5 S,6 S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8, 10, 12,14-
heptam ethyl-
15-oxo-l-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-y1
N-acetyl-S-
(tert-buty1)-L-cysteinate (200-400 mg, 0.210-0.420 mmol) was added. The
mixture was stirred at
r.t. for 30 mins. The solvent was evaporated in vacuo to yield crude
(2S,3R,4S,6R)-4-
(dim ethyl amino)-2-(((2R,3 S,4R,5R,8R,1 OR,1 1 R,1 2S,1 3 S,1 4R)-2-ethy1-
3,4,1 O-trihydroxy-1 3-
(((2R,4R,5 S,6 S)-5 -hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-
yl)oxy)-
3,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-
methyltetrahydro-2H-pyran-3-y1 N-acetyl-S-((2-nitrophenyl)thio)-L-cysteinate
(180 - 375 mg) as
an orange oil. No purification was attempted. LCMS (Method A): Rt = 1.62min;
[M-4-1] = 1047.7.
105881 Step 5: (2S,3R,4S,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-
ethyl-3,4,10-trihydroxy-13-(((2R,4R,55,6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-211-
pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-
11-y1)oxy)-
6-methyhetrahydro-2H-pyran-3-y1 acetyl-L-cysteinate
-142-
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02,,,
SH
0
0
cl?
N
E HO
HO
0
_______________________________________________________________________________
ss, .....
0 ________________________________________________________ HOM1=7;\ 0
__________________________________ 4cµ
HOM"-N
0
0\
105891 Method /: To a solution of thioglycolic acid (10.0 p..L, 0.0900 mmol)
in acetone (1 mL)
was added crude (2S,3R,4S,6R)-4-
(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R,5 S,6 S)-5-
hy droxy-4-methoxy-4,6-dimethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 N-acetyl-S-
((2-nitrophenyl)thio)-L-cysteinate (180 mg, 0.0300 mmol) and DIPEA (10 !IL,
0.0573 mmol).
The resulting suspension was stirred at r.t. for lh. The solvent was
evaporated in vacuo. The crude
product was purified by flash chromatography (Biotage Isolera Four; lOg SNAP
cartridge) eluting
with 9:1 isohexane-acetone (1% TEA) ¨> 6:4 isohexane-acetone (1% TEA) to yield
(2 S,3R,4 S,6R)-4-(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-
ethy1-3 ,4, 10-
tri hy droxy-13 -(((2R,4R, 5 S,6 S)-5 -hy droxy-4-meth oxy-4,6-dim ethyl
tetrahy dro-2H-pyran-2-
yl)oxy)-3 ,5,6, 8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacy clopentadecan-11-
yl)oxy)-6-
methyltetrahydro-2H-pyran-3-y1 acetyl-L-cysteinate (5.0 mg, 2%) as a yellow
solid. LCMS
(Method A): Rt = 1.53min; [M--Hr= 894.7.
105901 Method 2: To a solution of thioglycolic acid (82.0 pL, 1.18 mmol) in
anhydrous acetone
(10 mL) was added (2S,3R,4S,6R)-4-
(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R,5 S,6 S)-5-
hy droxy-4-m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 N-acetyl-S-
((2-nitrophenyl)thio)-L-cysteinate (375 mg, 0.358 mmol) and TEA (110 L, 0.789
mmol). The
solvent was evaporated in vacuo and the resultant orange oil purified by
reversed-phase
preparative HPLC. To each fraction containing purified pure target material
was immediately
-143 ¨
CA 03196145 2023- 4- 18
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added water (10 mL), DCM (10 mL) and potassium acetate (0.300 g) and the
layers separated.
The organic phases were dried (Na2SO4), filtered, and the filtrates combined.
The solvent was
evaporated in vacuo to yield
(2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3S,4R,5R,8R, 1 OR,I1R,12S,13 S,14R)-2-ethyl-3,4, 10-trihydroxy-13-
(((2R,4R,5 S,6 S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15-ox o-1-ox a-6-azacy cl opentadecan-11-y1 )oxy)-6-m ethyl tetrahy dro-21- I-
py ran-3 -y1 acetyl -L-
cystei nate (79 mg, 21%) as a white solid. LCMS (Method A): Rt = 1.54 min;
[M+H] = 894.6.
Chemical Synthesis Example 6:
105911 Step 1: ((R)-2-Methyl-3-(tris(4-methoryphetty1)44-sulfaneyl)propanoy1)-
L-proline
\\O
HS
0 __________________________________________ )0.
0
OH -0 CI
OH
105921 Captopril (0.500 g, 2.30 mmol) was dissolved in DCM (8 mL) and 4,4',4"-
trimethoxytrityl
chloride (0.850 g, 2.30 mmol) added under N2. TEA (0.430 mL, 3.06 mmol) was
added dropwise,
and the solution stirred at r.t. for 1.5 h. Water (5 mL) was added and the
layers separated (phase
separator). The aqueous phase was diluted with sat. NH4C1(aq) (15 mL) and
extracted with DCM
(15 mL). The combined organics were dried (MgSO4), filtered and the solvent
evaporated in
vacuo. The crude product was purified by flash chromatography (Biotage Isolera
Four; 25g Sfar
cartridge) eluting with DCM
95:5 DCM-Me0H to yield ((R)-2-methy1-3-(tris(4-
methoxypheny1)-14-sulfaneyl)propanoy1)-L-proline (1.03 g, 88%) as an orange
solid. LCMS
(Method A): Rt = 2.95 min; EM-Hr = 548.7.
105931 Step 2: (2S,3R,4S,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-
ethyl-3,4,10-trihydroxy-13-(((2R,4R,55,6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pyran-2-y1)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-
11-y1)oxy)-
6-methyltetrahydro-2H-pyran-3-y1
((R)-2-methyl-3-(tris(4-methoxypheny1)-14-
sulfaneyl)propanoy1)-L-prohnate
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rJ
/0
HO HQ
0
0\
ss.
-0
0
''
0
HO
I
0 0 =ssssµµ
\ 0 2 OH
0
_______________________________________________________________________________
4NO41444,2
HO
0
\
OH \
105941 Azithromycin (681 mg, 0.910 mmol), COMU (1.36 g, 3.18 mmol) and DIPEA
(0.950 mL,
5.46 mmol) were dissolved in anhydrous DCM (45 mL). ((R)-2-Methy1-3-(tris(4-
methoxypheny1)-14-sulfaneyl)propanoy1)-L-proline (500 mg, 0.910 mmol) was
added and the
mixture stirred at r.t. for 5 days. The mixture was diluted with DCM (25 mL)
and the solution
washed with sat. NH4C100 (2 x 30 mL). The organic phase was dried (Na2SO4),
filtered and the
solvent evaporated in WWII() . The crude product was purified by flash
chromatography (Biotage
Isolera Four; 25g Sfar cartridge), eluting with 95:5 isohexane-acetone (1%
TEA) ¨> 60:40
i soh exan e-aceton e (1% TEA), to yield
(2 S,3R,4 S,6R)-4-(dim ethyl am i n o)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R,5 S,6 S)-5-
hy droxy-4-m ethoxy-4,6-dim ethyl tetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethy ltetrahy dro-2H-py
ran-3 -y1 ((R)-2-
m ethy1-3-(tri s(4-m eth oxyph eny1)-14-sul fan eyl )propan oy1)-L-prol i nate
(960 mg, 60%) as an
orange solid. LCMS (Method A): Rt = 2.06 min; [M-41] = 1280.9.
105951 Step 3: (2S,3R,45,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-
ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,65)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-2H-
pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacyclopentadecan-
11-yl)oxy)-
6-methyltetrahydro-2H-pyran-3-y1 ((R)-3-mercapto-2-methylpropanoy1)-L-
prolinate
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CA 03196145 2023- 4- 18
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N
HS
z0
S
0
0 0
0
\N 01
-0 ________________________________________________ 30.- i HO 0#
= ,,,,,,,,
-------N " ,
\010.=-<
1
0 '-'---- OH
0 HO \
n.H"O______
OH 0 e .i
HO , ""... =S
4,
4: 0
---?
..:.=
\ 0 E OH o\
105961 (2 S,3R,4 S,6R)-4-(Dimethylamino)-2-(((2R,3 S,4R,5R, 8R, 10R,
11R,12S,13 S,14R)-2-
ethy1-3 ,4,10-tri hy droxy-13 -(((2R,4R, 5 S,6 S)-5 -hy droxy-4 -m ethoxy-4,6-
dim ethyltetrahy dro-2H-
pyran-2-yl)oxy)-3 ,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacy cl
opentadecan-11-yl)oxy)-
6-methyltetrahydro-2H-pyran-3-y1
((R)-2-m ethyl -3 -(tri s(4-m ethoxyph eny1)-14-
sulfaneyl)propanoy1)-L-prolinate (960 mg, 0.570 mmol) and triethylsilane
(0.270 mL,
1.71mmol) were dissolved in anhydrous DCM (25 mL). Chloroacetic acid (3.95 g,
41.8 mmol)
was added, and the mixture stirred at r.t. for 14 h. The mixture was diluted
with DCM (20 mL),
water (25 mL) and triethylamine (5 mL) at 0 C. The organic phase was washed
with dilute
triethylamine in water (25 mL). The organic phase was dried (Na2SO4), filtered
and the solvent
evaporated in vacuo. The crude product was purified by flash chromatography
(Biotage Isolera
Four; 25g SFar cartridge) eluting with 95:5 isohexane-acetone (1% TEA) ¨>
60:40 isohexane-
acetone (1% TEA), to yield
(2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,1 1 R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R,5 S,6 S)-5-
hy droxy-4-methoxy-4,6-dimethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 ((R)-3-
mercapto-2-methylpropanoy1)-L-prolinate (31 mg, 6%) as a white solid. LCMS
(Method A): Rt
= 2.30 min; [M+H] = 948.8. 111-NMR (400 MHz, CDC13) 6 5.06 (d, J= 4.8 Hz, 1H),
4.55-4.75
(m, 1H), 4.43 (d, J= 7.3 Hz, 1H), 3.95-4.36 (m, 3H), 3.66 (t, J = 6.6 Hz, 2H),
3.51 (dd, J = 15.3,
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6.2 Hz, 1H), 3.28-3.37 (m, 4H), 3.15-3.28 (m, 1H), 3.02 (t, J =10.1 Hz, 1H),
2.53-2.85 (m, 4H),
2.38-2.53 (m, 2H), 2.24-2.38 (m, 9H), 1.40-2.23 (m, 13H), 1.01-1.39 (m, 33H),
0.79-0.95 (m, 9H).
Chemical Synthesis Example 7:
105971 [(2S,3R,4S,6R)-4-(Dimethylamino)-2-
[[(2R,3S,4R,5R,8R,I0R,IIR,12S,13S,14R)-2-
ethyl-3,4,10-trihydroxy-13-1(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-
tetrahydropyran-
2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadec-11-
ylloxyl-6-tnethyl-
tetrahydropyran-3-yll (2E,4E,6E,8E)-3,7-dimethy1-9-(2,6,6-
trimethylcyclohexen-l-y1)nona-
2,4,6,8-tetraenoate
HO HO,; N
0
µ01===--
0 \
0 HO
________________________________________________ )1.=
,,,,, = \04)
HO
ss.s=
0 umni
0
N 0 OH \ HO
e 0 0
\ 0
E
OH Ck
105981 Azithromycin (500 mg, 0.668 mmol), COMU (1.00 g, 2.34 mmol) and DIPEA
(0.700 mL,
4.02 mmol) were dissolved in anhydrous DCM (15 mL). Retinoic acid (all trans)
(201 mg, 0.668
mmol) was added, and the mixture stirred at 30 C for 20 h. The mixture was
diluted with DCM
(15 mL) and washed with sat. NH4C1(ao (2 x 15 mL). The organic phase was dried
(MgSO4),
filtered and the solvent evaporated in vacuo. The crude product was purified
by flash
chromatography (Biotage Isolera Four; 25g Sfar cartridge), eluting with 95:5
isohexane-acetone
(1% TEA) ¨> 60:40 isohexane-acetone (1% TEA) and further purified by flash
chromatography
(Biotage Isolera Four; lOg Sfar cartridge), eluting with 95:5 isohexane-
acetone (1% TEA) ¨>
70:30 isohexane-acetone (1% TEA) to yield [(2S,3R,4S,6R)-4-(dimethylamino)-2-
[[(2R,3 S,4R,5R,8R, 1 OR,I1R,12S,13 S,14R)-2-ethy1-3,4,10-trihydroxy-13-
[(2R,4R,5S,6S)-5-
hydroxy-4-methoxy-4,6-dimethyl-tetrahydropyran-2-yl]oxy-3,5,6,8,10,12,14-
heptamethy1-15-
oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-tetrahydropyran-3-yl]
(2E,4E,6E,8E)-3 ,7-
di m ethyl -9-(2,6,6-tri m ethyl cycl oh ex en-l-yl )n on a-2,4,6, 8-tetraen
oate (25 mg, 4%) as a yell ow
solid. LCMS (Method A): Rt = 2.30 min; [M+Hr = 1032Ø
Chemical Synthesis Example 8:
105991 Step 1: N-Acetyl-S-(pyridin-2-ylthio)-L-cy.sieine
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0
N
HO
N
HS
\/-
106001 2,2'-Dipyridyl disulfide (1.10 g, 4.90 mmol) and N-acetyl-L-cysteine
(400 mg, 2.45 mmol)
were dissolved in 1:1H20-Me0H (6.8 mL). The solution was stirred for 16 h at
r.t. The solvent
was evaporated in vacuo and the crude product purified by flash chromatography
eluting with
DCM
75:25 DCM-Me0H to yield N-acetyl-S-(pyridin-2-ylthio)-L-cysteine (386
mg, 55%) as
a yellow oil. LCMS (Method A): Rt = 1.60 min; [M+11]+ = 273.2.
106011 Step 2:
S-(((R)-2-Acetainido-3-(((25,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3S,4R,5R,8R,I0R,IIR,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-
(((2R,4R,5S,6S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-y1)oxy)-3,5,6,8,10,12,14-
heptainethyl-
15-oxo-1-oxa-6-azacyclopentadecon-11-y1)oxy)-6-inethyltetrahydro-2H-pyran-3-
y1)oxy)-3-
oxopropyl)thio)-N-acetyl-L-cysteine
0
HO)'X,d,r,
SH
0
)1\1
rs
0
HO
, µ01====-<
E HO
OH 0 __
0
0
= I...<
Wt. õ." 444.i ----N =
OH
0
\ 0
- 0
106021 To a solution of N-acetyl-S-(pyridin-2-ylthio)-L-cysteine (15.2 mg,
0.0600 mmol) in
chloroform (2.0 mL) was added TEA (10 tL, 0.060 mmol) and (2S,3R,4S,6R)-4-
(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3 ,4,10-
trihydroxy-13-
(((2R,4R,5 S, 6 S)-5 -hy droxy-4 -m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-
yl)oxy)-
3,5,6,8,10, 12,14-heptamethy1-15-oxo-l-oxa-6-azacycl opentadecan-11-yl)oxy)-6-
m ethyltetrahy dro-2H-pyran-3-y1 acetyl-L-cysteinate (25.0 mg, 0.030 mmol).
The mixture was
stirred at r.t. for 1 h. The solvent was evaporated in vacuo and the crude
product purified by
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reversed-phase preparative HPLC. The fraction containing product was frozen (-
78 C) and the
solvent evaporated in vacito (lyophilisation) to yield S-(((R)-2-acetamido-3-
(((2S,3R,4S,6R)-4-
(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R, 1 1R, 12 S,13 S,14R)-2-ethy1-3,4,10-
trihydroxy-13-
(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-
3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-
m ethyl tetrahy dro-2I I-pyran-3 -yl )oxy)-3 -ox opropyl)th o)-N-acetyl -L-
cysteine (10 mg, 34%) as a
white solid. LCMS (Method A): Rt = 2.20 min; [M+H] = 1055.9
Chemical Synthesis Example 9:
[0603] Step 1: Ethyl N-acetyl-L-cysteinate
0 0 H
HO Et0
HS HS
[0604] N-Acetyl-L-cysteine (470 mg, 2.88 mmol) was dissolved in ethanol (15
mL) and the
reaction mixture degassed with N2 before cooling to 0 C. Thionyl chloride (210
p.L, 2.88 mmol)
was added dropwise and the reaction mixture warmed to r.t. and stirred at this
temperature for 4
h. The solvent was evaporated in vacuo and the mixture diluted with water and
Et0Ac. The layers
were separated, and the aqueous phase extracted with Et0Ac (3x 10 mL). The
combined organics
were dried (MgSO4), filtered and the solvent evaporated in vacuo . The crude
product was purified
by flash chromatography (Biotage Isolera Four, 100g KPSil column) eluting with
75:25
isohexane-Et0Ac ¨> 15:85 i sohexane-Et0Ac to yield ethyl AT-acetyl-L-
cysteinate as a pale-yellow
oil, which crystallised upon extended drying (vac. oven) to give the title
compound as a white
solid (180 mg, 33%). 111-NMR (400 MHz, CHC13) 6 6.47 (d, J= 5.7 Hz, 1H), 4.79-
4.85 (m, 1H),
4.16-4.28 (m, 2H), 2.78-3.22 (m, 2H), 2.03 (s, 3H), 1.17-1.36 (m, 4H).
[0605] Step 2: Ethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate
0
0
Et0 S}
S N
HS
[0606] 2,2'-Dipyridyl disulfide (1.98 g, 4.90 mmol) and ethyl (2R)-2-acetamido-
3-sulfanyl-
propanoate (0.195 g, 1.02mmo1) were dissolved in a mixture of 1:1 water-Me0H
(6.8 mL). The
solution was stirred for 16 h at r.t. The solvent was evaporated in vacuo and
the crude product
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purified by reversed-phase preparative HPLC. Fractions containing product were
concentrated
under reduced pressure to give ethyl N-acetyl-S-(pyridin-2-ylthio)-L-
cysteinate (135 mg, 43%) as
a colourless oil. LCMS (Method A): Rt = 1.96 min; [M+H]+ = 301.1.
106071 Step 3: (2S, 3R,4S,6R)-4-(Dimethylamino)-2-((l2 R, 3S, 4R, 5R, 8R, I
OR, I IR, 12 S, I3S, I4R)-2-
ethy1-3, 4, 10-trihydroxy-13-(((2R, 4R, 5 S, 6S)-5-hydroxy-4-methoxy-4,6-
dimethyltetrahydro-21-1-
pyran-2-yl)oxy)-3, 5,6,8, 10, 12, 14-heptamethy1-15-oxo-l-oxa-6-
azacyclopentadecan-11-yl)oxy)-
6-methyltetrahydro-2H-pyran-3-y1 S-(((R)-2-acetamido-3-ethoxy-3-
oxopropyl)thio)-1V-acetyl-L-
cysteinate
0
N.,,.......,,.
SH
0 fro \
0
0
_
0 N
S HO
0e,
OH 0 . =
''::,_
OH
S , µ01===--
0
106081 To a solution of ethyl N-acetyl-S-(pyridin-2-ylthio)-L-cysteinate (15.0
mg, 0.050 mmol)
in chloroform (2.0 mL) was added TEA (10 j_IL, 0.060 mmol) and (2S,3R,4S,6R)-4-
(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3 ,4,10-
trihy droxy-13-
(((2R,4R,5 S, 6 S)-5 -hy droxy-4 -m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-
yl)oxy)-
3,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacy clopentadecan-11-yl)oxy)-6-
methyltetrahydro-2H-pyran-3-y1 acetyl-L-cysteinate (15.0 mg, 0.0168 mmol). The
mixture was
stirred at r.t. for 28 h. The solvent was evaporated in vacuo to yield the
crude product as a yellow
oil, which was purified by reversed-phase preparative HPLC. To each fraction
containing desired
product was added DCM (10 mL) and potassium acetate (0.50 g). The layers were
separated and
the combined organics dried (MgSO4), filtered and the solvent evaporated in
vacuo to yield
(2 S,3R,4 S,6R)-4-(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-
ethy1-3,4, 10-
tri hy droxy-13 -(((2R,4R, 5 S,6 S)-5 -hy droxy-4-methoxy-4,6-dim ethyl
tetrahy dro-2H-pyran-2-
yl)oxy)-3 ,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacy clopentadecan-11-
yl)oxy)-6-
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m ethyltetrahy dro-2H-pyran-3 -y1 S-(((R)-2-acetami do-3 -ethoxy-3 -
oxopropyl)thi o)-N-acetyl-L-
cy steinate (3.5 mg, 19%) as a white solid. LCMS (Method A): Rt. = 1.57 min;
[MA-1] = 1083.9.
Chemical Synthesis Example 10:
106091 (2R, 2 'R)-3, 3 '-(('R)-8-(a2S, 3R, 4S,6R)-4-(Dimethylamino)-2-
(((2R, 3S, 4R, 5R, 8R, 101-Z, 111-?, 12S, 13S, 14R) -2-ethyl-3 , 4 , 10-
trihydroxy- 13-(((2R, 4R, 55', 6S)-5 -
hydroxy-4 -inethoxy-4, 6-ditnethyltetrahydro-21-1-pyran-2-yl)oxy)-3 , 5 , 6,8,
10, 12, 14-heptainethyl-
15 -oxo- 1 -oxa-6-azacyclopentadecan- 11-yl)oxy)-6-me thyltetrahydro-2H-pyran-
3-yl)oxy)-8 -
orooctane- 1 , 3-diy1)hi s (di st i lfanediy1))bi s(2-acetainidopropanoi c
acid)
o
(:),.... o1-1
-0 0 NH
s \
)--(_ NH ---S'
HO S\ 8 )........
_ ---- + '....rO\ ...,.. -a.-
T HO 0,,., N =
= HO 0,
OH . 0
HO z
....14....
fr õµ HO . OH .ss 0
HO , ...=,...
p........OH__ .
0
.:=:.-- .: 0\ __µ\ µ, 1 ..;.: 0 0 . -ss 0
0 i 1
-z-l'= ,.:
106101 A mixture of
(2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R, 5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R, 5 S,6 S)-5-
hy droxy-4-m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 5 -((3R)-2 -
oxi do-1,2-dithi ol an-3 -yl)p entanoate and
(2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3,4,10-trihydroxy-13-
(((2R,4R,5S,6S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-
heptam ethyl -
15 -oxo-l-ox a-6-azacy cl op entad ec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 5 -((3R)-1 -
oxi do-1,2-dithi olan-3 -yl)pentanoate (80.0 mg, 0.0600 mmol) were dissolved
in THF (15 mL). N-
Acetyl-L-cysteine (41.1 mg, 0.250 mmol) was added and the mixture stirred
under N2 at r.t. for
48 h. The solvent was evaporated in men and the crude product purified by
reversed-phase
preparative HPLC. Fractions containing desired product were combined and the
solution passed
through a catch release cartridge (Biotage Isoluteg NH2; 1 g) washing with
MeCN (2 CV). The
washings were passed through a second catch release cartridge (Biotage
Isoluteg NH2; 1 g)
washing with MeCN (2 CV). Both cartridges were then eluted with 95:5 MeCN-AcOH
(2 CV)
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and the solutions combined, frozen (-78 C) and the solvent evaporated in
vacuo (lyophilisation)
to yield
(2 'S)-((2R,2'R)-3,3'-(((R)-8-(((2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3,4, 10-trihydroxy-13 -
(((2R,4R,5 S,6 S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8, 10, 12,14-
heptam ethyl-
15-oxo-l-oxa-6-azacy cl opentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3 -
yl)oxy)-8-
oxooctane-1,3 -diy1)bi s(di sulfanediy1))bi s(2-acetami dopropanoi c acid) (14
mg, 15%) as a white
solid. LCMS (Method A): Rt = 1.66 min; IM+Hr = 1262.2.
Chemical Synthesis Example 11:
106111 (2'S)-((2R,2'R)-3,3'-(((R)-8-(((2S, 3R,4S,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R, 5R, 8R, 10R, 11R, 12S, 13S,14R)-2-ethyl-3,4, 10-trihydroxy-13-
(((2R,4R, 5S,6S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-21-1-pyran-2-yl)oxy)-3,5,6,8, 10,
12,14-heptctmethyl-
15-oxo-l-oxet-6-cizacyclopentadeccin-11-y1)oxy)-6-methyltetrahydro-2H-pyran-3-
y1)oxy)-8-
oxooctane-1,3-diyObis(disulfanediy1))bis(2-methylpropanoy1))di-L-proline
. -7.
=----N j '''µ < ----N - --µ..Ø--A /--\----
, 0H
0 .u011:
../.õ.Qõ.
,0
0
0: N
N
T H
o\ .....õ. OH
S"
S
: s=-
_ O., N
pi.. LI---:00\ ,..... -v.-
= HO 0.1. N HO
0
= HO
(:).1............ ":" - S">:0 , HO ; ...._.- . ' AN
7 ..sss \ .'. \ ) ..=11- ) - 4
H 0 =
41. : ... 1.......1.:::
HO ,
\ 0 --
; OH'
106121 A mixture of
(2 S,3R,4 S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3,4, 10-trihydroxy-13 -
(((2R,4R,5 S,6 S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8, 10, 12,14-
heptam ethyl-
15-oxo-l-oxa-6-azacy cl opentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3 -
y1 5-((3R)-2-
oxi do-1,2-dithi ol an -3 -yl)pentanoate and
(2 S,3R,4 S,6R)-4-(di m ethyl amino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3,4, 10-trihydroxy-13 -
(((2R,4R,5 S,6 S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8, 10, 12,14-
heptam ethyl-
15-oxo-l-oxa-6-azacy cl opentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3 -
y1 5-((3R)-1 -
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oxido-1,2-dithiolan-3-yl)pentanoate (80.0 mg, 0.0629 mmol)) were dissolved in
anhydrous THF
(15 mL). Captopril (82 mg, 0.378 mmol) was added, and the mixture stirred at
r.t. for two weeks.
The solvent was evaporated in vactio and the crude product purified by
reversed-phase preparative
I-IPLC. Fractions containing desired product were combined and the solution
passed through a
catch release cartridge (Biotage Isolute NE12; 1g) washing with MeCN (2 CV)
and the product
eluted with 95:5 MeCN-Ac0II (2 CV). The eluent was frozen (-78 C) and the
solvent evaporated
in vacuo (1 yophili sati on)
to yield (2' S)-((2R,2'R)-3 ,3 '-(((R)-8-(((2S,3R,4 S,6R)-4-
(dimethylamino)-2-(((2R,3 S,4R,5R,8R,10R,11R,12S,13 S,14R)-2-ethy1-3 ,4,10-
trihydroxy-13-
(((2R,4R,5 S, 6 S)-5 -hy droxy-4 -m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-
yl)oxy)-
3,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacy clopentadecan-11-yl)oxy)-6-
m ethyltetrahydro-2H-pyran-3 -yl )oxy)-8-oxooctan e-1,3 -diy1)bi s(di
sulfanediy1))bi s(2-
methylpropanoy1))di-L-proline (15.0 mg, 17%) as a white solid. LCMS (Method
A): Rt = 1.93
min; [M-FH]+ = 1369.8.
Chemical Synthesis Example 12:
106131 (2R,2'R)-3, 3'-(((R)-8-(((2S, 3R, 4S,6R)-4-(Dimethylamino)-2 -
(((2R,3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10-trihydroxy- 13-
(((2R, 4R, 5S,6S)-5-
hydroxy-4-inethoxy-4, 6-diniethyltetrahydro-2H-pyrcin-2-y1)oxy)-3,5 , 6,8, 10,
12, 14-heptatnethyl-
15-oxo-1-oxa-6-azacyclopentadecsin-11-y1)oxy)-6-inethyltetrahydro-2H-pyran-3-
y1)oxy)-8-
oxooctane- 1, 3-diyObis(disulfanediy1))bis(2-(2-mercapto-2-
methylpropanamido)propanoic acid)
F,,,,,
o (DrOH
-0
0- \ 0 NH
Of c-:,..1S+
HO S\ s ),õ.....(SH
\./.3
.1....r0\ = 0.... _.õ... +
N
= HO = 0 N HO z
4- 0
-.- :
/-\----
106141 A mixture of
(2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,1 1 R,12 S,13 S,14R)-2-ethy1-3 ,4, 10-trihy droxy-13 -
(((2R,4R,5 S,6 S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
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15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 5 -((3R)-2 -
oxi do-1,2-dithi ol an-3 -yl)p entanoate and
(2S,3R,4S,6R)-4-(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, I OR, I IR, 12S, 13 S, I 4R)-2-ethy1-3,4, I 0-trihy droxy-
13 -(((2R,4R,5 S,6 S)-5-
hy droxy-4-methoxy-4,6-dimethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12, 14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -y1 5 -((3R)-1 -
oxi do-1,2-dithi ol an -3 -yl )pentan oate (80.0 mg, 0.0629 mmol) were
dissolved in anhydrous THF
(15 mL). Bucillamine (70.3 mg, 0.315 mmol) was added, and the mixture stirred
at r.t. for one
week. The solvent was evaporated in vacua and the crude product purified by
reverse-phase
preparative HPLC. Fractions containing desired product were combined and the
solution passed
through a catch release cartridge (Biotage Isolute NH2; 1g) washing with MeCN
(2 CV) and the
product eluted with 95:5 MeCN-AcOH (2 CV). The solution was frozen (-78 C)
and the solvent
evaporated in VaC110 (lyophilisation) to yield (2R,2'R)-3,3'-(((R)-8-
(((2S,3R,4S,6R)-4-
(dimethylamino)-2-(((2R,3 S,4R,5R,8R, I OR, 11R,12 S,13 S,14R)-2-ethy1-3 ,4,10-
trihydroxy-13-
(((2R,4R,5 S, 6 S)-5 -hy droxy-4 -m ethoxy-4,6-dim ethyltetrahydro-2H-pyran-2-
yl)oxy)-
3,5,6,8,10,12,14-heptamethy1-15-oxo-1-oxa-6-azacycl opentadecan-11-yl)oxy)-6-
m ethyltetrahy dro-2H-pyran-3 -yl)oxy)-8-oxooctan e-1,3 -diy1)b i s(di
sulfanediy1))b i s(2-(2-
mercapto-2 -methylpropanamido)propanoic acid) (5.0 mg, 17%) as a white solid.
LCMS (Method
F): Rt = 5.02 min; [(M+H)/2] = 690.7. LCMS (Method A): Rt = 2.00 min; [M+H] =
1379.8.
Chemical Synthesis Example 13:
106151 (4S,10R)-10-(5-(((2S,3R,4S,6R)-4-(Dimethylamino)-2-
(((2R, 3S, 4R, 5R, 812, 1012,11R, 12S, 135' , 14R)-2-ethy1-3, 4, 10-trihydroxy-
13-(((2R, 4R, 55' , 6S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydra-2H-pyran-2-y0oxy)-3,5,6,8,10,12,14-
heptamethyl-
15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-
yl)oxy)-5-
axopenty1)-7,7-dimethyl-6-axa-1,2,8,9-tetrathia-5-azacycladadecane-4-
carboxylic acid and
(4S,12S)-12-(5-(((2S,3R,4S,6R)-4-(Dimethylamino)-2-
(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethy1-3,4,10-trihydroxy-13-
(((2R,4R,5S,6S)-5-
hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-
heptamethyl-
15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-
yl)oxy)-5-
oxopenty1)-7,7-dimethyl-6-oxo-1,2,8,9-tetrathia-5-azacyclododecane-4-
carboxylic acid
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HO -40
v HN
HO
Lly0\
r HO C) HO Os.
>)
AO f
HO
HO s
OH<
wo. OH 0
HO
0 \ HO
=-= " . 0
\ 0
106161 A mixture of (2S,3R,4S,6R)-4-
(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3,4,10-trihydroxy-13-
(((2R,4R,5S,6S)-5-
hydroxy-4-m ethoxy-4,6-dim ethyl tetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-h eptam ethyl -
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyl tetrahy dro-2H-py
ran-3 -y1 5 -((3R)-2 -
oxi do-1,2-dithi olan-3 -yl)pentanoate and (2S,3R,4S,6R)-4-
(dimethylamino)-2-
(((2R,3 S,4R,5R, 8R, 10R,11R,12 S,13 S,14R)-2-ethy1-3,4,10-trihy droxy -13 -
(((2R,4R,5 S,6S)-5-
hy droxy-4-m ethoxy-4,6-dim ethyltetrahy dro-2H-pyran-2-yl)oxy)-3 ,5,6,8, 10,
12,14-heptam ethyl-
15 -oxo-l-ox a-6-azacy cl op entadec an-11-yl)oxy)-6-m ethyltetrahy dro-2H-py
ran-3 -yl 5 -((3R)-1 -
oxido-1,2-dithi olan-3 -yl)pentanoate (80.0 mg, 0.0629 mmol) were dissolved in
anhydrous THF
(15 mL). Bucillamine (70.3 mg, 0.315 mmol) was added, and the mixture stirred
at r.t. for one
week. The solvent was evaporated in vacuo and the crude product purified by
reverse-phase
preparative EfF'LC. Fractions containing desired product were passed through a
catch release
cartridge (Biotage Isolute NH2; 1 g) washing with MeCN (2 CV) and the product
eluted with 95:5
MeCN-AcOH (2 CV). The solution was frozen (-78 C) and the solvent evaporated
in vacuo
(lyophilisation) to yield the title compounds (7.0 mg, 1.5%) as a white solid.
LCMS (Method E):
Itt = 4.81 min. KM-41)/21+ = 580.1. LCMS(Method A) Rt = 1.90 min; [M+Hr =
1158.7.
106171 The compounds provided herein (e.g., in Table 1) are prepared according
to a similar
process as provided for any of the Chemical Synthesis Examples, such as, for
example, Chemical
Synthesis Example 1 hereinabove, such as, for example, starting from
azithromycin dihydrate.
II. Biological Evaluation
Example 1: Rabbit Cornea Homogenate Stability Assay
106181 Determining Rabbit Cornea Homogenate stability of the test compounds is
performed
using HPLC-MS. The assay is performed at two concentrations of Rabbit Cornea
Homogenate
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(0.15mg/m1 and 0.45mg/m1 total protein) so that any hydrolysis observed can be
assigned as
esterase dependent or not.
Rabbit Cornea Homogenisation
106191 Five rabbit corneas (e.g. New Zealand Whites) of approx. 50 mg each are
sliced and
scraped with a scalpel and tweezers until reduced to small (1-3mm), thin
pieces. These are
transferred into a tared vial and accurately weighed, then diluted with 10
volumes aqueous PBS
pH 7.4.
106201 Sample is cooled intermittently on ice and shear homogenized for 3
minutes, then
centrifuged for 3 min at 3000 rpm. The supernatant is pipetted off into a
vial, and total protein
concentration determined at 280nm. Sample was stored at -78 C.
Rabbit Cornea Esterase Assay
Preparation of stock solutions:
106211 10 mM Compound stocks are diluted to 100 1.1.M in a 96 deep-well plate:
10 .1 of 10 mM
Compound stock is added to 990 IA 50 mM HEPES, pH7.5 buffer. Compounds are
further diluted
to 10 M: 100 I.11 of 100 M compound is added to 900 050 mM HEPES, pH7.5
buffer. Esterase
homogenate is diluted to 300 ng/[11 and 900 ng/i.d.
Assay Conditions:
106221 A heater shaker is set to 37 C. Into a suitable 96 well plate (Run
Plate), 75 .1 of 300 or
900 ng/n1 esterase homogenate is pipetted into each of the required wells
(2min, 5min, 10min,
20min and 45 min). The plate is sealed and then warmed at 37 C for 5 min.
106231 Another 96 well PCR plate is put on ice (Kill Plate). To this is added
100 pi of MeCN to
each well, labelled Omin 2min, 5min, 10min, 20min and 45 min. The plate is
covered to minimize
evaporation.
106241 For the T=0 sample only, to the 100 n1 cold MeCN stop solution is added
50 n1 of 300 or
900 ng/[1.1 esterase homogenate followed by 50 .1 of 10 n..M compound
solution. For the remaining
timepoints, 75 IA of 10 i.tM compound solution is added to the Run Plate
starting from T=45 min
row and ending with T=2 min row. At the appropriate time point, 100 n1 of the
assay mixture is
added to the matching kill plate well containing 100 gl of cold MeCN. Samples
are analysed as
soon as practicable by LCMS (Waters Xevo TQ-S or Micromass Ultima).
106251 Parent conjugate and parent concentrations are determined against
appropriate standard
response curves and the half-life (T1/2) of the parent conjugate is calculated
using the peak area
of the parent conjugate at each time point in the linear region of the log ¨
linear plot.
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Example 2: Aqueous hydrolysis stability assay
106261 Determination of aqueous stability of the test compounds was performed
using HPLC-
MS. A test compound 10 mM stock solution is prepared in DMSO. 10 1.1L of the
DMSO stock
solution is dissolved in 990 i.t1 of 50 mM HEPES pH 7.5 buffer or 1:1 (v/v) of
Acetonitrile:Water
to make a 100 [tM solution. Final DMSO concentration is 1%. The solution is
kept at room
temperature and injected without delay into the LCMS (Waters Xevo TQ-S or
Micromass Ultima).
Additional injections are performed at appropriate time points.
106271 Half-life (T112) of the parent conjugate is calculated using the peak
area of the parent
conjugate at each time point in the linear region of the log ¨ linear plot.
Table 2
Hydrolytic %
Comp Azithromycin formation Temp
Buffer
at [time]
39 B [43 min] 10 C
HEPES
6, 7, 8, and 9 B [43 min] 37 C
DPBS
B [43 min] 37 C DPBS
33 B [43 min] 37 C
DPBS
34 A [44 min] 37 C
DPBS
31 A [40 min] 37 C
DPBS
44 C [10 min] 37 C
DPBS
45 C [20 min] 37 C
DPBS
46 A[40 min] 37 C
DPBS
47 B [43 min] 37 C
DPBS
A: percent active pharmaceutical ingredient (API) formation <30%; B: percent
API formation 30-
90%; C: percent API formation >90%.
Example 3: Aqueous hydrolysis stability assay
Compounds with Slow Hydrolysis Rate
106281 Determination of aqueous stability of the test compounds was performed
using UPLC-
MS. A test compound 10 mM stock solution was prepared in dry DMSO or DMF. 10
tit of the
DMSO or DMF stock solution was dissolved in 990 !IL of DPBS pH 7.4 buffer to
make a 100 j.tM
solution. This solution was used "as is" or immediately diluted further with
DPBS to 25 itt.M. Final
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DMSO concentration was <1%. The solution was immediately placed in an
autosampler
maintained at 37 C and injected without delay into the UPLCMS (Waters Xevo TQ-
S or G2-XS).
Additional injections were performed at appropriate time points. Half-life of
the parent compound
was determined from the MS response.
Compounds with Fast (<5 minutes) Hydrolysis Rate
106291 Determination of aqueous stability of the test compounds was performed
using UPLC-
MS. A test compound 10 mM stock solution was prepared in dry DMSO or DMF. 50
uL of the
DMSO or DMF stock solution was further diluted with 150 jiL of dry DMSO or DMF
(as
appropriate) to 2.5 mM. 10 uL of the 2.5 mM DMSO or DMF stock solution was
dissolved in 990
[IL of DPBS pH 7.4 buffer to make a 25 jiM solution. Final DMSO concentration
was 1%. The
solution was immediately placed in an autosampler maintained at 37 C and
injected without delay
into the UPLCMS (Waters Xevo TQ-S or G2-XS). Additional injections were
performed at
appropriate time points. Half-life of the parent compound was determined from
the MS response.
Table 3
Hydrolytic %
Comp Azithromycin formation Aq Ti/2 (min)
at 45 Min
51 B 66.1
6, 7, 8, and 9 B 31.5
B 10.5
44 C <5
45 C <5
46 A 65.1
47 B 102
33 B 70.6
31 A >120
39 C <5
34 A 70.8
A. percent active pharmaceutical ingredient (API) formation <30%, B. percent
API formation 30-
90%; C: percent API formation >90%.
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Example 4: Mouse Model of Experimental Dry Eye Disease
106301 Female C57BL/6 mice (6-8 weeks old) or female HEL BCR Tg mice (6-8
weeks old) are
commercially obtained. Experimental dry eye is induced as described by
Niederkorn, et al. (J.
Immunol. 2006,176:3950-3957) and Dursun et al. (Invest. Ophthalmol. Vis. Sci.
2002, 43:632-
638). In brief, mice are exposed to desiccating stress in perforated cages
with constant airflow
from fans positioned on both sides and room humidity maintained at 30% to 35%.
Injection of
scopolamine hydrobromide (0.5 mg/0.2 mL; Sigma-Aldrich, St. Louis, MO) is
administered
subcutaneously, three times a day (8:00 AM, 12:00 noon, and 5.00 PM), on
alternating hind-flanks
to augment disease. Mice are exposed to desiccating stress for 3 weeks.
Untreated control mice
are maintained in a nonstressed environment at 50% to 75% relative humidity
without exposure
to forced air. Test animals are exposed to test compound and subsequently tear
samples are
obtained to determine stability of test compounds, and tissue samples are
taken to determine
presence of pro-inflammatory biomarkers.
III. Preparation of Pharmaceutical Dosage Forms
Example 1: Solution for topical ophthalmic use
106311 The active ingredient is a compound of Table 1, or a pharmaceutically
acceptable salt
thereof, and is formulated as a solution with a concentration of from 0.1-1.5
% w/v.
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