NZ718150B2 - Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof - Google Patents
Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof Download PDFInfo
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- NZ718150B2 NZ718150B2 NZ718150A NZ71815012A NZ718150B2 NZ 718150 B2 NZ718150 B2 NZ 718150B2 NZ 718150 A NZ718150 A NZ 718150A NZ 71815012 A NZ71815012 A NZ 71815012A NZ 718150 B2 NZ718150 B2 NZ 718150B2
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- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
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- 239000012258 stirred mixture Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-M sulfinate Chemical compound [O-]S=O BUUPQKDIAURBJP-UHFFFAOYSA-M 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
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- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- BORJONZPSTVSFP-UHFFFAOYSA-N tetradecyl 2-hydroxypropanoate Chemical compound CCCCCCCCCCCCCCOC(=O)C(C)O BORJONZPSTVSFP-UHFFFAOYSA-N 0.000 description 1
- YRZGMTHQPGNLEK-UHFFFAOYSA-N tetradecyl propanoate Chemical compound CCCCCCCCCCCCCCOC(=O)CC YRZGMTHQPGNLEK-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
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- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
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Classifications
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- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Abstract
Disclosed herein is the use of 6-(3-chloro-4-cyclopropyloxyphenyl)pyrimidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disorder mediated by Kynurenine 3-monooxygenase activity in a subject in need of such a treatment. Also disclosed are pharmaceutical compositions comprising these Kynurenine-3-monooxygenase inhibitor compounds and their use in the treatment of conditions mediated by Kynurenine-3-monooxygenase, particularly neurodegenerative conditions such as Huntington's disease. treatment. Also disclosed are pharmaceutical compositions comprising these Kynurenine-3-monooxygenase inhibitor compounds and their use in the treatment of conditions mediated by Kynurenine-3-monooxygenase, particularly neurodegenerative conditions such as Huntington's disease.
Description
KynurenineMonooxygenase Inhibitors, Pharmaceutical
Compositions, and Methods of Use Thereof
This application claims the benefit of priority of U.S. Application No.
61/528,998, filed August 30, 2011, which is incorporated herein in its entirety for all
purposes. This application is also divisional of New Zealand Patent Application No.
621471, the entire contents of which are incorporated herein by reference.
Provided herein are certain kynureninemonooxygenase inhibitors,
pharmaceutical compositions thereof, and methods of their use.
Kynureninemonooxygenase (KMO) is an enzyme in the tryptophan
degradation pathway that catalyzes the conversion of kynurenine (KYN) into 3-
hydroxykynurenine (3-HK), which is further degraded to the excitotoxic NMDA receptor
agonist QUIN (3-hydroxyanthranilate oxygenase). 3-OH-KYN and QUIN act
synergistically, i.e. 3-OH-KYN significantly potentiates the excitotoxic actions of QUIN.
Studies from several laboratories have provided evidence that the shift of KYN pathway
metabolism away from the 3-OH-KYN/QUIN branch to increase the formation of the
neuroprotectant KYNA in the brain leads to neuroprotection. In addition to having effects
in the brain, the inhibition of KMO is further contemplated to impact peripheral tissues.
Thus, the inhibition of KMO may be useful in the treatment of peripheral diseases as well
as diseases of the brain. Furthermore, the relationship between KMO inhibition and
elevations in AA (Anthranilic acid) could also have significant biological effects.
It has also been reported that KMO expression increases in inflammatory
conditions or after immune stimulation. 3-OH-KYN, the product of its activity,
accumulates in the brain of vitamin B-6 deficient neonatal rats and it causes cytotoxicity
when added to neuronal cells in primary cultures or when locally injected into the brain.
Recently, it was reported that relatively low concentrations (nanomolar) of 3-OH-KYN
may cause apoptotic cell death of neurons in primary neuronal cultures. Structure-activity
studies have in fact shown that 3-OH-KYN, and other o-amino phenols, may be subject to
oxidative reactions initiated by their conversion to quinoneimines, a process associated
with concomitant production of oxygen-derived free radicals. The involvement of these
reactive species in the pathogenesis of ischemic neuronal death has been widely studied in
the last several years and it has been shown that oxygen derived free radicals and glutamate
mediated neurotransmission co-operate in the development of ischemic neuronal death.
It was also recently demonstrated that KMO activity is particularly
elevated in the iris-ciliary body and that neo-formed 3-OH-KYN is secreted into the fluid
of the lens. An excessive accumulation of 3-OH-KYN in the lens may cause cataracts.
QUIN is an agonist of a subgroup of NMDA receptors and when directly
injected into brain areas it destroys most neuronal cell bodies sparing fibers en passant
and neuronal terminals. QUIN is a relatively poor agonist of the NMDA receptor
complex containing either NR2C or NR2D subunits, while it interacts with relatively high
affinity with the NMDA receptor complex containing NR2A and NR2B subunits. The
neurotoxicity profile found after intrastriatal injection of QUIN resembles that found in
the basal nuclei of Huntington's disease patients: while most of the intrinsic striatal
neurons are destroyed, NADH-diaphorase-staining neurons (which are now considered
able to express nitric oxide synthetase) and neurons containing neuropeptide Y seem to be
spared together with axon terminals and fiber en passant.
In vivo- infusion of KYNA has shown to modulate synaptic release of
critical neurotransmitters implicated in cognitive processes and affective mental faculties,
such as Acetylcholine, dopamine, and glutamate; therefore elevation of KYNA in brain
can have effects in cognitive disorders and disorders arising from, or influenced by,
changes in the levels of the neurotransmitters glutamate, dopamine, or Ach (such as
Alzheimers, MCI, PD, schizophrenia, HD, OCD, Tourette’s).
In vitro, the neurotoxic effects of the compound have been studied in
different model systems with variable results: chronic exposure of organotypic cortico-
striatal cultures to submicromolar concentration of QUIN causes histological signs of
pathology, similar results have been obtained after chronic exposure of cultured neuronal
cells.
In models of inflammatory neurological disorders such as experimental
allergic encephalitis, bacterial and viral infections, forebrain global ischemia or spinal
trauma, brain QUIN levels are extremely elevated. This increased brain QUIN
concentration could be due to either an elevated circulating concentration of the
excitotoxin or to an increased de novo synthesis in activated microglia or in infiltrating
macrophages. In retrovirus-infected macaques, it has been proposed that most of the
increased content of brain QUIN (approximately 98%) is due to local production. In fact,
a robust increase in the activities of IDO, KMO and kynureninase has been found in areas
of brain inflammation.
Previous studies have shown that agents able to increase brain KYNA
content cause sedation, mild analgesia, increase in the convulsive threshold and
neuroprotection against excitotoxic or ischemic damage. In addition to the above
reported evidences, it has been recently demonstrated that a number of compounds able to
increase brain KYNA formation may cause a robust decrease in glutamate (GLU)
mediated neurotransmission by reducing GLU concentrations in brain extracellular
spaces.
There remains a need for compounds that are effective inhibitors of KMO
and may be used in treating neurodegenerative disorders.
Provided is at least one chemical entity chosen from compounds of
Formula I
Formula I
and pharmaceutically acceptable salts and prodrugs thereof wherein:
X and Y are independently chosen from –N– and –CH–, provided that at least one
of X and Y is –N–;
R is aryl or monocyclic heteroaryl, each of which is substituted with
a first group of the formula –Z-R wherein
Z is chosen from –O–, –S–, –S(O)–, –S(O) –, –CR R –,
2 11 12
–OCR R –, –NR –, –NR CR R –, –CR R NR –,
11 12 13 13 11 12 11 12 13
–C(O)– where R , R , and R are independently chosen
11 12 13
from hydrogen, lower alkyl, hydroxyl, and lower alkoxy,
R is chosen from hydrogen, optionally substituted C -C alkyl,
6 1 6
optionally substituted cycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, and optionally
substituted heterocycloalkyl, provided that if Z is –O–, then
R is not optionally substituted benzyl or optionally
substituted pyridylmethyl, or
R and R , taken together with the nitrogen to which they are
6 13
bound form an optionally substituted 5- to 7-membered
heterocycloalkyl ring, and
a second group chosen from halo and lower alkyl optionally substituted
with halo, or
R is chosen from 2,3-dihydrobenzofuranyl, chromanyl, 1,3-benzodioxol
yl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzoxazolyl, benzoimidazol-
-yl, 1,3-benzoxazolyl, 2-oxo-2,3-dihydro-1,3-benzoxazolyl,
benzothiophenyl, benzothiazolyl, benzofuranyl, 1H-indolyl,
1H-indazolyl, isoindolinyl, benzo[c][1,2,5]oxadiazolyl, 1,2,3,4-
tetrahydroquinolinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-
a]pyridineyl, quinolinyl, quinazolinyl, quinazolinyl, and
quinoxalinyl, each of which is optionally substituted, or
R and R , taken together with intervening atoms form a bicyclic ring of the
formula
which is optionally substituted where m is 0 or 1 and n is 0 or 1, provided
that at least one of m and n is 1 and W is –O-, or –N(R )- where R is
hydrogen or lower alkyl;
R is chosen from hydrogen and optionally substituted lower alkyl;
R is chosen from hydrogen, halo, optionally substituted lower alkyl, hydroxyl,
optionally substituted lower alkoxy, and optionally substituted amino;
L is chosen from -C(O)-, -C(O)O-, -C(O)N(R )-, -C(O)N(OR )-, -N(R )S(O) -,
4 7 4 2
-S(O) N(R )-, and-C(O)N(R )-S(O) -;
2 4 4 2
R is chosen from hydrogen and lower alkyl;
R is chosen from hydrogen, optionally substituted lower alkyl, optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, and optionally substituted heterocycloalkyl; provided that when
L is -N(R )S(O) -, then R is not hydrogen, or
4 2 5
R and R taken together with the nitrogen to which they are bound form an
optionally substituted 4- to 7-membered heterocycloalkyl ring, which is
optionally fused to an optionally substituted cycloalkyl, optionally
substituted heterocycloalkyl, optionally substituted aryl or optionally
substituted heteroaryl ring; or
R and R , taken together with the intervening atoms, form an optionally
substituted 5- to 7-membered ring; and
R is chosen from hydrogen and lower alkyl;
provided that the compound of Formula I is not chosen from
6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid methyl ester;
6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid;
6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester; and
6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid.
Also provided is a pharmaceutical composition comprising at least one
chemical entity described herein and at least one pharmaceutically acceptable excipient.
Also provided is a method of treating a condition or disorder mediated by
Kynurenine 3-mono-oxygenase activity in a subject in need of such a treatment which
method comprises administering to the subject a therapeutically effective amount of at
least one chemical entity described herein.
Also provided is a method of treating a condition or disorder mediated by
Kynurenine 3-mono-oxygenase activity in a subject in need of such a treatment which
method comprises administering to the subject a therapeutically effective amount of at
least one chemical entity described herein.
Also provided is a packaged pharmaceutical composition comprising at
least one pharmaceutical composition described herein and instructions for using the
composition to treat a subject suffering from a condition or disorder mediated by
Kynurenine 3-mono-oxygenase activity.
As used in the present specification, the following words, phrases and
symbols are generally intended to have the meanings as set forth below, except to the
extent that the context in which they are used indicates otherwise. The following
abbreviations and terms have the indicated meanings throughout:
A dash (“-“) that is not between two letters or symbols is used to indicate a
point of attachment for a substituent. For example, -CONH is attached through the
carbon atom.
By “optional” or “optionally” is meant that the subsequently described
event or circumstance may or may not occur, and that the description includes instances
where the event or circumstance occurs and instances in which it does not. For example,
“optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined
below. It will be understood by those skilled in the art, with respect to any group
containing one or more substituents, that such groups are not intended to introduce any
substitution or substitution patterns that are sterically impractical, synthetically non-
feasible and/or inherently unstable.
“Alkyl” encompasses straight chain and branched chain having the
indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8
carbon atoms, such as 1 to 6 carbon atoms. For example C -C alkyl encompasses both
straight and branched chain alkyl of from 1 to 6 carbon atoms. Examples of alkyl groups
include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,
isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. Alkylene is
another subset of alkyl, referring to the same residues as alkyl, but having two points of
attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2
to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, C alkylene indicates
a covalent bond and C alkylene is a methylene group. When an alkyl residue having a
specific number of carbons is named, all geometric isomers having that number of
carbons are intended to be encompassed; thus, for example, "butyl" is meant to include n-
butyl, sec-butyl, isobutyl and t-butyl; "propyl" includes n-propyl and isopropyl. “Lower
alkyl” refers to alkyl groups having 1 to 4 carbons.
“Cycloalkyl” indicates a saturated hydrocarbon ring group, having the
specified number of carbon atoms, usually from 3 to 7 ring carbon atoms. Examples of
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as well as
bridged and caged saturated ring groups such as norbornane.
By “alkoxy” is meant an alkyl group of the indicated number of carbon
atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy,
propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy,
isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. An
alkoxy group is further meant to encompass a cycloalkyl group, as defined above, that is
likewise attached through an oxygen bridge. Alkoxy groups will usually have from 1 to 6
carbon atoms attached through the oxygen bridge. “Lower alkoxy” refers to alkoxy
groups having 1 to 4 carbons.
“Aryl” encompasses:
- and 6-membered carbocyclic aromatic rings, for example, benzene;
bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for
example, naphthalene, indane, and tetralin; and
tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for
example, fluorene.
For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to
7-membered heterocycloalkyl ring containing 1 or more heteroatoms chosen from N, O,
and S, provided that the point of attachment is at the carbocyclic aromatic ring. Bivalent
radicals formed from substituted benzene derivatives and having the free valences at ring
atoms are named as substituted phenylene radicals. Bivalent radicals derived from
univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one
hydrogen atom from the carbon atom with the free valence are named by adding "-idene"
to the name of the corresponding univalent radical, e.g., a naphthyl group with two points
of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in
any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic
aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is
heteroaryl, not aryl, as defined herein.
The term “halo” includes fluoro, chloro, bromo, and iodo, and the term
“halogen” includes fluorine, chlorine, bromine, and iodine.
“Heteroaryl” encompasses:
- to 7-membered aromatic, monocyclic rings containing one or more, for
example, from 1 to 4, or In some embodiments, from 1 to 3, heteroatoms
chosen from N, O, and S, with the remaining ring atoms being carbon; and
bicyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4,
or In some embodiments, from 1 to 3, heteroatoms chosen from N, O, and
S, with the remaining ring atoms being carbon and wherein at least one
heteroatom is present in an aromatic ring.
For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring
fused to a 5- to 7-membered cycloalkyl ring. For example, heteroaryl also includes a 5-
or 6-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered aryl ring.
For such fused, bicyclic heteroaryl ring systems wherein only one of the rings contains
one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the
cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds
1, those heteroatoms are not adjacent to one another. In some embodiments, the total
number of S and O atoms in the heteroaryl group is not more than 2. In some
embodiments, the total number of S and O atoms in the aromatic heterocycle is not more
than 1. Examples of heteroaryl groups include, but are not limited to, (as numbered from
the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl,
3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl,
isoxazolyl, isoxazolinyl, oxazolyl, oxazolinyl, oxadiazolyl, thiazolinyl, thiadiazolinyl,
tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl,
benzooxazolyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-
tetrahydroisoquinoline. Bivalent radicals derived from univalent heteroaryl radicals
whose names end in "-yl" by removal of one hydrogen atom from the atom with the free
valence are named by adding "-idene" to the name of the corresponding univalent radical,
e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not
encompass or overlap with aryl as defined above.
Substituted heteroaryl also includes ring systems substituted with one or
more oxide (-O ) substituents, such as pyridinyl N-oxides.
By “heterocycloalkyl” is meant a single aliphatic ring, usually with 3 to 7
ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms
independently selected from oxygen, sulfur, and nitrogen, as well as combinations
comprising at least one of the foregoing heteroatoms. “Heterocycloalkyl” also refers to 5-
and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl
ring containing 1 or more heteroatoms chosen from N, O, and S, provided that the point
of attachment is at the heterocycloalkyl ring. Suitable heterocycloalkyl groups include,
for example (as numbered from the linkage position assigned priority 1), 2-pyrrolinyl,
2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperdyl, and 2,5-
piperzinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-
morpholinyl (numbered wherein the oxygen is assigned priority 1). Substituted
heterocycloalkyl also includes ring systems substituted with one or more oxo moieties,
such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxothiomorpholinyl and 1,1-
dioxothiomorpholinyl.
The term “substituted”, as used herein, means that any one or more
hydrogens on the designated atom or group is replaced with a selection from the indicated
group, provided that the designated atom's normal valence is not exceeded. When a
substituent is oxo (i.e., =O) then 2 hydrogens on the atom are replaced. Combinations of
substituents and/or variables are permissible only if such combinations result in stable
compounds or useful synthetic intermediates. A stable compound or stable structure is
meant to imply a compound that is sufficiently robust to survive isolation from a reaction
mixture, and subsequent formulation as an agent having at least practical utility. Unless
otherwise specified, substituents are named into the core structure. For example, it is to
be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of
attachment of this substituent to the core structure is in the alkyl portion.
The terms “substituted” alkyl (including without limitation lower alkyl),
cycloalkyl, aryl (including without limitation phenyl), heterocycloalkyl (including without
limitation morpholinyl, 3,4-dihydroquinolin-1(2H)-yl, indolinyl, 3-oxopiperazin
yl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, and isoindolinyl), and
heteroaryl (including without limitation pyridinyl), unless otherwise expressly defined,
refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one
or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a
substituent independently chosen from:
a b b
R , OR , O(C C alkyl)O (e.g., methylenedioxy-), SR , guanidine, guanidine
wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group,
b c b b
NR R , halo, cyano, oxo (as a substituent for heterocycloalkyl), nitro, COR , CO R ,
b c b a b c c b c a c b c
CONR R , OCOR , OCO R , OCONR R , NR COR , NR CO R , NR CONR R ,
a a b c c a
SOR , SO R , SO NR R , and NR SO R ,
2 2 2
where R is chosen from optionally substituted C C alkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
heterocycloalkyl, and optionally substituted heteroaryl;
R is chosen from H, optionally substituted C C alkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
heterocycloalkyl, and optionally substituted heteroaryl; and
R is chosen from hydrogen and optionally substituted C C alkyl; or
b c
R and R , and the nitrogen to which they are attached, form an optionally
substituted heterocycloalkyl group; and
where each optionally substituted group is unsubstituted or independently
substituted with one or more, such as one, two, or three, substituents independently
selected from C C alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl,
arylC C alkyl, heteroarylC C alkyl, C C haloalkyl-, OC C alkyl,
1 4 1 4 1 4 1 4
OC C alkylphenyl, -C C alkylOH, -C C alkylO-C C alkyl, OC C haloalkyl,
1 4 1 4 1 4 1 4 1 4
halo, OH, NH , C C alkylNH , N(C C alkyl)(C C alkyl), NH(C C alkyl),
2 1 4 2 1 4 1 4 1 4
N(C C alkyl)(C C alkylphenyl), NH(C C alkylphenyl), cyano, nitro, oxo (as a
1 4 1 4 1 4
substitutent for heteroaryl), CO H, C(O)OC C alkyl, CON(C C alkyl)(C C alkyl),
2 1 4 1 4 1 4
CONH(C C alkyl), CONH , NHC(O)(C C alkyl), NHC(O)(phenyl),
1 4 2 1 4
N(C C alkyl)C(O)(C C alkyl), N(C C alkyl)C(O)(phenyl), C(O)C C alkyl,
1 4 1 4 1 4 1 4
C(O)C C phenyl, C(O)C C haloalkyl, OC(O)C C alkyl, -SO (C C alkyl), -
1 4 1 4 1 4 2 1 4
SO (phenyl), -SO (C C haloalkyl), -SO NH , SO NH(C C alkyl), SO NH(phenyl), -
2 2 1 4 2 2 2 1 4 2
NHSO (C C alkyl), -NHSO (phenyl), and NHSO (C C haloalkyl).
2 1 4 2 2 1 4
The term “substituted alkoxy” refers to alkoxy wherein the alkyl
constituent is substituted (i.e., -O-(substituted alkyl)) wherein “substituted alkyl” is as
described herein. “Substituted alkoxy” also includes glycosides (i.e., glycosyl groups)
and derivatives of ascorbic acid.
d d d
The term “substituted amino” refers to the group –NHR or –NR R where
each R is independently chosen from: hydroxy, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted acyl, aminocarbonyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally
substituted alkoxycarbonyl, sulfinyl and sulfonyl, each as described herein, and provided
that only one R may be hydroxyl. The term “substituted amino” also refers to N-oxides
d d d
of the groups –NHR , and NR R each as described above. N-oxides can be prepared by
treatment of the corresponding amino group with, for example, hydrogen peroxide or m-
chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction
conditions for carrying out the N-oxidation.
“Aminocarbonyl” encompasses a group of the formula –(C=O)(optionally
substituted amino) wherein substituted amino is as described herein.
“Acyl” refers to the groups (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)-
; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the
parent structure through the carbonyl functionality and wherein alkyl, cycloalkyl, aryl,
heteroaryl, and heterocycloalkyl are as described herein. Acyl groups have the indicated
number of carbon atoms, with the carbon of the keto group being included in the
numbered carbon atoms. For example a C acyl group is an acetyl group having the
formula CH (C=O)-.
By “alkoxycarbonyl” is meant an ester group of the formula
(alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the
indicated number of carbon atoms. Thus a C -C alkoxycarbonyl group is an alkoxy group
having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
By “amino” is meant the group -NH .
The term “sulfinyl” includes the groups: -S(O)-(optionally substituted (C -
C )alkyl), -S(O)-optionally substituted aryl), -S(O)-optionally substituted
heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(O)-(optionally
substituted amino).
The term “sulfonyl” includes the groups -S(O )-(optionally substituted (C -
C )alkyl), -S(O )-optionally substituted aryl), -S(O )-optionally substituted heteroaryl), -
6 2 2
S(O )-(optionally substituted heterocycloalkyl), -S(O )-(optionally substituted
alkoxy), -S(O )-optionally substituted aryloxy), -S(O )-optionally substituted
heteroaryloxy), -S(O )-(optionally substituted heterocyclyloxy); and -S(O )-(optionally
substituted amino).
The term “substituted acyl” refers to the groups (substituted alkyl)-C(O)-;
(substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-;
and (substituted heterocycloalkyl)-C(O)-, wherein the group is attached to the parent
structure through the carbonyl functionality and wherein substituted alkyl, cycloalkyl,
aryl, heteroaryl, and heterocycloalkyl are as described herein.
The term “substituted alkoxycarbonyl” refers to the group (substituted
alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl
functionality and wherein substituted alkyl is as described herein.
“Glycosides” refer to any of a number of sugar derivatives that contain a
non-sugar group bonded to an oxygen or nitrogen atom of a sugar and that on hydrolysis
yield that sugar. An example of a glycosyl group is glucosyl.
“Derivatives of ascorbic acid” or “ascorbic acid derivatives” refer to any of
a number of derviatives that contain a non-sugar group bonded to an oxygen or nitrogen
atom of ascorbic acid and that on hydrolysis yield ascorbic acid (i.e., (R)((S)-1,2-
dihydroxyethyl)-3,4-dihydroxyfuran-2(5H)-one).
Compounds described herein include, but are not limited to, their optical
isomers, racemates, and other mixtures thereof. In those situations, the single
enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric
synthesis or by resolution of the racemates. Resolution of the racemates can be
accomplished, for example, by conventional methods such as crystallization in the
presence of a resolving agent, or chromatography, using, for example a chiral high-
pressure liquid chromatography (HPLC) column. In addition, such compounds include Z-
and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds.
Where compounds described herein exist in various tautomeric forms, the term
“compound” is intended to include all tautomeric forms of the compound. Such
compounds also include crystal forms including polymorphs and clathrates. Similarly,
the term “salt” is intended to include all tautomeric forms and crystal forms of the
compound.
Chemical entities include, but are not limited to compounds described
herein and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable
forms of the compounds recited herein include pharmaceutically acceptable salts,
prodrugs, and mixtures thereof. In some embodiments, the compounds described herein
are in the form of pharmaceutically acceptable salts and prodrugs. Hence, the terms
“chemical entity” and “chemical entities” also encompass pharmaceutically acceptable
salts, prodrugs, and mixtures thereof.
“Pharmaceutically acceptable salts” include, but are not limited to salts
with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate,
sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as
malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate,
p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate
such as acetate, HOOC-(CH ) -COOH where n is 0-4, and like salts. Similarly,
pharmaceutically acceptable cations include, but are not limited to sodium, potassium,
calcium, aluminum, lithium, and ammonium.
In addition, if the compounds described herein are obtained as an acid
addition salt, the free base can be obtained by basifying a solution of the acid salt.
Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically
acceptable addition salt, may be produced by dissolving the free base in a suitable organic
solvent and treating the solution with an acid, in accordance with conventional procedures
for preparing acid addition salts from base compounds. Those skilled in the art will
recognize various synthetic methodologies that may be used to prepare non-toxic
pharmaceutically acceptable addition salts.
As noted above, prodrugs also fall within the scope of chemical entities
described herein. In some embodiments, the “prodrugs” described herein include any
compound that becomes a compound of Formula I when administered to a patient, e.g.,
upon metabolic processing of the prodrug. Examples of prodrugs include derivatives of
functional groups, such as a carboxylic acid group, in the compounds of Formula I.
Exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic
acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl
esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester,
acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid
derivatives.
Other exemplary prodrugs include amides of carboxylic acids. Exemplary
amide prodrugs include metabolically labile amides that are formed, for example, with an
amine and a carboxylic acid. Exemplary amines include NH , primary, and secondary
x x y x
amines such as NHR , and NR R , wherein R is hydrogen, (C -C )-alkyl, (C -C )-
1 18 3 7
cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, (C -C )-aryl which is unsubstituted or
3 7 1 4 6 14
substituted by a residue (C -C )-alkyl, (C -C )-alkoxy, fluoro, or chloro; heteroaryl-, (C -
1 2 1 2 6
C )-aryl-(C -C )-alkyl- where aryl is unsubstituted or substituted by a residue (C -C )-
14 1 4 1 2
alkyl, (C -C )-alkoxy, fluoro, or chloro; or heteroaryl-(C -C )-alkyl- and in which R has
1 2 1 4
x x y
the meanings indicated for R with the exception of hydrogen or wherein R and R ,
together with the nitrogen to which they are bound, form an optionally substituted 4- to 7-
membered heterocycloalkyl ring which optionally includes one or two additional
heteroatoms chosen from nitrogen, oxygen, and sulfur. A discussion of prodrugs is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of
the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug
Design, American Pharmaceutical Association and Pergamon Press, 1987, and in Design
of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
A “solvate” is formed by the interaction of a solvent and a compound. The
term “compound” is intended to include solvates of compounds. Similarly, “salts”
includes solvates of salts. Suitable solvates are pharmaceutically acceptable solvates,
such as hydrates, including monohydrates and hemi-hydrates.
A “chelate” is formed by the coordination of a compound to a metal ion at
two (or more) points. The term “compound” is intended to include chelates of
compounds. Similarly, “salts” includes chelates of salts.
A “non-covalent complex” is formed by the interaction of a compound and
another molecule wherein a covalent bond is not formed between the compound and the
molecule. For example, complexation can occur through van der Waals interactions,
hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-
covalent complexes are included in the term “compound’.
The term "hydrogen bond" refers to a form of association between an
electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom
attached to a second, relatively electronegative atom (also known as a hydrogen bond
donor). Suitable hydrogen bond donor and acceptors are well understood in medicinal
chemistry (G. C. Pimentel and A. L. McClellan, The Hydrogen Bond, Freeman, San
Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic
Crystals", Accounts of Chemical Research, 17, pp. 320-326 (1984)).
“Hydrogen bond acceptor” refers to a group comprising an oxygen or
nitrogen, such as an oxygen or nitrogen that is sp –hybridized, an ether oxygen, or the
oxygen of a sulfoxide or N-oxide.
The term "hydrogen bond donor" refers to an oxygen, nitrogen, or
heteroaromatic carbon that bears a hydrogen.group containing a ring nitrogen or a
heteroaryl group containing a ring nitrogen.
As used herein the terms "group", "radical" or "fragment" are synonymous
and are intended to indicate functional groups or fragments of molecules attachable to a
bond or other fragments of molecules.
The term “active agent” is used to indicate a chemical entity which has
biological activity. In some embodiments, an “active agent” is a compound having
pharmaceutical utility. For example an active agent may be an anti-neurodegenerative
therapeutic.
The term "therapeutically effective amount" of a chemical entity described
herein means an amount effective, when administered to a human or non-human subject,
to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease
progression, or prevention of disease e.g., a therapeutically effective amount may be an
amount sufficient to decrease the symptoms of a disease responsive to inhibition of KMO
activity and modulation of kynurenine pathway metabolites (such as kynurenine,
kynurenic acid, anthranilic acid, 3-OH-kynurenine, 3-OH anthranilic acid, or quinolinic
acid). In some embodiments, a therapeutically effective amount is an amount sufficient to
treat the symptoms of neurodegenerative pathway or disease. In some embodiments a
therapeutically effective amount is an amount sufficient to reduce the signs or side effects
of a neurodegenerative disease. In some embodiments, a therapeutically effective amount
of a chemical entity is an amount sufficient to prevent a significant increase or
significantly reduce the level of neuronal cell death. In some embodiments, a
therapeutically effective amount of a chemical entity is an amount sufficient to prevent a
significant increase or significantly reduce the level of QUIN associated with neuronal
cell death. In some embodiments, a therapeutically effective amount of a chemical entity
is an amount sufficient to effect an increase in the level of KYNA associated with
neuronal cell health. In some embodiments, a therapeutically effective amount of a
chemical entity is an amount sufficient to increase the anticonvulsant and neuroprotective
properties associated with lowered levels of QUIN and increased levels of KYNA. In
some embodiments, a therapeutically effective amount is an amount sufficient to
modulate an inflammatory process in the body, including but not limited to inflammation
in the brain, spinal cord, and peripheral nervous sytem, or meninges. In some
embodiments, a therapeutically effective amount is an amount sufficient to modulate the
production of cytokines responsible for mounting an effective immune response (such as
IL-1 beta or TNF-alpha) or an amount sufficient to affect monocyte/macrophage pro-
inflammatory activity in the periphery or in the brain in conditions where the blood-brain
barrier is compromised, such as in multiple sclerosis).
In methods described herein for treating a neurodegenerative disorder, a
therapeutically effective amount may also be an amount sufficient, when administered to
a patient, to detectably slow the progression of the neurodegenative disease, or prevent
the patient to whom the chemical entity is given from presenting symptoms of the
neurodegenative disease. In some methods described herein for treating a
neurodegenative disease, a therapeutically effective amount may also be an amount
sufficient to produce a detectable decrease in the level of neuronal cell death. For
example, in some embodiments a therapeutically effective amount is an amount of a
chemical entity described herein sufficient to significantly decrease the level of neuronal
death by effecting a detectable decrease in the amount of QUIN, and an increase in the
amount of kynurenine, KYNA, or anthranilic acid.
In addition, an amount is considered to be a therapeutically effective amout
if it is characterized as such by at least one of the above criteria or experimental
conditions, regardless of any inconsistent or contradictory results under a different set of
criteria or experimental conditions.
The term “inhibition” indicates a significant decrease in the baseline
activity of a biological activity or process. “Inhibition of KMO activity” refers to a
decrease in KMO activity as a direct or indirect response to the presence of at least one
chemical entity described herein, relative to the activity of KMO in the absence of at least
one chemical entity. The decrease in activity may be due to the direct interaction of the
compound with KMO, or due to the interaction of the chemical entity(ies) described
herein with one or more other factors that in turn affect KMO activity. For example, the
presence of the chemical entity(ies) may decrease KMO activity by directly binding to the
KMO, by causing (directly or indirectly) another factor to decrease KMO activity, or by
(directly or indirectly) decreasing the amount of KMO present in the cell or organism.
“Inhibition of KMO activity” refers to a decrease in KMO activity as a
direct or indirect response to the presence of at least one chemical entity described herein,
relative to the activity of KMO in the absence of the at least one chemical entity. The
decrease in activity may be due to the direct interaction of the compound with KMO or
with one or more other factors that in turn affect KMO activity.
Inhibition of KMO activity also refers to an observable inhibition of 3-HK
and QUIN production in a standard assay such as the assay described below. The
inhibition of KMO activity also refers to an observable increase in the production of
KYNA. In some embodiments, the chemical entity described herein has an IC value
less than or equal to 1 micromolar. In some embodiments, the chemical entity has an IC
value less than or equal to less than 100 micromolar. In some embodiments, the chemical
entity has an IC value less than or equal to 10 nanomolar.
“KMO activity” also includes activation, redistribution, reorganization, or
capping of one or more various KMO membrane-associated proteins (such as those
receptors found in the mitochondria), or binding sites can undergo redistribution and
capping that can initiate signal transduction. KMO activity also can modulate the
availability of kynurenine, which can effect the the synthesis or production of QUIN,
KYNA, anthranilic acid, and/or 3-HK.
A “disease responsive to inhibition of KMO activity” is a disease in which
inhibiting KMO provides a therapeutic benefit such as an amelioration of symptoms,
decrease in disease progression, prevention or delay of disease onset, prevention or
amelioration of an inflammatory response, or inhibition of aberrant activity and/or death
of certain cell-types (such as neuronal cells).
“Treatment” or “treating” means any treatment of a disease in a patient,
including:
a) preventing the disease, that is, causing the clinical symptoms of the disease
not to develop;
b) inhibiting the progression of the disease;
c) slowing or arresting the development of clinical symptoms; and/or
d) relieving the disease, that is, causing the regression of clinical symptoms.
“Subject” or “patient’ refers to an animal, such as a mammal, that has been
or will be the object of treatment, observation or experiment. The methods described
herein may be useful in both human therapy and veterinary applications. In some
embodiments, the subject is a mammal; and in some embodiments the subject is human.
Provided is at least one chemical entity chosen from compounds of
Formula I
Formula I
and pharmaceutically acceptable salts and prodrugs thereof wherein:
X and Y are independently chosen from –N– and –CH–, provided that at least one
of X and Y is –N–;
R is aryl or monocyclic heteroaryl, each of which is substituted with
a first group of the formula –Z-R wherein
Z is chosen from –O–, –S–, –S(O)–, –S(O) –, –CR R –,
2 11 12
–OCR R –, –NR –, –NR CR R –, –CR R NR –,
11 12 13 13 11 12 11 12 13
–C(O)– where R , R , and R are independently chosen
11 12 13
from hydrogen, lower alkyl, hydroxyl, and lower alkoxy,
R is chosen from hydrogen, optionally substituted C -C alkyl,
6 1 6
optionally substituted cycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, and optionally
substituted heterocycloalkyl, provided that if Z is –O–, then
R is not optionally substituted benzyl or optionally
substituted pyridylmethyl, or
R and R , taken together with the nitrogen to which they are
6 13
bound form an optionally substituted 5- to 7-membered
heterocycloalkyl ring, and
a second group chosen from halo and lower alkyl optionally substituted
with halo, or
R is chosen from 2,3-dihydrobenzofuranyl, chromanyl, 1,3-benzodioxol
yl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzoxazolyl, 1,3-
benzoxazolyl, 2-oxo-2,3-dihydro-1,3-benzoxazolyl, benzothiophen-
-yl, benzothiazolyl, benzoimidazolyl, benzofuranyl, 1H-indol
yl, 1H-indazolyl, isoindolinyl, benzo[c][1,2,5]oxadiazolyl,
1,2,3,4-tetrahydroquinolinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-
a]pyridineyl, quinolinyl, quinazolinyl, quinazolinyl, and
quinoxalinyl, each of which is optionally substituted,
R and R , taken together with intervening atoms form a bicyclic ring of the
formula
which is optionally substituted where m is 0 or 1 and n is 0 or 1, provided
that at least one of m and n is 1 and W is –O-, or –N(R )- where R is
hydrogen or lower alkyl;
R is chosen from hydrogen and optionally substituted lower alkyl;
R is chosen from hydrogen, halo, optionally substituted lower alkyl, hydroxyl,
optionally substituted lower alkoxy, and optionally substituted amino;
L is chosen from -C(O)-, -C(O)O-, -C(O)N(R )-, -C(O)N(OR )-, -N(R )S(O) -, -
4 7 4 2
S(O) N(R )-, and-C(O)N(R )-S(O) -;
2 4 4 2
R is chosen from hydrogen and lower alkyl;
R is chosen from hydrogen, optionally substituted lower alkyl, optionally
substituted aryl, optionally substituted heteroaryl, optionally substituted
cycloalkyl, and optionally substituted heterocycloalkyl; provided that when
L is -N(R )S(O) -, then R is not hydrogen, or
4 2 5
R and R taken together with the nitrogen to which they are bound form an
optionally substituted 4- to 7-membered heterocycloalkyl ring, which is
optionally fused to an optionally substituted cycloalkyl, optionally
substituted heterocycloalkyl, optionally substituted aryl or optionally
substituted heteroaryl ring; or
R and R , taken together with the intervening atoms, form an optionally
substituted 5- to 7-membered ring; and
R is chosen from hydrogen and lower alkyl;
provided that the compound of Formula I is not chosen from
6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid methyl ester;
6-(3-chloromethyl-phenyl)-pyrimidinecarboxylic acid;
6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester; and
6-(3-chloromethoxy-phenyl)-pyrimidinecarboxylic acid.
In some embodiments, R is phenyl substituted with
a first group of the formula –Z-R wherein Z is chosen from –O–, –S–, –
S(O) –,
–S(O) –, and –CR R –; and R is chosen from hydrogen,
2 11 12 6
optionally substituted C -C alkyl, optionally substituted
cycloalkyl, and optionally substituted heterocycloalkyl, and
a second group chosen from halo and lower alkyl optionally substituted
with halo.
In some embodiments, R is pyridinyl substituted with
a first group of the formula –Z-R wherein Z is chosen from –O–, –S–, –
S(O) –,
–S(O) –, and –CR R –; and R is chosen from hydrogen,
2 11 12 6
optionally substituted C -C alkyl, optionally substituted
cycloalkyl, and optionally substituted heterocycloalkyl, and
a second group chosen from halo and lower alkyl optionally substituted
with halo.
In some embodiments, Z is –O–.
In some embodiments, Z is –S–.
In some embodiments, Z is –S(O) –.
In some embodiments, Z is –CR R –.
11 12
In some embodiments, R is chosen from hydrogen, methyl,
difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoromethyl-ethyl, isopropyl, (S)-sec-
butyl, (R)-sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-morpholinyl-ethyl, 2-
piperidinyl-ethyl, pyrrolidinyl, and tetrahydro-furanyl.
In some embodiments, R is chosen from 3-chlorocyclobutoxy-phenyl,
3-chlorocyclopentyloxy-phenyl, 3-chlorocyclopropoxy-phenyl, 3-chloro
isopropoxy-phenyl, 3-chloromethoxy-phenyl, [4-chloro(2-morpholinyl-ethoxy)-
phenyl, 3-chloro(2-piperidinyl-ethoxy)-phenyl, 3-chloro(pyrrolidinyloxy)-
phenyl, 4-(S)-sec-butoxychloro-phenyl, 4-(R)-sec-butoxychloro-phenyl, 4-chloro
(tetrahydro-furanyloxy)-phenyl, 3-chlorotrifluoromethoxy-phenyl, 3-chloro
(2,2,2-trifluoromethyl-ethoxy, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-
dimethoxyphenyl, 3-chloroisopropylphenyl, 3-fluoromethylphenyl, and 3-fluoro
isopropylphenyl, 3,4-bis(methylsulfanyl)phenyl, 3,4-bis(methylsulfonyl)phenyl, 3,4-
bis(trifluoromethoxy)phenyl, 3-chloro(difluoromethoxy)phenyl, 3-chloro
(methylsulfanyl)phenyl, 3-chloro(methylsulfonyl)phenyl, 3-chloro
(trifluoromethoxy)phenyl, 3-chloro(cyclopropoxymethyl)phenyl, 3-chloro
(cyclopropylmethyl)phenyl, 3-chloro(cyclopropanesulfinyl)phenyl, 3-chloro
(cyclopropanesulfonyl)phenyl, 3-chloro[cyclopropyl(hydroxy)methyl]phenyl, 3-
chloro(1-cyclopropoxyethyl)phenyl, 3-chlorocyclopropanecarbonylphenyl, 3-
chlorocyclopropylphenyl, 4-(aziridinylmethyl)chlorophenyl, 3-chloro
[(dimethylamino)methyl]phenyl, 3-chloro(cyclopropylamino)phenyl, 3-chloro
[cyclopropyl(methyl)amino]phenyl, 3-chloro[(cyclopropylamino)methyl]phenyl, 3-
chloro{[cyclopropyl(methyl)amino]methyl}phenyl, 3-chloro(1-
methoxycyclopropyl)phenyl, 4-chloro[(1,1,1-trifluoropropanyl)oxy]phenyl, 4-
chloro(trifluoromethoxy)phenyl, 4-chloro(2-methylpropoxy)phenyl, 4-chloro
(propanyloxy)phenyl, 4-chloro(propanyloxy)phenyl, 4-chloromethoxyphenyl,
4-chlorocyclopropoxyphenyl, and 3-chloro{[1-(morpholinyl)propan
yl]oxy}phenyl.
In some embodiments, R is chosen from 3-chloromethoxy-phenyl, 3-
chloro(trifluoromethoxy)phenyl, 3-chlorocyclobutoxy-phenyl, 3-chloro
cyclopropoxy-phenyl, 3-chloroisopropoxy-phenyl, 3-chloromethoxy-phenyl, 3-
chloro(pyrrolidinyloxy)-phenyl, 4-(S)-sec-butoxychloro-phenyl, 4-(R)-sec-
butoxychloro-phenyl, 4-chloro(tetrahydro-furanyloxy)-phenyl, 3-chloro
trifluoromethoxy-phenyl, 3-chloro(2,2,2-trifluoromethyl-ethoxy, 3-methoxy-phenyl,
4-methoxy-phenyl, 3,4-dimethoxyphenyl, 3-chloroisopropylphenyl, 3-fluoro
methylphenyl, and 3-fluoroisopropylphenyl, 3,4-bis(trifluoromethoxy)phenyl, 3-
chloro(difluoromethoxy)phenyl, 3-chloro(trifluoromethoxy)phenyl, 3-chloro
(cyclopropoxymethyl)phenyl, 3-chloro(cyclopropylmethyl)phenyl, 3-chloro
(cyclopropanesulfinyl)phenyl, 3-chloro(cyclopropanesulfonyl)phenyl, 3-chloro
[cyclopropyl(hydroxy)methyl]phenyl, 3-chloro(1-cyclopropoxyethyl)phenyl, 3-chloro-
4-cyclopropanecarbonylphenyl, 3-chlorocyclopropylphenyl, 4-(aziridinylmethyl)
chlorophenyl, 3-chloro[(dimethylamino)methyl]phenyl, 3-chloro
(cyclopropylamino)phenyl, 3-chloro[cyclopropyl(methyl)amino]phenyl, 3-chloro
[(cyclopropylamino)methyl]phenyl, 3-chloro
{[cyclopropyl(methyl)amino]methyl}phenyl, 3-chloro(1-methoxycyclopropyl)phenyl,
4-chloro[(1,1,1-trifluoropropanyl)oxy]phenyl, 4-chloro(trifluoromethoxy)phenyl,
4-chloro(2-methylpropoxy)phenyl, 4-chloro(propanyloxy)phenyl, 4-chloro
(propanyloxy)phenyl, 4-chloromethoxyphenyl, and 4-chlorocyclopropoxyphenyl.
In some embodiments, R is chosen from 1,3-benzodioxolyl, chroman-
6-yl, 2,3-dihydrobenzofuranyl, benzofuranyl, 2,3-dihydro-1H-isoindolyl, 1,3-
benzoxazolyl, 2-oxo-2,3-dihydro-1,3-benzoxazolyl, 1,3-benzoxazolyl,
imidazo[1,2-a]pyridinyl, 1,3-benzoxazolyl, quinolinyl, and pyrazolo[1,5-
a]pyridinyl, each of which is optionally substituted with one or two groups chosen
from halo, lower alkyl optionally substituted with halo, cycloalkyl, and lower alkoxy
optionally substituted with halo.
In some embodiments, R is chosen from 1,3-benzodioxolyl, 2,2-
difluoro-1,3-benzodioxolyl, 8-chloro-chromanyl, 7-chloro-benzofuranyl, 7-
chlorocyclopropyl-2,3-dihydro-1H-isoindolyl, 7-chloromethyl-1,3-benzoxazol
yl, 7-chlorooxo-2,3-dihydro-1,3-benzoxazolyl, 7-chloromethyloxo-2,3-
dihydro-1,3-benzoxazolyl, 7-chlorocyclopropyl-1,3-benzoxazolyl, 8-
chloroimidazo[1,2-a]pyridinyl, 4-chloro-1,3-benzoxazolyl, quinolinyl, and
pyrazolo[1,5-a]pyridinyl.
In some embodiments, R is chosen from 1,3-benzodioxolyl, 2,2-
difluoro-1,3-benzodioxolyl, 8-chloro-chromanyl, 7-chloro-benzofuranyl, 7-
chloromethyl-1,3-benzoxazolyl, 7-chlorocyclopropyl-1,3-benzoxazolyl, 8-
chloroimidazo[1,2-a]pyridinyl, 4-chloro-1,3-benzoxazolyl, quinolinyl, and
pyrazolo[1,5-a]pyridinyl.
In some embodiments, R is hydrogen.
In some embodiments, R is lower alkyl.
In some embodiments, R is methyl or ethyl.
In some embodiments, R is methyl.
In some embodiments, R is hydrogen.
In some embodiments, R is fluoro or chloro.
In some embodiments, R is methyl.
In some embodiments, R is –CH OH.
In some embodiments, X is –N–.
In some embodiments, Y is –N–.
In some embodiments, X and Y are –N–.
In some embodiments, L is -C(O)O-.
In some embodiments, L is -C(O)N(R )-.
In some embodiments, L is -N(R )S(O) -.
In some embodiments, R is hydrogen.
In some embodiments, R is lower alkyl.
In some embodiments, R is hydrogen.
In some embodiments, R and R taken together with the nitrogen to which
they are bound form an optionally substituted 5- to 7-membered heterocycloalkyl ring. In
some embodiments, R and R taken together with the nitrogen to which they are bound
form a ring chosen from 3-oxopiperazinyl, 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-
7(8H)-yl, 4-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, piperidinyl, azetidinyl, 5-
oxo-1,4-diazepanyl, 1,4-diazepanyl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, 3-
oxo-3,4-dihydroquinoxalin-1(2H)-yl, 7,8-dihydro-1,6-naphthyridin-6(5H)-yl, 4-
oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 4-oxodihydro-1H-pyrido[1,2-a]pyrazin-
2(6H,7H,8H,9H,9aH)-yl, pyrrolidinyl, 1,1-dioxido-1,2,5-thiadiazinanyl, 5,7-
dihydro-6H-pyrrolo[3,4-d]pyrimidinyl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, and
2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridinyl, each of which is optionally
substituted. In some embodiments, the optional substituents are one or two groups
independently chosen from halo, lower alkyl optionally substituted with halo, cycloalkyl,
and lower alkoxy optionally substituted with halo.
Also provided is at least one chemical entity chosen from compounds of
Formula II
Formula II
and pharmaceutically acceptable salts and prodrugs thereof, wherein n is chosen from 1
and 2 and wherein R , R , X, and Y are as described for compounds of Formula I.
In some embodiments, n is 1. In some embodiments, n is 2.
Also provided is a compound chosen from
6-(4-Chloromethoxy-phenyl)-pyrimidinecarboxylic acid,
6-(3-Aminochloro-phenyl)-pyrimidinecarboxylic acid,
6-[4-Chloro(tetrahydro-furanyloxy)-phenyl]-pyrimidinecarboxylic acid,
6-[4-Chloro(tetrahydro-furanyloxy)-phenyl]-pyrimidinecarboxylic acid pyridin-
3-ylamide,
6-[4-Chloro(2-morpholinyl-ethoxy)-phenyl]-pyrimidinecarboxylic acid pyridin-
3-yl-amide,
6-(3-Chloroisopropyl-phenyl)-pyrimidinecarboxylic acid,
6-(3-Fluoromethyl-phenyl)-pyrimidinecarboxylic acid,
6-(3-Chloroisopropoxy-phenyl)-pyrimidinecarboxylic acid,
6-(3-Chloroisopropoxy-phenyl)methyl-pyrimidinecarboxylic acid,
6-(3-Fluoromethyl-phenyl)methyl-pyrimidinecarboxylic acid,
6-(3-Chlorocyclopentyloxy-phenyl)-pyrimidinecarboxylic acid,
6-(3-Chlorotrifluoromethoxy-phenyl)-pyrimidinecarboxylic acid,
6-(3-Fluoroisopropyl-phenyl)-pyrimidinecarboxylic acid,
6-(4-(R)-sec-Butoxychloro-phenyl)-pyrimidinecarboxylic acid,
6-(4-(S)-sec-Butoxychloro-phenyl)-pyrimidinecarboxylic acid,
6-(3-Chlorocyclopropoxy-phenyl)-pyrimidinecarboxylic acid,
6-[3-Chloro(2,2,2-trifluoromethyl-ethoxy)-phenyl]-pyrimidinecarboxylic acid,
4-(3-Chlorocyclopropoxy-phenyl)-pyridinecarboxylic acid,
6-(4-(R)-sec-Butoxychloro-phenyl)-pyridinecarboxylic acid,
6-(4-(S)-sec-Butoxychloro-phenyl)-pyridinecarboxylic acid,
4-(3-Chloroisopropoxy-phenyl)-pyridinecarboxylic acid,
4-(3-Chlorotrifluoromethoxy-phenyl)-pyridinecarboxylic acid,
6-(3-Chlorocyclobutoxy-phenyl)-pyrimidinecarboxylic acid,
6-[3-Chloro(2-piperidinyl-ethoxy)-phenyl]-pyrimidinecarboxylic acid,
6-Quinolinyl-pyrimidinecarboxylic acid,
6-(8-Chloro-chromanyl)-pyrimidinecarboxylic acid,
6-(7-Chloro-benzofuranyl)-pyrimidinecarboxylic acid,
6-[3-Chloro(pyrrolidinyloxy)-phenyl]-pyrimidinecarboxylic acid,
6-(8-chloromethyl-1,2,3,4-tetrahydroquinolinyl)pyrimidinecarboxylic acid,
6-(8-chloroquinolinyl)pyrimidinecarboxylate,
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl]benzenesulfonamide,
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl]fluorobenzenesulfonamide,
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl](trifluoromethoxy)benzene
sulfonamide,
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl](trifluoromethoxy)benzene
sulfonamide,
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl]fluorobenzenesulfonamide,
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl]cyclopropanesulfonamide,
6-(8-chloro-1,2,3,4-tetrahydroquinolinyl)pyrimidinecarboxylate,
6-(3-chlorocyclopropoxyphenyl)methylpyrimidinecarboxylate,
6-{3-chloro[2-(morpholinyl)ethoxy]phenyl}pyrimidinecarboxylate,
6-[3-chloro(cyclopropylmethoxy)phenyl]pyrimidinecarboxylate,
6-[3-chloro(oxetanyloxy)phenyl]pyrimidinecarboxylate,
4-(3-chlorocyclopropoxyphenyl)-5H,7H-furo[3,4-d]pyrimidinone,
6-(3-chlorocyclopropoxyphenyl)(hydroxymethyl)pyrimidinecarboxylic acid,
4-(3-chlorocyclopropoxyphenyl)-5H,6H,8H-pyrano[3,4-d]pyrimidinone,
[(2R,3S,4S,5R)-3,4,5,6-tetrahydroxyoxanyl]methyl 6-(3-chloro
cyclopropoxyphenyl)pyrimidinecarboxylate,
6-(3-chloro{[1-(morpholinyl)propanyl]oxy}phenyl)pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropoxymethyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropylmethyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropylsulfanyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropanesulfinyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropanesulfonyl)phenyl]pyrimidinecarboxylic acid,
6-{3-chloro[cyclopropyl(hydroxy)methyl]phenyl}pyrimidinecarboxylic acid,
6-[3-chloro(1-cyclopropoxyethyl)phenyl]pyrimidinecarboxylic acid,
6-(3-chlorocyclopropanecarbonylphenyl)pyrimidinecarboxylic acid,
6-(3-chlorocyclopropylphenyl)pyrimidinecarboxylic acid,
6-[4-(aziridinylmethyl)chlorophenyl]pyrimidinecarboxylic acid,
6-{3-chloro[(dimethylamino)methyl]phenyl}pyrimidinecarboxylic acid
6-[3-chloro(cyclopropylamino)phenyl]pyrimidinecarboxylic acid,
6-{3-chloro[cyclopropyl(methyl)amino]phenyl}pyrimidinecarboxylic acid,
6-{3-chloro[(cyclopropylamino)methyl]phenyl}pyrimidinecarboxylic acid,
6-(3-chloro{[cyclopropyl(methyl)amino]methyl}phenyl)pyrimidinecarboxylic acid,
6-(7-chlorocyclopropyl-2,3-dihydro-1H-isoindolyl)pyrimidinecarboxylic acid,
6-[3-chloro(furanyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(1-methoxycyclopropyl)phenyl]pyrimidinecarboxylic acid,
6-(2,3-dihydro-1,4-benzodioxinyl)pyrimidinecarboxylic acid,
6-(7-chloromethyl-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-(7-chlorooxo-2,3-dihydro-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-(7-chloromethyloxo-2,3-dihydro-1,3-benzoxazolyl)pyrimidinecarboxylic
acid,
6-(7-chlorocyclopropyl-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-{8-chloroimidazo[1,2-a]pyridinyl}pyrimidinecarboxylic acid,
6-(4-chloro-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-(quinolinyl)pyrimidinecarboxylic acid,
6-{pyrazolo[1,5-a]pyridinyl}pyrimidinecarboxylic acid,
6-(4-chlorocyclopropoxyphenyl)pyrimidinecarboxylic acid,
6-(4-chloromethoxyphenyl)pyrimidinecarboxylic acid,
6-[4-chloro(propanyloxy)phenyl]pyrimidinecarboxylic acid,
6-[4-chloro(2-methylpropoxy)phenyl]pyrimidinecarboxylic acid,
6-[4-chloro(trifluoromethoxy)phenyl]pyrimidinecarboxylic acid,
6-{4-chloro[(1,1,1-trifluoropropanyl)oxy]phenyl}pyrimidinecarboxylic acid,
6-(benzo[d][1,3]dioxolyl)pyrimidinecarboxylic acid,
6-(2,2-difluorobenzo[d][1,3]dioxolyl)pyrimidinecarboxylic acid,
6-(2,3-dihydrobenzo[b][1,4]dioxinyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[b]thiophenyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[d]thiazolyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[d]oxazolyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[c][1,2,5]oxadiazolyl)pyrimidinecarboxylic acid,
6-(7-chloro-2,3,3a,7a-tetrahydrobenzofuranyl)pyrimidinecarboxylic acid,
6-(7-chloro-3a,7a-dihydro-1H-indolyl)pyrimidinecarboxylic acid,
6-(7-chloromethyl-3a,7a-dihydro-1H-indazolyl)pyrimidinecarboxylic acid,
6-(8-chloroquinazolinyl)pyrimidinecarboxylic acid,
6-(5-chloroquinazolinyl)pyrimidinecarboxylic acid,
6-(8-chloroquinoxalinyl)pyrimidinecarboxylic acid,
6-(8-chloro-1,2,3,4-tetrahydroquinolinyl)pyrimidinecarboxylic acid,
6-(7-chloro-1H-benzo[d]imidazolyl)pyrimidinecarboxylic acid,
6-(3-chloro(1-methylcyclopropyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(1-(trifluoromethyl)cyclopropyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(3-methyloxetanyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(1H-imidazolyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(1H-pyrrolyl)phenyl)pyrimidinecarboxylic acid,
6-(4-tert-butylchlorophenyl)pyrimidinecarboxylic acid, and
7-chlorocyclopropoxy-5H-chromeno[4,3-d]pyrimidinecarboxylic acid.
or a pharmaceutically acceptable salt or prodrug thereof.
Also provided is a compound chosen from
6-[3-chloro(methylsulfanyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(methylsulfinyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(methylsulfonyl)phenyl]pyrimidinecarboxylic acid,
6-{3-chloro[cyclopropyl(hydroxy)methyl]phenyl}pyrimidinecarboxylic acid,
6-(3-chlorocyclopropanecarbonylphenyl)pyrimidinecarboxylic acid,
6-[3-chloro(methoxymethyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(1-methoxyethyl)phenyl]pyrimidinecarboxylic acid,
6-{3-chloro[(dimethylamino)methyl]phenyl}pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropylamino)phenyl]pyrimidinecarboxylic acid,
6-{3-chloro[cyclopropyl(methyl)amino]phenyl}pyrimidinecarboxylic acid,
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidinecarboxylic acid,
6-(7-chloromethyl-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-(8-chloroquinoxalinyl)pyrimidinecarboxylic acid,
6-(7-chloro-2,3-dihydrobenzofuranyl)pyrimidinecarboxylic acid,
6-(7-chlorocyclopropyl-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-(4-chloromethyl-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-(7-chloromethyloxo-2,3-dihydro-1,3-benzoxazolyl)pyrimidinecarboxylic
acid,
6-(2H-1,3-benzodioxolyl)pyrimidinecarboxylic acid,
4-(3,4-dichlorophenyl)methylpyridinecarboxylic acid,
6-(3-chloro{[1-(morpholinyl)propanyl]oxy}phenyl)pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropoxymethyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(cyclopropylmethyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(1-cyclopropoxyethyl)phenyl]pyrimidinecarboxylic acid,
6-(3-chlorocyclopropylphenyl)pyrimidinecarboxylic acid,
6-[4-(aziridinylmethyl)chlorophenyl]pyrimidinecarboxylic acid,
6-{3-chloro[(cyclopropylamino)methyl]phenyl}pyrimidinecarboxylic acid,
6-(3-chloro{[cyclopropyl(methyl)amino]methyl}phenyl)pyrimidinecarboxylic acid,
6-(7-chlorocyclopropyl-2,3-dihydro-1H-isoindolyl)pyrimidinecarboxylic acid,
6-[3-chloro(furanyl)phenyl]pyrimidinecarboxylic acid,
6-[3-chloro(1-methoxycyclopropyl)phenyl]pyrimidinecarboxylic acid,
6-(2,3-dihydro-1,4-benzodioxinyl)pyrimidinecarboxylic acid,
6-(7-chlorooxo-2,3-dihydro-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-{8-chloroimidazo[1,2-a]pyridinyl}pyrimidinecarboxylic acid,
6-(4-chloro-1,3-benzoxazolyl)pyrimidinecarboxylic acid,
6-(quinolinyl)pyrimidinecarboxylic acid,
6-{pyrazolo[1,5-a]pyridinyl}pyrimidinecarboxylic acid,
6-(4-chlorocyclopropoxyphenyl)pyrimidinecarboxylic acid,
6-(4-chloromethoxyphenyl)pyrimidinecarboxylic acid,
6-[4-chloro(propanyloxy)phenyl]pyrimidinecarboxylic acid,
6-[4-chloro(2-methylpropoxy)phenyl]pyrimidinecarboxylic acid,
6-[4-chloro(trifluoromethoxy)phenyl]pyrimidinecarboxylic acid,
6-{4-chloro[(1,1,1-trifluoropropanyl)oxy]phenyl}pyrimidinecarboxylic acid,
6-(2,2-difluorobenzo[d][1,3]dioxolyl)pyrimidinecarboxylic acid,
6-(2,3-dihydrobenzo[b][1,4]dioxinyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[b]thiophenyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[d]thiazolyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[d]oxazolyl)pyrimidinecarboxylic acid,
6-(7-chlorobenzo[c][1,2,5]oxadiazolyl)pyrimidinecarboxylic acid,
6-(7-chloro-3a,7a-dihydro-1H-indolyl)pyrimidinecarboxylic acid,
6-(7-chloromethyl-3a,7a-dihydro-1H-indazolyl)pyrimidinecarboxylic acid,
6-(8-chloroquinazolinyl)pyrimidinecarboxylic acid,
6-(5-chloroquinazolinyl)pyrimidinecarboxylic acid,
6-(7-chloro-1H-benzo[d]imidazolyl)pyrimidinecarboxylic acid,
6-(3-chloro(1-methylcyclopropyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(1-(trifluoromethyl)cyclopropyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(3-methyloxetanyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(1H-imidazolyl)phenyl)pyrimidinecarboxylic acid,
6-(3-chloro(1H-pyrrolyl)phenyl)pyrimidinecarboxylic acid,
6-(4-tert-butylchlorophenyl)pyrimidinecarboxylic acid, and
7-chlorocyclopropoxy-5H-chromeno[4,3-d]pyrimidinecarboxylic acid,
or a pharmaceutically acceptable salt or prodrug thereof.
Methods for obtaining the chemical entitites described herein will be
apparent to those of ordinary skill in the art, suitable procedures being described, for
example, in examples below, and in the references cited herein.
Provided is a method of inhibiting the catalytic activity of KMO,
comprising contacting said KMO with an effective amount of at least one chemical entity
described herein.
Also provided is a method of treating a condition or disorder mediated by
KMO activity in a subject in need of such a treatment, comprising administering to the
subejct a therapeutically effective amount of at least one chemical entity described herein.
Also provided is a method of treating a neurodegenerative pathology
mediated by KMO activity in a subject in need of such a treatment, comprising
administering to the subject a therapeutically effective amount of at least one chemical
entity described herein.
Also provided is a method for treating disorders mediated by (or at least in
part by) the presence 3-OH-KYN, QUIN and/or KYNA. Also provided is a method of
treating a degenerative or inflammatory condition in which an increased synthesis in the
brain of QUIN, 3-OH-KYN or increased release of GLU are involved and which may
cause neuronal damage.
Such diseases include, for example, Huntington's disease and other
polyglutamine disorders such as spinocerebellar ataxias neurodegenerative diseases,
psychiatric of neurological diseases or disorders, Alzheimer's disease, Parkinson's disease,
amyotropic lateral sclerosis, Creutzfeld-Jacob disease, trauma-induced
neurodegeneration, high-pressure neurological syndrome, dystonia, olivopontocerebellar
atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consequences of
stroke, cerebral ischemia, ischemic disorders including stroke (focal ischemia), hypoxia,
multi-infarct dementia, consequences of cerebral trauma or damage, damage to the spinal
cord, Dementia such as senile dementia and AIDS-dementia complex, AIDS-induced
encephalopathy, other infection related encephalopathy, viral or bacterial meningitis,
infectious diseases caused by viral, bacterial and other parasites, for example, general
central nervous system (CNS) infections such as viral, bacterial or parasites, for example,
poliomyelitis, Lyme disease (Borrelia burgdorferi infection) septic shock, and malaria,
cancers, cancers with cerebral localization, hepatic encephalopathy, systemic lupus,
analgesia and opiate withdrawal symptoms, feeding behavior, psychiatric disorders, such
as insomnia, depression, schizophrenia, severe deficit in working memory, severe deficit
in long term memory storage, decrease in cognition, severe deficit in attention, severe
deficit in executive functioning, sloweness in information processing, slowness in neural
activity, anxiety, generalized anxiety disorders, panic anxiety, obsessive compulsive
disorders, social phobia, performance anxiety, post-traumatic stress disorder, acute stress
reaction, adjustment reaction, separation anxiety disorder, alcohol withdrawal anxiety,
depressive disorders, disorders of the developing or aged brain, diabetes, and
complications thereof, Tourette's syndrome, Fragile X syndrome, autism spectrum
disorders, disorders that cause severe and pervasive impairment in thinking feeling,
language and the ability to relate to others, mood disorders, psychological disorders
characterized by abnormalities of emotional state, such as without limitation, bipolar
disorder, unipolar depression, major depression, ondougenous depression, involutional
depression, reactive depression, psychotic depression, depression caused by underlying
medical conditions, depressive disorders, cyclothymic disorders, dysthymic disorders,
mood disorders due to general medical condition, mood disorders not otherwise specified
and substance-induced mood disorders. Such disease also include, for example, Acute
necrotizing Pancreatitis, AIDS (disease), Analgesia, Aseptic meningitis, Brain disease, for
example, Gilles de la Tourette syndrome, Asperger syndrome, Rett syndrome, pervasive
developmental disorders, aging-related Brain disease, and developmental Brain disease,
burnout syndrome, carbon monoxide poisoning, cardiac arrest or insufficiency and
hemorrhagic shock (global brain ischemia), cataract formation and aging of the eye,
Central nervous system disease, Cerebrovascular disease, chronic fatigue syndrome,
Chronic Stress, Cognitive disorders, convulsive Disorders, such as variants of Grand mal
and petit mal epilepsy and Partial Complex Epilepsy, Diabetes mellitus, Disease of the
nervous system (e.g., dyskinesia, L-DOPA induced movement disorders, drug addiction,
pain and cataract), Drug dependence, Drug withdrawal, feeding disorders, Guillain Barr
Syndrome and other neurophaties, Hepatic encephalopathy, Immune disease, immunitary
disorders and therapeutic treatment aimed at modifying biological responses (for instance
administrations of interferons or interleukins), Inflammation (systemic inflammatory
response syndrome), inflammatory disorders of the central and/or peripheral nervous
system, Injury (trauma, polytrauma), Mental and behavioral disorders, Metabolic disease,
pain disease, or disorder selected from a group of inflammatory pain, neurophathic pain
or migraine, allodynia, hyperalgesis pain, phantom pain, neurophatic pain related to
diabetic neuropathy, Multiple organ failure, near drowning, Necrosis, neoplasms of the
brain, neoplastic disorders including lymphomas and other malignant blood disorders,
Nervous system disease (high-pressure neurol. Syndrome, infection), nicotine addiction
and other addictive disorders including alcoholism, cannabis, benzodiazepine, barbiturate,
morphine and cocaine dependence, change in appetite, sleep disorders, changes in sleep
patern, lack of energy, fatigue, low self steem, self-reproach inappropriate guilt, frequent
thoughts of death or suicide, plans or attemps to commit suicide, feelings of hopelessness
and worthlessness, psychomotor agitation or retardation, diminished capacity for thinking,
concentration, or decisiveness, as a Neuroprotective agents, Pain, Post-traumatic stress
disorder, Sepsis, Spinal cord disease, Spinocerebellar ataxia, Systemic lupus
erythematosis, traumatic damage to the brain and spinal cord, and tremor syndromes and
different movement disorders (diskynesia). Poor balance, brakykinesia, rigidity, tremor,
change in speech, loss of facial expression, micrographia, difficulty swallowing, drooling,
dementia, confussion, fear, sexual disfunction, language impairment, impairment in
decision making, violent outbursts, aggression, hallucination, apathy, impairment in
abstract thinking.
Such diseases include, for example, cardiovascular diseases, which refers
to diseases and disorders of the heart and circulatory system. These diseases are often
associated with dyslipoproteinemias and/or dyslipidemias. Cardiovascular diseases
include but are not limited to cardiomegaly, atherosclerosis, myocardial infarction, and
congestive heart failure, coronary heart disease, hypertension and hypotension.
Other such diseases include hyperproliferative diseases of benign or
malignant behaviour, in which cells of various tissues and organs exhibit aberrant patterns
of growth, proliferation, migration, signaling, senescence, and death. Generally
hyperpoliferative disease refers to diseases and disorders associated with, the uncontrolled
proliferation of cells, including but not limited to uncontrolled growth of organ and tissue
cells resulting in cancers and benign tumors. Hyperproliferative disorders associated with
endothelial cells can result in diseases of angiogenesis such as angiomas, endometriosis,
obesity, Age-related Macular Degeneration and various retinopaties, as well as the
proliferation of ECs and smooth muscle cells that cause restenosis as a consequence of
stenting in the treatment of atherosclerosis. Hyperproliferative disorders involving
fibroblasts (i.e., fibrogenesis) include but are not limited to disorers of excessive scaring
(i.e., fibrosis) such as Age-related Macular Degeneration, cardiac remodeling and failure
associated with myocardial infarction, excessive wound healing such as commonly occurs
as a consequence of surgery or injury, keloids, and fibroid tumors and stenting.
Additional diseases include transplant rejection (suppression of T-cells)
and graft vs host disease, chronic kidney disease, systemic inflammatory disorders, brain
inflammatory disorders including malaria and African trypanosomiasis, stroke, and
pneumococcal meningitis.
Also provided are methods of treatment in which at least one chemical
entity described herein is the only active agent given to the subject and also includes
methods of treatment in which at least one chemical entity described herein is given to the
subject in combination with one or more additional active agents.
In general, the chemical entities described herein will be administered in a
therapeutically effective amount by any of the accepted modes of administration for
agents that serve similar utilities. The actual amount of the compound, i.e., the active
ingredient, will depend upon numerous factors such as the severity ofthe disease to be
treated, the age and relative health of the subject, the potency of the compound used, the
route and fonn of administration, and other factors well know to the skilled artisan. The
drug can be administered at least once a day, such as once or twice a day.
In some embodiments, the chemical entities described herein are
administered as a pharmaceutical composition. Accordingly, provided are pharmaceutical
compositions comprising at least one chemical entity described herein, together with at
least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and
excipients.
Pharmaceutically acceptable vehicles must be of sufficiently high purity
and sufficiently low toxicity to render them suitable for administration to the animal being
treated. The vehicle can be inert or it can possess pharmaceutical benefits. The amount
of vehicle employed in conjunction with the chemical entity is sufficient to provide a
practical quantity of material for administration per unit dose of the chemical entity.
Exemplary pharmaceutically acceptable carriers or components thereof are
sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato
starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants,
such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable
oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as
propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid;
phosphate buffer solutions; emulsifiers, such as the TWEENS; wetting agents, such
sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers;
antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer
solutions.
Optional active agents may be included in a pharmaceutical composition,
which do not substantially interfere with the activity of the chemical entity described
herein.
Effective concentrations of at least one chemical entity described herein
are mixed with a suitable pharmaceutically acceptable vehicle. In instances in which the
chemical entity exhibits insufficient solubility, methods for solubilizing compounds may
be used. Such methods are known to those of skill in this art, and include, but are not
limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such
as TWEEN, or dissolution in aqueous sodium bicarbonate.
Upon mixing or addition of a chemical entity described herein, the
resulting mixture may be a solution, suspension, emulsion or the like. The form of the
resulting mixture depends upon a number of factors, including the intended mode of
administration and the solubility of the chemical entity in the chosen vehicle. The
effective concentration sufficient for ameliorating the symptoms of the disease treated
may be empirically determined.
Chemical entities described herein may be administered orally, topically,
parenterally, intravenously, by intramuscular injection, by inhalation or spray,
sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution,
or by other means, in dosage unit formulations.
Pharmaceutical compositions may be formulated for oral use, such as for
example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or elixirs. Pharmaceutical
compositions intended for oral use may be prepared according to any method known to
the art for the manufacture of pharmaceutical compositions and such compositions may
contain one or more agents, such as sweetening agents, flavoring agents, coloring agents
and preserving agents, in order to provide pharmaceutically elegant and palatable
preparations. In some embodiments, oral pharmaceutical compositions contain from 0.1
to 99% of at least one chemical entity described herein. In some embodiments, oral
pharmaceutical compositions contain at least 5% (weight %) of at least one chemical
entity described herein. Some embodiments contain from 25% to 50% or from 5% to 75
% of at least one chemical entity described herein.
Orally administered pharmaceutical compositions also include liquid
solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the
like. The pharmaceutically acceptable carriers suitable for preparation of such
compositions are well known in the art. Oral pharmaceutical compositions may contain
preservatives, flavoring agents, sweetening agents, such as sucrose or saccharin, taste-
masking agents, and coloring agents.
Typical components of carriers for syrups, elixirs, emulsions and
suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid
sucrose, sorbitol and water. Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such pharmaceutical
compositions may also contain a demulcent.
Chemical entities described herein can be incorporated into oral liquid
preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,
for example. Moreover, pharmaceutical compositions containing these chemical entities
can be presented as a dry product for constitution with water or other suitable vehicle
before use. Such liquid preparations can contain conventional additives, such as
suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin,
hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and
hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monsoleate, or
acacia), non-aqueous vehicles, which can include edible oils (e.g., almond oil,
fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and
preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).
For a suspension, typical suspending agents include methylcellulose,
sodium carboxymethyl cellulose, Avicel RC-591, tragacanth and sodium alginate; typical
wetting agents include lecithin and polysorbate 80; and typical preservatives include
methyl paraben and sodium benzoate.
Aqueous suspensions contain the active material(s) in admixture with
excipients suitable for the manufacture of aqueous suspensions. Such excipients are
suspending agents, for example sodium carboxymethylcellulose, methylcellulose,
hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and
gum acacia; dispersing or wetting agents; may be a naturally-occurring phosphatide, for
example, lecithin, or condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of ethylene oxide with long
chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty acids and a hexitol such
as polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with
partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan substitute. The aqueous suspensions may also contain one or more preservatives,
for example ethyl, or n- propyl p-hydroxybenzoate.
Oily suspensions may be formulated by suspending the active ingredients
in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a
mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent,
for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set
forth above, and flavoring agents may be added to provide palatable oral preparations.
These pharmaceutical compositions may be preserved by the addition of an anti-oxidant
such as ascorbic acid.
Pharmaceutical compositions may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or a
mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents
may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-
occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and
condensation products of the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monoleate.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the active ingredient in admixture with a
dispersing or wetting agent, suspending agent and one or more preservatives. Suitable
dispersing or wetting agents and suspending agents are exemplified by those already
mentioned above.
Tablets typically comprise conventional pharmaceutically acceptable
adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol,
lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as
starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid
and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of
the powder mixture. Coloring agents, such as the FD&C dyes, can be added for
appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol,
peppermint, and fruit flavors, can be useful adjuvants for chewable tablets. Capsules
(including time release and sustained release formulations) typically comprise one or
more solid diluents disclosed above. The selection of carrier components often depends
on secondary considerations like taste, cost, and shelf stability.
Such pharmaceutical compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that the chemical entity is
released in the gastrointestinal tract in the vicinity of the desired topical application, or at
various times to extend the desired action. Such dosage forms typically include, but are
not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate,
hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and
shellac.
Pharmaceutical compositions for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for
example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
Pharmaceutical compositions may be in the form of a sterile injectable
aqueous or oleaginous suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and suspending agents that
have been mentioned above. The sterile injectable preparation may also be sterile
injectable solution or suspension in a non-toxic parentally acceptable vehicle, for example
as a solution in 1,3-butanediol. Among the acceptable vehicles that may be employed are
water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium. For this purpose
any bland fixed oil may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid can be useful in the preparation of injectables.
Chemical entities described herein may be administered parenterally in a
sterile medium. Parenteral administration includes subcutaneous injections, intravenous,
intramuscular, intrathecal injection or infusion techniques. Chemical entities described
herein, depending on the vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics,
preservatives and buffering agents can be dissolved in the vehicle. In many
pharmaceutical compositions for parenteral administration the carrier comprises at least
90% by weight of the total composition. In some embodiments, the carrier for parenteral
administration is chosen from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and
sesame oil.
Chemical entites described herein may also be administered in the form of
suppositories for rectal administration of the drug. These pharmaceutical compositions
can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at
ordinary temperatures but liquid at rectal temperature and will therefore melt in the
rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
Chemical entities described herein may be formulated for local or topical
application, such as for topical application to the skin and mucous membranes, such as in
the eye, in the form of gels, creams, and lotions and for application to the eye. Topical
pharmaceutical compositions may be in any form including, for example, solutions,
creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches, and
the like.
Such solutions may be formulated as 0.01% -10% isotonic solutions, pH 5-
7, with appropriate salts. Chemical entities described herein may also be formulated for
transdermal administration as a transdermal patch.
Topical pharmaceutical compositions comprising at least one chemical
entity described herein can be admixed with a variety of carrier materials well known in
the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A
and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
Other materials suitable for use in topical carriers include, for example,
emollients, solvents, humectants, thickeners and powders. Examples of each of these
types of materials, which can be used singly or as mixtures of one or more materials, are
as follows:
Representative emollients include stearyl alcohol, glyceryl
monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl
alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl
alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecanol, isocetyl alcohol,
cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-
propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene
glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols,
petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate,
lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants, such as
propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents,
such as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol
monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,
dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin,
sorbitol, sodium 2-pyrrolidonecarboxylate, soluble collagen, dibutyl phthalate, and
gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal
silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl
ammonium smectites, chemically modified magnesium aluminium silicate, organically
modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl
polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.
The chemical entities described herein may also be topically administered
in the form of liposome delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety
of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Other pharmaceutical compositions useful for attaining systemic delivery
of the chemical entity include sublingual, buccal and nasal dosage forms. Such
pharmaceutical compositions typically comprise one or more of soluble filler substances
such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline
cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Glidants,
lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may
also be included.
Pharmaceutical compositions for inhalation typically can be provided in
the form of a solution, suspension or emulsion that can be administered as a dry powder
or in the form of an aerosol using a conventional propellant (e.g.,
dichlorodifluoromethane or trichlorofluoromethane).
The pharmaceutical compositions may also optionally comprise an activity
enhancer. The activity enhancer can be chosen from a wide variety of molecules that
function in different ways to enhance or be independent of therapeutic effects of the
chemical entities described herein. Particular classes of activity enhancers include skin
penetration enhancers and absorption enhancers.
Pharmaceutical compositions may also contain additional active agents
that can be chosen from a wide variety of molecules, which can function in different ways
to enhance the therapeutic effects of at least one chemical entity described herein. These
optional other active agents, when present, are typically employed in the pharmaceutical
compositions at a level ranging from 0.01% to 15%. Some embodiments contain from
0.1% to 10% by weight of the composition. Other embodiments contain from 0.5% to 5%
by weight of the composition.
Also provided are packaged pharmaceutical compositions. Such packaged
compositions include a pharmaceutical composition comprising at least one chemical
entity described herein, and instructions for using the composition to treat a subject
(typically a human patient). In some embodiments, the instructions are for using the
pharmaceutical composition to treat a subject suffering a condition or disorder mediated
by Kynurenine 3-mono-oxygenase activity. The packaged pharmaceutical composition
can include providing prescribing information; for example, to a patient or health care
provider, or as a label in a packaged pharmaceutical composition. Prescribing
information may include for example efficacy, dosage and administration,
contraindication and adverse reaction information pertaining to the pharmaceutical
composition.
In all of the foregoing the chemical entities can be administered alone, as
mixtures, or in combination with other active agents.
The methods described herein include methods for treating Huntington's
disease, including treating memory and/or cognitive impairment associated with
Huntington's disease, comprising administering to a subject, simultaneously or
sequentially, at least one chemical entity described herein and one or more additional
agents used in the treatment of Huntington's disease such as, but not limited to,
Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline,
Terabenazine, Haloperidol, Chloropromazine, Thioridazine, Sulpride, Quetiapine,
Clozapine, and Risperidone. In methods using simultaneous administration, the agents
can be present in a combined composition or can be administered separately. As a result,
also provided are pharmaceutical compositions comprising at least one chemical entity
described herein and one or more additional pharmaceutical agents used in the treatment
of Huntington's disease such as, but not limited to, Amitriptyline, Imipramine,
Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline, Terabenazine, Haloperidol,
Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.
Similarly, also provided arepackaged pharmaceutical compositions containing a
pharmaceutical composition comprising at least one chemical entity described herein, and
another composition comprising one or more additional pharmaceutical agents used in the
treatment of Huntington's disease such as, but not limited to, Amitriptyline, Imipramine,
Despiramine, Nortriptyline, Paroxetine, Fluoxetine, Setraline, Terabenazine, Haloperidol,
Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.
Also provided are methods for treating Parkinson's disease, including
treating memory and/or cognitive impairment associated with Parkinson's disease,
comprising administering to a subject, simultaneously or sequentially, at least one
chemical entity described herein and one or more additional agents used in the treatment
of Parkinson's disease such as, but not limited to, Levodopa, Parlodel, Permax, Mirapex,
Tasmar, Contan, Kemadin, Artane, and Cogentin. In methods using simultaneous
administration, the agents can be present in a combined composition or can be
administered separately. Also provided are pharmaceutical compositions comprising at
least one chemical entity described herein, and one or more additional pharmaceutical
agents used in the treatment of Parkinson's disease, such as, but not limited to, Levodopa,
Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin. Also
provided are packaged pharmaceutical compositions containing a pharmaceutical
composition comprising at least one chemical entity described herein, and another
composition comprising one or more additional pharmaceutical agents gent used in the
treatment of Parkinson's disease such as, but not limited to, Levodopa, Parlodel, Permax,
Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin.
Also provided are methods for treating memory and/or cognitive
impairment associated with Alzheimer's disease, comprising administering to a subject,
simultaneously or sequentially, at least one chemical entity described herein and one or
more additional agents used in the treatment of Alzheimer's disease such as, but not
limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen
and Cliquinol. In methods using simultaneous administration, the agents can be present
in a combined composition or can be administered separately. Also provided are
pharmaceutical compositions comprising at least one chemical entity described herein,
and one or more additional pharmaceutical agents used in the treatment of Alzheimer's
disease such as, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol,
Neotropin, Eldepryl, Estrogen and Cliquinol. Similarly, also provided are packaged
pharmaceutical compositions containing a pharmaceutical composition comprising at
least one chemical entity described herein, and another composition comprising one or
more additional pharmaceutical agents used in the treatment of Alzheimer's disease such
as, but not limited to Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl,
Estrogen and Cliquinol.
Also provided are methods for treating memory and/or cognitive
impairment associated with dementia or cognitive impairment comprising administering
to a subject, simultaneously or sequentially, at least one chemical entity and one or more
additional agents used in the treatment of dementia such as, but not limited to,
Thioridazine, Haloperidol, Risperidone, Cognex, Aricept, and Exelon. In methods using
simultaneous administration, the agents can be present in a combined composition or can
be administered separately. Also provided are pharmaceutical compositions comprising at
least one chemical entity described herein, and one or more additional pharmaceutical
agents used in the treatment of dementia such as, but not limited to, Thioridazine,
Haloperidol, Risperidone, Cognex, Aricept, and Exelon. Also provided are packaged
pharmaceutical compositions containing a pharmaceutical composition comprising at
least one chemical entity described herein, and another composition comprising one or
more additional pharmaceutical agents used in the treatment of dementia such as, but not
limited to, Thioridazine, Haloperidol, Risperidone, Cognex, Aricept, and Exelon.
Also provided are methods for treating memory and/or cognitive
impairment associated with epilepsy comprising administering to a subject,
simultaneously or sequentially, at least one chemical entity described herein and one or
more additional agents used in the treatment of epilepsy such as, but not limited to,
Dilantin, Luminol, Tegretol, Depakote, Depakene, Zarontin, Neurontin, Barbita, Solfeton,
and Felbatol. In methods using simultaneous administration, the agents can be present in
a combined composition or can be administered separately. Also provided are
pharmaceutical compositions comprising at least one chemical entity described herein,
and one or more additional pharmaceutical agents used in the treatment of epilepsy such
as, but not limited to, Dilantin, Luminol, Tegretol, Depakote, Depakene, Zarontin,
Neurontin, Barbita, Solfeton, and Felbatol. Also provided are packaged pharmaceutical
compositions containing a pharmaceutical composition comprising at least one chemical
entity described herein, and another composition comprising one or more additional
pharmaceutical agents used in the treatment of epilepsy such as, but not limited to,
Dilantin, Luminol, Tegretol, Depakote, Depakene, Zarontin, Neurontin, Barbita, Solfeton,
and Felbatol.
Also provided are methods for treating memory and/or cognitive
impairment associated with multiple sclerosis comprising administering to a subject,
simultaneously or sequentially, at least one chemical entity described herein and one or
more additional agents used in the treatment of multiple sclerosis such as, but not limited
to, Detrol, Ditropan XL, OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and
Copaxone. In methods using simultaneous administration, the agents can be present in a
combined composition or can be administered separately. Also provided are
pharmaceutical compositions comprising at least one chemical entity described herein,
and one or more additional pharmaceutical agents used in the treatment of multiple
sclerosis such as, but not limited to, Detrol, Ditropan XL, OxyContin, Betaseron, Avonex,
Azothioprine, Methotrexate, and Copaxone. Also provided are packaged pharmaceutical
compositions containing a pharmaceutical composition comprising at least one chemical
entity described herein, and another composition comprising one or more additional
pharmaceutical agents used in the treatment of multiple sclerosis such as, but not limited
to, Detrol, Ditropan XL, OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and
Copaxone.
When used in combination with one or more additional pharmaceutical
agent or agents, the described herein may be administered prior to, concurrently with, or
following administration of the additional pharmaceutical agent or agents.
The dosages of the compounds described herein depend upon a variety of
factors including the particular syndrome to be treated, the severity of the symptoms, the
route of administration, the frequency of the dosage interval, the particular compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and
the presence of any deleterious side-effects, among other considerations.
The chemical entities described herein are typically administered at dosage
levels and in a manner customary for KMO inhibitors. For example, the chemical entities
can be administered, in single or multiple doses, by oral administration at a dosage level
of generally 0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, such as 0.1-70
mg/kg/day, for example, 0.5-10 mg/kg/day. Unit dosage forms can contain generally
0.01-1000 mg of at least one chemical entity described herein, for example, 0.1-50 mg of
at least one chemical entity described herein. For intravenous administration, the
compounds can be administered, in single or multiple dosages, at a dosage level of, for
example, 0.001-50 mg/kg/day, such as 0.001-10 mg/kg/day, for example, 0.01-1
mg/kg/day. Unit dosage forms can contain, for example, 0.1-10 mg of at least one
chemical entity described herein.
A labeled form of a chemical entity described herein can be used as a
diagnostic for identifying and/or obtaining compounds that have the function of
modulating an activity of KMO as described herein. The chemical entities described
herein may additionally be used for validating, optimizing, and standardizing bioassays.
By "labeled" herein is meant that the compound is either directly or
indirectly labeled with a label which provides a detectable signal, e.g., radioisotope,
fluorescent tag, enzyme, antibodies, particles such as magnetic particles,
chemiluminescent tag, or specific binding molecules, etc. Specific binding molecules
include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc. For the
specific binding members, the complementary member would normally be labeled with a
molecule which provides for detection, in accordance with known procedures, as outlined
above. The label can directly or indirectly provide a detectable signal.
In carrying out the procedures of the methods described herein, it is of
course to be understood that reference to particular buffers, media, reagents, cells, culture
conditions and the like are not intended to be limiting, but are to be read so as to include
all related materials that one of ordinary skill in the art would recognize as being of
interest or value in the particular context in which that discussion is presented. For
example, it is often possible to substitute one buffer system or culture medium for another
and still achieve similar, if not identical, results. Those of skill in the art will have
sufficient knowledge of such systems and methodologies so as to be able, without undue
experimentation, to make such substitutions as will optimally serve their purposes in
using the methods and procedures disclosed herein.
EXAMPLES
The chemical entities, compositions, and methods described herein are
further illustrated by the following non-limiting examples.
As used herein, the following abbreviations have the following meanings.
If an abbreviation is not defined, it has its generally accepted meaning.
CDI = carbonyldiimidazole
DCM = dichloromethane
DME = dimethyl ether
DMEM = Dulbecco's modified Eagle's medium
DMF = N,N-dimethylformamide
DMSO = dimethylsulfoxide
EDC·HCl = 1-Ethyl(3-dimethylaminopropyl)carbodiimide
hydrochloride
EtOH = ethanol
Et O = diethylether
EtOAc = ethyl acetate
g = gram
hr = hour
hrs = hours
HOBt = 1-Hydroxybenzotriazol
LiHMDS = lithium hexamethyl-disilazide
LC/MS = liquid chomatography / mass spectrometry
mg = milligram
min = minutes
mL = milliliter
mmol = millimoles
mM = millimolar
ng = nanogram
nm = nanometer
nM = nanomolar
PBS = phosphate buffered saline
rt = room temperature
TBME = t-butyl methyl ether
THF = tetrahydrofuran
TMOF = trimethylorthoformate
L = microliter
M = micromolar
1g/1ml = 1 vol
Experimental
Commercially available reagents and solvents (HPLC grade) were used
without further purification.
Thin-layer chromatography (TLC) analysis was performed with Kieselgel
60 F254 (Merck) plates and visualized using UV light. Microwave reactions were carried
out using CEM focussed microwaves.
Analytical HPLC-MS was performed on Agilent HP1100 and Shimadzu
2010, systems using reverse phase Atlantis dC18 columns (5 m, 2.1 X 50 mm), gradient
-100% B ( A= water/ 0.1% formic acid, B= acetonitrile/ 0.1% formic acid) over 3 min,
injection volume 3 l, flow = 1.0 ml/min. UV spectra were recorded at 215 nm using a
Waters 2487 dual wavelength UV detector or the Shimadzu 2010 system. Mass spectra
were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per second
using Waters ZMD and over m/z 100 to 1000 at a sampling rate of 2Hz using
Electrospray ionisation, by a Shimadzu 2010 LC-MS system or analytical HPLC-MS was
performed on Agilent HP1100 and Shimadzu 2010, systems using reverse phase Water
Atlantis dC18 columns (3 m, 2.1 X 100 mm), gradient 5-100% B (A= water/ 0.1%
formic acid, B= acetonitrile/ 0.1% formic acid) over 7 min, injection volume 3 l, flow =
0.6 ml/min. UV spectra were recorded at 215 nm using a Waters 2996 photo diode array
or on the Shimadzu 2010 system. Mass spectra were obtained over the range m/z 150 to
850 at a sampling rate of 2 scans per second using Waters ZQ and over m/z 100 to 1000
at a sampling rate of 2Hz using Electrospray ionisation, by a Shimadzu 2010 LC-MS
system. Data were integrated and reported using OpenLynx and OpenLynx Browser
software or via Shimadzu PsiPort software.
Example 1
Reaction Scheme 1
R1 R1
N N N N
R2 R2
Cl Cl
Stage 1 Stage 2
N N R4
Stage 3 Stage 4 X
Referring to Reaction Scheme 1, Stage 1, to a stirred suspension of
dichloropyrimidine (1eq) in 1,4-dioxane (15vol) was added boronic acid (0.7eq) and
Pd(PPh3)4 (0.025eq). A 2M K2CO3 solution (7.5vol) was added to the resulting mixture,
which was heated at 90oC overnight under an atmosphere of N2. The reaction mixture
was cooled to room temperature and concentrated in vacuo. The residue was dissolved in
EtOAc : water (1:1) (100vol) and the resulting solution filtered through celite. The
organic layer was separated and the aqueous layer further extracted with EtOAc (50vol).
The combined organic layers were washed with saturated aqueous NaCl (20vol), dried
over Na2SO4, filtered and the solvent removed in vacuo. The resulting residue was
purified by flash column chromatography (eluent: [0:1 to 1:19] EtOAc:heptane) to afford
the required target compounds.
Referring to Reaction Scheme 1, Stage 2, 4-chlorosubstituted-phenyl-
pyrimidine (1eq), PdCl2(dppf).DCM (0.05eq) and triethylamine (2eq) were suspended in
degassed MeOH (50vol) in a bomb fitted with a magnetic stirrer bar. The atmosphere in
the reaction vessel was replaced with N2 by successive evacuation and charging with N2
gas (this process was repeated three times). The bomb was then flushed with CO by
successive charging with CO and evacuation. The vessel was pressurised to 5bar of CO
and heated at 50oC with stirring for 5 hours. The reaction vessel was allowed to cool to
room temperature before venting CO and flushing with N2. The reaction mixture was
concentrated in vacuo and the resulting residue dissolved in EtOAc (30vol) and water
(30vol). The solution was filtered through cotton wool and the organic layer was
separated, washed with saturated aqueous NaCl (15vol), dried over Na2SO4, filtered and
concentrated under reduced pressure. Purification by flash column chromatography
(eluent: [0:1 to 1:9] EtOAc:heptane) yielded the target compounds.
Referring to Reaction Scheme 1, Stage 3, 6-substituted-phenyl-pyrimidine-
4-carboxylic acid methyl ester (1eq) was suspended in MeOH (20vol), 1M NaOH
solution (20vol) and stirred at room temperature for 4 hours. The reaction mixture was
acidified with 2M HCl. Soluble products were extracted with DCM (2 x 20vol) and the
combined organic layers were dried over MgSO4, filtered and concentration under
reduced pressure afforded the target compounds. Insoluble products were filtered, washed
with water (3 x 10vol) and heptane (3 x 10vol) before drying in vacuo to yield the target
compounds.
Referring to Reaction Scheme 1, Stage 4, the required amide analogues
were prepared following the procedures described in method A, B, C or D.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
264.67 [M+H] = 265/267, 100%
@ rt = 3.53 and 3.70 min
276.72 [M+H] = 277/279, 99.9%
@ rt = 4.32 min
232.22 [M+H] = 232, 100% @ rt
= 3.52 min
246.24 [M+H] = 247, 100% @ rt
= 3.66 min
260.27 [M+H] = 261.4, 100% @
rt = 4.13 min
251.25 [M+H] = 252, 99% @ rt =
2.32 min
319.75 [M+H]+= 320, 97% @ rt =
2.29 min
Example 2
Reaction Scheme 2
B(OH)
COOH
Stage 1 Stage 2
Referring to Reaction Scheme 2, Stage 1, to a degassed stirred solution of
4-chloronitro-benzene boronic acid (1eq) and 4,6-dichloropyrimidine (1.44eq) in 1,4-
dioxane (16vol) and 2N K2CO3 (8vol) was added Pd(PPh3)4 (0.06eq) and the mixture
heated to 90°C for 3.75 hours under an atmosphere of nitrogen gas. The cooled reaction
mixture had the solvents removed under reduced pressure. DCM (25vol) and water
(25vol) were then added and the undissolved material removed by filtration through
celite. The organic phase from the filtrate was concentrated under reduced pressure
whilst adsorbing on to silica gel (8.2g). The residue was purified using dry flash
chromatography (gradient up to 10% EtOAc:heptane) to afford the target compound.
Referring to Reaction Scheme 2, Stage 2, in a metal vessel equipped to
carry out high pressure reactions, a degassed suspension of 4-chloro(4-chloronitro-
phenyl)-pyrimidine (1eq) was stirred in MeOH (62vol). Triethylamine (2eq) and
Pd(PPh3)4 (0.05eq) was then added and the vessel sealed. The vessel was then charged
with carbon monoxide gas to a pressure of 5 bar and heated to 50°C for 18 hours. After
extrusion of excess carbon monoxide gas, the organic solvent was concentrated under
reduced pressure. To the residue was added DCM (26vol) and the undissolved material
was filtered off and washed with DCM (10vol). The filtrate was washed with 2N HCl
(10vol), a 1:1 mixture of water and brine (10vol) and then concentrated under reduce
pressure whilst adsorbing onto silica gel (3.2g). The residue was purified by dry flash
column chromatography (gradient up to 60% EtOAc:heptane) to give a mixture of
products, the major identified as the methyl ester. The solid was then dissolved in 2N
HCl (30vol) and washed with TBME (1 x 30 vol & 1 x 20 vol). The aqueous layer was
adjusted to pH7 and the precipitate formed was filtered off, washed with water (2 x 5vol)
and air dried to afford the target compound.
Structure Molecular Weight Mass Spec Result
249.66 [M+H] = 250/252,
96% @ rt = 3.43
Example 3
Reaction Scheme 3
B(OH)
2 N N
Cl Cl
O Cl
Stage 1
Stage 2 Cl
Stage 3
Stage 4 Cl
Stage 6
Stage 5 OH
Stage 7
Stage 8
Referring to Reaction Scheme 3, Stage 1, 5-bromochloro anisole (1eq)
in toluene (8vol) and THF (3vol) at -78oC was added n-BuLi (1.5eq) drop wise. The
resulting mixture was stirred at -78oC for 30 minutes under an atmosphere of N2.
Trimethylborate (2eq) was then added to the reaction mixture and this was allowed to
warm to room temperature and stirred for 16 hours. The reaction mixture was quenched
with 1M HCl and the organic layer was separated. The organic layer was washed with
saturated aqueous NaCl (20vol), dried over Na2SO4, filtered and the solvent removed in
vacuum. The resulting residue was purified by flash column chromatography (eluent:
[1:1] EtOAc:heptane) to afford the required target compound (1.15g, 31%).
Referring to Reaction Scheme 3, Stage 2, to a stirred suspension of
dichloropyrimidine (1eq) in 1,4-dioxane (20vol) was added boronic acid (0.7eq) and
Pd(PPh3)4 (0.05eq). A 2M K2CO3 solution (10vol) was added to the resulting mixture,
which was heated at 90oC for 3 hours under an atmosphere of N2. The reaction mixture
was cooled to room temperature and concentrated in vacuo. The residue was dissolved in
EtOAc : water (1:1) (100vol) and the resulting solution filtered through celite. The
organic layer was separated and the aqueous layer further extracted with EtOAc (50vol).
The combined organic layers were washed with saturated aqueous NaCl (20vol), dried
over Na2SO4, filtered and the solvent removed in vacuo. The resulting residue was
purified by flash column chromatography (eluent: [1:8] EtOAc:heptane) to afford the
required target compound (1.14g, 73%).
Referring to Reaction Scheme 3, Stage 3, 4-chlorosubstituted-phenyl-
pyrimidine (1eq), PdCl2(dppf).DCM (0.05eq) and triethylamine (2eq) were suspended in
degassed MeOH (50vol) in a bomb fitted with a magnetic stirrer bar. The atmosphere in
the reaction vessel was replaced with N2 by successive evacuation and charging with N2
gas (this process was repeated three times). The bomb was then flushed with CO by
successive charging with CO and evacuation. The vessel was pressurised to 5bar of CO
and heated at 50oC with stirring for 16 hours. The reaction vessel was allowed to cool to
room temperature before venting CO and flushing with N2. The reaction mixture was
concentrated in vacuo and the resulting residue dissolved in EtOAc (30vol) and water
(30vol). The organic layer was separated, washed with saturated aqueous NaCl (15vol),
dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by
flash column chromatography (eluent: [2:3] EtOAc:heptane) yielded the target compound
(1.15g, 96%).
Referring to Reaction Scheme 3, Stage 4, to a solution of 6-Substituted-
phenyl-pyrimidinecarboxylic acid methyl ester (1eq) in DCM (80vol) at -78oC was
added BBr3 (3eq) under nitrogen. The reaction mixture was warm to 0oC and stirred for
1hour then allowed to stir at room temperature for 16 hours. The reaction mixture was
poured into ice (100vol) and extracted with EtOAc (150vol). The organic layer was
separated, washed with saturated aqueous NaCl (15vol), dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude mixture (0.45g) was used in the next step
without further purification.
Referring to Reaction Scheme 3, Stage 5, a solution of 6-substituted-
phenyl-pyrimidinecarboxylic acid (1eq) in MeOH (100vol) was added concentrated
H2SO4 (2 drops). The reaction mixture was refluxed for 4 hours. The reaction mixture
was concentrated in vacuo and the resulting residue dissolved in EtOAc (30vol) and water
(30vol). The organic layer was separated, washed with saturated aqueous NaCl (15vol),
dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture
(0.48g) was used in the next step without further purification.
Referring to Reaction Scheme 3, Stage 6, to a solution of 6-substituted-
phenyl-pyrimidinecarboxylic acid methyl ester (1.05eq) in THF (10vol) were added 3-
hydroxy furan (1eq) and PPh3 (1.5eq) under nitrogen. The reaction mixture was cooled to
0oC and DIAD (1.5eq) was added slowly. Reaction mixture was allowed to warm to room
temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo and
the resulting residue was triturated with EtOAc and heptane (1:2) and solid was filtered to
give the desired compound (0.42g, 70%).
Referring to Reaction Scheme 3, Stage 7, 6-substituted-phenyl-pyrimidine-
4-carboxylic acid methyl ester (1eq) was suspended in THF (20vol), 2M NaOH (3.14ml,
6.28mmol, 5eq) and stirred at room temperature for 4 hours. The THF was removed under
vacuo, MeCN (10vol) was added and the reaction mixture was acidified with 6M HCl.
The resulting solid was filtered and washed with water and a mixture of MeCN: water
(1:1) to give desired product (0.335g. 83%).
Referring to Reaction Scheme 3, Stage 3, the required amide analogue was
prepared following the procedure described in method B.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
320.73 [M+H] = 321/323, 100%
O @ rt = 3.55-3.82 min
396.84 [M+H] = 397/399, 98% @
N rt = 3.7 min
Cl N
Example 4
Reaction Scheme 4
Cl Cl
OH O Cl
Stage 2
Stage 1
Stage 3
Stage 5
Stage 6
Stage 4
Stage 7
Referring to Reaction Scheme 4, Stage 1, N-(2-hydroxyethyl)morpholine
(1eq) in DCM (70vol) at 00C was added dibromo triphenyl phosphorane (1.2eq). The
reaction mixture was allowed to warm to room temperature and stirred for 16 hrs. The
solvent removed in vacuum. DCM (10vol) was added to the reaction mixture. The
precipitate was filtered to afford the target compound. The crude mixture was used in the
next step without further purification.
Referring to Reaction Scheme 4, Stage 2, N-(2-bromoethyl)morpholine
(1.1eq) in DMF (15vol) were added 2-chloroiodophenol (1eq) and Cs2CO3 (2.5eq).
The reaction mixture was refluxed for 3hours under nitrogen. The reaction mixture was
allowed to cool to room temperature and EtOAc (40vol) and aq ammonia (40vol) were
added. The organic layer was separated and the aqueous layer further extracted with
EtOAc (50vol). The combined organic layers were washed with saturated aqueous NaCl
(20vol), dried over Na2CO3, filtered and the solvent removed in vacuo. The resulting
residue was purified by flash column chromatography (eluent: [3:1] EtOAc:heptane) to
afford the required target compound.
Referring to Reaction Scheme 4, Stage 3, to a stirred suspension of 3-
subtituted-4 –chloro-iodobenzene (1eq) in degassed DMF (15vol) was added bis-diborane
(1.05eq), Pd(OAc)2 (0.04eq) and KOAc (3.0eq). The reaction mixture was heated at
90oC for 5hrs under an atmosphere of N2. The reaction mixture was cooled to room
temperature and filtered through celite then concentrated in vacuo to give crude product.
Crude was used in the next step without further purification.
Referring to Reaction Scheme 4, Stage 4, to a stirred suspension of
dichloropyrimidine (1eq) in 1,4-dioxane (90vol) was added boronic ester (1.0eq) and
Pd(PPh3)4 (0.03eq). A 2M K2CO3 (3eq) solution was added to the resulting mixture,
which was heated at 90oC for 16hrs under an atmosphere of N2. The reaction mixture
was cooled to room temperature and concentrated in vacuo. The residue was dissolved in
EtOAc : water (1:1) (100vol) and the resulting solution filtered through celite. The
organic layer was separated and the aqueous layer further extracted with EtOAc (50vol).
The combined organic layers were washed with saturated aqueous NaCl (20vol), dried
over Na2SO4, filtered and the solvent removed in vacuo. The resulting residue was
purified by flash column chromatography (eluent: [3:1] EtOAc:heptane) to afford the
required target compound.
Referring to Reaction Scheme 4, Stage 5, 4-chlorosubstituted-phenyl-
pyrimidine (1eq), PdCl2(dppf).DCM (0.05eq) and triethylamine (2eq) were suspended in
degassed MeOH (50vol) in a bomb fitted with a magnetic stirrer bar. The atmosphere in
the reaction vessel was replaced with N2 by successive evacuation and charging with N2
gas (this process was repeated three times). The bomb was then flushed with CO by
successive charging with CO and evacuation. The vessel was pressurised to 5bar of CO
and heated at 50oC with stirring for 16 hours. The reaction vessel was allowed to cool to
room temperature before venting CO and flushing with N2. The reaction mixture was
concentrated in vacuo and the resulting residue dissolved in EtOAc (30vol) and water
(30vol). The organic layer was separated, washed with saturated aqueous NaCl (15vol),
dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by re-
crystallisation using MeOH yielded the target compound.
Referring to Reaction Scheme 4, Stage 6, 6-substituted-phenyl-pyrimidine-
4-carboxylic acid methyl ester (1eq) was suspended in THF (20vol), 2M NaOH (2.5eq)
and stirred at room temperature for 4 hours. Solvent (THF) was removed and reaction
mixture was acidified with 2M HCl. Resulting solid was filtered and was with water to
give desired product.Referring to Reaction Scheme 4, Stage 7, the required amide
analogue was prepared following the procedure described in method B.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
400.26 [M+H] = 364,
98% @ rt = 2.41
439.91 [M+H] = 440,
N 99% @ rt = 2.54
292.72 [M+H] = 293/295,
100% @ rt = 4.18
306.75 [M+H] = 307/309,
100% @ rt = 4.10
318.76 [M+H] = 319,
100% @ rt = 4.61
306.75 [M+H] = 307/309,
100% @ rt = 4.37
306.75 [M+H] = 307/309,
100% @ rt = 4.37
290.71 [M+H] = 291/293,
100% @ rt = 3.93
346.69 [M+H] = 347/349,
F 92/8% @ rt = 4.22
304.79 [M+H] = 305/307,
100% @ rt = 4.20
360.82 [M+H] = 362/364,
100% @ rt = 2.55
303.75 [M+H]+= 304,
100% @ rt = 3.78
307.67 [M+H]+= 286/288,
99% @ rt = 3.26
363.8 [M+H]+ = 364/366
100% @ rt = 2.29
302.72 [M-Na]-= 303/305
100% @ rt = 4.14
305.89 [M+H]+ = 307/309,
95%@ rt = 3.37
289.71 [M+H]+= 290,
100% @ rt = 3.74
Example 5
Reaction Scheme 5
N N N N S
R1 N R2
R1 Cl R1 NH
Stage 1 Stage 2
Cl R3
R1 N R3
Stage 3
Referring to Reaction Scheme 5, Stage 1, 4-(chlorosubstituted)-phenyl-
pyrimidine (1eq) was suspended in 1,4-dioxane (3vol) and ammonium hydroxide (6vol)
was added to the suspension. The reaction mixture was heated at 95oC in a pressure tube
for 16 hours with stirring. The reaction mixture was cooled to room temperature and the
precipitate was filtered off and washed with water to yield the target compound.
Referring to Reaction Scheme 5, Stage 2, 6-(substituted-phenyl)-
pyrimidinylamine (1eq) was suspended in 1,4-dioxane (20vol). Sodium hydride (6eq)
was added and the suspension was stirred for 1 hour at ambient temperature. 3-
Pyridinesulfonyl chloride or benzenesulfonyl chloride (1.2eq) were added and the
reaction mixture was stirred at 80oC for 24 hours. In the case of pyridinesulfonyl chloride
derivative, the reaction was quenched by the addition of water and the solvent was
removed in vacuo. Purification by flash column chromatography (eluent: [0:1 to 1:4]
MeOH:EtOAc) afforded the target compound. In the case of benzenesulfonyl chloride
derivative, acetonitrile/water was added and the solid filtered off. The filtrate was
concentrated in vacuo and the residue was triturated in EtOAc to furnish the sodium salt
as a powder. The sodium salt was then washed with a citric acid aqueous solution
followed by water and dried to furnish the desired compound.
Referring to Reaction Scheme 5, Stage 3, 6-substituted-phenyl-pyrimidin-
4-ylamine (1eq) was suspended in 1,4-dioxane or DMF (20vol). Sodium hydride (3eq)
was added and the suspension stirred for 10 to 60 minutes at room temperature. The
appropriate acid chloride (1.5eq) was added and the reaction mixture stirred at room
temperature for 1 hour. The reaction was monitored by LCMS. If the reaction was not
complete, sodium hydride (1eq) was added to the reaction mixture, which was then heated
at 50oC for 16 hours. Upon completion, the reaction was quenched with water. If
precipitation occurred, the precipitate was filtered and purified further by flash column
chromatography using an appropriate eluent, if not the desired material was extracted
with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried
with MgSO4, filtered and the solvent removed in vacuo. The desired compound was
further purified either by trituration or prep HPLC when required.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
401.87 [M+H]+=402, 99% @ rt =
4.53 min
419.87 [M+H]+=420, 100% @ rt =
O O 4.61 min
485.87 [M+H]+=486, 100% @ rt =
.01 min
485.87 [M+H]+=487, 100% @ rt =
4.91 min
S O F
419.87 [M+H]+=420, 99.5% @ rt =
N N F
4.51 min
365.84 [M+H]+=366, 100% @ rt =
4.28 min
Example 6
Reaction Scheme 6
R1 R1
Stage 1
Referring to Reaction Scheme 6, Stage 1, to a stirred solution of 6-(3-
chloro-phenyl)-pyrimidinecarboxylic acid (1eq) or 6-(3,4-dichloro-phenyl)-
pyrimidinecarboxylic acid methyl ester in THF (20vol) was added dropwise a 1M
NaOH solution. The mixture was stirred at ambient temperature and the resulting
precipitate was filtered and washed with water/THF or with water then heptane to furnish
the described salts.
Structure Molecular Mass Spec Result
Weight
312.68 [M+H] = 291/293, 100%
@ rt = 3.97 min
O Na
383.81 [M+H] = 362/364, 100%
@ rt = 2.55 min
O Na
328.73 [M+H] = 307/309, 100%
@ rt = 4.35 min
O Na
307.67 [M+H]+= 286/288, 99% @
rt = 3.26 min
385.8 [M-Na+2H]+ = 364/366
100% @ rt = 2.29 min
328.69 [M+H]+ = 307/309, 87%@
N N rt = 3.37 min
O Na
Example 7
Reaction Scheme 7
HCl N
R1 R1
O Stage 2
Stage 4
Stage 1
N HCl
O R1
Stage 3
Referring to Reaction Scheme 7, Stage 1, to a stirred suspension of 4-
bromo-pyridinecarboxylic acid methyl ester (1eq) in 1,4-dioxane (20vol) was added
the appropriate substituted phenyl boronic acid (1.1eq) and Pd(PPh3)4 (0.05eq). A 2M
K2CO3 solution (7.5vol) was added and the reaction mixture was heated at 90oC with
stirring for 16 hours under an atmosphere of N2. The reaction mixture was cooled to room
temperature and the resulting precipitate was isolated by filtration to furnish the acid
intermediate as the potassium salt, which was used without further purification in the
stage. In the case of the 3-chlorophenyl analogue no precipitate was formed upon cooling,
hence the solvent was removed in vacuo. The resulting residue was dissolved in EtOAc
and water. Both phases were separated. EtOAc was removed in vacuo and the resulting
residue was purified by flash column chromatography (eluent: [5:95] methanol:DCM) to
furnish the desired 4-(3-chloro-phenyl)-pyridinecarboxylic acid methyl ester. The
aqueous phase was acidified and the resulting precipitate was isolated by filtration and
used as such in stage 2. Further purification was carried out by prep HPLC to furnish the
required 4-(3-chloro-phenyl)-pyridinecarboxylic acid.
Referring to Reaction Scheme 7, Stage 2, the required amide analogues
were prepared following the procedure described in method A from 4-(3-chloro-phenyl)-
pyridinecarboxylic acid, hydrochloride salt and were purified by trituration in
acetonitrile/water (1/1) or in water followed by heptane.
Referring to Reaction Scheme 7, Stage 3, the potassium salt isolated in
stage 1 was suspended in HCl (2M) and stirred at ambient temperature for 2 hours. The
solid was filtered and washed with water to furnish the desired target compound.
Referring to Reaction Scheme 7, Stage 4, the required amide analogues
were prepared following the procedure described in method A from 4-(substituted-
phenyl)-pyridinecarboxylic acid potassium salt and were purified by trituration in
acetonitrile/water (1/1) or in water followed by heptane.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
289.72 [M+H] = 290/292, 98% @
rt = 3.31 min
305.76 [M+H] =306/308, 99% @
rt = 3.73 min
305.76 [M+H] 306/308, 99% @
rt = 3.71 min
291.74 [M+H] =292/294, 100% @
rt = 3.44 min
Example 8
Reaction Scheme 8
NH N
2 F F
F F N
F O F O
F F F
Stage 1 Stage 2
Cl Cl Cl
N N N N
Cl Cl
F Cl F
F O F O
Stage 3 Stage 4
Cl Cl
Stage 5a O
Stage 5b F O
F O F
Referring to Reaction Scheme 8, Stage 1 a solution of NaNO2 (2.4eq) in
water (5vol) was slowly added over 30 min to a suspension of [3-chloro
(trifluoromethoxy)phenyl]amine (1eq) in (7vol) of 15% HCl at -5oC. The solid material
was removed by filtration and a solution of NaBF4 (1.6eq) in water (4vol) was mixed
with the filtrate. The resulting solid was collected by filtration, washed with minimum
water and dried on a sinter funnel under vacuum for 1 hour. It was then dried in the
vacuum oven at 40oC until constant weight to give the required product.
Referring to Reaction Scheme 8, Stage 2, 3-chloro
(trifluoromethoxy)benzenediazonium tetrafluoroboranide (1eq) was mixed with
bis(pinacolato) diboron (1.05eq) in a flask cooled by an ice bath. MeOH (8vol) was added
and the mixture was de-gassed with nitrogen for 10 minutes before PdCl2(dppf)2.DCM
(0.025eq) was added. The mixture was stirred at room temperature overnight before
analysis by LCMS. The reaction was evaporated to dryness, re-dissolved in DCM, dry
loaded onto silica and purified by dry flash chromatography running a slow gradient from
0-20% EtOAc in heptane. Clean fractions were combined and evaporated to dryness to
give the required product as an oil.
Referring to Reaction Scheme 8, Stage 3, 4,6-dichloropyrimidine (1eq) and
2-[3-chloro(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.7eq)
were dissolved in dioxane (12vol) at room temperature and 2M potassium carbonate (2eq)
was added. The solution was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (0.05eq)
was added and the reaction was stirred at 90oC for 2 hours before analysis by LCMS. The
reaction was cooled to room temperature and the solvent was evaporated. DCM was
added and the organic layer was washed with water, brine and dried using MgSO4. The
solvent was evaporated to dryness to give an oil which was purified by dry-flash
chromatography eluting with 0-6% EtOAc in heptane. The resulting oil was dried in the
vacuum oven at 40oC to give the required product.
Referring to Reaction Scheme 8, Stage 4, 4-Chloro(3-chloro
trifluoromethoxy-phenyl)-pyrimidine (1eq), and triethylamine (2eq) were dissolved in
MeOH and degassed for 5 minutes with nitrogen. Pd(dppf)2Cl2.DCM (0.05eq) was added
and the reaction was sealed inside a 500ml bomb. The bomb was charged with CO (5 bar)
and heated at 50oC overnight before analysis by LCMS. The reaction was cooled to room
temperature and the solvent evaporated. The residue was re-dissolved in EtOAc and
washed with water, brine and dried using MgSO4. The solvent was evaporated and the
resulting solid purified by dry flash chromatography eluting with 30-40% EtOAc in
heptane to give the required product.
Referring to Reaction Scheme 8, Stage 5a, 6-(3-Chloro
trifluoromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester was dissolved in
THF (16vol) and 2M NaOH (2eq) was added. The reaction mixture was allowed to stir at
room temperature for 17 hours. Water (32vol) was added and the mixture extracted with
EtOAc (2 x 32vol). 2 M HCl (2eq) was added and the solution extracted with EtOAc (3 x
32vol). The combined organic layers were dried over MgSO4 and the solvent removed to
dryness. The crude compound was re-crystallised from acetonitrile (20vol), filtered and
dried in a vacuum oven at 40oC to give the desired target 6-(3-chlorotrifluoromethoxy-
phenyl)-pyrimidinecarboxylic acid.
Referring to Reaction Scheme 8, Stage 5b, 6-(3-Chloro
trifluoromethoxy-phenyl)-pyrimidinecarboxylic acid methyl ester was dissolved in
THF. 2M NaOH (2eq) was added and the reaction was stirred at room temperature for 12
hours before analysis by LCMS. The reaction was evaporated to dryness and the resulting
solid was washed with water and diethyl ether. The solid was dried in a vacuum oven at
40oC to give the target compound 6-(3-chlorotrifluoromethoxy-phenyl)-pyrimidine
carboxylic acid as a sodium salt.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
318.64 [M+H] = 319/321, 74%
@ rt = 4.32 min
340.62 [M+H] = 319/321, 100%
@ rt = 4.19 min
Example 9
Reaction Scheme 9
NH N
2 F F
F F N
F O F O
F F F
Stage 1 Stage 2
Cl Cl Cl
Br CO Me
F CO H
Stage 3
Referring to Reaction Scheme 9, Stage 1 a solution of NaNO2 (2.4eq) in
water (5vol) was slowly added over 30 min to a suspension of [3-chloro
(trifluoromethoxy)phenyl]amine (1eq) in (7vol) of 15% HCl at -5oC. The solid material
was removed by filtration and a solution of NaBF4 (1.6eq) in water (4vol) was mixed
with the filtrate. The resulting solid was collected by filtration, washed with minimum
water and dried on a sinter funnel under vacuum for 1 hour. It was then dried in the
vacuum oven at 40oC until constant weight to give the required product.
Referring to Reaction Scheme 9, Stage 2, 3-chloro
(trifluoromethoxy)benzenediazonium tetrafluoroboranide (1eq) was mixed with
bis(pinacolato) diboron (1.05eq) in a flask cooled by an ice bath. MeOH (8vol) was added
and the mixture was de-gassed with nitrogen for 10 minutes before PdCl2(dppf)2.DCM
(0.025eq) was added. The mixture was stirred at room temperature overnight before
analysis by LCMS. The reaction was evaporated to dryness, re-dissolved in DCM, dry
loaded onto silica and purified by dry flash chromatography running a slow gradient from
0-20% EtOAc in heptane. Clean fractions were combined and evaporated to dryness to
give the required product as an oil.
Referring to Reaction Scheme 9, Stage 3, to a stirred suspension of 4-
bromo-pyridinecarboxylic acid methyl ester (1eq) in 1,4-dioxane (20vol) was added
the appropriate substituted phenyl boronic acid (1.1eq) and Pd(PPh3)4 (0.05eq). A 2M
K2CO3 solution (7.5vol) was added and the reaction mixture was heated at 90oC with
stirring for 16 hours under an atmosphere of N2. The reaction mixture was cooled to room
temperature and the resulting precipitate was isolated by filtration to furnish the acid
product as the potassium salt which was suspended in HCl (2M) and stirred at ambient
temperature for 2 hours. The solid was filtered and washed with water to furnish the
desired target compound.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
317.65 [M+H] =317, 100% @ rt
= 3.76 min
Example 10
Reaction Scheme 10
Br Br
HO O Stage 3
Stage 2
Stage 1 HO
Cl Cl
Stage 4
Stage 5 O
Stage 6
Stage 7
Referring to Reaction Scheme 10, Stage 1. Sodium hydride (1.1eq) was
added portion wise to a cool (0oC), stirred solution of 4-bromochlorophenol (1.0eq) in
DMF (6vol) and the mixture stirred at this temperature under a nitrogen atmosphere for
minutes. After this time, 3-bromopropene (1.1eq) was added dropwise and the
reaction mixture was allowed to warm to room temperature before being stirred at this
temperature overnight. After this time, the reaction mixture was poured onto ice-water
(10vol), the mixture was extracted with ethyl acetate (3 x), the organic layers were
combined, washed with brine (5vol), dried (MgSO4), filtered and concentrated. The
resulting residue was purified by flash column chromatography (elution: 20% ethyl
acetate, 80% heptane) to give the desired compound as a yellow gum.
Referring to Reaction Scheme 10, Stage 2. 1-Allyloxybromochloro
benzene (1eq) was suspended in mesitylene (12vol) and the mixture heated to 160oC and
stirred at this temperature overnight. After this time, the reaction mixture was cooled to
room temperature and concentrated. The resulting residue was purified using a Biotage
Isolera (340g silica column eluting with a gradient from heptane to 100% DCM) to give
the desired compound as a yellow oil.
Referring to Reaction Scheme 10, Stage 3. Borane (1M solution in THF,
1eq) was added drop wise to a stirred solution of 2-allylbromochloro-phenol (1eq)
in THF (10vol) and the reaction mixture was stirred at room temperature under a nitrogen
atmosphere for 4 hours. After this time, the reaction mixture was quenched by the
sequential addition of water (1eq), NaOH (1eq) and hydrogen peroxide (1eq) and the
mixture stirred at room temperature for a further 2 hours. The resulting mixture was
partitioned between diethyl ether (5vol) and water (5vol). The organic layer was
separated, washed with brine (2vol), dried (MgSO4), filtered and to give the desired
compound as a colourless gum.
Referring to Reaction Scheme 10, Stage 3. Diethyl diazene-1,2-
dicarboxylate (1eq) was added dropwise to a stirred solution of triphenyl phospane (1eq)
and 4-bromochloro(3-hydroxy-propyl)-phenol (1eq) and the reaction mixture was
stirred at room temperature under a nitrogen atmosphere overnight After this time, the
reaction mixture was concentrated and purified using a Biotage Isolera (50g silica column
eluting with a gradient from 0% heptane to 20% ethyl acetate / 80% heptane) to give the
desired compound as a pale yellow oil.
Referring to Reaction Scheme 10, Stage 4. Bis-pinacol borane (1.5eq) was
added in one portion to a cool (0oC), stirred solution of 6-bromochloro-chroman
(1.0eq) and potassium acetate (3.5eq) in DMSO (5vol). The mixture was degassed with
nitrogen for 5 minutes, after which time Pd(dppf)2Cl2 (0.1eq) was added in one portion,
the mixture was allowed to warm to room temperature and was stirred at this temperature
under a nitrogen atmosphere for 1 hour. After this time the inorganic precipitate was
removed by filtration and the filtrate was concentrated. The resulting residue was purified
using a Biotage Isolera (50g silica column eluting with a gradient from 0% heptane to
40% DCM / 60% heptane) to give the desired compound as a pale yellow oil.
Referring to Reaction Scheme 10, Stage 5. Tripotassium phosphate (2eq)
was added in one portion to a stirred solution of 8-chloro(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolanyl)-chroman (1eq) and methyl 4-bromopyridinecarboxylate
(2eq) in DMF (10vol). The mixture was degassed with nitrogen for 5 minutes, after which
time Pd(dppf)2Cl2 (0.2eq) was added in one portion, the mixture was then heated to 60oC
and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time
the reaction mixture was cooled to room temperature and partitioned between ethyl
acetate (5vol) and water (5vol). The organic layer was separated, washed sequentially
with water (5vol) then brine (5vol) before being dried (MgSO4), filtered and
concentrated. The resulting residue was purified using a Biotage Isolera (100g silica
column eluting with a gradient from 0% heptane to 80% DCM / 20% heptane) to give the
desired compound as a white solid.
Referring to Reaction Scheme 10, Stage 5. 2M NaOH (4eq) was added in
one portion to a stirred solution of 6-(8-chloro-chromanyl)-pyrimidinecarboxylic
acid methyl ester (1eq) in ethanol (1vol) and the mixture was stirred at room temperature
for 2 hours. After this time the reaction mixture was diluted with water and the ethanol
removed under reduced pressure. The remaining solution was acidifed to pH 1 with 1M
HCl and the resulting precipitate was collected by filtration, washed with water (5vol) and
TBME (5vol) and dried in a vacuum oven at 40oC overnight to afford the desired
compound as a white solid.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
290.71 [M+H]+= 291, 100% @ rt
= 3.71 min
Example 11
Reaction Scheme 11
Br Br
Stage 1 O
Stage 2 Stage 3
O Cl
Cl Cl
Stage 4
Stage 5 O
Referring to Reaction Scheme 11, Stage 1. Potassium carbonate (2eq) was
added portion wise to a stirred solution of 4-bromochlorophenol (1eq) and
bromoacetaldehyde diethyl acetal (1.5eq) in DMF (6vol) and the mixture was heated to
140oC and heated at this temperature under a nitrogen atmosphere for 3 hours. After this
time the reaction mixture was cooled to room temperature and concentrated. The resulting
residue was partitioned between ethyl acetate (20vol) and water (5vol), the organic layer
was separated, dried (MgSO4), filtered and concentrated. The resulting residue was
purified using a Biotage Isolera (340g silica column eluting with a gradient from 0%
DCM to 60% DCM / 40% heptane) to afford the desired compound as a colourless oil.
Referring to Reaction Scheme 11, Stage 2. 4-Bromochloro(2,2-
diethoxy-ethoxy)-benzene (1eq) was added portion wise as a solution in toluene (5vol) to
polyphosphonic acid (8eq)) at 0oC. The resulting suspension was allowed to warm to
room temperature before being heated to reflux and stirred for 1 hour. After this time the
mixture was cooled to room temperature and partitioned between water (10vol) and ethyl
acetate (30vol). The resulting residue was partitioned between ethyl acetate (30vol) and
water (5vol), the organic layer was separated, dried (MgSO4), filtered and concentrated.
The resulting residue was purified using a Biotage Isolera (340g silica column eluting
with 100% heptane) to afford the desired compound as a white solid.
Referring to Reaction Scheme 11, Stage 3. Potassium acetate (3eq) was
added in one portion to a stirred solution of 5-bromochloro-benzofuran (1eq) and bis-
pinacol borane (1.1eq) in DMF (3vol). The mixture was degassed with nitrogen for 5
minutes, after which time Pd(dppf)2Cl2 (0.3eq) was added in one portion, the mixture
was then heated to 80oC and stirred at this temperature for 18 hours under a nitrogen
atmosphere. After this time the reaction mixture was cooled to room temperature and
partitioned between ethyl acetate (20vol) and water (10vol). The biphasic suspension was
filtered through glass fiber filter paper and the organic layer was separated, washed
sequentially with water (3 x) before being dried (MgSO4), filtered and concentrated. The
resulting residue was purified purified using a Biotage Isolera (100g silica column eluting
with 100% heptane to 50% DCM / 50% heptane) to afford the desired compound as a
white solid.
Referring to Reaction Scheme 11, Stage 4. Tripotassium phosphate (1.4eq)
was added in one portion to a stirred solution of, 7-chloro(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolanyl)-benzofuran (1eq) and methyl 6-chloropyrimidinecarboxylate
(2eq) in DMF (4vol). The mixture was degassed with nitrogen for 5 minutes, after which
time Pd(dppf)2Cl2 (0.2eq) was added in one portion, the mixture was then heated to 60oC
and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time
the reaction mixture was cooled to room temperature and partitioned between ethyl
acetate (20vol) and water (10vol). The organic layer was separated, washed sequentially
with water (10vol) then brine (10vol) before being dried (MgSO4), filtered and
concentrated. The resulting residue was purified purified using a Biotage Isolera (50g
silica column eluting with 100% heptane to 20% ethyl acetate / 50% heptane) to afford
the desired compound as a white solid.
Referring to Reaction Scheme 11, Stage 5. NaOH (1.5eq) was added in
one portion to a stirred solution of 6-(7-chloro-benzofuranyl)-pyrimidinecarboxylic
acid methyl ester (1.0eq) in THF (8vol) and the mixture was stirred at room temperature
for 16 hours. After this time, the resulting precipitate was collected by filtration, washed
with water (1vol) and DCM (2vol) before being dried under vacuum. This solid was then
suspended in HCl (2M solution, 6vol) and acetonitrile (6vol), heated to 80oC until
complete dissolution then cooled to room temperature. The acetonitrile was removed
under reduced pressure and the solid precipitate was collected by filtration, washed with
water (1vol) before being dried in a vacuum over overnight to give the hydrochloride salt
of the desired compound as a white solid.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
274.67 [M+H]+=275/277, 98%
@ rt = 3.70 min
Example 12
Reaction Scheme 12
Referring to Reaction Scheme 12, Stage 1. Potassium carbonate (2M
solution, 52.0ml, 104.0mmol) was added in one portion to a stirred solution of 3,4-
dichlorophenyl boronic acid (6.9g, 37.0mmol) and 4,6-dichloromethyl pyrimidine
(8.5g, 52.0mmol) in dioxane (150ml). The mixture was degassed with nitrogen for 5
minutes, after which time palladium tetrakis triphenylphosphine (3.0g, 3.0mmol) was
added in one portion, the mixture was then heated to 90oC and stirred at this temperature
for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled
to room temperature and concentrated. The resulting residue was dissolved in DCM
(500ml), washed sequentially with water (500ml) then brine (500ml) before being dried
(MgSO4), filtered and concentrated. The resulting residue was purified by flash column
chromatography (elution: 6% EtOAc, 94% Heptane) to give the desired compound
(6.05g, 42% yield) as a white solid. δH (500 MHz, DMSO) 8.91 - 9.00 (1 H, m) 7.88 -
7.96 (1 H, m) 7.76 - 7.88 (1 H, m) 7.58 - 7.69 (1 H, m) 2.36 (3 H, s). Tr = 2.30 min m/z
(ES+) (M+H+) 275, 277.
Referring to Reaction Scheme 12, Stage 2. Triethylamine (6.1ml,
44.0mmol) was added in one portion to a calorimeter containing a stirred solution of 4-
chloro(3,4-dichloro-phenyl)methyl-pyrimidine (5.95g, 22.0mmol) in methanol
(80ml). The mixture was degassed with nitrogen for 5 minutes, after which time
Pd(dppf)2Cl2 (0.9g, 1.0mmol) was added in one portion, the calorimeter was sealed,
pressurised with carbon monoxide (5 bar) and was heated to 50oC overnight. After this
time the reaction mixture was cooled to room temperature, diluted with methanol and
concentrated. The resulting residue was dissolved in DCM (300ml) and washed
sequentially with water (250ml) and brine (250ml). The organic layer was separated,
dried (MgSO4), filtered, concentrated and the resulting residue purified by flash column
chromatography (elution: 40% EtOAc, 60% heptane) to give the desired compound (5.2g,
80% yield) as a white solid. δH (500 MHz, DMSO) 9.19 (1 H, s) 7.92 - 7.97 (1 H, m)
7.79 - 7.85 (1 H, m) 7.63 - 7.70 (1 H, m) 3.95 (3 H, s) 2.30 - 2.42 (3 H, m). Tr = 2.10 min
m/z (ES+) (M+H+) 297, 299.
Referring to Reaction Scheme 12, Stage 3. NaOH (2M solution, 1.1ml,
2.0mmol) was added in one portion to a stirred solution of 6-(3,4-dichloro-phenyl)
methyl-pyrimidinecarboxylic acid methyl ester (0.32g, 1.0mmol) in THF (10ml) and
the mixture was stirred at room temperature for 16 hours. After this time, the resulting
precipitate was collected by filtration, washed with water (1ml) and DCM (20ml) before
being dried under vacuum. This solid was then suspended in HCl (2M solution, 60ml) and
acetonitrile (60ml), heated to 80oC until complete dissolution then cooled to room
temperature. The acetonitrile was removed under reduced pressure and the solid
precipitate was collected by filtration, washed with water (10ml) before being dried in a
vacuum over overnight to give the hydrochloride salt of the desired compound (0.22g,
75% yield) as a white solid.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
304.72 [M+H]+= 305/307, 100%
@ rt = 3.64 min
Example 13
Reaction Scheme 13
Referring to Reaction Scheme 13, Stage 1. Sodium bicarbonate (0.46g,
.0mmol) was added in one portion to a stirred solution of 5-bromomethyl(3,4-
dichloro-phenyl)-pyrimidinecarboxylic acid methyl ester (0.24g, 0.64mmol) in DMSO
(5ml), and the mixture was stirred at room temperature under a nitrogen atmosphere for
hours. After this time the mixture was partitioned between ethyl acetate (20ml) and
water (20ml), the organic layer was separated and the aqueous layer extracted with ethyl
acetate (2 x 20ml). The organic layers were combined, dried (MgSO4), filtered,
concentrated and the resulting residue was triturated with diethyl ether. The resulting
precipitate was collected by filtration and dried under vacuum to give the desired
compound (0.08g, 45% yield) as an orange solid.
Referring to Reaction Scheme 13, Stage 2. Sodium methoxide (0.02g,
0.36mmol) was added in one portion to a stirred solution of 4-(3,4-dichloro-phenyl)-5H-
furo[3,4-d]pyrimidinone (0.05g, 0.18mmol) in methanol (5ml), and the mixture was
stirred at room temperature under a nitrogen atmosphere for 20 hours. After this time,
sodium hydroxide (2M solution, 0.05ml, 0.89mmol) was added and the mixture was
heated to 70oC and stirred at this temperature for a further 4 hours. After this time the
reaction mixture was cooled to room temperature and the resulting precipitate was
collected by filtration, washed with methanol (5ml) and dried under vacuum to give the
desired compound (0.01g, 5% yield) as an off-white solid.
Referring to Reaction Scheme 13, Stage 3. Sodium methoxide (0.03g,
0.53mmol) was added in one portion to a stirred solution of 5-bromomethyl(3,4-
dichloro-phenyl)-pyrimidinecarboxylic acid methyl ester (0.1g, 0.26mmol) in methanol
(5ml), and the mixture was stirred at room temperature under a nitrogen atmosphere for
hours. After this time the mixture was concentrated and the resulting residue taken up
in DCM (10ml). The solution was washed consecutively with water (2 x 50ml) and brine
(2 x 50ml), before being separated, dried (MgSO4), filtered and concentrated. The
resulting residue was purified by flash column chromatography (elution: 100% DCM to
99% DCM: 1% Methanol) to give the desired compound (0.02g, 20% yield) as a white
solid. Tr = 2.11 min m/z (ES+) (M+H+) 327, 329.
Referring to Reaction Scheme 13, Stage 4. Sodium hydroxide (0.05ml,
0.1mmol) was added in one portion to a stirred solution of methyl 6-(3,4-dichlorophenyl)-
-(methoxymethyl)pyrimidinecarboxylate (0.1g, 0.26mmol) in THF (5ml) and the
mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours. After
this time the resulting precipitate was collected by filtration, washed with water (1ml) and
dried under vaccuum to give the desired compound (0.004g, 15% yield) as a white solid.
The following compounds were prepared substantially as described above.
Structure Molecular Mass Spec Result
Weight
302.72 [M+H]+ = 303/305, 100%@
rt = 4.20 min
320.72 [M+H]+ = 321/323, 100%@
rt = 3.29 min
O OH
316.75 [M+H]+ = 317/319, 100%@
rt = 3.89 min
Example 14
Reaction Scheme 14
N N OH
N N O N N O
O O OH
R Step 2 R
Step 1
Referring to Reaction Scheme 14, Stage 1. 2,2-Dimethylpropanoyl
chloride (0.07ml, 0.53mmol) was added dropwise to a stirred solution of 6-(3-chloro
cyclopropoxy-phenyl)-pyrimidinecarboxylic acid (0.15g, 0.48mmol) in THF (10ml)
and the mixture was stirred at room temperature for 2 hours. After this time the mixture
was added portion wise to a solution of (1R)[(3aR,5R,6S,6aR)hydroxy-2,2-
dimethyl-tetrahydro-2H-furo[2,3-d][1,3]dioxolyl]ethane-1,2-diol (0.32g, 1.44mmol) in
pyridine (10ml) and the reaction mixture was stirred at room temperature under a nitrogen
atmosphere for 18 hours. The resulting mixture was concentrated and the residue
partitioned between DCM (50ml) and water (20ml). The organic layer was separated,
dried (MgSO4), filtered and concentrated. The resulting residue was then purified by flash
column chromatography (elution: 100% ethyl acetate) to give the desired compound
(0.095g, 34% yield) as a colourless oil. Tr = 1.95 min m/z (ES+) (M+H+) 493.
Referring to Reaction Scheme 14, Stage 2. 4M HCl in dioxane solution
(5ml) was added in one portion to a stirred solution of 6-(3-chlorocyclopropoxy-
phenyl)-pyrimidinecarboxylic acid 6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-
d][1,3]dioxolylmethyl ester (0.095g, 0.19mmol) in dioxane (2ml) and the mixture was
stirred at room temperature overnight. The resulting mixture was concentrated and the
resulting residue was then purified by prep HPLC to give the title compound (0.01g, 13%
yield) as a colourless glass.
Structure Molecular Weight Mass Spec Result
452.85 [M+Na]+ = 475.0 @ rt
= 3.36+3.41min
N N O
Example 15
Reaction Scheme 15
N N N N
O O O O
Step 1 HO Step 2 Cl
Step 3
Step 4
Referring to Reaction Scheme 15, Stage 1. Triethylamine (19.01ml,
146.92mmol) was added dropwise to a solution of diethyl butynedioate (25.0 g, 146.92
mmol) and formamidine hydrochloride (11.83 g, 146.92 mmol) in acetonitrile (500 mL).
The resulting red solution was heated at 80oC for 2.5 hours. After this time the reaction
mixture was cooled to 5oC using a saturated NaCl/ice bath and the reaction was stirred at
this temperature for 25 minutes. After this time the resulting solid precipitate was
collected under suction and dried on a sinter funnel for 30 minutess under vacuum at
room temperature before drying in the vacuum oven at room temperature for 3 hours to
give the desired compound (21.3 g, 86% yield) as a pale brown solid. Tr = 0.85 min (3.5
minute method) m/z (ES+) (M+H+) 169.
Referring to Reaction Scheme 15, Stage 2. Ethyl 6-hydroxypyrimidine
carboxylate (21.3 g, 126.67 mmol) was dissolved in dry DMF (100 mL) in a 2 neck flask.
The flask was purged with a stream of nitrogen while cooling in an ice bath for 10
minutes. After this time, thionyl chloride (15.6 mL, 215.6 mmol) was added dropwise
over 20 minutes, before being warmed to room temperature and stirred under a nitrogen
atmosphere for 2 hours. After this time, the reaction mixture was carefully poured onto
~100 mL ice water. TBME (100 mL) was added, the organic layer was separated and the
aqueous extracted with further TBME (3 x 100 mL). The combined organic layers were
washed consecutively with water (2 x 100 mL), and brine (100 mL) before being dried
(MgSO4), filtered and concentrated to give the desired compound (8.8 g, 37% yield) as a
light orange powder. δH (500 MHz, DMSO) 9.23 (d, J=0.95 Hz, 1 H), 8.16 (d, J=1.10
Hz, 1 H), 4.39 (q, J=7.09 Hz, 2 H), 1.34 (t, J=7.17 Hz, 3 H). Tr = 1.43 min (3.5 minute
method) m/z (ES+) (M+H+) 187.
Referring to Reaction Scheme 15, Stage 3. Tripotassium phosphate (1.12
g, 5.63 mmol) was added in one portion to a stirred solution of 2-(2H-1,3-benzodioxol
yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.93 g, 3.75 mmol) and ethyl 6-
chloropyridinecarboxylate (0.7 g, 3.75 mmol) in DMF (20 mL). The mixture was
degassed with nitrogen for 5 minutes, after which time Pd(dppf)2Cl2 (0.14 g, 0.19 mmol)
was added in one portion, the mixture was then heated to 80oC and stirred at this
temperature for 16 hours under a nitrogen atmosphere. After this time the reaction
mixture was cooled to room temperature and partitioned between ethyl acetate (200mL)
and water (100mL). The organic layer was separated, washed sequentially with water
(100mL) then brine (100mL) before being dried (MgSO4), filtered and concentrated. The
resulting brown solid was purified by flash column chromatography (elution: 40%
EtOAc, 60% Heptane) to give the desired compound (0.31 g, 31% yield) as a white solid.
Tr = 1.87 min m/z (ES+) (M+H+) 273.
Referring to Reaction Scheme 15, Stage 4. NaOH (2M solution, 0.63 mL,
1.27 mmol) was added in one portion to a stirred solution of ethyl 6-(2H-1,3-benzodioxol-
-yl)pyrimidinecarboxylate (0.31 g, 1.15 mmol) in THF (10mL) and the mixture was
stirred at room temperature for 16 hours before being heated to reflux for 2 hours. After
this time, the reaction mixture was cooled to room temperature and the resulting
precipitate was collected by filtration, washed with THF (20 mL) before being dried
under vacuum to give the desired compound (0.17g, 56% yield, >99% purity) as a white
solid.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
244.04 [M+H]+= 245/247, 99% @ rt = 3.08 min
280.73 [M+H]+= 281/283, 99% @ rt = 2.61 min
278.04 [M+H]+= 279/281, 100% @ rt = 3.65 min
286.2 [M+H]+= 287/289, 100% @ rt = 3.03 min
Example 16
Reaction Scheme 16
N N N N
Step 1 Step 2
R1 R1
Cl Cl
R1 = MeS(O)- R1 = MeS(O)-
R1 = MeS(O) - R1 = MeS(O) -
Referring to Reaction Scheme 16, Stage 1. A solution of oxone (0.25 g,
0.40 mmol) in water (12 mL) was added portion wise over 15 minutes to a stirred
solution of ethyl 6-[3-chloro(methylsulfanyl)phenyl]pyrimidinecarboxylate (0.25 g,
81 mmol) in acetone (12 mL) and the resulting mixture was stirred at room temperature
under a nitrogen atmosphere for 18 hours. After this time, the reaction was partitioned
between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, and
the aqueous further extracted with ethyl acetate (2 x 50 mL). The combined organic
extracts were then dried (MgSO4), filtered and concentrated. The resulting residue was
purified on a Biotage isolera (15% ethyl acetate, 90% heptanes to 100 % ethyl acetate) to
give the desired compound (0.2 g, 76% yield) as a white solid. δH (500 MHz, DMSO-d6)
9.48 (d, J = 1.20 Hz, 1H), 8.66 (d, J = 1.22 Hz, 1H), 8.56 (dd, J = 1.64, 8.22 Hz, 1H), 8.48
(d, J = 1.58 Hz, 1H), 8.02 (d, J = 8.21 Hz, 1H), 4.43 (q, J = 7.11 Hz, 2H), 2.87 (s, 3H),
1.38 (t, J = 7.11 Hz, 3H). Tr = 1.64 min m/z (ES+) (M+H+) 325, 327.
Referring to Reaction Scheme 16, Stage 2. NaOH (2M solution, 0.33 mL,
0.66 mmol) was added in one portion to a stirred solution of ethyl 6-(3-chloro
methanesulfinylphenyl)pyrimidinecarboxylate (0.19 g, 0.61 mmol) in THF (30mL) and
the mixture was stirred at room temperature for 7 hours. After this time, the resulting
precipitate was collected by filtration, washed with THF (10 mL) before being dried
under vacuum to give the desired compound (0.17g, 84% yield, >99% purity) as a white
solid.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
296.73 [M+H]+=297/299 98.9% @ rt = 2.83min
O Cl
312.73 [M+H]+ = 313/315 100% @ rt = 2.92 min
Example 17
Reaction Scheme 17
Br Br
Step 1 Step 2
O Cl O Cl
Step 3
O Cl
N N N N N N
O O O
O O O
Step 5 Step 4
O Cl O Cl O Cl
Referring to Reaction Scheme 17, Stage 1. Cyclopropylmagnesium
bromide (0.5M solution in THF, 100.0mL, 50.0mmol) was added portion wise over 1
hour to a cold (-78oC), stirred solution of 4-bromochlorobenzaldehyde (5.5g,
.0mmol) in THF (100mL) and the mixture was stirred for 1 hour before being allowed
to warm to room temperature and stirred for a further 18 hours. After this time, the
reaction was quenched by the addition of saturated ammonium chloride (100mL) and the
mixture extracted with ethyl acetate (3 x 100mL). The combined organic extracts were
combined, washed with water (100mL) and brine (100mL) before being dried (MgSO4),
filtered and concentrated. The resulting residue was purified by flash column
chromatography (elution: 10% ethyl acetate, 90% heptanes) to give the desired compound
(5.05g, 77% yield) as a pale yellow oil. δH (500 MHz, DMSO) 7.66 (d, J=1.89 Hz, 1 H)
7.50 - 7.60 (m, 2 H) 5.43 (br. s., 1 H) 4.59 (d, J=5.20 Hz, 1 H) 1.04 - 1.15 (m, 1 H) 0.29 -
0.46 (m, 4 H).
Referring to Reaction Scheme 17, Stage 2. Potassium acetate (3.72g,
40.0mmol) was added in one portion to a stirred solution of (4-bromo
chlorophenyl)(cyclopropyl)methanol (3.3g, 1.3mmol) and bis-pinacol borane (3.85g,
1.5mmol) in DMSO (35mL). The mixture was degassed with nitrogen for 5 minutes, after
which time Pd(dppf)2Cl2 (0.46g, 0.6mmol) was added in one portion, the mixture was
then heated to 80oC and stirred at this temperature for 16 hours under a nitrogen
atmosphere. After this time the reaction mixture was cooled to room temperature and
partitioned between ethyl acetate (100mL) and water (50mL). The biphasic suspension
was filtered through glass fiber filter paper and the organic layer was separated, washed
sequentially with water (3 x 100mL) before being dried (MgSO4), filtered and
concentrated. The resulting residue was purified by flash column chromatography
(elution: 80% heptane, 20% DCM and 2mL of triethylamine) to give the desired
compound (3.5g, 90% yield) as a colourless oil. δH (500 MHz, DMSO) 7.61 (s, 2 H) 7.56
(s, 1 H) 5.39 (d, J=4.41 Hz, 1 H) 4.66 (t, J=5.20 Hz, 1 H) 1.24 - 1.36 (m, 12 H) 1.05 - 1.12
(m, 1 H) 0.24 - 0.47 (m, 4 H).
Referring to Reaction Scheme 17, Stage 3. Tripotassium phosphate (1.03g,
4.8mmol) was added in one portion to a stirred solution of [2-chloro(tetramethyl-1,3,2-
dioxaborolanyl)phenyl](cyclopropyl)methanol (1.0g, 3.2mmol) and ethyl 6-
chloropyrimidinecarboxylate (0.73g, 3.89mmol) in DMF (20mL). The mixture was
degassed with nitrogen for 5 minutes, after which time Pd(dppf)2Cl2 (0.13g, 0.16mmol)
was added in one portion, the mixture was then heated to 60oC and stirred at this
temperature for 16 hours under a nitrogen atmosphere. After this time the reaction
mixture was cooled to room temperature and partitioned between ethyl acetate (100mL)
and water (50mL). The organic layer was separated, washed sequentially with water
(50mL) then brine (50mL) before being dried (MgSO4), filtered and concentrated. The
resulting red gum was purified by flash column chromatography (elution: 40% EtOAc,
60% Heptane) to give the desired compound (0.74g, 65% yield) as a colourless oil. δH
(500 MHz, DMSO) 9.42 (d, J=1.10 Hz, 1 H) 8.57 (d, J=1.10 Hz, 1 H) 8.22 - 8.36 (m, 2 H)
7.79 (d, J=8.20 Hz, 1 H) 5.52 (br. s., 1 H) 4.72 (d, J=5.99 Hz, 1 H) 4.43 (q, J=7.09 Hz, 2
H) 1.38 (t, J=7.09 Hz, 3 H) 1.15 - 1.22 (m, 1 H) 0.29 - 0.53 (m, 4 H). Tr = 2.27 min m/z
(ES+) (M+H+) 321.
Referring to Reaction Scheme 17, Stage 4. NaOH (2M solution, 0.24mL,
0.48mmol) was added in one portion to a stirred solution of ethyl 6-{3-chloro
[cyclopropyl(hydroxy)methyl]phenyl}pyrimidinecarboxylate (0.16g, 0.48mmol) in
THF (2mL) and the mixture was stirred at room temperature for 16 hours. After this time,
the resulting precipitate was collected by filtration, washed with water (1mL) and DCM
(20mL) before being dried under vacuum to give the desired compound (0.065g, 41%
yield) as a white solid.
Referring to Reaction Scheme 17, Stage 5. Dess-Martin Periodinane
(0.36g, 1.08mmol) was added portion wise to a cooled (0oC), stirred solution of 6-{3-
chloro[cyclopropyl(hydroxy)methyl]phenyl}pyrimidinecarboxylic acid (0.36g,
1.08mmol) in DCM (3mL) and the mixture was allowed to warm to room temperature
and stirred for 18 hours. After this time, the mixture was partitioned between DCM
(20mL) and saturated sodium bicarbonate (20mL). The organic layer was separated,
washed with water (100mL) and brine (50mL) before being dried (MgSO4), filtered and
concentrated. The resulting residue was purified by flash column chromatography
(elution: 20% ethyl acetate, 80% heptanes) to give the desired compound (0.26g, 74%
yield) as a white solid.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
304.74 [M+H]+ = 305/307, 98%@ rt = 3.25 min
O Cl
302.72 [M+H]+ = 303/305, 100%@ rt = 3.54 min
O Cl
Example 18
Reaction Scheme 18
N N N N
OH OH
Step 1 Step 2 O Step 3 N O
O Cl
O Cl Cl
O Cl
Referring to Reaction Scheme 18, Stage 1. To a stirred solution of 4-
bromochlorobenzaldehyde (0.51 g, 2.32 mmol) in a mixture of dry dioxane (2.5 mL)
and dry DMF (0.60 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-
dioxaborolane (0.64 g, 2.52 mmol) and potassium acetate (0.7 g, 7.13 mmol). The
mixture was degassed and then 1,1'-bis(diphenylphosphanyl)ferrocene -
dichloropalladium (1:1) (0.08 g, 0.11 mmol) was added. The mixture was further
degassed before heating to 80ºC for 3 hours under an atmosphere of nitrogen gas. To the
cooled reaction mixture was added water (30 mL) and EtOAc (15 mL); the organic layer
was then washed with a 3:1 mixture of water and brine (2 x 40 mL), brine (5 mL), dried
(MgSO4), filtered and concentrated. The resulting residue was then absorbed onto silica
gel (1.6 g) and purified by dry flash chromatography (0-20% EtOAc in heptane) to give
the desired compound (0.25 g, 37% yield @ 90% NMR purity) as a white partial solid.
Tr = 1.46 min (63%) & 2.45 min (30%) m/z (ES+) (M+H+) no ionisation.
Referring to Reaction Scheme 18, Stage 2. To a degassed stirred solution
of ethyl 6-chloropyrimidinecarboxylate (0.17 g, 0.9 mmol) and 2-chloro
(tetramethyl-1,3,2-dioxaborolanyl)benzaldehyde (0.22 g, 0.81 mmol) in dioxane (2.5
mL) was added 2M K2CO3 (1.25 mL). Pd(PPh3)4 (57 mg, 0.05 mmol) was then added
and the reaction mixture was further degassed before heating to 90ºC under an
atmosphere of nitrogen gas for 2 hours. After this time, the reaction mixture was cooled
to room temperature and concentrated. Water (5 mL) was then added and the solid
filtered, washed with water (2 mL), acetone (3 x 2 mL) and dried under vacuum. The
solid was suspended in a mixture of EtOAc (30 mL) and 1N HCl (10 mL) and then heated
to achieve partial solution. The cooled two-phase system was then sonicated to achieve
full dissolution. The aqueous layer was re-extracted with EtOAc (10 mL); the combined
organics were washed with brine (5 mL), dried (MgSO4), filtered and concentrated to
give the desired compound (0.1 g, 42% yield @ 85% purity) as a beige solid. Tr = 1.58
min m/z (ES+) (M+H+) 263/265.
Referring to Reaction Scheme 18, Stage 3. To a stirred suspension of 6-(3-
chloroformylphenyl)pyrimidinecarboxylic acid (93 mg, 0.35 mmol) in 1,2-
dichloroethane (5 mL) was added dimethylamine (2M solution in THF, 0.53 mL) at room
temperature followed by molecular sieves and sodium triacetoxyborohydride (125 mg,
0.59 mmol). After 1.5 hours, acetic acid (31 µl, 0.54 mmol) was added and the reaction
stirred at room temperature for 2.5 days. Further dimethylamine (2M solution in THF,
1.0 mL) and sodium triacetoxyborohydride (130mg) were added and the mixture stirred
for 6h before a further amount of dimethylamine (2M in THF, 1.0 mL), sodium
triacetoxyborohydride (130 mg) and AcOH (62 L). The mixture was then stirred for 18
hours. The reaction mixture was filtered and the filtrate was concentrated. A solution of
1:1 (v/v) MeCN:water (0.5 mL) was added to the resulting residue and then concentrated
HCl (0.5 mL) was added dropwise. The crude product dissolved and was purified by
preparative HPLC (acetonitrile and water) to give 14 mg of an off-white solid. The solid
was further purified by sonication in TBME (1 mL) and collected by filtration. The solid
was washed with TBME (4 x 1mL) and dried to give the desired compound (7.8 mg,
7.9% yield @ 95% purity) as a off-white solid.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
291.74 [M+H]+= 292/294,100% @ rt = 2.00 min
Example 19
Reaction Scheme 19
Referring to Reaction Scheme 19, Stage 1. 4-Bromochloroaniline (2.0
g, 9.69 mmol), 1,4-dibromobutane (2.31 ml, 19.4 mmol), potassium carbonate (2.68 g,
19.4 mmol), water (25 mL) and dioxane (10 mL) were heated to 100oC overnight with
vigorous stirring. The reaction mixture was allowed to cool then extracted with EtOAc (2
x 25 mL). The combined organics were washed with brine (15 mL), dried (MgSO4),
filtered and concentrated to give an orange oil. Column chromatography (Elution: 0-20%
EtOAc-heptane) afforded the desired compound (1.16 g, 45% yield) as a yellow oil. δH
(500 MHz, DMSO-d6) 7.48 (d, J = 2.36 Hz, 1H), 7.33 (dd, J = 2.36, 8.83 Hz, 1H), 6.87
(d, J = 8.83 Hz, 1H), 3.29 - 3.33 (m, 4H), 1.87 (td, J = 3.43, 6.38 Hz, 4H); Tr (3 min) =
2.68 min m/z (ES+) (M+H)+ 260, 262.
Referring to Reaction Scheme 19, Stage 2. Potassium acetate (1.31 g, 13.4
mmol), bis(pinacolato)diboron (1.36 g, 5.32 mmol) and 1-(4-bromo
chlorophenyl)pyrrolidine (1.16 g, 4.45 mmol) were suspended in DMSO (15 mL). The
solution was degassed with N2 for 5 min. PdCl2(dppf) (0.16 g, 0.22 mmol) was added
and the reaction mixture was heated to 80 oC for 3 h. The reaction was cooled to rt.
Water (30 mL) was added to the reaction and the aqueous was extracted using EtOAc (5 x
mL). The combined organic layers were washed with water (100 mL), brine (50 mL),
dried (MgSO4), filtered, and concentrated to give a black oil. Column chromatography
(Elution; 8% EtOAc-heptane) afforded the desired compound (1.14 g, 83% yield) as a
pale yellow oil. Tr (3 min) = 2.70 min m/z (ES+) (M+H)+ 307.
Referring to Reaction Scheme 19, Stages 3 & 4 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
303.74 [M+H]+= 304/306, 100% @ rt = 4.14 min
Example 20
Reaction Scheme 20
H N Br
2 Br
N Br
Stage 1 Stage 2 Stage 3 Stage 4
Cl Cl
N N N N
O OH
Stage 5 Stage 6
Cl Cl
Referring to Reaction Scheme 20, Stage 1. In a three neck flask with
dropping funnel, thermometer and nitrogen bubbler (no nitrogen input), 4-bromo
chlorophenol (5.0 g, 0.024 mol) was fully dissolved in acetic acid (25 mL) at room
temperature. Nitric acid (70%, 2.9 mL, 0.048 mol) was added slowly dropwise over
approx 15 minutes keeping the temperature at below 30oC. The reaction turned orange
with an orange precipitate. The reaction was stirred for a further 4 hours at 20oC. After
this time the reaction mixture was cautiously transferred via pipette onto approximately
50 mL ice. Once the ice had melted the yellow precipitate was filtered and washed with
water (50 mL). The yellow solid was air dried under vacuum for 1 hour before being
dissolved in DCM and dry loaded onto 5.5g silica. The compound was purified by flash
column chromatography (elution; 100% heptane, to 20% DCM in heptane, to 40% DCM
in heptane, to 50% DCM in heptanes) to give the desired compound (4.38 g, 72% yield @
100% UV purity) as a yellow solid. Tr = 1.97min m/z (ES+) no ionisation.
Referring to Reaction Scheme 20, Stage 2. 4-Bromochloro
nitrophenol (4.38 g, 17.35 mmol) was dissolved in ethanol (120 mL). Water (28 mL) and
saturated aqueous ammonium chloride (28 mL) were added followed by iron powder
(7.75 g, 139 mmol). The reaction was heated to 50oC and stirred for 1 hour, after which
time the reaction was cooled to room temperature and filtered through a pad of celite
(approx. 5cm in a Jones tube), washing with 50 mL EtOH followed by excess EtOAc
until the liquid ran clear. The organic layer was washed with water (50 mL). The water
was re-extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed
with brine (20 mL), dried (MgSO4), filtered and concentrated. The resulting residue was
dry loaded onto 5g silica and purified by flash column chromatography (elution; 0-30%
EtOAc in heptanes) to give the desired compound (2.76g, 72% yield @ 100% UV purity)
as a pale brown solid. Tr = 1.65min m/z (ES+) (M+H+) 222/224/226.
Referring to Reaction Scheme 20, Stage 3. 2-Aminobromo
chlorophenol (2.66 g, 11.96 mmol) was dissolved in triethylorthoacetate (24 mL). pTSA
monohydrate (0.068 g, 0.359 mmol) was added and the reaction was stirred at 140oC
overnight. After this time the reaction was cooled to room temperature and the resulting
solid was collected by filtration and dried under suction at room temperature for 2 hours
to give the title compound (1.58 g, 54% yield @ 100% UV purity) as a white solid. Tr =
2.07min m/z (ES+) (M+H+) 246/248.
Referring to Reaction Scheme 20, Stages 4, 5 & 6 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
289.68 [M+H]+= 290/292, 100% @ rt = 3.42 min
Example 21
Reaction Scheme 21
Stage 2 Stage 3
Stage 1 HO HO
Stage 6
Stage 4 Stage 5
Stage 7
CO Na
Referring to Reaction Scheme 21, Stage 1. A solution of 4-bromo
chlorophenol (10.0 g, 48.0 mmol) in anhydrous DMF (30 mL) was added to a stirred
suspension of sodium hydride (2.31 g, 58.0 mmol) in DMF (20 mL) cooled to 0oC under
nitrogen over 15 min, and stirring continued for 30 min. 3-Bromopropene (7.00 g,
58.0 mmol) was added dropwise at 0 oC. After 1 h, the mixture was allowed to warm to
room temperature and then stirred for 3 d. Aqueous saturated NH4Cl (50 mL) was added
over 10 min with ice-cooling, and the mixture was concentrated. The residue was treated
with water (100 mL) and the mixture extracted with ethyl acetate (3 x 120 mL). The
combined, dried (Na2SO4) organic extracts were concentrated to give an oil which
contained DMF. A solution of the oil in ethyl acetate (100 mL) was washed with water
(100 mL) and the dried (Na2SO4) organic layer was concentrated to give the desired
compound (11.6 g, 87% yield) as a colourless oil. δH (500 MHz, CDCl3) 7.50 (d, J =
2.40 Hz, 1H), 7.30 (dd, J = 2.40, 8.77 Hz, 1H), 6.79 (d, J = 8.78 Hz, 1H), 6.04 (ddt, J =
.10, 10.38, 17.14 Hz, 1H), 5.45 (dd, J = 1.44, 17.26 Hz, 1H), 5.32 (dd, J = 1.33, 10.57
Hz, 1H), 4.59 (d, J = 5.10 Hz, 2H).
Referring to Reaction Scheme 21, Stage 2. A solution of 1-allyloxy
bromochloro-benzene (90%, 11.6 g, 42 mmol) in mesitylene (200 mL) was heated
under nitrogen for 48 h at 190 oC with stirring. The reaction was concentrated and
purified by column chromatography (Elution: 0-10% EtOAc-heptane) to afford the
desired compound (4.66 g, 36% yield) as a colourless oil. Tr (3 min) = 2.22 min m/z
(ES+) (M+H+) 245, 247.
Referring to Reaction Scheme 21, Stage 3. Sodium periodate (9.04 g, 42.3
mmol) was added to a stirred mixture of 2-allylbromochloro-phenol (5.23 g, 21.1
mmol), THF (100 mL) and water (100 mL) at room temperature. After 5 min, osmium
tetroxide (13.5 ml of a 0.157 M solution in water, 2.1 mmol) was added and stirring
continued for 1.5 h. The mixture was poured into brine (100 mL) and extracted with ethyl
acetate (2 x 100 mL) and the combined, dried (Na2SO4) organic extracts were
concentrated to give a dark oil. A stirred solution of the dark oil in methanol (100 mL)
under nitrogen was cooled to 0oC, and treated with sodium borohydride (2.40 g, 63.4
mmol) in small portions over 20 min, maintaining the temperature between 0 and 10 oC.
After stirring for 16 h, the mixture was concentrated, treated with aqueous 1M
hydrochloric acid (80 mL) and extracted with ethyl acetate (2 x 100 mL). The combined,
dried (Na2SO4) organic extracts were concentrated, and the residue purified by column
chromatography (Elution: 5-40% EtOAc-heptane) to afford the desired compound (1.60
g, 27% yield) as a colourless oil. Tr (3 min) = 1.81 min m/z (ES+) (M+H+) 249, 251.
Referring to Reaction Scheme 21, Stage 4. DIAD (1.52 ml, 7.70 mmol)
was added to a stirred solution of 4-bromochloro(2-hydroxy-ethyl)-phenol (1.49 g,
.92 mmol) and triphenylphosphine (2.02 g, 7.70 mmol) in dry THF (1.5 mL) under
nitrogen, with ice-cooling. After stirring for 16 h at rt, the solution was evaporated and the
residual oil purified by column chromatography (Elution: 0-10% EtOAc-heptane)
afforded the desired compound (1.20 g, 68% yield) as a colourless oil. Tr (3 min) = 2.27
min m/z (ES+) no ionization.
Referring to Reaction Scheme 21, Stages 5, 6 & 7 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
276.03 [M+H]+= 277/279, 100% @ rt = 3.53 min
Example 22
Reaction Scheme 22
Referring to Reaction Scheme 22, Stage 1. 4-Bromochlorophenol (14.0
g, 0.067 mol) was dissolved in acetic acid (75 mL) at room temperature. Nitric acid (70%,
8.00 ml, 0.145 mol) was added dropwise over approx 30 min keeping the temperature at
roughly 20-22 oC. After 1 h at rt, the reaction mixture was cautiously transferred via
pipette onto approx 100 mL ice. Once the ice had melted the yellow precipitate was
filtered, washing with a very small volume of water. The yellow solid was dried under
suction. Purification by dry flash chromatography (Elution: 0-50% DCM-heptane)
afforded the desired compound (12.0 g, 70% yield) as a yellow powder. δH (500 MHz,
DMSO) 11.35 (br. s., 1 H) 8.09 (d, J=2.52 Hz, 1 H) 8.07 (d, J=2.52 Hz, 1 H); Tr (3 min) =
1.97 min m/z (ES+) no ionization.
Referring to Reaction Scheme 22, Stage 2. 4-Bromochloro
nitrophenol (12.0 g, 47.5 mmol) was dissolved in ethanol (350 mL). Water (80 mL) and
saturated aqueous ammonium chloride (80 mL) were added, followed by iron powder
(21.2 g, 380 mmol). The reaction was heated to 50 oC and stirred for 2 h. The reaction
was cooled to rt and filtered through a prewashed pad of celite, washing with 100 mL
EtOH followed by excess EtOAc (approx 1.5 l) until the liquid ran clear. The filtrate was
concentrated to remove organic solvents. EtOAc (approx 400 mL) was added to the
aqueous residue and the layers were separated. The organic phase was washed with water
(150 mL) and brine (100 mL). The aqueous layers were re-extracted with EtOAc (2 x 150
mL). The combined organics were filtered to remove a pale brown solid and evaporated
to dryness to give a purple solid. Dry flash chromatography (Elution: 0-30% EtOAc-
heptane) afforded the desired compound (6.5 g, 61% yield) as a pale solid. δH (500 MHz,
DMSO) 9.01 (br. s., 1 H) 6.71 (d, J=2.36 Hz, 1 H) 6.66 (d, J=2.36 Hz, 1 H) 5.23 (br. s., 2
H); Tr (3 min) = 1.70 min m/z (ES+) (M+H)+ 222, 224, 226.
Referring to Reaction Scheme 22, Stage 3. 2-Aminobromo
chlorophenol (2.04 g, 9.18 mmol) was dissolved in DCM (anhydrous, 30 ml).
Triethylamine (1.6 ml, 11.5 mmol) was added and the reaction was stirred at rt for 1 h
under nitrogen. The reaction was cooled in an ice bath for 15 min and then
cyclopropanecarbonyl chloride (0.700 mL, 7.65 mmol) was added dropwise over a period
of 20 min. The reaction was allowed to gradually warm to rt and stirred for 2 h at rt. The
reaction was cooled in an ice bath and an extra 0.2 eq. acid chloride was added dropwise.
The reaction was allowed to warm to rt and stirred at rt for 2 h. DCM (20 mL) was
added to the reaction followed by water (50 mL). The organic and aqueous layers were
separated. The organic layer was washed with water (3 x 50 mL), brine (30 mL), dried
(MgSO4), filtered and concentrated to give the desired product which was carried forward
without further purification.
Referring to Reaction Scheme 22, Stage 4. A crude 4:1:1 mixture of N-(5-
bromochlorohydroxyphenyl)cyclopropanecarboxamide, 2-aminobromo
chlorophenylcyclopropanecarboxylate and 4-bromochlorocyclopropaneamido
phenylcyclopropanecarboxylate (2.77 g) was dissolved in toluene (30 mL).
TsOH monohydrate (2.54 g, 13.4 mmol) was added and the reaction was stirred at 115 oC
for 16 h. The reaction was cooled to rt and concentrated to give a brown oil. The residue
was re-dissolved in EtOAc (100 mL). The solution was washed with saturated aqueous
sodium bicarbonate (3 x 100 mL), water (3 x 100 mL), brine (50mL) and dried (MgSO4).
Filtration and concentration gave a brown oil. Column chromatography (Elution: 0-10%
EtOAc-heptane) afforded the desired compound (1.18 g, 42%) as an orange crystalline
solid. δH (500 MHz, DMSO) 7.85 (d, J=1.73 Hz, 1 H) 7.68 (d, J=1.58 Hz, 1 H) 2.27 -
2.40 (m, 1 H) 1.08 - 1.38 (m, 4 H); Tr (3 min) = 2.38 min m/z (ES+) (M+H)+ 272, 274.
Referring to Reaction Scheme 22, Stages 5, 6 & 7 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
315.72 [M+H]+= 316/318, 100% @ rt = 3.84 min
Example 23
Reaction Scheme 23
Referring to Reaction Scheme 23, Stage 1. 2-aminobromo
chlorophenol (2.50 g, 11.2 mmol) was dissolved in THF (30 ml). CDI (2.73 g, 16.9
mmol) was added and the reaction was stirred at 65 oC. After 2 h the reaction was cooled
to rt and concentrated to give an orange solid. The residue was redissolved in EtOAc (100
mL) and the organic phase was washed with water (50 mL), 2M HCl (3 x 50 mL), water
(100 mL) and brine (20 mL) and dried (MgSO4). Filtration and concentration afforded the
desired compound (2.7 g, 97% yield) as a white solid. δH (500 MHz, DMSO-d6) 12.01
(br. s., 1 H) 7.44 (d, J=1.73 Hz, 1 H) 7.26 (d, J=1.73 Hz, 1 H); Tr (3 min) = 1.87 min m/z
(ES-) (M-H)- 246, 248.
Referring to Reaction Scheme 23, Stage 2. 5-Bromochloro-2,3-dihydro-
1,3-benzoxazolone (0.60 g, 2.4 mmol) was dissolved in anhydrous DMF (10 mL) and
the reaction was cooled in an ice bath. Sodium hydride (60% in oil, 0.15 g, 3.6 mmol) was
added portionwise and the reaction was stirred in the ice bath for 1 h. Methyl iodide (0.18
ml, 0.29 mmol) was added and the reaction was stirred at rt for 2 hours. The reaction was
cooled in a slush bath. Water (5 mL) was added cautiously followed by EtOAc (20 mL).
The layers were separated. The aqueous was re-extracted with EtOAc (2 x 15 mL). The
combined organic layers were washed with water (10 mL) and brine (10mL) and dried
(MgSO4). Filtration and concentration gave a colourless oil. Column chromatography
(Elution: 0-20% EtOAc-heptane) afforded the desired compound (540 mg, 85% yield) as
a pink solid. δH (500 MHz, CDCl3) 7.30 (d, J=1.73 Hz, 1 H) 7.03 (d, J=1.73 Hz, 1 H)
3.41 (s, 3 H); Tr (3 min) = 1.97 min m/z (ES+) No ionisation.
Referring to Reaction Scheme 23, Stages 3, 4 & 5 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
305.68 [M+H]+= 306/308, 98% @ rt = 3.35 min
Example 24
Reaction Scheme 24
Referring to Reaction Scheme 24, Stage 1. Methylmagnesium bromide
(1.4M in toluene/THF, 1.5 mL, 0.046 mol) was added drop wise over 1 hour to a cold (-
78 oC), stirred solution of 4-bromochlorobenzaldehyde (5.0 g, 0.023 mol) in THF (100
mL) and the mixture was stirred at this temperature under a nitrogen atmosphere for 1
hour. After this time, the reaction mixture was allowed to warm to room temperature over
1 hour before being stirred for a further 1.5 hours. The reaction mixture was then cooled
to 5 oC in an ice bath and stirred for 10 minutes before saturated ammonium chloride (40
mL) was added drop wise and stirring continued at this temperature for a further 10
minutes before being allowed to warm to room temperature. The resulting mixture was
then extracted with ethyl acetate (1 x 100 mL), the organic layer was washed sequentially
with water (100 mL), and brine (100 mL) before being dried (MgSO4), filtered and
concentrated. The resulting residue was purified by flash column chromatography
(elution: 10% ethyl acetate, 90% heptanes) to give the desired compound (4.33 g, 81%
yield) as a colourless oil. δH (500 MHz, DMSO) 7.64 (d, J =1.58 Hz, 1 H) 7.49 - 7.60 (m,
2 H) 5.47 (d, J = 3.00 Hz, 1 H) 4.96 (dd, J = 6.07, 2.60 Hz, 1 H) 1.28 (d, J = 6.31 Hz, 3
Referring to Reaction Scheme 24, Stage 2. Sodium hydride (60% in oil,
0.38 g, 9.6 mmol) was added portion wise over 5 minutes to a cooled (0 oC), stirred
solution of 1-(4-bromochlorophenyl)ethanol (1.5 g, 6.4 mmol) in DMF (15 mL) and
the reaction was stirred at this temperature for 20 minutes under a nitrogen atmosphere.
After this time, methyl iodide (0.48 mL, 7.6 mmol) was added in one portion and the
reaction mixture was allowed to warm to room temperature before being stirred for a
further 18 hours. The reaction was quenched by the drop wise addition of water (15 mL)
over 10 minutes and the resulting solution was extracted with ethyl acetate (2 x 30 mL).
The combined organic extracts were washed sequentially with water (100 mL) and brine
(10 mL) before being dried (MgSO4), filtered and concentrated to give the desired
compound (1.5 g, 99% yield) as a yellow oil. δH (500 MHz, DMSO) 7.71 (d, J=1.89 Hz,
1 H) 7.60 (dd, J=8.35, 1.89 Hz, 1 H) 7.39 (d, J=8.35 Hz, 1 H) 4.63 (q, J=6.46 Hz, 1 H)
3.16 (s, 3 H) 1.26 - 1.38 (m, 3 H).
Referring to Reaction Scheme 24, Stages 3, 4 & 5 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
292.72 [M+H]+ = 293/295, 99%@ rt = 3.72 min
Example 25
Reaction Scheme 25
Referring to Reaction Scheme 25, Stage 1. [(1-
Ethoxycyclopropyl)oxy](trimethyl)silane (5.6 mL, 27.85 mmol) was added drop wise
over 10 minutes to a stirred solution of 4-bromochloroaniline (5.0 g, 24.22 mmol) in a
mixture of methanol (50 mL) and acetic acid (95 mL) and the resulting solution was
heated to 70 oC and stirred at this temperature for 4 hours. After this time, the reaction
mixture was cooled to room temperature and concentrated. The resulting residue was then
dissolved in THF (25 mL) and added drop wise to a cooled (0 oC), stirred solution of
sodium borohydride (1.87 g, 49.4 mmol) and (diethyl ether)(trifluoro)boron (6.2 mL, 48.9
mmol) in THF (50 mL). The resulting mixture was then heated to 70 oC and stirred at this
temperature for 4 hours before being cooled to room temperature and allowed to stand
overnight. The resulting reaction mixture was quenched by the addition of water (100
mL) before being extracted with ethyl acetate (3 x 30 mL). The combined organic extracts
were washed sequentially with water (100 mL) and brine (100 mL) before being dried
(MgSO4), filtered and concentrated. The resulting residue was purified on a Biotage
isolera (5% ethyl acetate, 95% heptanes) to give the desired compound (4.8 g, 76% yield)
as a colourless oil. Tr = 2.44min m/z (ES+) (M+H+) 246/248.
Referring to Reaction Scheme 25, Stage 2. Sodium hydride (60%
dispersion in oil, 0.29 g, 7.28 mmol) was added in one portion to a cooled (0 ºC) stirred
solution of 4-bromochloro-N-cyclopropylaniline (1.4 g, 5.68 mmol) in dry DMF (35
mL) and the resulting solution was stirred for 5 minutes. After this time, iodomethane
(0.35 mL, 5.62 mmol) was added and the reaction mixture was stirred for 10 minutes
before being allowed to warm to room temperature and stirred for a further 6 hours under
a nitrogen atmosphere. The resulting reaction mixture was extracted with ethyl acetate (3
x 25 mL) and the organic layer washed sequentially with water (75 mL) and brine (75 ml)
before being dried (MgSO4), filtered and concentrated. The resulting residue was purified
by dry flash chromatography (elution: 100% heptanes) to give the desired compound
(1.44 g, 78% yield) as a colourless oil. δH (500 MHz, DMSO) 7.56 (d, J = 2.36 Hz, 1 H),
7.46 (dd, J = 8.67, 2.36 Hz, 1 H), 7.31 (d, J = 8.67 Hz, 1 H), 2.81 (s, 3 H), 2.53 - 2.58 (m,
1 H), 0.63 - 0.69 (m, 2 H), 0.27 - 0.33 (m, 2 H).
Referring to Reaction Scheme 25, Stages 3, 4 & 5 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
289.72 [M+H]+ = 290/292, 98%@ rt = 3.77 min
303.75 [M+H]+= 304/306, 100% @ rt = 4.40 min
CH Cl
Example 26
Reaction Scheme 26
Referring to Reaction Scheme 26, Stage 1. Bromine (0.54 mL, 10.4 mmol)
was added drop wise to a cooled (0 oC), stirred solution of 2-aminochlorophenol (1.0
g, 6.97 mmol) in DCM (50 mL) and the resulting solution was warmed to room
temperature and stirred for 16 hours. After this time, the reaction mixture was cooled in
an ice-bath and bromine (0.11 mL, 2.09 mmol) was added before being warmed to room
temperature and stirred for a further 1 hour. The resulting solid precipitate was collected
by filtration, suspended in DCM (100 mL) and washed with saturated sodium bicarbonate
(50 mL). The organic layer was removed, washed sequentially with water (10 mL) and
brine (10 mL), before being dried (MgSO4), filtered and concentrated to give the desired
compound (1.0 g, 64% yield) as a red solid. δH (500 MHz, DMSO) 10.13 (br. s., 1 H),
6.89 (d, J = 2.21 Hz, 1 H), 6.75 (d, J = 2.21 Hz, 1 H), 4.82 (br. s., 2 H).
Referring to Reaction Scheme 26, Stage 2. p-Toluene sulfonic acid (0.02 g,
0.12 mmol) was added in one portion to a stirred solution of 2-aminobromo
chlorophenol (0.9 g, 4.05 mmol) in triethylorthoacetate (10 mL) and the resulting
reaction mixture was heated to 140 °C and stirred at this temperature for 18 hours. After
this time, the reaction mixture was cooled to room temperature and partitioned between
water (10 mL) and ethyl acetate (20 mL). The organic layer was removed, washed
sequentially with water (10 mL), saturated sodium bicarbonate (2 x 20 mL) and brine (10
mL) before being dried (MgSO4), filtered and concentrated. The resulting residue was
purified on a Biotage isolera (0% ethyl acetate, 100% heptanes to 40% ethyl acetate, 60%
heptanes) to give the desired compound (0.68 g, 48% yield) as a red solid. δH (500 MHz,
CDCl3) 7.58 (d, J = 1.42 Hz, 1 H), 7.50 (d, J = 1.58 Hz, 1 H), 2.61 - 2.73 (m, 3 H).
Referring to Reaction Scheme 26, Stages 3, 4 & 5 were carried out as
described in Reaction Scheme 15.
The following compounds were prepared substantially as described above.
Structure Molecular Weight Mass Spec Result
289.67 [M+H]+=290/292 100% @ rt = 3.26min
Example 27
The following compounds may be prepared substantially as described
above.
6-(3-chloro{[1-(morpholinyl)propan
yl]oxy}phenyl)pyrimidinecarboxylic acid
O 6-[3-chloro(cyclopropoxymethyl)phenyl]pyrimidine-
4-carboxylic acid
6-[3-chloro(cyclopropylmethyl)phenyl]pyrimidine
carboxylic acid
6-[3-chloro(cyclopropylsulfanyl)phenyl]pyrimidine-
4-carboxylic acid
6-[3-chloro(cyclopropanesulfinyl)phenyl]pyrimidine-
4-carboxylic acid
O Cl
6-[3-chloro(cyclopropanesulfonyl)phenyl]pyrimidine-
4-carboxylic acid
6-{3-chloro
[cyclopropyl(hydroxy)methyl]phenyl}pyrimidine
carboxylic acid
6-[3-chloro(1-cyclopropoxyethyl)phenyl]pyrimidine-
4-carboxylic acid
6-(3-chlorocyclopropanecarbonylphenyl)pyrimidine-
4-carboxylic acid
6-(3-chlorocyclopropylphenyl)pyrimidine
carboxylic acid
6-[4-(aziridinylmethyl)chlorophenyl]pyrimidine
carboxylic acid
6-{3-chloro
[(dimethylamino)methyl]phenyl}pyrimidine
carboxylic acid
6-[3-chloro(cyclopropylamino)phenyl]pyrimidine
H carboxylic acid
6-{3-chloro
N [cyclopropyl(methyl)amino]phenyl}pyrimidine
CH Cl
3 carboxylic acid
6-{3-chloro
[(cyclopropylamino)methyl]phenyl}pyrimidine
carboxylic acid
6-(3-chloro
{[cyclopropyl(methyl)amino]methyl}phenyl)pyrimidine-
4-carboxylic acid
6-(7-chlorocyclopropyl-2,3-dihydro-1H-isoindol
yl)pyrimidinecarboxylic acid
6-[3-chloro(furanyl)phenyl]pyrimidine
carboxylic acid
O Cl
6-[3-chloro(1-
methoxycyclopropyl)phenyl]pyrimidinecarboxylic
Cl acid
6-(2,3-dihydro-1,4-benzodioxinyl)pyrimidine
carboxylic acid
6-(7-chloromethyl-1,3-benzoxazolyl)pyrimidine
carboxylic acid
6-(7-chlorooxo-2,3-dihydro-1,3-benzoxazol
Cl yl)pyrimidinecarboxylic acid
6-(7-chloromethyloxo-2,3-dihydro-1,3-
benzoxazolyl)pyrimidinecarboxylic acid
6-(7-chlorocyclopropyl-1,3-benzoxazol
yl)pyrimidinecarboxylic acid
6-{8-chloroimidazo[1,2-a]pyridinyl}pyrimidine
carboxylic acid
6-(4-chloro-1,3-benzoxazolyl)pyrimidine
carboxylic acid
O 6-(quinolinyl)pyrimidinecarboxylic acid
6-{pyrazolo[1,5-a]pyridinyl}pyrimidinecarboxylic
N acid
O 6-(4-chlorocyclopropoxyphenyl)pyrimidine
carboxylic acid
6-(4-chloromethoxyphenyl)pyrimidinecarboxylic
acid
6-[4-chloro(propanyloxy)phenyl]pyrimidine
O carboxylic acid
6-[4-chloro(2-methylpropoxy)phenyl]pyrimidine
carboxylic acid
6-[4-chloro(trifluoromethoxy)phenyl]pyrimidine
carboxylic acid
Cl 6-{4-chloro[(1,1,1-trifluoropropan
O yl)oxy]phenyl}pyrimidinecarboxylic acid
6-(benzo[d][1,3]dioxolyl)pyrimidinecarboxylic
acid
6-(2,2-difluorobenzo[d][1,3]dioxolyl)pyrimidine
carboxylic acid
6-(2,3-dihydrobenzo[b][1,4]dioxinyl)pyrimidine
carboxylic acid
6-(7-chlorobenzo[b]thiophenyl)pyrimidine
carboxylic acid
6-(7-chlorobenzo[d]thiazolyl)pyrimidinecarboxylic
S acid
6-(7-chlorobenzo[d]oxazolyl)pyrimidinecarboxylic
O acid
6-(7-chlorobenzo[c][1,2,5]oxadiazolyl)pyrimidine
carboxylic acid
6-(7-chloro-2,3,3a,7a-tetrahydrobenzofuran
yl)pyrimidinecarboxylic acid
6-(7-chloro-3a,7a-dihydro-1H-indolyl)pyrimidine
carboxylic acid
6-(7-chloromethyl-3a,7a-dihydro-1H-indazol
yl)pyrimidinecarboxylic acid
6-(8-chloroquinazolinyl)pyrimidinecarboxylic acid
6-(5-chloroquinazolinyl)pyrimidinecarboxylic acid
O 6-(8-chloroquinoxalinyl)pyrimidinecarboxylic acid
6-(7-chloro-1H-benzo[d]imidazolyl)pyrimidine
carboxylic acid
6-(3-chloro(1-methylcyclopropyl)phenyl)pyrimidine-
4-carboxylic acid
6-(3-chloro(1-
(trifluoromethyl)cyclopropyl)phenyl)pyrimidine
carboxylic acid
CF Cl
6-(3-chloro(3-methyloxetanyl)phenyl)pyrimidine-
4-carboxylic acid
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidine
carboxylic acid
O 6-(3-chloro(pyrrolidinyl)phenyl)pyrimidine
carboxylic acid
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidine
carboxylic acid
N Cl
6-(3-chloro(1H-imidazolyl)phenyl)pyrimidine
carboxylic acid
N Cl
6-(3-chloro(1H-pyrrolyl)phenyl)pyrimidine
carboxylic acid
N Cl
6-(4-tert-butylchlorophenyl)pyrimidinecarboxylic
acid
7-chlorocyclopropoxy-5H-chromeno[4,3-
d]pyrimidinecarboxylic acid
Example 28
A generalized procedure for monitoring L-Kynurenine (KYN)
hydroxylation to form product 3-Hydroxy-Kynurenine (3OH-KYN) by LC/MS is
described below. Product is quantified by multiple reaction monitoring using MS.
Key reagents:
Compound: Stock concentrations: 10mM in 100% DMSO
Cell line: CHO GST HIS KMO cell line, 1E4 cells/well/100µl in 96well
cell plate
Substrate: L-Kynurenine (Sigma: Cat# K3750, stock concentration:
10mM in 100 mM potassium phosphate buffer, pH 7.4)
Assay conditions:
Medium: OptiMem (Reduced Serum Medium 1x, +L-Glutamine +
HEPES – Phenol Red; GIBCO: Cat# 11058)
Assay Volume: 200 µl
Plate Format: 96 well plate, transparent (Corning)
Read-Out: product (3OH-KYN) quantification using product specific
Reader: LC/MS/MS
Assay protocol:
o prepare serial dilution (factor 3) of compound in 100% DMSO (top concentration =
6.67mM, 100% DMSO)
[8 points: 6.67mM; 2.22mM; 0.74mM; 0.247mM; 0.082mM; 0.027mM; 0.009mM;
0.003mM]
o prepare 300-fold concentrated solution of each compound concentration (top
concentration 22.22µM, 0.3% DMSO)in OptiMem medium
[22.2µM; 7.41µM; 2.47µM; 0.82 µM; 0.27µM; 0.09µM; 0.03µM; 0.01µM]
o prepare substrate (10mM) at concentration of 1.1mM in medium
o medium of cell plate is drawed off
o cells are washed with OptiMem (100µl/well) and drawed off again
o assay mix: 90µl OptiMem/well + 90µl compound/well of each concentration
[final compound top concentration: 10µM; 0.15%DMSO]
[final compound bottom concentration: 0.004µM; 0.15%DMSO]
o pre-incubation: 30min at 37°C
o add 20µl/well of the 1.1mM substrate solution (final assay concentration: 100µM)
o positive control: 200µl OptiMem
o negative control: 180µl OptiMem + 20µl 1.1mM substrate
o incubate ~24h at 37°C
o transfer 100µl of each well in a transparent 96well plate (Corning)
o add 100µl/well 10% trichloro acetic acid (TCA) in water
o centrifugate plate for 3min at 4000rpm
o detect product by LC/MS (injection of 50µl/well; 2.5fold overfill of the 20µl sample
loop)
Data analysis: IC ´s are calculated using automated fitting algorithm (A+
Analysis).
Example 29
A method of monitoring L-Kynurenine (KYN) hydroxylation to form
product 3-Hydroxy-Kynurenine (3OH-KYN) by LC/MS is described below. Product is
quantified by multiple reaction monitoring.
Key reagents:
Compound: Stock concentrations: 10mM in 100% DMSO
Enzyme: KMO enzyme prepared at Evotec via mitochondria isolation
from CHO-GST HIS KMO cells
Substrate: L-Kynurenine (Sigma: Cat# K3750)
[stock concentration: 10mM in 100 mM potassium phosphate
buffer, pH 7.4]
Assay conditions:
Buffer: 100 mM potassium phosphate, pH 7.4, 200µM NADPH,
0.4U/ml G6P-DH (Glucose 6-phosphate dehydrogenase), 3mM
G6P (D-Glucose 6-phosphate)
Assay Volume: 40 µl
Plate Format: 384 well plate, transparent (Matrix)
Read-Out: product (3OH-KYN) quantification using product specific
Reader: LC/MS/MS
Assay protocol:
o prepare serial dilution (factor 3)of compound in 100% DMSO (top concentration =
10mM, 100% DMSO)
[8 points: 10mM; 3.33mM; 1.11mM; 0.37mM; 0.12mM; 0.04mM; 0.0137mM; 0.0045mM,
0.0015mM]
o prepare 3.33-fold concentrated solution of each compound concentration (top
concentration 300µM, 3% DMSO)in assay buffer
[concentrations: 300µM; 100µM; 33.3µM; 11.1µM; 3.70µM; 1.23µM; 0.41µM; 0.137µM]
o prepare substrate (10mM) at concentration of 1mM in assay buffer
o assay mix: 4µl compound/well of each concentration + 24µl assay buffer/well + 8µl
KMO human enzyme + 4µl 1mM substrate (final concentration=100µM)
[final compound top concentration: 30µM; 0.3%DMSO]
[final compound bottom concentration: 0.0137µM; 0.3%DMSO]
o positive control: 4µl 50µM FCE28833 in assay buffer [0.5%DMSO] (final assay
concentration=5µM) + 24µl assay buffer/well + 8µl KMO human enzyme + 4µl 1mM
substrate (final concentration=100µM)
o negative control: 28µl assay buffer/well + 8µl KMO human enzyme + 4µl 1mM
substrate (final concentration=100µM)
o incubate 400min at RT
o add 40µl/well 10% trichloro acetic acid in water to stop the assay and precipitate
protein
o centrifuge plate for 3min at 4000rpm
o product detection by LC/MS (injection of 50µl/well; 2.5fold overfill of the 20µl
sample loop)
Data analysis: IC ´s are calculated using automated fitting algorithm (A+
Analysis).
Example 30
A method of monitoring L-Kynurenine (KYN) hydroxylation to form 3-
Hydroxy-Kynurenine (3OH-KYN) by LC/MS is described. Product is quantified by
multiple reaction monitoring (MRM method).
Key reagents:
Compound: Stock concentrations: 10mM in 100% DMSO
Enzyme: KMO enzyme prepared at Evotec from mouse liver (4-6 weeks
old) via mitochondria isolation as described in the literature
Substrate: L-Kynurenine (Sigma: Cat# K3750, stock concentration:
10mM in 100 mM potassium phosphate buffer, pH 7.4)
Assay conditions:
Buffer: 100 mM potassium phosphate, pH 7.4, 200µM NADPH,
0.4U/ml G6P-DH (Glucose 6-phosphate Dehydrogenase), 3mM
G6P (D-Glucose 6-phosphate)
Assay Volume: 40 µl
Plate Format: 384 well plate, transparent (Matrix)
Read-Out: product (3OH-KYN) quantification using product specific
Reader: LC/MS/MS
Assay protocol:
o prepare serial dilution (factor 3)of compound in 100% DMSO (top concentration =
10mM, 100% DMSO)
[8 points: 10mM; 3.33mM; 1.11mM; 0.37mM; 0.12mM; 0.04mM; 0.0137mM; 0.0045mM,
0.0015mM]
o prepare 3.33-fold concentrated solution of each compound concentration (top
concentration 300µM, 3% DMSO)in assay buffer
[concentrations: 300µM; 100µM; 33.3µM; 11.1µM; 3.70µM; 1.23µM; 0.41µM; 0.137µM]
o prepare substrate (10mM) at concentration of 1mM in assay buffer
o assay mix: 4µl compound/well of each concentration + 24µl assaybuffer/well + 8µl
KMO mouse enzyme + 4µl 1mM substrate (final concentration=100µM)
[final compound top concentration: 30µM; 0.3%DMSO]
[final compound bottom concentration: 0.0137µM; 0.3%DMSO]
o positive control: 4µl 50µM FCE28833 in assay buffer, 0.5%DMSO [final assay
concentration=5µM] + 24µl assaybuffer/well + 8µl KMO mouse enzyme + 4µl 1mM
substrate [final concentration=100µM]
o negative control: 28µl assay buffer/well + 8µl KMO mouse enzyme + 4µl 1mM
substrate [final concentration=100µM]
o incubate 40min at RT
o add 40µl/well 10% trichloro acetic acid in water to stop the assay and precipitate
protein
o centrifuge plate for 3min at 4000rpm
o product detection by LC/MS (injection of 20µl/well, 2fold overfill of the 10µl sample
loop)
Data analysis: IC ´s are calculated using automated fitting algorithm (A+
Analysis).
Example 31
Using procedures similar to those described herein, the following
compounds were assayed for activity.
IUPAC name % Inhibition at 10uM*
6-(4-Chloromethoxy-phenyl)-pyrimidinecarboxylic 99.62
acid
6-(3-Aminochloro-phenyl)-pyrimidinecarboxylic 101.01
acid
6-[4-Chloro(tetrahydro-furanyloxy)-phenyl]- 88.39
pyrimidinecarboxylic acid pyridinylamide
6-[4-Chloro(2-morpholinyl-ethoxy)-phenyl]- 61.41
pyrimidinecarboxylic acid hydrochloride salt
6-(3-Chloroisopropyl-phenyl)-pyrimidinecarboxylic 100
acid
6-(3-Fluoromethyl-phenyl)-pyrimidinecarboxylic 100
IUPAC name % Inhibition at 10uM*
acid
6-(3-Chloroisopropoxy-phenyl)-pyrimidine 100
carboxylic acid
6-(3-Chloroisopropoxy-phenyl)methyl-pyrimidine 70
carboxylic acid
6-(3-Fluoromethyl-phenyl)methyl-pyrimidine 96
carboxylic acid
6-(3-Chlorocyclopentyloxy-phenyl)-pyrimidine 97
carboxylic acid
6-(3-Chlorotrifluoromethoxy-phenyl)-pyrimidine 100
carboxylic acid
6-(3-Fluoroisopropyl-phenyl)-pyrimidinecarboxylic 85
acid
6-(4-(R)-sec-Butoxychloro-phenyl)-pyrimidine 100
carboxylic acid
6-(4-(S)-sec-Butoxychloro-phenyl)-pyrimidine 100
carboxylic acid
6-(3-Chlorocyclopropoxy-phenyl)-pyrimidine 100
carboxylic acid
6-[3-Chloro(2,2,2-trifluoromethyl-ethoxy)-phenyl]- 94
pyrimidinecarboxylic acid
4-(3-Chlorocyclopropoxy-phenyl)-pyridine 100
carboxylic acid
6-(4-(R)-sec-Butoxychloro-phenyl)-pyridine 50
carboxylic acid
6-(4-(S)-sec-Butoxychloro-phenyl)-pyridine 82
carboxylic acid
4-(3-Chloroisopropoxy-phenyl)-pyridinecarboxylic 80
acid
4-(3-Chlorotrifluoromethoxy-phenyl)-pyridine 89
carboxylic acid
6-(3-Chlorocyclobutoxy-phenyl)-pyrimidine 100
carboxylic acid
6-[3-Chloro(2-piperidinyl-ethoxy)-phenyl]- 90
pyrimidinecarboxylic acid
6-Quinolinyl-pyrimidinecarboxylic acid 100
6-(8-Chloro-chromanyl)-pyrimidinecarboxylic acid 100
6-(7-Chloro-benzofuranyl)-pyrimidinecarboxylic 100
acid
6-[3-Chloro(pyrrolidinyloxy)-phenyl]-pyrimidine 80
carboxylic acid
6-(8-chloromethyl-1,2,3,4-tetrahydroquinolin 100
yl)pyrimidinecarboxylic acid
6-(8-chloroquinolinyl)pyrimidinecarboxylate 100
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidin 73
yl]benzenesulfonamide
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl] 98
fluorobenzenesulfonamide
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl] 88
IUPAC name % Inhibition at 10uM*
(trifluoromethoxy)benzenesulfonamide
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl] 77
(trifluoromethoxy)benzenesulfonamide
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidinyl] 96
fluorobenzenesulfonamide
N-[6-(3-chlorocyclopropoxyphenyl)pyrimidin 33
yl]cyclopropanesulfonamide
6-(8-chloro-1,2,3,4-tetrahydroquinolinyl)pyrimidine 100
carboxylate
6-(3-chlorocyclopropoxyphenyl)methylpyrimidine- 100
4-carboxylate
6-{3-chloro[2-(morpholin 99
yl)ethoxy]phenyl}pyrimidinecarboxylate
6-[3-chloro(cyclopropylmethoxy)phenyl]pyrimidine 101
carboxylate
6-[3-chloro(oxetanyloxy)phenyl]pyrimidine 100
carboxylate
4-(3-chlorocyclopropoxyphenyl)-5H,7H-furo[3,4- 100
d]pyrimidinone
6-(3-chlorocyclopropoxyphenyl) 100
(hydroxymethyl)pyrimidinecarboxylic acid
4-(3-chlorocyclopropoxyphenyl)-5H,6H,8H- 100
pyrano[3,4-d]pyrimidinone
[(2R,3S,4S,5R)-3,4,5,6-tetrahydroxyoxanyl]methyl 6- 102
(3-chlorocyclopropoxyphenyl)pyrimidinecarboxylate
6-[3-chloro(methylsulfanyl)phenyl]pyrimidine 103
carboxylic acid
6-[3-chloro(methylsulfinyl)phenyl]pyrimidine 100
carboxylic acid
6-[3-chloro(methylsulfonyl)phenyl]pyrimidine 100
carboxylic acid
6-{3-chloro 90
[cyclopropyl(hydroxy)methyl]phenyl}pyrimidine
carboxylic acid
6-(3-chlorocyclopropanecarbonylphenyl)pyrimidine 101
carboxylic acid
6-[3-chloro(methoxymethyl)phenyl]pyrimidine 105
carboxylic acid
6-[3-chloro(1-methoxyethyl)phenyl]pyrimidine 101
carboxylic acid
6-{3-chloro 65
[(dimethylamino)methyl]phenyl}pyrimidinecarboxylic
acid
6-[3-chloro(cyclopropylamino)phenyl]pyrimidine 101
carboxylic acid
6-{3-chloro 96
[cyclopropyl(methyl)amino]phenyl}pyrimidine
carboxylic acid
6-(3-chloro(pyrrolidinyl)phenyl)pyrimidine 100
IUPAC name % Inhibition at 10uM*
carboxylic acid
6-(7-chloromethyl-1,3-benzoxazolyl)pyrimidine 102
carboxylic acid
6-(8-chloroquinoxalinyl)pyrimidinecarboxylic acid 102
6-(7-chloro-2,3-dihydrobenzofuranyl)pyrimidine 102
carboxylic acid
6-(7-chlorocyclopropyl-1,3-benzoxazol 100
yl)pyrimidinecarboxylic acid
6-(4-chloromethyl-1,3-benzoxazolyl)pyrimidine 102
carboxylic acid
6-(7-chloromethyloxo-2,3-dihydro-1,3-benzoxazol- 100
-yl)pyrimidinecarboxylic acid
6-(2H-1,3-benzodioxolyl)pyrimidinecarboxylic acid 101
* Some portion of activity of amides may be due to contribution of acid precursor.
Example 32: General procedures
Method A. Amide coupling. To a solution of carboxylic acid (1eq) in
DMF were added EDC.HCl (1eq) and HOBt (1 to 1.2eq) or HATU (1 to 1.2eq). The
reaction mixture was stirred at ambient temperature for 30 minutes after which time the
appropriate amine (1eq) was added. The reaction was monitored by LCMS to completion
whereupon the reaction mixture was poured into water. The resultant precipitate was
filtered, washed with water (x 2), heptane (x 2) and dried in vacuo to yield the target
compound. If a precipitate was not formed the reaction mixture was extracted with EtOAc
(x 3) and the combined organic layers were washed with water (x 2), saturated aqueous
NaCl (x 2), dried (Na2SO4 or MgSO4) and the solvent removed in vacuo to afford the
crude product. Purification was carried out by flash column chromatography, prep HPLC,
or a combination of both.
Method B. Amide coupling. To a solution of carboxylic acid (1eq) in
DCM (20vol) under nitrogen were added oxalyl chloride (3eq) and 1 drop of DMF (cat.).
The reaction mixture was stirred at ambient temperature for 30 minutes after which time
the solvents were removed in vacuo. DCM (20vol) or THF (20vol) was added, followed
by the required amine (1 to 3eq) and triethylamine (2eq) or DIPEA (1.5eq). The reaction
mixture was stirred at ambient temperature. The reaction was monitored by LCMS to
completion whereupon water was added. The reaction mixture was then extracted with
DCM and the organic layer was washed with water, saturated aqueous NaCl, dried over
Na2SO4 or MgSO4 and the solvent removed in vacuo to afford the crude product.
Purification was carried out by flash column chromatography, prep HPLC, a combination
of both or by trituration with an appropriate solvent.
Method C. Amide coupling. To a solution of carboxylic acid (1eq) in
DMF were added EDC.HCl (1eq) and HOBt (1eq). The reaction mixture was stirred at
ambient temperature for 30 minutes after which time the appropriate amine was added.
The reaction was monitored by LCMS. After completion the reaction mixture was poured
into water after which a precipitate came out of solution and was filtered, washed with
water, heptane and dried in vacuo to yield the target compound or if a precipitate was not
formed the reaction mixture was extracted with EtOAc (3 X) and the combined organic
layers were washed with water, saturated aqueous NaCl, dried (Na2SO4 or MgSO4) and
the solvent removed in vacuo to afford the crude product. Purification was carried out by
flash column chromatography, prep HPLC, or a combination of both.
Method D. Amide coupling. To a solution of carboxylic acid (1eq) in
DCM (20vol) under nitrogen were added oxalyl chloride (3eq) and DMF (cat). The
reaction mixture was stirred at ambient temperature for 30 minutes after which time the
solvents were removed in vacuo. DCM (20vol) or THF (20vol) was added, followed by
the required amine (1 to 3eq) and triethylamine (2eq) and the reaction mixture was stirred
at ambient temperature. The reaction was monitored by LCMS to completion whereupon
water was added. The reaction mixture was then extracted with DCM and the organic
layer was washed with water, saturated aqueous NaCl, dried over Na2SO4 or MgSO4 and
the solvent removed in vacuo to afford the crude product. Purification was carried out by
flash column chromatography, prep HPLC, a combination of both or by trituration with
an appropriate solvent.
While some embodiments have been shown and described, various
modifications and substitutions may be made thereto without departing from the spirit and
scope of the invention. For example, for claim construction purposes, it is not intended
that the claims set forth hereinafter be construed in any way narrower than the literal
language thereof, and it is thus not intended that exemplary embodiments from the
specification be read into the claims. Accordingly, it is to be understood that the present
invention has been described by way of illustration and not limitations on the scope of the
claims.
The reference in this specification to any prior publication (or information
derived from it), or to any matter which is known, is not, and should not be taken as an
acknowledgment or admission or any form of suggestion that that prior publication (or
information derived from it) or known matter forms part of the common general
knowledge in the field of endeavour to which this specification relates.
Throughout this specification and the claims which follow, unless the
context requires otherwise, the word "comprise", and variations such as "comprises" and
"comprising", will be understood to imply the inclusion of a stated integer or step or
group of integers or steps but not the exclusion of any other integer or step or group of
integers or steps.
Claims (5)
1. Use of 6-(3-chlorocyclopropoxy-phenyl)-pyrimidinecarboxylic acid, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disorder mediated by Kynurenine 3-mono- oxygenase activity in a subject in need of such a treatment.
2. The use of claim 1 wherein said condition or disorder involves a neurodegenerative pathology.
3. The use of claim 1 wherein said disease or condition is selected from: Huntington’s disease, spinocerebellar ataxias neurodegenerative diseases, psychiatric or neurological diseases or disorders, Alzheimer's disease, Parkinson's disease, amyotropic lateral sclerosis, Creutzfeld- Jacob disease, trauma-induced neurodegeneration, high- pressure neurological syndrome, dystonia, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consequences of stroke, cerebral ischemia, ischemic disorders including stroke (focal ischemia), hypoxia, multi-infarct dementia, consequences of cerebral trauma or damage, damage to the spinal cord, Dementia, senile dementia, AIDS-dementia complex, AIDS-induced encephalopathy, other infection related encephalopathy, viral or bacterial meningitis, infectious diseases caused by viral, bacterial and other parasites, general central nervous system (CNS) infections such as viral, bacterial or parasites, poliomyelitis, Lyme disease (Borrelia burgdorferi infection), septic shock, malaria, cancers, cancers with cerebral localization, hepatic encephalopathy, systemic lupus, analgesia and opiate withdrawal symptoms, feeding behavior, psychiatric disorders, insomnia, depression, schizophrenia, severe deficit in working memory, severe deficit in long term memory storage, decrease incognition, severe deficit in attention, severe deficit in executive functioning, slowness in information processing, slowness in neural activity, anxiety, generalized anxiety disorders, panic anxiety, obsessive compulsive disorders, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, adjustment reaction, separation anxiety disorder, alcohol withdrawal anxiety, depressive disorders, disorders of the developing or aged brain, diabetes, Tourette's syndrome, Fragile X syndrome, autism spectrum disorders, disorders that cause severe and pervasive impairment in thinking, feeling, language and the ability to relate to others, mood disorders, psychological disorders characterized by abnormalities of emotional state, bipolar disorder, unipolar depression, major depression, ondougenous depression, involutional depression, reactive depression, psychotic depression, depression caused by underlying medical conditions, depressive disorders, cyclothymic disorders, dysthymic disorders, mood disorders due to general medical condition, mood disorders not otherwise specified and substance-induced mood disorders, Acute necrotizing Pancreatitis, AIDS (disease), Analgesia, Aseptic meningitis, Brain disease, Gilles de la Tourette syndrome, Asperger syndrome, Rett syndrome, pervasive developmental disorders, aging-related Brain disease, and developmental Brain disease, burnout syndrome, carbon monoxide poisoning, cardiac arrest or insufficiency and hemorrhagic shock (global brain ischemia), cataract formation and aging of the eye, Central nervous system disease, Cerebrovascular disease, chronic fatigue syndrome, Chronic Stress, Cognitive disorders, convulsive Disorders, variants of Grand mal and petit mal epilepsy and Partial Complex Epilepsy, Diabetes mellitus, disease of the nervous system, dyskinesia, L-DOPA induced movement disorders, drug addiction, pain and cataract, Drug dependence, Drug withdrawal, feeding disorders, Guillain Ban-Syndrome and other neurophaties, Hepatic encephalopathy, Immune disease, immunitary disorders and therapeutic treatment aimed at modifying biological responses (administrations of interferons or interleukins), Inflammation (systemic inflammatory response syndrome), inflammatory disorders of the central and/or peripheral nervous system, Injury (trauma, polytrauma), Mental and behavioral disorders, Metabolic disease, pain disease, inflammatory pain, neuropathic pain, migraine, allodynia, hyperalgesis pain, phantom pain, neuropathic pain related to diabetic neuropathy, Multiple organ failure, near drowning, Necrosis, neoplasms of the brain, neoplastic disorders including lymphomas and other malignant blood disorders, Nervous system disease (high-pressure neurol. Syndrome, infection), nicotine addiction, alcoholism, cannabis addiction, benzodiazepine addiction, barbiturate addiction, morphine addiction, cocaine dependence, change in appetite, sleep disorders, changes in sleep pattern, lack of energy, fatigue, low self esteem, self-reproach inappropriate guilt, frequent thoughts of death or suicide, plans or attempts to commit suicide, feelings of hopelessness and worthlessness, psychomotor agitation or retardation, diminished capacity for thinking, concentration, or decisiveness, Neuroprotective agents, Pain, Post-traumatic stress disorder, Sepsis, Spinal cord disease, Spinocerebellar ataxia, Systemic lupus erythematosis, traumatic damage to the brain and spinal cord, tremor syndromes and different movement disorders (diskynesia), poor balance, brakykinesia, rigidity, tremor, change in speech, loss of facial expression, micrographia, difficulty swallowing, drooling, dementia, confussion, fear, sexual disfunction, language impairment, impairment in decision making, violent outbursts, aggression, hallucination, apathy, impairment in abstract thinking, cardiovascular diseases, dyslipoproteinemia, dyslipidemias, cardiomegaly, atherosclerosis, myocardial infarction, congestive heart failure, coronary heart disease, hypertension, hypotension, benign hyperproliferative diseases, malignant hyperproliferative diseases, angiomas, endometriosis, obesity, Age-related Macular Degeneration, retinopathy, proliferation of ECs and smooth muscle cells that cause restenosis as a consequence of stenting in the treatment of atherosclerosis, hyperproliferative disorders involving fibroblasts cardiac remodeling and failure associated with myocardial infarction, excessive wound healing, transplant rejection, graft versus host disease, chronic kidney disease, systemic inflammatory disorders, and brain inflammatory disorders including malaria and African trypanosomiasis, stroke, and pneumococcal meningitis.
4. Use according to claim 3, wherein the disease or condition is acute necrotizing pancreatitis, disorders of the developing or aged brain, psychiatric disorders, Alzheimer's disease, inflammation, cancer, schizophrenia, neurodegenerative disease, or transplant rejection.
5. Use of a compound of formula: or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Huntington’s disease.
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US201161528998P | 2011-08-30 | 2011-08-30 | |
US61/528,998 | 2011-08-30 | ||
NZ621471A NZ621471B2 (en) | 2011-08-30 | 2012-08-28 | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
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