IMIDAZOPYRIDAZINE DERIVATIVES AS GABAA RECEPTOR MODULATORS
Field of the Invention
The present invention relates to imidazopyridazine derivatives. More particularly, it
relates to 4-(biphenyl-3-yl)-7H-imidazo[4,5-c]pyridazine derivatives. The
imidazopyridazine derivatives of the present invention modulate the activity of the
GABAA receptor. They are useful in the treatment of a number of conditions,
including pain.
Background
Gamma-am inobutyric acid (GABA) has been identified as a major inhibitory
neurotransmitter, and agents that modulate GABAergic neurotransmission are used
extensively in the treatment of conditions such as epilepsy, anxiety and depression.
Two families of GABA receptor have been described, termed GABAA and GABAB.
The GABAA receptor is a member of the ligand-gated ion channel superfamily. The
functional receptor generally comprises a number of subunits. At least 16 such
subunits have been characterized, including 6 alpha subunits (a -6 ) , 3 beta subunits
(b _3) , 3 gamma subunits ( 1-3) , and delta, epsilon, pi and theta subunits (d, e, p, q) .
Most GABAA receptors are made up of 2 alpha, 2 beta and one gamma subunit.
Several drug binding sites have been described. These include the binding site for
the endogenous ligand (GABA), and allosteric binding sites. Drugs that bind at the
allosteric binding sites may be positive allosteric modulators, which increase
responsiveness, negative allosteric modulators, which decrease receptor
responsiveness, or neutral, which term refers to compounds that bind to the allosteric
binding sites without modulating the activity of the receptor. Recent evidence has
suggested that GABAA receptors comprising either the a 2 or a 3 subunit (herein
termed GABAA 2/3 receptors) may be involved in certain pain states, and that
positive allosteric modulators of these receptors may be useful analgesics (Mirza,
N R. and Munro, G., Drug News and Perspectives, 201 0 , 23(6), 351-360).
4-(Biphenyl-3-yl)-7H-imidazo[4,5-c]pyridazine derivatives have not been reported as
having an interaction with GABA A 2 / 3 receptors. International patent applications
PCT/GB01/04948 (published as WO2002/038568) and PCT/GB 02/031 4 (published
as WO2003/00841 8) disclose 7-phenylimidazo[1 ,2-Jb][1 ,2,4]triazine derivatives that
have affinity for the 2 , 3 and/or s subunits. International patent application
PCT/US99/14935 (published as WO2000/001697) discloses inter alia 4-phenyl-7Himidazo[
4,5-c]pyridazine derivatives which are corticotrophin releasing factor
antagonists.
There is a continuing interest in finding new compounds that interact with GABA A
receptors, and particularly for compounds that have a reduced propensity for causing
the adverse events such as drowsiness that are associated with the currently
available GABA A modulators such as benzodiazepines. It is thought that these
adverse effects are a result of modulation of subunit-containing receptors, and so
preferred compounds will have a high affinity for the a 2 / 3 subunit-containing receptors
with good efficacy as positive allosteric modulators, while having low efficacy at
receptors with other a subunits, particularly the subunit-containing receptors.
These drug candidates should additionally have one or more of the following
properties: be well absorbed from the gastrointestinal tract; be metabolically stable;
have a good metabolic profile, in particular with respect to the toxicity or allergenicity
of any metabolites formed; or possess favourable pharmacokinetic properties whilst
still retaining their activity profile. They should be non-toxic and demonstrate few
side-effects. Ideal drug candidates should exist in a physical form that is stable, nonhygroscopic
and easily formulated.
Summary of the Invention
In a first aspect, the present invention provides a compound of formula (I)
(I)
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from ( -C4)alkyl, (C3-C4)cycloalkyl, NH2, and NH(d-C 4)alkyl
and R2 is H; or
R and R2 together are -CH 2-CH2- or -N(CH 3)-CH 2- ;
R3 is selected from H, F, CHF2, OCH3 and CN;
R4 is selected from H, F, CI, OH, OCH3 and CN; and
R5 is selected from (C2-C4)alkyl, (C3-C5)cycloalkyl and methyl-substituted (C3-
C 5)cycloalkyl,
The compounds of formula (I) and their pharmaceutically acceptable salts are referred
to herein as "the compounds of the invention". The definition above is referred to
herein as embodiment E1 of this aspect. Further embodiments of this aspect of the
invention are described in detail below.
In another aspect, the invention provides for a compound of formula (I) as described
above, or in any one of the preferred embodiments, or a pharmaceutically acceptable
salt thereof, for use as a medicament. In an embodiment according to this aspect the
compound of formula (I), or a pharmaceutically acceptable salt thereof, is for use in
the treatment of pain.
In another aspect, the invention provides for a pharmaceutical composition
comprising a compound of formula (I) as described above, or in any one of the
preferred embodiments, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
In another aspect, the invention provides for a method of treating pain comprising
administering a therapeutically effective amount of a compound of formula (I) as
described above, or in any one of the preferred embodiments, or a pharmaceutically
acceptable salt thereof, to an individual in need of such treatment.
In another aspect, the invention provides for the use of a compound of formula (I) as
described above, or in any one of the preferred embodiments, or a pharmaceutically
acceptable salt thereof, for the manufacture of a medicament for treating pain.
In another aspect, the invention provides for the use of a compound of formula (I) as
described above, or in any one of the preferred embodiments, or a pharmaceutically
acceptable salt thereof, for the treatment of pain.
In another aspect, the invention provides for a combination comprising a compound of
formula (I) as described above, or in any one of the preferred embodiments, or a
pharmaceutically acceptable salt thereof, and a second pharmaceutically active
agent.
Detailed description of the Invention
AlkyI groups, containing the requisite number of carbon atoms, can be unbranched or
branched. (Ci-C 4)Alkyl includes methyl, ethyl, n-propyl ( 1-propyl) and isopropyl (2-
propyl, 1-methylethyl), n-butyl ( 1-butyl), sec-butyl (2-butyl, 1-methylpropyl), isobutyl
(2-methylpropyl), and e -butyl ( 1 , 1 -dimethylethyl).
(C3-C5)Cycloalkyl includes cyclopropyl, cyclobutyl and cyclopentyl. Methylsubstituted
( C 3-C 5)cycloalkyl includes 1-methylcyclopropyl, 2-methylcyclopropyl, 1-
methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 1-methylcyclopentyl, 2-
methylcyclopentyl and 3-methylcyclopentyl.
In compounds of formula (I) wherein R and R2 together are -N(CH 3)-CH 2- it should
be understood that the nitrogen atom corresponds to "R " and the methylene carbon
atom corresponds to "R2" , so providing a compound of formula (l ) .
(|A)
Further specific embodiments of the compounds of the invention are as follows.
In embodiment E2, there is provided a compound according to embodiment E1 or a
pharmaceutically acceptable salt thereof, wherein R is (C2-C4)alkyl and R2 is H
In embodiment E3, there is provided a compound according to embodiment E1 or E2,
or a pharmaceutically acceptable salt thereof, wherein R3 is selected from F and
OCH3.
In embodiment E4, there is provided a compound according to any one of
embodiments E1, E2 or E3 or a pharmaceutically acceptable salt thereof, wherein R4
is selected from H and F.
In embodiment E5, there is provided a compound according to any one of
embodiments E1, E2, E3 or E4, or a pharmaceutically acceptable salt thereof,
wherein R5 is (C2 -C4)alkyl.
Preferred compounds of the invention include:
7-ethyl-4-(6-fluoro-4'-((1 -methylethyl)sulfonyl)biphenyl-3-yl)-7H-imidazo[4,5-
c]pyridazine;
4-(4'-ethanesulfonyl-6-fluoro-2'-methoxybiphenyl-3-yl)-7-ethyl-7H-imidazo[4,5-
c]pyridazine;
7-cyclopropyl-4-(4'-ethylsulfonyl-6-fluorobiphenyl-3-yl)-7H-imidazo[4,5-c]pyridazine;
and
4-(4'-ethanesulfonyl-2',6-difluorobiphenyl-3-yl)-7-(1 -methylethyl)-7H-imidazo[4,5-
c]pyridazine.
A particularly preferred compound of the invention is 4-(4'-ethanesulfonyl-6-fluoro-2'-
methoxybiphenyl-3-yl)-7-ethyl-7H-imidazo[4,5-c]pyridazine.
Certain compounds of formula (I) include one or more stereogenic centers and so
may exist as optical isomers, such as enantiomers and disastereomers. All such
isomers and mixtures thereof are included within the scope of the present invention.
Hereinafter, all references to compounds of the invention include compounds of
formula (I) or pharmaceutically acceptable salts, solvates, or multi-component
complexes thereof, or pharmaceutically acceptable solvates or multi-component
complexes of pharmaceutically acceptable salts of compounds of formula (I), as
discussed in more detail below.
Preferred compounds of the invention are compounds of formula (I) or
pharmaceutically acceptable salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts.
Examples include the acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate,
edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate,
hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate,
palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate,
trifluoroacetate and xinofoate salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate salts.
The skilled person will appreciate that the aforementioned salts include ones wherein
the counterion is optically active, for example d-lactate or l-lysine, or racemic, for
example dl-tartrate or dl-arginine.
For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties,
Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by
one or more of three methods:
(i) by reacting the compound of formula (I) with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of
the compound of formula (I) using the desired acid or base; or
(iii) by converting one salt of the compound of formula (I) to another by reaction with
an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt may
precipitate out and be collected by filtration or may be recovered by evaporation of the
solvent. The degree of ionisation in the resulting salt may vary from completely
ionised to almost non-ionised.
The compounds of formula (I) or pharmaceutically acceptable salts thereof may exist
in both unsolvated and solvated forms. The term 'solvate' is used herein to describe
a molcular complex comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof and one or more pharmaceutically acceptable solvent
molcules, for example, ethanol. The term 'hydrate' is employed when said solvent is
water. Pharmaceutically acceptable solvates in accordance with the invention include
those wherein the solvent of crystallization may be isotopically substituted, e.g. D20 ,
d6-acetone and d6-DMSO.
A currently accepted classification system for organic hydrates is one that defines
isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in
Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995),
incorporated herein by reference. Isolated site hydrates are ones in which the water
molcules are isolated from direct contact with each other by intervening organic
molcules. In channel hydrates, the water molcules lie in lattice channels where they
are next to other water molcules. In metal-ion coordinated hydrates, the water
molcules are bonded to the metal ion.
When the solvent or water is tightly bound, the complex will have a well-defined
stoichiometry independent of humidity. When, however, the solvent or water is
weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent
content will be dependent on humidity and drying conditions. In such cases, nonstoichiometry
will be the norm.
The compounds of the invention may exist in a continuum of solid states ranging from
fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which
the material lacks long range order at the molcular level and, depending upon
temperature, may exhibit the physical properties of a solid or a liquid. Typically such
materials do not give distinctive X-ray diffraction patterns and, while exhibiting the
properties of a solid, are more formally described as a liquid. Upon heating, a change
from solid to liquid properties occurs which is characterised by a change of state,
typically second order ('glass transition'). The term 'crystalline' refers to a solid phase
in which the material has a regular ordered internal structure at the molcular level and
gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when
heated sufficiently will also exhibit the properties of a liquid, but the change from solid
to liquid is characterised by a phase change, typically first order ('melting point').
Also included within the scope of the invention are multi-component complexes (other
than salts and solvates) of compounds of formula (I) or pharmaceutically acceptable
salts thereof wherein the drug and at least one other component are present in
stoichiometric or non-stoichiometric amounts. Complexes of this type include
clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically
defined as crystalline complexes of neutral molcular constituents which are bound
together through non-covalent interactions, but could also be a complex of a neutral
molcule with a salt. Co-crystals may be prepared by melt crystallisation, by
recrystallisation from solvents, or by physically grinding the components together -
see Chem Commun, 17 , 1889-1 896, by 0 . Almarsson and M. J . Zaworotko (2004),
incorporated herein by reference. For a general review of multi-component
complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975),
incorporated herein by reference.
The compounds of the invention may also exist in a mesomorphic state (mesophase
or liquid crystal) when subjected to suitable conditions. The mesomorphic state is
intermediate between the true crystalline state and the true liquid state (either melt or
solution). Mesomorphism arising as the result of a change in temperature is
described as 'thermotropic' and that resulting from the addition of a second
component, such as water or another solvent, is described as 'lyotropic'. Compounds
that have the potential to form lyotropic mesophases are described as 'amphiphilic'
and consist of molcules which possess an ionic (such as -COO Na+, -COO K+, or -
S0 3 Na+) or non-ionic (such as -N N+(CH 3)3) polar head group. For more information,
see Crystals and the Polarizing Microscope by N. H. Hartshorne and A . Stuart, 4th
Edition (Edward Arnold, 1970), incorporated herein by reference.
The compounds of the invention may be administered as prodrugs. Thus certain
derivatives of compounds of formula (I) which may have little or no pharmacological
activity themselves can, when administered into or onto the body, be converted into
compounds of formula (I) having the desired activity, for example, by hydrolytic
cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the
use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS
Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug
Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical
Association).
Prodrugs can, for example, be produced by replacing appropriate functionalities
present in a compound of formula (I) with certain moieties known to those skilled in
the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H
Bundgaard (Elsevier, 1985).
Examples of prodrugs include phosphate prodrugs, such as dihydrogen or dialkyl
(e.g. di-tert-butyl) phosphate prodrugs. Further examples of replacement groups in
accordance with the foregoing examples and examples of other prodrug types may be
found in the aforementioned references.
Also included within the scope of the invention are metabolites of compounds of
formula (I), that is, compounds formed in vivo upon administration of the drug. Some
examples of metabolites in accordance with the invention include, where the
compound of formula (I) contains a phenyl (Ph) moiety, a phenol derivative thereof
(-Ph > -PhOH);
Compounds of the invention containing one or more asymmetric carbon atoms can
exist as two or more stereoisomers. Included within the scope of the invention are all
stereoisomers of the compounds of the invention and mixtures of one or more thereof.
Conventional techniques for the preparation/isolation of individual enantiomers
include chiral synthesis from a suitable optically pure precursor or resolution of the
racemate (or the racemate of a salt or derivative) using, for example, chiral high
pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable
optically active compound, for example, an alcohol, or, in the case where the
compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-
phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be
separated by chromatography and/or fractional crystallization and one or both of the
diastereoisomers converted to the corresponding pure enantiomer(s) by means well
known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in
enantiomerically-enriched form using chromatography, typically HPLC, on an
asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane
or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to
20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
Concentration of the eluate affords the enriched mixture.
Mixtures of stereoisomers may be separated by conventional techniques known to
those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by
E. L . Eliel and S. H. Wilen (Wiley, New York, 1994).
The scope of the invention includes all crystal forms of the compounds of the
invention, including racemates and racemic mixtures (conglomerates) thereof.
Stereoisomeric conglomerates may also be separated by the conventional techniques
described herein just above.
The scope of the invention includes all pharmaceutically acceptable isotopicallylabelled
compounds of the invention wherein one or more atoms are replaced by
atoms having the same atomic number, but an atomic mass or mass number different
from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include
isotopes of hydrogen, such as 2H and H, carbon, such as C, C and 4C, chlorine,
such as 6CI, fluorine, such as 8F, iodine, such as 2 l and 25 l , nitrogen, such as N
and 5N, oxygen, such as 50 , 70 and 80 , phosphorus, such as 2P, and sulphur,
such as 5S.
Certain isotopically-labelled compounds of the invention, for example, those
incorporating a radioactive isotope, are useful in drug and/or substrate tissue
distribution studies. The radioactive isotopes tritium, i.e. H, and carbon-14, i.e. 4C,
are particularly useful for this purpose in view of their ease of incorporation and ready
means of detection. Substitution with isotopes such as deuterium, i.e. 2H, may afford
certain therapeutic advantages resulting from greater metabolic stability, for example,
increased in vivo half-life or reduced dosage requirements, and hence may be
preferred in some circumstances. Substitution with positron emitting isotopes, such
as C, 8F, 50 and N, can be useful in Positron Emission Topography (PET)
studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of formula (I) can generally be prepared by
conventional techniques known to those skilled in the art or by processes analogous
to those described in the accompanying Examples and Preparations using an
appropriate isotopically-labeled reagent in place of the non-labeled reagent previously
employed.
Also within the scope of the invention are intermediate compounds as hereinafter
defined, all salts, solvates and complexes thereof and all solvates and complexes of
salts thereof as defined hereinbefore for compounds of formula (I). The invention
includes all polymorphs of the aforementioned species and crystal habits thereof.
The compounds of the invention may be prepared by any method known in the art for
the preparation of compounds of analogous structure. In particular, the compounds of
the invention can be prepared by the procedures described by reference to the
Schemes that follow, or by the specific methods described in the Examples, or by
similar processes to either.
The skilled person will appreciate that the experimental conditions set forth in the
schemes that follow are illustrative of suitable conditions for effecting the
transformations shown, and that it may be necessary or desirable to vary the precise
conditions employed for the preparation of compounds of formula (I). It will be further
appreciated that it may be necessary or desirable to carry out the transformations in a
different order from that described in the schemes, or to modify one or more of the
transformations, to provide the desired compound of the invention.
In addition, the skilled person will appreciate that it may be necessary or desirable at
any stage in the synthesis of compounds of the invention to protect one or more
sensitive groups, so as to prevent undesirable side reactions. In particular, it may be
necessary or desirable to protect amino or carboxylic acid groups. The protecting
groups used in the preparation of the compounds of the invention may be used in
conventional manner. See, for example, those described in 'Greene's Protective
Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, third
edition, (John Wiley and Sons, 1999), in particular chapters 7 ("Protection for the
Amino Group") and 5 ("Protection for the Carboxyl Group"), incorporated herein by
reference, which also describes methods for the removal of such groups.
Where ratios of solvents are given, the ratios are by volume.
In the Schemes that follow, X is CI, Br or I , and M is a boronic ester or boronic acid.
According to a first process, compounds of formula (I) may be prepared by the
process illustrated in Scheme 1.
( Ml) ( I I)
Scheme 1
Compounds of formula (I) may be prepared from compounds of formula (II) or (IV)
according to process step (i), a Suzuki cross coupling reaction with compounds of
formula (V) or (VI). Typical conditions for the metal catalysed cross coupling reaction
comprise a palladium catalyst such as dichloro [ 1 , 1 -bis(di-tertbutylphosphino)]
ferrocene palladium (II) or tetrakis(triphenylphosphine)palladium (0)
or tris(dibenzylideneacetone)palladium (0) with a suitable ligand such as
tricyclohexylphosphine, with a base such as sodium, potassium or cesium carbonate
in dioxane/water or DMF/water either heating to reflux thermally, or heating up to
120°C under microwave irradiation. Preferred conditions comprise
tetrakis(triphenylphosphine)palladium (0) with sodium carbonate in dioxane/water at
110°C. During this step, if compounds of formula (V) and (VI) need to be converted to
the boronic acid or ester, an additional step may be used to convert X to M. Typical
conditions comprise dichloro [ 1 , 1 -bis(di-tert-butylphosphino)]ferrocene palladium (II)
with potassium acetate in dioxane at 110°C.
Compounds of formula (VI) are either commercially available or are well-known to
those skilled in the art with reference to literature precedents and/or the preparations
described herein, or may be prepared according to Scheme 4 .
Compounds of formula (IV) are either commercially available or are well-known to
those skilled in the art with reference to literature precedents and/or the preparations
described herein or may be prepared according to Schemes 2 and 3 .
Compounds of formula (V) may be prepared according to Scheme 4 .
Compounds of formula (II) may be prepared from compounds of formula (III)
according to process step (ii), an electrophilic halogenation reaction. Typical
conditions comprise 1,3-diiodo-5,5-dimethylhydantoin or 1,3-dibromo-5,5-
dimethylhydantoin in concentrated sulphuric acid at from 0°C to room temperature.
Compounds of formula (III) may be prepared from compounds of formula (IV) and
(VII) according to process step (i), a Suzuki cross coupling reaction as described
above. Preferred conditions comprise tetrakis(triphenylphosphine)palladium (0) and
sodium carbonate in DMF and water at reflux.
Compounds of formula (VII) are either commercially available or are well-known to
those skilled in the art with reference to literature precedents and/or the preparations
described herein.
According to a second process, compounds of formula (IV) may be prepared by the
process illustrated in Scheme 2 .
(VIII) (IV)
Scheme 2
Compounds of formula (IV) may be prepared from compounds of formula (VIII)
according to process step (iii) a condensation reaction at elevated temperature.
Typical conditions comprise heating compounds of formula (VIII) neat with
triethylorthoformate at 130°C.
Compounds of formula (VIII) may be prepared from compounds of formula (IX)
according to process step (iv) a nucleophilic aromatic substitution reaction with
compounds of formula (XII). Typical conditions comprise heating compounds of
formula (XII) with compounds of formula (IX) either in a sealed vessel or under
microwave irradiation at from 100-150°C either neat or in a suitable solvent such as
water or acetic acid.
Compounds of formula (XII) are commercially available.
Compounds of formula (IX) may be prepared from compounds of formula (X)
according to process step (v), a nucleophilic aromatic substitution reaction with
ammonia. Preferred conditions comprise heating compounds of formula (X) with
ammonia in a suitable solvent such as ethanol under microwave irradiation at 120°C.
Compounds of formula (X) may be prepared from compounds of formula (XI)
according to process step (vi), a dehydrating chlorination reaction. Typical conditions
comprise heating compounds of formula (XI) neat in POCI3 at 110°C.
The compound of formula (XI) is commercially available.
According to a third process, compounds of formula (IV) may also be prepared by the
process illustrated in Scheme 3 .
Scheme 3
Compounds of formula (IV) may be prepared from compounds of formula (Xlll)
according to process step (vii), an aromatic cyclisation reaction. Preferred conditions
comprise a suitable catalyst such as copper (I) bromide with a suitable ligand such as
1, 1 0-phenanthroline in a solvent such as DMF in the presence of an inorganic base
such as cesium carbonate at elevated temperature.
Compounds of formula (Xlll) may be prepared from compounds of formula (XIV)
according to process step (viii) a nucleophilic substitution reaction with compounds of
formula (XII) in the presence of a suitable base such as sodium hydride in a solvent
such as THF at from 0°C to room temperature.
Compounds of formula (XIV) may be prepared from compounds of formula (IX)
according to process step (ix), an alkylation reaction with triethylorthoformate. Typical
conditions comprise pyridinium para-toluenesulfonate with triethylorthoformate at
100°C.
Compounds of formula (IX) may be prepared as described in Scheme 2 .
According to a fourth process, compounds of formulae (VI) and (V) may also be
prepared by the processes illustrated in Scheme 4 .
Scheme 4
Compounds of formula (V) may be prepared from compounds of formula (VI)
according to process step (i) a Suzuki cross-coupling reaction as described in
Scheme 1
Compounds of formula (VI) may be prepared from compounds of formula (XVII)
according to process step (xii), a displacement of the sulfonyl chloride with an alkyl
halide of formula (XVIII) via a sulfonyl hydrazide. Typical conditions comprise
hydrazine monohydrate in THF at 0°C followed by sodium acetate and compounds of
formula (XVIII) in IMS at 85°C.
Compounds of formula (VI) may also be prepared from compounds of formula (XV)
according to process step (x), an oxidation reaction in the presence of a suitable
oxidising reagent. Preferred conditions comprise meta-chloroperoxybenzoic acid in
DCM at from 0°C to room temperature.
Compounds of formula (XV) may be prepared from compounds of formula (XVI) and
(XIX) according to process step (xi), a nucleophilic aromatic substitution reaction.
Preferred conditions comprise a sodium salt of compounds of formula (XIX) in DMSO
at elevated temperature.
Compounds of formula (XV) may also be prepared from compounds of formula (XX)
and (XVIII) according to process step (xiii), and alkylation reaction in the presence of
a suitable base. Typical conditions comprise either potassium tert-butoxide or cesium
carbonate in DMSO at from 70-90°C.
Compounds of formula (XIX), (XVIII), (XVI) and (XX) are either commercially available
or are well-known to those skilled in the art with reference to literature precedents
and/or the preparations described herein
Compounds of the invention intended for pharmaceutical use may be administered as
crystalline or amorphous products or may exist in a continuum of solid states ranging
from fully amorphous to fully crystalline. They may be obtained, for example, as solid
plugs, powders, or films by methods such as precipitation, crystallization, freeze
drying, spray drying, or evaporative drying. Microwave or radio frequency drying may
be used for this purpose.
They may be administered alone or in combination with one or more other
compounds of the invention or in combination with one or more other drugs (or as any
combination thereof). Generally, they will be administered as a formulation in
association with one or more pharmaceutically acceptable excipients. The term
'excipient' is used herein to describe any ingredient other than the compound(s) of the
invention. The choice of excipient will to a large extent depend on factors such as the
particular mode of administration, the effect of the excipient on solubility and stability,
and the nature of the dosage form.
In another aspect the invention provides a pharmaceutical composition comprising a
compound of the invention together with one or more pharmaceutically acceptable
excipients.
Pharmaceutical compositions suitable for the delivery of compounds of the present
invention and methods for their preparation will be readily apparent to those skilled in
the art. Such compositions and methods for their preparation may be found, for
example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing
Company, 1995).
Suitable modes of administration include oral, parenteral, topical, inhaled/intranasal,
rectal/intravaginal, and ocular/aural administration.
Formulations suitable for the aforementioned modes of administration may be
formulated to be immediate and/or modified release. Modified release formulations
include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention may be administered orally. Oral administration may
involve swallowing, so that the compound enters the gastrointestinal tract, or buccal
or sublingual administration may be employed by which the compound enters the
blood stream directly from the mouth. Formulations suitable for oral administration
include solid formulations such as tablets, capsules containing particulates, liquids, or
powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels,
solid solution, liposome, films, ovules, sprays, liquid formulations and
buccal/mucoadhesive patches..
Liquid formulations include suspensions, solutions, syrups and elixirs. Such
formulations may be employed as fillers in soft or hard capsules and typically
comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil, and one or more emulsifying agents and/or
suspending agents. Liquid formulations may also be prepared by the reconstitution of
a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fastdisintegrating
dosage forms such as those described in Expert Opinion in Therapeutic
Patents, V\_ (6), 981 -986, by Liang and Chen (2001 ) .
For tablet dosage forms, depending on dose, the drug may make up from 1 weight %
to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of
the dosage form. In addition to the drug, tablets generally contain a disintegrant.
Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl
cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone,
polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkylsubstituted
hydroxypropyl cellulose, starch, pregelatinised starch and sodium
alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %,
preferably from 5 weight % to 20 weight % of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation.
Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene
glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain
diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the
like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch
and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl
sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When
present, surface active agents may comprise from 0.2 weight % to 5 weight % of the
tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium
stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate
with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10
weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible
ingredients include anti-oxidants, colourants, flavouring agents, preservatives and
taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90
weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2
weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about
10 weight % lubricant. Tablet blends may be compressed directly or by roller to form
tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or meltgranulated,
melt congealed, or extruded before tabletting. The final formulation may
comprise one or more layers and may be coated or uncoated; it may even be
encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage
Forms: Tablets", Vol. 1, by H. Lieberman and L . Lachman (Marcel Dekker, New York,
1980).
Suitable modified release formulations for the purposes of the invention are described
in US Patent No. 6,1 06,864. Details of other suitable release technologies such as
high energy dispersions and osmotic and coated particles are to be found in
"Pharmaceutical Technology On-line", 25(2), 1-14, by Verma et al (2001 ) . The use of
chewing gum to achieve controlled release is described in WO 00/35298.
The compounds of the invention may also be administered directly into the blood
stream, into muscle, or into an internal organ. Suitable means for parenteral
administration include intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial, intramuscular and
subcutaneous. Suitable devices for parenteral administration include needle
(including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients
such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9),
but, for some applications, they may be more suitably formulated as a sterile non
aqueous solution or as a dried form to be used in conjunction with a suitable vehicle
such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by
lyophilisation, may readily be accomplished using standard pharmaceutical
techniques well known to those skilled in the art.
The solubility of compounds of formula (I) used in the preparation of parenteral
solutions may be increased by the use of appropriate formulation techniques, such as
the incorporation of solubility-enhancing agents. Formulations for parenteral
administration may be formulated to be immediate and/or modified release. Modified
release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and
programmed release. Thus compounds of the invention may be formulated as a solid,
semi-solid, or thixotropic liquid for administration as an implanted depot providing
modified release of the active compound. Examples of such formulations include
drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
The compounds of the invention may also be administered topically to the skin or
mucosa, that is, dermally or transdermally. Typical formulations for this purpose
include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders,
dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages
and microemulsions. Liposomes may also be used. Typical carriers include alcohol,
water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol
and propylene glycol. Penetration enhancers may be incorporated - see, for example,
J Pharm Sci, 88 ( 10), 955-958, by Finnin and Morgan (October 1999).
Other means of topical administration include delivery by electroporation,
iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g.
Powderject™, Bioject™, etc.) injection.
The compounds of the invention can also be administered intranasally or by
inhalation, typically in the form of a dry powder (either alone, as a mixture, for
example, in a dry blend with lactose, or as a mixed component particle, for example,
mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or
as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably
an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or
without the use of a suitable propellant, such as 1,1 , 1 ,2-tetrafluoroethane or
1, 1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a
bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or
suspension of the compound(s) of the invention comprising, for example, ethanol,
aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or
extending release of the active, a propellant(s) as solvent and an optional surfactant,
such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised
to a size suitable for delivery by inhalation (typically less than 5 microns). This may be
achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed
jet milling, supercritical fluid processing to form nanoparticles, high pressure
homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters
and cartridges for use in an inhaler or insufflator may be formulated to contain a
powder mix of the compound of the invention, a suitable powder base such as lactose
or starch and a performance modifier such as l-leucine, mannitol, or magnesium
stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably
the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol,
fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to
produce a fine mist may contain from 1 g to 20mg of the compound of the invention
per actuation and the actuation volume may vary from 1m I to 0OmI . A typical
formulation may comprise a compound of formula (I), propylene glycol, sterile water,
ethanol and sodium chloride. Alternative solvents which may be used instead of
propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol, or sweeteners, such as
saccharin or saccharin sodium, may be added to those formulations of the invention
intended for inhaled/intranasal administration.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by
means of a valve which delivers a metered amount. Units in accordance with the
invention are typically arranged to administer a metered dose or "puff" containing from
1 g to 100mg of the compound of formula (I). The overall daily dose will typically be
in the range 1 g to 200mg which may be administered in a single dose or, more
usually, as divided doses throughout the day.
The compounds of the invention may be administered rectally or vaginally, for
example, in the form of a suppository, pessary, microbicide, vaginal ring or enema.
Cocoa butter is a traditional suppository base, but various alternatives may be used
as appropriate.
The compounds of the invention may also be administered directly to the eye or ear,
typically in the form of drops of a micronised suspension or solution in isotonic, pHadjusted,
sterile saline. Other formulations suitable for ocular and aural administration
include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non
biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular
systems, such as niosomes or liposomes. A polymer such as crossed-linked
polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,
hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a
heteropolysaccharide polymer, for example, gelan gum, may be incorporated together
with a preservative, such as benzalkonium chloride. Such formulations may also be
delivered by iontophoresis.
The compounds of the invention may be combined with soluble macromolcular
entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycolcontaining
polymers, in order to improve their solubility, dissolution rate, tastemasking,
bioavailability and/or stability for use in any of the aforementioned modes of
administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most
dosage forms and administration routes. Both inclusion and non-inclusion complexes
may be used. As an alternative to direct complexation with the drug, the cyclodextrin
may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most
commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins,
examples of which may be found in International Patent Applications Nos. WO
9 1/ 11172, WO 94/0251 8 and WO 98/551 48.
For administration to human patients, the total daily dose of the compounds of the
invention is typically in the range 1mg to 10g, such as 10mg to 1g , for example 25mg
to 500mg depending, of course, on the mode of administration and efficacy. For
example, oral administration may require a total daily dose of from 50mg to 100mg.
The total daily dose may be administered in single or divided doses and may, at the
physician's discretion, fall outside of the typical range given herein. These dosages
are based on an average human subject having a weight of about 60kg to 70kg. The
physician will readily be able to determine doses for subjects whose weight falls
outside this range, such as infants and the elderly.
The compounds of the invention are useful because they exhibit pharmacological
activity, i.e., GABAA channel modulation. More particularly, the compounds of the
invention are positive allosteric modulators of the GABAA channel. Preferred
compounds of the invention are selective modulators of the 2 , 3 and/or s
subtypes, with lower efficacy and/or affinity at the a i, a 4 and & subtypes. The
compounds of the invention are accordingly of use in the treatment of disorders in
animals for which a GABAA positive allosteric modulator is indicated. Preferably the
animal is a mammal, more preferably a human.
In a further aspect of the invention there is provided a compound of the invention for
use as a medicament.
In a further aspect of the invention there is provided a compound of the invention for
the treatment of a disorder for which a GABAA positive allosteric modulator is
indicated.
In a further aspect of the invention there is provided use of a compound of the
invention for the preparation of a medicament for the treatment of a disorder for which
a GABAA positive allosteric modulator is indicated.
In a further aspect of the invention there is provided a method of treating a disorder in
an animal (preferably a mammal, more preferably a human) for which a GABAA
positive allosteric modulator is indicated, comprising administering to said animal a
therapeutically effective amount of a compound of the invention.
The GABAA positive allosteric modulators of formula (I) may be used:
• as analgesics, for example for the treatment of pain, including acute pain,
chronic pain, neuropathic pain, nociceptive (including inflammatory) pain,
somatic pain, visceral pain, and dysfunctional pain, as further discussed below,
and in particular for pain conditions wherein there is a brain or spinal
component to the underlying mechanism;
as anticonvulsants, for example for the treatment of epilepsy and epilepsy
associated disorders, including Lennox-Gastaut syndrome, Dravet's disease,
and generalised epilepsy with febrile seizures plus (GEFS+);
as anxiolytic agents, for example for the treatment of panic disorder,
generalized anxiety disorder, stress disorders such as post-traumatic stress
disorder, acute stress disorder and substance-induced stress disorder, phobias
such as agoraphobia, social phobia and animal phobias, and obsessivecompulsive
disorder; and
as muscle relaxants, for example for the treatment of muscle spasm, dystonia,
spasticity (including generalised and focal spasticity) and essential tremor.
The GABAA positive allosteric modulators of formula (I) may also be used for the
treatment of autism, or as antipsychotic agents, for example for the treatment of
schizophrenia.
Other therapeutic indications for the GABA A positive allosteric modulators of formula
(I) include use as antidepressant agents, for example for the treatment of depressive
and bipolar disorders and cyclothymia; as antiemetic agents, for example for the
treatment of chemotherapy- or radiation-induced emesis, post-operative nausea and
vomiting, and motion sickness; as cognition-enhancing agents, for example for the
treatment of neurodegenerative disorders, such as Alzheimer's disease, and cerebral
ischemia; as sleep improving agents, for example for the treatment of sleep disorders
such as insomnia and circadian rhythm disorders such as jet-lag, or for use as pre
medication prior to anaesthesia or endoscopy; and use in the treatment of addiction
phenotypes such as alcoholism, Angelman syndrome, attention deficit hyperactivity
disorder, bladder urgency, bowel abnormalities, eating disorders such as anorexia
nervosa and bulimia nervosa, Fragile X syndrome, hearing disorders such as tinnitus
and age-related hearing impairment, multiple sclerosis, neuroses, overactive bladder
with sensory disturbance, premenstrual syndrome, restless legs syndrome, and
urinary incontinence.
A preferred use for the compounds of formula (I) is the treatment of pain. Pain may
be either acute or chronic and additionally may be of central and/or peripheral origin.
Pain may be of a neuropathic and/or nociceptive and/or inflammatory nature, such as
pain affecting either the somatic or visceral systems, as well as dysfunctional pain
affecting multiple systems.
Physiological pain is an important protective mechanism designed to warn of danger
from potentially injurious stimuli from the external environment. The system operates
through a specific set of primary sensory neurones and is activated by noxious stimuli
via peripheral transducing mechanisms (see Meyer et al., 2006, Wall and Melzack's
Textbook of Pain (5th Ed), Chapterl ) . These sensory fibres are known as
nociceptors, and are characteristically small diameter axons with slow conduction
velocities, of which there are two main types, A-delta fibres (myelinated) and C fibres
(non-myelinated). Nociceptors encode the intensity, duration and quality of noxious
stimulus and by virtue of their topographically organised projection to the spinal cord,
the location of the stimulus. The activity generated by nociceptor input is transferred,
after complex processing in the dorsal horn, either directly, or via brain stem relay
nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of
pain is generated.
Pain may generally be classified as acute or chronic. Acute pain begins suddenly and
is short-lived (usually twelve weeks or less). It is usually, although not always,
associated with a specific cause such as a defined injury, is often sharp and severe
and can result from numerous origins such as surgery, dental work, a strain or a
sprain. Acute pain does not generally result in any persistent psychological response.
When a substantial injury occurs to body tissue, via disease or trauma, the
characteristics of nociceptor activation may be altered such that there is sensitisation
in the periphery, locally around the injury and centrally where the nociceptors
terminate. These effects lead to a hightened sensation of pain. In acute pain these
mechanisms can be useful, in promoting protective behaviours which may better
enable repair processes to take place. The normal expectation would be that
sensitivity returns to normal once the injury has healed. However, in many chronic
pain states, the hypersensitivity far outlasts the healing process and is often due to
nervous system injury or alteration which can be associated with maladaptation and
aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768). As such, chronic
pain is long-term pain, typically persisting for more than three months and leading to
significant psychological and emotional problems. Common examples of chronic pain
are neuropathic pain (e.g. painful diabetic neuropathy or postherpetic neuralgia),
carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic
post-surgical pain, but may include any chronic painful condition affecting any system,
such as those described by the International Association for the Study of Pain
(Classification of Chronic Pain, a publication freely available for download at
http://www.iasp-pain.org).
The clinical manifestation of pain is present when discomfort and abnormal sensitivity
feature among the patient's symptoms. Patients tend to be quite heterogeneous and
may present with various pain symptoms. Such symptoms can include: 1)
spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain
responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally
innocuous stimuli (allodynia) (Meyer et al., 2006, Wall and Melzack's Textbook of
Pain (5th Ed), Chapterl ) . Although patients suffering from various forms of acute and
chronic pain may have similar symptoms, the underlying mechanisms may be
different and may, therefore, require different treatment strategies. Apart from acute
or chronic, pain can also be broadly categorized into: nociceptive pain, affecting either
the somatic or visceral systems, which can be inflammatory in nature (associated with
tissue damage and the infiltration of immune cells); or neuropathic pain.
Nociceptive pain can be defined as the process by which intense thermal,
mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve
fibers, called nociceptors, and can be induced by tissue injury or by intense stimuli
with the potential to cause injury. Pain afferents are activated by transduction of
stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at
the level of their termination. This is then relayed up the spinal tracts to the brain
where pain is perceived (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5th
Ed), Chapterl ) . Myelinated A-delta fibres transmit rapidly and are responsible for
sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower
rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a
prominent feature of pain from strains/sprains, burns, myocardial infarction and acute
pancreatitis, post-operative pain (pain following any type of surgical procedure),
posttraumatic pain, pain associated with gout, cancer pain and back pain. Cancer
pain may be chronic pain such as tumour related pain (e.g. bone pain, headache,
facial pain or visceral pain) or pain associated with cancer therapy (e.g. in response to
chemotherapy, immunotherapy, hormonal therapy or radiotherapy). Back pain may
be due to herniated or ruptured intervertabral discs or abnormalities of the lumber
facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.
Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it
becomes a chronic condition which can be particularly debilitating.
Nociceptive pain can also be related to inflammatory states. The inflammatory
process is a complex series of biochemical and cellular events, activated in response
to tissue injury or the presence of foreign substances, which results in swelling and
pain (McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter3).
A common inflammatory condition assoiciated with pain is arthritis. It has been
estimated that almost 27 million Americans have symptomatic osteoarthritis (OA) or
degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most
patients with osteoarthritis seek medical attention because of the associated pain.
Arthritis has a significant impact on psychosocial and physical function and is known
to be the leading cause of disability in later life. Rheumatoid arthritis is an immunemediated,
chronic, inflammatory polyarthritis disease, mainly affecting peripheral
synovial joints. It is one of the commonest chronic inflammatory conditions in
developed countries and is a major cause of pain.
In regard to nociceptive pain of visceral origin, visceral pain results from the activation
of nociceptors of the thoracic, pelvic, or abdominal organs (Bielefeldt and Gebhart,
2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter48). This includes the
reproductive organs, spleen, liver, gastrointestinal and urinary tracts, airway
structures, cardiovascular system and other organs contained within the abdominal
cavity. As such visceral pain refers to pain associated with conditions of such organs,
such as painful bladder syndrome, interstitial cystitis, prostatitis, ulcerative colitis,
Crohn's disease, renal colic, irritable bowl syndrome, endometriosis and
dysmenorrhea! (Classification of Chronic Pain, available at http://www.iasp-pain.org).
Currently the potential for a neuropathic contribution (either through central changes
or nerve injury/damage) to visceral pain states is poorly understood but may play a
role in certain conditions (Aziz et al., 2009, Dig Dis 27, Suppl 1, 3 1-41 )
Neuropathic pain is currently defined as pain arising as a direct consequence of a
lesion or disease affecting the somatosensory system. Nerve damage can be caused
by trauma and disease and thus the term 'neuropathic pain' encompasses many
disorders with diverse aetiologies. These include, but are not limited to, peripheral
neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back
pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel
syndrome, central post-stroke pain and pain associated with chronic alcoholism,
hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease,
epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no
protective role. It is often present well after the original cause has dissipated,
commonly lasting for years, significantly decreasing a patient's quality of life (Dworkin,
2009, Am J Med, 122, S 1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa
et al., 2009, Am J Med, 122, S 13-S21 ) . The symptoms of neuropathic pain are
difficult to treat, as they are often heterogeneous even between patients with the
same disease (Dworkin, 2009, Am J Med, 122, S 1-S2; Geber et al., 2009, Am J Med,
122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21 ) . They include
spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked
pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia
(sensitivity to a normally innocuous stimulus).
It should be noted that some types of pain have multiple aetiologies and thus can be
classified in more than one area, e.g. back pain, cancer pain and even migaine
headaches may include both nociceptive and neuropathic components.
Similarly other types of chronic pain, perhaps less well understood, are not easily
defined by the simplistic definitions of nociceptive or neuropathic. Such conditions
include in particular fibromyalgia and chronic regional pain syndrome, which are often
described as dysfunctional pain states e.g. fibromyalgia or complex regional pain
syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744), but which are included in
classifications of chronic pain states (Classification of Chronic Pain, available at
http://www.iasp-pain.org).
A GABAA positive allosteric modulator may be usefully combined with another
pharmacologically active compound, or with two or more other pharmacologically
active compounds, particularly in the treatment of pain. Such combinations offer the
possibility of significant advantages, including patient compliance, ease of dosing and
synergistic activity.
In the combinations that follow the compound of the invention may be administered
simultaneously, sequentially or separately in combination with the other therapeutic
agent or agents.
For the treatment of pain, a GABAA positive allosteric modulator of formula (I), or a
pharmaceutically acceptable salt thereof, as defined above, may be administered in
combination with one or more agents selected from:
· a selective Nav1 .3 channel modulator, such as a compound disclosed in
WO2008/1 18758;
• a selective Nav1 .7 channel modulator, such as a compound disclosed in
WO201 0/079443, e.g. 4-[2-(5-amino-1 H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-
2-fluoro-N-1 ,3-thiazol-4-ylbenzenesulfonamide or 4-[2-(3-amino-1 H-pyrazol-4-yl)-
4-(trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1 ,3-thiazol-4-
ylbenzenesulfonamide, or a pharmaceutically acceptable salt of either;
• a selective Nav1 .8 channel modulator;
• a selective Nav1 .9 channel modulator;
• a compound which modulates activity at more than one Nav channel, including a
non-selective modulator such as bupivacaine, carbamazepine, lamotrigine,
lidocaine, mexiletine or phenytoin;
• any inhibitor of nerve growth factor (NGF) signaling, such as: an agent that binds
to NGF and inhibits NGF biological activity and/or downstream pathway(s)
mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75
antagoinsist, or an agent that inhibits downstream signaling in regard to NGF
stimulated TrkA or P75 signalling;
• an inhibitor of neurotrophic pathways, where such inhibition is achieved by: (a) an
agent that binds to nerve growth factor (NGF) (e.g. tanezumab, fasinumab or
fulranumab), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or
neurotrophin-4 (NT-4), or to more than one of the aforementioned neurotrophins
(e.g. soluble P75); or (b) an agent that inhibits receptor function at one or more of
TrKA, TrKB, TrKC or P75, either at the orthosteric site, an allosteric site or by
inhibition of the catalytic activity of the receptor(s);
• a compound which increases the levels of endocannabinoid, such as a compound
with fatty acid amid hydrolase inhibitory (FAAH) or monoacylglycerol lipase
(MAGL) activity;
• an analgesic, in particular paracetamol;
· an opioid analgesic, such as: buprenorphine, butorphanol, cocaine, codeine,
dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, levallorphan
levorphanol, meperidine, methadone, morphine, nalmefene, nalorphine, naloxone,
naltrexone, nalbuphine, oxycodone, oxymorphone, propoxyphene or pentazocine;
• an opioid analgesic which preferentially stimulates a specific intracellular pathway,
for example G-protein as opposed to beta arrestin recruitment, such as
TRV1 30;an opioid analgesic with additional pharmacology, such as: noradrenaline
(norepinephrine) reuptake inhibitory (NRI) activity, e.g. tapentadol; serotonin and
norepinephrine reuptake inhibitory (SNRI) activity, e.g. tramadol; or nociceptin
receptor (NOP) agonist activity, such as GRT6005;
· a nonsteroidal antiinflammatory drug (NSAID), such as a non-selective
cyclooxygenase (COX) inhibitor, e.g. aspirin, diclofenac, diflusinal, etodolac,
fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone,
naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,
piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; or a COX-2 selective
inhibitor, e.g. celecoxib, deracoxib, etoricoxib, mavacoxib or parecoxib;
• a prostaglandin E2 subtype 4 (EP4) antagonist;
• a microsomal prostaglandin E synthase type 1 (mPGES-1 ) inhibitor;
• a sedative, such as glutethimide, meprobamate, methaqualone or
dichloralphenazone;
• a GABAA modulator with broad subtype modulatory effects mediated via the
benzodiazepine binding site, such as chlordiazepoxide, alprazolam, diazepam,
lorazepam, oxazepam, temazepam, triazolam, clonazepam or clobazam;
• a GABAA modulator with subtype-selective modulatory effects mediated via the
benzodiazepine binding site with reduced adverse effects, for example sedation,
such as TPA023, TPA023B, L-838,41 7 , CTP354 or NSD72;
• a GABAA modulator acting via alternative binding sites on the receptor, such as
barbiturates, e.g. amobarbital, aprobarbital, butabital, mephobarbital,
methohexital, pentobarbital, phenobartital, secobarbital, or thiopental;
neurosteroids such as alphaxalone, alphadolone or ganaxolone; b-subunit ligands,
such as etifoxine; or d-preferring ligands, such as gaboxadol;
• a GlyR3 agonist or positive allosteric modulator;
· a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone,
cyclobenzaprine, metaxolone, methocarbamol or orphrenadine;
• a glutamate receptor antagonist or negative allosteric modulator, such as an
NMDA receptor antagonist, e.g. dextromethorphan, dextrorphan, ketamine or,
memantine; or an mGluR antagonist or modulator;
· an alpha-adrenergic, such as clonidine, guanfacine or dexmetatomidine;
• a beta-adrenergic such as propranolol;
• a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or
nortriptyline;
• a tachykinin (NK) antagonist, such as aprepitant or maropitant;
· a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium
chloride, darifenacin, solifenacin, temiverine and ipratropium;
• a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1 734), varenicline or
nicotine;
• a Transient Receptor Potential V 1 (TRPV1 ) receptor agonist (e.g. resinferatoxin or
capsaicin) or antagonist (e.g. capsazepine or mavatrap);
• a Transient Receptor Potential A 1 (TRPA1 ) receptor agonist (e.g. cinnamaldehyde
or mustard oil) or antagonist (e.g. GRC1 7536 or CB-625);
• a Transient Receptor Potential M8 (TRPM8) receptor agonist (e.g. menthol or
icilin) or antagonist;
· a Transient Receptor Potential V3 (TRPV3) receptor agonist or antagonist (e.g.
GRC-1 5300);
• a corticosteroid such as dexamethasone;
• a 5-HT receptor agonist or antagonist, particularly a 5-HT B/ID agonist, such as
eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
• a 5-HT2A receptor antagonist;
• a PDEV inhibitor, such sildenafil, tadalafil or vardenafil;
· an alpha-2-delta ligand such as gabapentin, gabapentin enacarbil or pregabalin, ;
• a serotonin reuptake inhibitor (SRI) such as sertraline, demethylsertraline,
fluoxetine, norfluoxetine, fluvoxamine, paroxetine, citalopram,
desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,
cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
· an NRI, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,
tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion,
nomifensine and viloxazine, especially a selective noradrenaline reuptake inhibitor
such as reboxetine;
• an SNRI, such as venlafaxine, O-desmethylvenlafaxine, clomipramine,
desmethylclomipramine, duloxetine, milnacipran and imipramine;
• an inducible nitric oxide synthase (iNOS) inhibitor;
• a leukotriene B4 antagonist;
• a 5-lipoxygenase inhibitor, such as zileuton;
• a potassium channel opener or positive modulator, such as an opener or positive
modulator of KCNQ/Kv7 (e.g. retigabine or flupirtine), a G protein-coupled
inwardly-rectifying potassium channel (GIRK), a calcium-activated potassium
channel (Kca) or a potassium voltage-gated channel such as a member of
subfamily A (e.g. Kv1 . 1 ) , subfamily B (e.g. Kv2.2) or subfamily K (e.g. TASK,
TREK or TRESK);
· a P2X3 receptor antagonist (e.g. AF219) or an antagonist of a receptor which
contains as one of its subunits the P2X3 subunit, such as a P2X2/3 heteromeric
receptor;
• a Ca 2.2 calcium channel blocker (N-type), such as ziconotide; and
• a Ca 3.2 calcium channel blocker (T-type), such as ethosuximide.
There is also included within the scope the present invention combinations of a
compound of the invention together with one or more additional therapeutic agents
which slow down the rate of metabolism of the compound of the invention, thereby
leading to increased exposure in patients. Increasing the exposure in such a manner
is known as boosting. This has the benefit of increasing the efficacy of the compound
of the invention or reducing the dose required to achieve the same efficacy as an
unboosted dose. The metabolism of the compounds of the invention includes
oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4
and conjugation by UDP glucuronosyl transferase and sulphating enzymes. Thus,
among the agents that may be used to increase the exposure of a patient to a
compound of the present invention are those that can act as inhibitors of at least one
isoform of the cytochrome P450 (CYP450) enzymes. The isoforms of CYP450 that
may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6,
CYP2C9, CYP2C1 9 and CYP3A4. Suitable agents that may be used to inhibit CYP
3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2-
{[(4-methoxypyridin-3-yl)amino]sulfonyl}benzamide and N-(1 -(2-(5-(4-fluorobenzyl)-3-
(pyridin-4-yl)-1 H-pyrazol-1 -yl)acetyl)piperidin-4-yl)methanesulfonamide.
It is within the scope of the invention that two or more pharmaceutical compositions,
at least one of which contains a compound of the invention, may conveniently be
combined in the form of a kit suitable for coadministration of the compositions. Thus
the kit of the invention comprises two or more separate pharmaceutical compositions,
at least one of which contains a compound of the invention, and means for separately
retaining said compositions, such as a container, divided bottle, or divided foil packet.
An example of such a kit is the familiar blister pack used for the packaging of tablets,
capsules and the like. The kit of the invention is particularly suitable for administering
different dosage forms, for example, oral and parenteral, for administering the
separate compositions at different dosage intervals, or for titrating the separate
compositions against one another. To assist compliance, the kit typically comprises
directions for administration and may be provided with a so-called memory aid.
In another aspect the invention provides a pharmaceutical product (such as in the
form of a kit) comprising a compound of the invention together with one or more
additional therapeutically active agents as a combined preparation for simultaneous,
separate or sequential use in the treatment of a disorder for which a Na 1.8
modulator is indicated.
It is to be appreciated that all references herein to treatment include curative,
palliative and prophylactic treatment.
In the non-limiting Examples and Preparations that are set out later in the description,
and in the aforementioned Schemes, the following the abbreviations, definitions and
analytical procedures may be referred to:
AcOH is acetic acid;
APCI is atmospheric pressure chemical ionisation mass spectrum;
Arbocel is a filter agent;
br is broad;
Celite® is a filter agent;
CDI is N,N'-carbonyldiimidazole;
Cs2C0 3 is caesium carbonate;
Cu(acac) 2 is copper (II) acetylacetonate;
Cul is copper (I) iodide;
Cu(OAc)2 is copper (II) acetate;
d is chemical shift;
d is doublet;
DABCO is 1,4-diazabicyclo[2.2.2]octane;
DAD is diode array detector;
DCM is dichloromethane; methylene chloride;
DCC is N,N'-dicyclohexylcarbodiimide;
DDQ is 2,3-Dichloro-5,6-Dicyanobenzoquinone;
DIPEA is N-ethyldiisopropylamine, N,N-diisopropylethylamine;
DMAP is 4-dimethylaminopyridine;
DMF is N,N-dimethylformamide;
DMSO is dimethyl sulphoxide;
EDCI.HCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
EDCI.Mel is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide methyliodide;
EDTA is ethylenediaminetetraacetic acid;
ELSD is evaporative light scattering detection;
ES is electrospray ionization;
Et20 is diethyl ether;
EtOAc is ethyl acetate;
EtOH is ethanol;
HATU is 2-(7-azabenzotriazol-1 -yl)-1 ,1,3,3-tetramethyluronium hexafluorophosphate;
HBTU is 0-benzotriazol-1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate;
HCI is hydrochloric acid;
HOBT is N-hydroxybenzotriazole hydrate;
HPLC is high pressure liquid chromatography;
IPA is isopropanol;
lr2(OMe) 2COD2 is bis(1 ,5-cyclooctadiene)di-p-methoxydiiridium (I);
K2CO3 is potassium carbonate;
KHS0 4 is potassium hydrogen sulphate;
KOAc is potassium acetate;
KOH is potassium hydroxide;
K3P0 4 is potassium phosphate tribasic;
L is litre
LCMS is liquid chromatography mass spectrometry (Rt = retention time);
LiOH is lithium hydroxide;
m is multiplet;
MeOH is methanol;
2-MeTHF is 2-methyltetrahydrofuran;
MgS0 4 is magnesium sulphate;
m/z is mass spectrum peak;
NaH is sodium hydride;
NaHC0 3 is sodium hydrogencarbonate;
Na2C0 3 is sodium carbonate;
NaHS0 is sodium bisulphite;
NaHS0 4 is sodium hydrogensulphate;
NaOH is sodium hydroxide;
Na2S0 4 is sodium sulphate;
NBS is N-bromosuccinimide
NH4CI is ammonium chloride;
NMP is A/-Methyl-2-pyrrolidone;
NMR is nuclear magnetic resonance;
Pd-1 18 is dichloro [ 1 , 1 ' bis(di-tert-butylphosphino)]ferrocene palladium (II);
PdCl2(dtbpf) is dicloro [ 1 , 1 '-bis(di-tert-butylphosphino)]ferrocene palladium (II);
Pd/C is palladium on carbon;
Pd(PPh 3)4 is palladium tetrakis(triphenylphosphine);
Pd(dppf) 2Cl2.DCM is [ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll),
complex with dichloromethane;
Pd2(dba) 3 is tris(dibenzylideneacetone)dipalladium(0);
Pd(OAc) 2 is palladium acetate;
Pd(OH) 2/C is palladium hydroxide on carbon;
Prep is preparation;
POBr 3 is phosphorus oxybromide;
psi is pounds per square inch;
PyBop is (Benzotriazol-l -yloxy)tripyrrolidinophosphonium hexafluorophosphate;
q is quartet;
Rt is retention time;
s is singlet;
SPhos is 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl;
t is triplet;
TBAF is tetrabutyl ammonium fluoride;
TBME is tert-butyl dimethyl ether;
THF is tetrahydrofuran;
THP is tetrahydropyran;
TLC is thin layer chromatography;
UV is ultraviolet; and
WSCDI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
The Preparations and Examples that follow illustrate the invention but do not limit the
invention in any way. All starting materials are available commercially or described in
the literature. All temperatures are in °C. Flash column chromatography was carried
out using Merck silica gel 60 (9385). Thin layer chromatography (TLC) was carried
out on Merck silica gel 60 plates (5729). "Rf" represents the distance travelled by a
compound divided by the distance travelled by the solvent front on a TLC plate.
Melting points were determined using a Gallenkamp MPD350 apparatus and are
uncorrected. H-NMR spectra were recorded on a Varian Mercury 300 or 400MHz,
Bruker Avance 400 MHz NMR or Jeol ECX 400MHz. NMR spectra were obtained as
DMSO-d6 solutions (reported in ppm). Other NMR solvents were used as needed.
When peak multiplicities are reported, the following abbreviations are used: s =
singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets,
dt = doublet of triplets.
LCMS indicates liquid chromatography mass spectrometry (Rt = retention time). Where
ratios of solvents are given, the ratios are by volume.
Mass spectra (MS) were recorded using either electrospray ionisation (ESI) or
atmospheric pressure chemical ionisation (APCI). Mass spectroscopy was carried out
using a Finnigan Navigator single quadrupole electrospray mass spectrometer,
Finnigan aQa APCI mass spectrometer or Applied Biosystem Q-Trap
Where it is stated that compounds were prepared in the manner described for an
earlier Preparation or Example, the skilled person will appreciate that reaction times,
number of equivalents of reagents and reaction temperatures may have been
modified for each specific reaction, and that it may nevertheless be necessary, or
desirable, to employ different work-up or purification conditions.
LCMS systems
Where singleton compounds are analysed by LCMS, there are 16 methods used,
shown below:
System 1
A: 0.1 % formic acid in water
B: 0.1 % formic acid in acetonitrile
Column: Agilent Extend C 18 phase 50 x 3mm with 3 micron particle size
Gradient: 95-0% A over 3.5 min, 1 min hold, 0.4 min re-equilibration, 1.2 mL/min flow
rate
UV: 2 10nm - 450nm DAD
Temperature: 50°C
System 2
A: 0.1 % formic acid in water
B: 0.1 % formic acid in acetonitrile
Column: C 18 phase Waters Sunfire 50 x 4.6mm with 5 micron particle size
Gradient: 95-5% A over 3 min, 1 min hold, 2 min re-equilibration, 1 mL/min flow rate
UV: 2 10nm - 450nm DAD
Temperature: 50°C
System 3
A: 0.1 % formic acid in water
B: 0.1 % formic acid in acetonitrile
Column: C 18 phase Phenomenex 20 x 4.0mm with 3 micron particle size
Gradient: 98-2% A over 1.5min, 0.3 min hold, 0.2 re-equilibration, 1.8 mL/min flow
rate
UV: 2 10nm - 450nm DAD
Temperature: 75°C
System 4
A: 0.1 % formic acid in water
B: 0.1 % formic acid in 70% MeOH:30% IPA
Column: C 18 phase Phenomenex 20 x 4.0mm with 3 micron particle size
Gradient: 98-10% A over 1.5min, 0.3 min hold, 0.2 re-equilibration, 2 mL/min flow rate
UV: 2 10nm - 450nm DAD
Temperature: 75°C
System 5
A: 0.05 % formic acid in water
B: 0.05% formic acid in acetonitrile
Column: C 18 phase Phenomenex Gemini, 50 x 4.60 mm with 3 micron particle size.
Gradient: 5% B to 95% B over 3.5 minutes. Hold to 4.5 minutes. 2.0 mL/min flow rate
UV: 200 nm- 400 nm DAD
Temperature: 40°C.
System 6
A: water
B : acetonitrile
D: 1.0% formic acid in acetonitrile
Column: XBridge C 18 2.1 x 30 mm with 5 micron particle size
Gradient: 5% B to 95% B over 2.3 minutes. Hold to 3.5 minutes. 1.0 mL/min flow rate
UV: 2 15 nm-350 nm DAD
Temperature: 25°C.
System 7
A: 10 mM Ammonium Acetate in water (basic Buffer)
B: Acetonitrile
Column: Xbridge C 18 4.6 X 50 mm with 5 micron particle size
Gradient: from 90% [Buffer] and 10% [MeCN] to 70% [Buffer] and 30% [MeCN] in 1.5
min, further to 10% [buffer] and 90% [MeCN] in 3.0 min, held for 4 min and back to
initial condition in 5 min),
1.2 mL/m inflow rate
UV: 220nm
Temperature: 25°C
System 8
A: 0.1 % Formic acid in water (v/v) [Buffer]
B: 0.1 % Formic acid in acetonitrile (v/v) [MeCN]
Column: Phenomenex Gemini-NX C 18 4.6 X 50 mm with 3 micron particle size
Gradient: From 95% [Buffer] and 5% [MeCN] to 0% [Buffer] and 100% [MeCN] from
0.0 - 4.1 min, held from 4.1 -4.5 min and finally back to initial condition from 4.5-5.0
min, 1.5 mL/min flow rate
UV: 200nm - 450nm DAD
Temperature: 60°C
System 9
A: 0.05% Formic acid in water (acidic buffer)
B: Acetonitrile
Column: Gemini C 18 4.6 X 50 mmwith 5 micron particle size
Gradient: From 90% [Buffer] and 0% [MeCN] to 70% [Buffer] and 30% [MeCN] in 1.5
min, further to 10% [buffer] and 90% [MeCN] in 3.0 min, held for 4 min and finally
back to initial condition in 5 min), 1.2 mL/min flow rate
UV: 220nm
Temperature: 25°C
System 10
A: 20 mM Ammonium formate in water (basic Buffer)
B: Acetonitrile
Column: Gemini-NX 5 m C18 110A 50 4.6 mm column
Gradient: 5-95% A over 3.5 min, 1 min hold, 95-5% A over 0.1 min, 2 mL/min flow
rate
UV: 2 10 nm - 450 nm DAD 2 mL/min flow rate
UV: 260nm
Temperature: 40°C
System 11
A: 20 mM Ammonium formate in water (basic Buffer)
B: Acetonitrile
Column: XBridge C 18 5 m 50 4.6 mm column
Gradient: 5-95% A over 3.5 min, 1 min hold, 95-5% A over 0.1 min, 2 mL/min flow
rate
UV: 2 10 nm - 450 nm DAD 2 mL/min flow rate
Temperature: 25°C
System 12
A: 0.05% Formic acid in water (acidic buffer)
B: 0.05% Formic acid in Acetonitrile
Column: Gemini-NX 5 m C18 110A 50 4.6 mm column
5-95% A over 3.5 min, 1 min hold, 95-5% A over 0.1 min, 2 mL/min flow rate
UV: 2 10 nm - 450 nm DAD 2 mL/min flow rate
Temperature: 40°C
System 13
A: 0.05% Formic acid in water (acidic buffer)
B: 0.05% Formic acid in Acetonitrile
Column: XBridge C 18 5 m 50 4.6 mm column
5-95% A over 3.5 min, 1 min hold, 95-5% A over 0.1 min, 2 mL/min flow rate
UV: 2 10 nm - 450 nm DAD 2 mL/min flow rate
Temperature: 25°C
System 14
A: 0 .1% formic acid in water (v/v)
B: 0.1 % formic acid in acetonitrile (v/v)
Column: Acid: Waters Acquity UPLC BEH, 2.1 mmx50mm, C 18 , 1.7mi
Gradient Profiles: Flow-1 .25ml/min
1.5 min Run: Initial conditions: A-95%:B-5%; hold at initial from 0.0-0.1 min; Linear
Ramp to A-5%:B-95% over 0.1 - 1 .Omin; hold at A-5%:B-95% from 1.0-1 .1min; return
to initial conditions 1. 1 - 1 .5min
Temperature: 60°C
System 15
Column: Waters symmetry 2.1 *50mm 5 m
Mobile phase: from 0% MeCN (0.1 %TFA) in water (0.1 %TFA) to 60% MeCN
(0. 1%TFA) in water (0. 1%TFA)
Wavelength: 220nm
System 16
A: 0.0375% TFA in water
B: 0.01 875% TFA in MeCN
Column: Welch XB-C1 8 2.1 x50mm 5 m
Gradient: From 99% [A] and 1% [B] to 95% [A] and 5% [B] in 1 min, further to 100%
[B] in 4.0 min and finally back to initial condition in 4.30 min, 0.8 mL/minflow rate
UV: API-ES
Temperature 50°C
Preparative HPLC:
Where singleton compounds are purified by preparative HPLC, there are two methods
used, shown below:
Method 1 acidic conditions
Column Gemini NX C 18 , 5um 2 1.2 x 100mm
Temperature Ambient
Detection ELSD-MS
Mobile Phase A 0.1 % formic acid in water
Mobile Phase B 0.1 % formic acid in acetonitrile
Gradient initial 0%B, 1 mins- 5%B; 7 mins - 98% B; 9 mins - 98% B; 9.1 mins -
5% B; 10 mins -5% B
Flow rate 18 mL/min
Injection volume 1000uL
Method 2 basic conditions
Column Gemini NX C 18 , 5um 2 1.2 x 100mm
Temperature Ambient
Detection ELSD-MS
Mobile Phase A 0.1 % diethylamine in water
Mobile Phase B 0.1 % diethylamine in acetonitrile
Gradient initial 0%B, 1 mins- 5%B; 7 mins - 98% B; 9 mins - 98% B; 9.1 mins -
5% B; 10 mins -5% B
Flow rate 18 mL/min
Injection volume 1000uL
Example 1
7-Ethyl-4-[6-fluoro-4'-(propan-2-ylsulfonyl)biphenyl-3-yl1-7/-/-imidazo[4,5-clpyridazine
To a solution of 7-ethyl-4-(4-fluoro-3-iodophenyl)-7/-/-imidazo[4,5-c]pyridazine
(Preparation 10, 4 1 mg, 0.1 1 mmol) and 4-(isopropylsulfonyl)phenylboronic acid (38
mg, 0.1 7 mmol) in anhydrous dioxane (2.0 ml_) was added aqueous Na2C0 3 ( 1M
solution, 0.56 ml_, 0.56 mmol) and the solution was degassed.
Tetrakis(triphenylphosphine)palladium(0) (6.9 mg, 0.0060 mmol) was added and the
reaction mixture was heated to 100°C for 2 hours. The reaction was allowed to cool
to room temperature, then EtOAc ( 10 ml_) and water (10 ml_) were added. The layers
were separated and the organic layer was dried over anhydrous MgS0 4, filtered and
evaporated in vacuo. The residue was purified by preparative HPLC (Method 1) to
afford the title compound in 64% yield, 29.7 mg.
LCMS (System 6) Rt= 1.47 minutes MS m/z 425 [M+H]+
Example 2
Prepared according to the method described above for Example 1 using 4-(3-iodo-4-
fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 11, 50 mg, 0.16
mmol) and 2-fluoro-4-(methylsulfonyl)phenylboronic acid (68 mg, 0.31 mmol). The
crude product was purified by silica gel column chromatography eluting with EtOAc to
afford the title compound as a white solid in 83% yield, 53.8 mg.
H-NMR (400 MHz, CDCI3) : d ppm 1.69 (t, 3H), 3.14 (s, 3H), 4.59 (q, 2H), 7.43 (dd,
1H), 7.72 (dd, 1H), 7.79-7.83 (m, 1H), 7.85-7.88 (m, 1H), 8.28-8.32 (m, 1H), 8.29 (s,
1H), 8.32-8.36 (m, 1H), 9.38 (s, 1H).
LCMS (System 5) Rt = 1 .19 minutes MS m/z 4 15 [M+H]+
Example 3
5'-(7-Ethyl-7 -imid -clpyridazin-4-yl)-2'-fluorobiphen l-4-sulfonamide
Prepared according to the method described above for Example 1 using 7-ethyl-4-(4-
fluoro-3-iodophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 10) and 4-(4,4,5,5-
tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenesulfonamide (Preparation 80) to afford
the title compound in 57% yield, 24.8 mg.
LCMS (System 6) Rt = .27 minutes MS m/z 398 [M+H]+
Example 4
7-Ethyl-4-[4'-(ethylsulfonyl)-6-fluoro-2'-methoxybiphenyl-3-yl1-7H-imidazo[4,5-
clpyridazine
A stirred solution of 7-ethyl-4-(4-fluoro-3-iodophenyl)-7H-imidazo[4,5-c]pyridazine
(Preparation 10, 100 mg, 0.27 mmol), 2-(4-ethylsulfonyl-2-methoxyphenyl)-4, 4,5,5-
tetramethyl-[1 ,3,2]dioxaborolane (Preparation 2 1, 88 mg, 0.27 mmol) and cesium
carbonate (177 mg, 0.54 mmol) in dioxane (5 ml_) and water ( 1 ml_) was degassed
with argon for 10 minutes followed by the addition of 1, 1 '-bis(di-fe/f-butylphosphino)
ferrocene palladium dichloride (4.4 mg, 0.005 mmol). The resulting mixture was
heated at 100°C for 16 hours, cooled to room temperature and diluted with EtOAc ( 15
ml_). The organic layer was washed with water ( 10 ml_) and saturated brine solution
( 10 ml_) then dried over Na2S0 4, filtered and concentrated in vacuo. Purification by
silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 afforded the title
compound as off white solid in 13% yield, 15 mg.
H NMR (400MHz, CDCI3) : d ppm1 .36 (t, 3H), 1.68 (t, 3H), 3.18 (q, 2H), 3.90 (s, 3H),
4.58 (q, 2H), 7.35 (t, 1H), 7.50 (s, 1H), 7.54-7.60 (m, 2H), 8.21 (dd, 1H), 8.26 (s, 1H),
8.27-8.29 (m, 1H), 9.35 (s, 1H).
LCMS (System 7) Rt = 2.94 minutes MS m/z = 441 [M+H]+
Example 5
5'-(7-Ethyl-7H-imidazo[4,5-c1pyndazin-4-yl)-2'-fluoro-4-(isopropylsulfonyl)-[1 , 1 '-
biphenyll-2-carbonitrile
A solution of 6-(3-bromo-4-fluorophenyl)-9-ethyl-9H-imidazo[4,5-c]pyridazine
(Preparation 11, 58 mg, 0.1 8 mmol), bis(pinacolato)diboron (69 mg, 0.27 mmol) and
potassium acetate (35 mg, 0.35 mmol) in dioxane (5.0 ml_) at room temperature was
purged with nitrogen gas for 30 minutes. [ 1 , 1 -
bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ( 15 mg, 0.02 mmol) was added
to the reaction mixture, which was purged with nitrogen gas for a further 10 minutes.
The reaction mixture was heated under reflux at 110°C for 3 hours. The reaction was
cooled to 40°C and 2-bromo-5-(isopropylsulfonyl)benzonitrile, (Preparation 25, 60
mg, 0.21 mmol), sodium carbonate (74 mg, 0.70 mmol) in H20 (0.3 ml_) and [ 1 , 1 -
bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (16.0 mg, 0.02 mmol) were
added and the reaction mixture was purged with nitrogen gas for 30 minutes. The
reaction mixture was heated at 110°C for 16 hours. The reaction mixture was filtered
through a pad of celite, eluting with EtOAc (20 ml_). The filtrate was washed with
water (20 ml_), brine ( 10 ml_), dried over Na2S0 4 and concentrated under reduced
pressure to give a dark brown oil. The oil was purified by silica gel column
chromatography eluting with EtOAc to afford the title compound as a pale yellow oil.
The material was further purified by silica gel column chromatography eluting with
EtOAc:CH 2CI2:MeOH 1: 1 :0.1 followed by elution through an SCX-2 cartridge using
CH2CI2, MeOH and NH3/MeOH. The title compound was obtained as an off-white
solid, 26% yield, 2 1 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.39 (d, 6H), 1.70 (t, 3H) 3.30 (q, 2H) 4.61 (m,
11-1) 7.50 (m, 11-1) 7.85 (m, 1H) 8.1 9 (m, 1H) 8.33-8.43 (m, 4H) 9.45 (s, 1H).
LCMS (System 12) Rt = 2.46 minutes MS m/z 450 [M+H]+
Example 6
4-(4'-(Cvclobutylsulfonyl)-6-fluoro-2'-methoxy -ri 1'-biphenyll-3-yl)-7-ethyl-7Himidazo[
4,5-clpyridazine
A mixture of 6-(3-bromo-4-fluorophenyl)-9-ethyl-9H-imidazo[4,5-c]pyridazine
(Preparation 11, 50 mg, 0.1 56 mmol), 2-(4-(cyclobutylsulfonyl)-2-methoxyphenyl)-
4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Preparation 30, 82 mg, 0.233 mmol) and
sodium carbonate (50 mg, 0.468 mmol) in dioxane (2.5 mL) and water (0.5 mL) was
purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) ( 18 mg,
0.02 mmol) was added and the reaction heated at 98°C for 16 hours. The mixture was
diluted with CH2CI2 (30 mL), washed with water ( 10 mL), dried over Na2S0 4 and
concentrated in vacuo. The resulting gum was purified by silica gel column
chromatography eluting with EtOAc followed by preparative HPLC to afford the title
compound as a white solid 44% yield, 32 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.70 (t, 3H), 2.05(m, 2H), 2.27 (m, 2H), 2.65 (m,
2H), 2.82-2.95, (m, 4H), 4.61 (q, 2H), 6.38 (m, 1H), 6.42-6.58 (m, 3H), 8.25 (m, 1H),
8.33 (m, 1H), 8.42 (s, 1H), 9.42 (s, 1H).
LCMS (System 11) Rt = 2.88 minutes MS m/z 467 [M+H]+
Example 7
4-(4'-(Cvclopropylsulfonyl)-6-fluoro-2'-methoxy -r 1'-biphenvH-3-yl)-7-ethyl-7Himidazo[
4,5-clpyridazine
Step 1
To a degassed solution of 1-bromo-4-(cyclopropylsulfonyl)-2-methoxybenzene
(Preparation 33, 85 mg, 0.29 mmol), bis(pinacolato)diboron ( 1 11 mg, 0.44 mmol) and
potassium acetate (86 mg, 0.88 mmol) in dioxane (2 mL) was added 1, 1 '-
bis(diphenylphosphino)ferrocene-palladium(ll)dichloride (24 mg, 0.03 mmol). The
resulting mixture was stirred at 100°C for 3 hours.
Step 2
After cooling to room temperature, 6-(3-bromo-4-fluorophenyl)-9-ethyl-9Himidazo[
4,5-c]pyridazine (Preparation 11 , 84 mg, 0.26 mmol), sodium carbonate (96
mg, 0.88 mmol) and water (0.5 mL) were added, and the resulting mixture degassed
and flushed with nitrogen gas, followed by addition of
tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol). After stirring at 90°C for
1.5 hours, the mixture was cooled to room temperature and left to stand for 16 hours.
Water (3 mL) and ethyl acetate (3 mL) were added, and the resulting mixture passed
through a short pad of arbocel, then partitioned. The aqueous was extracted with
ethyl acetate (2x3 mL), and the combined organic layers dried over MgS0 4 then
concentrated in vacuo. Purification by silica gel column chromatography eluting with
1:39:60 MeOH/EtOAc/CH 2CI2 yielded a brown solid that was triturated with methanol
to afford the title compound as an off-white solid 37% yield, 49 mg,
H NMR (400 MHz, CDCI3) : d ppm 1. 15 (m, 2H), 1.41 (m, 2H), 1.71 (t, 3H), 2.54 (m,
1H), 3.91 (s, 3H), 4.59 (q, 2H), 7.40 (t, 1H), 7.53 (m, 2H), 7.60 (m, 1H), 8.30 (m, 1H),
8.36 (m, 1H), 8.47 (s, 1H), 9.46 (s, 1H).
LCMS (System 12): Rt = 2.51 minutes MS m/z 453 [M+H]+
Examples 8 - 15 were prepared according to the method described above for
Example 7 using either Step 1 and Step 2 combined or just Step 2 alone as
described, using 6-(3-bromo-4-fluorophenyl)-9-ethyl-9H-imidazo[4,5-c]pyridazine
(Preparation 11) or 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8) and
the appropriate aryl bromide or boronic ester as described.
W.
e (
0
X
I
1 I 5'-(7-Ethyl-7H-imidazor4,5-clpyndazin-4-yl)-4-(ethylsulfonyl)-2'-fluoro -ri , 1 '-
biphenyll-2-carbonitrile
Using 4-(ethylsulfonyl)-2'-fluoro-5'-(4,4,5,5-
ioxaborolan-2-yl)-[1,1-
trile (Preparation 79) and
: Rt = 2.42 min
MS m/z 436 [M+H]+
2 I 7-Ethyl-4-(6-fluoro-2'-methoxy-4'-(methylsulfonyl )-ri ,1'-biphenyll-3-yl)-7Himidazo[
4,5-clpyridazine
Using 2-(6-fluoro-2'-methoxy-4'-
)-[1,1'-biphenyl]-3-yl)-4 ,4,5,5-
,2-dioxaborolane (Preparation
11) : Rt = 2.1 8 min
MS m/z 427 [M+H]+
3 I 7-Ethyl-4-(6-fluoro-4'-(isopropylsulfonyl)-2'-methoxy -ri ,1'-biphenyl1-3-yl)-7Himidazo[
4,5-c]pyridazine
Using 2-(6-fluoro-4'-(isopropylsulfonyl)-2'-
methoxy-[1 ,1-biphenyl]-3-yl)-4, 4,5,5-
tetramethyl-1 ,3,2-dioxaborolane
(Preparation 38) and Step 2
LCMS (System 11) : Rt = 2.44 min
MS m/z 455 [M+H]+
Eampex
1 4 4-(2'-(Difluoromethvl)-4'-(ethvlsulfonvl)-6-fluoro-[1 , '-biphenvll-3-vl)-7-ethvl-7Himidazo[
4,5-clpvridazine
fluoromethyl)-4-(ethylr
e p a r a t io n 52)
Rt = 2.54 min
1 5 4-(4'-Ethanesulfonvl-6,2'-difluoro-biphenvl-3-vD-7-ethvl-7H-imidazo[4,5-
clpvn dazine
Using 2-[4-(ethylsulfonyl)-2-fluorophenyl]-
4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
Ar = (Preparation 45) and Step 2 .
LCMS (System 7) Rt = 3.05 min
MS m/z 429 [M+H]+
Examples 1 6 and 1 7 were prepared according to the method described above for
Step 2 Example 7 , using 3-(7-ethyl-7H-imidazo[4,5-c]pyridazin-4-yl)benzene boronic
acid (Preparation 63), cesium carbonate as base, and the appropriate aryl bromide
as described. The crude residues were purified by preparative HPLC (Method 1)
eluting from between 33-67% organic over a gradient time of 10 minutes.
LCMS conditions used: System 16
El
ampex
1 6 7-Ethvl-4 -r4'-(methvlsulfonvl)biphenvl-3-vll-7H-imidazor4,5-clpvridazine
lmethylsulfone
1 7 4-[3-( 1,1-dioxido-2,3-dihvdro-1 -benzothiophen-5-vl)phenvH-7-ethvl-7/-/-
imidazor4,5-clpvridazine
ihydrobenzo[b]thiophene-
Appl. WO2004/009086)
Example 1 8
5'-(7-cvclopropyl-7H-imidazo[4,5-c1pyridazin-4-yl)-2'-fluoro-4-(isopropylsulfonyl)-[1 , 1 '-
biphenyll-2-carbonitrile
Step 1
A solution of 6-(3-bromo-4-fluorophenyl)-9-cyclopropyl-9H-imidazo[4,5-c]pyridazine
(Preparation 84, 50.0 mg, 0.1 50 mmol), bis(pinacolato)diboron (57.0 mg, 0.23 mmol),
potassium acetate (29.0 mg, 0.30 mmol) in dioxane (3.5 mL) at room temperature
was purged with nitrogen for 30 minutes. [ 1 , 1 -
bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ( 1 1.0 mg, 0.02 mmol) was
added to the reaction mixture, which was further purged with nitrogen for 20 minutes.
The reaction mixture was heated to reflux for 62 hours.
Step 2
The reaction was cooled to room temperature and 2-bromo-5-
(isopropylsulfonyl)benzonitrile (Preparation 25, 48.0 mg, 0.165 mmol), sodium
carbonate (56.0 mg, 0.530 mmol) in water (0.2 mL) was added. The mixture was
purged with nitrogen for 20 minutes. [ 1 , 1 -
Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ( 1 1.0 mg, 0.01 50 mmol) was
added and the mixture was purged with nitrogen for 10 minutes and heated to 110°C.
The reaction mixture was cooled to room temperature after 1.5 hours, filtered through
celite and concentrated in vacuo. Te residue was purified using silica gel column
chromatography eluting with EtOAc/heptanes 1: 1 to 1:0 to afford an orange solution
which crystallised upon concentration. The solid was washed with EtOAc (3x5 mL)
before being diluted in acetonitrile and concentrated in vacuo 3 times. The title
compound was afforded as an off-white solid 13% yield, 10 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.25 (br s , 2H), 1.30-1 .39 (m, 8H), 3.29 (m, 1H),
3.70 (br s , 1H), 7.48 (t, 1H), 7.84 (d, 1H), 8.1 8 (d, 1H), 8.30 (s, 1H), 8.32-8.45 (m,
3H), 9.49 (s, 1H).
9F NMR (376 MHz, CDCI3 with drop of CD3OD): d - 1 11.27 ppm.
LCMS (System 13): Rt = 2.59 minutes MS m/z 462 [M+H] +
Example 19
4-Ethylsulfonylphenyl boronic acid ( 19 mg, 0.09 mmol) and 6-(3-bromo-4-
fluorophenyl)-9-cyclopropyl-9H-imidazo[4,5-c]pyridazine (Preparation 84, 25 mg,
0.075 mmol) were reacted as described in Example 18 to afford the title compound
as a pale yellow solid in 38% yield, 12 mg.
H NMR (400MHz, CDCI3) : d ppm 1.24-1 .35 (m, 7H), 3.1 7 (q, 2H), 3.69-3.72 (m, 1H),
7.40 (t, 1H), 7.83 (d, 2H), 8.01 (d, 2H), 8.1 8-8.20 (m, 1H), 8.26 (s, 1H), 8.37 (dd, 1H),
9.39 (s, 1H).
Eampex LCMS (System 7): Rt = 2.99 minutes MS m/z 423 [M+H]+
Examples 2 0 t o 2 5 were prepared according to the method described above for
Example 18, using 6-(3-bromo-4-fluorophenyl)-9-cyclopropyl-9H-imidazo[4,5-
c]pyridazine (Preparation 84) or 6-(3-iodo-4-fluorophenyl)-9-cyclopropyl-9Himidazo[
4,5-c]pyridazine (Preparation 94) or an alternative as described and the
appropriate boronic acid or ester as described.
2 0 5'-(7-Cvclopropvl-7H-imidazo[4,5-clpvridazin-4-vD-2'-fluoro-[1 ,1 '-biphenvll-4-
sulfonamide
Using 4-bromo-N-methylbenzenesulfonamide
L H I LCMS (System 11) Rt = 2.32 min
H 3C MS m/z = 4 10 [M+H]+
0 0
2 1 7-Cvclopropvl-4-(6-fluoro-4'-(methvlsulfonvl)biphenvl-3-vD-7H-imidazor4,5-
clpvridazine
Using 6-(3-chloro-4-fluorophenyl)-9-cyclopropyl-
9H-imidazo[4,5-c]pyridazine (Preparation 92)
and 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-
yl)benzenesulfonamide (Preparation 80) and
Step 2 using palladium acetate, cataCXium A
and cesium fluoride in methanol
LCMS (System 14): Rt = 0.74 mins
MS m/z 409 [M+H]+

W. e(0
X
I
5'-(7-Cvclopropyl-7H-imidazo[4,5-c1pyridazin-4-yl)-4-(ethylsulfonyl)-2'-fluoro-[1 , '-
biphenyll-2-carbonitrile
hylsulfonyl)benzonitrile
Rt = 2.45 min
Example 26
7-Cvclobutyl-4-(4'-(ethylsulfonyl)-2',6-difluoro -ri , 1 '-biphenyll-3-yl)-7H-imidazor4,5-
dpyridazine
A solution of 2-(4'-(ethylsulfonyl)-2',6-difluoro-[1 , 1 '-biphenyl]-3-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (Preparation 83, 64 mg, 0.16) in dioxane (2.5 mL) was added to
6-chloro-9-cyclobutyl-9H-imidazo[4,5-c]pyridazine (Preparation 99, 33 mg, 0.16
mmol), tetrakis(triphenylphosphine)palladium(0) ( 18 mg, 0.016 mmol), sodium
carbonate (50 mg, 0.471 mmol) and water (0.5 mL). Nitrogen gas was bubbled
through the solution for 10 minutes, and the reaction was then warmed to 80°C and
stirred for 18 hours. The reaction was cooled, diluted with EtOAc ( 10 mL), filtered
through a pad of celite washing with EtOAc ( 10 mL). The organic layers were washed
with water ( 10 mL) and brine ( 10 mL), dried over MgSO4 , filtered and the solvent
removed in vacuo. The crude material was passed through a SCX-2 cartridge
washing first with MeOH, and then 25% 7M NH3 (in MeOH) in MeOH (50 mL). The
residue was further purified by preparative HPLC (System X) to afford the title
compound as an off-white solid 15% yield, 11 mg.
H NMR (400 MHz, DMSO-d 6) : d ppm 1. 18 (t, 3H), 1.92-2.00 (m, 2H), 2.56 (m, 2H),
2.82 (m, 2H), 3.46 (q, 2H), 5.33 (m, 1H), 7.66 (m, 1H), 7.92 (m, 3H), 8.62 (m, 2H),
9.02 (s, 1H), 9.61 (s, 1H).
9F NMR (376 MHz, DMSO-d 6) : d - 1 11.4 (m, 1F), - 112.6 (m, 1F) ppm.
LCMS (System 13): Rt = 2.77 min; m/z = 455 [M+H]+
Example 27
4-[4'-(Ethylsulfonyl)-6-fluorobiphenyl-3-yl1-7-(1 -methylcyclopropyl)-7H-imidazo[4,5-
dpyridazine
Prepared according to the method described for Example 26 using 4-chloro-7-(1 -
methylcyclopropyl)-7H-imidazo[4,5-c]pyridazine (Preparation 97) and 2-(4'-
ethylsulfonyl-6-fluorobiphenyl-3-yl)-4,4,5,5-tetramethyl[1 ,3,2] dioxaborolane
(Preparation 48) to afford the title compound as an off white solid in 32% yield, 20
mg
H NMR (400MHz, CDCI3) : d ppm 1.02 (t, 3H), 1.33 (t, 3H), 2.06-2.12 (m, 2H), 3.16
(q, 2H), 4.48 (q, 2H), 7.40 (t, 1H), 7.84 (d, 2H), 8.01 (d, 2H), 8.21 -8.23 (t, 1H), 8.25 (s,
1H), 8.42 (dd, 1H), 9.37 (s, 1H).
LCMS (System 7): Rt = 3.1 0 minutes MS m/z 437 [M+H] +
Example 28
Prepared according to the method described for Example 26 using 4-chloro-7-
cyclobutyl-7H-imidazo[4,5-c]pyridazine (Preparation 99) and 2-(4'-ethylsulfonyl-6-
fluorobiphenyl-3-yl)-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane (Preparation 48) to
afford the title compound as an off white solid in 10% yield, 10 mg.
H NMR (400MHz, CDCI3) : d ppm 1.33 (t, 3H), 2.01 -2.1 1 (m, 2H), 2.71 -2.83 (m, 4H),
3.16 (q, 2H), 5.28-5.34 (m, 1H), 7.40 (t, 1H), 7.83 (d, 2H), 8.01 (d, 2H), 8.21 -8.23 (m,
1H), 8.34 (s, 1H), 8.39 (d, 1H), 9.36 (s, 1H).
LCMS (System 7): Rt = 3.35 minutes MS m/z 437 [M+H] +
Example 29
7-Cvclobutyl-4-(6-fluoro-2'-methoxy-4'-(methylsulfonyl )-ri 1'-biphenyl1-3-yl)-7Himidazo[
4,5-c]pyridazine
Prepared according to the method described for Example 26 using 2-(6-fluoro-2'-
methoxy-4'-(methylsulfonyl)-[1 ,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolane (Preparation 18) and 6-chloro-9-cyclobutyl-9H-imidazo[4,5-
c]pyridazine (Preparation 99) to afford the title compound as a colourless solid in
50% yield, 200 mg.
H NMR (400 MHz, CDCI3) : d ppm 2.01 -2.14 (m, 2H), 2.69-2.85 (m, 4H), 3.1 3 (s,
3H), 3.91 (s, 3H), 5.31 (m, 1H), 7.36 (t, 1H), 7.55-7.57 (m, 2H), 7.64 (dd, 1H), 8.22
(dd, 1H), 8.27-8.31 (m, 1H), 8.38 (s, 1H), 9.37 (s, 1H).
9F NMR (376 MHz, CDCI3) : d - 1 ppm.
LCMS (System 13): Rt = 2.61 minutes MS m/z 453 [M+H] +
Example 30
4-[4'-(Ethylsulfonyl)-6-fluorobiphenyl-3-yl1-7-propyl-7H-imidazo[4,5-clpyridazine
Prepared according to the method described for Example 26 using 4-chloro-7-
propyl-7H-imidazo[4,5-c]pyridazine (Preparation 101) and 2-(4'-ethylsulfonyl-6-
fluorobiphenyl-3-yl)-4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane (Preparation 48) to
afford the title compound as an off white solid in 10% yield, 10 mg.
H NMR (400MHz, CDCI3) : d ppm 1.02 (t, 3H), 1.33 (t, 3H), 2.06-2.12 (m, 2H), 3.16
(q, 2H), 4.48 (q, 2H), 7.40 (t, 1H), 7.84 (d, 2H), 8.01 (d, 2H), 8.21 -8.23 (t, 1H), 8.25 (s,
1H), 8.42 (dd, 1H), 9.37 (s, 1H) ppm.
LCMS (System 7): Rt = 3.27 minutes MS m/z 425 [M+H]+
Example 3 1
4-[4'-(Ethylsulfonyl)-6-fluorobiphenyl-3-yl1-7-(propan-2-yl)-7H-imidazo[4,5-c/pyridazine
A stirred solution of 4'-ethylsulfonyl-6-fluorobiphenyl-3-yl-boronic acid (Preparation
65, 30 mg, 0.097 mmol), 4-chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine
(Preparation 6 , 15 mg, 0.077 mmol) and potassium phosphite (33 mg, 0.1 54 mmol)
in dioxane (3 mL) and water (0.7 mL) was degassed with argon for 10 minutes
followed by the addition of tricyclohexylphosphine ( 1 .72 mg, 0.006 mmol) and
t s(dibenzylideneacetone)palladium(0) (2.82 mg, 0.003 mmol). The resulting mixture
was heated at 100°C for 16 hours. The reaction mixture was filtered to remove
inorganics and the filtrate was concentrated in vacuo to remove the volatiles.
Purification of the crude residue by preparative TLC eluting with 2% MeOH in DCM
afforded the title compound as off white solid in 27% yield, 9 mg.
H NMR (400MHz, CDCI3) : d ppm 1.33 (t, 3H), 1.76 (d, 6H), 3.18 (q, 2H), 5.20-5.24
(m, 1H), 7.40 (t, 1H), 7.82 (d, 2H), 8.00 (d, 2H), 8.20-8.23 (m, 1H), 8.32 (s, 1H), 8.41
(d, 1H), 9.36 (s, 1H).
LCMS (System 9): Rt = 3.27 minutes MS m/z 425 [M+H]+
Example 32
To 4-Chloro-7-isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6 , 50 mg, 0.254
mmoles) and 2'-fluoro-5'-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)biphenyl-4-
sulfonamide (Preparation 2 , 13 1 mg, 0.254 mmoles) in dioxane (2.5 mL) was added
Na2C0 3 (80 mg, 0.759 mmol) pre dissolved in water (0.5 mL) and [ 1 , 1 -
bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (7.3 mg, 0.009 mmol). The
reaction was degassed with nitrogen and heated under microwave irradiation at 90°C
for 15 minutes. After cooling, ethyl acetate and Na2S0 4 were added and the mixture
decanted and washed with ethyl acetate. Purification by silica gel column
chromatography eluting with DCM: MeOH 1:0 to 9:1 yielded the title product in 50%
yield, 57 mg.
H NMR (400 MHz, DMSO-d6): ppm 1.68 (d, 6H), 5.13 (s, 1H), 7.46 (s, 2H), 7.62
(dd, 1H), 7.85-7.91 (m, 2H), 7.94-8.01 (m, 2H), 8.54 (s, 1H), 8.63 (dd, 1H), 8.95 (s,
1H), 9.62 (s, 1H).
LCMS Rt = 0.68 minutes; MS m/z 412 [M+H]+
Example 33
2'-Fluoro-/V-methyl-5'-[7-(propan-2-yl)-7/-/-imidazo[4,5-clpyridazin-4-yl1biphenyl-4-
sulfonamide
To a solution of 2'-fluoro-/V-methyl-5'-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-
yl)biphenyl-4-sulfonamide (Preparation 44, 112 mg, 0.29 mmol) and 4-chloro-7-
isopropyl-7H-imidazo[4,5-c]pyridazine (Preparation 6 , 54 mg, 0.27 mmol) in
anhydrous dioxane ( 1 .6 mL) was added aqueous Na2C03 solution (2M, 0.41 mL,
0.81 mmol) and a stream of nitrogen gas was bubbled through the suspension for 5
minutes. Tetrakistriphenylphosphine palladium(O) (5.8 mg, 0.005 mmol) was added
and the mixture was heated under microwave irradiation at 120°C for 12 minutes. The
reaction mixture was cooled and diluted with EtOAc ( 15 mL) and water (30 mL). The
organic phase was extracted and the aqueous layer was back-extracted with EtOAc
(2 x 15 mL). The organic layers were combined, washed with brine, dried over
Na2SO4, filtered and the filtrate was evaporated in vacuo to leave a tan solid that was
suspended in EtOAc (2.5 mL) and stirred at room temperature for 18 hours. The solid
was filtered, rinsed with EtOAc (2x1 mL) and further dried to afford the title compound
as an off-white solid in 82% yield, 120 mg.
H NMR (500 MHz, CDCI3) : d ppm 1.79 (d, 6H), 2.75 (d, 3H), 4.52 (q, 1H), 5.24 (spt,
1H), 7.42 (dd, 1H), 7.81 (m, 2H), 7.99 (d, 2H), 8.26 (ddd, 1H), 8.38 (s, 1H), 8.43 (dd,
1H), 9.42 (s, 1H).
MS m/z 426 [M+H]+
Example 34
4-r4'-(Ethylsulfonyl)-2',6-difluorobiphenyl-3-yl1-7-(propan-2-yl)-7/-/-imidazor4,5-
clpyridazine
To a solution of 2-[4'-(ethylsulfonyl)-2',6-difluorobiphenyl-3-yl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (Preparation 47, 48 mg, 0.12 mmol) and 4-chloro-7-isopropyl-
7H-imidazo[4,5-c]pyridazine (Preparation 6 , 22 mg, 0.1 1 mmol) in anhydrous
dioxane (0.56 mL) was added aqueous Na2CO3 solution (2M, 0.1 7 mL, 0.34 mmol)
and a stream of nitrogen gas was bubbled through the suspension for 5 minutes.
Tetrakistriphenylphosphine palladium(O) (2.3 mg, 0.002 mmol) was added and the
mixture was heated under microwave irradiation at 120°C for a total of 15 minutes.
The reaction mixture was cooled, diluted with water (20 mL) and extracted with EtOAc
(3 x 15 mL). The organic layers were combined, washed with brine, dried over
Na2S0 4, filtered and the filtrate was evaporated in vacuo to leave a tan sticky solid
that was purified by silica gel column chromatography eluting with heptane:EtOAc to
afford the title compound as a tan solid in 80% yield, 40 mg.
H NMR (500 MHz, CDCI3) : d ppm 1.37 (t, 3H), 1.78 (d, 6H), 3.21 (q, 2H), 5.23 (spt,
1H), 7.44 (t, 1H), 7.71 - 7.75 (m, 1H), 7.78 (dd, 1H), 7.83 (dd, 1H), 8.30 - 8.39 (m,
3H), 9.40 (s, 1H).
LCMS (System 8): Rt = 3.12 minutes; MS m/z 443 [M+H] +
Example 35
2'-Fluoro-5'-(7-isopropyl-7H-imidazo[4,5-c1pyridazin-4-yl)-4-(isopropylsulfonylH1 , 1 '-
biphenyll-2-carbonitrile
A solution of 6-(3-bromo-4-fluorophenyl)-9-isopropyl-9H-imidazo[4,5-c]pyridazine
(Preparation 87, 50.0 mg, 0.1 50 mmol), bis(pinacolato) diboron (57.0 mg, 0.225
mmol), potassium acetate (29.0 mg, 0.300 mmol) in dioxane (3.5 ml_) at room
temperature was purged with nitrogen for 30 minutes. [ 1 , 1 -
Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ( 1 1.0 mg, 0.01 50 mmol) was
added to the reaction mixture, which was further purged with nitrogen for 10 minutes.
The reaction mixture was heated at reflux for 62 hours. The reaction was cooled to
room temperature and 2-bromo-5-(isopropylsulfonyl)benzonitrile (Preparation 25,
48.0 mg, 0.165 mmol), sodium carbonate (56.0 mg, 0.530 mmol) in water (0.2 ml_)
was added, purged with nitrogen for 0.25 hours. [ 1 , 1 -
Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) ( 1 1.0 mg, 0.01 50 mmol) was
added and the reaction mixture was purged with nitrogen for 10 minutes and heated
to 110°C. The reaction was cooled to room temperature after 1.5 hours, filtered
through celite and concentrated in vacuo. The residue was purified using silica gel
column chromatography eluting with EtOAc/heptanes 1: 1 to 0:1 to afford a yellow
solution which crystallised upon concentration. The solid was washed with EtOAc (3 x
Eampex 5 mL) before being diluted in acetonitrile and concentrated in vacuo. The title
compound was afforded as an off-white solid 12% yield, 9.1 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.39 (d, 6H), 1.78 (d, 6H), 3.30 (br m, 1H), 5.22 (br
m, 1H), 7.50 (br s , 1H), 7.84 (br s , 1H), 8.20 (br s , 1H), 8.30-8.49 (m, 4H), 9.44 (s,
1H).
9F NMR (376 MHz, CDCI3) : d - 1 11.53 ppm.
LCMS (System 13): Rt = 2.61 minutes; MS m/z 464 [M+H]+
Examples 3 6 to 4 1 were prepared according to the method described above for
Example 35, starting from 6-(3-bromo-4-fluorophenyl)-9-cyclopropyl-9H-imidazo[4,5-
c]pyridazine (Preparation 87) unless otherwise described and the appropriate
bromide or boronic acid as described.
3 6 4-(2',6-Difluoro-4'-(isopropvlsulfonvlW1 ,1'-biphenvll-3-vl)-7-isopropvl-7Himidazo[
4,5-clpvridazine
-4-(isopropylsulfonyl)-
34)
= 2.74 min
3 7 4-(6-Fluoro-4'-(isopropvlsulfonvD-2'-methoxv - ,1'-biphenvll-3-vD-4-isopropvl-4Himidazo[
4,5-clpvridazine
Using 2-(4-(isopropylsulfonyl)-2-methoxy-
)-4,4,5,5-tetramethyl-1,3,2-
orolane (Preparation 36) and Step
(System 13): Rt = 2.76 min
MS m/z 469 [M+H]+
Eampex
8 4-(6-Fluoro-2'-methoxv-4'-(methvlsulfonvD - ,1'-biphenvll-3-vl)-7-isopropvl-7Himidazo[
4,5-clpvridazine
Using 4-chloro-7-isopropyl-7H-imidazo[4,5-
c]pyridazine (Preparation 6 ) and 2-(6-fluoro-
2'-methoxy-4'(methylsulfonyl)-[1 ,1'-biphenyl]-
Ar = 3-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
(Preparation 18) and Step 2 .
LCMS (System 3): Rt = 2.51 min
MS m/z 441 [M+H]+
9 4-(2'-Chloro-4'-(ethvlsulfonvl)-6-fluoro-[1 ,1'-biphenvll-3-vl)-7-isopropvl-7Himidazor4,5-
clpvridazine
chloro-
0 4-(4'-(Ethylsulfonyl)-6-fluoro-2'-methoxy-[1 ,1'-biphenyl]-3-yl)-7-isopropyl-7Himidazo[
4,5-c]pyhdazine
Using 2-(4'-(ethylsulfonyl)-6-fluoro-2'-
methoxy-[1 ,1'-biphenyl]-3-yl)-4, 4,5,5-
tetramethyl-1 ,3,2-dioxaborolane
(Preparation 42) and 4-chloro-7-isopropyl-
7H-imidazo[4,5-c]pyridazine (Preparation
6 ) and Step 2 .
LCMS (System 12): Rt = 2.66 min
MS m/z 455 [M+H]+
El
ampex
4 1 4-(Ethvlsulfonvl)-2'-fluoro-5'-(7-isopropvl-7H-imidazo[4,5-clpvridazin-4-vD - ,1'-
biphenvH-2-carbonitrile
hylsulfonyl)benzonitrile
Rt = 2.49 min
Example 4 2
7-Cvclopentyl-4-(6-fluoro-2'-methoxy-4'-(methylsulfonyl )-ri 1'-biphenyl1-3-yl)-7Himidazo[
4,5-clpyridazine
To a solution of 2-(6-fluoro-2'-methoxy-4'-(methylsulfonyl)-[1 , 1 '-biphenyl]-3-yl)-4, 4,5,5-
tetramethyl-1 ,3,2-dioxaborolane (Preparation 18, 376 mg, 0.99 mmol) and 6-chloro-
9-cyclopentyl-9H-imidazo[4,5-c]pyridazine (Preparation 13, 200 mg, 0.90 mmol) in
dioxane (20 mL) was added Na2C0 3 (286 mg, 2.70 mmol) in water (5 mL). The
resulting solution was degassed with nitrogen then
tetrakis(triphenylphosphine)palladium(0) ( 104 mg, 0.09 mmol) was added and the
reaction mixture was degassed again and heated at 110°C for 18 hours. The reaction
was cooled to room temperature, diluted with EtOAc ( 100 mL) and washed with water
( 150 mL). The aqueous layer was re-extracted with EtOAc (2 x 100 mL) and the
combined organic layers were dried (Na2SO4) , filtered and concentrated under
reduced pressure to give the crude product. This material was purified by silica gel
column chromatography eluting with 30-60% EtOAc: Heptane followed by elution
through an SCX cartridge using CH2CI2 , EtOAc, THF, MeOH and 7N ammonia in
MeOH to provide the title compound as a yellow solid in 26% yield, 108 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.81 - 1 .93 (m, 2H), 1.96-2.05 (m, 2H), 2.12-2.21
(m, 2H), 2.38-2.46 (m, 2H), 3.1 3 (s, 3H), 3.91 (s, 3H), 5.25 (m, 1H), 7.36 (t, 1H), 7.55-
7.57 (m, 2H), 7.64 (dd, 1H), 8.22 (dd, 1H), 8.27-8.31 (m, 1H), 8.33 (s, 1H), 9.37 (s,
1H).
9F NMR (376 MHz, CDCI3): d - 1 11 ppm.
LCMS (System 13): Rt = 2.73 minutes MS m/z 467 [M+H] +
Example 43
7-Cvclopentyl-4-(4'-(ethylsulfonyl)-6-fluoro-2'-methoxy -ri ,1'-biphenyl1-3-yl)-7Himidazo[
4,5-c]pyridazine
A suspension of 6-chloro-9-cyclopentyl-9H-imidazo[4,5-c]pyridazine (Preparation 13,
52 mg, 0.23 mmol), 2-(4'-(ethylsulfonyl)-6-fluoro-2'-methoxy-[1 , 1 '-biphenyl]-3-yl)-
4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (Preparation 42, 100 mg, 0.24 mmol),
sodium carbonate (2.0 M aqueous solution, 0.36 ml_) in dioxane (6 ml_) were
degassed with nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (28
mg, 0.024 mmol) was added and the reaction warmed to 110°C and stirred for 18
hours. The reaction was cooled to room temperature, filtered through celite and the
celite pad was washed with CH2CI2 ( 10 ml_). Water ( 10 ml_) was added and the
product extracted with CH2CI2 (2 x 10 ml_). The organic layer was dried over Na2S0 4,
filtered and concentrated under vacuum. The residue was purified using silica gel
column chromatography eluting with EtOAc: heptanes 8:2 followed by elution through
an SCX cartridge using MeOH, EtOAc , THF, DCM, and 7N NH3 in MeOH to afford
the title compound as a pale yellow oil in 14% yield, 15.2 mg.
H NMR (400 MHz, CDCI3): d ppm 1.38 (t, 3H), 1.88 (m, 2H), 2.01 (m, 2H), 1.20 (m,
2H), 2.41 (m, 2H), 3.1 9 (q, 2H), 3.89 (s, 3H), 5.22 (m, 1H), 7.29 (dd, 1H), 7.54 (s,
1H), 7.63 (m, 2H), 8.21 (dd, 1H), 8.38 (m, 2H), 9.38 (s, 1H).
9F NMR (376 MHz, CDCI3) : - 1 11.3 ppm.
LCMS (System 12): Rt = 2.81 minutes MS m/z 481 [M+H] +
Example 44
7-Ethyl-4-(4'-(ethylsulfonyl)-2'-fluoro-6-methoxy -ri , 1 '-biphenyll-3-yl)-7H-imidazor4,5
dpyridazine
To 2-(4'-(ethylsulfonyl)-2'-fluoro-6-methoxy-[1 ,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (Preparation 69, 90 mg, 0.21 mmol) in dioxane (2.5 ml_) and
water ( 1 ml_) was added 4-chloro-7-ethyl-7H-imidazo[4,5-c/pyridazine (Preparation 8 ,
40 mg, 0.21 mmol) and sodium carbonate (68 mg, 0.64 mmol). The reaction was
degassed and tetrakis(triphenylphosphine) palladium(O) (25 mg, 0.02 mmol) was
added. The reaction was further degassed and then heated to 110°C for 2 hours and
then cooled to room temperature. The reaction mixture was diluted with EtOAc (40
ml_) was passed through celite and the solvent removed in vacuo. The crude material
was purified by reverse phase column chromatography eluting with a gradient of 0.1 %
formic acid in MeCN/water. The resulting residue was dissolved in DMSO ( 1 ml_) and
purified using preparative HPLC to give the title compound as a colourless solid in
26% yield, 24 mg.
H-NMR (400 MHz, CDCI3) : d ppm 1.37 (t, 3H), 1.68 (t, 3H), 3.1 9 (q, 2H), 3.91 (s,
3H), 4.57 (q, 2H), 7.22 (d, 1H), 7.64-7.72 (m, 2H), 7.76-7.78 (m, 1H), 8.23 (d, 1H),
8.25 (s, 1H), 8.33-8.36 (m, 1H) 9.37 (s, 1H).
LCMS (System 13): Rt = 2.22 minutes MS m/z 441 [M+H] +
Example 45
4-(6-Chloro-4'-(ethylsulfonyl)-2'-methoxy -r , 1 '-biphenyll-3-yl)-7-ethyl-7H-i
dpyridazine
Prepared according to the method described for Example 45 using 2-(6-chloro-4'-
(ethylsulfonyl)-2'-methoxy-[1 ,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
(Preparation 56) and 4-chloro-7-ethyl-7H-imidazo[4,5-c/pyridazine (Preparation 8)
to afford the title compound as an off white solid in 19% yield, 9.9 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.37 (t, 3H), 1.68 (t, 3H), 3.21 (q, 2H), 3.88 (s,
3H), 4.57 (q, 2H), 7.50 (m, 2H), 7.60 (dd, 1H), 7.68 (d, 1H), 8.14 (d, 1H), 8.24 (dd,
1H), 8.27 (s, 1H), 9.36 (s, 1H).
LCMS (system 11) : Rt = 2.44 minutes MS m/z 456 [M 5CI+H]+
Example 46
7-Ethyl-4-(4'-(ethylsulfonyl)-2',6-dimethoxy -ri , 1 '-biphenyll-3-yl)-7H-imidazor4,5-
clpyridazine
Prepared according to the method described for Example 45 using 2-(4'-
(Ethylsulfonyl)-2',6-dimethoxy-[1 ,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolane (Preparation 59) and 4-chloro-7-ethyl-7H-imidazo[4,5-c/pyridazine
(Preparation 8) to afford the title compound as an off white solid in 13% yield, 14.7
mg.
H NMR (400 MHz, CDCI3) : d ppm 1.38 (t, 3H), 1.68 (t, 3H), 3.19 (q, 2H), 3.87 (s,
6H), 4.56 (q, 2H), 7.1 9 (d, 1H), 7.53 (m, 3H), 8.12 (d, 1H), 8.25 (s, 1H), 8.35 (dd, 1H),
9.36 (s, 1H).
LCMS (System ) : Rt = 2.33 minutes MS m/z 453 [M+H]+
Example 47
5-(7-Ethyl-7H-imidazo[4,5-c1pyndazin-4-yl)-4'-(ethylsulfonyl)-2'-methoxy-[1 , 1 '-
biphenyll-2-carbonitrile
Prepared according to the method described for Example 45 using (6-cyano-4'-
(ethylsulfonyl)-2'-methoxy-[1 , 1 '-biphenyl]-3-yl)boronic acid (Preparation 67) and 4-
chloro-7-ethyl-7H-imidazo[4,5-c/pyridazine (Preparation 8) to afford the title
compound as a white solid in 10% yield, 10 .1 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.38 (t, 3H), 1.71 (t, 3H), 3.21 (q, 2H), 3.95 (s,
3H), 4.61 (q, 2H), 7.56-7.58 (m, 2H), 7.60-7.66 (m, 1H), 7.96 (d, 1H), 8.32 (s, 2H),
8.35-8.38 (m, 1H), 9.40 (s, 1H).
LCMS (System 11) : Rt = 2.30 minutes MS m/z 448 [M+H]+
Example 48
5-(7-Ethyl-7H-imidazo[4,5-c1pyridazin-4-yl)-4'-(ethylsulfonyl)-2'-methoxy-[1 , 1 '-
biphenyll-2-ol
To a stirred solution 4-chloro-7-ethyl-7H-imidazo[4,5-c/pyridazine (Preparation 8 , 80
mg, 0.44 mmol) and 4'-(ethylsulfonyl)-2'-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-[1 , 1 '-biphenyl]-2-ol (Preparation 89, 167 mg, 0.44 mmol) in
dioxane ( 15 mL) and water (5 mL) was added sodium carbonate ( 106 mg, 1.0 mmol)
and the reaction mixture was degassed before adding
tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol). The reaction was
heated to 100°C for 18 hours. After this time the reaction was allowed to cool to room
temperature, filtered through celite and the filtrate evaporated under reduced
pressure. The crude was purified by silica gel column chromatography eluting with
CH2CI2:MeOH from 95:5 to 9 :land then further purified by preparative HPLC to afford
the title compound as colourless solid 11%, 19 mg.
H NMR (400MHz CDCI3) : d ppm 1.38 (t, 3H), 1.69 (t, 3H), 3.21 (q, 2H), 4.03 (s, 3H),
4.57 (q, 2H), 7.23 (s, 1H), 7.59 (s, 1H), 7.64-7.69 (m, 2H), 8.22-8.25 (m., 3H), 9.37 (s,
1H).
LCMS: (System 13) Rt = 2.02 minutes MS m/z 439 [M+H] +
Example 49
7-Ethyl-4-[4'-(ethylsulfonyl)-6-fluorobiphenyl-3-yl1-7H-imidazo[4,5-clpyridazine
Prepared according to the method decribed for Example 44 using 4-chloro-7-ethyl-
7H-imidazo[4,5-c]pyridazine (Preparation 8) and 2-(4'ethylsulfonyl-6-fluorobiphenyl-
3-yl)-4,4,5,5-tetramethyl[1 ,3,2]dioxaborolane (Preparation 48). The crude residue
was triturated with EtOAc followed by recrystallisation from MeCN to afford the title
compound .
H NMR (400MHz CDCI3) : d ppm 1.34 (t, 3H), 1.70 (t, 3H), 3.1 7 (q, 2H), 4.61 (q, 2H),
7.42 (dd, 1H), 7.85 (d, 2H), 8.03 (d, 2H), 8.24 (ddd, 1H), 8.42 (dd, 1H), 9.39 (s, 1H).
LCMS Rt = 1.15 minutes MS m/z 4 11 [M+H]+
Example 50
7-Ethyl-4-r4-fluoro-3-(2-methyl-1 , -dioxido-2,3-dihvdro-1 ,2-benzisothiazol-5-
yl)phenyl1-7H-imidazo[4,5-clpyridazine
A solution of 7-ethyl-4-[4-fluoro-3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-
yl)phenyl]-7H-imidazo[4,5-c]pyridazine (Preparation 95, 70 mg, 0.1 90 mmol), 5-
bromo-2-methyl-2,3-dihydro-1 ,2-benzisothiazole 1, 1 -dioxide (Preparation 39, 50 mg,
0.1 90 mmol) cesium carbonate (124 mg, 0.380 mmol) in DMF (2 ml_) was degassed
with nitrogen for 30 minutes. Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
(12 mg, 0.01 9 mmol) was added and the reaction heated to 95°C for 18 hours. The
reaction was cooled and purified using silica gel column chromatography eluting with
0-1 00% EtOAc in DCM to afford the title compound (26 mg, 32%).
H NMR (400MHz CDCI3) : d ppm 1.68 (t, 3H), 3.00 (s, 3H), 4.42 (s, 2H), 4.59 (q, 2H),
7.41 (t, 1H), 7.63 (s, 1H), 7.78 (d, 1H), 7.93 (d, 1H), 8.20-8.25 (m, 1H), 8.27 (s, 1H),
8.39 (d, 1H), 9.38 (s, 1H).
LCMS Rt = 2.19 minutes MS m/z 424 [M+H] +
Preparations Section
Preparation 1
5'-Bromo-2'-fluorobiphenyl-4-sulfonamide
To 4-bromo-1 -fluoro-2-iodobenzene (361 mg, 1.2 mmol) and 4-sulfamoylphenylboronic
acid (240 mg, 1.20 mmol) in 4:1 dioxane/H 2O (5 ml_) was added
Na2CO3 (382 mg, 3.60 mmol) and [ 1 , 1 '-Bis(diphenylphosphino)-
ferrocene]dichloropalladium(ll) (34.3 mg, 0.042 mmol). The reaction was heated
under microwave irradiation at 120°C for 15 minutes, cooled and diluted with EtOAc
and water. The aqueous layer was extracted with EtOAc and the combined organic
layers dried over Na2SO4. The solvent was removed in vacuo and the resulting
residue purified via silica gel column chromatography eluting with EtOAc: heptanes 0:1
to 1:1 to afford the desired product 55%, 2 18 mg, 55%.
LCMS Rt= 0.79 minutes MS m/z 331 [M+H]+
Preparation 2
2'-Fluoro-5'-(4A5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)biphenyl-4-sulfonamide
5'-bromo-2'-fluorobiphenyl-4-sulfonamide (Preparation 1 , 118 mg, 0.303 mmol) and
bis(pinacolato)diboron ( 199 mg, 0.785 mmole), KOAc (123 mg, 1.25 mmoles) and
Pd(dppf)CI 2 (14.7 mg, 0.01 8 mmole) were suspended in dioxane (5 mL) and DMSO
(0.2 mL). The reaction was heated under microwave irradiation at 90°C for 20 minutes
and the solvents removed under reduced pressure. Purification via silica gel column
chromatography eluting with EtOAc: heptanes 0:1 to 1: 1 afforded the title compound in
8 1% yield, 110 mg.
H-NMR (400 MHz, CDCI3) : d ppm 1.25 (s, 12H), 6.20-6.29 (m, 2H), 7.04-7. 11 (m,
1H), 7.56-7.61 (m, 2H), 7.69-7.74 (m, 1H), 7.77-7.81 (m, 1H), 7.89 (d, 2H).
LCMS Rt = 0.89 minutes MS m/z 378 [M+H]+
Preparation 3
3,4,5-Trichloropyridazine
4,5-dichloropyridazin-3(2H)-one ( 10.0g, 60.6 mmole) in POCI3 (60 mL, 642 mmole)
was stirred at 110°C for 18 hours. Toluene was added and the solvents removed
under reduced pressure. EtOAc (200 mL) and water were added to the resulting
residue and the organic layer washed with water and brine and then dried over
MgSO4. Concentration under reduced pressure provided the desired product as an
off whie solid in 90% yield, 10 g .
H NMR (400 MHz, CDCI3) : d ppm 9.1 0 (d, 1H).
HPLC (Method 2): Rt = 3.35 minutes
Preparation 4
3,5-Dichloropyridazin-4-amine
A mixture of 3,4,5-trichloropyridazine (Preparation 3, 500 mg, 2.73 mmole) in EtOH
(5.5 mL) and NH4OH (5.5 mL) was heated under microwave irradiation 120°C for 25
minutes. Concentration under reduced pressure and purification via silica gel column
chromatography eluting with acetone:dichloromethane (0-1 5% acetone), provided the
title product in 36% yield, 163 mg.
H NMR (400 MHz, CDCI3) : d ppm 5.1 1 (br s , 2H), 8.74 (s, 1H).
LCMS Rt= 0.27 minutes MS m/z 164 [M+H] +
Preparation 5
5-Chloro-/V--isopropylpyridazine-3,4-diamine
HOAc (2.47 mL, 42.7 mmol) was added dropwise to a mixture of 3,5-
dichloropyridazin-4-amine (Preparation 4 , 1000 mg, 6.098 mmol) and isopropylamine
(7.27 mL, 85.4 mmol) cooled to 0°C. The resulting solid/suspension was heated under
microwave irradiation at 105°C for 5 hours. The reaction mixture was dissolved in
minimum amount of MeOH and purified by silica gel column chromatography eluting
with EtOAc: heptane: 10%-90% to provide the title compound as a slightly brownish
solid in 74% yield, 2.52 g .
H NMR (400 MHz, CDCI3) : d ppm 1.22-1 .25 (m, 6H), 4.37 (d, 1H), 4.91 (d, 1H), 5.06
(s, 2H), 8.29 (s, 1H).
LCMS Rt= 0.4 minutes MS m/z 187 [M 5CI+H]+
Preparation 6
4-Chloro-7-isopropyl-7H-imidazo[4,5-clpyridazine
A mixture of 5-chloro-/V -isopropylpyridazine-3,4-diamine (Preparation 5 , 1020 mg,
5.47 mmol) in triethyl orthoformate (9 mL) was heated at 130°C for 80 minutes. The
solvent was removed in vacuo and the residue dissolved in MeOH/DCM and purified
by silica gel column chromatography eluting with EtOAc:heptane 0-63% to provide the
titled product product as a white solid in 76% yield, 816 mg.
H NMR (400 MHz, CDCI3) : d ppm 1.76 (d, 6H), 5.10-5.23 (m, 1H), 8.34 (s, 1H), 9.14
(s, 1H).
LCMS Rt = 1. 1 minute MS m/z 197 [M 5CI+H]+
Preparation 7
5-Chloro-/V--ethylpyridazine-3,4-diamine
A mixture of 3,5-(dichloropyridazin-4-yl)amine (Preparation 4 , 15 g , 92 mmol) and
anhydrous ethylamine (50 mL) was heated to 120°C for 48 hours in a sealed tube.
The reaction mixture was cooled to room temperature, and then added to a mixture of
water (500 mL) and EtOAc (50 mL). The resulting precipitate was separated by
filtration and the filter cake was washed with tBME, and dried under vacuum to afford
the title compound as off-white solid in 5 1% yield, 8.1 g .
H-NMR (400 MHz, DMSO-d 6) : d ppm 1. 18 (t, 3H), 3.41 (q, 2H), 6.08-6.1 1 (m, 3H),
8.09 (s, 1H).
Preparation 8
4-Chloro-7-ethyl-7H-imidazo[4,5-c/pyridazine
A mixture of 5-chloro-/V -ethyl-pyridazine-3,4-diamine (Preparation 7 , 10.0 g , 58
mmol) and triethylorthoformate (60 mL) were heated to reflux for 4 hours. The
reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc
(50 mL) and filtered. The filter cake was washed with EtOAc and then the organic
layers were washed with saturated brine solution, dried over Na2SO4 and
concentrated in vacuo to afford the title compound as a yellow solid in 45% yield,
4.8g.
Preparation 9
7-Ethyl-4-(4-fluorophenyl)-7/-/-imidazo[4,5-clpyridazine
To a room temperature solution of 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine
(Preparation 8 , 9.6 g , 52.4 mmol) in dioxane (300 mL) was added 4-fluorobenzene
boronic acid (8.8 g , 63 mmol) and an aqueous solution of Na2CO3 ( 1M, 260 mL, 262
mmol). The reaction mixture was degassed and purged with nitrogen gas 3
times. Tetrakis(triphenylphosphine)palladium(0) ( 1 .2 g , 1.0 mmol) was then added and
the mixture was heated to reflux for 4 hours. The organic solvent was removed in
vacuo and the resulting aqueous mixture filtered. The filter cake was dried under
vacuum to afford the title compound as a yellow solid in 55% yield, 7g.
H NMR (400 MHz, CDCI3) : d ppm 1.62 (t, 3H), 4.50 (q, 2H), 7.1 9 (t, 2H), 8 .14-8.18
(m, 2H), 8.21 (s, 1H), 9.27 (s, 1H).
Preparation 10
7-Ethyl-4-(4-fluoro-3-iodophenyl)-7/-/-imidazo[4,5-clpyridazine
Concentrated sulphuric acid ( 10 mL) was carefully added to 7-ethyl-4-(4-
fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 9 , 825 mg, 2.4 mmol)
surrounded by an ice bath, and the resultant reaction mixture was gently stirred at
room temperature until a homogeneous solution was observed. To this was added
1,3-diiodo-5,5-dimethylhydantoin ( 1 .36 g , 3.58 mmol) portion-wise, and stirring was
continued for 5 minutes. The viscous mixture was then slowly poured into an
aqueous sodium hydroxide solution ( 1M, 10 ml_) at 0°C with stirring. The black
suspension slowly dissolved to give a blue solution. CH2CI2 (20 ml_) was added and
the layers were separated. The organic layer was washed with saturated aqueous
sodium bisulfite solution (20 ml_) then concentrated in vacuo. The residue was
purified using silica gel column chromatography eluting with heptane: EtOAc 1: 1 to
0:1 00 to afford the title compound as a white solid in 95% yield, 1.19g.
H-NMR (400 MHz, CDCI3) : d ppm 1.70 (t, 3H), 4.58 (q, 2H), 8.1 9-8.23 (m, 1H), 8.29
(s, 1H), 8.65 (dd, 1H), 9.32 (s, 1H).
LCMS Rt= 1.44 minutes MS m/z 369 [M+H] +
Preparation 11
4-(3-Bromo-4-fluoro-phenyl)-7-ethyl-7/-/-imidazo[4,5-clpyridazine
Concentrated sulphuric acid (66 g , 0.67 mol) was carefully added to 7-ethyl-4-(4-
fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 9 , 2.3 g , 9.5 mmol)
surrounded by an ice bath, and the resultant reaction mixture was gently stirred at
room temperature until a homogeneous solution was observed. To this solution was
added 1,3-dibromo-5,5-dimethylhydantoin (2.7 g , 9.5 mmol) portion-wise, and stirring
was continued at 0°C for 2 hours. The reaction mixture was poured carefully into
aqueous sodium bisulphite (200 ml_), and then basified with an aqueous sodium
hydroxide solution (2 M) to pH = 8 keeping the temperature below 20°C. EtOAc (50
ml_) was added and the layers were separated. The aqueous layer was extracted with
EtOAc (2 x 50 ml_). The combined organic phases were washed with saturated brine
solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by
silica gel column chromatography eluting with petroleum ether:CH 2CI2 1: 1 followed by
trituration with EtOAc to afford the title compound as a white solid in 4 1% yield, 1.25g.
H NMR (400 MHz, CDCI3): d ppm 1.70 (t, 3H), 4.58 (q, 2H), 7.26-7.34 (m, 1H), 8.16-
8.25 (m, 1H), 8.31 (s, 1H), 8.44-8.50 (m, 1H), 9.32 (s, 1H).
HPLC (System 15): Rt = 2.98 minutes LRMS MS m/z 323 [M8 Br+H]+
Preparation 12
5-Chloro-/V--cvclopentylpyridazine-3,4-diamine
3,5-Dichloropyridazin-4-amine (Preparation 4 , 1 g , 6.09 mmol) was added to
cyclopentylamine (3.0 mL, 30.41 mmol) and water ( 1 mL) in a stainless steel sealed
container. The mixture was heated for 16 hours at 150°C. The reaction mixture was
cooled to room temperature then evaporated in vacuo. The residue was purified by
silica gel column chromatography eluting with EtOAc to afford the title compound as
yellow solid in 90% yield, 1.17 g .
H NMR (400 MHz, CDCI3) : d ppm 1.43 (m, 2H), 1.76 (m, 4H), 2.21 (m, 2H), 4.1 7 (m,
1H), 4.39 (br s , 2H), 4.48 (m, 1H), 8.39 (s, 1H).
LCMS (System 12): Rt = 1. 15 minutes MS m/z 2 13 [M+H]+
Preparation 13
4-Chloro-7-cvclopentyl-7H-imidazo[4,5-clpyridazine
A mixture of 5-chloro-N-3-cyclopentylpyridazine-3,4-diamine (Preparation 12, 1.2 g ,
5.64 mmol) and triethylorthoformate ( 10 mL) were heated to reflux for 1.5 hours. The
reaction mixture was allowed to cool to room temperature, concentrated in vacuo and
triturated with EtOAc (20 mL). The solid was filtered and the filtrate was reduced to
dryness. The crude material was purified by silica gel column chromatography eluting
with EtOAc to afford the title compound as a yellow solid in 5 1% yield, 902 mg.
H NMR (400 MHz, CD3OD): d ppm 1.85 (m, 2H), 2.07 (m, 2H), 2.26 (m, 2H), 2.44
(m, 2H), 5.22 (dt, 1H), 8.82 (s, 1H), 9.1 9 (s, 1H).
LCMS (System 13): Rt = 1.97 minutes MS m/z 223 [M+H]+
Preparation 14
1-Bromo-2-fluoro-4-(methylsulfonyl)benzene
A solution of 4-bromo-3-fluorobenzene sulphonyl chloride ( 10 g , 36.56 mmol) in THF
( 100 mL) was cooled to 0°C and hydrazine monohydrate (6.2 mL, 127.96 mmol) was
added dropwise. After the addition, the reaction was left to stir at room temperature
for 1 hour before adding heptane (500 mL). The precipitate formed was filtered off
and re-dissolved in industrial methylated spirit (200 mL). Sodium acetate ( 18 g ,
2 19.36 mmol) was added followed by iodomethane ( 11.38 mL, 182.8 mmol). The
reaction mixture was stirred at reflux for 18 hours. The reaction was cooled to room
temperature and the solvent was concentrated to half of the initial volume. Water
(300 ml_) was added and the product was extracted with EtOAc (3x300 ml_). The
combined organic layers were washed with brine (300 ml_) and dried (Na2S0 4) ,
filtered and concentrated under reduced pressure. The crude residue was purified by
silica gel column chromatography eluting from 15% to 35% EtOAc/heptane to afford
the title compound as a colourless solid in 48% yield, 4.40 g .
H NMR (400 MHz, CDCI3) : d ppm 3.04 (s, 3H), 7.62 (dd, 1H), 7.70 (dd, 1H), 7.80
(dd, 1H).
9F NMR (376 MHz, CDCI3) : d - 102 ppm.
LCMS (System 13): Rt = 2.50 minutes MS m/z no ionisation.
Preparation 15
1-Bromo-2-methoxy-4-(methylsulfonyl)benzene
To a solution of 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (Preparation 14, 1.5 g ,
5.93 mmol) in MeOH (12 ml_) was added sodium methoxide (480 mg, 8.89 mmol) and
the reaction mixture was irradiated at 100°C in the microwave for 1.5 hours. After this
time the reaction was quenched with water (50 ml_) and the product was extract with
EtOAc (3x50 ml_). The combined organic layers were dried (Na2S0 4) , filtered and
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography eluting with 20-40% EtOAc in heptane to afford the title compound
as colourless solid in 53% yield.
H NMR (400 MHz, CDCI3) : d ppm 3.06 (s, 3H), 3.98 (s, 3H), 7.39-7.41 (m, 2H), 7.75
(d, 1H).
LCMS (System 13): Rt = 2.49 minutes MS m/z no ionisation.
Preparation 16
2-(2-Methoxy-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
To a solution of 1-bromo-2-methoxy-4-(methylsulfonyl)benzene (Preparation 15, 4.39
g , 16.56 mmol) in dioxane (100 ml_) was added bis(pinacolato)diboron (4.62 g , 18.21
mmol) and potassium acetate (4.88 g , 49.68 mmol). The resulting mixture was
degassed then [ 1 , 1 '-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll) ( 1 .21 g ,
1.66 mmol) was added and degassed again. The reaction mixture was heated at
reflux for 3 hours and cooled to room temperature for 18 hours. Water (300 ml_) was
added to the reaction mixture, which was then filtered through celite and the celite
washed with EtOAc (300 ml_). The filtrate phases were separated and the organic
layer was washed with brine (300 mL) then dried (Na2S0 4) , filtered and concentrated
under reduced pressure. The residue was purified using silica gel column
chromatography eluting with 20-50% EtOAc: heptane to afford the title compound as a
yellow solid in 59% yield, 3.04 g .
H NMR (400 MHz, CDCI3) : d ppm 1.36 (s, 12H), 3.04 (s, 3H), 3.91 (s, 3H), 7.36 (d,
1H), 7.49 (dd, 1H), 7.82 (d, 1H).
LCMS (System 13): Rt = 2.71 minutes MS m/z 330 [M+NH 4]+
Preparation 17
5'-Bromo-2'-fluoro-2-methoxy-4-(methylsulfonyl)-1 ,1'-biphenyl
A solution of 2-(2-methoxy-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolane (Preparation 16, 3.04 g , 9.74 mmol), 5-bromo-2-fluoro-iodobenzene
(2.66 g , 8.85 mmol), and Na2CO3 (2.80, 26.55 mmol) in dioxane (60 mL) and water
( 15 mL) was degassed, tetrakis(triphenylphosphine)palladium(0) was added and the
reaction mixture was degassed again. The reaction mixture was heated at 110°C for 3
hours before cooling to room temperature and concentrating under reduced pressure.
The residue was partitioned between water (100 mL) and EtOAc ( 100 mL). The
organic phase was separated and the aqueous layer was re-extracted with EtOAc
(2x1 00 mL). The combined organic layers were dried (Na2SO4) , filtered and
concentrated under reduced pressure to give the crude. The crude was purified by
silica gel column chromatography eluting with 10-30% EtOAc/heptane to afford the
title compound in 7 1% yield, 2.25 g .
H NMR (400 MHz, CDCI3) : d ppm 3.1 1 (s, 3H), 3.89 (s, 3H), 7.04 (t, 1H), 7.43-7.51
(m, 4H), 7.60 (dd, 1H).
9F NMR (CDCIs, 376 MHz): d - 1 16 ppm.
LCMS (System 13): Rt = 3.1 0 minutes MS m/z no ionization.
Preparation 18
2-(6-Fluoro-2'-methoxy-4'-(methylsulfonyl )-ri ,1'-biphenyl1-3-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane
A solution of 5'-bromo-2'-fluoro-2-methoxy-4-(methylsulfonyl)-1 , 1 '-biphenyl
(Preparation 17, 2.25 g , 6.26 mmol), bis(pinacolato)diboron ( 1 .75 g , 6.89 mmol) and
potassium acetate ( 1 .84 g , 18.78 mmol, 3 eq) in dioxane (75 mL) was degassed then
[ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (51 1 mg, 0.626 mmol)
was added and the mixture was degassed again. The reaction mixture was heated at
reflux for 18 hours. The reaction was cooled to room temperature, diluted with
CH2CI2 ( 100 ml_), and filtered through celite and the celite washed with CH2CI2. The
filtrate was concentrated under reduced pressure to give the crude material, which
was purified by silica gel column chromatography eluting with 15% to 30% EtOAc in
heptane to afford the title compound as colourless oil in quantitative yield, 2.80 g .
H NMR (400 MHz, CDCI3) : d ppm 1.33 (s, 12H), 3.10 (s, 3H), 3.87 (s, 3H), 7.1 3 (dd,
1H), 7.46-7.49 (m, 2H), 7.58 (dd, 1H), 7.75 (dd, 1H), 7.81 -7.85 (m, 1H).
9F NMR (376 MHz, CDCI3) : d - 109 ppm.
LCMS (System 13): Rt = 3.38 minutes MS m/z no ionisation.
Preparation 19
1-Bromo-4-(ethylsulfonyl)-2-fluorobenzene
To solution of 4-bromo-3-fluorobenzene-1 -sulfonyl chloride (50 g , 0.1 84 mol) in THF
(800 ml_) at 0°C was added hydrazine monohydrate (40-50%, 4 1.26 g , 0.644 mol)
dropwise over 45 minutes. The reaction was stirred for 4 hours at room temperature
and then the solvent was removed under reduced pressure to low volume. Heptane
( 100 ml_) was added and the solid was filtered and washed several times with
heptanes. The resulting solid was dissolved in ethanol (800 ml_). Sodium acetate
(90.56 g , 1. 104 mol) and ethyl iodide (143.49 g , 0.92 mol) were added and the
reaction heated to reflux for 18 hours. The reaction was allow to cool to room
temperature, the solvent was removed under reduced pressure to 30% of the initial
volume. The reaction mixture was diluted with water (500 ml_) and extracted with
CH2CI2 (3x 250 ml_). The combined organic layers were washed with brine (2x300
ml_), dried over Na2S0 4, filtered and reduced to dryness to give a yellow oil. The
crude was absorbed onto silica and purified (using siica gel column chromatography
eluting with cyclohexane/EtOAc 8/2 to give the title compound as yellow solid in 64%
yield, 3 1.70 g .
H NMR (400 MHz, CDCI3) : d ppm 1.29 (t, 3H), 3.14 (q, 2H), 7.57-7.59 (m, 1H), 7.65
(dd, 1H), 7.89 (dd, 1H).
LCMS (System 13): Rt = 2.26 minutes MS m/z no ionization.
Preparation 20
1-Bromo-4-(ethylsulfonyl)-2-methoxybenzene
In a sealed vessel 1-bromo-4-(ethylsulfonyl)-2-fluorobenzene (Preparation 19, 34.89
g , 0.1 3 1 mol) was dissolved in MeOH (400 mL) and sodium methoxide (35.3 g , 0.653
mol) was added. The reaction was heated at 100°C for 12 hours and then allowed to
cool to room temperature. The reaction mixture was diluted with water (750 mL) and
the aqueous layer was extracted with CH2CI2 (2x250 mL). The combined organic
layers were washed with brine (300 mL), dried over Na2S0 4, filtered and reduced to
dryness to give a solid. The crude was purified by silica gel column chromatography
eluting with cyclo-hexane/EtOAc gradient from 95/5 to 8/2 to afford the title
compound as colourless solid in 75% yield, 27.32 g .
H NMR (400 MHz, CDCI3) : d ppm 1.29 (t, 3H), 3.12 (q, 2H), 3.97 (s, 3H), 7.35-7.38
(m, 2H), 7.74 (d, 1H).
LCMS (System 13): Rt = 2.26 minutes MS m/z no ionization.
1-Bromo-4-(ethylsulfonyl)-2-methoxybenzene may also be prepared according to the
following Preparation:
Step 1
To a pre-cooled suspension of 2-bromo-5-fluorophenol (5 g , 26.1 8 mmol) and
potassium carbonate ( 10.84 g , 78.54 mmol) in DMF ( 15 mL) at 0-5 °C, was added
methyl iodide (4.75 mL, 39.27 mmol) and the resulting reaction mixture was stirred at
room temperature for 16 hours. The reaction mixture was partitioned between water
(20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer
was further extracted with EtOAc (3 x 50 mL). The organic layers were combined,
washed with saturated brine solution (20 mL) and dried over Na2SO4, filtered and
concentrated in vacuo to afford 1-bromo-4-fluoro-2-methoxybenzene as a colourless
liquid in 93% yield, 5.00 g .
H NMR (400MHz, DMSO-d 6) : d ppm 3.86 (s, 3H), 6.74-6.79 (m, 1H), 7.06 (dd, 1H),
7.57-7.65 (m, 1H).
Step 2
To a room temperature solution of 1-bromo-4-fluoro-2-methoxybenzene (5.00 g ,
24.39 mmol) in DMF ( 15 mL) was added sodium ethanethiolate (2.66 g , 3 1.7 1mmol)
and the resulting reaction mixture was stirred for 72 hours. The reaction mixture was
partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was
separated and the aqueous layer was further extracted with EtOAc (3 x 50 mL). The
organic layers were combined and washed with saturated brine solution (20 mL) then
dried over Na2SO4, filtered and concentrated in vacuo. The crude material was
purified by silica gel column chromatography eluting with hexane: EtOAc 98:2 to afford
1-bromo-4-ethylthio-2-methoxybenzene as a colourless liquid in 17% yield, 1.00 g .
H NMR (400MHz, DMSO-d 6) : d ppm 1.24 (t, 3H), 3.01 (q, 2H), 3.85 (s, 3H), 6.82 (dd,
1H), 6.98 (s, 1H), 7.48 (d, 1H) ppm.
Step 3
To a room tempertature solution of 1-bromo-4-ethylthio-2-methoxybenzene ( 1 .00 g ,
4.05 mmol) in acetic acid (60 mL) was added sodium perborate monohydrate (889
mg, 8.91 mmol) and the resulting reaction mixture was stirred for 16 hours. The
reaction was concentrated in vacuo and the resulting crude was partitioned between
water (20 mL) and CH2CI2 (50 mL). The organic layer was separated, washed with
saturated brine solution (20 mL) then dried over Na2SO4, filtered and concentrated to
afford the title product as a colorless liquid in 88% yield, 900 mg.
H NMR (400MHz, DMSO-d 6) : d ppm 1. 1 1 (t, 3H), 3.34 (q, 2H), 3.96 (s, 3H), 7.38 (dd,
1H), 7.47 (d, 1H), 7.88 (d, 1H).
Preparation 2 1
2-(4-(Ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
A suspension of 1-bromo-4-(ethylsulfonyl)-2-methoxybenzene (Preparation 20, 2.00
g , 7.1 7 mmol), bis(pinacolato)diboron (3.16 g , 10.75 mmol),
bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (293 mg, 0.359 mmol) and
potassium acetate ( 1 .76 g , 17.93 mmol) in dioxane (40 mL) was degassed with
nitrogen for 20 minutes and placed on a pre-heated hot plate at 100°C. The reaction
was stirred at 100°C for 18 hours. The reaction was cooled to room temperature,
filtered through celite and washed with EtOAc (50 mL). Water (75 mL) was added
and the product extracted with EtOAc (2x50 mL), dried over Na2SO4, filtered and
concentrated under vacuum.

Claims
wherein
R is selected from (Ci-C 4)alkyl, (C3-C4)cycloalkyl, NH2, and NH(Ci-
C4)alkyl and R2 is H; or
R and R2 together are -CH 2-CH 2- or -N(CH 3)-CH2- ;
R3 is selected from H, F, CHF2, OCH3 and CN;
R4 is selected from H, F, CI, OH, OCH3 and CN; and
R5 is selected from (C2-C4)alkyl, (C3-C5)cycloalkyl and methylsubstituted
(C3-C5)cycloalkyl,
or a pharmaceutically acceptable salt thereof.
2 . The compound according to claim 1 wherein R is (C2-C4)alkyl and R2 is H, or
a pharmaceutically acceptable salt thereof.
3 . The compound according to claim 1 or claim 2 wherein R3 is selected from F
and OCH3, or a pharmaceutically acceptable salt thereof.
4 . The compound according to any one of claims 1 to 3 wherein R4 is selected
from H and F, or a pharmaceutically acceptable salt thereof.
5 . The compound according to any one of claims 1 to 4 wherein R5 is (C2-
C4)alkyl, or a pharmaceutically acceptable salt thereof.
6 . The compound according to claim 1 selected from:
7-ethyl-4-(6-fluoro-4'-((1 -methylethyl)sulfonyl)biphenyl-3-yl)-7H-imidazo[4,5-
c]pyridazine;
4-(4'-ethanesulfonyl-6-fluoro-2'-methoxybiphenyl-3-yl)-7-ethyl-7H-imidazo[4,5-
c]pyridazine;
7-cyclopropyl-4-(4'-ethylsulfonyl-6-fluorobiphenyl-3-yl)-7H-imidazo[4,5-
c]pyridazine; and
4-(4'-ethanesulfonyl-2',6-difluorobiphenyl-3-yl)-7-(1 -methylethyl)-7Himidazo[
4,5-c]pyridazine.
7 . The compound according to claim 1 which is 4-(4'-ethanesulfonyl-6-fluoro-2'-
methoxybiphenyl-3-yl)-7-ethyl-7H-imidazo[4,5-c]pyridazine.
8 . A compound according to any one of claims 1 to 7 for use as a medicament.
9 . The compound according to claim 8 for use in the treatment of pain.
10 . A pharmaceutical composition comprising a compound according to any one
of claims 1 to 7 and a pharmaceutically acceptable excipient.
11. A method of treating pain comprising the administration to a subject in need of
such treatment of an effective amount of a compound according to any one of
claims 1 to 7 .
12. The use of a compound according to any one of claims 1 to 7 for the
manufacture of a medicament for treating pain.
13 . The use of a compound according to any one of claims 1 to 7 for treating pain.
14. A combination comprising a compound according to any one of claims 1 to 7
and a second pharmaceutically active agent.