Patent Application
20120004244
This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of the production of leukotrienes, such as leukotriene C4. The compounds are of potential utility in the treatment of respiratory and/or inflammatory diseases. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.
Arachidonic acid is a fatty acid that is essential in the body and is stored in cell membranes. They may be converted, e.g. in the event of inflammation, into mediators, some of which are known to have beneficial properties and others that are harmful. Such mediators include leukotrienes (formed by the action of 5-lipoxygenase (5-LO), which acts by catalysing the insertion of molecular oxygen into carbon position 5) and prostaglandins (which are formed by the action of cyclooxygenases (COXs)). Huge efforts have been devoted towards the development of drugs that inhibit the action of these metabolites as well as the biological processes that form them.
Of the leukotrienes, leukotriene (LT) B4 is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C4, D4 and E4 (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma. It has also been suggested that the CysLTs play a role in inflammatory mechanisms. The biological activities of the CysLTs are mediated through two receptors designated CysLT, and CysLT2, but the existence of additional CysLT receptors has also been proposed. Leukotriene receptor antagonists (LTRas) have been developed for the treatment of asthma, but they are often highly selective for CysLT1. It may be hypothesised that better control of asthma, and possibly also COPD, may be attained if the activity of both of the CysLT receptors could be reduced. This may be achieved by developing unselective LTRas, but also by inhibiting the activity of proteins, e.g. enzymes, involved in the synthesis of the CysLTs; 5-LO, 5-lipoxygenase-activating protein (FLAP), and leukotriene C4 synthase may be mentioned. However, a 5-LO or a FLAP inhibitor would also decrease the formation of LTB4. For a review on leukotrienes in asthma, see H.-E Claesson and S.-E. Dahlén J. Internal Med. 245, 205 (1999).
There are many diseases/disorders that are inflammatory in their nature or have an inflammatory component. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).
Asthma is a chronic inflammatory disease affecting 6% to 8% of the adult population of the industrialized world. In children, the incidence is even higher, being close to 10% in most countries. Asthma is the most common cause of hospitalization for children under the age of fifteen.
Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled β-agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds on a regular basis.
There is a considerable under-treatment of asthma, which is due at least in part to perceived risks with existing maintenance therapy (mainly inhaled corticosteroids). These include risks of growth retardation in children and loss of bone mineral density, resulting in unnecessary morbidity and mortality. As an alternative to steroids, LTRas have been developed. These drugs may be given orally, but are considerably less efficacious than inhaled steroids and usually do not control airway inflammation satisfactorily.
This combination of factors has led to at least 50% of all asthma patients being inadequately treated.
A similar pattern of under-treatment exists in relation to allergic disorders, where drugs are available to treat a number of common conditions but are underused in view of apparent side effects. Rhinitis, conjunctivitis and dermatitis may have an allergic component, but may also arise in the absence of underlying allergy. Indeed, non-allergic conditions of this class are in many cases more difficult to treat.
Chronic obstructive pulmonary disease (COPD) is a common disease affecting 6% to 8% of the world population. The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of COPD.
Other inflammatory disorders which may be mentioned include:
Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several malignancies are known to have inflammatory components adding to the symptomatology of the patients.
Thus, new and/or alternative treatments for respiratory and/or inflammatory disorders would be of benefit to all of the above-mentioned patient groups. In particular, there is a real and substantial unmet clinical need for an effective anti-inflammatory drug capable of treating inflammatory disorders, in particular asthma and COPD, with no real or perceived side effects.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
International patent application WO 2008/107661 discloses various biphenyl/diphenyl compounds that may be useful as LTC4 synthase inhibitors, and of use therefore in the treatment of inflammation. However, the two phenyl rings are linked together with via a methylene group. Further, international patent application WO 2009/030887 discloses, for that same use, various biaryl compounds linked together with a carbonyl group (i.e. diarylketones). However, there is no specific disclosure in that application of a biaryl/diaryl compound in which one of the requisite aromatic rings is a heteroaryl group.
According to the invention, there is provided a compound of formula I,
wherein
one of E2a, E2b and E2, represents —C(-L3-Y3)═ and the other two respectively represent E2 and E3;
Y represents —C(O)— or —C(═N—OR28)—;
R28 represents hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms;
at least one or two of D1, D2 and D3 represent(s) —N═; and/or
at least one or two of E1, E2, E3 and E4 represent(s) —N═; and
those (or the) remaining D1, D2 and D3 group(s) each independently represent —C(R1)═; and
those remaining E1, E2, E3 and E4 groups each independently represent —C(R2)═;
each R1 independently represents, on each occasion when used herein, hydrogen or a substituent selected from X1;
each R2 independently represents, on each occasion when used herein, hydrogen or a substituent selected from X2;
Y1 represents —C(O)OR9a or 5-tetrazolyl;
R9a represents:
(i) hydrogen; or
(ii) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1;
one of Y2 and Y3 represents an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A) and the other represents either:
(a) an aryl group or a heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A); or
(b) C1-12 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1;
A represents, on each occasion when used herein:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
II) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or
III) a G1 group;
X1, X2, G1 and B independently represent halo, —R5a, —C(O)R5b, —CN, —NO2, —C(O)N(R6a)R7a, —N(R6b)R7b, —N(R5c)C(O)R6c, —N(R5d)C(O)OR6d, —OR5e, —OS(O)2R5f, —S(O)mR5g, —OC(O)R5h or —S(O)2N(R6e)R7e;
R5b to R5e, R5g, R5h, R6a to R6c, R6e, R7a, R7b and R7e independently represent, on each occasion when used herein, H or R5a; or
any of the pairs R6a and R7a, R6b and R7b, or R6e and R7e may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by one or more substituents selected from fluoro, ═O, —OR5e and/or R5a;
R5f and R6d independently represent R5a;
R5a represents, on each occasion when used herein:
(i) C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —OR8a, —N(R8b)R8c, —S(O)nR8d and/or —S(O)2N(R8e)R8f; or
(ii) aryl or heteroaryl, both of which are optionally substituted by one or more substituents selected from halo, —CN, —OR8a, —N(R8b)R8c, —S(O)nR8d and/or —S(O)2N(R8e)R8f;
n represents 0, 1 or 2;
each R8b, R8d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, ═O, —OR11a and/or —N(R12a)R12b;
each R8a, R8c and R8f independently represent H or C1-3 alkyl optionally substituted by one or more substituents selected from F, ═O, —OR13a, —N(R14a)R14b, —S(O)2CH3, —S(O)2CHF2 and/or —S(O)2CF3; or
R8b and R8c and/or R8e and R8f may be linked together to form, along with the atom(s) to which they are attached, a 3- to 6-membered ring, optionally substituted by one or more substituents selected from fluoro and C1-2 alkyl;
R11a and R13a independently represent H or C1-3 alkyl optionally substituted by one or more fluoro atoms;
R12a, R12b, R14a and R14b independently represent H, —CH3 or —CH2CH3;
Z1 represents, on each occasion when used herein, ═O or ═NOR16b;
R16b represents hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms;
L1 represents a single bond or —(CH2)p-Q-(CH2)q—;
Q represents —C(Ry1)(Ry2)—, —C(O)—, —N(Ry3)— or —O—;
p and q independently represent 0, 1 or 2, but wherein the sum of p and q does not exceed 2;
L2 and L3 independently represent a single bond or a spacer group selected from —S(O)n1—, —C(Ry4)(Ry5)-A16, —N(R17a)-A16-, —OA17- and —C(O)-A17-;
n1 represents 0, 1 or 2;
A16 represents a direct (i.e. a single) bond, —C(Ry6)(Ry7)—, —C(O)—, —C(O)N(R17b)—, —C(O)C(Ry6)(Ry7)— or —S(O)2—;
each A17 independently represents a direct bond or —C(Ry8)(Ry9)—;
each Ry1, Ry2, Ry5, Ry5, Ry6, Ry7, Ry8 and Ry9 independently represent H, fluoro or C1-3 alkyl optionally substituted by one or more fluoro atoms; or
Ry1 and Ry2, Ry4 and Ry5, Ry6 and Ry7 and Ry8 and Ry9 may be linked together to form a 3- to 6-membered ring optionally substituted by one or more substituents selected from fluoro and C1-2 alkyl;
Ry3 represents hydrogen or C1-3 alkyl;
R17a and R17b independently represent hydrogen, C1-6 alkyl (optionally substituted by one or more substituents selected from heterocycloalkyl, aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from R30), fluoro, —CN, —OR19 and/or ═O), aryl or heteroaryl (both of which latter two groups are optionally substituted by one or more substituents selected from R31);
R30 and R31 independently represent halo, —R18a, —C(O)R18b, —CN, —C(O)N(R18c)R18d, —N(R18e)R18f, —N(R18g)C(O)R18h, —N(R18i)C(O)OR18j, —OR18k, —OS(O)2R18m, —S(O)mR18n, —OC(O)R18p or —S(O)2N(R18q)R18r);
m represents, on each occasion when used herein, 0, 1 or 2;
R18a, R18b, R18c, R18d, R18e, R18f, R18g, R18h, R18i, R18k, R18n, R18p, R18q and R18r independently represent hydrogen or C1-3 alkyl optionally substituted by one or more fluoro atoms;
R18j and R18m independently represent C1-3 alkyl optionally substituted by one or more fluoro atoms;
R19 represents hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms;
or a pharmaceutically-acceptable salt thereof,
which compounds and salts are referred to hereinafter as “the compounds of the invention”. Such compounds are characterised in that at least one of D1, D2, D3, E1, E2, E3 and E4 represents —N═. That is, either one of (or both) the D1 to D3-containing ring and the E1 to E4-containing ring contains (at least one) —N═.
Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
Unless otherwise specified, C1-q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3-q-cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C2-q alkenyl or a C2-q alkynyl group). Where the number of carbon atoms permits, C1-q alkyl groups may also be spiro-groups (i.e. two cycloalkyl rings linked together by a single common carbon atom), although they are preferably not so.
The term “halo”, when used herein, includes fluoro, chloro, bromo and iodo.
Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten and, most preferably, between three and eight, e.g. a 5- or 6-membered heterocycloalkyl group). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C2-q (e.g. C4-q) heterocycloalkenyl (where q is the upper limit of the range) or a C7-q, heterocycloalkynyl group. C2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called “spiro”-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S-oxidised form. At each occurrence when mentioned herein, a heterocycloalkyl group is preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or 6-membered heterocycloalkyl group).
For the avoidance of doubt, the term “bicyclic” (e.g. when employed in the context of heterocycloalkyl groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term “bridged” (e.g. when employed in the context of heterocycloalkyl groups) refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
Aryl groups that may be mentioned include C6-14 (such as C6-13 (e.g. C6-10)) aryl groups. Such groups may be monocyclic or bicyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. C6-14 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are preferably linked to the rest of the molecule via an aromatic ring.
Heteroaryl groups that may be mentioned include those which have between 5 and 14 (e.g. 10) members. Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom). Heteroaryl groups that may be mentioned include oxazolopyridyl (including oxazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl and, in particular, oxazolo[4,5-c]pyridyl and oxazolo[5,4-c]pyridyl), thiazolopyridyl (including thiazolo[4,5-b]pyridyl, thiazolo[5,4-b]pyridyl and, in particular, thiazolo[4,5-c]pyridyl and thiazolo[5,4-c]pyridyl) and, more preferably, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazopyridyl (such as imidazo[4,5-b]pyridyl, imidazo[5,4-b]pyridyl and, preferably, imidazo[1,2-a]pyridyl), indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. However, when heteroaryl groups are polycyclic, they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups may also be in the N- or S-oxidised form.
Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur.
For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which X1 and X2 both represent R5a, i.e. a C1-6 alkyl group optionally substituted as hereinbefore defined, the alkyl groups in question may be the same or different. Similarly, when groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent. For example, when there are two X1 substituents present, which represent —R5a and —C(O)R5b in which R5b represents R5a, then the identities of the two R5a groups are not to be regarded as being interdependent. Likewise, when Y2 or Y3 are substituted by more than one G1 group, then such substituents are not interdependent (i.e. they may be the same or different G1 groups). For example, when Y2 or Y3 represent e.g. an aryl group substituted by G1 in addition to, for example, C1-8 alkyl, which latter group is substituted by G1, the identities of the two G1 groups are not to be regarded as being interdependent.
For the avoidance of doubt, when a term such as “R5a to R5h” is employed herein, this will be understood by the skilled person to mean R5a, R5b, R5c, R5d, R5e, R5f, R5g and R5h inclusively.
For the avoidance of doubt, when the term “an R5 group” is referred to herein, we mean any one of R5a to R5f. For the avoidance of doubt, the term “E1 to E4-containing ring” refers to the ring containing E1, E2a, E2b, E2c and E4. Further, the term “D1 to D3-containing ring” refers to the ring containing D1, D2 and D3.
For the avoidance of doubt, the following compounds of formula Ia, Ib and Ic are included within the scope of the compounds of formula I:
wherein the integers are as defined above. The skilled person will further appreciate that compounds of formula Ia and Ic may be identical, due to rotation around the bond linking the Y group to the E1 to E4-containing ring or to the D1 to D3-containing ring. Hence, the skilled person will appreciate that, given that there is an essential ‘-L3-Y3’ group present in the compound of formula I, then one -L3-Y3 group, as it is an essential feature.
Compounds of the invention, for instance those compounds of formula I in which L2 represents —C(O)— (and Y2 is as defined herein), L1 represents a single bond and Y1 represents —C(O)OR9a (and R9a is preferably hydrogen), may exist in cyclised form and/or in equilibrium with a corresponding compound in cyclised form. By cyclised form, we mean a form in which two substituents of the same molecule undergo an intramolecular cyclisation (e.g. a reversible intramolecular cyclisation), including the following compounds of formula IA,
in which the integers are as defined herein (i.e. in respect of compounds of formula I and other preferred compounds of the invention). Such compounds may exist in particular when Y2 represents C1-12 alkyl as hereinbefore defined (e.g. acyclic C1-12 alkyl). Such compounds are encompassed within the scope of compounds of the invention (and fall within the scope of compounds of formula I). Hence, compounds of formula I in which Y2 represents —C(O)— may exist as such, may exist as compounds of formula IA, or may exist as a mixture of both (i.e. the compounds may be in equilibrium, such as a slow or rapid equilibrium measured on an NMR time scale). In such instances, the exact amount of compound of formula I or compound of formula IA may depend on the acidity of the environment, the solvent, concentration, temperature, and other factors known to the skilled person. In a further embodiment of the invention, there is provided a compound of formula IA as such and as defined above (which would include corresponding compounds of formula I in which Y2 represents —C(O)—).
Compounds of the invention that may be mentioned include those in which:
n1 represents 1;
L2 and L3 independently represent a single bond or a spacer group selected from —S(O)—, —C(Ry4)(Ry5)—, —N(R17a)—A16- and —OA17-;
A16 represents a direct bond, —C(O)—, —C(O)N(R17b)—, —C(O)C(Ry6)(Ry7)— or —S(O)2—;
R5a represents, on each occasion when used herein, C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —OR8a, —N(R8b)R8c, —S(O)nR8d and/or —S(O)2N(R8e)R8f;
R17a and R17b independently represent hydrogen, C1-6 alkyl (optionally substituted by one or more substituents selected from fluoro, —CN, —OR19 and/or ═O), aryl or heteroaryl (both of which latter two groups are optionally substituted by one or more substituents selected from halo, —R18a, —C(O)R18b, —CN, —C(O)N(R18c)R18d, —N(R18e)R18f, —N(R18g)C(O)R18h—N(R18i)C(O)OR18j, —OR18k, —OS(O)2R18m, —S(O)mR18n, —OC(O)R18p or —S(O)2N(R18q)R18r);
X1, X2, G1 and B independently represent halo, —R5a, —C(O)R5b, —CN, —C(O)N(R6a)R7a, —N(R6b)R7b, —N(R5c)C(O)R6c, —N(R5d)C(O)OR6d, —OR5e, —OS(O)2R5f, —S(O)mR5g, —OC(O)R5h or —S(O)2N(R6e)R7e;
each R8a, R8b, R8d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, ═O, —OR11a and/or —N(R12a)R12b;
when L2 or L3 represent C(Ry4)(Ry5)-A16 in which A16 is other than a direct/single bond, then A16 is preferably —C(O)—.
Other compounds of the invention that may be mentioned include those in which one of L2 and L3 represents —C(O)-A17- (e.g. —C(O)—) and the other is as hereinbefore defined (e.g. the other may represent a single bond or a spacer group selected from —S(O)n1— (e.g. —S(O)—), —C(Ry4)(Ry5)—, —N(R17a)-A16-, —OA17- and —C(O)-A17- (e.g. —C(O)—)).
Further compounds of the invention that may be mentioned include those in which:
L2 represents a single bond or, preferably, a spacer group selected from —C(Ry4)(Ry5)—, —N(R17a)-A16-, —OA17- and —C(O)-A17- (e.g. —C(O)—));
L3 independently represents a group defined by L2 above.
Further compounds of the invention that may be mentioned include those in which:
when D1, D2, D3, E1, E2, E3 and E4 represents —C(R1)═ or —C(R2)=(as appropriate), in which R1 or R2 represent a substituent defined by R5a, then R5a preferably represents C1-6 alkyl optionally substituted as defined herein;
when L2 or L3 (especially L2) represents a single bond, then Y2 preferably does not represent a 5-membered heteroaryl group, an ortho-substituted phenyl group (in which the ortho substituent is e.g. an aromatic group, alkyl or heterocycloalkyl moiety, especially an aromatic group), naphthyl, a 9- or 10-membered heteroaryl group, a cycloalkyl group or a vinyl moiety (e.g. a bicyclic 5,6-fused heteroaryl group linked via the 5-membered ring; a 5-membered heteroaryl group substituted with at least one aromatic, alkyl or heterocycloalkyl (e.g. aromatic) group; a phenyl group substituted at the ortho-position e.g. with an aromatic group; or a vinylic moiety terminally substituted with e.g. an aromatic group).
Further compounds of the invention that may be mentioned include those in which:
L2 represents a single bond or a spacer group selected from —C(Ry4)(Ry5)—, —N(R17a)-A16- and —OA17-;
L2 represents a spacer group selected from —S(O)—, —C(Ry4)(Ry5)—, —N(R17a)-A16- and —OA17-;
L2 represent a spacer group selected from —C(Ry4)(Ry5)—, —N(R17a)-A16- and —OA17-;
L3 independently represents a group defined by L2 above.
Compounds of the invention that may be mentioned include those in which:
when R5a represents C1-6 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both ═O and —OR8a (hence, when Rya represents C1-6 alkyl, then it may not be substituted by a —C(O)OR8a group);
when R5a represents C1-6 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both ═O and —N(R8b)R8c (hence, when Rya represents C1-6 alkyl, then it may not be substituted by a —C(O)N(R8b)R8c group); when any of R8a, R8b, R8d and R8e represent C1-6 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both ═O and —OR11a (hence, when such groups represent C1-6 alkyl, then it may not be substituted by a —C(O)OR11a group);
when any of R8a, R8b, R8d and R8e represent C1-6 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both ═O and —N(R12a)R12b (hence, when such groups represent C1-6 alkyl, then it may not be substituted by a —C(O)N(R12a)R12b group);
when any of R8c and/or R8f represent C1-3 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both ═O and —OR13a (hence, when such groups represent C1-3 alkyl, then it may not be substituted by a —C(O)OR13a group);
when any of R8c and/or R8f represent C1-3 alkyl, then that alkyl group may not be substituted at a terminal position of the alkyl group by both ═O and —N(R14a)R14b (hence, when such groups represent C1-3 alkyl, then it may not be substituted by a —C(O)N(R14a)R14b group);
when R17a or R17b represent a C1-6 alkyl group, then that alkyl group may not be substituted at a terminal position by both a ═O and —OR19, i.e. it may not be substituted by a —COOR19 group.
Further compounds of the invention that may be mentioned include those in which:
R5a represents, on each occasion when used herein, C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —CN, —OR8a, —N(R8b)R8c, —S(O)nR8d and/or —S(O)2N(R8e)R8f; or
R5a represents, on each occasion when used herein, C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —N(R8b)R8c, —S(O)nR8d and/or —S(O)2N(R8e)R8f;
R8a, R8b, R8d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —OR11a and/or —N(R12a)R12b; or
R8a, R8b, R8d and R8e independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, ═O and/or —N(R12a)E12b;
R8c and R8f independently represent H or C1-3 alkyl optionally substituted by one or more substituents selected from F, —OR13a, —N(R14a)R14b, —S(O)2CH3, —S(O)2CHF2 and/or —S(O)2CF3; or
R8c and R8f independently represent H or C1-3 alkyl optionally substituted by one or more substituents selected from F, ═O, —N(R14a)R14b, —S(O)2CH3, —S(O)2CHF2 and/or —S(O)2CF3; and/or
when R17a and R17b represent optionally substituted C1-6 alkyl, then the optional substituents are preferably selected from fluoro, —CN and/or —OR19 (or may alternatively be selected from fluoro, —CN and ═O);
when alkyl groups mentioned herein are substituted by halo, then that halo group is preferably fluoro.
In the compounds of the invention, when any of the pairs R6a and R7a, R6b and R7b and/or R6e and R7e are linked together to form a 3- to 6-membered ring, then preferably:
such rings are preferably 5- or 6-membered;
the ring so formed does not contain any further heteroatoms (other than the
requisite nitrogen atom to which the relevant R6 and R7 groups are necessarily attached);
when such rings are substituted with R5a then R5a represents C1-3 alkyl (e.g. ethyl, n-propyl or, more preferably, methyl) optionally substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl or difluoromethyl group);
such rings may be substituted with one or more substitutents selected from —OR5h (e.g. —OH, —OCH3, —OCF3 or —OCHF2) and, preferably, fluoro, ═O and, especially, R5a (for example, as defined above), but are more preferably unsubstituted.
In the compounds of the invention, when any of the pairs R8b and R8c and/or R8e and R8f, are linked together to form a 3- to 6-membered ring, then preferably: such rings are preferably 5- or 6-membered;
when such rings are substituted, then they are preferably substituted with one or two substituents;
such rings are preferably unsubstituted.
In the compounds of the invention, when any of the pairs Ry1 and Ry2, Ry4 and Ry5, Ry8 and Ry7 and/or Ry8 and Ry9 are linked together to form a 3- to 6-membered ring, then preferably: such rings are preferably 4-membered or, more preferably, 3-membered;
when such rings are substituted, then they are preferably substituted with one or two substituents;
such rings are preferably unsubstituted.
As stated herein, compounds of the invention that may be mentioned include those in which one or two of D1, D2 and D3 represent(s) —N═ and/or one or two of E1, E2, E3 and E4 represent(s) —N═. The skilled person will appreciate that in the compounds of the invention at least one of the D1 to D3-containing ring and E1 to E4-containing ring contains (a) nitrogen atom(s) (i.e. either one of those rings, or both of those rings contains two or preferably one nitrogen atom(s)). Preferably, either one or the other of those D1 to D3-containing ring and E1 to E4-containing rings (preferably the E1 to E4-containing ring) contains two or preferably one nitrogen atom(s), and the other does not contain any nitrogen atoms (i.e. the relevant moieties D1, D2, D3, E1, E2, E3 and E4 represent —C(R1)═ or —C(R2)═ as appropriate).
Compounds of the invention that may be mentioned include those in which:
any one or two of E1, E2, E3 and E4 represent(s) —N═, and the others each independently represent —C(R2)═);
each of D1, D2 and D3 independently represent —C(R1)═, or each of D1, D2 and D3 may alternatively and independently represent —N═.
Preferred compounds of the invention include those in which:
The most preferred of the above preferences are (i) and, especially, (iv).
Preferred compounds of the invention that may be mentioned include those in which:
Y2 and Y3 independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
when Y2 or Y3 represent optionally substituted C1-12 alkyl, then it is preferably optionally substituted cycloalkyl (such as C3-12 (e.g. C3-8) cycloalkyl and, preferably, C5-6 alkyl);
Y2 and Y3 independently represent cyclic groups optionally substituted as defined herein, i.e. aryl, heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from A), cycloalkyl or heterocycloalkyl (which latter two groups are as defined herein; and both of which are optionally substituted by one or more substituents selected from G1 and/or Z1);
Y represents —C(O)—.
Further preferred compounds of the invention that may be mentioned include those in which:
when Y2 and Y3 each represent an optionally substituted aryl or heteroaryl group, then L2 and L3 do not both represent single bonds; one of (and preferably both) L2 and L3 represent(s) a spacer group selected from —C(Ry4)(Ry5)—, —N(R17a)-A16-, and —OA17-; (e.g. one of) Y2 and Y3 represent an aryl group optionally substituted as defined herein;
when L2 or L3 represent —N(R17a)A16-, in which A16 represents a single bond and R17a represents H, then Y2 or Y3 (as appropriate) preferably does/do not represent a benzimidazolyl (e.g. benzimidazol-2-yl) group.
Preferred rings that the D1 to D3-containing ring may represent include 2- or 4-pyridyl (relative to the point of attachment to the —C(O)— moiety) or, most preferably, phenyl.
Preferred rings that the E1 to E4-containing ring may represent include pyrazinyl, pyrimidinyl, pyridazinyl and, preferably, pyridyl groups. For example:
when two of E1, E2, E3 and E4 represent —N═, then preferably the E1 to E4 containing ring represents a pyrazinyl, pyrimidinyl or pyridazinyl (e.g. E1 and E2c, E2a and E4, E1 and E2b, E2a and E2c, E2b and E4, E1 and E4, E1 and E2a, E2a and E2b, E2b and E2c, or E2c and E4 may be the two E1 to E4 groups that represent —N═, so forming for example, a 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl or 4-pyridazinyl) group (especially preferred are 2-pyrimidinyl groups);
preferably, only one of E1, E2a, E2b, E2c and E4 (e.g. E2b, preferably, E2a or Etc, or, especially, one of E1 or E4, i.e. one of the ortho positions, relative to the point of attachment with the Y moiety) represents —N═ (and the others each independently represent —C(R2)═, as appropriate), and hence the E1 to E4-containing ring is preferably a pyridyl (e.g. 4-pyridyl, 3-pyridyl or especially a 2-pyridyl) group.
Preferred aryl and heteroaryl groups that Y2 and Y3 may independently represent include optionally substituted (i.e. by A) phenyl, naphthyl (e.g. 5,6,7,8-tetrahydronaphthyl), pyrrolyl, furanyl, thienyl (e.g. 2-thienyl or 3-thienyl), imidazolyl (e.g. 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, group. Preferred groups include thienyl, thiazolyl, oxazolyl and phenyl.
Preferred substituents on Y2 and Y3 groups include:
halo (e.g. bromo or, preferably, fluoro or chloro);
cyano;
C1-6 alkyl, which alkyl group may be cyclic, part-cyclic, unsaturated or, preferably, linear or branched (e.g. C1-4 alkyl (such as ethyl, n-propyl, isopropyl, t-butyl or, preferably, n-butyl or methyl), all of which are optionally substituted with one or more halo (e.g. fluoro) groups (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl);
heterocycloalkyl, such as a 5- or 6-membered heterocycloalkyl group, preferably containing a nitrogen atom and, optionally, a further nitrogen or oxygen atom, so forming for example morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, which heterocycloalkyl group is optionally substituted by one or more (e.g. one or two) substituents selected from C1-3 alkyl (e.g. methyl) and ═O;
—S(O)mR26 (in which m is 0, 1 or 2);
wherein R26 and R27 independently represent, on each occasion when used herein, H, C1-6 alkyl, such as C1-4 alkyl (e.g. ethyl, n-propyl, t-butyl or, preferably, n-butyl, methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) groups (so forming e.g. a perfluoroethyl or, preferably, a trifluoromethyl group) or aryl (e.g. phenyl) optionally substituted by one or more halo or C1-3 (e.g. C1-2) alkyl groups (which alkyl group is optionally substituted by one or more halo (e.g. fluoro) atoms). Preferably, when the substituent is —S(O)R26 or —S(O)2R26, then R26 does not represent hydrogen.
Preferred compounds of the invention include those in which:
any two (preferably any one or, more preferably, none) of D1, D2 and D3 represents —N═;
any one of E1, E2, E3 and E4 represents —N═ and the others independently represent —C(R2)═;
E1 (or E4) represents —N═ or —C(R2)═;
E2a (or E2c) represents —C(R2)═ or —N═;
E2b represents —C(-L3-Y3)═;
when three R2 groups are present, then at least one (e.g. at least two) of those R2 groups represents hydrogen;
when two R2 groups are present, then at least one of them represents hydrogen;
at least one (e.g. at least two) R1 group that may be present represents hydrogen;
X1, X2, G1 and B independently represent —C(O)N(R6a)R7a, —N(R6b)R7b or, preferably, halo (e.g. chloro or fluoro), —R5a, —OR5e or —S(O)mR5g;
R8a, R8b, R8d and R8e independently represent hydrogen or C1-6 (e.g. C1-3) alkyl optionally substituted by one or more substituents selected from —OR11a, preferably, ═O, and especially, fluoro (most preferably, R8a, R8b, R8d and R8e independently represent —CF3, methyl or particularly, hydrogen);
R8c and R8f independently represent hydrogen or C1-3 (e.g. C1-2) alkyl optionally substituted by one or more substituents selected from —OR13a, preferably, ═O, and especially, fluoro (most preferably, R8c and R8f independently represent —CF3, methyl or particularly, hydrogen);
R11a and R13a independently represent —CF3, preferably ethyl, and particularly hydrogen and/or methyl;
R12a, R12b, R14a and R14b independently represent methyl or hydrogen (particularly, methyl);
L1 represents a single bond;
Y1 represents 5-tetrazolyl (which is preferably unsubstituted) or, preferably, —C(O)OR9a;
R9a represents C1-6 alkyl (optionally substituted by one or more G1 and/or Z1 substituents; but preferably unsubstituted) or, preferably, hydrogen; at least one of Y2 and Y3 represents aryl (e.g. phenyl) optionally substituted as defined herein;
Y2 and Y3 may be the same or different;
A represents aryl or heteroaryl (e.g. aryl, such as phenyl optionally substituted by halo, e.g. fluoro or chloro), but A preferably represents G1 or C1-6 (e.g. C1-4) alkyl (e.g. butyl (such as n-butyl) or methyl) optionally substituted by one or more substituents selected from G1;
R5a represents C1-6 (e.g. C1-4) alkyl optionally substituted by one or more substituents selected from —N(R8b)R8c and, preferably, fluoro and —OR8a;
R6a and R7a, R6b and R7b and/or R6e and R7e are preferably not linked together;
when R5e represents R5a, then R5a preferably represents C1-6 (e.g. C1-4) alkyl (which group may be substituted by one or more fluoro atoms, but is more preferably unsubstituted);
Z1 represents ═O;
R16b represents C1-2 alkyl (e.g. methyl) or, preferably, hydrogen;
L1 represents a single bond;
Q represents —C(Ry1)(Ry2)—;
p and q represent 0 or 1;
the sum of p and q is 0 or 1;
Ry1 and Ry2 independently represent fluoro, methyl or, preferably, hydrogen;
Ry1 and Ry2 are preferably not linked together;
Ry3 represents hydrogen or methyl;
L2 and L3 independently represent a single bond or, more preferably, —N(R17a)-A16- or —OA17-;
A16 represents a direct bond, —C(O)— or —S(O)2—;
Ry4, Ry5, Ry6, Ry7, Ry8 and Ry9 independently represent fluoro, methyl or, preferably, hydrogen;
Ry4 and Ry5, Ry6 and Ry7 and/or Ry8 and Ry9 are preferably not linked together;
when R17a or R17b represent optionally substituted aryl or heteroaryl, then those optional substituents are preferably selected from halo (e.g. fluoro and chloro) and R18a;
R17a and R17b represents hydrogen or C1-6 alkyl optionally substituted as hereinbefore defined (for example, by one or more substituents selected from fluoro, —CN, —OH, —OCH3 and —OCH2CH3);
R18j, R18b, R18c, R18d, R18e, R18f, R18g, R18h, R18i, R18k, R18n, R18p, R18q and R18r independently represent —CHF2 or, preferably, hydrogen, methyl or —CF3;
R18j and R18m independently represent —CHF2 or, preferably, methyl or —CF3;
when Y2 and/or Y3 represent an optionally substituted phenyl group, then that phenyl group may be substituted with a single substituent (e.g. at the para-, meta- or ortho-position) or with two substituents (e.g. with one at the para-position and the other at the meta-position or with one at the ortho- and the other at the meta-position, so forming for example a 3,4-substituted or 2,5-substituted phenyl group);
R28 represents hydrogen or unsubstituted C1-3 (e.g. C1-2) alkyl (e.g. methyl).
More preferred compounds of the invention include those in which:
E2b represents —C(-L3-Y3)=(and hence, Ea and E2, respectively represent E2 and E3);
E1 represents —N═;
E4 represents —N═ or, preferably, —C(R2)═;
E2 and E3 independently represent —C(R2)═;
each R2 independently represents hydrogen;
D2 represents —C(R1)═;
D1 and D3 independently represent —C(R1)═ or —N═;
most preferably, each D1, D2 and D3 independently represents —C(R1)=(e.g. D1,
D2 and D3 independently represent —C(H)═);
each R1 independently represents, on each occasion when used herein, hydrogen;
only one of the D1 to D3-containing ring and the E1 to E4-containing ring (preferably the E1 to E4-containing ring) contains a nitrogen atom (i.e. —N═) and the other (preferably the D1 to D3-containing ring) does not contain a nitrogen atom;
when the D1 to D3-containing ring contain a nitrogen atom, then preferably, either D1 or D3 represents —N═ and D2 represents —C(R1)═ (so forming, for example, a 2-pyridyl group);
when the E1 to E4-containing ring contains a nitrogen atom, then preferably, either E1 or E4 or both E1 and E4 represent(s) —N═ and E2 and E3 independently represent —C(R2)=(so forming, for example, a 2-pyridyl group or a 2-pyrimidinyl group);
X1, X2 and B independently represent halo (e.g. chloro or fluoro), —R5a or —OR5e (most preferably, X1, X2 and B independently represent —R5a or, preferably, halo (e.g. chloro or fluoro));
Y represents —C(O)—;
L1 represents a single bond;
Y1 represents —C(O)OR9a;
R9a represents hydrogen;
L2 represents a single bond, or, preferably L2 represents —N(R17a)-A16- or —OA17-;
L3 represents —N(R17a)-A16-;
A16 represents a direct bond, —C(O)— or —S(O)2—;
when L3 represents —N(R17a)-A16-, then A16 preferably represents a direct bond;
A17 represents a direct bond;
R17a represents hydrogen or C1-6 alkyl optionally substituted by one or more (e.g. one) substituent(s) selected from —OCH3, —OCH2CH3 and —CN;
when R17a represents optionally substituted C1-6 alkyl, then that group may represent: a linear unsaturated C1-6 (e.g. C1-4, such as C1-3) alkyl group (e.g. methyl, ethyl or propyl) optionally substituted by —OCH3, —OCH2CH3 and/or —CN, so forming for example a methoxyethyl (i.e. —(CH2)2—OCH3), ethoxyethyl or cyanopropyl (i.e. —(CH2)3—CN); a part cyclic C1-6 alkyl group (for example C1-2 alkyl (e.g. methyl) substituted by C3-5 cycloalkyl), such as cyclopropylmethyl (i.e. —CH2-cyclopropyl), cyclobutylmethyl or cyclopentylmethyl; a linear saturated C1-6 (e.g. C1-4, such as C1-3) alkyl group (in which the unsaturation is preferably one double or one triple bond), such as allyl (i.e. —CH2—CH═CH) or propynyl (i.e. —CH2≡CHCH);
Y2 and Y3 independently represent an aryl (e.g. phenyl) or heteroaryl (e.g. triazolyl, or, preferably, thiazolyl, oxazolyl or thienyl) group optionally substituted by one or more substitutents selected from A;
A represents aryl (optionally substituted by halo, such as chloro), or, preferably, G1;
G1 represents halo (e.g. chloro or fluoro), —R5a, —OR5e or —S(O)mR5g;
R5g represents R5a;
R5a represents C1-6 (e.g. C1-4) alkyl (such as methyl or butyl, e.g. n- or t-butyl; which alkyl group is optionally substituted by one or more fluoro atoms, so forming for example, a —CF3 group);
when R5e represents R5a, then R5a preferably represents C1-6 (e.g. C1-4) alkyl (which group may be substituted by one or more fluoro atoms, but is more preferably unsubstituted);
when R5g represents R5a, then R5a preferably represents unsubstituted C1-4 (e.g. C1-3) alkyl.
Particularly preferred L2 groups include a single bond, or, L2 preferably represents —O—, —N(H)—, —N(H)C(O)— and —N(H)S(O)2— (especially preferred are —O— linker groups). Particularly preferred L3 groups include —N(CH3)—, —N(ethyl)-, —N(cyclopropylmethyl)-, —N(cyclobutylmethyl)-, —N(cyclopentylmethyl)-, —N(2-ethoxyethyl)-, —N(allyl)-, —N(2-propynyl) and —N(3-cyanopropyl)- (especially preferred are —N(CH3)—, —N(cyclobutylmethyl)-, —N(cyclopentylmethyl)-, —N(2-ethoxyethyl)-, —N(allyl)- and —N(2-propynyl).
Preferred Y2 and Y3 groups that may be mentioned include optionally substituted phenyl (e.g. halophenyl (such as monohalo- or dihalo-phenyl, in which the halo atom is/are preferably chloro and/or fluoro), trifluoromethylphenyl, tert-butylphenyl, thiomethylphenyl (i.e. methylsulfanylphenyl), methylsulfinylphenyl, methylsulfonylmethylphenyl, hydroxyphenyl, n-butoxyphenyl) and thienyl (e.g. 2-thienyl; which is preferably unsubstituted). Especially preferred are optionally substituted phenyl groups (e.g. chlorophenyl and trifluoromethylphenyl).
Particularly preferred phenyl groups that Y2 and Y3 may represent include unsubstituted phenyl, 4-chlorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, 4-tert-butylphenyl, 2-thiomethylphenyl (or 2-methylsulfanylphenyl, i.e. (2-SCH3)phenyl), 2-methylsulfinylphenyl (i.e. (2-S(O)CH3)Phenyl), methylsulfonylmethylphenyl (i.e. (2-S(O)2CH3)phenyl), 2-hydroxy-5-chlorophenyl and 4-n-butoxyphenyl. Especially preferred are unsubstituted phenyl and chlorophenyl (e.g. 4-chlorophenyl and 4-trifluoromethylphenyl).
Preferred substituents on Y2 and Y3 groups (e.g. when they represent aryl or heteroaryl) include halo (e.g. chloro or fluoro), C1-6 (e.g. C1-4) alkyl (such as methyl or butyl, e.g. n- or t-butyl; which alkyl group is optionally substituted by one or more fluoro atoms, so forming for example, a —CF3 group), —S—C1-3 alkyl (e.g. —S—CH3), —S(O)—C1-3 alkyl (e.g. —S(O)CH3), —S(O)2—C1-3 alkyl (e.g. —S(O)2CH3), hydroxy (i.e. —OH), —O—C1-6 (e.g. —O—C1-4) alkyl (e.g. —O-n-butyl). Especially preferred substituents on such Y2 and Y3 groups are halo (e.g. chloro) and C1-2 alkyl (e.g. methyl) optionally (and preferably) substituted by one or more fluoro atoms (so forming, for example, a trifluoromethyl group).
Particularly preferred compounds of the invention include those of the following formula:
wherein
Y represents —C(O)— or —C(═N—OR28)—;
R28 represents hydrogen or C1-3 alkyl;
either: one or two of D1, D2 and D3 represents —N═; or one or two of E1, E2, E3 and
E4 represent(s) —N═ (i.e. either the D1 to D3-containing ring or the E1 to E4-containing ring contains one or two —N═ moieties); either:
(i) one of E1, E2, E3 and E4 (e.g. E1 or E4) represents —N═ and the others independently represent —C(R2)═; and D1, D2 and D3 each independently represent —C(R1)═;
(ii) one of D1, D2 and D3 (e.g. D1 or D3) represents —N═ and the others independently represent —C(R1)═; and E1, E2, E3 and E4 each independently represent —C(R2)═; or
(iii) two of E1, E2, E3 and E4 (e.g. E1 and E4) represent —N═ and the others independently represent —C(R2)═; and D1, D2 and D3 each independently represent —C(R1)═;
each R1 and R2 independently represent H;
Y1 represents —C(O)OR9a;
R9a represents: (i) hydrogen; or (ii) C1-8 alkyl optionally substituted by one or more substituents selected from G1 and/or Z1 (but preferably unsubstituted);
L1 represents a single bond;
L2 represents a single bond, —OA17-, —N(R17a)-A16 (e.g. —N(R17a)—CH2—, —N(R17a)—, —N(R17a)—C(O)— or —N(R17a)—S(O)2—), —C(O)-A17 (e.g. —C(O)—, —C(O)—CH2— or —C(O)-cyclopropylene-, i.e. —C(O)—C—(—CH2—CH2—)—), —S— or —S(O)—;
L3 represents a single bond, —N(R17a)-A16-, (e.g. —N(R17a)—), —OA17 (e.g. —OCH2—);
For the avoidance of doubt, all individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).
Particularly preferred compounds of the invention include those of the examples described hereinafter.
Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises:
(i) for compounds of formula I in which Y represents —C(O)—, oxidation of a compound of formula II,
wherein ring E1, E2a, E2b, Etc, E2d, E4, D1, D2, D3, L1, Y1, L2 and Y2 are as hereinbefore defined, in the presence of a suitable oxidising agent;
(ia) for compounds of formula I in which Y represents —C(O)—, oxidation of a compound of formula IIA,
wherein E1, E2a, E2b, E2c, E2d, E4, D1, D2, D3, L1, Y1, L2 and Y2 are as hereinbefore defined, in the presence of a suitable oxidising agent, for example, pyridinium chlorochromate (PCC) or the like (e.g. pyridinium dichromate; PDC);
(ii) for compounds of formula I in which L2 and/or L3 represents —N(R17a)A16- in which R17a represents H (and, preferably, Y is —C(O)— or R28 is C1-6 alkyl optionally substituted by one or more halo atoms), reaction of a compound of formula III,
or a protected derivative thereof (e.g. an amino-protected derivative or a keto-protecting group, such as a ketal or thioketal) wherein one of E2a1, E2b1, E2c1 represents —C(-L3a)═ and the other two respectively represent E2 and E3, L2a represents —NH2 or —N(R17a)A16-Y2, L3a represents —NH2 or —N(R17a)A16-Y3, provided that at least one of L2a and L3a represents —NH2, and Y, E1, E2, E3, E4, D1, D2, D3, L1 and Y1 are as hereinbefore defined, with:
(A) when A16 represents —C(O)N(R17b)—, in which R17b represents H:
Ya—N═C═O IV
Ya—NH2 V
wherein, in both cases, Ya represents Y2 or Y3 (as appropriate/required) as hereinbefore defined. For example, in the case of (a) above, in the presence of a suitable solvent (e.g. THF, dioxane or diethyl ether) under reaction conditions known to those skilled in the art (e.g. at room temperature). In the case of (b), suitable conditions will be known to the skilled person, for example the reactions may be carried out in the presence of an appropriate catalyst system (e.g. a palladium catalyst), preferably under pressure and/or under microwave irradiation conditions. The skilled person will appreciate that the compound so formed may be isolated by precipitation or crystallisation (from e.g. n-hexane) and purified by recrystallisation techniques (e.g. from a suitable solvent such as THF, hexane (e.g. n-hexane), methanol, dioxane, water, or mixtures thereof). The skilled person will appreciate that for preparation of compounds of formula I in which -L2-Y2 represents —N(H)C(O)N(H)—Y2 and -L3-Y3 represents —N(H)C(O)N(H)—Y3 and Y2 and Y3 are different, two different compounds of formula IV or V (as appropriate) will need to be employed in successive reaction steps. For the preparation of such compounds starting from compounds of formula III in which both of L2a and L3a represent —NH2, then mono-protection (at a single amino group) followed by deprotection may be necessary, or the reaction may be performed with less than 2 equivalents of the compound of formula IV or V (as appropriate);
(B) when A16 represents a direct bond, with a compound of formula VI,
Ya-La VI
wherein La represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. —OS(O)2CF3, —OS(O)2CH3, —OS(O)2PhMe or a nonaflate) or —B(OH)2 (or a protected derivative thereof, e.g. an alkyl protected derivative, so forming, for example a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group) and Ya is as hereinbefore defined, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, CuI (or CuI/diamine complex), copper tris(triphenyl-phosphine)bromide, Pd(OAc)2, Pd2(dba)3 or NiCl2 and an optional additive such as Ph3P, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, N,N′-dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, t-BuONa or t-BuOK (or a mixture thereof, optionally in the presence of 4 Å molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof) or in the absence of an additional solvent when the reagent may itself act as a solvent (e.g. when Ya represents phenyl and La represents bromo, i.e. bromobenzene). This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiation;
(C) when A16 represents —S(O)2—, —C(O)— or —C(O)—C(Ry6)(Ry7)—, with a compound of formula VII,
Ya-A16a-La VII
wherein A16a represents —S(O)2—, —C(O)— or —C(O)—C(Ry6)(Ry7)—, and Ya and La are as hereinbefore defined, and La is preferably, bromo or chloro, under reaction conditions known to those skilled in the art, the reaction may be performed at around room temperature or above (e.g. up to 40-180° C.), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, N-ethyldiisopropylamine, N-(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)-amide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine);
(iii) for compounds of formula I in which one of L2 and L3 represents —N(R17a)C(O)N(R17b)— and the other represents —NH— (or a protected derivative thereof) or —N(R17a)C(O)N(R17b)—, in which R17a and R17b represent H (in all cases), and, preferably, Y is —C(O)— or R28 is C1-6 alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula VIII,
wherein one of E2a2, E2b2, E2c2 represents —C(-J1)= and the other two respectively represent E2 and E3, one of J1 and J2 represents —N═C=O and the other represents —NH2 (or a protected derivative thereof) or —N═C═O (as appropriate), and Y, E1, E2, E3, E4, D1, D2, D3, L1 and Y1 are as hereinbefore defined, with a compound of formula V as hereinbefore defined, under reaction conditions known to those skilled in the art, such as those described hereinbefore in respect of process step (ii)(A)(b) above;
(iv) for compounds of formula I in which, preferably, Y is —C(O)— or R28 is C1-6 alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula IX,
wherein one of E2a3, E2b3, E2c3 represents —C(—Zx)═ and the other two respectively represent E2 and E3, at least one of Zx and Zy represents a suitable leaving group and the other may also independently represent a suitable leaving group, or, ZY may represent -L2-Y2 and Zx may represent -L3-Y3, in which the suitable leaving group may independently be fluoro or, preferably, chloro, bromo, iodo, a sulfonate group (e.g. —OS(O)2CF3, —OS(O)2CH3, —OS(O)2PhMe or a nonaflate), —B(OH)2, —B(ORwx)2, —Sn(Rwx)3 or diazonium salts, in which each Rwx independently represents a C1-6 alkyl group, or, in the case of —B(ORwx)2, the respective Rwx groups may be linked together to form a 4- to 6-membered cyclic group (such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), and Y, E1, E2, E3, E4, D1, D2, D3, L1, Y1, L2, Y2, L3 and Y3 are as hereinbefore defined, with a (or two separate) compound(s) (as appropriate/required) of formula X,
Ya-Lx-H X
wherein Lx represents L2 or L3 (as appropriate/required; in which they are preferably and independently selected from —N(R17a)-A16- and —OA17-), and Ya is as hereinbefore defined, under suitable reaction conditions known to those skilled in the art, e.g. such as those hereinbefore described in respect of process (ii) above (e.g. (II)(B)), for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, CuI (or CuI/diamine complex), copper tris(triphenyl-phosphine)bromide, Pd(OAc)2, Pd2(dba)3 or NiCl2 and an optional additive such as Ph3P, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, N,N′-dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, t-BuONa or t-BuOK (or a mixture thereof, optionally in the presence of 4 Å molecular sieves), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof). Alternatively, for example, when L2 or L3 represent —O— or —S-(and hence the compound of formula X is an alcohol, e.g. a phenol or a thiol, e.g. thiophenol), or, L2 or L3 represent single bonds, and Y2 or Y3 are to be attached to the requisite biaryl moiety (of the compounds of the invention, which may alternatively be termed the diaryl; for the purposes herein both terms may be interchangeably employed) via a heteroatom, e.g. nitrogen), the reaction may be performed in the presence of a mixture of KF/Al2O3 (e.g. in the presence of a suitable solvent such as acetonitrile, at elevated temperature, e.g. at about 100° C.; in this instance the leaving group that Zx or ZY may represent in the compound of formula IX is preferably fluoro). The skilled person will appreciate that when compounds of formula I in which L2 and L3 are different are required, then reaction with different compounds of formula X (for example, first reaction with a compound of formula X in which Lx represents —N(R17a)A16-, followed by reaction with another, separate, compound of formula X in which Lx represents —OA17-) may be required;
(v) compounds of formula I in which there is a R17a or R17b group present that does not represent hydrogen (or if there is R5, R6, R7, R8, R9, R11, R12, R13, R14, R16, R17 or R18 group present, which is attached to a heteroatom such as nitrogen or oxygen, and which does/do not represent hydrogen), may be prepared by reaction of a corresponding compound of formula I in which such a group is present that does represent hydrogen with a compound of formula XI,
Rwy-Lb XI
wherein Rwy represents either R17a or R17b (as appropriate) as hereinbefore defined provided that it does not represent hydrogen (or Rwy represents a R5 to R18 group in which those groups do not represent hydrogen), and Lb represents a suitable leaving group such as one hereinbefore defined in respect of La or —Sn(alkyl)3 (e.g. —SnMe3 or —SnBu3), or a similar group known to the skilled person, under reaction conditions known to those skilled in the art, for example such as those described in respect of process step (ii)(C) above. The skilled person will appreciate that various groups (e.g. primary amino groups) may need to be mono-protected and then subsequently deprotected following reaction with the compound of formula XI;
(vi) for compounds of formula I that contain only saturated alkyl groups, reduction of a corresponding compound of formula I that contains an unsaturation, such as a double or triple bond, in the presence of suitable reducing conditions, for example by catalytic (e.g. employing Pd) hydrogenation;
(vii) for compounds of formula I in which Y1 represents —C(O)OR9a, in which R9a represent hydrogen (or other carboxylic acid or ester protected derivatives (e.g. amide derivatives)), hydrolysis of a corresponding compound of formula I in which R9a does not represent H, under standard conditions, for example in the presence of an aqueous solution of base (e.g. aqueous 2M NaOH) optionally in the presence of an (additional) organic solvent (such as dioxane or diethyl ether), which reaction mixture may be stirred at room or, preferably, elevated temperature (e.g. about 120° C.) for a period of time until hydrolysis is complete (e.g. 5 hours). Alternatively, non-hydrolytic means may be employed to convert esters to acids e.g. by hydrogentation or oxidation (e.g. for certain benzylic groups) known to those skilled in the art;
(viii) for compounds of formula I in which Y1 represent —C(O)OR9a and R9a does not represent H:
R9zaOH XII
in which R9za represents R9a provided that it does not represent H, for example further in the presence of acid (e.g. concentrated H2SO4) at elevated temperature, such as at the reflux temperature of the alcohol of formula XII;
(ix) for compounds of formula I in which Y1 preferably represents —C(O)OR9a, in which R9a is other than H, and L1 is as hereinbefore defined, provided that it does not represent —(CH2)p-Q-(CH2)q— in which p represents 0 and Q represents —O—, and, preferably, Y is —C(O)— or R28 is C1-6 alkyl optionally substituted by one or more halo atoms, reaction of a compound of formula XIII,
wherein L5a represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide, a zinc-based group or a suitable leaving group such as halo or —B(OH)2, or a protected derivative thereof (e.g. an alkyl protected derivative, so forming for example a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), and Y, E1, E2a, E2b, E2c, E4, D1, D2, D3, L2 and Y2 are as hereinbefore defined (the skilled person will appreciate that the compound of formula XIII in which L5a represents an alkali metal (e.g. lithium), a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XIII in which L5a represents halo, for example under conditions such as Grignard reaction conditions, halogen-lithium exchange reaction conditions, which latter two may be followed by transmetallation, all of which reaction conditions are known to those skilled in the art), with a compound of formula XIV,
L6-Lxy-Yb XIV
wherein Lxy represents L1 (provided that it does not represent —(CH2)p-Q-(CH2)q— in which p represents 0 and Q represents —O—) and Yb represents —C(O)OR8a, in which R9a is other than H, and L6 represents a suitable leaving group known to those skilled in the art, such as C1-3 alkoxy and, preferably, halo (especially chloro or bromo). For example, the compound of formula XIV may be Cl—C(O)OR9a. The reaction may be performed under standard reaction conditions, for example in the presence of a polar aprotic solvent (e.g. THF or diethyl ether);
(x) compounds of formula I in which L1 preferably represents a single bond, and Y1 represents 5-tetrazolyl (and, preferably, Y is —C(O)— or R28 is C1-6 alkyl optionally substituted by one or more halo atoms), may be prepared in accordance with the procedures described in international patent application WO 2006/077366;
(xi) for compounds of formula I in which L1 represents a single bond, and Y1 represents —C(O)OR8a in which R8a is H, (and, preferably, Y is —C(O)— or R28 is C1-6 alkyl optionally substituted by one or more halo atoms), reaction of a compound of formula XIII as hereinbefore defined but in which L5a represents either:
R9aOH XV
wherein R9a is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst, such as PdCl2, Pd(OAc)2, Pd(Ph3P)2Cl2, Pd(Ph3P)4, Pd2(dba)3 or the like) under conditions known to those skilled in the art;
(xiii) for compounds of formula I in which Y represents —C(O)—, reaction of either a compound of formula XVI or XVII,
respectively with a compound of formula XVIII or XIX,
wherein (in all cases) E1, E2a, E2b, E2c, E4, D1, D2, D3, L1, Y1, L2 and Y2 are as hereinbefore defined, in the presence of a suitable reagent that converts the carboxylic acid group of the compound of formula XVI or XVII to a more reactive derivative (e.g. an acid chloride or acid anhydride, or the like; which reactive derivative may itself be separately prepared and/or isolated, or where such a reactive derivative may be prepared in situ) such as POCl3, in the presence of ZnCl2, for example as described in Organic and Biomolecular Chemistry (2007), 5(3), 494-500 or, more preferably, PCl3, PCl5, SOCl2 or (COCl)2. Alternatively, such a reaction may be performed in the presence of a suitable catalyst (for example a Lewis acid catalyst such as SnCl4), for example as described in Journal of Molecular Catalysis A: Chemical (2006), 256(1-2), 242-246 or under alternative Friedel-crafts acylation reaction conditions (or variations thereupon) such as those described in Tetrahedron Letters (2006), 47(34), 6063-6066; Synthesis (2006), (21), 3547-3574; Tetrahedron Letters (2006), 62(50), 11675-11678; Synthesis (2006), (15), 2618-2623; Pharmazie (2006), 61(6), 505-510; and Synthetic Communications (2006), 36(10), 1405-1411. Alternatively, such a reaction between the two relevant compounds may be performed under coupling reaction conditions (e.g. Stille coupling conditions), for example as described in Bioorganic and Medicinal Chemistry Letters (2004), 14(4), 1023-1026;
(xiv) for compounds of formula I in which Y represents —C(O)—, reaction of either a compound of formula XX or XXI,
with a compound of formula XXII or XXIII,
respectively, wherein L5b represents L5a as hereinbefore defined, and which may therefore represent —B(OH)2 (or a protected derivative thereof), an alkali metal (such as lithium) or a —Mg-halide (such as —MgI or, preferably, —MgBr), and (in all cases) E1, E2a, E2b, E2c, E4, D1, D2, D3, L1, Y1, C and Y2 are as hereinbefore defined, and (in the case of compounds of formulae XXII and XXIII), for example in the presence of a suitable solvent, optionally in the presence of a catalyst, for example, as described in Organic Letters (2006), 8(26), 5987-5990. Compounds of formula I may also be obtained by performing variations of such a reaction, for example by performing a reaction of a compound of formula XX or XXI respectively with a compound of formula XVIII or XIX as hereinbefore defined, for example under conditions described in Journal of Organic Chemistry (2006), 71(9), 3551-3558 or US patent application US 2005/256102;
(xv) for compounds of formula I in which Y represents —C(O)—, reaction of an activated derivative of a compound of formula XVI or XVII as hereinbefore defined (for example an acid chloride; the preparation of which is hereinbefore described in process step (xiii) above), with a compound of formula XXII or XXIII (as hereinbefore defined), respectively, for example under reaction conditions such as those hereinbefore described in respect of process step (xiii) above;
(xvi) for compounds of formula I in which Y represents —C(═N—OR28)—, reaction of a corresponding compound of formula I in which Y represents —C(O)—, with a compound of formula XXIIIA,
H2N—O—R28 XXIIIA
wherein R28 is represents hydrogen or C1-6 alkyl optionally substituted by one or more halo atoms, under standard condensation reaction conditions, for example in the presence of an anhydrous solvent (e.g. dry pyridine, ethanol and/or another suitable solvent);
(xvii) for compounds of formula I in which Y represents —C(═N—OR28)— and R28 represents C1-6 alkyl optionally substituted by one or more halo atoms, reaction of a corresponding compound of formula I, in which R28 represents hydrogen, with a compound of formula XXIIIB,
R28a-L7 XXIIIB
wherein R28a represents R28, provided that it does not represent hydrogen and L7 represents a suitable leaving group, such as one hereinbefore defined in respect of La (e.g. bromo or iodo), under standard alkylation reaction conditions, such as those hereinbefore described in respect of process step (ii) (e.g. (ii)(C)).
Compounds of formula II may be prepared by reaction of a compound of formula XVIII with a compound of formula XIX, both as hereinbefore defined, with formaldehyde (e.g. in the form of paraformaldehyde or an aqueous solution of formaldehyde such as a 3% aqueous solution), for example under acidic conditions (e.g. in the presence of aqueous HCl) at or above room temperature (e.g. at between 50° C. and 70° C.). Preferably, the formaldehyde is added (e.g. slowly) to an acidic solution of the compound of formula XVIII at about 50° C., with the reaction temperature rising to about 70° C. after addition is complete. When acidic conditions are employed, precipitation of the compound of formula II may be effected by the neutralisation (for example by the addition of a base such as ammonia). Compounds of formula I may also be prepared in accordance with such a procedure, for example under similar reaction conditions, employing similar reagents and reactants.
Compounds of formula IIA may be prepared by reaction of a compound of formula XXIIIC or XXIIID,
wherein E1, E2a, E2b, E2c, E4, D1, D2, D3, L1, L2, Y1 and Y2 are as hereinbefore defined, with a compound of formula XXII or XXIII, respectively, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (xiii)).
Compounds of formulae III, VIII, IX and XIII in which Y represents —C(O)—, may be prepared by oxidation of a compound of formulae XXIV, XXV, XXVI and XXVII, respectively,
wherein E1, E2a1, E2b1, E2c1, E2a2, E2b2, E2c2, E2a, E2b, E2c, E4, D1, D2, D3, L1, Y1, L2a, J2, Zy, L2, Y2 and L5a are as hereinbefore defined, under standard oxidation conditions known to those skilled in the art, for example such as those hereinbefore described in respect of preparation of compounds of formula I (process step (i) above). The skilled person will appreciate that, similarly, compounds of formulae XXIV, XXV, XXVI and XXVII may be prepared by reduction of corresponding compounds of formulae III, VIII, IX and XIII, under standard reaction conditions, such as those described herein.
Compounds of formula III in which Y represents —C(O)—, or, preferably, compounds of formula XXIV (or protected, e.g. mono-protected derivatives thereof) may be prepared by reduction of a compound of formula XXVIII,
wherein T represents —C(O)— (in the case where compounds of formula III are to be prepared) or, preferably, —CH2— (in the case where compounds of formula XXIV are to be prepared), one of E2a4, E2b4 and E2c4 represents —C(—Zz2)═, and the others respectively represent E2 and E3, Zz1 represents —N3, —NO2, —N(R17a)A16-Y2 or a protected —NH2 group, Zz2 represents —N3, —NO2, —N(R17a)A16-Y3 or a protected —NH2 group, provided that at least one of Zzl and Zz2 represents —N3 or —NO2, under standard reaction conditions known to those skilled in the art, in the presence of a suitable reducing agent, for example reduction by catalytic hydrogenation (e.g. in the presence of a palladium catalyst in a source of hydrogen) or employing an appropriate reducing agent (such as trialkylsilane, e.g. triethylsilane). The skilled person will appreciate that where the reduction is performed in the presence of a —C(O)— group (e.g. when T represents —C(O)—), a chemoselective reducing agent may need to be employed.
Compounds of formula III in which both L2a and L3a represent —NH2 (or protected derivatives thereof) may also be prepared by reaction of a compound of formula IX as defined above, with ammonia, or preferably with a protected derivative thereof (e.g. benzylamine or Ph2C═NH), under conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (iv) above).
Compounds of formulae III, IX, XXIV or XXV in which L1 represents a single bond, and Y1 represents —C(O)OR9a, may be prepared by:
(I) reaction of a compound of formula XXIX,
wherein one of E2a5, E2b5 and E2c5 represents —C(—Zq2)═, and the others respectively represent E2 and E3, Zq1 and Zq2 respectively represent Zy and Zx (in the case of preparation of compounds of formulae IX or XXV), they respectively represent L2a and L3a (in the case of preparation of compounds of formulae III or XXIV), and E1, E2, E3, E4, D1, D2, D3, Zx, Zy, L2a, L3a and T are as hereinbefore defined, with a suitable reagent such as phosgene or triphosgene in the presence of a Lewis acid, followed by reaction in the presence of a compound of formula XV as hereinbefore defined, hence undergoing a hydrolysis or alcoholysis reaction step;
(II) for such compounds in which R9a represents hydrogen, formylation of a compound of formula XXIX as hereinbefore defined, for example in the presence of suitable reagents such as P(O)Cl3 and DMF, followed by oxidation under standard conditions;
(III) reaction of a compound of formula XXX,
wherein W1 represents a suitable leaving group such as one defined by Zx and Zy above, and E1, E2a5, E2b5, E2c5, E4, D1, D2, D3, Zq1 and T are as hereinbefore defined, are as hereinbefore defined, with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO)6 or CO2(CO)8) followed by reaction in the presence of a compound of formula XV as hereinbefore defined, under reaction conditions known to those skilled in the art, for example such as those hereinbefore described in respect of preparation of compounds of formula I (process step (ii), e.g. (ii)(A)(b) above), e.g. the carbonylation step being performed in the presence of an appropriate precious metal (e.g. palladium) catalyst;
(IV) reaction of a compound of formula XXXI,
wherein W2 represents a suitable group such as an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide or a zinc-based group, and E1, E2a5, E2b5, E2c5, E4, D1, D2, D3, Zq1 and T are as hereinbefore defined, with e.g. CO2 (in the case where R9a in the compounds to be prepared represents hydrogen) or a compound of formula XIV in which Lxy represents a single bond, Yb represents —C(O)OR9a, in which R9a is other than hydrogen, and L6 represents a suitable leaving group, such as chloro or bromo or a C1-14 (such as C1-6 (e.g. C1-3) alkoxy group), under reaction conditions known to those skilled in the art. The skilled person will appreciate that this reaction step may be performed directly after (i.e. in the same reaction pot) the preparation of compounds of formula XXXI (which is described hereinafter).
Compounds of formula IX in which Zx and Zy represent a sulfonate group may be prepared from corresponding compounds in which the ZX and r groups represent a hydroxy group, with an appropriate reagent for the conversion of the hydroxy group to the sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) under conditions known to those skilled in the art, for example in the presence of a suitable base and solvent (such as those described above in respect of process step (i), e.g. an aqueous solution of K3PO4 in toluene) preferably at or below room temperature (e.g. at about 10° C.).
Compounds of formulae XX and XXI may be prepared, for example, by reaction of a corresponding compound of formula XXIII or XXII, respectively (all of which are as hereinbefore defined, e.g. in which L5b represents bromo or, preferably, iodo), for example, in the presence of a nucleophile that is a source of cyano ions, e.g. potassium or, preferably, copper cyanide.
Compounds of formulae XXII and XXIII in which L5b represents a —Mg-halide may be prepared by reaction of a compound corresponding to a compound of formula XXII or XXIII but in which L5b represents a halo group (e.g. bromo or iodo), under standard Grignard formation conditions, for example in the presence of i-PrMgCl (or the like) in the presence of a polar aprotic solvent (such as THF) under inert reaction condition, and preferably at low temperature (such as at below 0° C., e.g. at about 30° C.). The skilled person will appreciate that these compounds may be prepared in situ (see e.g. the process for the preparation of compounds of formula I (process steps (xvi) and (xvii)).
Compounds of formulae XXIIIC or XXIIID may be prepared by reaction of a corresponding compound of formula XXIII or XXII, as hereinbefore defined (and preferably one in which L5b is a —Mg-halide, such as —Mg—I), with dimethylformamide (or a similar reagent for the introduction of the aldehyde group), under standard Grignard reaction conditions known to those skilled in the art (for example those described herein).
Compounds of formulae XXIX or XXX in which T represents —CH2— may be prepared by reduction of a corresponding compound of formulae XXIX or XXX in which T represents —C(O)— (or from compounds corresponding to compounds of formulae XXIX or XXX but in which T represents —CH(OH)—), for example under standard reaction conditions known to those skilled in the art, for example reduction in the presence of a suitable reducing reagent such as LiAlH4, NaBH4 or trialkylsilane (e.g. triethylsilane) or reduction by hydrogenation (e.g. in the presence of Pd/C).
Alternatively, compounds of formulae XXIX or XXX in which T represents —CH2— may be prepared by reaction of a compound of formula XXXII,
wherein Yy represents a suitable group such as —OH, bromo, chloro or iodo, and E1, E2a5, E2b5, E2c5 and E4 are as hereinbefore defined, with a compound of formula XXXIII,
wherein M represents hydrogen and Wq represents hydrogen (for compounds of formula XXIX) or W1 (for compounds of formula XXX) and D1, D2, D3 and Zq1 are as hereinbefore defined, under standard conditions, for example in the presence of a Lewis or Brønsted acid. Alternatively, such compounds may be prepared from reaction of a compound of formula XXXII in which Yy represents bromo or chloro with a compound corresponding to a compound of formula XXXIII but in which M represents —BF3K (or the like), for example in accordance with the procedures described in Molander et al, J. Org. Chem. 71, 9198 (2006).
Compounds of formulae XXIX or XXX in which T represents —C(O)— may be prepared by reaction of a compound of formula XXXIV,
wherein Tx represents —C(O)Cl or —C═N—NH(t-butyl) (or the like) E1, E2a5, E2b5, E2c5 and E4 are as hereinbefore defined, with a compound of formula XXXIII, as defined above, but in which M represents hydrogen or an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide or a zinc-based group, or, a bromo group, and D1, D2, D3, Zq1 and Wq are as hereinbefore defined, under reaction conditions known to those skilled in the art. For example in the case of reaction of a compound of formula XXXIV in which TX represents —C(O)Cl with a compound of formula XXXIII in which M represents hydrogen, in the presence of an appropriate Lewis acid. In the case where M represents an appropriate alkali metal group, a —Mg-halide or a zinc-based group, under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formulae III, IX, XXIV or XXV (process step (IV) above) and preparation of compounds of formula XXXI (see below). In the case of a reaction of a compound of formula XXXIV in which Tx represents —C═N—NH(t-butyl) (or the like) with a compound of formula XXXIII in which M represents bromo, under reaction conditions such as those described in Takemiya et al, J. Am. Chem. Soc. 128, 14800 (2006).
For compounds corresponding to compounds of formula XXIX or XXX but in which T represents —CH(OH)—, reaction of a compound corresponding to a compound of formula XXXIV, but in which Tx represents —C(O)H, with a compound of formula XXXIII as defined above, under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formulae XXIX or XXX in which T represents —C(O)—.
Compounds of formula XXXI may be prepared in several ways. For example, compounds of formula XXXI in which W2 represents an alkali metal such as lithium, may be prepared from a corresponding compound of formula XXIX (in particular those in which Zq1 and/or Zq2 represents a chloro or sulfonate group or, especially, a protected —NH2 group, wherein the protecting group is preferably a lithiation-directing group, e.g. an amido group, such as a pivaloylamido group, or a sulfonamido group, such as an arylsulfonamido group, e.g. phenylsulfonamide), by reaction with an organolithium base, such as n-BuLi, s-BuLi, t-BuLi, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine (which organolithium base is optionally in the presence of an additive (for example, a lithium co-ordinating agent such as an ether (e.g. dimethoxyethane) or an amine (e.g. tetramethylethylenediamine (TMEDA), (−)sparteine or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and the like)), for example in the presence of a suitable solvent, such as a polar aprotic solvent (e.g. tetrahydrofuran or diethyl ether), at sub-ambient temperatures (e.g. 0° C. to −78° C.) under an inert atmosphere. Alternatively, such compounds of formula XXXI may be prepared by reaction of a compound of formula XXX in which W1 represents chloro, bromo or iodo by a halogen-lithium reaction in the presence of an organolithium base such as t- or n-butyllithium under reaction conditions such as those described above. Compounds of formula XXXI in which W2 represents —Mg-halide may be prepared from a corresponding compound of formula XXX in which W1 represents halo (e.g. bromo), for example optionally in the presence of a catalyst (e.g. FeCl3) under standard Grignard conditions known to those skilled in the art. The skilled person will also appreciate that the magnesium of the Grignard reagent or the lithium of the lithiated species may be exchanged to a different metal (i.e. a transmetallation reaction may be performed), for example to form compounds of formula XXXI in which W2 represents a zinc-based group (e.g. using ZnCl2).
Compounds mentioned herein (e.g. those of formulae IV, V, VA, VI, VII, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIIIA, XXIIIB, XXV, XXVII, XXVIII, XXXII, XXXIII and XXXIV) are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I. Fleming, Pergamon Press, 1991. Further, the compounds described herein may also be prepared in accordance with synthetic routes and techniques described in international patent application WO 2006/077366.
The substituents E1, E2a, E2b, E2c, E4, D1, D2, D3, L1, Y1, L2, Y2, L3 and Y3 in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications (e.g. from a carboxylic acid, e.g. in the presence of H2SO4 and appropriate alcohol or in the presence of K2CO3 and alkyl iodide), etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. For example, in cases where Y1 represents —C(O)OR9a in which R9a does not initially represent hydrogen (so providing at least one ester functional group), the skilled person will appreciate that at any stage during the synthesis (e.g. the final step), the relevant R9a-containing group may be hydrolysed to form a carboxylic acid functional group (i.e. a group in which R9a represents hydrogen). In this respect, the skilled person may also refer to “Comprehensive Organic Functional Group Transformations” by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995. Other specific transformation steps include: the reduction of a nitro group to an amino group; the hydrolysis of a nitrile group to a carboxylic acid group; standard nucleophilic aromatic substitution reactions, for example in which an iodo-, preferably, fluoro- or bromo-phenyl group is converted into a cyanophenyl group by employing a source of cyanide ions (e.g. by reaction with a compound which is a source of cyano anions, e.g. sodium, copper (I), zinc or, preferably, potassium cyanide) as a reagent (alternatively, in this case, palladium catalysed cyanation reaction conditions may also be employed); the reduction of an azido group to an amino group (e.g. in the presence of FeCl3 trihydrate and zinc powder); and the oxidation of a sulfide to a sulfoxide or to a sulfone (e.g. conversion of a —SCH3 substituent to a —S(O)CH3 or —S(O)2CH3 substituent in the presence of a suitable oxidising agent such as Oxone or meta-chloroperbenzoic acid (MCPBA)), or the reverse reduction in the presence of a suitable reducing agent.
Other transformations that may be mentioned include: the conversion of a halo group (preferably iodo or bromo) to a 1-alkynyl group (e.g. by reaction with a 1-alkyne), which latter reaction may be performed in the presence of a suitable coupling catalyst (e.g. a palladium and/or a copper based catalyst) and a suitable base (e.g. a tri-(C1-6 alkyl)amine such as triethylamine, tributylamine or ethyldiisopropylamine); the introduction of amino groups and hydroxy groups in accordance with standard conditions using reagents known to those skilled in the art; the conversion of an amino group to a halo, azido or a cyano group, for example via diazotisation (e.g. generated in situ by reaction with NaNO2 and a strong acid, such as HCl or H2SO4, at low temperature such as at 0° C. or below, e.g. at about −5° C.) followed by reaction with the appropriate reagent/nucleophile e.g. a source of the relevant reagent/anion, for example by reaction in the presence of a reagent that is a source of halogen (e.g. CuCl, CuBr or NaI), or a reagent that is a source of azido or cyanide anions, such as NaN3, CuCN or NaCN; the conversion of —C(O)OH to a —NH2 group, under Schmidt reaction conditions, or variants thereof, for example in the presence of HN3 (which may be formed in by contacting NaN3 with a strong acid such as H2SO4), or, for variants, by reaction with diphenyl phosphoryl azide ((PhO)2P(O)N3) in the presence of an alcohol, such as tert-butanol, which may result in the formation of a carbamate intermediate; the conversion of —C(O)NH2 to —NH2, for example under Hofmann rearrangement reaction conditions, for example in the presence of NaOBr (which may be formed by contacting NaOH and Br2) which may result in the formation of a carbamate intermediate; the conversion of —C(O)N3 (which compound itself may be prepared from the corresponding acyl hydrazide under standard diazotisation reaction conditions, e.g. in the presence of NaNO2 and a strong acid such as H2SO4 or HCl) to —NH2, for example under Curtius rearrangement reaction conditions, which may result in the formation of an intermediate isocyanate (or a carbamate if treated with an alcohol); the conversion of an alkyl carbamate to —NH2, by hydrolysis, for example in the presence of water and base or under acidic conditions, or, when a benzyl carbamate intermediate is formed, under hydrogenation reaction conditions (e.g. catalytic hydrogenation reaction conditions in the presence of a precious metal catalyst such as Pd); halogenation of an aromatic ring, for example by an electrophilic aromatic substitution reaction in the presence of halogen atoms (e.g. chlorine, bromine, etc, or an equivalent source thereof) and, if necessary an appropriate catalyst/Lewis acid (e.g. AlCl3 or FeCl3).
Further, the skilled person will appreciate that the D1 to D3-containing ring, as well as the A ring may be heterocycles, which moieties may be prepared with reference to a standard heterocyclic chemistry textbook (e.g. “Heterocyclic Chemistry” by J. A. Joule, K. Mills and G. F. Smith, 3rd edition, published by Chapman & Hall, “Comprehensive Heterocyclic Chemistry II” by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996 or “Science of Synthesis”, Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006). Hence, the reactions disclosed herein that relate to compounds containing hetereocycles may also be performed with compounds that are pre-cursors to heterocycles, and which pre-cursors may be converted to those heterocycles at a later stage in the synthesis.
Compounds of the invention may be isolated (or purified) from their reaction mixtures using conventional techniques (e.g. crystallisations, recrystallisations or chromatographic techniques).
It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques. By ‘protecting group’ we also include suitable alternative groups that are precursors to the actual group that it is desired to protect. For example, instead of a ‘standard’ amino protecting group, a nitro or azido group may be employed to effectively serve as an amino protecting group, which groups may be later converted (having served the purpose of acting as a protecting group) to the amino group, for example under standard reduction conditions described herein. Protecting groups that may be mentioned include lactone protecting groups (or derivatives thereof), which may serve to protect both a hydroxy group and an α-carboxy group (i.e. such that the cyclic moiety is formed between the two functional groups.
The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
The use of protecting groups is described in e.g. “Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999).
Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.
Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the “active” compounds to which they are metabolised) may therefore be described as “prodrugs” of compounds of the invention.
By “prodrug of a compound of the invention”, we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
Furthermore, certain compounds of the invention, including, but not limited to:
Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the “active” compounds of the invention to which they are metabolised), may also be described as “prodrugs”.
Thus, the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
Compounds of the invention may inhibit leukotriene (LT) C4 synthase, for example as may be shown in the test described below, and may thus be useful in the treatment of those conditions in which it is required that the formation of e.g. LTC4, LTD4 or LTE4 is inhibited or decreased, or where it is required that the activation of a Cys-LT receptor (e.g. Cys-LT1 or Cys-LT2) is inhibited or attenuated. The compounds of the invention may also inhibit microsomal glutathione S-transferases (MGSTs), such as MGST-I, MGST-II and/or MGST-III (preferably, MGST-II), thereby inhibiting or decreasing the formation of LTD4, LTE4 or, especially, LTC4.
Compounds of the invention may also inhibit the activity of 5-lipoxygenase-activating protein (FLAP), for example as may be shown in a test such as that described in Mol. Pharmacol., 41, 873-879 (1992). Hence, compounds of the invention may also be useful in inhibiting or decreasing the formation of LTC4 and/or LTB4.
Compounds of the invention are thus expected to be useful in the treatment of disorders that may benefit from inhibition of production (i.e. synthesis and/or biosynthesis) of leukotrienes (such as LTC4), for example a respiratory disorder and/or inflammation.
The term “inflammation” will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
The term “inflammation” will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
Accordingly, compounds of the invention may be useful in the treatment of allergic disorders, asthma, childhood wheezing, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, and usual interstitial in pneumonia), ear nose and throat diseases (e.g. rhinitis, nasal polyposis, and otitis media), eye diseases (e.g. conjunctivitis and giant papillary conjunctivitis), skin diseases (e.g. psoriasis, dermatitis, and eczema), rheumatic diseases (e.g. rheumatoid arthritis, arthrosis, psoriasis arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis), vasculitis (e.g. Henoch-Schonlein purpura, Loffler's syndrome and Kawasaki disease), cardiovascular diseases (e.g. atherosclerosis), gastrointestinal diseases (e.g. eosinophilic diseases in the gastrointestinal system, inflammatory bowel disease, irritable bowel syndrome, colitis, celiaci and gastric haemorrhagia), urologic diseases (e.g. glomerulonephritis, interstitial cystitis, nephritis, nephropathy, nephrotic syndrome, hepatorenal syndrome, and nephrotoxicity), diseases of the central nervous system (e.g. cerebral ischemia, spinal cord injury, migraine, multiple sclerosis, and sleep-disordered breathing), endocrine diseases (e.g. autoimmune thyreoiditis, diabetes-related inflammation), urticaria, anaphylaxis, angioedema, oedema in Kwashiorkor, dysmenorrhoea, burn-induced oxidative injury, multiple trauma, pain, toxic oil syndrome, endotoxin chock, sepsis, bacterial infections (e.g. from Helicobacter pylori, Pseudomonas aerugiosa or Shigella dysenteriae), fungal infections (e.g. vulvovaginal candidasis), viral infections (e.g. hepatitis, meningitis, parainfluenza and respiratory syncytial virus), sickle cell anemia, hypereosinofilic syndrome, and malignancies (e.g. Hodgkins lymphoma, leukemia (e.g. eosinophil leukemia and chronic myelogenous leukemia), mastocytos, polycytemi vera, and ovarian carcinoma). In particular, compounds of the invention may be useful in treating allergic disorders, asthma, rhinitis, conjunctivitis, COPD, cystic fibrosis, dermatitis, urticaria, eosinophilic gastrointestinal diseases, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and pain.
Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
According to a further aspect of the present invention, there is provided a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, LTC4 synthase and/or a method of treatment of a disease in which inhibition of the synthesis of LTC4 is desired and/or required (e.g. respiratory disorders and/or inflammation), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
“Patients” include mammalian (including human) patients.
The term “effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.
The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of a respiratory disorder (e.g. leukotriene receptor antagonists (LTRas), glucocorticoids, antihistamines, beta-adrenergic drugs, anticholinergic drugs and PDE4 inhibitors and/or other therapeutic agents that are useful in the treatment of a respiratory disorder) and/or other therapeutic agents that are useful in the treatment of inflammation and disorders with an inflammatory component (e.g. NSAIDs, coxibs, corticosteroids, analgesics, inhibitors of 5-lipoxygenase, inhibitors of FLAP (5-lipoxygenase activting protein), immunosuppressants and sulphasalazine and related compounds and/or other therapeutic agents that are useful in the treatment of inflammation).
According to a further aspect of the invention, there is provided a combination product comprising:
Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
Thus, there is further provided:
(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(2) a kit of parts comprising components:
The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.
By “bringing into association”, we mean that the two components are rendered suitable for administration in conjunction with each other.
Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit of parts may be:
(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or
(ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.
Compounds of the invention may be administered at varying doses. Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day. For e.g. oral administration, the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Aqueous solubility is a fundamental molecular property that governs a large range of physical phenomena related to the specific chemical compound including e.g. environmental fate, human intestinal absorption, effectiveness of in vitro screening assays, and product qualities of water-soluble chemicals. By definition, the solubility of a compound is the maximum quantity of compound that can dissolve in a certain quantity of solvent at a specified temperature. Knowledge of a compound's aqueous solubility can lead to an understanding of its pharmacokinetics, as well as an appropriate means of formulation.
Compounds of the invention (especially those in which L2 represents —C(O)—) may exhibit improved solubility properties (for instance compared to certain compounds disclosed in the prior art). Greater aqueous solubility (or greater aqueous thermodynamic solubility) may have advantages related to the effectiveness of the compounds of the invention (especially those in which L2 represents —C(O)—), for instance improved absorption in vivo (e.g. in the human intestine) or the compounds may have other advantages associated with the physical phenomena related to improved aqueous stability (see above). Good (e.g. improved) aqueous solubility may aid the formulation of compounds of the invention, i.e. it may be easier and/or less expensive to manufacture tablets which will dissolve more readily in the stomach as potentially one can avoid esoteric and/or expensive additives and be less dependent on particle-size (e.g. micronization or grinding may be avoided) of the crystals, etc, and it may be easier to prepare formulations intended for intravenous administration.
Compounds of the invention may have the advantage that they are effective inhibitors of LTC4 synthase.
Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
In the assay, LTC4 synthase catalyses the reaction where the substrate LTA4 is converted to LTC4. Recombinant human LTC4 synthase is expressed in Piccia pastoralis and the purified enzyme is dissolved in 25 mM tris-buffer pH 7.8 supplemented with 0.1 mM glutathione (GSH) and stored at −80° C. The assay is performed in phosphate buffered saline (PBS) pH 7.4 and 5 mM GSH in 384-well plates.
The following is added chronologically to each well:
1.48 μL LTC4 synthase in PBS with 5 mM GSH. The total protein concentration in this solution is 0.5 μg/mL.
2. 1 μL inhibitor in DMSO (final concentration 10 μM).
3. Incubation of the plate at room temperature for 10 min.
4. 1 μL LTA4 (final concentration 2.5 μM).
5. Incubation of the plate at room temperature for 5 min.
6. 10 μL of the incubation mixture is analysed using homogenous time resolved fluorescent (HTRF) detection.
(a) Title compounds of the Examples were tested in the biological in vitro assay described above and were found to inhibit LTC4 synthase. Title compounds of the examples exhibit a certain IC50 value, which shows that they inhibit LTC4 synthase. IC50 values for title compounds of the examples are depicted in the tables hereinafter.
(b) Title compounds of the Examples were tested in the biological in vitro assay described above and were found to inhibit LTC4 synthase. Thus, when the total concentration of title compounds in the assay was 10 μM (unless otherwise specified), the following %-inhibition values where obtained for representative examples.
(c) Title compounds of Examples 15 and 16 were also tested in the biological in vitro assay described above and were found to inhibit LTC4 synthase. The IC50 values are depicted below.
(d) Title compounds of Examples 17 to 21 were also tested in the biological in vitro assay described above and were found to inhibit LTC4 synthase. The following IC50 values where obtained.
In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).
The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
aq aqueous
BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
brine saturated aqueous solution of NaCl
DCM dichloromethane
DMAP N,N-dimethyl-4-aminopyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
EtOH ethanol
MeCN acetonitrile
MeOH methanol
NMR nuclear magnetic resonance
Oxone potassium peroxymonosulfate (2 KHSO5.KHSO5.K2SO4)
Pd2 dba3 tris(dibenzylideneacetone)dipalladium(0)
rt room temperature
rx reflux
sat saturated
THF tetrahydrofuran
(a) 2-Fluoro-5-iodobenzoic acid methyl ester
A mixture of 2-fluoro-5-iodobenzoic acid (50.0 g, 188 mmol), iodomethane (23.4 mL, 376 mmol), K2CO3 (52.0 g, 376 mmol) and DMF (300 mL) was stirred at rt for 16 h. The mixture was filtered and concentrated. Extractive workup (EtOAc, H2O, brine) and purification by chromatography gave the sub-title compound.
Yield: 49 g (97%).
(b) 2-Fluoro-5-formylbenzoic acid methyl ester
i-PrMgCl.LiCl in THF (1.0 M, 70 mL, 70.0 mmol) was added to 2-fluoro-5-iodo-benzoic acid methyl ester (13.0 g, 46.4 mmol) in THF (80 mL) at −45° C. After 1 h at −40° C., DMF (2.7 mL, 35.7 mmol) was added. The cooling was removed and when the temperature had reached rt (about 1 h), HCl (1 M, aq) was added. Extractive workup (EtOAc, H2O, brine) and concentration gave the sub-title compound. Yield: 8.95 g (98%).
(c) 5-[(5-Bromo-2-pyridyl)hydroxymethyl]-2-fluorobenzoic acid methyl ester
i-PrMgCl in THF (2.0 M, 24 mL, 48.9 mmol) was added to 5-bromo-2-iodopyridine (13.2 g, 46.6 mmol) in THF (50 mL) at −15° C. After stirring at −15° C. for 1 h, 2-fluoro-5-formylbenzoic acid methyl ester (8.50 g, 48.9 mmol) in THF (50 mL) was added at −45° C. The mixture was stirred at rt for 6 h, and quenched with NH4Cl (aq, sat). Extractive workup (EtOAc, H2O, brine) and purification by chromatography gave the sub-title compound. Yield: 13.4 g (85%).
(d) 5-(5-Bromopicolinoyl)-2-fluorobenzoic acid methyl ester
Pyridinium chlorochromate (8.94 g, 41.5 mmol) was added to 5-[(5-bromo-2-pyridyl)hydroxymethyl]-2-fluorobenzoic acid methyl ester (13.4 g, 39.5 mmol) in DCM (400 mL) at rt. After 1 h the mixture was filtered through Celite, concentrated, treated with EtOAc:hexanes (1:2) and filtered through silica. Concentration gave the subtitle compound. Yield 10.7 g (80%).
(e) 5-(5-Bromopicolinoyl)-2-phenoxybenzoic acid methyl ester
A mixture of 5-(5-bromopicolinoyl)-2-fluorobenzoic acid methyl ester (4.55 g, 13.5 mmol), phenol (1.88 g, 20.0 mmol), KF/Al2O3 (10.7 g), 18-crown-6 (530 mg, 2.02 mmol) and MeCN (45 mL) was stirred at 100° C. in a sealed vessel for 8 h. Filtration through Celite, concentration of the filtrate and crystallization of the residue from MeCN gave the sub-title compound. Yield: 4.03 g (73%).
(f) 5-{5-[(4-Chlorophenyl)amino]picolinoyl}-2-phenoxybenzoic acid methyl ester
A mixture of 5-(5-bromopicolinoyl)-2-phenoxybenzoic acid methyl ester (1.040 g, 2.52 mmol), 4-chloroaniline (0.386 g, 3.03 mmol), Pd(OAc)2, (0.028 g, 0.13 mmol), BINAP (0.118 g, 0.19 mmol), Cs2CO3 (1.149 g, 3.53 mmol) and toluene (10 mL) was stirred at 80° C. for 20 h in a sealed tube. The mixture was diluted with EtOAc and filtered through Celite. Concentration and purification by chromatography gave the sub-title compound. Yield: 0.93 g (80%).
(g) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-phenoxybenzoic acid metyl ester
NaH (60% in mineral oil, 18 mg, 0.44 mmol) was added to a mixture of 5-{5-[(4-chlorophenyl)amino]picolinoyl}-2-phenoxybenzoic acid methyl ester (0.186 g, 0.41 mmol), iodomethane (0.167 g, 1.22 mmol) and DMF (3 mL) at 0° C. Stirring at rt for 1.5 h, extractive workup (EtOAc, aq HCl, brine), drying (Na2SO4), concentration and purification by chromatography gave the sub-title compound. Yield: 0.108 g (56%).
(h) 5-{5-[4-Chlorophenyl)(methyl)amino]picolinoyl}-2-phenoxybenzoic acid
NaOH (0.040 g, 1.00 mmol) in H2O (2 mL) was added to 5-{5-[(4-chlorophenyl)-(methyl)amino]picolinoyl}-2-phenoxybenzoic acid methyl ester (0.20 mmol, 0.94 g) dissolved in hot EtOH (10 mL). The mixture was heated at rx for 30 min, cooled, concentred and acidified with HCl (0.1 M) to pH ˜2. Extractive workup (EtOAc, H2O, brine), drying (Na2SO4), concentration and purification by chromatography gave the title compound. Yield: 0.058 g (63%). 1H NMR (DMSO-d6) δ: 13.4-12.8 (1H, br s) 8.51 (1H, d, J=2.2 Hz) 8.22 (1H, d, J=2.8 Hz) 8.17 (1H, dd, J=8.7, 2.2 Hz) 7.97 (1H, d, J=8.8 Hz) 7.55-7.50 (2H, m) 7.46-7.36 (4H, m) 7.30 (1H, dd, J=8.8, 2.8 Hz) 7.22-7.17 (1H, m) 7.08-7.03 (2H, m) 6.98 (1H, d, J=8.8 Hz) 3.41 (3H, s). IC60=110 nM.
(a) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-fluorobenzoic acid methyl ester
The sub-title compound was prepared from 5-(5-bromopicolinoyl)-2-fluorobenzoic acid methyl ester and 4-chloro-N-methylaniline in accordance with example 1:1 step (f).
(b) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-(3,4-difluorophenoxy)-benzoic acid
The title compound was synthesized from 5-{5-[(4-chlorophenyl)(methyl)-amino]picolinoyl}-2-fluorobenzoic acid methyl ester and 3,4-difluorophenol in accordance with Example 1:1, steps (e) and (h), see table 1. 1H NMR (DMSO-d6) δ 8.50-8.45 (1H, m) 8.19 (1H, d, J=3.1 Hz) 8.15 (1H, dd, J=8.6, 2.0 Hz) 7.95 (1H, d, J=9.0 Hz) 7.52-7.40 (3H, m) 7.38-7.33 (2H, m) 7.27 (1H, dd, J=9.0, 3.1 Hz) 7.26-7.20 (1H, m) 7.06 (1H, d, J=8.6 Hz) 6.87-6.81 (1H, m) 3.38 (3H, s). IC50=104 nM.
The title compounds were synthesized from 5-{5-[(4-chlorophenyl)(methyl)amino]-picolinoyl}-2-fluorobenzoic acid methyl ester and the appropriate phenol in accordance with Example 1:1, steps (e) and (h), see table 1.
The title compounds were synthesized from 5-(5-bromopicolinoyl)-2-fluorobenzoic acid methyl ester (see Example 1: 1, step (d)), phenol, the appropriate aniline and the appropriate alkyl halide in accordance with Example 1: 1, steps (e), (f), (g) and (h), see Table 1.
The title compound was synthesized from 5-(5-bromopicolinoyl)-2-fluorobenzoic acid methyl ester (see Example 1:1, step (d)), phenol and 4-chloroaniline in accordance with Example 1:1, steps (e), (f) and (h), see Table 1.
The title compound was prepared from 5-(5-bromopicolinoyl)-2-fluorobenzoic acid methyl ester and the appropriate aniline in accordance with example 1:1 step (f) followed by alkylation with the appropriate alkyl halide (or triflate) and coupling with the appropriate phenol in accordance with example 1:1 step (g), (e) and (h), see Table 1.
1H-NMR (DMSO-d6, δ)
The title compound was isolated in the last hydrolytic step in the synthesis of 5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-2-(2-methylsulfanylphenoxy)-benzoic acid (Example 1: 23). Yield: 18%. 1H NMR (DMSO-d6) δ: 8.58 (1H, d, J=2.0 Hz) 8.27-8.18 (2H, m) 8.00 (1H, d, J=8.8 Hz) 7.82 (1H, dd, J=7.7, 1.6 Hz) 7.56-7.49 (3H, m) 7.46-7.35 (3H, m) 7.30 (1H, dd, J=9.0, 2.8 Hz) 7.21 (1H, d, J=8.6 Hz) 6.87 (1H, d, J=8.2 Hz) 3.41 (3H, s) 2.88 (3H, s). IC50=1027 nM
Oxone (0.355, 0.58 mmol) in H2O (10 mL) was added to 5-{5-[5(4-chlorophenyl)-(methyl)amino]picolinoyl}-2-(2-methylsulfanylphenoxy)benzoic acid methyl ester (0.15 g, 0.29 mmol, obtained in the penultimate step in the synthesis of Example 1:23) in THF (10 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and at 40° C. for 1 h. Additional Oxone (200 mg) in H2O was added and the mixture stirred for another 16 h at rt. Washing (H2O, brine), drying (Na2SO4), concentration and purification by chromatography gave the methyl ester of the title compound. Yield: 0.10 g (63%). Hydrolysis in accordance with Example 1: 1, step (h) gave the title compound. 1H NMR (DMSO-d6) δ: 8.32 (1H, d, J=1.5 Hz) 8.24 (1H, d, J=2.5 Hz) 8.00-7.92 (2H, m) 7.90-7.85 (1H, m) 7.63-7.56 (1H, m) 7.55-7.48 (2H, m) 7.42-7.35 (2H, m) 7.31 (1H, dd, J=8.8, 2.8 Hz) 7.25 (1H, m) 7.02 (1H, d, J=8.4 Hz) 6.83 (1H, d, J=8.4 Hz) 6.50 (3H, s) 3.40 (3H, s). IC50=632 nM.
(a) 2-Azido-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester
A mixture of 5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-2-fluorobenzoic acid methyl ester (1.2 mmol, 0.48 g, see Example 1: 2, step (a)), NaN3 (0.16 g, 2.4 mmol) and DMSO (15 mL) was stirred at 60° C. for 2 h. Extractive workup (EtOAc, H2O, brine), drying (Na2SO4), concentration and crystallization of the residue from EtOH gave the sub-title compound. Yield: 0.48 g (95%).
(b) 2-Amino-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester
A mixture of 2-azido-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester (0.48 g, 1.14 mmol), FeCl3 trihydrate (1.71 mmol, 0.46 g), zink powder (0.11 g, 1.71 mmol) and EtOH (200 mL) was heated at rx for 30 min. Filtration, concentration, extractive workup (EtOAc, H2O, brine), drying (Na2SO4) and purification by chromatography gave the sub-title compound.
Yield: 0.44 g (97%).
(c) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-(4-trifluoromethylphenyl-amino)benzoic acid
The title compound was obtained from 2-amino-5-{5-[(4-chlorophenyl)(methyl)-amino]picolinoyl}benzoic acid methyl ester and 1-bromo-4-trifluoromethylbenzene in accordance with Example 1: 1, step (f), followed by hydrolysis in accordance with Example 1: 1, step (h). 1H NMR (DMSO-d6) δ: 8.72 (1H, d, J=2.0 Hz) 8.20 (1H, d, J=2.9 Hz) 8.08-8.03 (1H, m) 7.85 (1H, d, J=8.9 Hz) 7.66-7.61 (2H, m) 7.50-7.46 (2H, m) 7.42-7.31 (5H, m) 7.28 (1H, dd, J=8.8, 2.9 Hz) 3.37 (3H, s). IC50=53 nM.
(a) 5-[(4-Chlorophenyl)(methyl)amino]picolinaldehyde
Toluene (44 mL) and 4-chloro-N-methylaniline (1.6 mL, 12.9 mmol) were added to a mixture of Cs2CO3 (4.9 g, 15.05 mmol), Pd(OAc)2 (0.121 g, 0.538 mmol), BINAP (0.502 g, 0.806 mmol) and 5-bromopicolinaldehyde (2 g, 10.75 mmol). The mixture was stirred at 85° C. for 15 h and filtered through Celite. The solids were washed with EtOAc. The combined filtrates were concentrated and the residue purified by chromatography to give the sub-title compound. Yield: 1.537 g (58%).
(b) 2-Bromo-5-({5-[(4-chlorophenyl)(methyl)amino]pyridin-2-yl}(hydroxy)-methyl)benzoic acid methyl ester
i-PrMgCl (1.54 mL, 3.08 mmol, 2 M in THF) was added to 2-bromo-5-iodo-benzoic acid methyl ester (1.0 g, 2.93 mmol) in THF (10 mL) at −15° C. The mixture was cooled to −45° C. and a cold (−45° C.) solution of 5-[(4-chlorophenyl)(methyl)amino]picolinaldehyde (0.80 g, 3.23 mmol) in THF (20 mL) was added. The mixture was allowed to reach rt and stirred for 16 h. NH4Cl (aq, sat, 30 mL) was added at 0° C. and the mixture was stirred at rt for 30 min. Extractive workup (EtOAc, water, brine), drying (Na2SO4) and purification by chromatography gave the sub-title compound. Yield: 1.1 g (73%).
(c) 2-Bromo-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester
The title compound was obtained from 2-bromo-5-({5-[(4-chlorophenyl)(methyl)-amino]pyridin-2-yl}(hydroxy)methyl)benzoic acid methyl ester in accordance with Example 1: 1, step (d) to afford the sub-title compound. Yield: 344 mg (31%).
(d) 2-(4-tert-Butylcyclohexylamino)-5-{5-[(4-chlorophenyl)(methyl)amino]-picolinoyl}benzoic acid
The title compound was obtained from 2-bromo-5-{5-[(4-chlorophenyl)(methyl)-amino]picolinoyl}benzoic acid methyl ester and 4-tert-butylcyclohexylamine at 100° C. in accordance with Example 1: 1, step (f) followed by hydrolysis in accordance with Example 1: 1, step (h). 1H NMR (DMSO-d6) δ: 13.2-12.6 (1H, br s) 9.2-8.9 and 8.6-8.4 (1H, br s) 8.76-8.66 (1H, m) 8.18 (1H, d, J=2.7 Hz) 8.13-8.03 (1H, m) 7.80 (1H, dd, J=9.0, 2.3 Hz) 7.53-7.40 (2H, m) 7.35-7.29 (2H, m) 7.27 (1H, dd, J=9.0, 2.7 Hz) 6.86-6.74 (1H, m) 3.97-3.86 and 3.50-3.42 (1H, m) 3.35 (3H, s) 2.10-2.04 (1H, m) 1.87-1.72 (2H, m) 1.63-1.46 (2H, m) 1.21-1.03 (4H, m) 0.83 and 0.82 (9H, s). IC60=66 nM
The title compounds were synthesized in accordance with Example 2: 2 using 2-bromo-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl]benzoic acid methyl ester and the appropriate amine in step (d), see table 2.
1H-NMR (DMSO-d6, δ)
A mixture of 2-amino-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester (0.32 mmol, 125 mg, see Example 2: 1, step (b)), 4-trifluoromethyl-benzoyl chloride (0.352 mmol, 74 mg) and toluene (10 mL) was stirred at 110° C. for 2 h. MeOH (10 mL) was added and the mixture was concentrated. Purification by chromatography followed by hydrolysis in accordance with Example 1: 1, step (h) gave the title compound. Yield: 0.12 g (66%). 1H NMR (DMSO-d6) δ: 8.78 (1H, d, J=2.2 Hz) 8.76 (1H, d, J=8.8 Hz) 8.34 (1H, dd, J=8.8, 2.2 Hz) 8.20 (1H, d, J=2.9 Hz) 8.15 (2H, d, J=8.2 Hz) 8.00-7.94 (3H, m) 7.53-7.48 (2H, m) 7.39-7.34 (2H, m) 7.28 (1H, dd, J=8.8, 2.9 Hz) 3.39 (3H, s). IC50=33 nM.
The title compound was obtained in accordance with Example 3: 1 from 2-amino-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester and 2-acetoxy-5-chlorobenzoyl chloride, see Table 3.
The title compounds were obtained from 2-amino-5-{5-[(4-chlorophenyl)(methyl)-amino]picolinoyl}benzoic acid methyl ester and the appropriate aroyl chloride in accordance with Example 3: 1, see Table 3.
The title compounds was obtained from the proper 2-amino-5-{5-[(aryl)(alkyl)-amino]picolinoyl}benzoic acid methyl ester (prepared from 5-(5-bromopicolinoyl)-2-fluorobenzoic acid methyl ester and the appropriate amine in accordance with example 1:1 step (f) followed by alkylation with the appropriate alkyl halide in accordance with example 1:1 step (g), azide formation and reduction in accordance with Example 2: 1 steps (a) and (b)) and the appropriate aroyl chloride in accordance with Example 3: 1, see Table 3.
1H-NMR (DMSO-d6, δ)
Benzenesulfonyl chloride (1.0 mmol, 128 μL) was added to a mixture of 2-amino-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester (0.50 mmol, 198 mg, see Example 2.1, step (b)), DMAP (0.82 mmol, 100 mg) and pyridine (4 mL) at rt. The mixture was stirred at rt for 7 h. Extractive workup (EtOAc, H2O, 10% citric acid, H2O, brine), drying (Na2SO4) and purification by chromatography gave the methyl ester of the title compound. Hydrolysis in accordance with Example 1: 1, step (h) gave the title compound. Yield: 0.18 g (67%). 1H NMR (DMSO-d6) δ: 8.67 (1H, d, J=2.0 Hz) 8.26-8.16 (2H, m) 7.98-7.90 (3H, m) 7.74-7.57 (4H, m) 7.56-7.50 (2H, m) 7.42-7.36 (2H, m) 7.29 (1H, dd, J=9.0, 3.0 Hz) 3.40 (3H, s). IC50=39 nM.
The title compounds were prepared from 2-amino-5-{5-[(4-chlorophenyl)(methyl)-amino]picolinoyl}benzoic acid methyl ester and the appropriate arylsulfonyl chloride in accordance with Example 4: 1, see Table 4.
1H-NMR (DMSO-d6, δ)
The compounds of Example 5 (also see table 5) may exist as a cyclised form, i.e. in a form depicted hereinbefore by compounds of formula I (whereby the compound depicted below may undergo an intramolecular cyclisation). Hence, the characterising data (e.g. NMR data) presented below may refer to the cyclised form of that compound. Alternatively, the compounds (of formula I; e.g. see the compounds of Example 5 depicted below) may exist in rapid or slow equilibrium (on an NMR time scale) with the cyclised form (of formula IA) and hence the spectra may represent either one of the compounds or both of the compounds (e.g. spectra for single compounds may be observed, or spectra for two compounds, which spectra may for instance overlap or merge).
(a) 2-Benzoyl-5-bromobenzoic acid methyl ester
The sub-title compound was obtained from 5-bromo-2-iodobenzoic acid methyl ester and benzoyl chloride in accordance with Example 1: 1, step (c).
(b) 2-Benzoyl-5-iodobenzoic acid methyl ester
A mixture of 2-benzoyl-5-bromobenzoic acid methyl ester (5.207 g, 16.31 mmol), CuI (0.311 g, 1.63 mmol), NaI (4.889 g, 32.62 mmol), N1,N2-dimethylethane-1,2-diamine (0.351 μL, 3.26 mmol) and dioxane (20 mL) was heated at 120° C. for 18 h. Extractive workup (EtOAc, NH4Cl (aq, sat), H2O, brine), drying (Na2SO4), concentration and purification by chromatography gave the sub-title compound. Yield: 4.633 g (78%).
(c) 2-Benzoyl-5-[(5-bromo-2-pyridyl)hydroxymethyl]benzoic acid methyl ester
The sub-title compound was obtained from 2-benzoyl-5-iodobenzoic acid methyl ester and 5-bromopicolinaldehyde in accordance with Example 1: 1, step (c).
(d) 2-Benzoyl-5-(5-bromopicolinoyl)benzoic acid methyl ester
Oxidation of 2-benzoyl-5-[(5-bromo-2-pyridyl)hydroxymethyl]benzoic acid methyl ester in accordance with Example 1: 1, step (d) gave the sub-title compound.
(e) 2-Benzoyl-5-{5-[(4-chlorophenyl)methylamino]picolinoyl}benzoic acid methyl ester
The title compound was prepared from 2-benzoyl-5-(5-bromopicolinoyl)benzoic acid methyl ester and 4-chloro-N-methylaniline in accordance with Example 1: 1, step (f).
(f) 2-Benzoyl-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid
The title compound was prepared from 2-benzoyl-5-{5-[(4-chlorophenyl)-methylamino]picolinoyl}benzoic acid methyl ester in accordance with Example 1:1, step (h). 1H NMR (DMSO-d6) δ: 8.44-8.40 (1H, m) 8.20 (1H, d, J=2.8 Hz) 8.06-8.01 (1H, m) 7.97 (1H, d, J=8.9 Hz) 7.58-7.53 (2H, m) 7.53-7.46 (3H, m) 7.44-7.34 (4H, m) 7.31-7.23 (2H, m) 3.38 (3H, s). IC50=72 nM.
The title compounds were prepared in accordance with Example 5: 1 using the appropriate acid chloride in step (a), the appropriate amine in step (e), alkylation (when appropriate) in accordance with Example 1:1, step (g) followed by hydrolysis in accordance with Example 1:1, step (f).
(a) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-trimethylstannanyl-benzoic acid methyl ester
A mixture of 2-bromo-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester (100 mg, 0.217 mmol, see Example 2:2, step (c)), 1,1,1,2,2,2-hexa-methyldistannane (86 mg, 0.261 mmol), PdCl2(PPh3)2 (5 mg, 0.0073 mmol) and toluene (15 mL) was stirred at 105° C. for 5 h. The mixture was cooled to rt, filtered through Celite, washed with EtOAc, concentrated and purified by chromatography to give the sub-title compound. Yield: 95 mg (80%).
(b) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-(3-methoxybenzoyl)-benzoic acid methyl ester
A mixture of 5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-2-trimethylstannanyl-benzoic acid methyl ester (90 mg, 0.165 mmol), 3-methoxybenzoyl chloride (31 mg, 0.182 mmol), PdCl2(PPh3)2 (2.2 mg, 0.0032 mmol) and toluene (1 mL) was stirred at 105° C. for 3 h. The mixture was cooled to rt and MeOH (2 mL) was added. The mixture was stirred at rt for 10 min, filtered through Celite, washed with EtOAc, concentrated and purified by chromatography to give the sub-title compound. Yield: 35 mg (40%).
(c) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-(3-methoxybenzoyl)-benzoic acid
The title compound was prepared from 5-{5-[(4-chlorophenyl)(methyl)amino]-picolinoyl}-2-(3-methoxybenzoyl)benzoic acid methyl ester in accordance with Example 1:1, step (h). 1H NMR (DMSO-d6) δ: 8.54-8.43 (1H, m) 8.19 (1H, d, J=2.3 Hz) 8.10 (1H, d, J=6.7 Hz) 7.98 (1H, d, J=8.6 Hz) 7.55-7.45 (2H, m) 7.42-7.24 (5H, m) 7.22-7.15 (1H, m) 7.15-7.08 (1H, m) 7.04 (1H, d, J=7.4 Hz) 3.74 (3H, s) 3.38 (3H, s). IC50=36 nM.
The title compounds were prepared from 5-{5-[(4-chlorophenyl)(methyl)amino]-picolinoyl}-2-trimethylstannanylbenzoic acid methyl ester and the appropriate acid chloride in accordance with Example 5: 7, steps (b) and (c), see Table 5. The palladium source in step (b) was allylpalladium(II) chloride dimer, Pd2dba3, or Pd(P(t-Bu)3)2 with toluene or MeCN as solvent.
The title compounds were prepared in accordance with Example 5:1 using the appropriate amine in step (e), followed by hydrolysis in accordance with Example 1:1, step (f).
Table 5 (in which the compounds may exist as teh cyclised form; see above).
1H-NMR (DMSO-d6, δ)
(a) 4-Fluoro-3-methoxycarbonylphenylboronic acid
i-PrMgCl.LiCl in THF (1.2M, 70 mL, 70.0 mmol) was added to 2-fluoro-5-iodo-benzoic acid methyl ester (13.3 g, 47.5 mmol) in THF (150 mL) at −40° C. After stirring at −20° C. for 1 h, triethoxyborate (2.43 mL, 142 mmol) was added at −78° C. The cooling was removed and when the temperature had reached rt (about 2 h), HCl (1 M, aq) was added. Extractive workup (EtOAc, H2O, brine), concentration and crystallization from MeCN gave the sub-title compound.
Yield: 9.15 g (97%).
(b) 6-[(4-Chlorophenyl)(methyl)amino]nicotinonitrile
A mixture of 6-bromonicotinonitrile (5.00 g, 27 mmol), 4-chloro-N-methylaniline (3.32 mL, 27 mmol), Pd(OAc)2 (360 mg, 1.62 mmol), BINAP (2.02 g, 3.24 mmol), Cs2CO3 (13.2 g, 405 mmol) and toluene (50 mL) was stirred at 80° C. for 17 h in a sealed tube. The mixture was diluted with EtOAc, filtered through Celite and concentrated. Purification by chromatography and crystallization from MeOH gave the sub-title compound. Yield: 4.15 g (63%).
(c) 5-{6-[(4-Chlorophenyl)(methyl)amino]nicotinoyl}-2-fluorobenzoic acid methyl ester
A mixture of 6-[(4-chlorophenyl)(methyl)amino]nicotinonitrile (2.14 g, 8.78 mmol), 3-methoxycarbonyl-4-fluorophenylboronic acid (1.91 g, 9.66 mmol), Pd(OAc)2 (0.200 g, 0.89 mmol), DMSO (1.0 mL) and trifluoroacetic acid (20 mL) was stirred at 90° C. for 48 h. Extractive workup (EtOAc, Na2CO3 (aq, sat), H2O, brine), concentration and purification by chromatography gave the sub-title compound. Yield: 0.52 g (15%).
(d) 5-{6-[(4-Chlorophenyl)(methyl)amino]nicotinoyl}-2-phenoxybenzoic acid
The reaction between 5-{6-[(4-chlorophenyl)(methyl)amino]nicotinoyl}-2-fluoro-benzoic acid methyl ester and phenol in accordance with Example 1:1, step (f) gave 5-{5-[(4-chlorophenyl)(methyl)amino]nicotinoyl}-2-phenoxybenzoic acid methyl ester. Yield 270 mg (84%). Hydrolysis in accordance with Example 1: 1, step (h) gave the title compound. 1H NMR (DMSO-d6) δ: 13.6-12.7 (1H, br s) 8.60-8.51 (1H, m) 8.19-8.09 (1H, m) 7.95-7.80 (2H, m) 7.61-7.35 (6H, m) 7.26-7.15 (1H, m) 7.14-7.04 (2H, m) 7.03 (1H, d, J=8.8 Hz) 6.60 (1H, d, J=9.0 Hz) 3.48 (3H, s). IC50=667 nM.
The title compound was prepared from 5-{6-[(4-chlorophenyl)(methyl)amino]-nicotinoyl}-2-fluorobenzoic acid methyl ester (see Example 5: 1, step (c)) and 3,4-difluorophenol in accordance with Example 1; 1, step (f). See Table 3.
1H-NMR (DMSO-d6, δ)
A mixture of 5-(5-bromopicolinoyl)-2-phenoxybenzoic acid methyl ester (217 mg, 0.53 mmol, see Example 1: 1 step (e)), K3PO4 (225 mg, 1.06 mmol), Pd(PPh3)4 (30.6 mg, 0.0265 mmol), 3-chlorophenyl boronic acid (123.5 mg, 0.79 mmol) and dioxane was stirred at 80° C. for 12 h. The mixture was filtered through Celite and the solids washed with hot EtOAc. The filtrates were concentrated and the residue purified by chromatography. Hydrolysis in accordance with Example 1: 1, step (h) gave the title compound. Yield: 110 mg (47%). 1H-NMR (DMSO-d6, δ) 13.6-13.1 (1H, br s) 9.11 (1H, d, J=2.0 Hz) 8.46-8.39 (2H, m) 8.15-8.08 (2H, m) 7.98-7.95 (1H, m) 7.87-7.82 (1H, m) 7.61-7.54 (2H, m) 7.43 (2H, t, J=7.4 Hz) 7.19 (1H, t, J=7.4 Hz) 7.10-7.05 (2H, m) 6.98 (1H, d, J=8.7 Hz). IC50=1109 nM.
The title compounds were prepared from 5-(5-bromopicolinoyl)-2-phenoxybenzoic acid methyl ester, and the appropriate boronic acid in accordance with Example 7:1, see Table 7
1H-NMR (DMSO-d6, δ)
(a) 5-Chloro-2-iodoisonicotinic acid methyl ester
NaI (5.82 g, 38.83 mmol) and acetyl chloride (104 μL, 1.456 mmol) were added to 2,5-dichloroisonicotinic acid methyl ester (2 g, 9.707 mmol) in MeCN (18 mL). The mixture was heated in a sealed vial by microwave irradiation for 30 min at 90° C. Another portion of NaI (5.82 g, 38.83 mmol) and acetyl chloride (104 μL, 1.456 mmol) were added and the mixture was again heated for 30 min at 90° C. The addition/heating procedure was repeated a third time. Extractive workup (EtOAc, Na2S2O3 (aq, 10%), NaHCO3 (aq, sat), brine), drying (Na2SO4), concentration and crystallization from EtOH gave the sub-title compound. Yield: 800 mg (28%).
(b) 2-(4-Bromobenzoyl)-5-chloroisonicotinic acid methyl ester
The sub-title compound was prepared from 5-chloro-2-iodoisonicotinic acid methyl ester and 4-bromobenzaldehyde in accordance with Example 1:1 steps (c) and (d).
(c) 2-[4-(4-Chlorophenylamino)benzoyl]-5-phenoxyisonicotinic acid methyl ester
The sub-title compound was prepared from 2-(4-bromobenzoyl)-5-chloroiso-nicotinic acid methyl ester and phenol in accordance with Example 1: 1, steps (e) (but heating at 110° C. for 66 h), followed by coupling with 4-chloroaniline in accordance with Example 1: 1, step (f).
(d) 2-{4-[(4-Chlorophenyl)(cyclopropylmethyl)amino]benzoyl}-5-phenoxy-isonicotinic acid
The title compound was prepared by alkylation of 2-[4-(4-chlorophenylamino)-benzoyl]-5-phenoxyisonicotinic acid methyl ester with cyclopropylmethyl bromide (20 min at 65° C.) and hydrolysis in accordance with Example 1:1, steps (g) and (h). Yield: 44% and 88%. 1H NMR (DMSO-d6) δ: 8.27 (1H, s) 8.06 (1H, s) 7.83-7.78 (2H, m) 7.41-7.36 (2H, m) 7.35-7.28 (2H, m) 7.22-7.17 (2H, m) 7.11-7.06 (1H, m) 7.01-6.97 (2H, m) 6.70-6.65 (2H, m) 3.54 (2H, d, J=6.5 Hz) 1.01-0.92 (1H, m) 0.34-0.28 (2H, m) 0.03-(−0.02) (2H, m). IC60=82 nM.
The title compound was prepared from 2-(4-bromobenzoyl)-5-chloroisonicotinic acid methyl ester in accordance with Example 8:1 step (c) using 4-chloro-N-methylaniline, followed by hydrolysis in accordance with Example 1:1, step (h), see Table 8.
1H-NMR (DMSO-d6, δ)
(a) 3-Chloro-6-iodopicolinic acid methyl ester
A mixture of 3,6-dichloropicolinic acid methyl ester (5.0 g, 24 mmol), NaI (10 g, 66.7 mmol), acetyl chloride (2.5 mL) and MeCN (45 mL) was heated at rx for 8 h. Cooling, extractive workup (EtOAc, Na2S2O3 (aq, 10%), NaHCO3 (aq, sat), brine), drying (Na2SO4), concentration, purification by chromatography and crystallization gave the sub-title compound. Yield: 2.0 g (35%).
(b) 3-Chloro-6-cyanopicolinic acid methyl ester
A mixture of 3-chloro-6-iodopicolinic acid methyl ester (1.6 g, 5.38 mmol), CuCN (0.48 g, 5.36 mmol) and pyridine (40 mL) was heated at 80° C. for 6 h. Cooling, extractive workup (EtOAc, water), drying (Na2SO4), concentration and purification by chromatography gave the sub-title compound. Yield: 0.85 g (80%).
(c) 4-Bromo-4′-chloro-N-methyldiphenylamine
The sub-title compound was prepared from 1,4-dibromobenzene and 4-chloro-N-methylaniline in accordance with Example 6:1, step (b) at 110° C. for 16 h. The material was purified by vacuum distillation.
(d) 4-[N-(4-chlorophenyl)-N-methylamino]phenylboronic acid
The sub-title compound was prepared from 4-bromo-4′-chloro-N-methyldiphenyl-amine in accordance with Example 6: 1, step (a).
(e) 3-Chloro-6-{4-[(4-chlorophenyl)(methyl)amino]benzoyl}picolinic acid methyl ester
A mixture of 3-chloro-6-cyanopicolinic acid methyl ester (0.80 g, 4.1 mmol), 4-[N-(4-chlorophenyl)-N-methylamino]phenylboronic acid (1.6 g, 6.11 mmol), di-μ-hydroxo-bis[(2,2′-bipyridine)palladium(II)] trifluoromethanesulfonate (130 mg, 0.15 mmol), nitromethane (20 ml) and water (100 mL) was stirred for 16 h at 80° C. Concentration and purification by chromatography gave the sub-title compound. Yield: 130 mg (8%).
(f) 6-{4-[(4-Chlorophenyl)(methyl)amino]benzoyl}-3-phenoxypicolinic acid
The title compound was prepared from 3-chloro-6-{4-[(4-chlorophenyl)(methyl)-amino]benzoyl}picolinic acid methyl ester and phenol followed by hydrolysis in accordance with Example 1:1, steps (e) and (h). 1H NMR (DMSO-d6) δ: 8.05-7.97 (3H, m) 7.56-7.45 (5H, m) 7.35-7.30 (2H, m) 7.28-7.23 (1H, m) 7.18-7.13 (2H, m) 6.90-6.84 (2H, m) 3.36 (3H, s). IC50=742 nM.
The title compound was prepared from 3-chloro-6-{4-[(4-chlorophenyl)(methyl)-amino]benzoyl}picolinic acid methyl ester and 3,4-difluorophenol in accordance with Example 9:1, step (f). See Table 9.
1H-NMR (DMSO-d6, δ)
(a) 5-(5-Bromopyrimidine-2-carbonyl)-2-fluorobenzoic acid methyl ester
The sub-title compound was prepared from 2-fluoro-5-iodobenzoic acid methyl ester and 5-bromo-2-cyanopyrimidine in accordance with Example 1: 1, step (b).
(b) 5-{5-[(4-Chlorophenyl)(methyl)amino]pyrimidine-2-carbonyl}-2-fluoro-benzoic acid methyl ester
The sub-title compound was synthesized from 5-(5-bromopyrimidine-2-carbonyl)-2-fluorobenzoic acid methyl ester and 4-chloro-N-methylaniline in accordance with Example 1: 1, step (f).
(c) 5-{5-[(4-Chlorophenyl)(methyl)amino]pyrimidine-2-carbonyl}-2-(4-fluoro-phenyloxy)benzoic acid
The title compound was synthesized from 5-{5-[(4-chlorophenyl)(methyl)amino]-pyrimidine-2-carbonyl}-2-fluorobenzoic acid methyl ester and 4-fluorophenol, followed by hydrolysis, in accordance with Example 1:1, steps (e) and (h).
1H NMR (DMSO-d6) δ: 8.46 (2H, s) 8.39-8.36 (1H, m) 8.09-8.02 (1H, m) 7.59-7.51 (2H, m) 7.48-7.41 (2H, m) 7.31-7.22 (2H, m) 7.16-7.09 (2H, m) 7.01-6.92 (1H, m) 3.43 (3H, s). IC50=154 nM.
(a) 5-{5-[(4-Chlorophenyl)(methyl)amino]pyrimidine-2-carbonyl}-2-(1-hexyl-sulfanyl)benzoic acid methyl ester
The sub-title compound was synthesized from 5-{5-[(4-chlorophenyl)(methyl)-amino]pyrimidine-2-carbonyl}-2-fluorobenzoic acid methyl ester and 1-hexanethiol in accordance with Example 1:1, step (e).
(b) 5-{5-[(4-Chlorophenyl)(methyl)amino]pyrimidine-2-carbonyl}-2-(1-hexyl-sulfinyl)benzoic acid methyl ester
Oxone (0.35 g, 0.56 mmol) in H2O (20 mL) was added to 5-{5-[(4-chlorophenyl)(methyl)amino]pyrimidine-2-carbonyl}-2-(1-hexylsulfanyl)benzoic acid methyl ester (0.27 g, 0.54 mmol) in THF (20 mL). The mixture was stirred at 40° C. for 2 h. Extractive workup (EtOAc, H2O, brine), drying (Na2SO4) and purification by chromatography gave the sub-title compound. Yield: 275 mg (98%).
(c) 5-{5-[(4-Chlorophenyl)(methyl)amino]pyrimidine-2-carbonyl}-2-hexyl-sulfinylbenzoic acid
The title compound was prepared from 5-{5-[(4-chlorophenyl)(methyl)amino]-pyrimidine-2-carbonyl}-2-(1-hexylsulfinyl)benzoic acid methyl ester in accordance with Example 1: 1, step (h).
The title compounds were prepared from 5-[5-(4-chlorophenylamino)pyrimidine-2-carbonyl]-2-phenoxybenzoic acid methyl ester (prepared in accordance with Example 10:1 steps (a)-(c) using 4-chloroaniline and phenol) and the appropriate alkyl halide in accordance with Example 1:1, step (g), followed by hydrolysis in accordance with Example 1:1, step (h). See Table 10.
1H-NMR (DMSO-d6, δ)
(a) 2-Fluoro-5-(5-methoxypicolinoyl)benzoic acid methyl ester
The sub-title compound was prepared from 2-fluoro-5-iodobenzoic acid methyl ester and 2-cyano-5-methoxypyridine in accordance with Example 1:1, step (c).
(b) 2-Fluoro-5-(5-hydroxypicolinoyl)benzoic acid methyl ester
AlCl3 (2.28 g, 16.6 mmol) was added to 2-fluoro-5-(5-methoxypicolinoyl)benzoic acid methyl ester (0.8 g, 2.76 mmol) in CH2Cl2 (70 mL). The mixture was stirred for 2.5 h at rt, for 2 days at 40° C. and for 3 days at rt. Extractive workup (CH2Cl2, water, brine), drying (Na2SO4), concentration and crystallization from EtOAc and petroleum ether gave the sub-title compound. Yield: 0.7 g (92%).
(c) 5-[5-(3-Chlorobenzyloxy)picolinoyl]-2-fluorobenzoic acid methyl ester
NaH (60% in mineral oil, 116 mg, 2.8 mmol) was added to 2-fluoro-5-(5-hydroxy-picolinoyl)benzoic acid methyl ester (0.70 g, 2.55 mmol) in DMF at 0° C. The mixture was stirred at 0° C. for 20 min and 1-chloro-3-(chloromethyl)benzene (0.355 g, 2.8 mmol) was added. After 20 h at rt, NaI (57 mg, 0.38 mmol) an additional portion of 1-chloro-3-(chloromethyl)benzene (0.355 g, 2.8 mmol) was added. The mixture was stirred at rt for 1 day. Extractive workup (EtOAc, water, brine), drying (Na2SO4), concentration and purification by chromatography gave the sub-title compound. Yield: 0.65 g (64%).
(d) 5-[5-(3-Chlorobenzyloxy)picolinoyl]-2-phenoxybenzoic acid
The title compound was prepared from 5-[5-(3-chlorobenzyloxy)picolinoyl]-2-fluorobenzoic acid methyl ester and phenol followed by hydrolysis in accordance with Example 1:1 steps (e) and (h).
1H NMR (DMSO-d6) δ: 13.16 (1H, s) 8.51 (1H, d, J=3.0 Hz) 8.50 (1H, d, J=2.4 Hz) 8.17 (1H, dd, J=8.7 2.4 Hz) 8.10 (1H, d, J=8.7 Hz) 7.71 (1H, dd, J=8.8, 3.0 Hz) 7.62-7.56 (1H, m) 7.50-7.39 (5H, m) 7.23-7.15 (1H, m) 7.11-7.04 (2H, m) 7.01 (1H, d, J=8.8 Hz) 5.34 (2H, s). IC50=143 nM.
The title compounds were prepared from 2-fluoro-5-(5-hydroxypicolinoyl)benzoic acid methyl ester and the appropriate benzyl bromide, followed by the reaction with the appropriate phenol (or thiol) and hydrolysis in accordance with Example 11:1, steps (c) and (d). See Table 11.
1H-NMR (DMSO-d6, δ)
A mixture of 5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-2-bromobenzoic acid methyl ester (200 mg, 0.44 mmol, see Example 2: 2 step (c)), Pd2dba3 (18 mg, 0.02 mmol), BINAP (20.5 mg, 0.033 mmol), K3PO4 (187 mg, 0.88 mmol), 4-methoxybenzyl alcohol (122 mg, 0.88 mmol) and toluene (3 mL) was stirred at 90° C. for 22 h. The mixture was filtered through Celite and concentrated. The residue was purified by chromatography to give a mixture of methyl and benzyl esters. The mixture was hydrolyzed in accordance with Example 1: 1, step (h) to give the title compound. Yield: 75 mg (34%).
1H NMR (DMSO-d6) δ: 12.81 (1H, s) 8.41 (1H, d, J=2.3 Hz) 8.25-8.20 (2H, m) 7.93 (1H, d, J=9.0 Hz) 7.54-7.50 (2H, m) 7.45-7.41 (2H, m) 7.39-7.35 (2H, m) 7.31 (1H, d, J=8.8 Hz) 7.29 (1H, dd, J=9.0, 3.0 Hz) 6.98-6.93 (2H, m) 5.23 (2H, s) 3.76 (3H, s) 3.40 (3H, s). IC50=380 nM.
The title compounds were prepared from 5-{5-[(4-chlorophenyl)(methyl)amino]-picolinoyl}-2-bromobenzoic acid methyl ester and the appropriate benzyl alcohol in accordance with Example 12: 1. See Table 12.
1H-NMR (DMSO-d6, δ)
A mixture of 5-{5-[(4-Chlorophenyl)(cyclopropylmethyl)amino]picolinoyl}-2-phen-oxybenzoic acid (example 1:4) (204 mg, 0.41 mmol, see Example 1:4), MeONH2. HCl (68 mg, 0.82 mmol), EtOH (2 mL) and pyridine (6 mL) was stirred at 100° C. for 16 h. Concentration, extractive workup (EtOAc, water, brine), drying (Na2SO4), concentration and purification by chromatography gave the title compound as a mixture of cis and trans isomers. Yield: 145 mg (67%). 1H NMR (DMSO-d6) δ: 13.1-12.8 (1H, br s) 8.21 and 8.09 (1H, d, J=2.7 Hz) 7.85-7.70 (2H, m) 7.55-7.35 (5H, m) 7.33-7.28 (1H, m) 7.27-7.18 (2H, m) 7.17-7.09 (1H, m) 7.02-6.93 (3H, m) 3.91 (3H, s) 3.65 and 3.63 (2H, d, J=6.5 Hz) 1.11-1.00 (1H, m) 0.46-0.37 (2H, m) 0.15-0.09 (2H, m). IC50=242 nM.
The title compound was prepared from 5-{5-[(4-chlorophenyl)(cyclopropylmethyl)-amino]picolinoyl}-2-phenoxybenzoic acid (which exists as a mixture of cis and trans isomers) and HONH2.HCl in accordance with Example 13. Yield: 87 mg (33%).
1H NMR (DMSO-d6) δ: 13.1-12.7 (1H, br s) 11.60 and 11.50 (1H, s) 8.24 and 8.10 (1H, d, J=2.7 Hz) 7.83-7.74 (1H, m) 7.59-7.53 (2H, m) 7.49-7.30 (5H, m) 7.25-7.08 (3H, m) 7.00-6.92 (3H, m) 3.65 and 3.62 (2H, d, J=6.5 Hz) 1.15-1.02 (1H, m) 0.46-0.37 (2H, m) 0.16-0.09 (2H, m). IC50=1115 nM.
(a) 2-Fluoro-5-formylbenzoic acid methyl ester
i-PrMgCl.LiCl complex in THF (1.0 M, 70 mL, 70.0 mmol) was added to 2-fluoro-5-iodobenzoic acid methyl ester (13.0 g, 46.4 mmol) in THF (80 mL) at −45° C. After stirring at −40° C. for 1 h, DMF (2.7 mL, 35.7 mmol) was added. The temperature was allowed to reach rt over 1 h and HCl (1 M, aq, 300 mL) was added. Extractive workup (EtOAc, water, brine) and concentration gave the sub-title product. Yield: 8.95 g (98%).
(b) 5-[(5-Bromo-2-pyridyl)hydroxymethyl]-2-fluorobenzoic acid methyl ester
i-PrMgCl in THF (2.0M, 24 mL, 48.9 mmol) was added to 5-bromo-2-iodopyridine (13.2 g, 46.6 mmol) in THF (50 mL) at −15° C. After stirring at −15° C. for 1 h, 2-fluoro-5-formylbenzoic acid methyl ester (8.50 g, 48.9 mmol) in THF (50 mL) was added at −45° C. The mixture was stirred at rt for 6 h and quenched with NH4Cl (aq, sat). Extractive workup (EtOAc, water, brine) and purification by chromatography gave the sub-title compound. Yield: 13.4 g (85%).
(c) 5-(5-Bromopyridine-2-carbonyl)-2-fluoro-benzoic acid methyl ester
Pyridinium chlorochromate (8.94 g, 41.5 mmol) was added to 5-[(5-bromo-2-pyridinyl)hydroxymethyl]-2-fluorobenzoic acid methyl ester (13.4 g, 39.5 mmol) in CH2Cl2 (400 mL) at rt. After 1 h the mixture was filtered though Celite and concentrated. The residue was treated with EtOAc and hexane (1:2) and filtered through silica gel. Concentration of the combined filtrates gave the sub-title compound. Yield: 10.7 g (80%).
(d) 5-{5-[(4-Chlorophenyl)methylamino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester
The sub-title compound was prepared from 5-(5-bromopyridine-2-carbonyl)-2-fluorobenzoic acid methyl ester and 4-chloro-N-methylaniline. A mixture of 5-(5-bromopyridine-2-carbonyl)-2-fluorobenzoic acid methyl ester (e.g. 1.54 mmol), 4-chloro-N-methylaniline (e.g. 1.85 mmol), Pd(OAc)2 (e.g. 0.16 mmol), BINAP (e.g. 0.155 mmol), Cs2CO3 (e.g. 4.6 mmol) and toluene (e.g. 10 mL). The reaction may be heated e.g. at 80° C. for 16 h. To isolate the desired compound, the mixture may be diluted with EtOAc and filtered through Celite. The combined filtrates may be concentrated and the residue purified by chromatography to give the sub-title compound.
(e) 5-{5-[(4-Chlorophenyl)methylamino]pyridine-2-carbonyl}-2-(3,4-difluoro-benzenesulfinyl)benzoic acid
The title compound was prepared from 5-{5-[(4-chlorophenyl)methylamino]-pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester and 3,4-difluorothiophenol followed by oxidation and hydrolysis, in accordance with the procedures described herein, see Table 15.
For instance, a mixture of 5-{5-[(4-chlorophenyl)methylamino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester (e.g. 0.75 mmol) and 3,4-difluorothiophenol (e.g. 0.83 mmol), KF/Al2O3 (e.g. 0.2 g), 18-crown-6 (e.g. 0.06 mmol) and MeCN (e.g. 15 mL) may be heated at rx for 16 h. The mixture may be diluted with EtOAc, followed by extractive workup (EtOAc, H2O, brine) and purification by chromatography. The oxidation may be performed by the addition of oxone (e.g. 0.9 mmol) in H2O (5 mL) was added to the intermediate compound so formed (e.g. 0.28 mmol) in THF (e.g. 5 mL) at 0° C. The mixture may be stirred at 0° C. for 15 min and at rt overnight. Extractive workup (EtOAc, H2O, brine) and purification by chromatography may give the desired compound. The hydrolysis may be performed by mixing the methyl ester intermediate formed with NaOH (2 M, 2 mL) and dioxane (5 mL). Such a mixture may be stirred at rt for 30 min followed by neutralisation with HCl (2 M), extractive workup (EtOAc, H2O, brine), drying (Na2SO4) and concentration to give the title product.
(a) 5-{5-[(4-Chlorophenyl)cyclopropylmethylamino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester
The sub-title compound was prepared from 5-(5-bromopyridine-2-carbonyl)-2-fluorobenzoic acid methyl ester (see Example 15: 1, step (d)) and 4-chloro-N-cyclopropylmethylaniline in accordance with Example 15: 1, step (d).
(b) 5-{5-[(4-Chlorophenyl)cyclopropylmethylamino]pyridine-2-carbonyl}-2-O-trifluoromethylphenylsulfinyl)benzoic acid
The title compound was prepared from 5-{5-[(4-chlorophenyl)cyclopropylmethyl-amino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester and the appropriate thiol, followed by oxidation and hydrolysis in accordance with Example 15: 1, steps in procedure (e), see Table 15.
The title compounds were prepared in accordance with Example 15: 2, using the appropriate thiol, see Table 15.
(a) 5-(5-Bromopyrimidine-2-carbonyl)-2-fluorobenzoic acid methyl ester
The sub-title compound was prepared from 2-fluoro-5-iodobenzoic acid methyl ester and 5-bromo-2-cyanopyrimidine in accordance with the procedures described herein. For instance, i-PrMgCl.LiCl in THF (e.g. 5.0 mmol of a 1.1 M soln.) may be added to 2-fluoro-5-iodobenzoic acid methyl ester (e.g. 3.64 mmol) in THF (e.g. 15 mL) at −30° C. After 2 h at that temperature, the mixture may be cooled to −65° C. and 5-bromo-2-cyanopyrimidine (e.g. 8.02 mmol) in THF (e.g 10 mL) may be added. The mixture may be stirred at −65° C. for 1 h and at 5° C. overnight, NH4Cl (aq, sat) added. Extractive workup (EtOAc, H2O, brine) and purification by chromatography may give the sub-title compound.
(b) 5-(5-((4-Chlorophenyl)(methyl)amino)pyrimidine-2-carbonyl)-2-(1-hexyl-sulfinyl)benzoic acid
The title compound was synthesized from 5-(5-bromopyrimidine-2-carbonyl)-2-fluorobenzoic acid methyl ester in accordance with the steps in Example 15:1 (d) and (e), see Table 15.
The title compound was prepared in accordance with Example 15:1 from 5-{5-[(4-chlorophenyl)methylamino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester (see Example 15:1, step (d)) and 1-hexanethiol, followed by oxidation and hydrolysis in accordance with steps in Example 15:1, (e), see Table 15.
1H-NMR (DMSO-d6, δ)
The title compounds were prepared from 5-{5-[(4-chlorophenyl)methylamino]-pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester (see Example 15:1, step (d)) and the appropriate thiol followed by hydrolysis in accordance with steps in Example 15:1, (e), see Table 16.
The title compounds were prepared from 5-{5-[(4-chlorophenyl)cyclopropyl-methylamino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester (see Example 15:2, step (a)) and the appropriate thiol, followed by hydrolysis in accordance with steps in Example 15:1, (e), see Table 16.
(a) 2-Fluoro-5-(5-methoxypicolinoyl)benzoic acid methyl ester
The sub-title compound was prepared from 2-fluoro-5-iodobenzoic acid methyl ester and 2-cyano-5-methoxypyridine 5-bromo-2-cyanopyrimidine in accordance with Example 15:7, step (a).
(b) 2-Fluoro-5-(5-hydroxypicolinoyl)benzoic acid methyl ester
AlCl3 (2.28 g, 16.6 mmol) was added to 2-fluoro-5-(5-methoxypicolinoyl)benzoic acid methyl ester (0.8 g, 2.76 mmol) in CH2Cl2 (70 mL). The mixture was stirred for 2.5 h at rt, for 2 days at 40° C. and for 3 days at rt. Extractive workup (CH2Cl2, water, brine), drying (Na2SO4), concentration and re-crystallization from EtOAc and petroleum ether gave the sub-title compound. Yield: 0.7 g (92%).
(c) 5-(5-(3-Chlorobenzyloxy)picolinoyl)-2-fluorobenzoic acid methyl ester
NaH (60% in mineral oil, 116 mg, 2.8 mmol) was added to 2-fluoro-5-(5-hydroxy-picolinoyl)benzoic acid methyl ester (0.70 g, 2.55 mmol) in DMF at 0° C. The mixture was stirred at 0° C. for 20 min and 1-chloro-3-(chloromethyl)benzene (0.355 g, 2.8 mmol) was added. After 20 h at rt, NaI (57 mg, 0.38 mmol) and an additional portion of 1-chloro-3-(chloromethyl)benzene (0.355 g, 2.8 mmol) was added. The mixture was stirred at rt for 1 day. Extractive workup (EtOAc, water, brine), drying (Na2SO4), concentration and purification by chromatography gave the sub-title compound. Yield: 0.65 g (64%).
(d) 5-[5-(3-Chlorobenzyloxy)pyridine-2-carbonyl]-2-(3,4-difluorophenyl-sulfanyl)benzoic acid
The title compound was prepared from 5-(5-(3-chlorobenzyloxy)picolinoyl)-2-fluorobenzoic acid methyl ester and 3,4-difluorothiophenol, followed by hydrolysis, in accordance with step in Example 15: 1, (e) (coupling and hydrolysis), see Table 16.
The title compound was prepared from 5-(5-(3-chlorobenzyloxy)picolinoyl)-2-fluorobenzoic acid methyl ester and 4-methoxythiophenol in accordance with Example 16:15, see Table 16.
1H-NMR (DMSO-d6, δ)
(a) 2-Fluoro-5-formylbenzoic acid methyl ester
i-PrMgCl.LiCl complex in THF (1.0 M, 70 mL, 70.0 mmol) was added to 2-fluoro-5-iodobenzoic acid methyl ester (13.0 g, 46.4 mmol) in THF (80 mL) at −45° C. After stirring at −40° C. for 1 h, DMF (2.7 mL, 35.7 mmol) was added. The temperature was allowed to reach rt over 1 h and HCl (1 M, aq, 300 mL) was added. Extractive workup (EtOAc, water, brine) and concentration gave the sub-title product. Yield: 8.95 g (98%).
(b) 5-[(5-Bromo-2-pyridyl)hydroxymethyl]-2-fluorobenzoic acid methyl ester
i-PrMgCl in THF (2.0M, 24 mL, 48.9 mmol) was added to 5-bromo-2-iodopyridine (13.2 g, 46.6 mmol) in THF (50 mL) at −15° C. After stirring at −15° C. for 1 h, 2-fluoro-5-formylbenzoic acid methyl ester (8.50 g, 48.9 mmol) in THF (50 mL) was added at −45° C. The mixture was stirred at rt for 6 h and quenched with NH4Cl (aq, sat). Extractive workup (EtOAc, water, brine) and purification by chromatography gave the sub-title compound. Yield: 13.4 g (85%).
(c) 5-(5-Bromopyridine-2-carbonyl)-2-fluoro-benzoic acid methyl ester
Pyridinium chlorochromate (8.94 g, 41.5 mmol) was added to 5-[(5-bromo-2-pyridinyl)hydroxymethyl]-2-fluorobenzoic acid methyl ester (13.4 g, 39.5 mmol) in CH2Cl2 (400 mL) at rt. After 1 h the mixture was filtered though Celite and concentrated. The residue was treated with EtOAc and hexane (1:2) and filtered through silica gel. Concentration of the combined filtrates gave the sub-title compound. Yield: 10.7 g (80%).
(d) 5-{5-[(4-Chlorophenyl)methylamino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester
The sub-title compound was prepared from 5-(5-bromopyridine-2-carbonyl)-2-fluorobenzoic acid methyl ester and 4-chloro-N-methylaniline in accordance with Example 1, step (b).
(e) 2-Azido-5-(5-((4-chlorophenyl)(methyl)amino)picolinoyl)benzoic acid methyl ester
5-{5-[(4-Chlorophenyl)methylamino]pyridine-2-carbonyl}-2-fluoro-benzoic acid methyl ester (5.45 g, 13.66 mmol) was added to NaN3 (2.54 g, 39 mmol) in DMSO (200 mL). The mixture was stirred at 80° C. for 2 h, cooled to rt and pored into ice-wate. The solid was collected and crystallized from EtOH to give the sub-title compound. Yield: 4.20 g (75%).
(f) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-(5-phenyl-1,2,3-triazol-1-yl)benzoic acid methyl ester
Cp*RuClCOD (76 mg, 0.20 mmol) was added to a mixture of 2-azido-5-(5-((4-chlorophenyl)(methyl)amino)picolinoyl)benzoic acid methyl ester (422 mg, 1.0 mmol), 1-ethynylbenzene (0.12 mL, 1.1 mmol) and DMF (6 mL). The mixture was heated at 110° C. for 20 min in a sealed vessel using microwave irradiation. Extractive workup (EtOAc, H2O, brine), drying (Na2SO4), concentration and purification by chromatography gave the sub-title compound. Yield: 100 mg (19%).
(g) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-(5-phenyl-1,2,3-triazol-1-yl)benzoic acid
The title compound was prepared from 5-{5-[(4-chlorophenyl)(methyl)amino]-picolinoyl}-2-(5-phenyl-1,2,3-triazol-1-yl)benzoic acid methyl ester by hydrolysis in accordance with procedures described herein (e.g. basis hydrolysis reaction conditions, such as in the presence of NaOH in ethanol and H2O, which mixture may be heated at 80° C. for 30 min. The pH may then be adjusted to about 5 with HCl (1 M, aq), and the precipitate may then be collected, washed with H2O and recrystallised (e.g. from ethanol/THF/H2O)). Yield: 93 mg (96%).
1H NMR (DMSO-d6) δ: 13.5-13.2 (1H, br s) 8.55 (1H, d, J=2.0 Hz) 8.28 (1H, dd, J=8.2, 1.9 Hz) 8.24 (1H, d, J=2.7 Hz) 8.16 (1H, s) 8.06 (1H, d, J=8.9 Hz) 7.59 (1H, d, J=8.2 Hz) 7.59-7.51 (2H, m) 7.47-7.36 (5H, m) 7.36-7.26 (3H, m) 3.43 (3H, s).
The title compound was synthesized in accordance with example 17:1, using 1-chloro-4-ethynylbenzene in step (f), see Table 17.
(a) 5-[5-(4-Chlorophenylamino)picolinoyl]-2-fluorobenzoic acid methyl ester
The sub-title compound was prepared from 5-(5-bromopyridine-2-carbonyl)-2-fluorobenzoic acid methyl ester (see example 17:1 step (c)) and 4-chloroaniline in accordance with the procedures described herein. For instance, the 5-(5-bromopyridine-2-carbonyl)-2-fluorobenzoic acid methyl ester (e.g. 9.70 mmol), Pd(OAc)2 (e.g. 0.48 mmol), BINAP (e.g. 0.73 mmol), Cs2CO3 (e.g. 13.6 mmol) and toluene (e.g. 35 mL) may be stirred at rt for 10 min. 4-Chloroaniline (e.g. 11.64 mmol) may be added and the mixture heated at 110° C. for 20 h. The mixture may be diluted with EtOAc, and filtered through Celite. Concentration and purification by chromatography may give the sub-title compound.
(b) 5-{5-[(4-Chlorophenyl)(cyclopropylmethylamino]picolinoyl}-2-fluorobenzoic acid methyl ester
NaH (60% in mineral oil, 0.329 g, 8.25 mmol) was added to a mixture of 5-[5-(4-chlorophenylamino)picolinoyl]-2-fluorobenzoic acid methyl ester (2.86 g, 7.71 mmol), bromomethylcyclopropane (3.12 g, 23.13 mmol) and DMF (58 mL) at 0° C. The mixture was stirred at rt for 5 h. Extractive workup (EtOAc, water, brine), concentration and purification by chromatography gave the sub-title compound. Yield: 2.32 g, 69%.
(c) 5-{5-[(4-Chlorophenyl)(cyclopropylmethyl)amino]picolinoyl}-2-(5-phenyl-1,2,3-triazol-1-yl)benzoic acid
The title compound was synthesized from 5-{5-[(4-chlorophenyl)(cyclopropyl-methyl)amino]picolinoyl}-2-fluorobenzoic acid methyl ester and ethynylbenzene in accordance with Example 4:1 steps (e), (f) and (g), see Table 17.
The title compounds were synthesized in accordance with example 17:3, using the appropriate alkyne in step (c), see Table 17.
1H-NMR (DMSO-d6, δ)
NaH (60% in mineral oil, 76 mg, 1.9 mmol) was added to 3-phenyl-5-trifluoromethyl-pyrazole (385 mg, 1.81 mmol) in DMSO (2 mL), and the mixture was stirred at rt for 20 min. 5-{5-[(4-Chlorophenyl)(cyclopropylmethyl)amino]picolinoyl}-2-fluorobenzoic acid methyl ester (700 mg, 1.65 mmol) (see Example 17: 3, step (b)) in DMSO (5 mL) was added and the mixture was heated at 120° C. for 4 h. The mixture was poured into ice-water and extracted with EtOAc. The combined extracts were, washed with brine, dried (Na2SO4) and concentrated. Purification of the residue by chromatography and hydrolysis in accordance with Example 17: 1, step (g)) gave the title compound.
1H NMR (DMSO-d6) δ: 13.8-13.0 (1H, br s) 8.40 (1H, s) 8.15 (1H, d, J=2.8 Hz) 8.1-8.0 (1H, br s) 7.99 (1H, d, J=9.0 Hz) 7.57-7.51 (2H, m) 7.41-7.30 (8H, m) 7.24 (1H, dd, J=9.0, 2.8 Hz) 7.13 (1H, s) 3.71 (2H, d, J=6.6 Hz) 1.12-1.05 (1H, m) 0.47-0.40 (2H, m) 0.18-0.12 (2H, m).
The title compound was prepared from 5-{5-[(4-chlorophenyl)methylamino]-pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester (see Example 17: 1, step (d)) and 3-phenyl-5-trifluoromethylpyrazole in accordance with Example 18: 1, see Table 18.
5-{5-[(4-Chlorophenyl)methylamino]pyridine-2-carbonyl}-2-(5-phenyl-3-trifluoro-methylpyrazol-1-yl)benzoic acid methyl ester was isolated from the reaction of 5-{5-[(4-chlorophenyl)methylamino]pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester and 3-phenyl-5-trifluoromethylpyrazole (see Example 18:2). Hydrolysis in accordance with Example 17:1, step (g) gave the title compound, see Table 18.
5-{5-[(4-Chlorophenyl)(cyclopropylmethyl)amino]picolinoyl}-2-(3-phenyl-5-trifluoro-methylpyrazol-1-yl)benzoic acid methyl ester was isolated from the reaction of 5-{5-[(4-chlorophenyl)(cyclopropylmethyl)amino]picolinoyl}-2-fluorobenzoic acid methyl ester and 3-phenyl-5-trifluoromethylpyrazole (see Example 5: 1). Hydrolysis in accordance with Example 17: 1, step (g) gave the title compound, see Table 18.
The title compounds were prepared from 5-{5-[(4-chloro-phenyl)methylamino]-pyridine-2-carbonyl}-2-fluorobenzoic acid methyl ester (see Example 17:1, step (d)) and the appropriate pyrazole in accordance with Example 18:1, see Table 18.
1H-NMR (DMSO-d6, δ)
Sodium hydride (60% in mineral oil, 26 mg, 0.64 mmol) was added to 5-methyl-2-phenylimidazole (100 mg, 0.63 mmol) in DMSO (2 mL). The mixture was stirred at rt for 20 min and 5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-2-fluoro-benzoic acid methyl ester (0.25 g, 0.63 mmol, see Example 17: 1, step (d) in DMSO (1.5 mL), was added. The mixture was heated at 130° C. for 5 d, poured into ice and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by chromatography and hydrolysis in accordance with Example 17: 1, step (g), gave the title compound.
1H NMR (DMSO-d6) δ: 8.53 (1H, d, J=2.0 Hz) 8.33-8.26 (2H, m) 8.09 (1H, d, J=9.0 Hz) 7.64-7.58 (2H, m) 7.54 (1H, J=8.2 Hz) 7.50-7.43 (2H, m) 7.40-7.30 (6H, m) 7.16 (1H, d, J=1.0 Hz) 3.48 (3H, s) 2.28 (3H, s).
The title compound was prepared from 5-{5-[(4-chlorophenyl)methylamino]-pyridine-2-carbonyl}-2-fluoro-benzoic acid methyl ester (see Example 17: 1, step (d)) and 2-phenylimidazole in accordance with Example 19: 1.
1H NMR (DMSO-d6) δ: 13.3-13.0 (1H, br s) 8.48 (1H, d, J=1.8 Hz) 8.27-8.20 (2H, m) 8.02 (1H, d, J=8.8 Hz) 7.57-7.48 (3H, m) 7.42-7.35 (3H, m) 7.34-7.25 (6H, m) 7.16 (1H, d, J=1.2 Hz) 3.41 (3H, s).
A mixture of 2-(3-chlorophenyl)pyrrole (80 mg, 0.45 mmol), 5-{5-[(4-chloro-phenyl)(methyl)amino]picolinoyl}-2-fluorobenzoic acid methyl ester (180 mg, 0.45 mmol, see Example 4: 1, step (d)), 18-crown-6 (13.2 mg, 0.05 mmol), KF.Al2O3 (200 mg) was mixed in a vial using dry MeCN (3 mL) and then sealed and heated at 120° C. for 16 h. The reaction mixture was filtered through Celite and concentrated. Purification by chromatography and hydrolysis in accordance with Example 17: 1, step (g) gave the title compound.
1H NMR (DMSO-d6) δ: 8.65 (1H, d, J=2.0 Hz) 8.25 (1H, dd, J=8.2 2.0 Hz) 8.17 (1H, d, J=3.0 Hz) 8.04 (1H, d, J=8.6 Hz) 7.42-7.37 (2H, m) 7.28 (1H, d, J=8.2 Hz) 7.21-6.99 (6H, m) 6.83-6.79 (2H, m) 6.42 (1H, dd, J=3.4 1.6 Hz) 6.36-6.34 (1H, m) 3.40 (3H, s).
The title compound was prepared from 5-{5-[(4-chloro-phenyl)-methyl-amino]-pyridine-2-carbonyl}-2-fluoro-benzoic acid methyl ester (see Example 17: 1, step (g)) and 2-phenylpyrrole in accordance with Example 20:1.
1H NMR (DMSO-d6) δ: 8.62 (1H, d, J=1.8 Hz) 8.23 (1H, dd, J=8.2, 1.8 Hz) 8.17 (1H, d, J=2.8 Hz) 8.03 (1H, d, J=9.0 Hz) 7.42-7.36 (2H, m) 7.29 (1H, d, J=8.2 Hz) 7.19-7.05 (8H, m) 6.84-6.79 (1H, m) 6.41 (1H, dd, J=3.4, 1.6 Hz) 6.37-6.34 (1H, m) 3.39 (3H, s).
(a) 2-Amino-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester
THF (42 mL). Zn(s) (0.52 g, 8.0 mmol) and FeCl3.6H2O (4.32 g, 16.0 mmol) was added to 2-azido-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester (3.375 g, 8.0 mmol, see Example 17.1, step (e)) in EtOH (85 mL). The mixture was heated at rx for 30 min, Zn(s) (0.52 g, 8.0 mmol) was added and the mixture was heated at rx for 1 h. The mixture was filtered through Celite and concentrated. Extractive workup (EtOAc/THF/NaHCO3 (aq)), drying (Na2SO4) and concentration gave the sub-title compound. Yield: 3.24 g (100%).
(b) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-iodobenzoic acid methyl ester
Water (32 mL) and HCl (aq, sat, 8.1 mL) was added to 2-amino-5-{5-[(4-chloro-phenyl)(methyl)amino]picolinoyl}benzoic acid methyl ester (3.24 g, 8.18 mmol) in MeCN (50 mL) at rt. The mixture was cooled to 0° C. and sodium nitrite (0.57 g, 8.31 mmol) in water (2.4 mL) was added. The mixture was stirred at 0° C. for 15 min and KI (1.38 g, 8.31 mmol) in water (2.4 mL) was added dropwise. The mixture was stirred at rt for 10 min and at rx for 15 min and concentrated. NaHCO3 (aq, sat) was added. Extractive workup (EtOAc, brine), drying (Na2SO4) and purification by chromatography gave the sub-title compound. Yield: 2.6 g (64%).
(c) 4-{5-[(4-Chloro-phenyl)methylamino]pyridine-2-carbonyl}-2′-trifluoro-methylbiphenyl-2-carboxylic acid
A mixture of 5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-2-iodobenzoic acid methyl ester (0.200 g, 0.40 mmol), 2-trifluoromethylphenylboronic acid (0.152 g, 0.80 mmol), K3PO4 (0.425 g, 2.0 mmol) and Pd(OAc)2 (9.0 mg, 0.04 mmol) in toluene (3 mL) was stirred at rt for 15 min and heated at 80° C. for 3.5 h. After cooling to rt, EtOAc (70 mL) was added and the mixture was filtered through Celite. The filtrate was washed with NaHCO3 (aq, sat), water and brine, dried (Na2SO4) and concentrated. Purification by chromatography gave the title compound after hydrolysis in accordance with Example 17: 1, step (g).
1H NMR (DMSO-d6) δ: 12.9-12.7 (1H, br s) 8.57-8.50 (1H, m) 8.26-8.12 (2H, m) 8.05-7.97 (1H, m) 7.81-7.47 (5H, m) 7.43-7.25 (5H, m) 3.40 (3H, s).
The title compounds were prepared in accordance with Example 21: 1 using the appropriate arylboronic acid in step (c), see Table 21.
The title compounds were prepared in accordance with example 21:1 using the appropriate arylboronic acid but with Pd(PPh3)4 as the palladium source and toluene/water (95/1) as the solvent in step (c), See table 21.
1H-NMR (DMSO-d6, δ)
(a) 5-{5-[(4-Chloro-phenyl)(methyl)amino]picolinoyl}-2-phenylethynylbenzoic acid
A mixture of 2-bromo-5-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}benzoic acid (230 mg, 0.5 mmol), phenylacetylene (153 mg, 1.5 mmol), Pd(PPh3)4 (53 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol), Cs2CO3 (244 mg, 0.75 mmol) and toluene (5 mL) was heated at 70° C. for 16 h. The mixture was allowed to cool and filtered through Celite. The solids were washed with EtOAc and the filtrates concentrated. Purification by chromatography gave the sub-title compound. Yield: 204 mg (84%).
(b) 7-{5-[(4-Chlorophenyl)methylamino]pyridine-2-carbonyl}-3-phenylisochromen-1-one
5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-phenylethynylbenzoic acid methyl ester (see step (a)) (490 mg, 1 mmol) in trifluoroacetic acid (12 mL) was stirred at rt for 1 d. Extractive workup (EtOAc, NaHCO3 (aq, sat), H2O, brine), drying (Na2SO4), concentration and purification by chromatography gave the sub-title compound. Yield: 0.100 g (67%).
(c) 5-{5-[(4-Chlorophenyl)(methyl)amino]picolinoyl}-2-(2-oxo-2-phenylethyl)benzoic acid
Hydrolysis of 7-{5-[(4-chlorophenyl)methylamino]pyridine-2-carbonyl}-3-phenylisochromen-1-one in accordance with Example 1:1, step (h) gave the title compound.
1H-NMR (DMSO-d6, δ) 13.0-12.8 (1H, br s) 8.55 (1H, d, J=1.8 Hz) 8.22 (1H, d, J=2.8 Hz) 8.13 (1H, dd, J=1.8; 7.8 Hz) 8.09-7.93 (3H, m) 7.74-7.43 (6H, m) 7.43-7.34 (2H, m) 7.30 (1H, dd, J=2.8; 8.9 Hz) 4.86 (2H, s) 3.40 (3H, s).
By definition, the solubility of a compound is the maximum quantity of compound that can dissolve in a certain quantity of solvent at a specified temperature.
The method described here was developed to accurately determine the aqueous solubility of compounds of the invention in buffer solution at a given pH. The test is built as a classical thermodynamic solubility method with an assumption that saturation of solution incubated with an excess of solid material, is achieved after 24 h.
Solid material (1 mg) of test compound is added to a glass vial followed by 1 ml of buffer solution (pH 7.4 if another pH not is stated). The solution is left on an orbital shaker for 24 h at 20° C. After incubation, the remaining solid material is separated from solution and the solubility is quantified using LC-MS/MS.
Prepare 0.2 M monobasic potassium phosphate solution by dissolving 27.22 g of KH2PO4 (MW=136.09 g/mol) in water, dilute with water to 1000 mL.
Add 250 mL of the monobasic potassium phosphate solution in a 1000 mL volumetric flask together with 195.5 mL 0.2M NaOH (aq). Add water to 1000 mL. Check pH.
Compounds of the invention to be tested were provided as solid material, weighed into glass vials (2 mL). Each vial contains approximately 1 mg solid compound, two vials/compound are prepared, i.e. duplicate samples of each compound. If a freshly prepared 10 mM DMSO stock solution was available, this solution was used for MS optimization and preparation of standards. If a DMSO-stock solution was not available, a 10 mM solution from solid material 1 mg was prepared.
indicates data missing or illegible when filed
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2010/000438 | 3/12/2010 | WO | 00 | 9/12/2011 |
| Number | Date | Country | |
|---|---|---|---|
| 61202549 | Mar 2009 | US |
