# Patent

## Title
Compounds and uses

## Abstract

There is provided compounds of formula I,




wherein E1, E2, E3, E4, L1, Y1, Y2, Y3, Ra and z have meanings provided in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of leukotriene C4 synthase is desired and/or required, and particularly in the treatment of respiratory diseases and inflammation.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. §119(a)-(d) to Great Britain Application No. 1507753.0 filed on 6 May 2015.
FIELD OF THE INVENTION
This invention relates to novel compounds useful as inhibitors of leukotriene C4 synthase. 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.
BACKGROUND OF THE INVENTION
Arachidonic acid is a fatty acid that is essential in the body and is stored in cell membranes. It may be converted, e.g. in the event of inflammation, into mediators, some of which are known to have beneficial properties, such as the lipoxins and resolvins and others that are harmful. Such mediators include leukotrienes (formed by the action of 5-lipoxygenase (5-LO), which act by catalysing the insertion of molecular oxygen into carbon position 5 of arachidonic acid generating 5-hydroxyeicosatetraenoic acid and then LTA4), prostaglandins (which are formed by the action of cyclooxygenases (COXs)) and eoxins (formed by the action of 15-lipoxygenase (15-LO), which act by catalysing the insertion of molecular oxygen into carbon position 15), followed by conjugation with glutathione catalysed by leukotriene C4 synthase. Huge efforts have been devoted towards the development of drugs that inhibit the action of some of these metabolites as well as the biological processes that form them.
Of the leukotrienes, leukotriene (LT)B4 is formed by the action of 5-lipoxygenase and leukotriene A4 hydrolase. LTB4 is known to be involved in neutrophil recruitment and may play an important role in host defence. The cysteinyl-containing leukotrienes C4, D4 and E4 (CysLTs), formed by the action of 5-lipoxygenase and cysteine leukotriene C4 synthase, are both very potent bronchoconstrictors and proinflammatory mediators and have thus been implicated in the pathobiology of asthma. The biological activities of the CysLTs are mediated through two receptors designated CysLT1, which is the preferred receptor for LTD4, and CysLT2, which is the preferred receptor for LTC4, but the existence of additional CysLT receptors, such as CysLT3, a receptor with preference for LTE4, 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 may be attained if the activity of all the leukotrienes at 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, 5-LO inhibitors and/or FLAP inhibitors would also decrease the formation of LTB4, and pro-resolution lipids lipoxins and resolvins. In addition to inhibiting the synthesis of CysLTs, inhibition of leukotriene C4 synthase will inhibit the formation of eoxins that are known proinflammatory mediators, while preserving anti-inflammatory lipids such as the lipoxins. For a review on leukotrienes in asthma, see e.g., H.-E. Claesson and S.-E. Dahlén J. Internal Med. 245, 205 (1999). For a review on eoxins in asthma, see e.g., H.-E. Claesson Prostaglandins Other Lipid Mediat. 89, 120-125 (2009).
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 depend upon the severity of the condition. Mild cases are either untreated or are only treated with inhaled (3-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. For instance, 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.
Other inflammatory disorders which may be mentioned include: 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; pulmonary fibrosis (this is less common than COPD, but is a serious disorder with a very poor prognosis); inflammatory bowel disease (a group of disorders with a high morbidity rate—today only symptomatic treatment of such disorders is available); rheumatoid arthritis and osteoarthritis (common disabling inflammatory disorders of the joints—there are currently no curative, and only moderately effective symptomatic, treatments available for the management of such conditions); diabetes, a disease affecting over 3% of the world population, and growing, causing considerable morbidity and mortality; and cardiovascular disease.
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 have inflammatory components adding to the symptomatology of the patients. Inflammation may also play a role in cancer with leukotrienes involved in cancer cell proliferation and extending cancer cell lifetimes.
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, 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 publications WO 2009/030887, WO 2010/103297, WO 2010/103278, WO 2010/103279, WO 2010/103283 and WO 2011/110824 disclose bis-aromatic ketones thought to be LTC4 synthase inhibitors and their potential use in the treatment of respiratory and/or inflammatory diseases. These disclosures contain no teaching or suggestion relating to the use of cyclopropyl-substituted aryl and heteroaryl ketones.
DISCLOSURE OF THE INVENTION
In a first aspect of the invention, there is provided a compound of formula I,




wherein:

    
    
        each of E1, E2, E3 and E4 individually represent any one of —C(R1)═, —C(R2)═, —C(R3)═ and —C(R4)═; and/or any one or two of E1, E2, E3 and E4 may independently represent —N═;
        each of R1 to R4 independently represents hydrogen or a substituent selected from X1; and/or any one of R1 to R4 may independently represent —OY4; where present, each Ra independently represents fluoro or C1-6 alkyl (wherein the latter group is optionally substituted by one or more fluoro);
        z represents 0 to 4;
        L1 represents a direct bond or a C1-3 alkyl linker group, wherein the latter group is optionally substituted with one or more substituent selected from Z1 and G1;
        Y1 represents —C(O)OR1a, —C(O)N(H)S(O)2R1b or a tetrazolyl group of the following formula,
    
    






    
    
        R1a represents:
        
            (i) hydrogen; or
            (ii) C1-3 alkyl, optionally substituted by one or more fluoro;
        
        
        R1b represents:
        
            A) an aryl group, optionally substituted by one or more substituents selected from B1;
            B) a heteroaryl group, optionally substituted by one or more substituents selected from B2; or
            C) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G2 and/or Z2;
        
        
        R1c represents H or C1-6 alkyl (wherein the latter group is optionally substituted by one or more substituents selected from G3 and/or Z3);
        Y2, Y3 and Y4 each independently represent:
        
            (a) an aryl group, optionally substituted by one or more substituents selected from A1;
            (b) a heteroaryl group, optionally substituted by one or more substituents selected from A2;
            (c) a C1-12 alkyl (e.g. a C3-12 cycloalkyl) or a heterocycloalkyl group, wherein the latter two groups are optionally substituted by one or more substituents selected from G4 and/or Z4; and/or
        
        
        where L1 represents a direct bond, Y2 and Y3 may be linked together to form, along with the atom 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 G5 and/or Z5;
        A1 and A2 independently represent, on each occasion when used herein:
        
            I) an aryl group, optionally substituted by one or more substituents selected from B3;
            II) a heteroaryl group, optionally substituted by one or more substituents selected from B4;
            III) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G6 and/or Z6; or
            IV) a G7 group;
        
        
        X1 and G1 to G7 independently represent halo, —R2a, —C(O)R2b, —CN, —NO2, —C(O)N(R3a)R3b, —N(R4a)R4b, —N(R2c)C(O)R2d, —N(—R2e)C(O)OR2f, —OR2g, —OS(O)2R2h, —S(O)nR2i, —OC(O)R2j or —S(O)2N(R5a)R5b;
        n represents 0, 1 or 2;
        R2b to R2j, R3a, R3b, R4a, R4b, R5a and R5b independently represent, on each occasion when used herein, H or R2a; and/or any of the pairs R3a and R3b, R4a and R4b, or R5a and R5b 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, —OH, —OR7a and/or R7b;
        R7a and R7b independently represent R2a;
        R2a represents, on each occasion when used herein:
        
            (i) C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —R8a, —CN, ═O, —OR8b, —N(R8c)R8d, —S(O)mR8e and/or —S(O)2N(R8f)R8g;
            (ii) an aryl group, optionally substituted by one or more substituents selected from halo, —R8a, —CN, —OR8b, —N(R8c)R8d, —S(O)mR8e and/or —S(O)2N(R8f)R8g;
            (iii) a heteroaryl group, optionally substituted by one or more substituents selected from halo, —R8a, —CN, —OR8b, —N(R8c)R8d, —S(O)mR8e and/or —S(O)2N(R8f)R8g; or
            (iv) a heterocycloalkyl group, optionally substituted by one or more substituents selected from fluoro, —R8a, —CN, —OR8b, —N(R8c)R8d, —S(O)mR8e and/or —S(O)2N(R8f)R8g;
        
        
        m represents 0, 1 or 2;
        each R8a to R8g independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, ═O, —OR11a and/or —N(R12a)R12b; and/or R8c and R8d and/or R8f and R8g 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 and C1-2 alkyl, wherein the latter group is optionally substituted by one or more fluoro atoms;
        R11a, R12a and R12b independently represent H or C1-3 alkyl, wherein the latter group is optionally substituted by one or more fluoro atoms;
        B1 to B4 independently represent halo, —R14a, —C(O)R14b, —CN, —NO2, —C(O)N(R15a)R15b, —N(R16a)R16b, —N(R14c)C(O)R14d, —N(R14e)C(O)OR14f, —OR14g, —OS(O)2R14h, —S(O)pR14i, —OC(O)R14j or —S(O)2N(R17a)R17b;
        p represents 0, 1 or 2;
        R14b to R14j, R15a, R15b, R16a, R16b, R17a and R17b independently represent, on each occasion when used herein, H or R14a; and/or any of the pairs R15a and R15b, R16a and R16b, or R17a and R17b 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, —OH, —OR19a and/or R19b;
        R19a and R19b independently represent R14a;
        R14a represents, on each occasion when used herein C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —R20a, —CN, ═O, —OR20b, —N(R20c)R20d, —S(O)tR20e and/or —S(O)2N(R20f)R20g;
        t represents 0, 1 or 2;
        R20a represents C1-6 alkyl optionally substituted by one or more fluoro;
        each R20b to R20g independently represents H or C1-6 alkyl optionally substituted by one or more fluoro;
        Z1 to Z6 independently represent, on each occasion when used herein, ═O or ═NOR22a; and
        R22a represents hydrogen or C1-6 alkyl, wherein the latter group is 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”.

    
    


For the avoidance of doubt, the skilled person will appreciate that compounds of the invention are characterised in that they are based on cyclopropyl-substituted aryl and heteroaryl ketones. Moreover, compounds of the invention are further characterised in that:

    
    
        the essential aryl or heteroaryl group requires the presence of a substituted amino group in the 4-position relative to the essential ketone; and
        the essential cyclopropyl group requires the presence of a carboxylate, tetrazole or sulphonamide group in the 2-position relative to the essential ketone.
    
    


Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such acid addition salts and base addition 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.
Particular acid addition salts that may be mentioned include carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts), halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts (e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2-naphthalene-sulfonate or 1,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.
Particular base addition salts that may be mentioned include salts formed with alkali metals (such as Na and K salts), alkaline earth metals (such as Mg and Ca salts), organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine and lysine) and inorganic bases (such as ammonia and aluminium hydroxide). More particularly, base addition salts that may be mentioned include Mg, Ca and, most particularly, K and Na salts.
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. For example, in respect of compounds of the invention, where Y1 represents a tetrazole in respect of which R1c represents H then the tetrazole may exist in the tautomeric forms indicated directly below.




The skilled person will understand that where a bond shown in respect of a substituent is intersected with a wavy line (such as in the structures shown directly above) or shown as a dashed line (as in respect of certain examples herein below) that bond forms the point of attachment to the other portion of the molecule.
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. In particular, compounds of the invention may comprise asymmetric carbon atoms at the two points indicated with a dot in the structure (corresponding to compounds of formula I) shown directly below.




For the avoidance of doubt, the present invention includes compounds with any combination of stereochemistry in these positions. In at least one embodiment, compounds of the present disclosure include those wherein the Y1 and —C(O)— substituents in these positions are in the trans configuration.
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 (for example, a C4 alkyl may be represented by —CH2-cyclopropyl (i.e. cyclopropylmethyl) and a C5 alkyl may be represented by —CH2-(1-methyl)cyclopropyl (i.e. ((1-methyl)cyclopropyl)methyl)). 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 more particularly they are not so. The skilled person will understand that, where an alkyl group contains a sufficient number of carbon atoms (e.g. two or three) a substituent on such a group being present on any suitable carbon atom. For example, in respect of a linker group (such as L1 as herein defined) a substituent on such a group may be present on any suitable carbon atom (for example, where L1 is a C2 alkyl group, L1 may take the form of a —(CH)2— or —CH(CH3)— group, which linker groups are specifically contemplated by the present invention).
The term “halo”, independently at each instance when used herein, includes fluoro, chloro, bromo and iodo (for example, fluoro and chloro).
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), thianyl, 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 (or 5,6,7,8-tetrahydronaphthyl), indanyl, indenyl, dihydroindenyl, dihydroacenapthylenyl, acenaphthylenyl 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, aryl groups that may be mentioned are those 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-[b][1,4]-benzoxazinyl and 4H-benzo[b][1,4]-dioxazinyl), benzoxazolyl (including benzo[d][1,3]dioxolyl), 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. 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, oxygen, nitrogen and sulphur (for example, oxygen and nitrogen).
Where the E-containing ring (as described herein) may contain more than one nitrogen atom, particular such groups that may be mentioned include those wherein the two nitrogen atoms are non-adjacent (i.e. they are not directly bonded to each other).
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 G1 and G2 both represent R2a, the R2a 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 —R2a and —C(O)R2b, in which R2b represents R2a, then the identities of the two R2a groups are not to be regarded as being interdependent. Likewise, when Y2 or Y3 represent aryl substituted by more than one A1 group, then such substituents are not interdependent (i.e. they may be the same or different A1 groups).
For the avoidance of doubt, when a term such as “R2b to R2j” is employed herein, this will be understood by the skilled person to mean R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i and R2j inclusively. Unless otherwise stated, the same reasoning will apply to other such terms used herein.
For the avoidance of doubt, the term “E1 to E4-containing ring” or “E-containing ring” are synonymous and refer to the ring containing E1, E2, E3 and E4.
An embodiment of the invention include compounds of formula I wherein:

    
    
        E1, E2 and E3 individually represent C(R1), C(R2) and C(R3) respectively and E4 represents —N═ (particularly wherein R1 to R3 are represented by hydrogen or X1, or wherein R2 and R3 are represented by hydrogen or X1 and R1 is represented by —OY4);
        E1, E2 and E4 individually represent C(R1), C(R2) and C(R4) respectively and E3 represents —N═ (particularly wherein R2 and R4 are represented by hydrogen or X1 and R1 is represented by —OY4);
        E1, E2, E3 and E4 individually represent C(R1), C(R2), C(R3) and C(R4) respectively (particularly wherein R2 to R4 are represented by hydrogen or X1 and R1 is represented by —OY4);
        E2 and E3 individually represent C(R2) and C(R3) respectively and E1 and E4 each represent —N═ (particularly wherein R3 is represented by hydrogen or X1 and R2 is represented by —OY4);
        E1 and E3 individually represent any one of C(R1), C(R2) and C(R4) and E2 and E4 represent —N═ (particularly wherein R2 and R4 are represented by hydrogen and R1 is represented by —OY4).
    
    


Other embodiments include compounds of formula I wherein:

    
    
        E1, E2 and E3 individually represent C(R1), C(R2) and C(R3) respectively and E4 represents —N═ (particularly wherein R1 to R3 are represented by hydrogen, or wherein R2 and R3 are represented by hydrogen and R1 is represented by —OY4);
        E1, E2 and E4 individually represent C(R1), C(R2) and C(R4) respectively and E3 represents —N═ (particularly wherein R2 and R4 are represented by hydrogen and R1 is represented by —OY4);
        E1, E2, E3 and E4 individually represent C(R1), C(R2), C(R3) and C(R4) respectively (particularly wherein R2 to R4 are represented by hydrogen and R1 is represented by —OY4);
        E2 and E3 individually represent C(R2) and C(R3) respectively and E1 and E4 each represent —N═ (particularly wherein R3 is represented by hydrogen and R2 is represented by —OY4);
        E1 represent C(R1) and E3 represent C(R1a) respectively and E2 and E4 represent —N═ (particularly wherein R1 is represented by —OY4).
    
    


Compounds of formula I that may be mentioned include those in which at least one of R1 to R4 (where present) is represented by —OY4.
In a particular embodiment that may be mentioned, the compound of formula I is a compound of formula Ia,




wherein Y1 to Y4, L1, E2 to E4, Ra and z are as defined in respect of compounds of formula I.
Compounds of formula Ia that may be mentioned include those in which:

    
    
        E2 and E3 individually represent C(R2) and C(R3) respectively and E4 represents —N═; or
        E2 and E4 individually represent C(R2) and C(R4) respectively and E3 represents —N═.
        E3 represent C(R2) or C(R3) and E2 and E4 represents —N═.
    
    


Compounds of formula Ia that may be mentioned include those in which:

    
    
        E2 and E3 individually represent C(R2) and C(R3) respectively and E4 represents —N═, wherein R2 and R3 are represented by hydrogen; or
        E2 and E4 individually represent C(R2) and C(R4) respectively and E3 represents —N═, wherein R2 and R4 are represented by hydrogen.
        E3 represent C(R1a) and E2 and E4 represents —N═.
    
    


In a further particular embodiment that may be mentioned, the compound of formula I is a compound of formula Ib




wherein Y1 to Y4, L1, E1, E3, E4, Ra and z are as defined in respect of compounds of formula I.
Particular compounds of formula Ib that may be mentioned include those in which: E3 represents C(R3) and E1 and E4 each represent —N═.
More particular compounds of formula Ib that may be mentioned include those in which: E3 represents C(R3) and E1 and E4 each represent —N═, wherein R3 is represented by hydrogen.
For example, particular compounds of formula I that may be mentioned include those in which:

    
    
        (a) E1, E2 and E3 individually represent C(R1), C(R2) and C(R3) respectively, E4 represents —N═, R1 represents —OY4, and R2 and R3 represent H,
        (b) E1, E2 and E4 individually represent C(R1), C(R2) and C(R4) respectively, E3 represents —N═, R1 represents —OY4, and R2 and R4 represent H, or
        (c) E2 and E3 individually represent C(R2) and C(R3) respectively, E1 and E4 each represent —N═, R2 represents —OY4, and R3 represents H.
    
    


Particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which Y1 represents —C(O)OH, —C(O)N(H)S(O)2R1b or tetrazol-5-yl (i.e. an unsubstituted tetrazol-5-yl wherein R1c represents H), particularly wherein R1b represents:

    
    
        (a) an aryl group, optionally substituted by one or more substituents selected from B1;
        (b) C1-6 (e.g. C1-3) alkyl group, optionally substituted by one or more substituents selected from G2 and/or Z2.
    
    


More particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which Y1 represents —C(O)OH, —C(O)N(H)S(O)2R1b or tetrazol-5-yl, wherein R1b represents:

    
    
        (a) phenyl, optionally substituted by one or more (e.g. one) substituents selected from B1, particularly wherein B1 represents halo (such as fluoro) or —OR14g, particularly wherein R14g represents C1-3 (e.g. C1) alkyl optionally substituted by one or more fluoro;
        (b) a C1-6 (e.g. C1-3) alkyl group (such as cyclopropyl), optionally substituted by one or more fluoro (or, particularly, where the alkyl group is unsubstituted).
    
    


Particular Y1 groups that may be mentioned include —C(O)OH, —C(O)N(H)S(O)2R1b and tetrazol-5-yl, wherein R1b represents cyclopropyl, phenyl, (2-F)Ph, (4-OCH3)Ph and (4-OCF3)Ph.
Particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which:

    
    
        each Ra independently represents fluoro or methyl (wherein the latter group is optionally substituted by one or more fluoro or, particularly, wherein the methyl group is unsubstituted);
        z represents 0 to 4 (e.g. 4, 3, 2, 1 or 0).
    
    


More particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which z represents 0 (i.e. no Ra group is present).
Particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which L1 represents a direct bond or a C1 alkyl group, wherein the latter group is optionally substituted with one or more substituent selected from ═O or, particularly, G1 (such as one more fluoro).
Compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which L1 represents a direct bond or —CH2—.
Particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which:

    
    
        Y2 represents a C1-6 (e.g. C1-5) alkyl, straight-chain or branched-chain, optionally substituted by one or more substituents selected from G4 and ═O; and
        Y3 represents
        
            (a) an aryl group, optionally substituted by one or more substituents selected from A1; or
            (b) a heteroaryl group, optionally substituted by one or more substituents selected from A2.
        
        
    
    


More particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which:

    
    
        Y2 represents a C1-5 alkyl, straight-chain or branched-chain, optionally substituted by one or more substituents selected from G4, wherein G4 represents halo (such as fluoro) or —OR2g, wherein R2g represents R2a, wherein R2a represents C1-3 (e.g. C1) alkyl, optionally substituted by one more fluoro; and/or
        Y3 represents
        
            an aryl group (such as phenyl, naphthyl, dihydroacenaphthylenyl (e.g. 1,2-dihydroacenaphthylenyl) or dihydroindenyl (e.g. 2,3-dihydroindenyl)), optionally substituted by one or more substituents selected from A1, wherein each A1 independently represents: an aryl group (such as phenyl), wherein the latter group is optionally substituted by one or more B1 group (or, particularly, wherein the aryl group is unsubstituted), a C1-3 (e.g. C1) alkyl group, wherein the latter group is optionally substituted by one or more G4 group, or a G5 group, particularly wherein,
            
                G4 represents halo (such as fluoro),
                G5 represents halo (such as chloro or fluoro); or
            
            
            a heteroaryl group (such as quinolinyl, 4H-benzo[d][1,3]dioxinyl or benzo[d][1,3]dioxolyl), optionally substituted by one or more substituents selected from A2, wherein each A2 independently represents a C1-3 (e.g. C1) alkyl group, wherein the latter group is optionally substituted by one or more G4 group, or a G5 group, particularly wherein,
            
                G4 represents halo (such as fluoro),
                G5 represents halo (such as chloro or fluoro).
            
            
        
        
    
    


Particular Y2 groups that may be mentioned include substituted methylbutyl (for example, fluoro-methylbutyl), cyclopropylmethyl, ((1-trifluoromethyl)cyclopropyl)methyl and ((1-methyl)cyclopropyl)methyl, wherein the latter group is optionally substituted (e.g. on the 1-methyl group) with —OCH3.
Particular Y3 groups that may be mentioned include:

    
    
        particularly where L1 represents a direct bond,
        
            phenyl (optionally substituted with one or more chloro or methyl),
            naphthyl (e.g. naphth-1 or 2-yl; optionally substituted with one or more chloro, fluoro, —CF3 or methyl),
            quinolinyl (e.g. quinolin-5 or 8-yl; optionally substituted with one or more methyl or —CF3),
            dihydroindenyl (e.g. 2,3-dihydroinden-5-yl),
            dihydroacenaphthylenyl (e.g. 1,2-dihydroacenaphthylen-3 or 5-yl);
        
        
        particularly where L1 represents —CH2— (where optionally substituted with one or more fluoro or, particularly, unsubstituted),
        
            phenyl (optionally substituted with one or more methyl, —F, —Cl, —CF3, -Ph),
            naphthyl (e.g. naphth-1 or 2-yl; optionally substituted with one or more methyl),
            4H-benzo[d][1,3]dioxinyl (e.g. 4H-benzo[d][1,3]dioxin-8-yl; optionally substituted with halo, such as fluoro),
            benzo[d]dioxolyl (e.g. benzo[d]dioxol-4-yl; optionally substituted with halo, such as chloro).
        
        
    
    


Particular X1 groups that may be mentioned include —OR2g and, more particularly, halo (such as fluoro), —R2a, —CN and —N(R4a)R4b, such as fluoro.
Particular compounds of formula I that may be mentioned include those in which:

    
    
        each of R1 to R4 (where present) represent H; or
        any one of R1 to R4 (where present) represents —OY4 and the remainder of R1 to R4 (where present) represent H.
    
    


Particular compounds of formula Ia and/or Ib that may be mentioned include those in which each of R1 to R4 (where present) represent H.
Particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which Y4 represents: a C1-12 (e.g. C1-6) alkyl (including a C3-6 cycloalkyl), optionally substituted by one or more substituents selected from G4 and ═O.
More particular compounds of the invention (including compounds of formula I, Ia and Ib) that may be mentioned include those in which Y4 represents methyl optionally substituted by one or more fluoro (or, more particularly, where unsubstituted).
In a particular embodiment, there is provided compounds of the invention (including compounds of formula I, Ia and Ib) wherein:

    
    
        Y1 represents —C(O)OH, —C(O)N(H)S(O)2R1b or tetrazol-5-yl;
        Y2 represents a C1-6 (e.g. C1-5) alkyl, straight-chain or branched-chain, optionally substituted by one or more substituents selected from G4 and ═O;
        L1 represents a direct bond or a C1 alkyl group, wherein the latter group is optionally substituted with one or more substituent selected from ═O or G1;
        Y3 represents:
        
            an aryl group, optionally substituted by one or more substituents selected from A1; or
            a heteroaryl group, optionally substituted by one or more substituents selected from A2.
        
        
        X1 represents halo, —R2a, —N(R4a)R4b and —OR2g;
        z represents 0 to 4 (particularly, 0);
        Y4 represents a C1-6 alkyl (e.g. a C3-6 cycloalkyl), optionally substituted by one or more substituents selected from G4 and ═O.
    
    


In a more particular embodiment, there is provided compounds of the invention (including compounds of formula I, Ia and Ib) wherein:

    
    
        E1, E2 and E3 individually represent C(R1), C(R2) and C(R3) respectively and E4 represents —N═,
        E1, E2 and E4 individually represent C(R1), C(R2) and C(R4) respectively and E3 represents —N═,
        E1, E2, E3 and E4 individually represent C(R1), C(R2), C(R3) and C(R4) respectively, or
        E2 and E3 individually represent C(R2) and C(R3) respectively and E1 and E4 each represent —N═;
        Y1 represents —C(O)OH, —C(O)N(H)S(O)2R1b or tetrazol-5-yl, particularly wherein R1b represents:
        
            phenyl, optionally substituted by one or more (e.g. one) substituents selected from B1, wherein B1 represents halo (such as fluoro) or —OR14g, wherein R14g represents C1-3 (e.g. C1) alkyl optionally substituted by one or more fluoro;
            a C1-3 alkyl group (such as cyclopropyl), optionally substituted by one or more fluoro (or, particularly, where the alkyl group is unsubstituted);
        
        
        Y2 represents a C1-5 alkyl, straight-chain or branched-chain, optionally substituted by one or more substituents selected from G4, wherein G4 represents halo (such as fluoro) or —OR2g, wherein R2g represents R2a, wherein R2a represents C1-3 (e.g. C1) alkyl, optionally substituted by one more fluoro;
        L1 represents a direct bond or —CH2—;
        Y3 represents
        
            an aryl group (such as phenyl, naphthyl, dihydroacenaphthylenyl or dihydroindenyl), optionally substituted by one or more substituents selected from A1, wherein each A1 independently represents an aryl group (such as phenyl), wherein the latter group is optionally substituted by one or more B1 group (or, particularly, wherein the aryl group is unsubstituted), a C1-3 (e.g. C1) alkyl group, wherein the latter group is optionally substituted by one or more G4 group, or a G5 group, particularly wherein,
            
                G4 represents halo (such as fluoro),
                G5 represents halo (such as chloro or fluoro); or
            
            
            a heteroaryl group (such as quinolinyl, 4H-benzo[d][1,3]dioxinyl or benzo[d][1,3]dioxolyl), optionally substituted by one or more substituents selected from A2, wherein each A2 independently represents a C1-3 (e.g. C1) alkyl group, wherein the latter group is optionally substituted by one or more G4 group, or a G5 group, particularly wherein,
            
                G4 represents halo (such as fluoro),
                G5 represents halo (such as chloro or fluoro);
            
            
        
        
        z represents 0 to 4 (particularly, 0);
        in respect of compounds of formula I,
        
            each of R1 to R4 (where present) represent H; or
            any one of R1 to R4 (where present) represents —OY4 and the remainder of R1 to R4 (where present) represent H;
        
        
        in respect of compounds of formula Ia and/or Ib, each of R1 to R4 (where present) represent H; Y4 represents a C1-12 alkyl (e.g. a C1-3 alkyl, such as methyl), optionally substituted by one or more fluoro.
    
    


In a certain embodiment that may be mentioned, there is provided compounds of formula I wherein:

    
    
        E1, E2 and E3 individually represent C(R1), C(R2) and C(R3) respectively, E4 represents —N═, R1 represents —OY4, and R2 and R3 represent H,
        E1, E2 and E4 individually represent C(R1), C(R2) and C(R4) respectively, E3 represents —N═, R1 represents —OY4, and R2 and R4 represent H, or
        E2 and E3 individually represent C(R2) and C(R3) respectively, E1 and E4 each represent —N═, R2 represents —OY4, and R3 represents H;
        Y1 represents —C(O)OH;
        z represents 0;
        Y2 represents a C1-5 alkyl (e.g. —CH2-cyclopropyl), optionally substituted by one or more substituents selected from G4,
        L1 represents a direct bond;
        Y3 represents naphthyl (e.g. napht-1-yl), optionally substituted (e.g. in the 4-position) by one or more substituents selected from A1,
        Y4 represents a C1-12 (e.g. C1-6) alkyl, optionally substituted by one or more substituents selected from G4 and ═O.
    
    


In a certain embodiment that may be mentioned, there is provided compounds of formula I wherein:

    
    
        E1 represents C(R1), E2 and E3 represent C(R2), E4 represents —N═, R1 represents —OY4, and R2 represent H;
        Y1 represents —C(O)OH;
        z represents 0;
        Y2 represents a C1-5 alkyl (e.g. —CH2-cyclopropyl), optionally substituted by one or more substituents selected from halo,
        L1 represents a direct bond;
        Y3 represents phenyl, optionally substituted by one or more substituents independently selected from G7,
        G7 represents halo or R2a; R2a represents C1-3 alkyl optionally substituted by one or more substituents selected from fluoro,
        Y4 represents CH3, CH2F, CHF2 or CF3.
    
    


In a certain embodiment that may be mentioned, there is provided compounds of formula I wherein:

    
    
        E1 represents C(R1), E3 represent C(R2), E2 and E4 represent —N═, R1 represents —OY4, and R2 represent H;
        Y1 represents —C(O)OH;
        z represents 0;
        Y2 represents a C1-5 alkyl (e.g. —CH2-cyclopropyl), optionally substituted by one or more substituents selected from halo,
        L1 represents a direct bond;
        Y3 represents phenyl, optionally substituted by one or more substituents independently selected from G7,
        G7 represents halo or R2a; R2a represents C1-3 alkyl optionally substituted by one or more substituents selected from fluoro,
        Y4 represents CH3, CH2F, CHF2 or CF3.
    
    


In a certain embodiment that may be mentioned, there is provided compounds of formula I wherein:

    
    
        E1 represents C(R1), E2 and E3 represent C(R2), E4 represents —N═, R1 represents —OY4, and R2 represent H;
        Y1 represents —C(O)OH;
        z represents 0;
        Y2 represents a C1-5 alkyl (e.g. —CH2-cyclopropyl), optionally substituted by one or more substituents selected from halo,
        L1 represents a direct bond;
        Y3 represents phenyl, optionally substituted by one or more substituents independently selected from G7,
        G7 represents halo or R2a; R2a represents CH3, CH2F, CHF2 or CF3,
        Y4 represents CH3, CH2F, CHF2 or CF3.
    
    


In a certain embodiment that may be mentioned, there is provided compounds of formula I wherein:

    
    
        E1 represents C(R1), E3 represent C(R2), E2 and E4 represent —N═, R1 represents —OY4, and R2 represent H;
        Y1 represents —C(O)OH;
        z represents 0;
        Y2 represents a C1-5 alkyl (e.g. —CH2-cyclopropyl), optionally substituted by one or more substituents selected from halo,
        L1 represents a direct bond;
        Y3 represents phenyl, optionally substituted by one or more substituents independently selected from G7,
        G7 represents halo or R2a; R2a represents CH3, CH2F, CHF2 or CF3,
        Y4 represents CH3, CH2F, CHF2 or CF3.
    
    


In a certain embodiment that may be mentioned, there is provided compounds of formula I chosen from:

    (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid;
    (1R,2R)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid;
    (1S,2R)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}) carbonyl)cyclopropanecarboxylic acid;
    (1R,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}) carbonyl)cyclopropanecarboxylic acid; or a pharmaceutically acceptable salt thereof.


Particular compounds of the invention that may be mentioned include those of the examples described hereinafter, or isomers thereof or pharmaceutically-acceptable salts thereof.
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.
Methods of Preparation
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) oxidation of a compound of formula II,




wherein E1, E2, E3, E4, L1, Y1, Y2, Y3, Ra and z are as hereinbefore defined, or a suitably protected derivative thereof, in the presence of a suitable oxidising agent as known to those skilled in the art, for example, tert-butyl hydroperoxide or sodium periodate, and optionally in the presence of a suitable catalytic additive(s) (e.g. CrO3 or RhO4);
(ii) oxidation of a compound of formula III,




wherein E1, E2, E3, E4, L1, Y1, Y2, Y3, Ra and z are as hereinbefore defined, or a suitably protected derivative thereof, in the presence of a suitable oxidising agent, for example, manganese dioxide (MnO2), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), pyridinium chlorochromate (PCC) or the like (e.g. pyridinium dichromate (PDC));
(iii) reaction of a compound of formula IV,




wherein Ya represents either of Y2 or L1-Y3, and E1, E2, E3, E4, L1, Y1, Y2, Y3, Ra and z (as appropriate) are as hereinbefore defined, or a suitably protected derivative thereof, with a compound of formula V,

Yb-La  V

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 Yb represents the other of Y2 or L1-Y3 (i.e. that not present in the compound of formula IV as described herein) and Y2 or L1 and Y3 (as appropriate) 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 Yb represents phenyl and La represents bromo, i.e. bromobenzene), and wherein the 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) and/or using microwave irradiation;

(iv) reaction of a compound of formula VI,




wherein E1, E2, E3, E4, Y1, Ra and z are as hereinbefore defined and Lb represents a suitable leaving group, or a suitably protected derivative thereof, 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 and —B(ORza)2, in which each Rza independently represents a

C1-6 alkyl group, or, the respective Rza 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), with a compound of formula VII,

H—N(Y2)-L1-Y3  VII

wherein L1, Y2 and Y3 are 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 (iii) above, 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);

(v) 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;
(vi) for compounds of formula I in which Y1 represents —C(O)OR1a, in which R1a represents hydrogen, hydrolysis of a corresponding compound of formula I in which R1a does not represent hydrogen (e.g. R1a represents C1-3 alkyl or a suitable benzylic group as known to those skilled in the art), 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 THF or ethanol), which reaction mixture may be stirred at room or elevated temperature (e.g. about 60° C.) for a period of time until hydrolysis is complete (e.g. 5 hours); or, alternatively, using non-hydrolytic means suitable for converting esters to acids, such as by hydrogenation or oxidation (e.g. for certain benzylic groups) under conditions known to those skilled in the art;
(vii) for compounds of formula I in which Y1 represents —C(O)OR1a and R1a does not represent H:

    
    
        esterification (or the like) of a corresponding compound of formula I in which R1a represents H; or
        trans-esterification (or the like) of a corresponding compound of formula I in which R1a does not represent H (and does not represent the same value of the corresponding R1a group in the compound of formula I to be prepared),

under standard conditions in the presence of the appropriate alcohol of formula VIII,

R1zaOH  VIII

wherein R1za represents R1a 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 boiling temperature of the alcohol of formula VIII;

    
    


(viii) for compounds of formula I (particularly in which Y1 represents —C(O)OR1a, wherein R1a is other than H), reaction of a compound of formula IX,




wherein E1, E2, E3, E4, L1, Y2, Y3, Ra and z are as hereinbefore defined, or a suitably protected derivative thereof, and L represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a —Mg-halide, an organotin group or a suitable leaving group such as halo(wherein the skilled person will appreciate that the compound of formula IX in which Lc represents an alkali metal (e.g. lithium), a Mg-halide or an organotin group may be prepared from a corresponding compound of formula IX in which Lc 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 X,

Ld--Yc  X

wherein Yc represents —C(O)OR1a wherein R1a is as hereinbefore defined in respect of compounds of formula I, particularly in which R1a is other than H, and Ld 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 X may be Cl—C(O)OR1a. The reaction may be performed under standard reaction conditions known to those skilled in the art, for example in the presence of a polar aprotic solvent (e.g. THF or diethyl ether);

(ix) for compounds of formula I in which Y1 represents —C(O)OR1a in which R1a is H, reaction of a compound of formula IX as hereinbefore defined but in which Lc represents either:

    
    
        an alkali metal (for example, such as one defined in respect of process step (viii) above); or
        —Mg-halide (for example, wherein the halide is bromo or chloro),

with carbon dioxide, followed by acidification under standard conditions known to those skilled in the art, for example, in the presence of aqueous hydrochloric acid;

    
    


(x) for compounds of formula I in which Y1 represents —C(O)OR1a, reaction of a corresponding compound of formula IX as hereinbefore defined but in which Lc is a suitable leaving group known to those skilled in the art (such as a sulfonate group (e.g. a triflate) or, preferably, a halo (e.g. bromo or iodo) group) with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO)6 or Co2(CO)8)), in the presence of a compound of formula XI,

R1aOH  XI

wherein R1a 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;

(xi) reaction of a compound of formula XII,




or a suitably protected derivative thereof (e.g. in compounds of formula I where Y1 is represented by —C(O)OR1a it is instead represented as a suitable protecting group thereof, such as a suitable ester) with a compound of formula XIII,





wherein (in all cases and where present E1, E2, E3, E4, L1, Y1, Y2, Y3, Ra and z are as hereinbefore defined, or a suitably protected derivative thereof, in the presence of a suitable reagent that converts the free carboxylic acid group of the compound of formula XII 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 or, more preferably, PCl3, PCl5, SOCl2 or (COCl)2, under conditions known to those skilled in the art, such as in the presence of a suitable solvent (e.g. DCM). Alternatively, such a reaction may be performed in the presence of a suitable catalyst (for example a Lewis acid catalyst such as AlCl3) or under alternative Friedel-crafts acylation reaction conditions (or variations thereupon);

(xii) reaction of either a compound of formula XIV or XV,




with a compound of formula XVI or XVII,





respectively, wherein (in all cases and where present) E1, E2, E3, E4, L1, Y1, Y2, Y3, Ra and z are as hereinbefore defined and Le represents —B(OH)2 (or a protected derivative thereof as hereinbefore defined), an alkali metal (such as lithium) or a —Mg-halide (such as —MgI or, preferably, —MgBr), or a suitably protected derivative thereof, for example in the presence of a suitable solvent, optionally in the presence of a catalyst;

(xiii) reaction of an activated derivative of a compound of formula XII as hereinbefore defined (for example an acid chloride; the preparation of which is hereinbefore described in process step (xi) above), with a compound of formula XVI as hereinbefore defined, under reaction conditions known to those skilled in the art, for example those hereinbefore described in respect of process step (xii) above;
(xiv) for compounds of formula I wherein one of R1 to R4 represents —OY4, reaction of a corresponding compound of formula I wherein the —OY4 group is instead represented by —OH, with a suitable compound of formula XVIII,

Y4-Lf  XVIII

wherein Y4 is as hereinbefore defined in respect of compounds of formula I and Lf 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), 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 Y4 represents phenyl and Lf represents bromo, i.e. bromobenzene), and wherein the 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) and/or using microwave irradiation;

(xv) for compounds of formula I wherein one of R1 to R4 represents —OY4, reaction of a compound of formula XIX, or a suitably protected derivative thereof, wherein the compound of formula XIX takes the same definition as compounds of formula I with the exception that the respective R1 to R4 group(s) which is to represent —OY4 in the compound of formula I is instead an Lg group, wherein Lg represents a suitable leaving group, in which the suitable leaving group may independently be chloro, bromo, iodo or, preferably, fluoro, a sulfonate group (e.g. —OS(O)2CF3, —OS(O)2CH3, —OS(O)2PhMe or a nonaflate), —B(OH)2 or —B(ORza)2, in which each Rza independently represents a C1-6 alkyl group, or the respective Rza 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), with a suitable compound of formula XX,

H—OY4  XX

wherein Y4 is defined in respect of compounds of formula I, under suitable reaction conditions known to those skilled in the art, e.g. such as those hereinbefore described in respect of process step (iii) above, 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);

(xvi) for compounds of formula I wherein Y1 represents —C(O)N(H)S(O)2R1b, reaction of a corresponding compound of formula I wherein Y1 represents —C(O)OR1a in which R1a represents H, with a compound of formula XXI,

H2N—S(O)2R1b  XXI

wherein R1b is as defined in respect of compounds of formula I, under conditions known to those skilled in the art, such as under suitable peptide coupling conditions, for example in the presence of a suitable coupling reagent (such as HATU or EDC) and a suitable base (such as DIEA, DMAP and/or DBU) and in a suitable solvent (such as DMF). The skilled person will understand that the reaction may also be performed with an activated derivative of the relevant compound of formula I (for example an acid chloride; the preparation of which is hereinbefore described in process step (xi) above). Alternatively, the reaction may also be performed with a compound of formula I wherein Y1 represents —C(O)OR1a in which R1a represents other than H (e.g. a C1-8 alkyl group, such as —CH3), under conditions known to those skilled in the art, such as in a suitable solvent (such as DMF) and optionally in the presence of a suitable base (such as DMAP);

(xvii) for compounds of formula I wherein Y1 represents a tetrazolyl group, reaction of a compound of formula XXII,




wherein E1, E2, E3, E4, L1, Y2, Y3, Ra and z are as hereinbefore defined, with a suitable source of azide anion (such as sodium azide) under suitable conditions known to those skilled in the art, such as in the presence of a suitable solvent (such as toluene) and, optionally, in the presence of a suitable salt (such as triethylamine hydrochloride), followed by acidification (for example, with aq. hydrochloric acid);

(xviii) for compounds of formula I in which Y1 represents —C(O)OR1a, in which R1a represents hydrogen, hydrolysis of a corresponding compound of formula XXII, as hereinbefore defined, or a suitably protected derivative thereof, under standard conditions, for example in the presence of an aqueous solution of base (e.g. aqueous NaOH) optionally in the presence of an organic solvent (such as ethanol), which reaction mixture may be stirred at room or, preferably, elevated temperature (e.g. about 70° C.) for a period of time until hydrolysis is complete (e.g. 24 hours), followed by acidification using an aqueous acid (such as HCl).
Compounds of formula III may be prepared by reaction of a compound of formula XXIII,




wherein Y1, Ra and z are as hereinbefore defined, with a compound of formula XVI, for example under reaction conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (xii)).

Compounds of formula IV may be prepared by reaction of a compound of formula VI as hereinbefore defined with a compound of formula XXIV,

H2N—Ya  XXIV,

wherein Ya is as hereinbefore defined in respect of compounds of formula IV, under conditions known to those skilled in the art, such as those described in respect of process step (iv) above.

Compounds of formula VI may be prepared by reactions using compounds and conditions as described in respect of process steps (xi), (xii) or (xiii) above but wherein the substituent —N(Y2)-L1-Y3 is instead an Lb group, wherein Lb is as defined in respect of compounds of formula VI (or alternatively a suitable protected derivative or precursor of an Lb group, wherein the process further comprises conversion of the protected derivative or precursor to the required Lb group).
Compounds of formula IX may be prepared by reactions using compounds and conditions as described in respect of process steps (xi), (xii) or (xiii) above but wherein the substituent —Y1 is instead an Lc group, wherein Lc is as defined in respect of compounds of formula IX (or alternatively a suitable protected derivative or precursor of an Lc group, wherein the process further comprises conversion of the protected derivative or precursor to the required Lc group).
Compounds of formula XII may be prepared by reaction of a compound of formula XVII as hereinbefore defined but in which Le represents either:

    
    
        an alkali metal (for example, such as one defined in respect of process step (viii) above); or
        —Mg-halide (for example, wherein the halide is bromo or chloro),

with carbon dioxide, followed by acidification under standard conditions known to those skilled in the art, for example, in the presence of aqueous hydrochloric acid.

    
    


Compounds of formula XXIII may be prepared by reaction of a compound of formula XVII as hereinbefore defined but in which Le represents either:

    
    
        an alkali metal (for example, such as one defined in respect of process step (viii) above); or
        —Mg-halide (for example, wherein the halide is bromo or chloro),

with dimethylformamide (or a similar reagent for the introduction of an aldehyde group), under standard conditions known to those skilled in the art, for example, where Le represents a —Mg-halide, under Grignard reaction conditions known to those skilled in the art (such as those described herein).

    
    


Compounds of formula II, V, VII, VIII, X, XI, XIII to XXII and XXIV 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.
The groups E1 to E4, L1, Y1 to Y3 and Ra (and, where relevant, Y4), and substituents thereon, 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. 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-, chloro- 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 E1 to E4-containing ring may be a heterocycle, which moiety 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 heterocycles 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.
Further, the skilled person will understand that cyclopropane moieties present in compounds of the invention may be synthesised in accordance with techniques well-known in the art, for example as described in e-EROS Encyclopedia of Reagents for Organic Synthesis (e.g. using ethyl (dimethylsulfuranylidene)acetate).
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 ca-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).
Medical and Pharmaceutical Uses
Compounds of the invention are indicated as pharmaceuticals. Therefore, according to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical and/or for use in medicine.
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. Particular prodrugs of compounds of the invention that may be mentioned include pharmaceutically acceptable esters (for example, compounds of formula I wherein Y1 represents —C(O)OR1a, in which R1a is other than hydrogen).
Compounds of the invention may inhibit leukotriene (LT) C4 synthase, for example as may be shown in the biological test described below, and may therefore be useful in the treatment of those conditions in which such inhibition is desired and/or required. Thus, compounds of the invention may be useful in the treatment of those conditions in which it is desired and/or required that the formation of e.g. one or more of LTC4, LTD4 and LTE4 (such as LTC4) is inhibited or decreased (or where it is required that the activation of a Cys-LT receptor (e.g. Cys-LT1, Cys-LT2, or CysLT3) is inhibited or attenuated) and/or where it is required that the formation of one or more of eoxin (EX) C4, EXD4 and EXE4 (such as EXC4) is inhibited or decreased.
Compounds of the invention are thus expected to be useful in the treatment of disorders that may benefit from inhibition of LTC4 synthase and/or inhibition of the production (i.e. synthesis and/or biosynthesis) of cysteinyl-leukotrienes (such as LTC4) and/or eoxins (such as EXC4), for example a respiratory disease/disorder and/or inflammation and/or a disease that has an inflammatory component.
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 respiratory diseases/disorders, inflammation and/or disease/disorders having an inflammatory component, for example 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, Löffler's syndrome and Kawasaki disease), cardiovascular diseases (e.g. atherosclerosis, cerebrovascular diseases, acute ischemic heart attacks and post-heart attack treatment), 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 (inflammatory and neuropathic), endotoxin shock, 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), 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. Most particularly, compounds of the invention may be useful in treating asthma.
Accordingly, compounds of the invention may be useful in the treatment of cardiovascular disease in a mammal, particularly a human. Cardiovascular disease includes, but is not limited to, conditions associated with cardiac dysfunction and/or microvascular dysfunction and/or macrovascular pathology, such as atherosclerosis, arteriosclerosis, coronary artery disease including stable and high risk coronary artery disease (defined as recent acute coronary syndrome (ACS) or by biomarkers of microvascular and cardiac function), myocardial infarction, restenosis following revascularization procedures, heart failure, abdominal aortic aneurysm (AAA), peripheral artery disease (PAD) including erectile dysfunction due to vascular disease, stroke, transient ischemic attack (TIA) and reversible ischemic neurologic disease (RIND), multi-infarct dementia and renal arterial disease.
Treatment with the compounds of the invention are expected to lower the cardiovascular and/or cerebrovascular and/or renal and/or peripheral arterial disease morbidity and mortality associated with cardiac dysfunction and/or microvascular dysfunction and/or macrovascular pathology due to their anti-inflammatory properties and influence on vasoactive mechanisms.
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 cysteinyl-leukotrienes and/or eoxins (i.e. inhibition or decrease of the formation of one or more of LTC4, LTD4 and LTE4 and/or EXC4, EXD4 and EXE4) 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, 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 activating 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:

    
    
        a compound of the invention, as hereinbefore defined; and
        another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

    
    


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:

    
    
        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
        a kit of parts comprising components:
        
            a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
            a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of a respiratory disorder and/or inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

        
        
    
    


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, 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:

    
    
        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
        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.
Compounds of the invention may have the advantage that they are effective inhibitors of LTC4 synthase. Thus, compounds of the invention may have the advantage that they are able to inhibit or decrease the formation of one or more of LTC4, LTD4 and LTE4 and/or EXC4, EXD4 and EXE4, and therefore, are useful in the treatment of respiratory diseases/disorders, inflammation and/or disease/disorders having an inflammatory component.
Compounds of the invention may also have the advantage that they are able to effectively inhibit LTC4 synthase in a human whole blood assay, mimicking the situation in humans, and may therefore be expected to have therapeutic potential in treating respiratory diseases/disorders, inflammation and/or disease/disorders having an inflammatory component. In particular, compounds of the invention may show greater inhibition of LTC4 synthase in a human whole blood assay than compounds of the prior art.
In addition, compounds of the invention may 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.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the X-ray powder diffraction pattern for Example 62: (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}) carbonyl)cyclopropanecarboxylic acid.



EXAMPLES
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).
Abbreviations
aq aqueous
BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
Boc tert-butoxycarbonyl
brine saturated aqueous solution of NaClDBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DEA diethylamine
DCM dichloromethaneDIEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF dimethylformamide
DMS dimethylsulfide
DMSO dimethylsulfoxide
EDC.HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
ESI Electrospray Ionization
EtOAc ethyl acetate
EtOH ethanol
Ex example
FA Formic Acid
HATU O-(7-azabenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
HOBt 1-hydroxybenzotriazole
HPLC High Performance Liquid Chromatography
Int intermediate
KHMDS potassium bis(trimethylsilyl)amide
LAH lithium aluminium hydride
LC/MS Liquid Chromatography-Mass Spectroscopy
MeCN acetonitrile
MeOH methanolNBS N-bromosuccinimide
n-BuLi n-butyllithiumNMR nuclear magnetic resonance
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
rac racemic
rt room temperature
SFC supercritical fluid chromatography
sat. saturated
tBuOK potassium tert-butoxide
tBuONa sodium tert-butoxide
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphosphorinane-2,4,6-trioxide
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Experimental Procedures
Unless stated otherwise, starting materials were commercially available or previously described in the literature. All solvents and commercial reagents were of laboratory grade and were used as received unless otherwise stated.
Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were used. Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS) using electrospray ionization. Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvent used.
NMR spectra were recorded on a Bruker Avance, Avance II or Avance III spectrometer at a proton frequency of 400, 500 or 600 MHz. A JEOL EX-270 spectrometer was used if a proton frequency of 270 MHz is reported. The central peaks of CDCl3 (H 7.26 ppm), acetone (H 2.04 ppm), dichloromethane-d2 (H 5.32 ppm), CH3OD (H 3.30 ppm) or DMSO-d6 (H 2.50 ppm) were used as internal references.
LC/MS experiments were performed using a Waters Acquity UPLC system combined with a Waters Xevo Q-ToF Mass Spectrometer in ESI mode. LC was run in two set ups: 1) BEH C18 column (1.7 μm 2.1×50 mm) in combination with a gradient (2-95% B in 5 min) of aqueous 46 mM ammonium carbonate/ammonia buffer at pH 10 (A) and MeCN (B) at a flow rate of 1.0 mL/min. 2) HSS C18 column (1.8 μm 2.1×50 mm) with a gradient (2-95% B in 5 min) of aqueous 10 mM FA/1 mM ammonium formate buffer at pH 3 (A) and MeCN (B) at a flow rate of 1.0 ml/min.
Optical purity, indicated as enantiomeric excess (% ee), was determined by chiral HPLC using an Agilent 1100 series chromatograph. Method A: System equipped with Chiralpak IC 250×4.6 mm; 5 μm. As mobile phase heptane/iPrOH/ethanolamine (60:40:0.1) with a flow rate of 1 mL/min was used. The injection volume was 10 μL and compound detection was performed by UV at 268 nm. Method B: System quipped with Chiralpak IC 150×4.6 mm, 3 μm. As mobile phase CO2, 120 bar (A) and MeOH (0.5% DEA) (B) was used in a ratio A/B of 80/20 with a flow rate of 4 mL/min. The injection volume was 5 μL.
Preparative HPLC was performed with a Waters FractionLynx system with intergrated MS detection and equipped with Prep C18 OBD 5 μm 19×150 mm columns from X-Bridge or Sunfire. Alternatively Gilson GX-281 with intergrated UV detection was used, equipped with either Kromasil C8 10 μm, 20×250 ID or 50×250 ID mm. As eluent gradients of water/MeCN/AcOH (95/5/0.1) or water/0.05% TFA or water/0.1% NH4HCO3 (A) and MeCN (B) were applied.
Preparative SCF was performed with a Waters Prep 100 SCF system with intergrated MS detection, equipped with Waters Viridis 2-EP or Phenomenex Luna Hilic, 30×250 mm, 5 μm. As eluent gradients of CO2 (100 g/min, 120 bar, 40° C.) (A) and MeOH/NH3 (20 mM) or MeOH (5% FA) or MeOH (B) were applied.
For syntheses referencing procedures in other Examples, reaction conditions (such as length of reaction or temperature) may vary. In general, reactions were followed by thin layer chromatography or LC-MS, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide an appropriate Rf and/or retention time.
Unless otherwise stated, example compounds described herein containing a Y1 substituent on the essential cyclopropyl ring are thought to have trans configuration in respect of the Y1 and ketone substituents on the relevant cyclopropyl ring.
The X-ray diffraction analysis was performed according to standard methods, which can be found in e.g. Kitaigorodsky, A. I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.
Samples were mounted on single silicon crystal (SSC) wafer mounts and powder X-ray diffraction was recorded with a PANalytical X'Pert PRO (reflection geometry, wavelength of X-rays 1.5418 Å nickel-filtered Cu radiation, Voltage 45 kV, filament emission 40 mA). Automatic variable divergence and anti scatter slits were used and the samples were rotated during measurement. Samples were scanned from 2-50°2Theta using a 0.013° step width and 2362 seconds per step using a PIXCEL detector (active length 3.35°2Theta).
It is known that an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a power diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure (for further information see Jenkins, R & Snyder, R. L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons, 1996).
Generally, a measurement error of a diffraction angle in an X-ray powder diffractogram may be approximately +/−0.1°2-theta, and such a degree of a measurement error should be taken into account when considering the X-ray powder diffraction data.
Where applicable, compound names indicated in respect of examples 1-61 have been generated using the structure naming function of ChemBioDraw Ultra, Version 12.0, and the names for the examples 62-65 have been generated using the IUPAC name program ACD/Name 2014 from Acdlabs.
Preparation of intermediates used in the synthesis of compounds of the invention




Int 1:1 5-(Trifluoromethyl)quinolin-8-amine
tert-Butyl (5-(trifluoromethyl)quinolin-8-yl)carbamate
8-Bromo-5-trifluoromethyl-quinoline (50 mg, 0.18 mmol), carbamic acid tert-butyl ester (32 mg, 0.27 mmol), Pd2(dba)3 (8.2 mg, 0.010 mmol), Xantphos (15.6 mg, 0.027 mmol) and Cs2CO3 (117 mg, 0.36 mmol) were mixed in 1,4-dioxane (1 mL) and stirred at 105-110° C. for 44 h in a sealed tube. The reaction mixture was diluted (EtOAc), filtered through a celite pad and concentrated. Purification by column chromatography afforded the sub-title compound. Yield: 39 mg (69%).
5-(Trifluoromethyl)quinolin-8-amine
A solution of tert-butyl (5-(trifluoromethyl)quinolin-8-yl)carbamate (65 mg, 0.21 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at rt for 1.5 h, concentrated and redissolved in EtOAc. Extractive workup (saturated aq NaHCO3, water, brine) and concentration of the EtOAc extracts afforded the title compound. Yield: 47 mg (100%).




Int 2:1 4-Chloro-N-(cyclopropylmethyl)naphthalen-1-amine
To solution of 4-chloro-naphthalen-1-ylamine (1.00 g, 5.63 mmol) in THF (7 mL), tBuOK (695 mg, 6.19 mmol) was added at 0° C. in one portion. After stirring at 0° C. for 30 min, (bromomethyl)cyclopropane (0.58 mL, 5.91 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then quenched with water. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the title compound. Yield 8.26 g (51%).




A detailed illustrative synthetic procedure for the general procedure shown in Scheme B-2 is described for synthesis of Int 2:2 below.
Int 2:2 N-(Cyclopropylmethyl)-4-methylnaphthalen-1-amine




To a 100 mL round-bottom flask were added 1-bromo-4-methylnaphthalene (3.32 g, 15.0 mmol), cyclopropylmethanamine (2.67 mg, 37.5 mmol) and toluene (50 mL) to give a slightly turbid mixture. A premixed solution of Pd(OAc)2 (168 mg, 0.75 mmol) and Xantphos (651 mg, 1.12 mmol) in toluene (25 mL) was added to the reaction mixture followed by Cs2CO3 (9.78 g, 30.0 mmol). The round-bottom flask was sealed with a rubber septum and heated at 110° C. under stirring over night. The solvent was evaporated in vacuo and the product was purified by silica chromatography (isohexane:EtOAc 95:5) to provide 2.35 g (74% yield) of the desired product as a colorless oil.
The following intermediates were prepared in analogy to Int 2:2 described above in detail unless otherwise indicated.










TABLE 1








Reaction





conditions





according to


Int
Structure
Name
Scheme B-2







2:3




N-(Cyclopropylmethyl)-4- fluoronaphthalen-1-amine
Pd(OAc)2, BINAP, Cs2CO3, toluene, 90° C.


 


2:4




N-(Cyclopropylmethyl)-4- methylquinolin-8-amine
Pd(OAc)2, Xantphos, Cs2CO3, toluene, 90° C.













Int 2:5 4-Chloro-N-((1-methylcyclopropyl)methyl)aniline
N-(4-Chlorophenyl)-1-methylcyclopropanecarboxamide
1-Methylcyclopropanecarboxylic acid (1.04 g, 10.4 mmol), 4-chloroaniline (1.92 g, 15.1 mmol), HATU (4.28 g, 11.3 mmol), DIEA (4.0 mL, 23.0 mmol) and DCM (18 mL) was stirred overnight in a sealed reaction tube. The mixture was concentrated and the residue purified by column chromatography to afford the sub-title compound. Yield: 2.01 g (94%).
4-Chloro-N-((1-methylcyclopropyl)methyl)aniline
LAH (0.69 g, 18.2 mmol) was added in portions to a stirred solution of N-(4-chlorophenyl)-1-methylcyclopropanecarboxamide (2.01 g, 9.60 mmol) in THF (35 mL) at 0° C. After stirring at temperatures between 22-40° C. for 42 h the reaction mixture was cooled to 0° C. and quenched by addition of H2O (0.7 mL), 15% aqueous NaOH (0.7 mL) and H2O (2.1 mL). The mixture was filtered and concentrated, and the resulting residue was purified by column chromatography to afford the title compound. Yield: 1.26 g (67%).
The following intermediates were prepared in analogy to Int 2:5 described above in detail.









TABLE 2





Int
Structure
Name







2:6




4-Chloro-N-((1-(trifluoromethyl) cyclopropyl)methyl)aniline


 


2:7




N-((1-Methylcyclopropyl)methyl)- 2,3-dihydro-1H-inden-5-amine













Int 2:8 4-Chloro-N-((1-(methoxymethyl)cyclopropyl)methyl)aniline
A solution of (1-(methoxymethyl)cyclopropyl)methanamine hydrochloride (385 mg, 2.54 mmol) and DBU (0.79 mL, 5.28 mmol) in DMSO (1.5 mL) was added in one portion to a mixture of 1-chloro-4-iodobenzene (373 mg, 1.56 mmol) and Cu(OAc)2 (311 mg, 1.71 mmol) in DMSO (2.5 mL). The reaction mixture was heated to 150° C. for 1 h, and then cooled to rt. Extractive workup (toluene, water) and concentration of the toluene extracts followed by column chromatography afforded the title compound. Yield: 140 mg (40%).




Int 3:1 Ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate
Ethyl 2-((5-bromo-3-methoxypyridin-2-yl)(hydroxy)methyl)cyclopropanecarboxylate
To an oven-dried 250 mL round-bottom flask were added 5-bromo-2-iodo-3-methoxypyridine (12.6 g, 40.0 mmol) and THF (100 mL). The reaction mixture was stirred at rt until all solid material was completely dissolved. The round-bottom flask was transferred to a cooling bath and cooled to −70° C. After cooling for 1 h at −70° C., iPrMgCl.LiCl complex in THF (1.3 M, 33.9 mL, 44.1 mmol) was added dropwise over 30 min. The temperature was slowly raised to −20° C. and kept constant for 1 h after which it was lowered to −70° C. After cooling the reaction mixture at −70° C. for 30 min ethyl 2-formylcyclopropanecarboxylate (5.80 g, 41.0 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to slowly reach rt over night. After addition of HOAc (5 mL) under stirring, the reaction mixture was filtered through a short silica column and the column was thoroughly washed with EtOAc. The solvent was evaporated from the reaction mixture in vacuo. The crude reaction mixture was dissolved in DCM and purified by silica chromatography (isohexane:EtOAc 4:1) to give 9.34 g (71% yield) of a yellow-orange solid.
Ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate
Ethyl 2-((5-bromo-3-methoxypyridin-2-yl)(hydroxy)methyl)cyclopropanecarboxylate (9.34 g, 28.3 mmol) was dissolved in THF (200 mL) and MnO2 (24.6 g, 283 mmol) was added under stirring. The reaction mixture was stirred at rt over night. The reaction mixture was filtered and the filter was thoroughly washed with EtOAc. The filtrate was concentrated in vacuo and subjected to silica chromatography (isohexane:EtOAc 1:1) to provide 8.68 g (94% yield) of the title product as a pale yellow solid.




Int 3:2 Ethyl 2-(6-chloro-4-methoxynicotinoyl)cyclopropanecarboxylate
6-Chloro-4-methoxypyridin-3-amine
To solution of 2-chloro-4-methoxy-5-nitropyridine (2.00 g, 10.6 mmol) in THF (66 mL), Zn dust (3.5 g, 53 mmol) and aq NH4OH (24%, 22 mL) was added at 0° C. The mixture was stirred at 7° C. for 4 h, and then filtered through a celite pad. Extractive workup of the filtrate (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 1.50 g (89%).
2-Chloro-5-iodo-4-methoxypyridine
A solution of NaNO2 (0.72 g, 10.5 mmol) in H2O (3 mL) was added dropwise to a solution of 6-chloro-4-methoxypyridin-3-amine (1.39 g, 8.75 mmol) in H2O (60 mL) and H2SO4 (8.7 mL) at 0° C. After stirring at 0° C. for 1 h a solution of KI (1.89 g, 11.4 mmol) in H2O (9 mL) was added dropwise. The reaction mixture was stirred at rt for 1.5 h. Extractive workup (EtOAc, 1M NaOH, 10% Na2S2O3, 1M HCl, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 1.46 g (62%).
Ethyl 2-((6-chloro-4-methoxypyridin-3-yl)(hydroxy)methyl)cyclopropanecarboxylate
A solution of iPrMgCl.LiCl complex in THF (1.3 M, 3.80 mL, 4.97 mmol) was added dropwise to a solution of 2-chloro-5-iodo-4-methoxypyridine (1.03 g, 3.82 mmol) in THF (6 mL) at −20° C. After stirring at −20° C. for 2 h, ethyl 2-formylcyclopropanecarboxylate (0.66 mL, 4.97 mmol) was added dropwise at −20° C. The reaction mixture was allowed to reach rt, then quenched with saturated aq NH4Cl. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 1.20 g (94%).
Ethyl 2-(6-chloro-4-methoxynicotinoyl)cyclopropanecarboxylate
MnO2 (3.65 g, 40.2 mmol) was added to a solution of ethyl 2-((6-chloro-4-methoxypyridin-3-yl)(hydroxy)methyl)cyclopropanecarboxylate (1.20 g, 4.20 mmol) in toluene (3 mL). After stirring at 70° C. for 18 h, the reaction mixture was filtered through a silicagel pad. Concentration of the filtrate followed by column chromatography afforded the sub-title compound. Yield: 0.77 g (65%).




Int 3:3 Ethyl 2-(4-bromo-2-methoxybenzoyl)cyclopropanecarboxylate
Ethyl 2-((4-bromo-2-methoxyphenyl)(hydroxy)methyl)cyclopropanecarboxylate
A solution of iPrMgCl.LiCl complex in THF (1.3 M, 10.3 mL, 13.4 mmol) was added dropwise to a solution of 4-bromo-1-iodo-2-methoxybenzene (4.00 g, 12.8 mmol) in THF (25 mL) at −50° C. After stirring at −50° C. for 2 h, the reaction mixture was cooled to −70° C. and ethyl 2-formylcyclopropanecarboxylate (1.80 mL, 13.4 mmol) was added dropwise at −70° C. The reaction mixture was allowed to reach rt, then quenched with saturated aq NH4Cl. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 3.14 g (75%).
Ethyl 2-(4-bromo-2-methoxy-benzoyl)cyclopropanecarboxylate
MnO2 (8.29 g, 95.4 mmol) was added to a solution of ethyl 2-((4-bromo-2-methoxyphenyl)(hydroxy)methyl)cyclopropanecarboxylate (3.14 g, 9.54 mmol) in toluene (12 mL). After stirring at 80° C. for 16 h, the reaction mixture was filtered through a silicagel pad. Concentration of the filtrate followed by column chromatography afforded the sub-title compound. Yield: 2.40 g (77%).




Int 3:4 Ethyl 2-(5-bromopicolinoyl)cyclopropanecarboxylate
Ethyl 2-((5-bromopyridin-2-yl)(hydroxy)methyl)cyclopropanecarboxylate
Prepared in analogy to Int 3:3 (step a) using 5-bromo-2-iodopyridine (0.60 g, 2.11 mmol), ethyl 2-formylcyclopropanecarboxylate (0.30 mL, 2.30 mmol), iPrMgCl (2 M, 1.11 mL, 2.22 mmol) and THF (15 mL) at −30° C. Yield: 0.30 g (47%).
Ethyl 2-(5-bromopicolinoyl)cyclopropanecarboxylate
Prepared in analogy to Int 3:3 (step b) using ethyl 2-((5-bromopyridin-2-yl)(hydroxy)methyl)cyclopropanecarboxylate (0.30 g, 0.95 mmol), MnO2 (285 mg, 3.29 mmol) and toluene (8 mL) at 50° C. for 16 h. Yield: 0.22 g (78%).




Int 3:5 Ethyl 2-(5-bromo-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylate
5-Bromo-4-methoxypyrimidin-2-amine
N-Bromosuccinimide (6.05 g, 34.0 mmol) was added to a solution of 4-methoxypyrimidin-2-amine (3.87 g, 30.9 mmol) in MeCN (50 mL). The mixture was stirred at 80° C. for 2 h, and then the MeCN was partly evaporated. Extractive workup (DCM, water, brine) and concentration of the DCM extracts afforded the sub-title compound. Yield: 5.73 g (91%).
5-Bromo-2-iodo-4-methoxypyrimidine
tert-Butylnitrite (5.87 mL, 49.0 mmol) was added to a solution of 5-bromo-4-methoxypyrimidin-2-amine (2.00 g, 9.80 mmol) in MeCN (1 mL) and diiodomethane (5 mL) and the reaction mixture was stirred at 80° C. for 2 h. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 1.02 g (33%).
Ethyl 2-((5-bromo-4-methoxypyrimidin-2-yl)(hydroxy)methyl)cyclopropanecarboxylate
A solution of iPrMgCl.LiCl complex in THF (1.3 M, 2.62 mL, 3.40 mmol) was added dropwise to a solution of 5-bromo-2-iodo-4-methoxypyrimidine (1.02 g, 3.24 mmol) in THF (5 mL) −60° C. After stirring at −60-−50° C. for 30 min, the reaction mixture was cooled to −60° C. and ethyl 2-formylcyclopropanecarboxylate (1.80 mL, 13.4 mmol) was added dropwise. The reaction mixture was allowed to reach rt, then quenched with saturated aq NH4Cl. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 0.90 g (84%).
Ethyl 2-(5-bromo-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylate
MnO2 (1.35 g, 15.5 mmol) was added to a solution of ethyl 2-((5-bromo-4-methoxypyrimidin-2-yl)(hydroxy)methyl)cyclopropanecarboxylate (0.90 g, 2.72 mmol) in toluene (5 mL). After stirring at 80° C. for 24 h, the reaction mixture was filtered through a silicagel pad. Concentration of the filtrate followed by column chromatography afforded the sub-title compound. Yield: 0.67 g (75%).




Int 4:1 Ethyl 2-(5-((cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylate
To a test tube were added Pd(PPh3)4 (277 mg, 0.24 mmol), Xantphos (208 mg, 0.36 mmol) and toluene (5 mL). The mixture was stirred at rt for 15 min. To a 20 mL microwave vial were added ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (1.31 g, 4.0 mmol), cyclopropylmethanamine (370 mg, 5.2 mmol), Cs2CO3 (2.61 g, 8.0 mmol) and toluene (10 mL). The mixture was stirred at rt for 5 min before the catalyst slurry from the test tube was transferred to the microwave vial. The vial was sealed with a Teflon fitted septa and heated at 90° C. over night. The reaction mixture was filtered through a short silica column and the filtrate was concentrated in vacuo. The crude solid was dissolved in DCM and purified by silica chromatography (isohexane:EtOAc 1:1) to give 1.04 g (82% yield) of pure product as a pale yellow solid.
Synthesis of Compounds of the Invention




A detailed illustrative synthetic procedure for the general procedure shown in Scheme E-1 is described below.
Example 1
2-(5-((4-Chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid




Ethyl 2-(5-((4-chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylate
Ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (118 mg, 0.36 mmol), 4-chloro-N-(cyclopropylmethyl)naphthalen-1-amine (100 mg, 0.43 mmol), Pd(OAc)2 (4.0 mg, 0.018 mmol), rac-BINAP (16 mg, 0.025 mmol) and Cs2CO3 (164 mg, 0.50 mmol) were mixed in toluene (10 mL) and stirred in a sealed tube at 70° C. for 42 h. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 112 mg (81%).
2-(5-((4-Chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid
A mixture of ethyl 2-(5-((4-chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylate (75 mg, 0.16 mmol) and NaOH (31 mg, 0.78 mmol) in EtOH (2 mL) and water (1 mL) was stirred at 70° C. for 30 min. Acidification with 1M aq HCl (pH ̃3), extraction (EtOAc), washing (water and brine), drying (Na2SO4), filtration and evaporation furnished the title compound. Yield: 66 mg (93%). MS [M+H]+451. 1H-NMR 400 MHz (DMSO-d6, ppm) δ 8.36 (1H, d, J=8.5 Hz), 7.76-7.70 (2H, m), 7.69-7.63 (2H, m), 7.57-7.50 (1H, m), 7.42 (1H, d, J=7.8 Hz), 6.31-6.27 (1H, m), 4.04-3.76 (2H, m), 3.64 (3H, s), 3.62-3.30 (1H, m), 2.27-2.19 (1H, m), 1.61-1.55 (1H, m), 1.54-1.47 (1H, m), 1.24-1.14 (1H, m), 0.57-0.44 (2H, m), 0.16-0.03 (2H, m).
The following compounds were prepared in analogy to Example 1 described above in detail unless otherwise indicated.















TABLE 3











Pd-catalyst and






ligand





MS
according to



R1
R2
[M+H]+
Scheme E-1









Name


Ex.
1H-NMR














2








401
Pd(PPh3)4, Xantphos


 









2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.42 (1H, br s), 7.68 (1H, d, J = 2.3 Hz), 7.55-7.51



(2H, m), 7.39-7.35 (2H, m), 6.76 (1H, d, J = 2.4 Hz), 3.75 (3H, s), 3.72 (2H, d,



J = 6.7 Hz), 3.59 (1H, ddd, J = 7.8, 6.7, 3.9 Hz), 1.87 (1H, ddd, J = 7.4, 6.5, 3.9 Hz),



1.32-1.28 (2H, m), 1.15-1.05 (1H, m), 0.47-0.42 (2H, m), 0.17-0.13 (2H, m)


 











3








469
Pd(OAc)2, BINAP


 









2-(5-((4-Chlorophenyl)((1-(trifluoromethyl)cyclopropyl)methyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.52 (1H, br s), 7.63 (1H, d, J = 2.3 Hz), 7.58-7.54



(2H, m), 7.41-7.36 (2H, m), 6.78 (1H, d, J = 2.3 Hz), 4.26 (2H, app s), 3.74 (3H,



s), 3.58-3.53 (1H, m), 1.90-1.85 (1H, m), 1.33-1.28 (2H, m), 0.95-0.91 (2H,



m), 0.60-0.55 (2H, m)


 











4








445
Pd(OAc)2, BINAP


 









2-(5-((4-Chlorophenyl)((1-(methoxymethyl)cyclopropyl)methyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 7.59 (1H, d, J = 2.3 Hz), 7.54-7.50 (2H, m), 7.42-



7.37 (2H, m), 6.98 (1H, d, J = 2.3 Hz), 3.90 (1H, d, J = 15.7 Hz), 3.85 (1H, d,



J = 15.5 Hz), 3.77 (3H, s), 3.57 (1H, ddd, J = 8.0, 6.7, 3.9 Hz), 3.24 (3H, s), 3.21



(1H, d, J = 10.2 Hz), 3.18 (1H, d, J = 10.3 Hz), 1.89-1.84 (1H, m), 1.31-1.27 (2H,



m), 0.37-0.34 (2H, m), 0.19-0.16 (2H, m)


 











5








415
Pd(OAc)2, BINAP


 









2-(5-((4-Chlorophenyl)((1-methylcyclopropyl)methyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.47 (1H, br s), 7.69 (1H, d, J = 2.3 Hz), 7.5-7.51



(2H, m), 7.42-7.37 (2H, m), 6.78 (1H, d, J = 2.3 Hz), 3.83 (2H, app s), 3.74 (3H,



s), 3.59 (1H, ddd, J = 7.9, 6.7, 3.9 Hz), 1.89-1.84 (1H, m), 1.33-1.27 (2H, m),



1.11 (3H, s), 0.23-0.14 (4H, m)


 











6








421
Pd(OAc)2, BINAP


 









2-(5-((2,3-Dihydro-1H-inden-5-yl)((1-methylcyclopropyl)methyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 7.76 (1H, d, J = 2.3 Hz), 7.26 (1H, d, J = 8.0 Hz), 7.05



(1H, d, J = 2.2 Hz), 6.96 (1H, dd, J = 7.9, 2.0 Hz), 6.48 (1H, J = 2.4 Hz), 3.85



(1H, ddd, J = 8.8, 6.1, 3.9 Hz), 3.76 (3H, s), 3.71 (2H, app s), 2.96-2.90 (4H, m),



2.25 (1H, ddd, J = 8.5, 5.7, 3.9 Hz), 2.17-2.09 (2H, m), 1.59 (2H, ddd, J = 8.5, 6.0,



3.2 Hz), 1.51 (1H, ddd, J = 8.8, 5.7, 3.2 Hz), 1.17 (3H, s), 0.32-0.23 (4H, m)


 











7








435
Pd(OAc)2, BINAP


 









2-(5-((Cyclopropylmethyl)(4-fluoronaphthalen-1-yl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 8.19 (1H, d, J = 8.4 Hz), 7.73-7.67 (2H, m), 7.60



(1H, t, J = 7.6 Hz), 7.56-7.50 (1H, m), 7.42 (1H, dd, J = 8.2 4.9 Hz), 7.25-7.19



(1H, m), 6.27 (1H, m), 3.98-3.78 (2H, m), 3.65 (3H, s), 3.58-3.39 (1H, m),



2.27-2.19 (1H, m), 1.61-1.55 (1H, m), 1.54-1.47 (1H, m), 1.24-1.14 (1H, m),



0.58-0.42 (2H, m), 0.16-0.03 (2H, m)


 











8








432
Pd(OAc)2, Xantphos


 









2-(5-((Cyclopropylmethyl)(8-methylquinolin-5-yl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 9.00 (1H, dd, J = 4.2, 1.5 Hz), 8.06 (1H, dd, J = 8.6, 1.5



Hz), 7.74-7.68 (1H, m), 7.68-7.63 (1H, m), 7.45 (1H, d, J = 7.5 Hz), 7.40 (1H,



dd, J = 8.6, 4.2 Hz), 6.31-6.20 (1H, m), 3.86-3.54 (6H, m), 2.87 (3H, s), 2.28-



2.20 (1H, m), 1.62-1.55 (1H, m), 1.55-1.47 (1H, m), 1.23-1.12 (1H, m), 0.57-



0.42(2H, m), 0.16-0.01 (2H, m)


 











9








417
Pd(OAc)2, BINAP


 









2-(5-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 7.95 (1H, d, J = 8.2 Hz), 7.92 (1H, d, J = 8.2 Hz), 7.78-



7.71 (2H, m) 7.59-7.46 (4H, m) 6.29 (1H, s) 4.06-3.87 (1H, m) 3.86-3.81 (1H,



m) 3.64 (3H, s) 3.60-3.38 (1H, m) 2.27-2.22 (1H, m) 1.62-1.57 (1H, m) 1.54-



1.49 (1H, m) 1.28-1.18 (1H, m) 0.56-0.44 (2H, m) 0.16-0.04 (2H, m)


 











10








431
Pd(OAc)2, Xantphos


 









2-(5-((Cyclopropylmethyl)(4-methylquinolin-8-yl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 8.79-9.10 (1H, d, J = 4.4 Hz), 8.07 (1H, dd, J = 8.4, 1.4



Hz), 7.74 (1H, dd, J = 7.4, 1.4 Hz) 7.66-7.60 (2H, m), 7.31-7.28 (1H, m), 6.43



(1H, d, J = 2.1 Hz), 3.81-3.75 (3H, m), 3.71 (3H, s), 2.77 (3H, s), 2.23-2.16 (1H,



m), 1.55-1.49 (1H, m), 1.46-1.40 (1H, m), 1.20-1.09 (1H, m), 0.49-0.36 (2H,



m), 0.08-0.00 (2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme E-2 is described below.
Example 11
2-(5-((Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid




To a 20 mL vial were added Pd(OAc)2 (225 mg, 1.0 mmol), rac-BINAP (747 mg, 1.2 mmol) and toluene (15 mL). The mixture was sealed and stirred at 80° C. for 15 min. To a 250 mL round-bottom flask were added ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (3.28 g, 10.0 mmol), N-(cyclopropylmethyl)-4-methylnaphthalen-1-amine (2.33 g, 11.0 mmol) and toluene (150 mL). The reaction mixture was stirred at rt for 15 min and Cs2CO3 (6.52 g, 20.0 mmol) was added. To the round-bottom flask was added the catalyst mixture and the round-bottom flask was sealed with a rubber septum and heated at 100° C. for 48 h. The reaction mixture was filtered through a short silica column and the filtrate was concentrated in vacuo. The crude solid was dissolved in DCM and purified by silica chromatography (isohexane:EtOAc 95:5). The purified ester product was dissolved in THF/water and the pH was adjusted to 13 with addition of 2 M aq NaOH, and the reaction mixture was stirred at rt. Complete ester hydrolysis was obtained in 72 h. The reaction mixture was acidified with HOAc to pH 3 and EtOAc was added followed by extractive workup. The organic phases were collected and concentrated in vacuo to give a yellow residue. The crude product was purified by silica chromatography (isohexane:EtOAc 1:1, 1% HOAc) and washing (water/MeOH/MeCN 10:4:1, followed by 3× water) to provide 1.04 g (24% yield) of the pure product as a pale yellow solid. MS [M+H]+ 431. 1H-NMR 400 MHz (DMSO-d6, ppm) δ 12.38 (1H, br s), 8.13 (1H, d, J=8.4 Hz), 7.72 (1H, d, J=8.2 Hz), 7.62 (1H, ddd, J=8.3, 6.8, 1.4 Hz), 7.55-7.47 (3H, m), 7.30-7.25 (1H, m), 6.66-6.60 (1H, m), 4.03-3.90 (1H, m), 3.70 (3H, s), 3.62-3.52 (2H, m), 2.72 (3H, s), 1.84 (1H, ddd, J=8.2, 5.9, 3.9 Hz), 1.29-1.23 (2H, m), 1.18-1.08 (1H, m), 0.42-0.35 (2H, m), 0.14-0.07 (2H, m).




A detailed illustrative synthetic procedure for the general procedure shown in Scheme F is described below.
Example 12
2-(5-((Cyclopropylmethyl)(naphthalen-2-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid




To a test tube were added Pd(OAc)2 (5.6 mg, 0.025 mmol), Xantphos (21.7 mg, 0.038 mmol) and toluene (1 mL). The mixture was stirred at rt for 15 min. To a 5 mL microwave vial were added ethyl 2-(5-((cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylate (80 mg, 0.25 mmol), 2-bromonaphthalene (104 mg, 0.50 mmol), Cs2CO3 (163 mg, 0.50 mmol) and toluene (1 mL). The mixture was stirred at rt for 5 min before the catalyst slurry from the test tube was transferred to the microwave vial. The vial was sealed with a Teflon fitted septa and heated at 100° C. for 48 h. The reaction mixture was filtered through a short silica column and the filtrate was concentrated in vacuo. The crude solid was dissolved in DCM and purified by silica chromatography (isohexane:EtOAc 1:1) to give 49 mg of a pale yellow solid. The solid was dissolved in THF:MeOH and 2 M aq NaOH was added to reach pH 14. After stirring at rt for 2 h complete ester hydrolysis was achieved and the reaction mixture was acidified with 2 M aq HCl to pH 1. The solvent was evaporated in vacuo and the crude was dissolved in DMSO:MeOH and purified by HPLC to provide 38 mg (83% yield) of pure product as a pale yellow solid. MS [M+H]+ 417. 1H NMR 400 MHz (DMSO-d6, ppm) δ 12.47 (1H, br s), 8.02 (1H, d, J=8.7 Hz), 7.97-7.92 (2H, m), 7.90 (1H, d, J=2.2 Hz), 7.74 (1H, d, J=2.3 Hz), 7.57-7.50 (2H, m), 7.47 (1H, dd, J=8.8, 2.2 Hz), 6.82 (1H, d, J=2.3 Hz), 3.85 (2H, app d, J=6.7 Hz), 3.73 (3H, s), 3.62-3.57 (1H, m), 1.88 (1H, ddd, J=7.7, 6.6, 3.9 Hz), 1.32-1.28 (2H, m), 1.23-1.13 (1H, m), 0.48-0.43 (2H, m), 0.19-0.15 (2H, m).




A detailed illustrative synthetic procedure for the general procedure shown in Scheme G is described below.
Example 13
2-(5-((4-Chlorobenzyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid




To a 5 mL microwave vial were added ethyl 2-(5-((cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylate (159 mg, 0.50 mmol), NaH (60% in mineral oil, 40 mg, 1.00 mmol) and DMF (2 mL). The vial was sealed with a Teflon fitted septa and heated at 60° C. After 5 min heating, 4-cholorobenzylbromide (411 mg, 2.00 mmol) dissolved in DMF (1 mL) was added with a syringe. The reaction mixture was stirred and heated at 60° C. over night. The reaction mixture was reduced in vacuo and the crude was dissolved in THF:MeOH. To the reaction mixture was added 2 M aq NaOH to reach pH 14. After stirring for 2 h at rt complete ester hydrolysis was achieved and the reaction mixture was acidified to pH 1 with 2 M aq HCl. The solvent was evaporated in vacuo and the crude mixture was dissolved in DMSO:MeOH and purified by HPLC to give 87 mg (42% yield) of product as a pale yellow solid. MS [M+H]+ 415. 1H NMR 400 MHz (DMSO-d6, ppm) δ 12.41 (1H, br s), 7.84 (1H, d, J=2.4 Hz), 7.41-7.37 (2H, m), 7.31-7.27 (2H, m), 6.62 (1H, d, J=2.4 Hz), 4.82 (2H, app s), 3.72 (3H, s), 3.62 (1H, ddd, J=8.0, 6.8, 3.9 Hz), 3.52 (2H, app d, J=6.7 Hz), 1.87-1.82 (1H, m), 1.29-1.25 (2H, m), 1.22-1.11 (1H, m), 0.52-0.47 (2H, m), 0.34-0.30 (2H, m).
The following compounds were prepared in analogy to Example 13 described above in detail unless otherwise indicated.














TABLE 4








R1
MS [M + H]+
X in R1-X according to Scheme G









Name


Ex.
1H-NMR













14




396
Br


 









2-(5-((Cyclopropylmethyl)(4-methylbenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.40 (1H, br s), 7.83 (1H, d, J = 2.4 Hz), 7.17-7.12



(4H, m), 6.62 (1H, d, J = 2.4 Hz), 4.77 (2H, app s), 3.72-3.71 (3H, m), 3.62 (1H,



ddd, J = 8.1, 6.7, 3.9 Hz), 3.52 (2H, app d, J = 6.6 Hz), 2.26 (3H, s), 1.86-1.81



(1H, m), 1.29-1.25 (2H, m), 1.22-1.12 (1H, m), 0.52-0.48 (2H, m), 0.34-0.30 (2H, m)


 










15




396
Br


 









2-(5-((Cyclopropylmethyl)(3-methylbenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.37 (1H, br s), 7.84 (1H, d, J = 2.4 Hz), 7.23-7.19



(1H, m), 7.11-7.08 (1H, m), 7.08-7.03 (2H, m), 6.63 (1H, d, J = 2.4 Hz), 4.77



(2H, app s), 3.72 (3H, s), 3.63 (1H, ddd, J = 8.0, 6.7, 3.9 Hz), 3.53 (2H, app d,



J = 6.6 Hz), 2.27 (3H, s), 1.87-1.82 (1H, m), 1.29-1.25 (2H, m), 1.22-1.13 (2H,



m), 0.53-0.48 (2H, m), 0.35-0.31 (2H, m)


 










16




450
Br


 









2-(5-((Cyclopropylmethyl)(2,6-dichlorobenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.42 (1H, br s), 8.07 (1H, d, J = 2.1 Hz), 7.56-7.54



(2H, m), 7.44-7.39 (1H, m), 6.79 (1H, d, J = 2.2 Hz), 4.96 (2H, app s), 3.79 (3H,



s), 3.69-3.64 (1H, m), 3.29 (2H, app d, J = 6.3 Hz), 1.90-1.85 (1H, m), 1.32-1.28



(2H, m), 1.07-0.97 (1H, m), 0.42-0.37 (2H, m), 0.13-0.08 (2H, m)


 










17




431
Br


 









2-(5-((Cyclopropylmethyl)(naphthalen-2-ylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.42 (1H, br s), 7.96-7.82 (4H, m), 7.77 (1H, s),



7.51-7.42 (3H, m), 6.71 (1H, s), 4.99 (2H, app s), 3.71 (3H, s), 3.65-3.57 (3H,



m), 1.86-1.81 (1H, m), 1.30-1.14 (3H, m), 0.56-0.48 (2H, m), 0.39-0.32 (2H, m)


 










18




415
Br


 









2-(5-((3-Chlorobenzyl)(cyclopropylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.39 (1H, br s), 7.84 (1H, app s), 7.40-7.30 (3H,



m), 7.23 (1H, d, J = 7.6 Hz), 6.63 (1H, app s), 4.84 (2H, app s), 3.72 (3H, s),



3.65-3.58 (1H, m), 3.54 (2H, app d, J = 6.7 Hz), 1.87-1.82 (1H, m), 1.30-1.25



(2H, m), 1.23-1.13 (1H, m), 0.52-0.48 (2H, m), 0.36-0.31 (2H, m)


 










19




399
Br


 









2-(5-((Cyclopropylmethyl)(4-fluorobenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.43 (1H, br s), 7.85 (1H, d, J = 2.3 Hz), 7.33-7.28



(2H, m), 7.19-7.13 (2H, m), 6.62 (1H, d, J = 2.4 Hz), 4.80 (2H, app s), 3.72 (3H,



s), 3.65-3.58 (1H, m), 3.52 (2H, app d, J = 6.6 Hz), 1.87-1.82 (1H, m), 1.30-1.21



(2H, m), 1.21-1.12 (1H, m), 0.52-0.47 (2H, m), 0.34-0.30 (2H, m)


 










20




463
Br


 









2-(5-((Cyclopropylmethyl)(2-methyl-3-(trifluoromethyl)benzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.43 (1H, br s), 7.75 (1H, d, J = 2.3 Hz), 7.59 (1H,



d, J = 7.9 Hz), 7.34-7.29 (1H, dd, J = 7.9, 7.9 Hz), 7.21 (1H, d, J = 7.9 Hz), 6.63



(1H, d, J = 2.3 Hz), 4.86 (2H, app s), 3.74 (3H, s), 3.63-3.58 (1H, m), 3.51 (2H,



app d, J = 6.7 Hz), 2.43 (3H, s), 1.86-1.81 (1H, m), 1.29-1.14 (3H, m), 0.50-0.45



(2H, m), 0.33-0.29 (2H, m)


 










21




468
Br


 









2-(5-((Cyclopropylmethyl)(2-fluoro-4-(trifluoromethyl)benzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.42 (1H, br s), 7.85 (1H, d, J = 2.3 Hz), 7.72 (1H,



d, J = 10.1 Hz), 7.53 (1H, d, J = 8.1 Hz), 7.39-7.35 (1H, m), 6.69 (1H, d, J = 2.3



Hz), 4.96 (2H, app s), 3.75 (3H, s), 3.65-3.60 (1H, m), 3.53 (2H, app d, J = 6.7



Hz), 1.88-1.83 (1H, m), 1.30-1.27 (2H, m), 1.21-1.11 (1H, m), 0.50-0.45 (2H,



m), 0.32-0.28 (2H, m)


 










22




485
Br


 









2-(5-((2-Chloro-3-(trifluoromethyl)benzyl)(cyclopropylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.41 (1H, br s), 7.79 (1H, dd, J = 7.9, 1.6 Hz), 7.77



(1H, d, J = 2.4 Hz), 7.50 (1H, t, J = 7.8 Hz), 7.40 (1H, dd, J = 7.7, 1.5 Hz), 6.65



(1H, d, J = 2.4 Hz), 4.95 (2H, app s), 3.74 (3H, s), 3.64-3.59 (1H, m), 3.55 (2H,



app d, J = 6.7 Hz), 1.88-1.83 (1H, m), 1.31-1.26 (2H, m), 1.23-1.12 (1H, m),



0.50-0.45 (2H, m), 0.32-0.27 (2H, m)


 










23




445
Cl


 









2-(5-((Cyclopropylmethyl)((2-methylnaphthalen-1-yl)methyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.43 (1H, br s), 8.17 (1H, d, J = 2.3 Hz), 8.00 (1H,



d, J = 8.5 Hz), 7.92 (1H, dd, J = 7.9, 1.6 Hz), 7.86 (1H, d, J = 8.4 Hz), 7.54-7.42



(3H, m), 6.90 (1H, d, J = 2.4 Hz), 5.13 (2H, app s), 3.75 (3H, s), 3.70 (1H, ddd,



J = 8.0, 6.7, 3.9 Hz), 3.12 (2H, app d, J = 6.1 Hz), 2.51 (3H, s), 1.91-1.86 (1H, m),



1.34-1.29 (2H, m), 0.92-0.82 (1H, m), 0.27-0.22 (2H, m), −0.13-−0.19 (2H, m)


 










24




458
Cl


 









2-(5-(([1,1′-Biphenyl]-4-ylmethyl)(cyclopropylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.36 (1H, br s), 7.87 (1H, d, J = 2.3 Hz), 7.67-7.61



(4H, m), 7.47-7.42 (2H, m), 7.38-7.32 (3H, m), 6.69 (1H, d, J = 2.4 Hz), 4.88



(2H, app s), 3.74 (3H, s), 3.63 (1H, ddd, J = 7.7, 6.7, 3.9 Hz), 3.57 (2H, app d,



J = 6.6 Hz), 1.85 (1H, ddd, J = 7.5, 6.4, 3.9 Hz), 1.31-1.25 (2H, m), 1.26-1.15



(1H, m), 0.55-0.50 (2H, m), 0.38-0.34 (2H, m)


 










25




432
Cl


 









2-(5-((Cyclopropylmethyl)(naphthalen-1-ylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.38 (1H, br s), 8.11 (1H, dd, J = 8.0, 1.3 Hz), 7.98



(1H, dd, J = 7.4, 2.1 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.81 (1H, d, J = 2.4 Hz), 7.64-



7.56 (2H, m), 7.43 (1H, dd, J = 8.2, 7.1 Hz), 7.19 (1H, dd, J = 7.2, 1.2 Hz), 6.68



(1H, d, J = 2.4 Hz), 5.30 (2H, app s), 3.68 (3H, s), 3.64-3.59 (1H, m), 3.57 (2H,



app d, J = 6.6 Hz), 1.84 (1H, ddd, J = 8.0, 6.4, 3.9 Hz), 1.30-1.18 (3H, m), 0.51-



0.46 (2H, m), 0.34-0.30 (2H, m)


 










26




458
Cl


 









2-(5-((Cyclopropylmethyl)((6-fluoro-4H-benzo[d][1,3]dioxin-8-



yl)methyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.41 (1H, br s), 7.76 (1H, d, J = 2.4 Hz), 6.89 (1H,



dd, J = 8.6, 3.1 Hz), 6.72 (1H, dd, J = 9.5, 3.1 Hz), 6.63 (1H, d, J = 2.4 Hz), 5.34



(2H, app s), 4.91 (2H, app s), 4.71 (2H, app s), 3.75 (3H, s), 3.65-3.60 (1H, m),



3.53 (2H, d, J = 6.7 Hz), 1.88-1.83 (1H, m), 1.30-1.25 (2H, m), 1.21-1.13 (1H,



m), 0.52-0.47 (2H, m), 0.34-0.29 (2H, m)


 










27




460
Cl


 









2-(5-(((6-Chlorobenzo[d][1,3]dioxol-4-yl)methyl)(cyclopropylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.40 (1H, s), 7.75 (1H, d, J = 2.4 Hz), 7.14 (1H, s),



6.68 (1H, s), 6.59 (1H, d, J = 2.4 Hz), 6.04-6.03 (2H, m), 4.73 (2H, app s), 3.75



(3H, s), 3.65-3.60 (1H, m), 3.53 (2H, app d, J = 6.7 Hz), 1.89-1.83 (1H, m),



1.30-1.26 (2H, m), 1.22-1.12 (1H, m), 0.52-0.48 (2H, m), 0.34-0.29 (2H, m)


 










28




409
Br


 









2-(5-((Cyclopropylmethyl)(2,3-dimethylbenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.38 (1H, br s), 7.73 (1H, d, J = 2.4 Hz), 7.06 (1H,



d, J = 7.4 Hz), 6.99 (1H, dd, J = 7.6, 7.4 Hz), 6.79 (1H, d, J = 7.6 Hz), 6.62 (1H, d,



J = 2.4 Hz), 4.76 (2H, app s), 3.73 (3H, s), 3.65-3.60 (1H, m), 3.47 (2H, app d,



J = 6.6 Hz), 2.28 (3H, s), 2.20 (3H, s), 1.86-1.81 (1H, m), 1.30-1.24 (2H, m),



1.22-1.12 (1H, m), 0.51-0.46 (2H, m), 0.32-0.28 (2H, m)


 










29




435
Br


 









2-(5-((Cyclopropylmethyl)(2,3,4-trifluorobenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.40 (1H, br s), 7.87 (1H, d, J = 2.4 Hz), 7.30-7.21



(1H, m), 7.05-6.98 (1H, m), 6.69 (1H, d, J = 2.4 Hz), 4.89 (2H, app s), 3.76 (3H,



s), 3.66-3.60 (1H, m), 3.50 (2H, app d, J = 6.7 Hz), 1.88-1.83 (1H, m), 1.31-1.27



(2H, m), 1.20-1.09 (1H, m), 0.50-0.45 (2H, m), 0.32-0.28 (2H, m)


 










30




451
Br


 









2-(5-((3-Chloro-2,4-difluorobenzyl)(cyclopropylmethyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.41 (1H, br s), 7.87 (1H, d, J = 2.4 Hz), 7.25 (1H,



ddd, J = 8.7, 8.7, 1.5 Hz), 7.21-7.14 (1H, m), 6.69 (1H, d, J = 2.4 Hz), 4.89 (2H,



app s), 3.76 (3H, s), 3.63 (1H, ddd, J = 7.6, 6.8, 3.9 Hz), 3.50 (2H, app d, J = 6.7



Hz), 1.85 (1H, ddd, J = 7.6, 6.4, 3.8 Hz), 1.31-1.27 (2H, m), 1.20-1.09 (1H, m),



0.50-0.45 (2H, m), 0.32-0.28 (2H, m)


 










31




467
Br


 









2-(5-((Cyclopropylmethyl)(2-fluoro-3-(trifluoromethyl)benzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.40 (1H, s), 7.88 (1H, d, J = 2.4 Hz), 7.72-7.67



(1H, m), 7.50-7.45 (1H, m), 7.37-7.32 (1H, m), 6.69 (1H, d, J = 2.4 Hz), 4.96



(2H, app s), 3.75 (3H, s), 3.63 (1H, ddd, J = 7.7, 6.7, 3.9 Hz), 3.53 (2H, app d,



J = 6.7 Hz), 1.86 (1H, ddd, J = 7.5, 6.4, 3.8 Hz), 1.31-1.26 (2H, m), 1.21-1.11



(1H, m), 0.49-0.44 (2H, m), 0.32-0.28 (2H, m)


 










32 




431
Br


 









2-(5-((Cyclopropylmethyl)(2,6-difluoro-3-methylbenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.44 (1H, br s), 7.99 (1H, d, J = 2.4 Hz), 7.33-7.26



(1H, m), 7.06-7.00 (1H, m), 6.76 (1H, d, J = 2.4 Hz), 4.83 (2H, app s), 3.78 (3H,



s), 3.64 (1H, ddd, J = 8.4, 6.4, 3.9 Hz), 3.43 (2H, app d, J = 6.6 Hz), 2.21-2.18



(3H, m), 1.86 (1H, ddd, J = 7.9, 6.0, 3.9 Hz), 1.31-1.25 (2H, m), 1.15-1.05 (1H,



m), 0.50-0.45 (2H, m), 0.29-0.25 (2H, m)


 










33




431
Br


 









2-(5-((Cyclopropylmethyl)(2,3-difluoro-4-methylbenzyl)amino)-3-



methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.40 (1H, br s), 7.86 (1H, d, J = 2.4 Hz), 7.05-7.00



(1H, m), 6.91-6.86 (1H, m), 6.68 (1H, d, J = 2.4 Hz), 4.87 (2H, app s), 3.75 (3H,



s), 3.63 (1H, ddd, J = 7.9, 6.8, 3.9 Hz), 3.50 (2H, app d, J = 6.7 Hz), 2.25-2.24



(3H, m), 1.85 (1H, ddd, J = 7.4, 6.4, 3.9 Hz), 1.31-1.26 (2H, m), 1.20-1.10 (1H,



m), 0.51-0.46 (2H, m), 0.33-0.28 (2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme H-1 is described below.
Example 34
2-(5-((Cyclopropylmethyl)(4-(trifluoromethyl)naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid




Ethyl 2-(3-methoxy-5-((4-(trifluoromethyl)naphthalen-1-yl)amino)picolinoyl)cyclopropanecarboxylate
Ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (164 mg, 0.50 mmol), 4-(trifluoromethyl)naphthalen-1-amine (127 mg, 0.60 mmol), Pd(OAc)2 (6.0 mg, 0.025 mmol), rac-BINAP (22 mg, 0.035 mmol) and Cs2CO3 (228 mg, 0.70 mmol) were mixed in toluene (4 mL) and stirred at 90-95° C. for 18 h in a sealed tube. The reaction mixture was diluted (EtOAc), filtered through a celite pad, and concentrated. Purification by column chromatography afforded the sub-title compound. Yield: 80 mg (46%).
Ethyl 2-(5-((cyclopropylmethyl)(4-(trifluoromethyl)naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylate
NaH (60% dispersion in mineral oil, 7.0 mg, 0.18 mmol) was added in one portion to a stirred solution of ethyl 2-(3-methoxy-5-((4-(trifluoromethyl)naphthalen-1-yl)amino)picolinoyl)cyclopropanecarboxylate (75 mg, 0.16 mmol) in DMF (2 mL) at 0° C. After stirring at 0° C. for 10 min, (bromomethyl)cyclopropane (32 μL, 0.33 mmol) was added. The reaction mixture was stirred at rt for 18 h and then quenched with water. Extractive workup (EtOAc, water and brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound contaminated with a small amount of the corresponding cyclopropylmethylester. Yield: 73 mg (84%).
2-(5-((Cyclopropylmethyl)(4-(trifluoromethyl)naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid
A solution of NaOH (25 mg, 0.63 mmol) in water (4 mL) was added to a solution of ethyl 2-(5-((cyclopropylmethyl)(4-(trifluoromethyl)naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylate (65 mg, 0.13 mmol) in EtOH (3 mL), and the reaction mixture was stirred at 80° C. for 20 min. Acidification with 1M aq HCl (pH ̃3), extraction (EtOAc), washing (water and brine), drying (Na2SO4), filtration and evaporation furnished the title compound. Yield: 61 mg (99%). MS [M+H]+ 485. 1H NMR 400 MHz (CDCl3, ppm) δ 8.32-8.25 (1H, m), 7.99-7.95 (1H, m), 7.87-7.81 (1H, m), 7.72-7.65 (2H, m), 7.60-7.50 (2H, m), 6.35-6.28 (1H, m), 3.85-3.79 (1H, m), 3.78-3.60 (5H, m), 2.27-2.20 (1H, m), 1.62-1.55 (1H, m), 1.54-1.47 (1H, m), 1.25-1.17 (1H, m), 0.55-0.48 (2H, m), 0.13-0.06 (2H, m).
The following compound was prepared in analogy to Example 34 described above in detail with the exception that Xantphos was used instead of rac-BINAP.









TABLE 5









MS



Structure
[M + H]+









Name


Ex.
1H-NMR












35




486


 









2-(5-((Cyclopropylmethyl)(5-(trifluoromethyl)quinolin-8-yl)



amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.38 (1H, s), 8.97 (1H, dd, J =



4.0 1.6 Hz), 8.61-8.55 (1H, m) 8.21 (1H, d, J = 7.9 Hz), 8.00



(1H, d, J = 7.9 Hz), 7.78 (1H, dd, J = 8.8, 4.0 Hz), 7.33 (1H, d,



J = 2.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 3.87 (2H, app d, J = 6.7



Hz), 3.76 (3H, s), 3.57-3.51 (1H, m), 1.88-1.82 (1H, m), 1.31-



1.22 (2H, m), 1.12-1.04 (1H, m), 0.37-0.32 (2H, m), 0.08-0.03



(2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme H-2 is described below.
Example 36
2-(5-((Cyclopropylmethyl)(1,2-dihydroacenaphthylen-5-yl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid




Ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (164 mg, 0.50 mmol), 1,2-dihydroacenaphthylen-5-amine (127 mg, 0.75 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), Xantphos (22 mg, 0.038 mmol) and Cs2CO3 (326 mg, 1.00 mmol) were mixed in toluene (10 mL) and stirred at 110° C. over night in a sealed tube. The reaction mixture was diluted (EtOAc), filtered through a celite pad and concentrated. The crude product was purified by column chromatography and treatment with activate carbon followed by filtration through a short silica column. The purified product (146 mg, 0.35 mmol) was mixed with (bromomethyl)cyclopropane (95 mg, 0.70 mmol) and NaH (60% in mineral oil, 35 mg, 0.88 mmol) in DMF (6 mL) and the reaction mixture was stirred at rt over night. After evaporation of the solvent the crude mixture was dissolved in MeOH:THF and 2M aq NaOH (pH ̃13) was added. The reaction mixture was stirred at rt until complete hydrolysis. Acidification with 2M aq HCl (pH ̃2), evaporation and purification by HPLC afforded the title compound. Yield: 95 mg (43%). MS [M+H]+ 443. 1H NMR 400 MHz (DMSO-d6, ppm) δ 12.40 (1H, br s), 7.52-7.42 (3H, m), 7.39-7.31 (3H, m), 6.64 (1H, s), 3.79 (2H, br s), 3.69 (3H, s), 3.55 (1H, ddd, J=8.3, 6.2, 3.9 Hz), 3.47-3.39 (4H, m), 1.84 (1H, ddd, J=8.2, 5.9, 3.9 Hz), 1.29-1.23 (2H, m), 1.18-1.08 (1H, m), 0.41-0.36 (2H, m), 0.12-0.08 (2H, m).
The following compounds were prepared in analogy to Example 36 described above in detail with the exception that Pd(OAc)2 was used instead of Pd(PPh3)4.









TABLE 6









MS



Structure
[M + H]+









Name


Ex.
1H-NMR












37




485


 









2-(5-((Cyclopropylmethyl)(5-(trifluoromethyl)naphthalen-1-yl)



amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.38 (1H, s), 8.19 (1H, dd, J =



8.6, 1.5 Hz), 8.11-8.05 (2H, m), 7.91 (1H, dd, J = 8.7, 7.4 Hz),



7.79 (1H, dd, J = 7.3, 1.0 Hz), 7.68 (1H, t, J = 7.9 Hz), 7.29-7.21



(1H, m), 6.74-6.67 (1H, m), 3.91 (1H, br s), 3.76-3.58 (4H, m),



3.53 (1H, ddd, J = 8.5, 6.1, 3.9 Hz), 1.84 (1H, ddd, J = 8.3, 5.8,



3.9 Hz), 1.27 (2H, tdd, J = 5.7, 3.7, 2.9 Hz), 1.18-1.06 (1H, m),



0.44-0.31 (2H, m), 0.15-0.03 (2H, m)


 









38




443


 









2-(5-((Cyclopropylmethyl)(1,2-dihydroacenaphthylen-3-yl)



amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.37 (1H, s), 7.80 (1H, dd, J =



8.6, 0.9 Hz), 7.70 (1H, dd, J = 8.3, 0.9 Hz), 7.56-7.49 (2H, m),



7.41 (1H, d, J = 8.6 Hz), 7.38-7.34 (1H, m), 6.64 (1H, d, J = 2.3



Hz), 3.76 (2H, app d, J = 6.8 Hz), 3.72 (3H, s), 3.64-3.58 (1H,



m), 3.40-3.34 (2H, m), 3.17-3.10 (2H, m), 1.87 (1H, ddd, J =



8.0, 6.4, 3.9 Hz), 1.33-1.24 (2H, m), 1.20-1.08 (1H, m), 0.48-



0.39 (2H, m), 0.15-0.07 (2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme I is described below.
Example 39
2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)-N-(phenylsulfonyl)cyclopropanecarboxamide




2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)-3-methoxypicolinoyl)cyclopropanecarboxylic acid (20 mg, 0.05 mmol), HATU (21 mg, 0.06 mmol) and DIEA (23 mg, 0.18 mmol) were dissolved in DMF (1 mL). The mixture was stirred at rt for 1.5 h before the addition of benzenesulfonamide (28 mg, 0.18 mmol), DMAP (23 mg, 0.19 mmol) and DBU (29 mg, 0.19 mmol) in DMF. The reaction mixture was stirred at rt over weekend. The solvent was evaporated and the crude product was dissolved in DMSO:MeOH and purified by HPLC to give the title compound. Yield: 20 mg (82%). MS [M+H]+ 540. 1H NMR 400 MHz (DMSO-d6, ppm) δ 12.47 (1H, br s), 7.90-7.87 (2H, m), 7.69-7.64 (2H, m), 7.61-7.56 (2H, m), 7.54-7.50 (2H, m), 7.37-7.34 (2H, m), 6.73 (1H, d, J=2.3 Hz), 3.72 (3H, s), 3.70 (2H, app d, J=6.7 Hz), 3.49-3.44 (1H, m), 2.16-2.10 (1H, m), 1.28-1.18 (2H, m), 1.13-1.04 (1H, m), 0.46-0.41 (2H, m), 0.16-0.12 (2H, m).
The following compounds were prepared in analogy to Example 39 described above in detail.














TABLE 7








R3
MS [M + H]+
Name








Ex.
1H-NMR













40




504
2-(5-((4- Chlorophenyl)(cyclopropylmethyl)amino)- 3-methoxypicolinoyl)-N- (cyclopropylsulfonyl)- cyclopropanecarboxamide


 









400 MHz (DMSO-d6, ppm) δ 12.02 (1H, s), 7.69 (1H, d, J = 2.3 Hz), 7.55-



7.51 (2H, m), 7.39-7.35 (2H, m), 6.75 (1H, d, J = 2.3 Hz), 3.76 (3H, s), 3.72



(2H, app d, J = 6.7 Hz), 3.66-3.61 (1H, m), 2.98-2.91 (1H, m), 2.24-2.19



(1H, m), 1.37-1.33 (2H, m), 1.13-1.04 (5H, m), 0.47-0.42 (2H, m), 0.17-



0.13 (2H, m)


 










41




570
2-(5-((4- Chlorophenyl)(cyclopropylmethyl)amino)- 3-methoxypicolinoyl)-N-((4- methoxyphenyl)sulfonyl)- cyclopropanecarboxamide


 









400 MHz (DMSO-d6, ppm) δ 12.31 (1H, s), 7.85-7.81 (2H, m), 7.65 (1H, d,



J = 2.3 Hz), 7.54-7.50 (2H, m), 7.37-7.33 (2H, m), 7.12-7.08 (2H, m), 6.73



(1H, d, J = 2.4 Hz), 3.84 (3H, s), 3.72 (3H, s), 3.70 (2H, app d, J = 6.7 Hz),



3.47 (1H, ddd, J = 8.7, 6.0, 3.8 Hz), 2.16-2.11 (1H, m), 1.29-1.19 (2H, m),



1.13-1.03 (1H, m), 0.46-0.41 (2H, m), 0.16-0.12 (2H, m)


 










42




624
2-(5-((4- Chlorophenyl)(cyclopropylmethyl)amino)- 3-methoxypicolinoyl)-N-((4- (trifluoromethoxy)phenyl)- sulfonyl)cyclopropanecarboxamide


 









400 MHz (DMSO-d6, ppm) δ 12.63 (1H, br s), 8.05-8.01 (2H, m), 7.64 (1H,



d, J = 2.3 Hz), 7.61-7.57 (2H, m), 7.54-7.50 (2H, m), 7.37-7.33 (2H, m),



6.73 (1H, d, J = 2.3 Hz), 3.73 (3H, s), 3.70 (2H, app d, J = 6.7 Hz), 3.48 (1H,



ddd, J = 8.7, 6.1, 3.9 Hz), 2.18-2.12 (1H, m), 1.31-1.21 (2H, m), 1.13-1.03



(1H, m), 0.46-0.41 (2H, m), 0.16-0.12 (2H, m)


 










43




558
2-(5-((4- Chlorophenyl)(cyclopropylmethyl)amino)- 3-methoxypicolinoyl)-N-((2- fluorophenyl)sulfonyl)- cyclopropanecarboxamide


 









400 MHz (DMSO-d6, ppm) δ 12.86 (1H, br s), 7.91-7.85 (1H, m), 7.77-



7.69 (1H, m), 7.65 (1H, d, J = 2.3 Hz), 7.55-7.50 (2H, m), 7.46-7.34 (4H,



m), 6.74 (1H, d, J = 2.3 Hz), 3.74 (3H, s), 3.71 (2H, app d, J = 6.7 Hz), 3.50-



3.44 (1H, m), 2.25-2.14 (1H, m), 1.31-1.18 (2H, m), 1.14-1.04 (1H, m),



0.47-0.42 (2H, m), 0.16-0.12 (2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme J is described below.
Example 44
2-(6-(Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-4-methoxynicotinoyl)cyclopropanecarboxylic acid




Ethyl 2-(4-methoxy-6-((4-methylnaphthalen-1-yl)amino)nicotinoyl)cyclopropanecarboxylate
Ethyl 2-(6-chloro-4-methoxynicotinoyl)cyclopropanecarboxylate (110 mg, 0.39 mmol), 4-methylnaphthalen-1-amine (122 mg, 0.78 mmol), Pd(OAc)2 (4.4 mg, 0.019 mmol), rac-BINAP (19 mg, 0.031 mmol) and Cs2CO3 (177 mg, 0.54 mmol) were mixed in toluene (2.5 mL) and stirred at 95° C. for 16 h in a sealed tube. The reaction mixture was diluted (EtOAc), filtered through a celite pad and concentrated. Purification by column chromatography afforded the sub-title compound. Yield: 35 mg (23%).
Ethyl 2-(6-((cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-4-methoxynicotinoyl)cyclopropanecarboxylate
NaH (60% dispersion in mineral oil, 9 mg, 0.3 mmol) was added in one portion a to solution of ethyl 2-(4-methoxy-6-((4-methylnaphthalen-1-yl)amino)nicotinoyl)cyclopropanecarboxylate (98 mg, 0.24 mmol) and (bromomethyl)cyclopropane (59 μL, 0.73 mmol) in DMF (3 mL) at 0° C. The reaction mixture stirred at rt for 18 h then quenched with water. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded sub-title compound. Yield: 50 mg (45%).
2-(6-(Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-4-methoxynicotinoyl)cyclopropanecarboxylic acid
A mixture of ethyl 2-(6-((cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-4-methoxynicotinoyl)cyclopropanecarboxylate (70 mg, 0.15 mmol) and NaOH (31 mg, 0.76 mmol) in EtOH (3 mL) and water (1 mL) was stirred at rt for 4 h. The reaction mixture was acidified with 1M aq HCl (pH ̃5) and EtOH was partly evaporated. Extraction with EtOAc, drying (Na2SO4) and concentration afforded the title compound. Yield: 30 mg (46%). MS [M+H]+ 431. 1H-NMR 400 MHz (CDCl3, ppm) δ 8.63 (1H, s), 8.07 (1H, d, J=8.4 Hz), 7.78 (1H, d, J=8.4 Hz), 7.59-7.55 (1H, m), 7.49-7.45 (1H, m), 7.40 (2H, s), 5.28 (1H, s), 4.31 (1H, dd, J=14.1, 6.6 Hz), 3.64-3.59 (1H, m), 3.35 (3H, s), 3.24-3.19 (1H, m), 2.76 (3H, s), 2.22-2.18 (1H, m), 1.67-1.63 (1H, m), 1.47-1.43 (1H, m), 1.20-1.10 (1H, m), 0.44-0.32 (2H, m), 0.16-0.06 (2H, m).




A detailed illustrative synthetic procedure for the general procedure shown in Scheme K is described below.
Example 45
2-(4-((Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid




Ethyl 2-(4-((cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylate
Ethyl 2-(4-bromo-2-methoxybenzoyl)cyclopropanecarboxylate (193 mg, 0.59 mmol), N-(cyclopropylmethyl)-4-methylnaphthalen-1-amine (150 mg, 0.71 mmol), Pd(OAc)2 (6.7 mg, 0.030 mmol), rac-BINAP (28 mg, 0.044 mmol) and Cs2CO3 (288 mg, 0.89 mmol) were mixed in toluene (3 mL) and stirred at 80° C. for 16 h in a sealed tube. The reaction mixture was diluted (EtOAc), filtered through a celite pad and concentrated. Purification by column chromatography afforded the sub-title compound. Yield: 145 mg (54%).
2-(4-((Cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid
A mixture of ethyl 2-(4-((cyclopropylmethyl)(4-methylnaphthalen-1-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylate (145 mg, 0.32 mmol) and NaOH (63 mg, 1.58 mmol) in EtOH (2 mL) and water (1 mL) was stirred at rt for 2 h. The EtOH was partly evaporated and the reaction mixture was acidified with 1M aq HCl (pH ̃3) at 0° C. Filtration of the precipitate followed by washing (H2O) and drying afforded the title compound. Yield: 100 mg (74%). MS [M+H]+ 430. 1H-NMR 400 MHz (CDCl3, ppm) δ 10.8 (1H, br s), 8.06 (1H, d, J=8.4 Hz), 7.75 (1H, d, J=8.4 Hz), 7.62 (1H, d, J=9.0 Hz), 7.57-7.53 (1H, m), 7.47-7.42 (1H, m), 7.39-7.35 (2H, m), 6.20 (1H, d, J=8.4 Hz), 6.01 (1H, s), 3.98-3.86 (1H, m), 3.62 (3H, s), 3.42-3.37 (2H, m), 2.75 (3H, s), 2.21-2.17 (1H, m), 1.69-1.64 (1H, m), 1.48-1.43 (1H, m), 1.27-1.17 (1H, m), 0.50-0.42 (2H, m), 0.13-0.06 (2H, m).
The following compounds were prepared in analogy to Example 45 described above in detail unless otherwise indicated.














TABLE 8










Pd-catalyst and ligand



R1
MS [M + H]+
according to Scheme K









Name


Ex.
1H-NMR













46




434
Pd(OAc)2, BINAP


 









2-(4-((Cyclopropylmethyl)(4-fluoronaphthalen-1-yl)amino)-2-



methoxybenzoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 10.3 (1H, br s), 8.17 (1H, d, J = 8.4 Hz),



7.73 (1H, d, J = 8.4 Hz), 7.63 (1H, d, J = 8.8 Hz), 7.60-7.56 (1H, m),



7.52-7.48 (1H, m), 7.42-7.19 (2H, m), 6.21 (1H, d, J = 8.4 Hz), 5.98



(1H, s), 4.00-3.63 (1H, m), 3.62 (3H, s), 3.61-3.33 (1H, m), 3.41-3.36



(1H, m), 2.21-2.17 (1H, m), 1.69-1.64 (1H, m), 1.48-1.44 (1H, m),



1.23-1.15 (1H, m), 0.50-0.42 (2H, m), 0.13-0.01 (2H, m)


 










47




450
Pd(OAc)2, BINAP


 









2-(4-((4-Chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-2-



methoxybenzoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 8.34 (1H, d, J = 8.8 Hz), 7.78 (1H, d, J =



8.4 Hz), 7.66-7.62 (3H, m), 7.53-7.49 (1H, m), 7.40 (1H, d, J = 8.4



Hz), 6.21(1H, d, J = 8.4 Hz), 5.99 (1H, s), 3.85-3.43 (2H, m), 3.63



(3H, s), 3.40-3.36 (1H, m), 2.22-2.17 (1H, m), 1.69-1.65 (1H, m),



1.49-1.44 (1H, m), 1.24-1.15 (1H, m), 0.49-0.44 (2H, m), 0.07-0.03



(2H, m)


 










48




416
Pd(OAc)2, BINAP


 









2-(4-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-2-



methoxybenzoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 7.92 (1H, d, J = 7.2 Hz), 7.87 (1H, d, J =



8.0 Hz), 7.74 (1H, d, J = 8.0 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.57-7.42



(4H, m), 6.21 (1H, d, J = 8.6 Hz), 6.00 (1H, s), 3.87-3.47 (2H, m),



3.61 (3H, s), 3.41-3.36 (1H, m), 2.21-2.16 (1H, m), 1.68-1.64 (1H,



m), 1.48-1.43 (1H, m), 1.27-1.17 (1H, m), 0.48-0.44 (2H, m), 0.08-



0.04 (2H, m)


 










49




400
Pd(OAc)2, BINAP


 









2-(4-((4-Chlorophenyl)(cyclopropylmethyl)amino)-2-



methoxybenzoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.4 (1H, br s), 7.53-7.49 (2H, m),



7.47 (1H, d, J = 8.8 Hz), 7.33-7.29 (2H, m), 6.41 (1H, d, J = 2.1



Hz), 6.33 (1H, dd, J = 8.8, 2.1 Hz), 3.79 (3H, s), 3.68 (2H, d, J =



6.5 Hz), 3.23-3.16 (1H, m), 1.95-1.89 (1H, m), 1.47-1.40 (1H, m),



1.36-1.30 (1H, m), 1.15-1.06 (1H, m), 0.48-0.42 (2H, m), 0.17-



0.11 (2H, m)


 










50




394
Pd(OAc)2, BINAP


 









2-(4-((Cyclopropylmethyl)(3,4-dimethylphenyl)amino)-2-



methoxybenzoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 7.44 (1H, d, J = 8.9 Hz), 7.23 (1H, d,



J =7.9 Hz), 7.07 (1H, d, J = 2.0 Hz), 7.01 (1H, dd, J = 7.9, 2.0 Hz),



6.33 (1H, d, J = 2.0 Hz), 6.19 (1H, dd, J = 8.9, 2.0 Hz), 3.77 (3H, s),



3.63 (2H, app d, J = 6.5 Hz), 3.23-3.17 (1H, m), 2.26 (3H, s), 2.25



(3H, s), 1.93-1.86 (1H, m), 1.45-1.38 (1H, m), 1.34-1.27 (1H, m),



1.15-1.06 (1H, m), 0.49-0.42 (2H, m), 0.18-0.12 (2H, m)


 










51




414
Pd(OAc)2, BINAP


 









2-(4-((4-Chlorobenzyl)(cyclopropylmethyl)amino)-2-



methoxybenzoyl)cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.4 (1H, br s), 7.48 (1H, d, J = 8.9



Hz), 7.42-7.37 (2H, m), 7.30-7.25 (2H, m), 6.38 (1H, dd, J = 8.9,



2.0 Hz), 6.27 (1H, d, J = 2.0 Hz), 4.76 (2H, s), 3.77 (3H, s), 3.46



(2H, app d, J = 6.5 Hz), 3.23-3.16 (1H, m), 1.92-1.86 (1H, m),



1.43-1.37 (1H, m), 1.32-1.26 (1H, m), 1.20-1.11 (1H, m), 0.52-



0.46 (2H, m), 0.34-0.28 (2H, m)


 










52




431
Pd(OAc)2, Xantphos


 









2-(4-((Cyclopropylmethyl)(8-methylquinolin-5-yl)amino)-2-



methoxybenzoyl)cyclopropanecarboxylic acid



400 MHz (CDCl3, ppm) δ 8.99 (1H, dd, J = 4.2, 1.7 Hz), 8.08 (1H,



dd, J = 8.5, 1.7 Hz), 7.67-7.59 (2H, m), 7.43 (1H, d, J = 7.5 Hz),



7.36 (1H, dd, J = 8.5, 4.2 Hz), 6.24-6.16 (1H, m), 6.00-5.92 (1H, m),



3.80-3.50 (5H, m), 3.41-3.33 (1H, m), 2.87 (3H, s), 2.23-2.16 (1H,



m), 1.70-1.61 (1H, m), 1.50-1.42 (1H, m), 1.22-1.13 (1H, m), 0.50-



0.36 (2H, m), 0.11-0.00 (2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme L is described below.
Example 53
2-(4-((Cyclopropylmethyl)(5-(trifluoromethyl)quinolin-8-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid




Ethyl 2-(2-methoxy-4-((5-(trifluoromethyl)quinolin-8-yl)amino)benzoyl)cyclopropanecarboxylate
Ethyl 2-(4-bromo-2-methoxybenzoyl)cyclopropanecarboxylate (137 mg, 0.42 mmol), 5-(trifluoromethyl)quinolin-8-amine (90 mg, 0.42 mmol), Pd(OAc)2 (9.4 mg, 0.042 mmol), Xantphos (36 mg, 0.062 mmol) and Cs2CO3 (205 mg, 0.63 mmol) were mixed in toluene (3 mL) and stirred at 120° C. for 48 h in a sealed tube. The reaction mixture was diluted (EtOAc), filtered through a celite pad and concentrated. Purification by column chromatography afforded the sub-title compound. Yield: 125 mg (65%).
Ethyl 2-(4-((cyclopropylmethyl)(5-(trifluoromethyl)quinolin-8-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylate
NaH (60% dispersion in mineral oil, 11 mg, 0.28 mmol) was added in one portion to a solution of ethyl 2-(2-methoxy-4-((5-(trifluoromethyl)quinolin-8-yl)amino)benzoyl)cyclopropanecarboxylate (125 mg, 0.27 mmol) in DMF (2 mL) at 0° C. After stirring at 0° C. for 5 min (bromomethyl)cyclopropane (51 μL, 0.52 mmol) was added. The reaction mixture stirred at rt for 72 h then quenched with water. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 50 mg (36%).
2-(4-((Cyclopropylmethyl)(5-(trifluoromethyl)quinolin-8-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylic acid
A mixture of ethyl 2-(4-((cyclopropylmethyl)(5-(trifluoromethyl)quinolin-8-yl)amino)-2-methoxybenzoyl)cyclopropanecarboxylate (40 mg, 0.078 mmol) and NaOH (160 mg, 4.0 mmol) in EtOH (2 mL) and water (2 mL) was stirred at 80° C. for 30 min. The reaction mixture was acidified with 1M aq HCl (pH ̃3) at 0° C. Filtration of the precipitate followed by washing (H2O) and drying afforded the title compound. Yield: 36 mg (95%). MS [M+H]+ 485. 1H-NMR 400 MHz (DMSO-d6, ppm) δ 12.43 (1H, s), 8.98 (1H, dd, J=4.1, 1.6 Hz), 8.58-8.53 (1H, m), 8.19 (1H, d, J=7.9 Hz), 7.93 (1H, d, J=7.9 Hz), 7.77 (1H, dd, J=8.8, 4.1 Hz), 7.34 (1H, d, J=8.8 Hz), 6.37 (1H, d, J=2.1 Hz), 5.99 (1H, dd, J=8.8, 2.1 Hz), 3.83 (2H, app d, J=6.7 Hz), 3.76 (3H, s), 3.21-3.15 (1H, m), 1.91-1.85 (1H, m), 1.43-1.36 (1H, m), 1.33-1.26 (1H, m), 1.14-1.04 (1H, m), 0.38-0.30 (2H, m), 0.06-0.01 (2H, m).




A detailed illustrative synthetic procedure for the general procedure shown in Scheme M is described below.
Example 54
2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)picolinoyl)cyclopropanecarboxylic acid




Ethyl 2-(5-((4-chlorophenyl)(cyclopropylmethyl)amino)picolinoyl)cyclopropanecarboxylate
Prepared in analogy to example 45 step (a) using ethyl 2-(5-bromopicolinoyl)cyclopropanecarboxylate (109 mg, 0.37 mmol), 4-chloro-N-(cyclopropylmethyl)aniline (80 mg, 0.44 mmol), Pd(OAc)2 (4 mg, 0.018 mmol), rac-BINAP (17 mg, 0.027 mmol), Cs2CO3 (176 mg, 0.54 mmol) and toluene (2 mL) at 80° C. for 24 h. Yield: 120 mg (82%).
2-(5-((4-Chlorophenyl)(cyclopropylmethyl)amino)picolinoyl)cyclopropanecarboxylic acid
Prepared in analogy to example 45 step (b) using ethyl 2-(5-((4-chlorophenyl)(cyclopropylmethyl)amino)picolinoyl)cyclopropanecarboxylate (120 mg, 0.30 mmol), NaOH (48 mg, 1.20 mmol), EtOH (4 mL) and water (2 mL) at 60° C. for 3 h followed by column chromatography. Yield: 55 mg (50%). MS [M+H]+ 371. 1H-NMR 400 MHz (DMSO-d6, ppm) δ 12.5 (1H, br s), 8.18 (1H, d, J=3.0 Hz), 7.81 (1H, d, J=9.0 Hz), 7.56-7.51 (2H, m), 7.39-7.33 (2H, m), 7.20 (1H, dd, J=9.0, 3.0 Hz), 3.80-3.74 (1H, m), 3.70 (2H, app d, J=6.7 Hz), 2.02-1.95 (1H, m), 1.46-1.34 (2H, m), 1.14-1.03 (1H, m), 0.49-0.38 (2H, m), 0.18-0.09 (2H, m).
The following compound was prepared in analogy to Example 54 described above in detail.









TABLE 9









MS



Structure
[M + H]+









Name


Ex.
1H-NMR












55




385


 









2-(5-((4-Chlorobenzyl)(cyclopropylmethyl)amino)picolinoyl)



cyclopropanecarboxylic acid



400 MHz (DMSO-d6, ppm) δ 12.5 (1H, br s), 8.20 (1H, d, J = 3.0



Hz), 7.78 (1H, d, J = 9.0 Hz), 7.41-7.36 (2H, m), 7.29-7.23 (2H,



m), 7.17 (1H, dd, J = 9.0, 3.0 Hz), 4.81 (2H, app s), 3.79-3.72 (1H,



m), 3.52 (2H, app d, J = 6.6 Hz), 1.99-1.92 (1H, m), 1.42-1.32 (2H,



m), 1.20-1.09 (1H, m), 0.54-0.44 (2H, m), 0.35-0.27 (2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme N is described below.
Example 56
2-(5-((4-Chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylic acid




Ethyl 2-(5-((4-chloronaphthalen-1-yl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylate
Ethyl 2-(5-bromo-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylate (100 mg, 0.30 mmol), 4-chloronaphthalen-1-amine (65 mg, 0.37 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), rac-BINAP (14 mg, 0.023 mmol) and Cs2CO3 (139 mg, 0.43 mmol) were mixed in toluene (1 mL) and stirred at 85° C. for 20 h in a sealed tube. The reaction mixture was diluted (EtOAc), filtered through a celite pad and concentrated. Purification by column chromatography afforded the sub-title compound. Yield: 80 mg (62%).
Ethyl 2-(5-((4-chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylate
NaH (60% dispersion in mineral oil, 8 mg, 0.20 mmol) was added in one portion to solution of ethyl 2-(5-((4-chloronaphthalen-1-yl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylate (80 mg, 0.19 mmol) and (bromomethyl)cyclopropane (36 μL, 0.38 mmol) in DMF (2 mL) at 0° C. The reaction mixture stirred at 70° C. for 1 h then quenched with water. Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 80 mg (89%).
2-(5-((4-Chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylic acid
A mixture of ethyl 2-(5-((4-chloronaphthalen-1-yl)(cyclopropylmethyl)amino)-4-methoxypyrimidine-2-carbonyl)cyclopropanecarboxylate (80 mg, 0.17 mmol) and NaOH (32 mg, 0.83 mmol) in EtOH (4 mL) and water (1 mL) was stirred at 70° C. for 30 min. The reaction mixture was acidified with 1M aq HCl (pH ̃3) at 0° C. Filtration of the precipitate followed by washing (H2O) and drying afforded the title compound. Yield: 59 mg (78%). MS [M+H]+ 452. 1H-NMR 400 MHz (CDCl3, ppm) δ 8.32-8.28 (1H, m), 7.96 (1H, s), 7.95-7.91 (1H, m), 7.63-7.57 (1H, m), 7.54 (1H, d, J=7.9 Hz), 7.52-7.47 (1H, m), 7.25 (1H, d, J=7.9 Hz), 3.88-3.81 (4H, m), 3.72 (2H, app d, J=6.5 Hz), 2.32-2.25 (1H, m), 1.64-1.54 (2H, m), 1.17-1.09 (1H, m), 0.43-0.37 (2H, m), 0.05-0.00 (2H, m).
The following compounds were prepared in analogy to Example 56 described above in detail unless otherwise indicated.














TABLE 10








R1
MS [M + H]+
Name








Ex.
1H-NMR













57




418
2-(5-((Cyclopropylmethyl)(naphthalen-1- yl)amino)-4-methoxypyrimidine-2- carbonyl)cyclopropanecarboxylic acid


 









400 MHz (CDCl3, ppm) δ 7.90-7.85 (3H, m), 7.81-7.77 (1H, m), 7.52-7.40 (3H, m),



7.36 (1H, dd, J = 7.3, 1.0 Hz), 3.90 (3H, s), 3.90-3.84 (1H, m), 3.78 (2H, app d,



J = 6.5 Hz), 2.34-2.28 (1H, m), 1.68-1.56 (2H, m), 1.20-1.12 (1H, m), 0.43-0.37



(2H, m), 0.07-0.01 (2H, m)


 










58




436
2-(5-((Cyclopropylmethyl)(4- fluoronaphthalen-1-yl)amino)-4- methoxypyrimidine-2- carbonyl)cyclopropanecarboxylic acid


 









400 MHz (CDCl3, ppm) δ 8.17-8.11 (1H, m), 7.91 (1H, s), 7.91-7.86 (1H, m), 7.59-7.53



(1H, m), 7.53-7.47 (1H, m), 7.27 (1H, dd, J = 8.1 4.9 Hz), 7.12 (1H, dd, J = 9.9 8.1 Hz),



3.90-3.84 (1H, m), 3.87 (3H, s), 3.73 (2H, app d, J = 6.5 Hz), 2.35-2.29 (1H, m),



1.69-1.57 (2H, m), 1.18-1.09 (1H, m), 0.44-0.37 (2H, m), 0.05-0.00 (2H, m)


 










59




432
2-(5-((Cyclopropylmethyl)(4- methylnaphthalen-1-yl)amino)-4- methoxypyrimidine-2- carbonyl)cyclopropanecarboxylic acid


 









400 MHz (CDCl3, ppm) δ 8.05-8.00 (1H, m), 7.91-7.87 (1H, m), 7.80 (1H, s), 7.55-7.50



(1H, m), 7.46-7.41 (1H, m), 7.32-7.26 (2H, m), 3.93 (3H, s), 3.90-3.84 (1H, m),



3.77 (2H, app d, J = 6.5 Hz), 2.72 (3H, s), 2.34-2.28 (1H, m), 1.67-1.56 (2H, m),



1.20-1.11 (1H, m), 0.42-0.36 (2H, m), 0.07-0.02 (2H, m)













A detailed illustrative synthetic procedure for the general procedure shown in Scheme O is described below.
Example 60
(2-(1H-Tetrazol-5-yl)cyclopropyl)(5-((cyclopropylmethyl)(naphthalen-1-yl)amino)-3-methoxypyridin-2-yl)methanone




2-(5-Bromo-3-methoxypicolinoyl)cyclopropanecarboxylic acid
A mixture of ethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (1.32 g, 4.01 mmol) and NaOH (803 mg, 20.1 mmol) in EtOH (30 mL) and water (3 mL) was stirred at 80° C. for 30 min. The reaction mixture was acidified with 1M aq HCl (pH ̃5) and EtOH was partly evaporated. Extraction with EtOAc, drying (Na2SO4) and concentration of EtOAc extracts afforded the sub-title compound. Yield: 1.20 g (99%).
2-(5-Bromo-3-methoxypicolinoyl)cyclopropanecarboxamide
A mixture of 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylic acid (1.00 g, 3.33 mmol), EDC.HCl (703 mg, 3.66 mmol) and HOBt (495 mg, 3.66 mmol) in DMF (10 ml) was stirred at rt for 6 h. A solution of aq ammonia (25%, 0.65 ml) was added at 0° C., and the reaction mixture was stirred an additional 18 h at rt. Extractive workup (EtOAc, 0.1 M aq HCl, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 0.92 g (90%).
2-(5-Bromo-3-methoxypicolinoyl)cyclopropanecarbonitrile
Methanesulfonyl chloride (0.65 mL, 8.35 mmol) was added dropwise to a solution of 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxamid (490 mg, 1.64 mmol) in pyridine (3 mL) at 0° C. The reaction mixture was stirred at rt for 18 h and then poured into water (100 mL). Extractive workup (EtOAc, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the sub-title compound. Yield: 377 mg (82%).
2-(5-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarbonitrile
2-(5-Bromo-3-methoxypicolinoyl)cyclopropanecarbonitrile (200 mg, 0.71 mmol), N-(cyclopropylmethyl)naphthalen-1-amine (158 mg, 0.85 mmol), Pd(OAc)2 (8.1 mg, 0.036 mmol), rac-BINAP (31 mg, 0.040 mmol) and Cs2CO3 (325 mg, 1.00 mmol) were mixed in toluene (3 mL) and stirred at 70° C. for 60 h in a sealed tube. The reaction mixture was diluted with (EtOAc), filtered through celite pad and concentrated. Purification by column chromatography afforded the sub-title compound. Yield: 122 mg (43%).
(2-(1H-Tetrazol-5-yl)cyclopropyl)(5-((cyclopropylmethyl)(naphthalen-1-yl)amino)-3-methoxypyridin-2-yl)methanone
2-(5-((Cyclopropylmethyl)(naphthalen-1-yl)amino)-3-methoxypicolinoyl)cyclopropanecarbonitrile (110 mg, 0.28 mmol), NaN3 (45 mg, 0.69 mmol) and triethylamine hydrochloride (95 mg, 0.69 mmol) were mixed in toluene (2 mL) and stirred at 95-110° C. for 18 h in a sealed tube. After cooling to rt the reaction mixture was acidified with 1M aq HCl (pH ̃5). Extractive workup (EtOAc, water, brine) and concentration of the EtOAc extracts followed by column chromatography afforded the title compound. Yield: 377 mg (82%). MS [M+H]+ 441. 1H-NMR 400 MHz (CDCl3:TFA, ppm) δ 8.60-8.30 (1H, br m), 8.07-7.94 (2H, m), 7.67-7.45 (5H, m), 6.40-6.10 (1H, br m), 4.30-3.22 (6H, m), 3.14-3.00 (1H, m), 2.04-1.87 (2H, m), 1.20-1.08 (1H, m), 0.62-0.46 (2H, m), 0.21-0.05 (2H, m).
The following compound was prepared in analogy to Example 60 described above in detail.









TABLE 11









MS



Structure
[M + H]+









Name


Ex.
1H-NMR












61




459


 









(2-(1H-Tetrazol-5-yl)cyclopropyl)(5-((cyclopropylmethyl)(4-



fluoronaphthalen-1-yl)amino)-3-methoxypyridin-2-yl)methanone



400 MHz (CDCl3, ppm) δ 8.20 (1H, d, J = 8.5 Hz), 7.80-7.70 (1H,



m), 7.68-7.57 (2H, m), 7.55-7.48 (1H, m), 7.44-7.38 (1H, m), 7.25-



7.19 (1H, m), 6.33-6.24 (1H, m), 4.09-4.01 (1H, m), 3.97-3.87 (1H,



m), 3.78 (3H, s), 3.53-3.42 (1H, m), 3.26-3.17 (1H, m), 2.03-1.95



(1H, m), 1.80-1.73 (1H, m), 1.22-1.12 (1H, m), 0.56-0.44 (2H, m),



0.15-0.05 (2H, m)









Example 62
(1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid




(2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide




Into a 50-L 4-necked round-bottom flask, was placed acetone (25 L), ethyl 2-bromoacetate (10 kg, 59.88 mol, 1.00 equiv), (methylsulfanyl)methane (4.64 kg, 74.68 mol, 1.20 equiv). The resulting solution was stirred for 24 h at 20-30° C. The solids were collected by filtration. This resulted in 11.5 kg (84%) of (2-ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide as a white solid.
trans-1, 2-Diethyl-cyclopropane-1,2-dicarboxylate




Into a 50-L 4-necked round-bottom flask, was placed DMSO (30 L), (2-ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide (11.50 kg, 50.19 mol, 1.00 equiv), potassium carbonate (7.62 kg, 55.14 mol, 1.10 equiv) The mixture was cooled to 15° C., and ethyl prop-2-enoate (7.03 kg, 70.22 mol, 1.40 equiv) was added slowly. The resulting solution was stirred for 14 h at 15-35° C., after which the solids were filtered out. The resulting solution was diluted with 90 L of water and extracted with 3×15 L of ethyl acetate after which the organic layers were combined and washed with 1×10 L of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation. This resulted in 4.9 kg (52%) of trans-1,2-diethyl-cyclopropane-1,2-dicarboxylate as colorless oil.
trans-2-(Ethoxycarbonyl)cyclopropane-1-carboxylic acid




Into a 50-L 4-necked round-bottom flask, was placed ethanol (18 L), trans-1,2-diethyl-cyclopropane-1,2-dicarboxylate (3750 g, 20.14 mol, 1.00 equiv), a solution of EtONa (1370.5 g, 1.00 equiv) in ethanol (5329 g) and water (725 g, 40.24 mol, 2.00 equiv). The resulting solution was stirred for 14 h at 20-25° C. The mixture was concentrated under vacuum, and the resulting solution diluted with 20 L of water. The resulting solution was extracted with 3×10 L of dichloromethane and the aqueous layers combined. The pH value of the solution was adjusted to 3-4 with hydrogen chloride (12 M). The resulting solution was extracted with 4×8 L of dichloromethane, the organic layers combined and washed with 1×5 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from petroleum ether. This resulted in 2 kg (63%) of trans-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ 1.15-1.34 (5H, m), 1.90-2.12 (2H, m), 4.04-4.13 (2H, m), 12.65 (1H, s).
trans-Ethyl 2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate




Into a 50-L 4-necked round-bottom flask was placed dichloromethane (24 L), trans 2-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (4780 g, 30.22 mol, 1.00 equiv), (COCl)2 (4200 g, 33.09 mol, 1.10 equiv), DMF (110.5 g, 1.51 mol, 0.05 equiv), DIEA (9750.5 g, 75.44 mol, 2.50 equiv), methoxyammonium chloride (3537 g, 36.26 mol, 1.20 equiv). The resulting solution was stirred for 5-7 h at 0-10° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 20 L of DCM and the mixture washed with 1×8 L of 1 M HCl, 1×5 L of NaHCO3 (aq) and 1×5 L of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation. This resulted in 4100 g (67%) of trans-ethyl-2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate as colorless oil. 1H-NMR (300 MHz, CDCl3) δ 1.30-1.46 (5H, m), 2.13-2.19 (1H, m), 2.68 (1H, s), 3.17-3.21 (3H, m), 3.74-3.76 (3H, m), 4.13-4.20 (2H, m).
5-bromo-2-iodo-3-methoxypyrazine




CH2I2 (9.2 kg, 34.3 mol, 2.0 eq), CuI (0.3 kg, 1.7 mol, 0.1 eq) and isopentyl nitrite (6.0 kg, 51.6 mol, 3.0 eq), were charged into a 50 L reactor. The mixture was heated up to 70-80° C. in an oil bath. A solution of 5-bromo-3-methoxypyrazin-2-amine (3.5 kg, 17.2 mol, 1.0 eq) in THF (17.5 L) was added dropwise into the glass flask at 70-80° C. for 150 min. After addition, the solution was stirred for 2 h at 70-80° C. The reaction was monitored by HPLC (starting material:product, 0.6%:63.1%). The mixture was cooled to room temperature and filtered. The filter cake was washed with EtOAc (7.0 L). The filtrates were combined with another batch (3.5 kg) and concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa). The residual was swapped twice with heptane (7.0 L×2). The organic layer was concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa). Heptane (17.5 L) was added to the residue. The mixture was heated to reflux in oil bath and filtered at high temperature to remove not dissolved material. A filter was performed at higher temperature. The filtrate was cooled to 0-10° C. and stirred for 2 h, yellow solid precipitated. The suspension was filtered and washed with heptane (1000 ml). The solid was dried under vacuum (temperature: 30° C., vacuum: −0.08 Mpa). Finally, 3.1 kg of product (purity: 95.3%, yield: 28.9%) was obtained as a yellow solid. 1H-NMR: (300 MHz, CDCl3) δ 8.07 (s, 1H), 4.05 (s, 3H). MS ESI, m/z=314.9 (M+H)+.
N-(5-chloro-2,4-difluorophenyl)-2-fluoro-2-methylpropanamide




EtOAc (9.0 L), 5-chloro-2,4-difluorobenzenamine (1.0 kg, 6.1 mol, 1.0 eq), DMAP (820.3 g, 6.7 mol, 1.1 eq), DIEA (2.9 kg, 22.1 mol, 3.3 eq) was placed into a 20 L 4-neck flask. A solution of 2-fluoro-2-methylpropanoic acid (678.9 g, 6.4 mol, 1.05 eq) in EtOAc (1 L) was charged into reaction solution at 20-30° C. T3P (50% in EtOAc, 4.3 kg, 6.7 mol, 1.1 eq) was added dropwise into the reaction solution at 20-30° C., during 20 min. The mixture was stirred for 2 h. The reaction was monitored by HPLC (starting material:product, 1.9%:89.6%). EtOAc (10 L), NaHCO3 (aq) (10 L, 10% w/w) were charged into the reaction solution and stirred for 10-20 min. The mixture was separated and the organic layer was washed with NaHCO3 (aq) (10 L, 10% w/w) once. The organic layer was washed with NaCl (aq) (10 L, 15% w/w) once. The organic layers were combined and concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa). The residual was swapped twice with isopropanol (10 L*2). The organic layers was concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa) until about 2-3 volumes left. The residual was cooled to 5-10° C. and stirred for 2-3 h, when a white solid precipitated. The suspension was filtered and washed with isopropanol (1000 ml). The solid was dried under vacuum (temperature: 30° C., vacuum: −0.08 Mpa) to obtain 1.3 kg of product (purity: 99%, yield: 84.4%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.48-8.53 (t, 1H), 8.27 (s, 1H), 6.97-7.04 (m, 1H), 1.64-1.72 (d, 6H). MS ESI, m/z=252.1 (M+H)+.
5-chloro-2,4-difluoro-N-(2-fluoro-2-methylpropyl)aniline




BH3-DMS (1987 mL, 20.9 mol, 5.3 equiv), tetrahydrofuran (2.0 L) were charged into a 20 L 4-neck glass flask. A solution of N-(5-chloro-2,4-difluorophenyl)-2-fluoro-2-methylpropanamide (1000 g, 4.0 mol, 1.0 equiv) in THF (8.0 L) was added dropwise during about 6 h at 30 ̃40° C. The resulting solution was stirred for 1-2 h at 30-40° C. The reaction progress was monitored by HPLC (starting material:product, 1.2%:88.6%). The reaction was then quenched by the addition of 10 L of water/ice. The resulting solution was extracted with 10 L of ethyl acetate and the organic layers were combined. The solution was washed with saturated solution of sodium bicarbonate (5 L, twice) and 5 L of saturated solution of NaCl (aq). The organic layer was combined with another batch (1.0 kg) and dried over anhydrous sodium sulfate and concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa). This resulted in 900 g (purity: 94%, yield: 95%) of 5-chloro-2,4-difluoro-N-(2-fluoro-2-methylpropyl)aniline as light yellow oil. 1H-NMR (400 MHz, CDCl3) δ 7.28-7.34 (m, 1H), 6.94-6.98 (t, 1H), 5.67-5.69 (d, 1H), 3.25-3.34 (m, 2H), 1.31-1.36 (d, 6H). MS ESI, m/z=218.1 (M+H)+.
Ethyl-2-[(5-bromo-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate




THF (24 L), 5-bromo-2-iodo-3-methoxypyrazine (2.4 kg, 7.6 mol, 1.0 eq) and racemic trans-ethyl 2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate (1.5 kg, 7.6 mol, 1.0 eq) were placed in a 50 L reactor. The reaction solution was cooled to −78° C. in an bath of liquid N2 and EtOH. n-BuLi (2.5 M, 3.3 L, 8.4 mol, 1.1 eq) was added dropwise at this temperature during 1 h. The mixture was stirred for 30 min. The reaction was monitored by HPLC (starting material:product, 0.3%:65.8%). The reaction mixture was warmed to −10-0° C. and quenched by sat. NH4Cl (aq) (7.2 L) at −5-5° C. The reaction mixture was extracted with EtOAc (7.2 L). The organic layer was washed with by sat. NH4Cl (aq) (7.2 L) twice. The organic layer was combined with another batch (2.4 kg) and concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa) to obtain the crude product (8.9 kg) as a yellow oil. The crude product was purified by silica gel (EtOAc:petroleum ether=1:25) to obtain 2.2 kg of product (purity: 97.3%, yield: 44.0%) as light yellow solid. 1H-NMR: (400 MHz, CDCl3) δ 8.37 (s, 1H), 4.17-4.22 (m, 2H), 4.12 (s, 3H), 3.67-3.72 (m, 1H), 2.35-2.40 (m, 1H), 1.62-1.65 (t, 2H), 1.24-1.32 (m, 3H). MS ESI, m/z=329.0 (M+H)+.
Ethyl 2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylate




THF (1000 mL), ethyl-2-[(5-bromo-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate (200 g, 607.6 mmol, 1.0 eq), 5-chloro-2,4-difluoro-N-(2-fluoro-2-methylpropyl)aniline (166 g, 698.5 mmol, 1.1 eq) were charged into 5 L 4-necked round-bottom flask, that was purged and maintained with an inert atmosphere of nitrogen. KHMDS (565.2 mL, 565 mmol, 0.9 eq) was added with dropwise at −5-5° C. during about 15 min. The resulting solution was stirred for 20 min at −5-5° C. in an ice/salt bath. The reaction progress was monitored by HPLC (starting material:product 3.1%:75.4%). The reaction was then quenched by the addition of 200 mL saturated solution of NH4Cl (aq). The resulting solution was extracted with 600 mL of ethyl acetate and washed with 500 mL saturated solution of NH4Cl (aq). The organic layer was washed with 500 mL saturated solution of NaCl (aq). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa). The residue was purified by silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 180 g (97.3% purity, 61% yield) of ethyl 2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylate as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.49-7.52 (t, 1H), 7.36 (s, 1H), 7.11-7.15 (t, 1H), 4.12-4.22 (m, 4H), 4.02 (s, 3H), 3.74-3.09 (m, 1H), 2.26-2.31 (m, 1H), 1.51-1.58 (m, 11H). MS ESI, m/z=472.3 (M+H)+.
2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid




Tetrahydrofuran (6000 mL), ethyl 2-([5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl]carbonyl)cyclopropanecarboxylate (2.0 kg, 4.12 mol, 1.0 eq), water (6 L), sodium hydroxide (329.3 g, 8.2 mol, 2.0 eq) were charged into a 20 L 4-necked round-bottom flask. The reaction solution was stirred for 16 h at 15-25° C. The reaction progress was monitored by HPLC (starting material:product=0.4%:98.5%). The pH value of the solution was adjusted to 3 ̃4 with HCl (2 M). The resulting solution was extracted with 5 L of ethyl acetate and the organic layers combined and concentrated under vacuum (temperature: 40° C., vacuum: −0.08 Mpa) to obtain crude product. The crude product (1.98 kg) was charged into a 20 L 4-necked round-bottom flask. EtOAc (6.0 L) and hexane (6.0 L) were charged into the flask, the solid was not dissolved completely. The mixture slurry was stirred at 15-25° C. for 2 h. The solid was filtered and dried at 40-50° C. for 10 h. after that the solid was continued to dry at 70-80° C. for 10 h. This resulted in 1860 g (purity: 98%, yield: 96%) of 2-([5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl]carbonyl)cyclopropanecarboxylic acid as a light yellow solid.
1H-NMR (300 MHz, CDCl3) δ 7.49 (t, 1H), 7.35 (s, 1H), 7.11 (t, 1H), 4.17 (d, 2H), 4.00 (s, 3H), 3.80 (m, 1H), 2.24 (m, 1H), 1.62 (m, 1H), 1.53 (m, 1H), 1.44 (d, 6H). MS ESI, m/z=458.2 (M+H)+.
(1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid




The two enantiomers of 2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (2.3 Kg, 92% w/w, 4.62 mol) were separated on a SuperSep SFC fitted with a Chiralpak IC column (250×50 mm, 5 μm particle size) and 20% EtOH/FA 100/0.5 in CO2, 120 bar as eluent to yield (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}) carbonyl)cyclopropanecarboxylic acid and (1R,2R)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}) carbonyl)cyclopropanecarboxylic acid. The enantiomer (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid was suspended in heptane (5 L) and heated to 75° C. under slight reduced pressure (150-200 mbar) and the solvents removed (azeotroping the remaining formic acid from the separation). To the residue was added heptane (4 L) and isobutyl acetate (2 L) and the suspension stirred at 75° C. After stirring for one hour at 75° C. the temperature was decreased stepwise to 14° C. over 20 hours. Stirring continued at this temperature for another 20 hours. The obtained solid was filtered off and washed with heptane (2.5 L). Drying overnight at 40° C. in vacuo yielded (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid [(1008 g, 2.2 mol, 98.9% w/w, LC purity 98.8% @ 230 nm, 99.9% ee, 47.6% yield, [α]D20=+62° (c 1.0, acetonitrile)] as a white solid. 1H-NMR (600 MHz, DMSO-d6, 50° C.) δ 1.34 (m, 2H), 1.40 (d, J=21.6 Hz, 6H), 1.92 (ddd, J=8.4, 5.8, 3.9, Hz, 1H), 3.55 (ddd, J=8.6, 6.0, 3.9, Hz, 1H), 3.83 (s, 3H), 4.26 (d, J=21.8 Hz, 2H), 7.65 (br s, 1H), 7.71 (t, J=9.8 Hz, 1H), 7.98 (t, J=7.8 Hz, 1H), 12.34 (br s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 16.1, 23.9, 24.3 (br d, J=22.4 Hz), 25.3, 53.4, 57.4 (d, J=20.1 Hz), 96.9 (d, J=168.7 Hz), 106.6 (br t, J=27 Hz), 115.8 (br d, J=18.8 Hz), 121.4, 125.6, 127.8, 130.9, 153.7, 156.3 (dd, J=249.3, 11.9 Hz), 156.9 (dd, J=251.9, 11.2 Hz), 157.8, 173.0, 192.4. MS ESI, m/z=458.1105 (M+H)+, (calc. 458.1094).
The solid residue was found to be crystalline by XRPD and a typical diffractogram is displayed in FIG. 1. Characteristic peak positions are listed in Table 12 and Table 13 below.







TABLE 12





Five most characteristic peaks of Example 62


°2-theta















4.8


19.4


22.8


24.6
















TABLE 13





Ten most characteristic peaks of Example 62


°2-theta















4.8


9.4


11.5


13.3


16.3


19.4


22.8


24.6


25.5


27.7









Example 63
(1S,2S)-2-[(5-{(2-Fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylic acid




2-Fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-methylpropanamide




T3P (50% solution in EtOAc) (107 g, 167.49 mmol) was added to 2-fluoro-5-(trifluoromethyl)aniline (10 g, 55.83 mmol), 2-fluoro-2-methylpropanoic acid (6.52 g, 61.41 mmol) and DIPEA (39.0 mL, 223.32 mmol) in butyl acetate (60 mL) at 20° C. The resulting mixture was stirred at 80° C. for 30 min. The reaction mixture was poured into water (100 mL), extracted with EtOAc (2×100 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford brown solid. The crude product was purified by flash silica chromatography, elution gradient 0 to 1% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-methylpropanamide (12.00 g, 80%) as a yellow solid.
1H-NMR (400 MHz, CDCl3) δ 1.68 (s, 3H), 1.73 (s, 3H), 7.20-7.31 (m, 1H), 7.40 (ddd, 1H), 8.48 (s, 1H), 8.77 (dd, 1H). MS ESI, m/z=268 (M+H)+.
2-Fluoro-N-(2-fluoro-2-methylpropyl)-5-(trifluoromethyl)aniline




BH3THF (206 mL, 205.84 mmol) was added dropwise to 2-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-methylpropanamide (11 g, 41.17 mmol) in THF (30 mL) at 0° C. over a period of 2 min under air. The resulting solution was stirred at 60° C. for 3 h. The reaction mixture was quenched with ice-water (50 mL), the reaction mixture was acidified with 2 M HCl. The reaction mixture was adjusted to pH 8-9 with saturated NaHCO3 and was stirred at rt for 30 min, extracted with DCM (2×100 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford yellow liquid. The residue was purified by preparative TLC (petroleum ether:EtOAc=25:1), to afford 2-fluoro-N-(2-fluoro-2-methylpropyl)-5-(trifluoromethyl)aniline (5.30 g, 50.8%) as a yellow liquid. 1H-NMR (400 MHz, CDCl3) δ 1.47 (s, 3H), 1.52 (s, 3H), 3.33 (d, 2H), 6.93 (t, 2H), 7.07 (dd, 1H). MS ESI, m/z=254 (M+H)+.
trans-2-(Methoxycarbonyl)cyclopropane-1-carboxylic acid




A solution of LiOH.H2O (40.6 g, 966.68 mmol) in MeOH (500 mL) was added to a stirred solution of trans-1,2-diethyl-cyclopropane-1,2-dicarboxylate (Example 62(b)) (180 g, 966.68 mmol) in THF (3000 mL) at 0° C. The resulting solution was stirred at 20° C. for 16 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with H2O (400 mL). The reaction mixture was adjusted to pH=3-4 with 2 M HCl. The reaction mixture was extracted with DCM (6×500 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford yellow oil. The product was used in the next step directly without further purification. 1H NMR (400 MHz, CDCl3, 23° C.) δ 1.47-1.53 (m, 2H), 2.15-2.26 (m, 2H), 3.70 (s, 3H), 11.26 (s, 1H).
trans Methyl 2-(chlorocarbonyl)cyclopropanecarboxylate




Oxalyl dichloride (197 g, 1554.20 mmol) was added to trans-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (112 g, 777.10 mmol), DMF (8 mL, 103.32 mmol) and in DCM (1200 mL) at 0° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 h. The solvent was removed under reduced pressure. The compound (112 g, 89%) was used in the next step directly without further purification.
Methyl 2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate




A mixture of trans methyl 2-(chlorocarbonyl)cyclopropanecarboxylate (112 g, 688.93 mmol) in DCM (300 mL) was added dropwise to a stirred mixture of N,O-dimethylhydroxylamine hydrochloride (101 g, 1033.39 mmol) and triethylamine (279 g, 2755.72 mmol) in DCM (2000 mL) at 0° C., over a period of 30 min under nitrogen. The resulting mixture was stirred at 20° C. for 15 h. The reaction mixture was washed with saturated NaHCO3 (500 mL×4). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate (80 g, 62.3%) as a yellow liquid. 1H NMR (300 MHz, CDCl3, 27° C.) δ 1.40-1.48 (m, 2H, 2.15-2.21 (m, 1H), 2.69 (s, 1H), 3.21 (s, 3H), 3.71-3.75 (d, 6H).
Methyl 2-[(5-bromo-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate




Isopropylmagnesium chloride-LiCl complex (242 mL, 314.38 mmol) was added dropwise to 5-bromo-2-iodo-3-methoxypyrazine (90 g, 285.8 mmol) in THF (1500 mL) at −70° C. over a period of 5 min under nitrogen. The resulting solution was stirred at −50° C. for 40 min. Methyl 2-[methoxy(methyl)carbamoyl]cyclopropanecarboxylate (53.5 g, 285.80 mmol) in THF (150 mL) was added at −70° C. The resulting solution was stirred at −10° C. for 1 hour. The reaction mixture was quenched with saturated NH4Cl (300 mL), extracted with DCM (3×500 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford a red liquid. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 2-[(5-bromo-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate (37.0 g, 41.1%) as a white solid.
1H NMR (300 MHz, CDCl3, 27° C.) δ 1.56-1.65 (m, 2H), 2.32-2.38 (m, 1H), 3.65-3.72 (m, 4H), 4.09 (s, 3H), 8.35 (s, 1H). MS (ESI): m/z=315 [M+H]+
Methyl 2-[(5-(2-fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate




KHMDS (12.55 mL, 11.42 mmol) was added to 2-fluoro-N-(2-fluoro-2-methylpropyl)-5-(trifluoromethyl)aniline (2.411 g, 9.52 mmol), methyl 2-[(5-bromo-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate (3 g, 9.52 mmol) in THF (10 mL) at −20° C. over a period of 2 minutes under N2 (g). The resulting solution was stirred at −20° C. for 5 min. The reaction mixture was poured into ice (20 mL), extracted with EtOAc (2×50 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford orange oil. The residue was purified by preparative TLC (petroleum ether: EtOAc=4:1), to afford methyl 2-[(5-{(2-fluoro-2-methylpropyl) [2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate (4.30 g, 93%) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ 1.44 (s, 3H), 1.47-1.62 (m, 5H, 2.25-2.34 (m, 1H), 3.69 (s, 3H), 3.73-3.83 (m, 1H), 4.02 (s, 3H), 4.23 (s, 1H), 4.28 (s, 1H), 7.33-7.44 (m, 2H), 7.72 (t, 2H). MS ESI, m/z=488 (M+H)+.
2-[(5-{(2-Fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylic acid




A solution of NaOH (2.95 g, 73.86 mmol) in water (20 mL) was added dropwise to a stirred solution of methyl 2-[(5-{(2-fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate (3.6 g, 7.39 mmol) in MeOH (350 mL) at 0° C. The resulting solution was stirred at 20° C. for 36 h. The reaction mixture was poured into ice-water (1 L), extracted with DCM (2×1 L), the organic layer was dried over Na2SO4, filtered and evaporated to afford 2-[(5-{(2-fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylic acid (3.24 g, 93%) as a pale yellow solid. MS ESI, m/z=474 (M+H)+.
(1S,2S)-2-[(5-{(2-Fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylic acid




2-[(5-{(2-fluoro-2-methylpropyl)[2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylic acid product was purified by preparative SFC on a Chiralpak IA column, eluting isocratically with 30% MeOH in CO2 (modified with 0.05% AcOH) as eluent. The fractions containing the desired compound (first eluting isomere) were evaporated to dryness to afford (1S,2S)-2-[(5-{(2-fluoro-2-methylpropyl) [2-fluoro-5-(trifluoromethyl)phenyl]amino}-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylic acid (1.200 g, 32.4%) as a white solid.
1H-NMR (400 MHz, DMSO-d6) δ 1.30-1.41 (m, 5H), 1.43 (s, 3H), 1.87-1.96 (m, 1H), 3.57 (ddd, 1H), 3.78 (s, 3H), 4.30-4.36 (d, 2H), 7.64 (t, 2H), 7.86 (d, 1H), 8.13 (d, 1H), 12.49 (s, 1H). MS ESI, m/z=474 (M+H)+.
Example 64
(1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid




(a) 5-Chloro-2,4-difluoro-N-propylaniline




Propionaldehyde (178 mg, 3.06 mmol) was added dropwise to 5-chloro-2,4-difluoroaniline (500 mg, 3.06 mmol) in 1,2-dichloroethane (5 mL) at 20° C. The resulting solution was stirred at 20° C. for 2 h. The reaction was cooled to 0° C. after which sodium triacetoxyborohydride (1296 mg, 6.11 mmol) was added slowly. The resulting mixture was stirred at 20° C. overnight. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (75 ml), saturated NaHCO3 (2×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The residue was purified by preparative TLC (petroleum ether: EtOAc=20:1), to afford 5-chloro-2,4-difluoro-N-propylaniline (266 mg, 42.3%) as a yellow liquid.
1H-NMR (300 MHz, CDCl3) δ 0.98-1.03 (t, 3H), 1.62-1.72 (m, 2H), 3.03-3.08 (t, 2H), 6.61-6.64 (t, 1H), 6.83-6.87 (t, 1H).
MS ESI, m/z=206 (M+H)+.
(b) Methyl 2-({5-[(5-chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylate




Potassium bis(trimethylsilyl)amide (0.837 mL, 0.76 mmol) was added dropwise to methyl 2-[(5-bromo-3-methoxypyrazin-2-yl)carbonyl]cyclopropanecarboxylate (Example 63 (f)) (200 mg, 0.63 mmol) and 5-chloro-2,4-difluoro-N-propylaniline (157 mg, 0.76 mmol) in THF (15 mL) at −20° C. over a period of 10 minutes under nitrogen. The resulting mixture was stirred at −20° C. for 30 min. The reaction mixture was quenched with ice-water (100 mL), extracted with EtOAc (3×100 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford a red liquid. The residue was purified by preparative TLC (petroleum ether:EtOAc, 2:1), to afford methyl 2-({5-[(5-chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylate (145 mg, 51.9%) as a yellow oil.
MS ESI, m/z=440 (M+H)+.
(c) 2-({5-[(5-Chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid




A solution of lithium hydroxide hydrate (267 mg, 6.37 mmol) in water (0.5 mL) was added dropwise to a stirred mixture of methyl 2-({5-[(5-chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylate (140 mg, 0.32 mmol) in MeOH (2 mL) cooled to 0° C., over a period of 10 min under air. The resulting mixture was stirred at 60° C. for 1 h. The reaction mixture was poured into ice (100 mL), the reaction mixture was adjusted to pH 3-4 with 2 M HCl, extracted with DCM (3×100 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford a yellow solid. The crude product was purified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-({5-[(5-chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (119 mg, 88%) as a yellow solid.
MS ESI, m/z=426 (M+H)+.
(d) (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid




2-({5-[(5-Chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid
was purified by preparative chiral-HPLC on a Chiralpak IB column, eluting isocratically with 30% EtOH in hexane (modified with 0.1% HAc) as eluent. The fractions containing the desired compound (first isomer) were evaporated to dryness to afford (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)(propyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid (50.0 mg, 42.0%) as a yellow solid.
1H-NMR (400 MHz, CD3OD) δ 1.00 (m, 3H), 1.44-1.49 (m, 2H), 1.69-1.78 (m, 2H), 2.07-2.12 (m, 1H), 3.73-3.98 (m, 6H), 7.42-7.47 (t, 2H), 7.74-7.78 (t, 1H).
MS ESI, m/z=426 (M+H)+.
Example 65
(1S,2S)-2-[(5-{[2-Fluoro-5-(trifluoromethyl)phenyl](2-methylpropyl)amino}-3-methoxypyridin-2-yl)carbonyl]cyclopropanecarboxylic acid




(a) 2-fluoro-N-isobutyl-5-(trifluoromethyl)aniline




Isobutyryl chloride (1.12 mL, 10.7 mmol) was added in portions to 2-fluoro-5-(trifluoromethyl)aniline (1.79 g, 10.0 mmol) in DCM (50 ml) and TEA (1.49 mL, 10.7 mmol) stirred at rt. After 15 minutes the reaction was partitioned between aq (100 ml) with conc. HCl (5 mL) and EtOAc/heptane: 1/1. The organic phase was evaporated to dryness and heated in BH3-THF at 55° C. overnight under N2. After cooling the reaction was quenched in aq (150 mL) with some NH3 (aq). Extraction with EtOAc/heptane: 1/1 and evaporation afforded the title compound 2-fluoro-N-isobutyl-5-(trifluoromethyl)aniline (2.03 g, 86% yield) as a colourless oil.
1H-NMR (500 MHz, DMSO-d6) δ 0.91 (d, 6H), 1.88 (dp, 1H), 2.86-2.99 (m, 2H), 5.69-6.37 (m, 1H), 6.8-6.85 (m, 1H), 6.87 (dd, 1H), 7.19 (dd, 1H).
(b) (1S,2S)-2-[(5-{[2-fluoro-5-(trifluoromethyl)phenyl](2-methylpropyl)amino}-3-methoxypyridin-2-yl)carbonyl]cyclopropanecarboxylic acid




To a 50 ml round bottom flask ethyl-2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (Int 3:1) (0.492, 1.5 mmol), 2-fluoro-N-isobutyl-5-(trifluoromethyl)aniline (0.353 g, 1.5 mmol), cesium carbonate (0.746 g, 2.3 mmol), BINAP (0.187 g, 0.30 mmol) and Pd(OAc)2 (0.067 g, 0.30 mmol). After toluene (15 mL) was added the stirred reaction mixture was deoxygenated (N2 bubbling) and heated to 110° C. on a oil bath for 24 hours under nitrogen. After cooling and evaporation the crude material was dissolved in a small amount EtoAc and elated through a SiO2 plug (ca 10 cm3). The SiO2 was washed with EtoAc/heptane 1/1 mixture (ca 100 mL) and the combined eluates was evaporated to dryness to afford a colourless oil. The oil was solved in THF (10 ml) methanol (5 ml) and water (5 ml). Lithium hydroxide (0.113 g, 4.7 mmol) was added and the esterhydrolysis was allowed to proceed 1.5 hours at rt.
The reaction was quenched with acetic acid (0.6 ml) and evaporated. Preparative HPLC as described in general methods followed by chiral chromatography (Chiralpak 1C, 250×20 mm, heptane/EtOH/TEA:60/40/0.1) afforded the title compound (1S,2S)-2-[(5-{[2-fluoro-5-(trifluoromethyl)phenyl](2-methylpropyl)amino}-3-methoxypyridin-2-yl)carbonyl]cyclopropanecarboxylic acid (0.107 g, 0.24 mmol) in 16% yield as a white solid.
1H NMR (500 MHz, DMSO-d6) δ 0.93 (d, 6H), 1.26-1.37 (m, 2H), 1.83-1.98 (m, 2H), 3.53-3.64 (m, 1H), 3.74 (d, 2H), 3.75 (s, 3H), 6.69 (d, 1H), 7.55-7.72 (m, 2H), 7.83 (d, 1H), 8.02 (d, 1H), 12.45 (s, 1H).
MS ESI, m/z=455.4 (M+H)+.
Optical rotation (1 g/100 ml, acetonitrile, 20° C., 589 nm)=+44°
Biological Tests
Abbreviations
DMSO dimethyl sulphoxide
GSH glutathione
PBS phosphate buffered saline
In Vitro hLTC4 Synthase Enzyme Assay (Test A)
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.
In order to obtain IC50-values for the compounds, the following procedure was used:
A volume (24 μL) of 0.25 μg/mL LTC4 synthase in 75 mM tris (pH ̃8.5), 0.5 mM MgCl2 and 3 mM GSH was preincubated for 10 min with 0.5 μL of compound of interest in DMSO at ten different concentrations, typically in the range 10−9.5-10−5 M as well as with DMSO only. The buffer is used as background. Runs are performed in duplicates.
The enzymatic reaction is initiated by addition of 0.5 μL LTA4 in diglyme (final assay concentration 8 μM).
The reaction is stopped after 1 min by addition of double the reaction volume of a stop solution (MeOH:H2O:acetic acid 70:30:1).
After 15 fold dilution in PBS, LTC4 formation is detected with LTC4 HTRF kit (Cisbio, cat. No 64LC4PEC) and a fluorescence reader. Typically 6 μL of sample is mixed with 3 μL of each of the HTRF reagents d2 and k and analyzed as described in the kit manual.
The detected product concentration, with background subtracted, is plotted versus compound concentration and IC50 is determined as 50% of maximum inhibition.
In Vitro hLTC4 Synthase Enzyme Assay (Test B)
In the assay, LTC4 synthase catalyses the reaction where the substrate LTA4 methyl ester is converted to LTC4 methyl ester.
In order to obtain IC50-values for the compounds, the following procedure was used:
10 mL of 0.6 nM of human recombinant purified LTC4 synthase expressed from Pichia Pastoris in buffer 50 mM tris (pH 7.5), 0.05% BSA 0.03% DD M 100 mM NaCl was preincubated for 30 min with 10 mL of substrate mix containing 6 mM LTA4-methyl ester substrate and 1 mM glutathione in 50 mM Tris pH7.5 0.05% BSA 0.03% DDM 100 mM NaCl together with 0.1 μL of compound of interest in DMSO at ten different concentrations, typically in the range 10−9.5-10−5 M as well as with DMSO only.
The enzymatic reaction is initiated by addition of 10 μL LTC4S enzyme solution to 10 μL substrate solution to the assay plate containing 0.5 mL of compound in DMSO or 0.5 mL DMSO control-
The reaction is stopped after 30 min by addition of 40 μL 75% (w/v) acetonitrile in H2O.
After stopping the reaction the LTC4 methyl ester product was detected by LCMSMS,
The detected product concentration, with background subtracted, is plotted versus compound concentration and IC50 is determined as 50% of maximum inhibition.
Compounds of the invention have been tested in the above assay and have shown to be LTC4 synthase inhibitors as shown in Table A below. The IC50-values presented in Table A below are median values of at least two determinations. The values for Examples 1-61 were generated by Test A, and the values from Examples 62-65 were generated by Test B.










TABLE A








hLTC4




synthase IC50



Ex.
[nM]



















1
18



2
86



3
149



4
263



5
38



6
47



7
18



8
279



9
24



10
445



11
35



12
28



13
34



14
22



15
171



16
800



17
34



18
39



19
105



20
88



21
53



22
112



23
1839



24
2178



25
66



26
478



27
588



28
67



29
370



30
152



31
331



32
1671



33
185



34
19



35
229



36
9



37
25



38
31



39
68



40
356



41
81



42
277



43
74



44
56



45
62



46
26



47
61



48
46



49
65



50
75



51
68



52
359



53
152



54
424



55
636



56
17



57
50



58
19



59
18



60
96



61
39



62
0.289



63
0.248



64
0.483



65
0.658

## Claims

1. A compound which is (1 S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid:



or a pharmaceutically-acceptable salt thereof.

2. A pharmaceutical formulation, wherein the formulation comprises the compound of claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

3. A compound which is (1 S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic acid:

4. A pharmaceutical formulation, wherein the formulation comprises the compound of claim 3, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.