Imidazopyridine derivatives as modulators of TNF activity

A series of imidazo[1,2-a]pyridine derivatives of formula (I), being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

This application is a U.S. national phase of International Application No. PCT/EP2013/064331 filed on Jul. 5, 2013, which claims priority to Great Britain Patent Application No. 1212512.6 filed on Jul. 13, 2012 and Great Britain Patent Application No. 1221920.0 filed on Dec. 5, 2012.

The present invention relates to a class of fused imidazole derivatives, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted imidazo[1,2-a]pyridine derivatives. These compounds are modulators of the signalling of TNFα, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders.

TNFα is the prototypical member of the Tumour Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death. One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors. By way of example, TNFα exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints.

Various products capable of modulating TNFα activity are already commercially available. All are approved for the treatment of inflammatory and autoimmune disorders such as rheumatoid arthritis and Crohn's disease. All currently approved products are macromolecular and act by inhibiting the binding of human TNFα to its receptor. Typical macromolecular TNFα inhibitors include anti-TNFα antibodies; and soluble TNFα receptor fusion proteins. Examples of commercially available anti-TNFα antibodies include fully human antibodies such as adalimumab (Humira®) and golimumab (Simponi®), chimeric antibodies such as infliximab (Remicade®), and pegylated Fab′ fragments such as certulizumab pegol (Cimzia®). An example of a commercially available soluble TNFα receptor fusion protein is etanercept (Enbrel®).

TNF superfamily members, including TNFα itself, are implicated in a variety of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance (see, for example, M. G. Tansey & D. E. Szymkowski,Drug Discovery Today,2009, 14, 1082-1088; and F. S. Carneiro et al.,J. Sexual Medicine,2010, 7, 3823-3834).

The compounds in accordance with the present invention, being potent modulators of human TNFα activity, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

In addition, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, in one embodiment, the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds. In an alternative embodiment, certain compounds of this invention may be useful for coupling to a fluorophore to provide fluorescent conjugates that can be utilised in assays (e.g. a fluorescence polarisation assay) for detecting pharmacologically active compounds.

The compounds in accordance with the present invention potently neutralise the activity of TNFα in a commercially available HEK-293 derived reporter cell line known as HEK-Blue™ CD40L. This cell line is a stable transfectant expressing SEAP (secreted alkaline phosphatase) under the control of the IFNβ minimal promoter fused to five NF-κB binding sites. Secretion of SEAP by these cells is stimulated in a concentration-dependent manner by TNFα. When tested in the HEK-293 bioassay, the compounds of the present invention exhibit an IC50value of 50 μM or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC50figure denotes a more active compound).

The present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:

wherein

E represents a covalent bond; or E represents —O—, —S—, —S(O)—, —S(O)2— or —N(R5)—; or E represents an optionally substituted straight or branched C1-4alkylene chain;

Y represents C3-7cycloalkyl, aryl, C3-7heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;

Z represents hydrogen, halogen or trifluoromethyl; or Z represents C1-6alkyl, C3-7cycloalkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z1-Z2or —Z1—C(O)—Z2, either of which moieties may be optionally substituted by one or more substituents;

Z1represents a divalent radical derived from an aryl, C3-7heterocycloalkyl or heteroaryl group;

Rarepresents C1-6alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;

Rband Rcindependently represent hydrogen or trifluoromethyl; or C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7heterocycloalkyl, C3-7heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or

Rband Rc, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents;

Rdrepresents hydrogen; or C1-6alkyl, C3-7cycloalkyl, aryl, C3-7heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and

Rerepresents C1-6alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

The present invention also provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

The present invention also provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

The present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFα function is indicated.

In another aspect, the present invention provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

The present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFα function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.

In another aspect, the present invention provides a method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.

Where any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.

For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of use in the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; ammonium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts, and meglumine salts.

The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.

The present invention also includes co-crystals within its scope. The technical term “co-crystal” is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (seePharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012). Typical examples of co-crystal formers, which may be present in the co-crystal alongside the active pharmaceutical ingredient, include L-ascorbic acid, citric acid, glutaric acid, urea and nicotinamide.

The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, inDesign of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched C1-6alkyl groups, for example C1-4alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as “C1-6alkoxy”, “C1-6alkylthio”, “C1-6alkylsulphonyl” and “C1-6alkylamino” are to be construed accordingly.

The expression “C1-4alkylene chain” refers to a divalent straight or branched alkylene chain containing 1 to 4 carbon atoms. Typical examples include methylene, ethylene, methylmethylene, ethylmethylene and dimethylmethylene.

Suitable C2-6alkenyl groups include vinyl and allyl.

Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

The term “C3-7heterocycloalkenyl” as used herein refers to monounsaturated or polyunsaturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof. Suitable heterocycloalkenyl groups include thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl and 1,2,3,6-tetrahydropyridinyl.

The term “halogen” as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.

Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (I) may exist as tautomers, for example keto (CH2C═O)⇄enol (CH═CHOH) tautomers or amide (NHC═O)⇄hydroxyimine (N═COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.

It is to be understood that each individual atom present in formula (I), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter, may be present as a1H,2H (deuterium) or3H (tritium) atom, preferably1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a12C,13C or14C atom, preferably12C.

In one aspect, the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein

Z represents C3-7cycloalkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z1-Z2or —Z1—C(O)—Z2, either of which moieties may be optionally substituted by one or more substituents; and

In another aspect, the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein

In another aspect, the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

In another aspect, the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

Where the compounds in accordance with the invention comprise an optionally substituted straight or branched alkylene chain, typical values thereof include methylene (—CH2—), (methyl)methylene, ethylene (—CH2CH2—), (ethyl)methylene, (dimethyl)-methylene, (methyl)ethylene, propylene (—CH2CH2CH2—), (propyl)methylene and (dimethyl)ethylene, any of which chains may be optionally substituted by one or more substituents. Suitably, such chains are unsubstituted, monosubstituted or disubstituted. Typically, such chains are unsubstituted or monosubstituted. In one embodiment, such chains are unsubstituted. In another embodiment, such chains are monosubstituted. In a further embodiment, such chains are disubstituted.

Examples of typical substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, trifluoromethyl, oxo, hydroxy, C1-6alkoxy, trifluoromethoxy, amino, C1-6alkylamino, di(C1-6)alkylamino, carboxy, tetrazolyl, aminocarbonyl, C1-6alkylaminocarbonyl and di(C1-6)alkylaminocarbonyl. Additional examples include cyano, carboxy(C1-6)alkoxy, C2-6alkylcarbonylamino and benzyloxycarbonyl.

Examples of suitable substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, trifluoromethyl, hydroxy, C1-6alkoxy, amino, carboxy and tetrazolyl. Additional examples include cyano, carboxy-(C1-6)alkoxy, C2-6alkylcarbonylamino and benzyloxycarbonyl.

Specific examples of suitable substituents on the alkylene chain which may be present in a compound in accordance with the invention include fluoro, trifluoromethyl, hydroxy, methoxy, amino, carboxy and tetrazolyl. Additional examples include cyano, carboxymethoxy, acetylamino and benzyloxycarbonyl.

In a first embodiment, E represents a covalent bond, whereby the integer Y is attached directly to the imidaz[1,2-a]pyridine nucleus.

In a second embodiment, E represents —O—, —S—, —S(O)—, —S(O)2— or —N(R5)—. In a first aspect of that embodiment, E represents —O—. In a second aspect of that embodiment, E represents —S—. In a third aspect of that embodiment, E represents —S(O)—. In a fourth aspect of that embodiment, E represents —S(O)2—. In a fifth aspect of that embodiment, E represents —N(R5)—.

In a third embodiment, E represents an optionally substituted straight or branched C1-4alkylene chain. In a first aspect of that embodiment, E represents an optionally substituted methylene (—CH2—) linkage. In a second aspect of that embodiment, E represents an optionally substituted (methyl)methylene linkage. In a third aspect of that embodiment, E represents an optionally substituted (ethyl)methylene linkage.

Generally, E represents a covalent bond; or E represents —N(R5)—; or E represents an optionally substituted straight or branched C1-4alkylene chain.

Typically, E represents —N(R5)—; or E represents an optionally substituted straight or branched C1-4alkylene chain.

Suitably, E represents a covalent bond; or E represents —N(R5)—; or E represents methylene (—CH2—), (methyl)methylene or (ethyl)methylene, any of which groups may be optionally substituted by one or more substituents.

Generally, E represents —N(R5)—; or E represents methylene (—CH2—) or (ethyl)methylene, either of which groups may be optionally substituted by one or more substituents.

Appositely, E represents —N(R5)—, or optionally substituted methylene.

Selected examples of typical substituents on the linkage represented by E include halogen, trifluoromethyl, hydroxy, C1-6alkoxy, trifluoromethoxy, amino, C1-6alkylamino, di(C1-6)alkylamino, carboxy and tetrazolyl. Additional examples include carboxy(C1-6)-alkoxy, C2-6alkylcarbonylamino and benzyloxycarbonyl.

Selected examples of suitable substituents on the linkage represented by E include hydroxy, C1-6alkoxy, carboxy(C1-6)alkoxy, amino, C2-6alkylcarbonylamino, carboxy and benzyloxycarbonyl.

Specific examples of typical substituents on the linkage represented by E include fluoro, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, carboxy and tetrazolyl. Additional examples include carboxymethoxy, acetylamino and benzyloxycarbonyl.

Specific examples of suitable substituents on the linkage represented by E include hydroxy, methoxy, carboxymethoxy, amino, acetylamino, carboxy and benzyloxycarbonyl.

A particular example of a typical substituent on E is hydroxy.

Typical values of E include —N(R5)—, —CH2—, —CH(OH)—, —CH(CH3)— and —CH(CH2CH3)—; or E may represent a covalent bond.

Suitable values of E include —N(R5)—, —CH2— and —CH(OH)—. In one embodiment, E represents —N(R5)—. In another embodiment, E represents —CH2—. In a further embodiment, E represents —CH(OH)—.

In another embodiment, E represents —CH(OCH3)—.

In another embodiment, E represents —CH(NH2)—.

In an additional embodiment, E represents —CH(CH3)—. In a particular aspect of that embodiment, the —CH(CH3)— linkage represented by E is in the (S) stereochemical configuration.

In a further embodiment, E represents —C(CH3)(OH)—.

In a first embodiment, Q represents a covalent bond, whereby the integer Z is attached directly to the imidazo[1,2-a]pyridine nucleus.

In a second embodiment, Q represents —O—, —S—, —S(O)—, —S(O)2—, —N(R6)—, —C(O)N(R6)—, —N(R6)C(O)—, —S(O)2N(R6)— or —N(R6)S(O)2—. In a first aspect of that embodiment, Q represents —O—. In a second aspect of that embodiment, Q represents —S—. In a third aspect of that embodiment, Q represents —S(O)—. In a fourth aspect of that embodiment, Q represents —S(O)2—. In a fifth aspect of that embodiment, Q represents —N(R6)—. In a sixth aspect of that embodiment, Q represents —C(O)N(R6)—. In a seventh aspect of that embodiment, Q represents —N(R6)C(O)—. In an eighth aspect of that embodiment, Q represents —S(O)2N(R6)—. In a ninth aspect of that embodiment, Q represents —N(R6)S(O)2—.

In a third embodiment, Q represents an optionally substituted straight or branched C1-6alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from —O—, —S—, —S(O)—, —S(O)2—, —N(R6)—, —C(O)N(R6)—, —N(R6)C(O)—, —S(O)2N(R6)— and —N(R6)S(O)2—. In a first aspect of that embodiment, Q represents an optionally substituted straight or branched C1-6alkylene chain. In a second aspect of that embodiment, Q represents an optionally substituted straight or branched C1-6alkylene chain comprising one heteroatom-containing linkage independently selected from —O—, —S—, —S(O)—, —S(O)2—, —N(R6)—, —C(O)N(R6)—, —N(R6)C(O)—, —S(O)2N(R6)— and —N(R6)S(O)2—. In a third aspect of that embodiment, Q represents an optionally substituted straight or branched C1-6alkylene chain comprising two heteroatom-containing linkages independently selected from —O—, —S—, —S(O)—, —S(O)2—, —N(R6)—, —C(O)N(R6)—, —N(R6)C(O)—, —S(O)2N(R6)— and —N(R6)S(O)2—. In a fourth aspect of that embodiment, Q represents an optionally substituted straight or branched C1-6alkylene chain comprising three heteroatom-containing linkages independently selected from —O—, —S—, —S(O)—, —S(O)2—, —N(R6)—, —C(O)N(R6)—, —N(R6)C(O)—, —S(O)2N(R6)— and —N(R6)S(O)2—. In a fifth aspect of that embodiment, Q represents an optionally substituted straight or branched C1-6alkylene chain comprising one, two or three heteroatom-containing linkages independently selected from —O—, —S—, —N(R6)—, —C(O)N(R6)— and —N(R6)C(O)—.

Typically, Q represents a covalent bond; or Q represents —S(O)— or —S(O)2—; or Q represents an optionally substituted straight or branched C1-6alkylene chain optionally comprising one or two heteroatom-containing linkages selected from —O—, —S—, —N(R6)—, —C(O)N(R6)—, and —N(R6)C(O)—.

Selected examples of typical substituents on the linkage represented by Q include halogen, trifluoromethyl, hydroxy, C1-6alkoxy and amino. An additional example is cyano.

Selected examples of suitable substituents on the linkage represented by Q include cyano, hydroxy and C1-6alkoxy.

Specific examples of typical substituents on the linkage represented by Q include fluoro, trifluoromethyl, hydroxy, methoxy and amino. An additional example is cyano.

Specific examples of suitable substituents on the linkage represented by Q include cyano, hydroxy and methoxy.

Particular values of Q include —CH2—, —CH(OH)—, —CH2O—, —CH2S— and —CH2OCH2—. In a first embodiment, Q represents —CH2—. In a second embodiment, Q represents —CH(OH)—. In a third embodiment, Q represents —CH2O—. In a fourth embodiment, Q represents —CH2S—. In a fifth embodiment, Q represents —CH2OCH2—.

Generally, Y represents C3-7cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

Typically, Y represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.

In a first embodiment, Y represents optionally substituted C3-7cycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C3-7cycloalkyl. In another aspect of that embodiment, Y represents monosubstituted C3-7cycloalkyl. In a further aspect of that embodiment, Y represents disubstituted C3-7cycloalkyl.

In a second embodiment, Y represents optionally substituted aryl. In one aspect of that embodiment, Y represents unsubstituted aryl. In another aspect of that embodiment, Y represents monosubstituted aryl. In a further aspect of that embodiment, Y represents disubstituted aryl.

In a third embodiment, Y represents optionally substituted C3-7heterocycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C3-7heterocycloalkyl. In another aspect of that embodiment, Y represents monosubstituted C3-7heterocycloalkyl.

In a further aspect of that embodiment, Y represents disubstituted C3-7heterocycloalkyl. In a fourth embodiment, Y represents optionally substituted heteroaryl. In one aspect of that embodiment, Y represents unsubstituted heteroaryl. In another aspect of that embodiment, Y represents monosubstituted heteroaryl. In a further aspect of that embodiment, Y represents disubstituted heteroaryl.

Suitably, Y represents benzocyclobutenyl, phenyl, thienyl, thiazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.

Appropriately, Y represents phenyl, thienyl or thiazolyl, any of which groups may be optionally substituted by one or more substituents.

Appositely, Y represents phenyl, which may be optionally substituted by one or more substituents.

Selected examples of optional substituents on the moiety Y include halogen, C1-6alkyl, difluoromethoxy and (C1-6)alkylsulfonyloxy.

Typical examples of optional substituents on the moiety Y include halogen, C1-6alkyl and difluoromethoxy.

Selected examples of particular substituents on the moiety Y include fluoro, chloro, methyl, difluoromethoxy and methylsulfonyloxy.

Typical examples of particular substituents on the moiety Y include chloro, methyl and difluoromethoxy.

Suitable values of Y include dichlorophenyl, dimethylphenyl, (difluoromethoxy)-phenyl, methylthienyl and dimethylthiazolyl.

In one embodiment, Y represents 2,5-dichlorophenyl.

In another embodiment, Y represents 2,5-dimethylphenyl.

In a particular embodiment, Y represents 2-(difluoromethoxy)phenyl.

In another embodiment, Y represents (difluoromethoxy)(fluoro)phenyl.

In another embodiment, Y represents 3-methylthien-2-yl.

In another embodiment, Y represents 2,4-dimethyl-1,3-thiazol-5-yl.

In one embodiment, Z represents hydrogen.

In another embodiment, Z is other than hydrogen.

In a selected embodiment, Z represents hydrogen; or Z represents C1-6alkyl, C3-7cycloalkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z1-Z2or —Z1—C(O)—Z2, either of which moieties may be optionally substituted by one or more substituents.

In a further embodiment, Z represents C1-6alkyl, C3-7cycloalkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z1-Z2or —Z—C(O)—Z2, either of which moieties may be optionally substituted by one or more substituents.

Suitably, Z represents hydrogen; or Z represents C1-6alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z1-Z2, which moiety may be optionally substituted by one or more substituents.

Appositely, Z represents hydrogen; or Z represents methyl, phenyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z1-Z2, which moiety may be optionally substituted by one or more substituents.

The moiety Z1represents a divalent radical derived from an aryl, C3-7heterocycloalkyl or heteroaryl group, any of which groups may be optionally substituted by one or more substituents. Typically, the moiety Z1represents a divalent radical derived from a phenyl, pyrrolidinyl, piperazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl or pyridinyl group, any of which groups may be optionally substituted by one or more substituents. Typical values of the moiety Z1include the groups of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh) and (Zj):

wherein

the symbols # represent the points of attachment of the moiety Z1to the remainder of the molecule; and

the asterisks (*) represent the site of attachment of optional substituents.

Additional values of the moiety Z1include the group of formula (Zk):

wherein

# and * are as defined above.

Particular values of the moiety Z1include the groups of formula (Za), (Zc), (Ze), (Zf), (Zg), (Zh) and (Zj) as depicted above.

The moiety Z2represents aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents. Typically, Z2represents phenyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, morpholinyl, imidazolinyl, thiazolyl, imidazolyl, tetrazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of optional substituents on the moiety Z, Z1or Z2include oxo and C1-6alkylsulfonyl.

Selected examples of optional substituents on the moiety Z, Z1or Z2include oxo and methylsulfonyl.

Selected values of Z2include oxopyrrolidinyl and (oxo)oxazolidinyl. In one embodiment, Z2represents oxopyrrolidinyl. In another embodiment, Z2represents (oxo)oxazolidinyl.

Particular values of Z include hydrogen, methyl, methylsulfonylphenyl, pyridinyl, oxopyrrolidinylphenyl, (hydroxy)(oxo)pyrrolidinylphenyl and (oxo)oxazolidinylphenyl. Additionally, Z may represent methylsulfonylpyridinyl. In a first embodiment, Z represents hydrogen. In a second embodiment, Z represents methyl. In a third embodiment, Z represents methylsulfonylphenyl. In one aspect of that embodiment, Z represents 3-(methylsulfonyl)phenyl. In another aspect of that embodiment, Z represents 4-(methylsulfonyl)phenyl. In a fourth embodiment, Z represents pyridinyl. In one aspect of that embodiment, Z represents pyridin-4-yl. In a fifth embodiment, Z represents oxopyrrolidinylphenyl. In one aspect of that embodiment, Z represents 3-(2-oxopyrrolidin-1-yl)phenyl. In a sixth embodiment, Z represents (hydroxy)(oxo)pyrrolidinylphenyl. In one aspect of that embodiment, Z represents 3-(3-hydroxy-2-oxopyrrolidin-1-yl)phenyl. In another aspect of that embodiment, Z represents 3-(4-hydroxy-2-oxopyrrolidin-1-yl)phenyl. In a seventh embodiment, Z represents (oxo)oxazolidinylphenyl. In one aspect of that embodiment, Z represents 3-(2-oxo-oxazolidinyl-3-yl)phenyl. In an eighth embodiment, Z represents methylsulfonylpyridinyl.

Suitably, R1, R2, R3and R4independently represent hydrogen, halogen, cyano, trifluoromethyl or —CO2Rd; or C1-6alkyl, C2-6alkynyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)cycloalkyl-heteroaryl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1, R2, R3and R4may independently represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9)bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

By the expression “carboxylic acid isostere or prodrug moiety” is meant any functional group, structurally distinct from a carboxylic acid moiety, that will be recognised by a biological system as being similar to, and thus capable of mimicking, a carboxylic acid moiety, or will be readily convertible by a biological system in vivo into a carboxylic acid moiety. A synopsis of some common carboxylic acid isosteres is presented by N. A. Meanwell inJ. Med. Chem.,2011, 54, 2529-2591 (cf. in particular FIGS. 25 and 26). Typical examples of suitable carboxylic acid isostere or prodrug moieties represented by Ω include the functional groups of formula (i) to (xli):

wherein

the asterisk (*) represents the site of attachment to the remainder of the molecule;

n is zero, 1 or 2;

X represents oxygen or sulphur;

Rhrepresents hydrogen, cyano or —CO2Rd, in which Rdis as defined above; and

In one embodiment, n is zero. In another embodiment, n is 1. In a further embodiment, n is 2.

In one embodiment, X represents oxygen. In another embodiment, X represents sulphur.

In one embodiment, Rgrepresents C1-6alkyl, especially methyl. In another embodiment, Rgrepresents trifluoromethyl, —CH2CH2F, —CH2CHF2, —CH2CF3or —CF2CF3. In a first aspect of that embodiment, Rgrepresents trifluoromethyl. In a second aspect of that embodiment, Rgrepresents —CH2CH2F. In a third aspect of that embodiment, Rgrepresents —CH2CHF2. In a fourth aspect of that embodiment, Rgrepresents —CH2CF3. In a fifth aspect of that embodiment, Rgrepresents —CF2CF3.

In a selected embodiment, Ω represents tetrazolyl, especially a C-linked tetrazolyl moiety of formula (xxiv) or (xxv) as depicted above, in particular a group of formula (xxiv) as depicted above.

In another embodiment, Ω represents C1-6alkylsulphonylaminocarbonyl, i.e. a moiety of formula (iii) as depicted above wherein Rgrepresents C1-6alkyl.

In another embodiment, Ω represents C1-6alkylaminosulphonyl, i.e. a moiety of formula (x) as depicted above wherein Rgrepresents C1-6alkyl.

In a further embodiment, Ω represents (C1-6)alkylcarbonylaminosulphonyl, i.e. a moiety of formula (v) as depicted above wherein Rgrepresents C1-6alkyl.

Additional examples of suitable carboxylic acid isostere or prodrug moieties represented by Ω include the functional group of formula (xlii):

wherein

the asterisk (*) represents the site of attachment to the remainder of the molecule.

Typical examples of optional substituents which may be present on R1, R2, R3or R4include one, two or three substituents independently selected from C1-6alkyl, hydroxy, C1-6alkoxy, oxo, amino, C1-6alkylsulphonylamino, carboxy and C2-6alkoxycarbonyl.

Typically, R1represents hydrogen, halogen, cyano or —CO2Rd; or C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl-(C1-6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent C2-6alkynyl or (C3-7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9)bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

Suitably, R1represents halogen, cyano or —CO2Rd; or C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent C2-6alkynyl or (C3-7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9)bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

Generally, R1represents halogen or cyano; or C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent C2-6alkynyl or (C3-7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9)bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

More generally, R1represents halogen or cyano; or C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent C2-6alkynyl, (C3-7)cycloalkyl-heteroaryl- or (C4-7)cycloalkenyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9)bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

Still more generally, R1represents C1-6alkyl, C2-6alkynyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)cycloalkyl-heteroaryl-, (C4-7)-cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9)bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

Even more generally, R1represents C1-6alkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl-heteroaryl- or (C4-9)heterobicycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.

In a first embodiment, R1represents hydrogen.

In a second embodiment, R1represents halogen. In one aspect of that embodiment, R1represents bromo.

In a third embodiment, R1represents cyano.

In a fourth embodiment, R1represents —CO2Rd.

In a fifth embodiment, R1represents optionally substituted C1-6alkyl. In one aspect of that embodiment, R1represents optionally substituted ethyl.

In a sixth embodiment, R1represents optionally substituted C2-6alkynyl. In one aspect of that embodiment, R1represents optionally substituted butynyl.

In a seventh embodiment, R1represents optionally substituted aryl. In one aspect of that embodiment, R1represents optionally substituted phenyl.

In an eighth embodiment, R1represents optionally substituted C3-7heterocycloalkyl.

In a ninth embodiment, R1represents optionally substituted C3-7heterocycloalkenyl.

In a tenth embodiment, R1represents optionally substituted heteroaryl. In selected aspects of that embodiment, R1represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents. In a further aspect, R1represents optionally substituted thiazolyl.

In an eleventh embodiment, R1represents optionally substituted (C3-7)-heterocycloalkyl(C1-6)alkyl-aryl-. In a first aspect of that embodiment, R1represents optionally substituted pyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R1represents optionally substituted piperazinylmethylphenyl-.

In a twelfth embodiment, R1represents optionally substituted heteroaryl(C3-7)-heterocycloalkyl-. In one aspect of that embodiment, R1represents optionally substituted pyridinylpiperazinyl-.

In a thirteenth embodiment, R1represents optionally substituted (C3-7)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R1represents optionally substituted cyclohexylpyrazolyl-. In a second aspect of that embodiment, R1represents optionally substituted cyclohexylpyridinyl-. In a third aspect of that embodiment, R1represents optionally substituted cyclopropylpyrimidinyl-. In a fourth aspect of that embodiment, R1represents optionally substituted cyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R1represents optionally substituted cyclopentylpyrimidinyl-. In a sixth aspect of that embodiment, R1represents optionally substituted cyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R1represents optionally substituted cyclohexylpyrazinyl-.

In a fourteenth embodiment, R1represents optionally substituted (C4-7)-cycloalkenyl-heteroaryl-.

In a fifteenth embodiment, R1represents optionally substituted (C3-7)-heterocycloalkyl-heteroaryl-. In a first aspect of that embodiment, R1represents optionally substituted pyrrolidinylpyridinyl-. In a second aspect of that embodiment, R1represents optionally substituted tetrahydropyranylpyridinyl-. In a third aspect of that embodiment, R1represents optionally substituted piperidinylpyridinyl-. In a fourth aspect of that embodiment, R1represents optionally substituted piperazinylpyridinyl-. In a fifth aspect of that embodiment, R1represents optionally substituted morpholinylpyridinyl-. In a sixth aspect of that embodiment, R1represents optionally substituted thiomorpholinylpyridinyl-. In a seventh aspect of that embodiment, R1represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R1represents optionally substituted oxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R1represents optionally substituted azetidinylpyrimidinyl-. In a tenth aspect of that embodiment, R1represents optionally substituted tetrahydrofuranylpyrimidinyl-. In an eleventh aspect of that embodiment, R1represents optionally substituted pyrrolidinylpyrimidinyl-. In a twelfth aspect of that embodiment, R1represents optionally substituted tetrahydropyranylpyrimidinyl-. In a thirteenth aspect of that embodiment, R1represents optionally substituted piperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R represents optionally substituted piperazinylpyrimidinyl-. In a fifteenth aspect of that embodiment, R1represents optionally substituted morpholinylpyrimidinyl-. In a sixteenth aspect of that embodiment, R1represents optionally substituted thiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment, R1represents optionally substituted azepanylpyrimidinyl-. In an eighteenth aspect of that embodiment, R represents optionally substituted oxazepanylpyrimidinyl-. In a nineteenth aspect of that embodiment, R1represents optionally substituted diazepanylpyrimidinyl-. In a twentieth aspect of that embodiment, R1represents optionally substituted thiadiazepanylpyrimidinyl-. In a twenty-first aspect of that embodiment, R1represents optionally substituted piperidinylpyrazinyl-.

In a sixteenth embodiment, R1represents optionally substituted (C3-7)-heterocycloalkyl(C1-6)alkyl-heteroaryl-. In a first aspect of that embodiment, R1represents optionally substituted morpholinylmethylthienyl-. In a second aspect of that embodiment, R1represents optionally substituted morpholinylethylpyrazolyl-.

In a seventeenth embodiment, R1represents optionally substituted (C3-7)-heterocycloalkenyl-heteroaryl-.

In an eighteenth embodiment, R1represents optionally substituted (C4-9)-heterobicycloalkyl-heteroaryl-.

In a nineteenth embodiment, R1represents optionally substituted (C4-9)-spiroheterocycloalkyl-heteroaryl-.

In a twentieth embodiment, R1represents optionally substituted (C3-7)cycloalkyl-(C1-6)alkyl-heteroaryl-. In one aspect of that embodiment, R1represents optionally substituted cyclohexylmethylpyrimidinyl-.

Suitable examples of optional substituents on R1include one, two or three substituents independently selected from C1-6alkyl, hydroxy, C1-6alkoxy, oxo, amino, C1-6alkylsulphonylamino, carboxy and C2-6alkoxycarbonyl.

In a particular embodiment, R1is substituted by hydroxy(C1-6)alkyl. In one aspect of that embodiment, R1is substituted by hydroxyisopropyl, especially 2-hydroxyprop-2-yl.

Typical examples of optional substituents on R2include C2-6alkoxycarbonyl.

Typical examples of particular substituents on R2include ethoxycarbonyl.

In a first embodiment, R2represents hydrogen. In a second embodiment, R2represents halogen. In one aspect of that embodiment, R2represents fluoro. In another aspect of that embodiment, R2represents chloro. In a third embodiment, R2represents trifluoromethyl. In a fourth embodiment, R2represents optionally substituted C1-6alkyl. In one aspect of that embodiment, R2represents unsubstituted methyl. In another aspect of that embodiment, R2represents unsubstituted ethyl. In a further aspect of that embodiment, R2represents monosubstituted methyl or monosubstituted ethyl. In a fifth embodiment, R2represents —ORa.

Typical values of R2include hydrogen, fluoro, trifluoromethyl, methyl and ethoxycarbonylethyl. Additional values include chloro and —ORa.

Suitable values of R2include hydrogen, fluoro, trifluoromethyl and methyl. Additional values include chloro and —ORa.

In a first embodiment, R3represents hydrogen. In a second embodiment, R3represents halogen. In one aspect of that embodiment, R3represents fluoro. In a third embodiment, R3represents C1-6alkyl. In one aspect of that embodiment, R3represents methyl. In another aspect of that embodiment, R3represents ethyl.

In a particular embodiment, R4represents hydrogen.

In a first embodiment, R5represents hydrogen. In a second embodiment, R5represents C1-6alkyl, especially methyl.

In a first embodiment, R6represents hydrogen. In a second embodiment, R6represents C1-6alkyl, especially methyl or ethyl. In one aspect of that embodiment, R6represents methyl. In another aspect of that embodiment, R6represents ethyl.

Suitably, Rarepresents C1-6alkyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Selected values of Rainclude methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on Rainclude C1-6alkoxy and oxo.

Selected examples of specific substituents on Rainclude methoxy and oxo.

In one embodiment, Rarepresents optionally substituted C1-6alkyl. In one aspect of that embodiment, Raideally represents unsubstituted C1-6alkyl, especially methyl. In another aspect of that embodiment, Raideally represents substituted C1-6alkyl, e.g. methoxyethyl. In another embodiment, Rarepresents optionally substituted aryl. In one aspect of that embodiment, Rarepresents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Rarepresents monosubstituted aryl, especially methylphenyl. In another embodiment, Rarepresents optionally substituted aryl(C1-6)alkyl, ideally unsubstituted aryl(C1-6)alkyl, especially benzyl. In a further embodiment, Rarepresents optionally substituted heteroaryl. In a further embodiment, Rarepresents optionally substituted heteroaryl(C1-6)alkyl, e.g. dioxoisoindolylpropyl.

Specific values of Rainclude methyl, methoxyethyl, benzyl and dioxoisoindolylpropyl.

In a particular aspect, Rbrepresents hydrogen or trifluoromethyl; or C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7heterocycloalkyl, C3-7heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Selected values of Rbinclude hydrogen; or C1-6alkyl, aryl(C1-6)alkyl, C3-7heterocycloalkyl or C3-7heterocycloalkyl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Typical values of Rbinclude hydrogen and C1-6alkyl.

Representative values of Rbinclude hydrogen; or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.

Selected values of Rcinclude hydrogen; or C1-6alkyl, C3-7cycloalkyl or C3-7heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.

Representative values of Rcinclude hydrogen; or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on Rcinclude C2-6alkylcarbonyl and C2-6alkoxycarbonyl.

Selected examples of specific substituents on Rcinclude acetyl and tert-butoxycarbonyl.

Suitably, Rdrepresents hydrogen; or C1-6alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable values for Rdinclude hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.

Suitably, Rerepresents C1-6alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on Reinclude C1-6alkyl, especially methyl.

In one embodiment, Rerepresents optionally substituted C1-6alkyl, ideally unsubstituted C1-6alkyl, e.g. methyl or propyl, especially methyl. In another embodiment, Rerepresents optionally substituted aryl. In one aspect of that embodiment, Rerepresents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Rerepresents monosubstituted aryl, especially methylphenyl. In a further embodiment, Rerepresents optionally substituted heteroaryl.

Selected values of Reinclude methyl, propyl and methylphenyl.

One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:

wherein

E, Q and Z are as defined above.

The present invention also provides a compound of formula (IIA) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

The present invention also provides a compound of formula (IIA) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

R11represents halogen or cyano; or C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl-(C3-7)heterocycloalkyl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents; and

Aptly, R11represents halogen or cyano; or C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl-(C3-7)heterocycloalkyl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl-(C1-6)alkyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11may represent C2-6alkynyl, (C3-7)cycloalkyl-heteroaryl- or (C4-7)cycloalkenyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9) bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

Generally, R11represents C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl-(C3-7)heterocycloalkyl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11may represent C2-6alkynyl or (C3-7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R11may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9) bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

More generally, R11represents C1-6alkyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl-(C3-7)heterocycloalkyl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl-(C1-6)alkyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spirohetero-cycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11may represent C2-6alkynyl, (C3-7)cycloalkyl-heteroaryl- or (C4-7)cycloalkenyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9) bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

Still more generally, R11represents C1-6alkyl, C2-6alkynyl, aryl, C3-7heterocycloalkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)cycloalkyl-heteroaryl-, (C4-7)-cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11may represent (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl- or (C4-9) bicycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.

Even more generally, R11represents C1-6alkyl, C3-7heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl-heteroaryl- or (C4-9)heterobicycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.

In a first embodiment, R11represents halogen. In one aspect of that embodiment, R11represents bromo.

In a second embodiment, R11represents cyano.

In a third embodiment, R11represents optionally substituted C1-6alkyl. In one aspect of that embodiment, R11represents optionally substituted ethyl.

In a fourth embodiment, R11represents optionally substituted C2-6alkynyl. In one aspect of that embodiment, R11represents optionally substituted butynyl.

In a fifth embodiment, R11represents optionally substituted aryl. In one aspect of that embodiment, R11represents optionally substituted phenyl.

In a sixth embodiment, R11represents optionally substituted C3-7heterocycloalkyl.

In a seventh embodiment, R11represents optionally substituted C3-7heterocycloalkenyl.

In an eighth embodiment, R11represents optionally substituted heteroaryl. In selected aspects of that embodiment, R11represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents. In a further aspect, R11represents optionally substituted thiazolyl.

In a ninth embodiment, R11represents optionally substituted (C3-7)-heterocycloalkyl(C1-6)alkyl-aryl-. In a first aspect of that embodiment, R11represents optionally substituted pyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R11represents optionally substituted piperazinylmethylphenyl-.

In a tenth embodiment, R11represents optionally substituted heteroaryl(C3-7)-heterocycloalkyl-. In one aspect of that embodiment, R11represents optionally substituted pyridinylpiperazinyl-.

In an eleventh embodiment, R11represents optionally substituted (C3-7)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R11represents optionally substituted cyclohexylpyrazolyl-. In a second aspect of that embodiment, R11represents optionally substituted cyclohexylpyridinyl-. In a third aspect of that embodiment, R11represents optionally substituted cyclopropylpyrimidinyl-. In a fourth aspect of that embodiment, R11represents optionally substituted cyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R11represents optionally substituted cyclopentylpyrimidinyl-. In a sixth aspect of that embodiment, R11represents optionally substituted cyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R11represents optionally substituted cyclohexylpyrazinyl-.

In a twelfth embodiment, R11represents optionally substituted (C4-7)cycloalkenyl-heteroaryl-.

In a thirteenth embodiment, R11represents optionally substituted (C3-7)-heterocycloalkyl-heteroaryl-. In a first aspect of that embodiment, R11represents optionally substituted pyrrolidinylpyridinyl-. In a second aspect of that embodiment, R11represents optionally substituted tetrahydropyranylpyridinyl-. In a third aspect of that embodiment, R11represents optionally substituted piperidinylpyridinyl-. In a fourth aspect of that embodiment, R11represents optionally substituted piperazinylpyridinyl-. In a fifth aspect of that embodiment, R11represents optionally substituted morpholinylpyridinyl-. In a sixth aspect of that embodiment, R11represents optionally substituted thiomorpholinylpyridinyl-. In a seventh aspect of that embodiment, R11represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R11represents optionally substituted oxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R11represents optionally substituted azetidinylpyrimidinyl-. In a tenth aspect of that embodiment, R11represents optionally substituted tetrahydrofuranylpyrimidinyl-. In an eleventh aspect of that embodiment, R11represents optionally substituted pyrrolidinylpyrimidinyl-. In a twelfth aspect of that embodiment, R11represents optionally substituted tetrahydropyranylpyrimidinyl-. In a thirteenth aspect of that embodiment, R11represents optionally substituted piperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R11represents optionally substituted piperazinylpyrimidinyl-. In a fifteenth aspect of that embodiment, R11represents optionally substituted morpholinylpyrimidinyl-. In a sixteenth aspect of that embodiment, R11represents optionally substituted thiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment, R11represents optionally substituted azepanylpyrimidinyl-. In an eighteenth aspect of that embodiment, R11represents optionally substituted oxazepanylpyrimidinyl-. In a nineteenth aspect of that embodiment, R11represents optionally substituted diazepanylpyrimidinyl-. In a twentieth aspect of that embodiment, R11represents optionally substituted thiadiazepanylpyrimidinyl-. In a twenty-first aspect of that embodiment, R11represents optionally substituted piperidinylpyrazinyl-.

In a fourteenth embodiment, R11represents optionally substituted (C3-7)-heterocycloalkyl(C1-6)alkyl-heteroaryl-. In a first aspect of that embodiment, R11represents optionally substituted morpholinylmethylthienyl-. In a second aspect of that embodiment, R11represents optionally substituted morpholinylethylpyrazolyl-.

In a fifteenth embodiment, R11represents optionally substituted (C3-7)-heterocycloalkenyl-heteroaryl-.

In a sixteenth embodiment, R11represents optionally substituted (C4-9)-heterobicycloalkyl-heteroaryl-.

In a seventeenth embodiment, R11represents optionally substituted (C4-9)-spiroheterocycloalkyl-heteroaryl-.

In an eighteenth embodiment, R11represents optionally substituted (C3-7)-cycloalkyl(C1-6)alkyl-heteroaryl-. In one aspect of that embodiment, R11represents optionally substituted cyclohexylmethylpyrimidinyl-.

In a nineteenth embodiment, R11represents optionally substituted (C4-9)-bicycloalkyl-heteroaryl-.

Suitable examples of optional substituents on R11include one, two or three substituents independently selected from C1-6alkyl, hydroxy, C1-6alkoxy, oxo, amino, C1-6alkylsulphonylamino, carboxy and C2-6alkoxycarbonyl.

In a particular embodiment, R11is substituted by hydroxy(C1-6)alkyl. In one aspect of that embodiment, R11is substituted by hydroxyisopropyl, especially 2-hydroxyprop-2-yl.

Typical examples of optional substituents on R12include C2-6alkoxycarbonyl.

Typical examples of particular substituents on R12include ethoxycarbonyl.

In a first embodiment, R12represents hydrogen. In a second embodiment, R12represents halogen. In one aspect of that embodiment, R12represents fluoro. In another aspect of that embodiment, R12represents chloro. In a third embodiment, R12represents trifluoromethyl. In a fourth embodiment, R12represents optionally substituted C1-6alkyl. In one aspect of that embodiment, R12represents unsubstituted methyl. In another aspect of that embodiment, R12represents unsubstituted ethyl. In a further aspect of that embodiment, R12represents monosubstituted methyl or monosubstituted ethyl.

In a first embodiment, R15represents hydrogen. In a second embodiment, R15represents halogen. In a first aspect of that embodiment, R15represents fluoro. In a second aspect of that embodiment, R15represents chloro. In a third embodiment, R15represents C1-6alkyl. In one aspect of that embodiment, R15represents methyl. In a fourth embodiment, R15represents trifluoromethyl. In a fifth embodiment, R15represents C1-6alkoxy. In one aspect of that embodiment, R15represents methoxy. In a sixth embodiment, R15represents difluoromethoxy. In a seventh embodiment, R15represents trifluoromethoxy.

Suitable values of R15include chloro, methyl and difluoromethoxy.

Illustrative values of R16include hydrogen, halogen and C1-6alkyl.

In a first embodiment, R16represents hydrogen. In a second embodiment, R16represents halogen. In a first aspect of that embodiment, R16represents fluoro. In a second aspect of that embodiment, R16represents chloro. In a third embodiment, R16represents C1-6alkyl. In one aspect of that embodiment, R16represents methyl. In a fourth embodiment, R16represents trifluoromethyl. In a fifth embodiment, R16represents difluoromethoxy. In a seventh embodiment, R16represents amino.

Suitable values of R16include hydrogen, chloro and methyl.

In a particular embodiment, R16is attached at the para-position of the phenyl ring relative to the integer R15.

A particular sub-group of the compounds of formula (IIA) above is represented by the compounds of formula (IIB) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:

wherein

The present invention also provides a compound of formula (IIB) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

R23represents hydrogen or C1-6alkyl; and

The present invention also provides a compound of formula (IIB) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, wherein

In one embodiment, V represents C—R22. In another embodiment, V represents N.

Suitably, R21represents hydroxy or C1-6alkoxy; or R21represents (C3-7)heterocycloalkyl or (C4-9)heterobicycloalkyl, either of which groups may be optionally substituted by one or more substituents.

Where R21represents an optionally substituted (C3-7)cycloalkyl group, typical values include cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, any of which groups may be optionally substituted by one or more substituents. An additional value is cyclopropyl.

Where R21represents an optionally substituted (C3-7)cycloalkyl(C1-6)alkyl group, a typical value is cyclohexylmethyl, which group may be optionally substituted by one or more substituents.

Where R21represents an optionally substituted (C4-7)cycloalkenyl group, typical values include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, any of which groups may be optionally substituted by one or more substituents.

Where R21represents an optionally substituted (C4-9)bicycloalkyl group, typical values include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl, any of which groups may be optionally substituted by one or more substituents.

Where R21represents an optionally substituted (C3-7)heterocycloalkyl group, typical values include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepanyl and thiadiazepanyl, any of which groups may be optionally substituted by one or more substituents. Additional values include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, azepanyl and oxazepanyl, any of which groups may be optionally substituted by one or more substituents.

Where R21represents an optionally substituted (C3-7)heterocycloalkenyl group, a typical value is optionally substituted 1,2,3,6-tetrahydropyridinyl.

Where R21represents an optionally substituted (C4-9)heterobicycloalkyl group, typical values include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl and 3,9-diazabicyclo[4.2.1]nonanyl, any of which groups may be optionally substituted by one or more substituents. Additional values include 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]-nonanyl and 3-oxa-7-azabicyclo[3.3.1]nonanyl, any of which groups may be optionally substituted by one or more substituents.

Where R21represents an optionally substituted (C4-9)spiroheterocycloalkyl group, typical values include 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.5]nonanyl and 2-oxa-7-azaspiro[3.5]nonanyl, any of which groups may be optionally substituted by one or more substituents. Additional values include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl and 2,4,8-triazaspiro[4.5]-decanyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of particular substituents on R21include one, two or three substituents independently selected from oxo and carboxy.

In a particular embodiment, R21represents hydroxy(C1-6)alkyl. In one aspect of that embodiment, R21represents hydroxyisopropyl, especially 2-hydroxyprop-2-yl.

In one embodiment, R22represents hydrogen. In another embodiment, R22represents C1-6alkyl, especially methyl. In a further embodiment, R22represents halogen. In one aspect of that embodiment, R22represents fluoro. In another aspect of that embodiment, R22represents chloro.

Particular sub-groups of the compounds of formula (IIB) above are represented by the compounds of formula (IIC), (IID) and (IIE) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:

wherein

T represents —CH2— or —CH2CH2—;

U represents C(O) or S(O)2;

In a first embodiment, T represents —CH2—. In a second embodiment, T represents —CH2CH2—.

In a first embodiment, U represents C(O). In a second embodiment, U represents S(O)2.

In a first embodiment, W represents O. In a second embodiment, W represents S. In a third embodiment, W represents S(O). In a fourth embodiment, W represents S(O)2. In a fifth embodiment, W represents N(R31). In a sixth embodiment, W represents C(R32)(R33).

In a first aspect of the sixth embodiment, W represents CF2. In a second aspect of the sixth embodiment, W represents CH(CO2H). In a third aspect of the sixth embodiment, W represents CH(tetrazolyl).

Suitable values of R31include hydrogen, carboxyethyl and tetrazolylmethyl.

A particular value of R31is hydrogen.

In a selected embodiment, R32represents carboxy.

In a first embodiment, R33represents hydrogen. In a second embodiment, R33represents halogen. In one aspect of that embodiment, R33represents fluoro. In a third embodiment, R33represents C1-6alkyl. In a first aspect of that embodiment, R33represents methyl. In a second aspect of that embodiment, R33represents ethyl. In a third aspect of that embodiment, R33represents isopropyl. In a fourth embodiment, R33represents trifluoromethyl. In a fifth embodiment, R33represents hydroxy. In a sixth embodiment, R33represents hydroxy(C1-6)alkyl. In one aspect of that embodiment, R33represents hydroxymethyl. In a seventh embodiment, R33represents C1-6alkoxy. In one aspect of that embodiment, R33represents methoxy. In an eighth embodiment, R33represents amino. In a ninth embodiment, R33represents carboxy.

Another sub-group of the compounds of formula (IIB) above is represented by the compounds of formula (IIF) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:

wherein

In a first embodiment, R34represents hydrogen. In a second embodiment, R34represents halogen. In one aspect of that embodiment, R34represents fluoro. In a third embodiment, R34represents halo(C1-6)alkyl. In one aspect of that embodiment, R34represents fluoromethyl. In a fourth embodiment, R34represents hydroxy. In a fifth embodiment, R34represents C1-6alkoxy, especially methoxy. In a sixth embodiment, R34represents C1-6alkylthio, especially methylthio. In a seventh embodiment, R34represents C1-6alkylsulphinyl, especially methylsulphinyl. In an eighth embodiment, R34represents C1-6alkylsulphonyl, especially methylsulphonyl. In a ninth embodiment, R34represents amino. In a tenth embodiment, R34represents C1-6alkylamino, especially methylamino. In an eleventh embodiment, R34represents di(C1-6)alkylamino, especially dimethylamino. In a twelfth embodiment, R34represents (C2-6)alkylcarbonylamino, especially acetylamino. In a thirteenth embodiment, R34represents (C2-6)alkylcarbonylamino(C1-6)alkyl, especially acetylaminomethyl. In a fourteenth embodiment, R34represents (C1-6)alkylsulphonylamino, especially methylsulphonylamino. In a fifteenth embodiment, R34represents (C1-6)alkylsulphonylamino(C1-6)alkyl, especially methylsulphonylaminomethyl.

Further sub-groups of the compounds of formula (IIB) above are represented by the compounds of formula (IIG), (IIH), (IIJ), (IIK) and (IIL) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:

wherein

-M- represents —CH2— or —CH2CH2—; and

An alternative sub-class of compounds according to the invention is represented by the compounds of formula (IIM) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:

wherein

With specific reference to formula (IIM), the integer W is suitably O, S or N—R31, especially S or N—R31.

Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof, and co-crystals thereof.

The compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g. during heart failure), and sexual disorders (including erectile dysfunction and female sexual dysfunction). Modulators of TNFα function may also be of use in the treatment and/or prevention of myocardial infarction (see J. J. Wu et al.,JAMA,2013, 309, 2043-2044).

Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.

The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

The compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

In addition to the formulations described above, the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.

For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

For topical administration the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.

For ophthalmic administration the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum.

For rectal administration the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

The quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.

If desired, a compound in accordance with the present invention may be co-administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule such as methotrexate or prednisolone.

The compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):

The leaving group L1is typically a halogen atom, e.g. bromo.

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a C1-4alkanol such as ethanol, or a cyclic ether such as 1,4-dioxane.

The compounds of formula (I) above wherein E represents —C(O)— may be prepared by a process which comprises reacting a compound of formula (V) with a compound of formula (VI):

The leaving group L2is typically a halogen atom, e.g. bromo.

The reaction is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, a hydrocarbon solvent such as toluene, or a C1-4alkanol such as ethanol.

The intermediates of formula (V) above may be prepared by reacting a compound of formula (III) as defined above with a compound of formula (VII):

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a hydrocarbon solvent such as toluene, or a C1-4alkanol such as methanol.

The compounds of formula (I) above wherein E represents —CH(OH)— may be prepared by a process which comprises reacting a compound of formula Y—MgHal with a compound of formula (VIII):

The halogen atom Hal is typically bromo.

The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

The intermediates of formula (VIII) above may be prepared by treating a compound of formula (IX):

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.

The compounds of formula (I) above wherein E represents —CH2— and Y represents optionally substituted aryl or heteroaryl may be prepared by a process which comprises reacting a compound of formula Y1—H with a compound of formula (X):

wherein Q, Z, R1, R2, R3and R4are as defined above, and Y1represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; in the presence of a sulfonic acid derivative.

The sulfonic acid derivative of use in the foregoing reaction is suitably an organic sulfonic acid derivative such as methanesulfonic acid. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. water.

The intermediates of formula (X) above may be prepared by treating a compound of formula (IX) as defined above with formaldehyde. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. water.

The intermediates of formula (IX) above may be prepared by reacting a compound of formula (III) as defined above with a compound of formula (XI):

wherein Q, Z and L1are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).

The compounds of formula (I) above wherein -Q-Z represents —CH2OH may be prepared by a process which comprises treating a compound of formula (XII):

The reducing agent of use in the foregoing reaction is suitably an alkali metal borohydride such as lithium borohydride. The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or a C1-4alkanol such as methanol, or a mixture thereof.

Alternatively, the reducing agent of use in the foregoing reaction may suitably be diisobutylaluminium hydride. The reaction is conveniently effected at a temperature in the region of 0° C. in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

The intermediates of formula (XII) above may be prepared by reacting a compound of formula (III) as defined above with a compound of formula (XIII):

wherein E, Y, Rzand L1are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).

The compounds of formula (I) above wherein E represents —N(H)— may be prepared by a process which comprises reacting a compound of formula (III) as defined above with an isocyanide derivative of formula Y—NC and an aldehyde derivative of formula OHC-Q-Z; in the presence of a transition metal catalyst.

The transition metal catalyst of use in the foregoing reaction is suitably a zirconium derivative, e.g. a zirconium halide such as zirconium(IV) chloride. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a C1-4alkanol such as n-butanol.

The compounds of formula (I) above wherein Q represents —CH2N(H)— may be prepared by a process which comprises reacting a compound of formula Z—NH2with a compound of formula (XIV):

wherein E, Y, R1, R2, R3and R4are as defined above; in the presence of a reducing agent.

The reducing agent of use in the above reaction is suitably sodium borohyride.

The intermediates of formula (XIV) may be prepared from the corresponding compound of formula (I) wherein Q-Z represents —CH2OH by treatment with an oxidising agent such as Dess-Martin periodinane.

Where they are not commercially available, the starting materials of formula (III), (IV), (VI), (VII), (XI) and (XIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of example, a compound of formula (I) wherein E represents —C(O)— may be converted into the corresponding compound wherein E represents —CH(OH)— by treatment with a reducing agent such as sodium borohydride.

A compound of formula (I) wherein E represents —CH(OH)— may be converted into the corresponding compound wherein E represents —CH2— by heating with elemental iodine and phosphinic acid in acetic acid; or by treating with triethylsilane and an acid, e.g. an organic acid such as trifluoroacetic acid, or a Lewis acid such as boron trifluoride diethyl etherate; or by a two-step procedure which comprises: (i) treatment with thionyl bromide; and (ii) treatment of the product thereby obtained with a transition metal catalyst, e.g. (2,2′-bipyridine)dichlororuthenium(II) hydrate, in the presence of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (Hantzsch ester) and a base, e.g. an organic base such as N,N-diisopropylethylamine.

A compound of formula (I) wherein E represents —CH2— may be converted into the corresponding compound wherein E represents —CH(CH3)— by treatment with a methyl halide, e.g. methyl iodide, in the presence of a base such as lithium hexamethyldisilazide.

A compound of formula (I) which contains a hydroxy group may be alkylated by treatment with the appropriate alkyl halide in the presence of a base, e.g. sodium hydride, or silver oxide. A compound of formula (I) wherein -Q-Z represents —CH2OH may be arylated in a two-step procedure which comprises: (i) treatment with thionyl chloride; and (ii) treatment of the chloro derivative thereby obtained with the appropriate aryl or heteroaryl hydroxide. A compound of formula (I) wherein -Q-Z represents —CH2OH may be converted into the corresponding compound of formula (I) wherein -Q-Z represents —CH2S—Z via a two-step procedure which comprises: (i) treatment with thionyl chloride; and (ii) treatment of the chloro derivative thereby obtained with a compound of formula Z—SH, typically in the presence of a base, e.g. an inorganic base such as potassium carbonate. A compound of formula (I) wherein -Q-Z represents —CH2OH may be converted into the corresponding compound of formula (I) wherein -Q-Z represents —CH2CN via a two-step procedure which comprises: (i) treatment with thionyl chloride; and (ii) treatment of the chloro derivative thereby obtained with a cyanide salt such as sodium cyanide. A compound of formula (I) which contains hydroxy may be converted into the corresponding fluoro-substituted compound by treatment with diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (BAST). A compound of formula (I) which contains hydroxy may be converted into the corresponding difluoro-substituted compound via a two-step procedure which comprises: (i) treatment with an oxidising agent, e.g. manganese dioxide; and (ii) treatment of the carbonyl-containing compound thereby obtained with DAST.

A compound of formula (I) which contains an N—H moiety may be alkylated by treatment with the appropriate alkyl halide, typically at an elevated temperature in an organic solvent such as acetonitrile; or at ambient temperature in the presence of a base, e.g. an alkali metal carbonate such as potassium carbonate or cesium carbonate, in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide. Alternatively, a compound of formula (I) which contains an N—H moiety may be alkylated by treatment with the appropriate alkyl tosylate in the presence of a base, e.g. an inorganic base such as sodium hydride, or an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

A compound of formula (I) which contains an N—H moiety may be methylated by treatment with formaldehyde in the presence of a reducing agent, e.g. sodium triacetoxyborohydride.

A compound of formula (I) which contains an N—H moiety may be acylated by treatment with the appropriate acid chloride, e.g. acetyl chloride, or with the appropriate carboxylic acid anhydride, e.g. acetic anhydride, typically at ambient temperature in the presence of a base, e.g. an organic base such as triethylamine.

A compound of formula (I) which contains an N—H moiety may be converted into the corresponding compound wherein the nitrogen atom is substituted by C1-6alkylsulphonyl, e.g. methylsulphonyl, by treatment with the appropriate C1-6alkylsulphonic acid anhydride, e.g. methanesulphonic anhydride, typically at ambient temperature in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine.

A compound of formula (I) substituted by amino (—NH2) may be converted into the corresponding compound substituted by C1-6alkylsulphonylamino, e.g. methylsulphonylamino, or bis[(C1-6)alkylsulphonyl]amino, e.g. bis(methylsulphonyl)amino, by treatment with the appropriate C1-6alkylsulphonyl halide, e.g. a C1-6alkylsulphonyl chloride such as methanesulphonyl chloride. Similarly, a compound of formula (I) substituted by hydroxy (—OH) may be converted into the corresponding compound substituted by C1-6alkyl-sulphonyloxy, e.g. methylsulphonyloxy, by treatment with the appropriate C1-6alkylsulphonyl halide, e.g. a C1-6alkylsulphonyl chloride such as methanesulphonyl chloride.

A compound of formula (I) containing the moiety —S— may be converted into the corresponding compound containing the moiety —S(O)— by treatment with 3-chloroperoxybenzoic acid. Likewise, a compound of formula (I) containing the moiety —S(O)— may be converted into the corresponding compound containing the moiety —S(O)2— by treatment with 3-chloroperoxybenzoic acid. Alternatively, a compound of formula (I) containing the moiety —S— may be converted into the corresponding compound containing the moiety —S(O)2— by treatment with Oxone® (potassium peroxymonosulfate).

A compound of formula (I) containing an aromatic nitrogen atom may be converted into the corresponding N-oxide derivative by treatment with 3-chloroperoxybenzoic acid.

A bromophenyl derivative of formula (I) may be converted into the corresponding optionally substituted 2-oxopyrrolidin-1-ylphenyl or 2-oxooxazolidin-3-ylphenyl derivative by treatment with pyrrolidin-2-one or oxazolidin-2-one, or an appropriately substituted analogue thereof. The reaction is conveniently effected at an elevated temperature in the presence of copper(I) iodide, trans-N,N′-dimethylcyclohexane-1,2-diamine and an inorganic base such as potassium carbonate.

A compound of formula (I) wherein R1represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1represents an optionally substituted aryl or heteroaryl moiety by treatment with the appropriately substituted aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol. The reaction is typically effected in the presence of a transition metal catalyst, e.g. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tetrakis(triphenylphosphine)palladium(0), or bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex, or tetrakis(triphenylphosphine)palladium(0), and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate, or potassium phosphate.

A compound of formula (I) wherein R1represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1represents an optionally substituted aryl, heteroaryl or heterocycloalkenyl moiety via a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron or bis(neopentyl glycolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriately functionalised halo- or tosyloxy-substituted aryl, heteroaryl or heterocycloalkenyl derivative. Step (i) is conveniently effected in the presence of a transition metal catalyst such as [1,1′-bis-(diphenylphosphino)ferrocene]dichloropalladium(II), or bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex. Step (ii) is conveniently effected in the presence of a transition metal catalyst such as tetrakis-(triphenylphosphine)palladium(0), or bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex, and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.

A compound of formula (I) wherein R1represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1represents an optionally substituted C2-6alkynyl moiety by treatment with an appropriately substituted alkyne derivative, e.g. 2-hydroxybut-3-yne. The reaction is conveniently accomplished with the assistance of a transition metal catalyst, e.g. tetrakis(triphenylphosphine)palladium(0), typically in the presence of copper(I) iodide and a base, e.g. an organic base such as triethylamine.

A compound of formula (I) wherein R1represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1represents an optionally substituted imidazol-1-yl moiety by treatment with the appropriately substituted imidazole derivative, typically in the presence of copper(II) acetate and an organic base such as N,N,N′,N′-tetramethylethylenediamine (TMEDA).

A compound of formula (I) wherein R1represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1represents 2-(methoxycarbonyl)-ethyl via a two-step procedure which comprises: (i) reaction with methyl acrylate; and (ii) catalytic hydrogenation of the alkenyl derivative thereby obtained, typically by treatment with a hydrogenation catalyst, e.g. palladium on charcoal, under an atmosphere of hydrogen gas. Step (i) is typically effected in the presence of a transition metal catalyst, e.g. palladium(II) acetate or bis(dibenzylideneacetone)palladium(0), and a reagent such as tri(ortho-tolyl)phosphine.

In general, a compound of formula (I) containing a —C═C— functionality may be converted into the corresponding compound containing a —CH—CH— functionality by catalytic hydrogenation, typically by treatment with a hydrogenation catalyst, e.g. palladium on charcoal, under an atmosphere of hydrogen gas, optionally in the presence of a base, e.g. an alkali metal hydroxide such as sodium hydroxide.

A compound of formula (I) wherein R1represents 6-methoxypyridin-3-yl may be converted into the corresponding compound wherein R1represents 2-oxo-1,2-dihydropyridin-5-yl by treatment with pyridine hydrochloride; or by heating with a mineral acid such as hydrochloric acid. By utilising similar methodology, a compound of formula (I) wherein R1represents 6-methoxy-4-methylpyridin-3-yl may be converted into the corresponding compound wherein R1represents 4-methyl-2-oxo-1,2-dihydropyridin-5-yl; and a compound of formula (I) wherein R1represents 6-methoxy-5-methylpyridin-3-yl may be converted into the corresponding compound wherein R1represents 3-methyl-2-oxo-1,2-dihydropyridin-5-yl.

A compound of formula (I) wherein R1represents 2-oxo-1,2-dihydropyridin-5-yl may be converted into the corresponding compound wherein R1represents 2-oxopiperidin-5-yl by catalytic hydrogenation, typically by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as platinum(IV) oxide.

A compound of formula (I) containing an ester moiety, e.g. a C2-6alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may be converted into the corresponding compound containing a carboxy (—CO2H) moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid.

A compound of formula (I) containing an N-(tert-butoxycarbonyl) moiety may be converted into the corresponding compound containing an N—H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

A compound of formula (I) containing an ester moiety, e.g. a C2-6alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may alternatively be converted into the corresponding compound containing a carboxy (—CO2H) moiety by treatment with a base, e.g. an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide and potassium hydroxide; or an organic base such as sodium methoxide or sodium ethoxide.

A compound of formula (I) containing a carboxy (—CO2H) moiety may be converted into the corresponding compound containing an amide moiety by treatment with the appropriate amine in the presence of a condensing agent such as 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide.

A compound of formula (I) containing a carbonyl (C═O) moiety may be converted into the corresponding compound containing a —C(CH3)(OH)— moiety by treatment with methylmagnesium bromide. Similarly, a compound of formula (I) containing a carbonyl (C═O) moiety may be converted into the corresponding compound containing a —C(CF3)(OH)— moiety by treatment with (trifluoromethyl)trimethylsilane and cesium fluoride. A compound of formula (I) containing a carbonyl (C═O) moiety may be converted into the corresponding compound containing a —C(CH2NO2)(OH)— moiety by treatment with nitromethane.

A compound of formula (I) containing a hydroxymethyl moiety may be converted into the corresponding compound containing a formyl (—CHO) moiety by treatment with an oxidising agent such as Dess-Martin periodinane. A compound of formula (I) containing a hydroxymethyl moiety may be converted into the corresponding compound containing a carboxy moiety by treatment with an oxidising agent such as tetrapropylammonium perruthenate.

A compound of formula (I) wherein R1represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom, may be prepared by reacting a compound of formula (I) wherein R1represents halogen, e.g. bromo, with the appropriate compound of formula R1—H [e.g. 1-(pyridin-3-yl)piperazine or morpholine]. The reaction is conveniently effected with the assistance of a transition metal catalyst, e.g. tris(dibenzylideneacetone)dipalladium(0), in the presence of an amination ligand such as 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl (XPhos) or 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) and a base, e.g. an inorganic base such as sodium tert-butoxide. Alternatively, the reaction may be effected using palladium diacetate, in the presence of a reagent such as [2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane and a base, e.g. an inorganic base such as cesium carbonate.

A compound of formula (I) containing an oxo moiety can be concerted into the corresponding compound containing an ethoxycarbonylmethylidene moiety by treatment with triethyl phosphonoacetate in the presence of a base such as sodium hydride.

A compound of formula (IIB) wherein R21represents ethenyl may be prepared by reacting a compound of formula (IIB) wherein R21represents halogen, e.g. chloro, with potassium vinyl trifluoroborate. The reaction is typically effected in the presence of a transition metal catalyst, e.g. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base, e.g. an organic base such as triethylamine.

A compound of formula (IIB) wherein R21represents halogen, e.g. chloro, may be converted into the corresponding compound wherein R21represents an optionally substituted C4-7cycloalkenyl moiety by treatment with the appropriately substituted cycloalkenyl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol. The reaction is typically effected in the presence of a transition metal catalyst, e.g. bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex, and a base, e.g. an inorganic base such as potassium carbonate.

A compound of formula (IIB) wherein R21represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom, may be prepared by reacting a compound of formula (IIB) wherein R21represents halogen, e.g. chloro, with the appropriate compound of formula R21—H [e.g. 2-methoxyethylamine, N-methyl-L-alanine, 2-aminocyclopentanecarboxylic acid, 3-aminocyclopentanecarboxylic acid, 1-(aminomethyl)cyclopropanecarboxylic acid, methyl azetidine-3-carboxylate, pyrrolidin-3-ol, pyrrolidine-3-carboxylic acid, piperidine-2-carboxylic acid, piperidine-3-carboxylic acid, 4-(1H-tetrazol-5-yl)piperidine, piperazine, 1-(methylsulfonyl)piperazine, piperazin-2-one, 2-(piperazin-1-yl)propanoic acid, morpholine, morpholine-2-carboxylic acid, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-diazepan-5-one, 2-oxa-5-azabicyclo[2.2.1]heptane or an appropriately substituted azaspiroalkane], optionally in the presence of a base, e.g. an organic base such as triethylamine or N,N-diisopropylethylamine and/or 1-methyl-2-pyrrolidinone, or pyridine, or an inorganic base such as potassium carbonate.

Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.

The following Examples illustrate the preparation of compounds according to the invention.

The compounds in accordance with this invention potently inhibit TNFα-induced NF-κB activation in the following assay.

Inhibition of TNFα-Induced NF-κB Activation

Stimulation of HEK-293 cells by TNFα leads to activation of the NF-κB pathway. The reporter cell line used to determine TNFα activity was purchased from InvivoGen. HEK-Blue™ CD40L is a stable transfectant expressing SEAP (secreted alkaline phosphatase) under the control of the IFNβ minimal promoter fused to five NF-κB binding sites. Secretion of SEAP by these cells is stimulated in a dose-dependent manner by TNFα (0.5 ng/mL). Compounds were diluted from 10 mM DMSO stocks (final assay concentration 0.3%) to generate a 10-point 3-fold serial dilution curve (30,000 nM to 2 nM final concentration). They were mixed with cells and stimulating ligand in a 384-well microtitre plate and incubated for 18 h. SEAP activity was determined in the supernatant using the colorimetric substrate QUANTI-Blue™ (InvivoGen). Percentage inhibitions for compound dilutions were calculated between a DMSO control and maximum inhibition (by excess control compound) and an IC50calculated using XLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the above assay, the compounds of the accompanying Examples were all found to exhibit IC50values of 50 μM or better.

EXAMPLES

Compounds were named with the aid of ACD/Name Batch (Network) version 11.01, and/or Accelrys Draw 4.0.

Analytical Conditions

NMR spectra were obtained using a Bruker DPX 250 MHz NMR spectrometer; a Bruker Fourier 300 MHz NMR spectrometer; a Bruker AVIII 400 MHz NMR spectrometer; a Bruker DRX 500 MHz NMR spectrometer; or an AV 600 MHz NMR spectrometer. Chemical shift values are reported in ppm (δ) with zero corresponding to the corrected residual deuterated solvent shift as an internal reference, or with zero corresponding to tetramethylsilane as an internal standard. The NMR spectra were recorded at a temperature ranging from 5 to 110° C. When more than one conformer was detected the chemical shifts for the most abundant conformer are reported.

Analytical HPLC

Method A

A degassed mixture of 2-amino-5-bromopyridine (3.5 g, 20.23 mmol), 6-methoxypyridin-3-ylboronic acid (3.71 g, 24.28 mmol) and bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (413 mg, 0.51 mmol) in 1,4-dioxane (36 mL) and a 2M aqueous potassium carbonate solution (36.4 mL) was heated at 90° C. under a nitrogen atmosphere for approximately 16 h. The reaction mixture was allowed to cool to room temperature and diluted with diethyl ether (100 mL). The organic phase was separated off, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with DCM (10 mL) and filtered, to afford the title compound (3.36 g, 83%) as a light brown solid. Method C LCMS: MH+ m/z 202, RT 0.60 minutes.

Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately −20° C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl[bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3×200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes.

A solution of bromine (1.25 mL, 24.44 mmol) in glacial acetic acid (20 mL) was added dropwise over 60 minutes to a stirring solution of Intermediate 2 (4.6 g, 24.4 mmol) in glacial acetic acid (20 mL) in the dark. When the addition was complete the reaction was diluted with DCM (200 mL) and washed with water (200 mL). The aqueous layer was then extracted with DCM (50 mL). To the combined organic layers was added saturated aqueous sodium carbonate solution (100 mL), and further solid sodium carbonate was added portionwise with vigorous stirring until the mixture was neutralised. The organic phase was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated under vacuum to afford the title compound (6.48 g, 82%) as a light yellow oil. δH(500 MHz, CDCl3) 7.83 (m, 1H), 7.58 (td, J 8.3, 1.7 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J 8.3 Hz, 1H), 6.64 (t, J 72.9 Hz, 1H), 4.53 (s, 2H). Method C HPLC-MS: MH+ m/z 265/267, RT 1.32 minutes (80%).

Intermediate 3 (9.94 g, 41.1 mmol) and Intermediate 4 (10.9 g, 41.1 mmol) were combined in toluene (120 mL) and heated at 140° C. for 10 minutes. The mixture was then allowed to cool gradually in the heating block for 1 h, before being cooled to room temperature. The volatiles were removed under vacuum and the residue was taken up in ethyl acetate (300 mL) and methanol (30 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (150 mL) and the organic layer was dried over sodium sulphate, filtered and concentrated under vacuum to afford a red oil (˜15 g). The residue was purified by flash chromatography, eluting with a gradient of 0-100% ethyl acetate in heptane, to afford the title compound (9.94 g, 63.5%) as a pink solid. δH(500 MHz, CDCl3) 9.96 (s, 1H), 7.58 (m, 3H), 7.38 (m, 3H), 6.52 (t, J 73.5 Hz, 1H), 2.03 (s, 3H).

Intermediate 5 (9.94 g, 26.1 mmol) was suspended in methanol (200 mL). The mixture was then cooled to 0° C. in an ice bath and sodium borohydride (1.03 g, 27.4 mmol) was added. After 10 minutes the mixture was warmed to room temperature and stirred for 1 h, after which time a light-coloured precipitate had formed. The mixture was reduced in volume in vacuo by approximately two-thirds and then diluted with ethyl acetate (400 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (200 mL), dried over sodium sulphate and filtered, then concentrated in vacuo, to afford the title compound (9.8 g, 98%) as a cream-coloured solid. δH(500 MHz, CD3OD) 8.54 (s, 1H), 7.94 (m, 1H), 7.39 (m, 4H), 7.12 (m, 1H), 6.54 (m, 2H), 2.29 (s, 3H).

Intermediate 6 (9.6 g, 25.1 mmol) was suspended in DCM (200 mL). Boron trifluoride diethyl etherate (7.5 mL, 60.8 mmol) and triethylsilane (8 mL, 50.1 mmol) were added and the mixture was stirred at room temperature for 6 h, before being left to stand at room temperature over the weekend. LCMS analysis indicated incomplete conversion, so further boron trifluoride diethyl etherate (3 mL, 24.3 mmol) and triethylsilane (2 mL, 12.5 mmol) were added and the mixture was stirred at room temperature for 6 h. The mixture was diluted with methanol (30 mL) to dissolve a small amount of precipitate, then the mixture was washed with saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to afford an orange gum. DCM (50 mL) was added, which caused a white precipitate to form. This was filtered off and washed further with DCM (100 mL) and methanol (20 mL) to afford the title compound (5.58 g, 54%) as a white solid. The filtrate was concentrated under vacuum and purified by flash chromatography, eluting with a gradient of 30-100% ethyl acetate in heptane, to afford a further quantity of the title compound (1.18 g, 12%) as a pale orange solid. Method C HPLC-MS: MH+ m/z 367/369, RT 1.01 minutes (90%).

Intermediate 7 (200 mg, 0.54 mmol) and tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (316 mg, 0.81 mmol) were dissolved in 1,4-dioxane (20 mL) and a 2M aqueous solution of potassium carbonate (1 mL) was added. The mixture was flushed with nitrogen and bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (12 mg, 0.01 mmol) was added. The mixture was heated at 90° C. under nitrogen for 16 h. LCMS indicated incomplete conversion so additional tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (150 mg, 0.39 mmol) and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (12 mg, 0.01 mmol) were added and the mixture was heated at 90° C. under nitrogen for 4 h. The mixture was diluted with ethyl acetate (30 mL) and washed with water (2×10 mL), then brine (10 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under vacuum to yield a dark grey solid. This was purified by flash chromatography, eluting with a gradient of 0-100% ethyl acetate in heptane, followed by 0-20% methanol in ethyl acetate. The resultant material was further purified by flash chromatography, eluting with a gradient of 0-5% methanol in DCM. The resultant material was then further purified by preparative HPLC (Preparative Method B) to afford the title compound (66 mg, 22%) as an off-white solid. δH(250 MHz, CD3OD) 8.35-8.17 (m, 2H), 7.81-7.58 (m, 3H), 7.42-6.59 (m, 6H), 4.42 (s, 2H), 3.55 (br s, 8H), 2.48 (br s, 3H), 1.49 (s, 9H).

(Chloromethylene)dimethyliminium chloride (1.03 g, 8.05 mmol) was added to N,N-dimethylformamide (10 mL) at 0° C. and stirred for 5 minutes. Intermediate 9 (85% pure, 1 g, 4.03 mmol) was added. The mixture was warmed to room temperature and then heated at 80° C. for 1 h. The mixture was cooled to room temperature and quenched by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with water (50 mL) followed by brine (50 mL), then dried over magnesium sulphate and concentrated under vacuum. The residue was purified by flash chromatography to afford the title compound (500 mg, 47%) as an orange solid. Method B HPLC-MS: MH+ m/z 239/241, RT 1.49 minutes (83%).

Intermediate 10 (100 mg, 0.42 mmol) was suspended in THF (1 mL) and added dropwise to a stirred 0.5M solution of 3-methylthien-2-ylmagnesium bromide in THF (1 mL, 0.50 mmol) at 0° C. The mixture was then warmed to room temperature and stirred for 2 h. The mixture was quenched by adding saturated aqueous ammonium chloride solution, then the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water and brine (20 mL), then dried over magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography to afford the title compound (100 mg, 71%) as a pale yellow solid. Method B HPLC-MS: MH+ m/z 337/339, RT 1.37 minutes (84%).

Intermediate 11 (100 mg, 0.3 mmol) was suspended in DCM (5 mL) and cooled to 0° C. Boron trifluoride diethyl etherate (73.53 μL, 0.6 mmol) was added dropwise, followed by triethylsilane (94.54 μL, 0.59 mmol), then the mixture was warmed to room temperature and stirred for 3 h. The mixture was washed with saturated aqueous sodium bicarbonate solution (5 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography to afford the title compound (80 mg, 71.4%) of as a brown solid. Method B HPLC-MS: MH+ m/z 321/323, RT 1.47 minutes (81%).

2,5-Dichloroacetophenone (20.9 g, 0.11 mol) was dissolved in diethyl ether (300 mL) and the reaction mixture was cooled to 0° C. Bromine (5.66 mL, 0.11 mol) was added slowly dropwise and the reaction mixture was allowed to warm to room temperature over 20 minutes. The reaction mixture was treated with saturated aqueous NaHCO3solution (250 mL). The organic layer was separated, dried over MgSO4and concentrated in vacuo, yielding the title compound (20.0 g, 68%) as a yellow oil. δH(d6-DMSO) 7.94 (dd, J 2.2, 0.3 Hz, 1H), 7.61 (m, 2H), 4.88 (s, 2H).

To a nitrogen-flushed solution of Intermediate 22 (50 g, 185 mmol) in dichloromethane (500 mL) were added rhodium(II) acetate dimer (0.818 g, 1.85 mmol) and triethylsilane (35.5 mL, 25.8 g, 222 mmol). The resulting mixture was stirred at reflux. Additional triethylsilane (10 mL, 7.28 g, 62.6 mmol) and rhodium(II) acetate dimer (0.2 g, 0.453 mmol) were added after 4 h. Heating at reflux was continued for 16 h. The reaction mixture was cooled to room temperature and filtered over a tight pad of kieselguhr. The resulting material was rinsed with DCM and concentrated in vacuo to yield the title compound (61 g) as a clear yellow oil that was employed in subsequent steps with no further purification.

To a stirred solution of Intermediate 23 (69 g, 179 mmol) in anhydrous tetrahydrofuran (700 mL) at room temperature was added NBS (35.0 g, 196 mmol). The resulting mixture was stirred at reflux for 2 h before being cooled to room temperature. The reaction mixture was concentrated to approximately one-third of its original volume. DCM (500 mL) was added and the resulting mixture was washed with saturated aqueous NaHCO3solution (700 mL), then extracted with DCM (250 mL), dried over Na2SO4and concentrated in vacuo, to yield a crude yellow oil (97 g). After storage overnight at room temperature under nitrogen, the product had partly solidified. The resulting material was triturated in diisopropyl ether (300 mL) for 1 h at room temperature. The precipitate was removed by filtration. The filtrate was concentrated in vacuo yielding a clear yellow-brown oil (88 g). Purification by flash column chromatography (1.5 kg silica, 2-20% EtOAc in heptane) afforded the title compound (58.3 g) as a light brown oil. δH(CDCl3, 300 MHz) 1.38 (t, J 7.1 Hz, 3H), 3.32 (dd, J 14.5, 7.8 Hz, 1H), 3.55 (dd, J 14.5, 7.1 Hz, 1H), 4.36 (q, J 7.1 Hz, 2H), 5.37 (dd, J 7.8, 7.1 Hz, 1H), 6.58 (t, J 73.5 Hz, 1H), 7.09-7.19 (m, 2H), 7.26-7.33 (m, 2H). MS [ES+] m/z 271 [M-Br]+.

A mixture of Intermediate 21 (5.2 g, 19 mmol) and Intermediate 3 (3.6 g, 15 mmol) in ethanol (25 mL) was heated at 75° C. for 4 h, then stood at room temperature overnight. The mixture was concentrated in vacuo, then the residue was partitioned between EtOAc and saturated aqueous NaHCO3solution. The organic layer was separated and extracted into EtOAc. The combined organic layers were washed with water and brine, then dried (MgSO4), filtered and concentrated in vacuo. The resulting material was subjected to column chromatography (SiO2, eluent hexane to 50% EtOAc). The resulting material was washed with diethyl ether to give the title compound (3.6 g, 63%) as a beige solid. δH(400 MHz, DMSO-d6) 9.80 (d, 1H, J 1.4 Hz), 7.90 (dd, 1H, J 9.4, 2.0 Hz), 7.81 (d, 1H, J 9.4 Hz), 7.72 (s, 1H), 7.70 (m, 2H), 1.92 (s, 3H). MH+ 383.0.

Intermediate 7 (1.0 g, 2.72 mmol) and 2-chloropyrimidin-5-ylboronic acid (517 mg, 3.3 mmol) were dissolved in 1,4-dioxane (10 mL) and a 2M aqueous solution of potassium carbonate (4.9 mL) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (111.2 mg, 0.14 mmol) was added. The reaction mixture was heated at 90° C. under nitrogen for 18 h. The reaction mixture was re-treated with additional 2-chloropyrimidin-5-ylboronic acid (517.5 mg, 3.27 mmol) and heated at 90° C. under nitrogen for a further 24 h. The reaction mixture was diluted with EtOAc, washed with water (×2) and brine, filtered to remove a black solid, then dried over sodium sulfate and dried under vacuum. The residue obtained was purified by column chromatography, eluting with 0-90% EtOAc in heptanes, to yield the title compound (130 mg, 12%). δH(500 MHz, DMSO-d6) 9.14 (s, 2H), 8.73 (s, 1H), 7.64 (s, 2H), 7.46-7.09 (m, 5H), 4.40 (s, 2H), 2.30 (s, 3H). Method B HPLC-MS: MH+ m/z 401/403, RT 1.47 minutes (88%).

Intermediate 7 (250 mg, 0.68 mmol) and 6-chloropyridin-3-ylboronic acid (130 mg, 0.83 mmol) were dissolved in 1,4-dioxane (15 mL) and a 2M aqueous solution of potassium carbonate (1.25 mL) was added. The mixture was flushed with nitrogen and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (15 mg, 0.02 mmol) was added. The mixture was heated at 90° C. under nitrogen for 16 h. The mixture was diluted with ethyl acetate (30 mL), then washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with a gradient of 0-10% methanol in DCM. The crude product was further purified by preparative HPLC (Method B) to afford the title compound (295 mg, 92%) as a brown solid. Method C HPLC-MS: MH+ m/z 400, RT 1.00 minutes (85%).

N,N,N-Trimethylanilinium bromide-bromine (1:1:1) (1.84 g, 4.9 mmol) was added to a solution of 1-(2,4-dimethyl-1,3-thiazol-5-yl)ethanone (800 mg, 5.15 mmol) in diethyl ether (9 mL) and acetonitrile (3 mL), and HBr in acetic acid (33% w/w, 4 mL). The mixture was stirred for 1 h. The reaction mixture was diluted with diethyl ether (25 mL) and washed with aqueous Na2S2O5solution (5% w/v, 20 mL). The organic phase was separated off, and the aqueous phase was extracted with diethyl ether (25 mL). The organic phases were combined, then washed with saturated aqueous NaHCO3solution (2×25 mL) and brine. The residue was dried over sodium sulfate, then filtered and concentrated under vacuum, to give the title compound (764 mg, 63%) as a light brown oil. δH(250 MHz, CDCl3) 4.22 (s, 2H), 2.69-2.76 (br s, 6H).

A mixture of Intermediate 1 (626 mg, 3.11 mmol) and N,N-dimethylacetamide dimethyl acetal (2.27 mL, 15.55 mmol) in MeOH (3 mL) was heated at 80° C. in a sealed tube for 1 h. The reaction mixture was allowed to cool to ambient temperature, and concentrated under vacuum. The crude mixture was taken up in DCM (20 mL), then washed with saturated aqueous NaHCO3solution (2×25 mL) and brine The residue was dried over sodium sulfate, filtered and concentrated under vacuum, to afford the title compound (810 mg, 87%) as a brown viscous oil. Method C HPLC-MS: MH+ m/z 271, RT 0.81 minutes (90%).

Sodium borohydride (74.7 mg, 1.97 mmol) was added to Intermediate 34 (1.41 g, 1.97 mmol) in MeOH (14 mL) and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under vacuum. The crude mixture was taken up in saturated aqueous NaHCO3solution (20 mL) and chloroform (20 mL). The organic phase was separated off, and the aqueous phase was extracted with chloroform (20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum, to afford the title compound (865 mg, 97%) as a light brown solid. Method C HPLC-MS: MH+ m/z 381, RT 0.87 minutes (95%).

A mixture of 2-chloropyrimidin-5-ylboronic acid (3 g, 19.0 mmol), morpholine (1.66 mL, 19 mmol) and triethylamine (1.67 mL, 19.19 mmol) in EtOH (20 mL) was stirred at 80° C. for 5 h. LCMS indicated completion of the reaction. The reaction mixture was concentrated in vacuo and the residue was taken up in ethanol (approximately 5 mL). Diethyl ether was added, and the triethylamine hydrochloride salt that crystallised out was filtered and discarded. The filtrate was concentrated in vacuo and water (approximately 10 mL) was added. The mixture was placed in a refrigerator for 1 h, after which time the resulting solid was filtered off, washed with the minimum amount of water and dried by suction, to give the title compound (2.7 g, 68%) as an off-white solid. δH(DMSO-d6) 8.64 (s, 2H), 8.08 (s, 2H), 3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES+) 210 (M+H)+, RT 0.15 minutes.

2-Amino-5-iodopyridine (5 g, 22.73 mmol) was dissolved in ethanol (20 mL). Chloroacetone (2.29 mL, 25 mmol) was added and the mixture was heated at reflux overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was dried over MgSO4, filtered and evaporated. The resulting crude residue (4.8 g) was triturated with ethyl acetate to afford pure title compound (2.2 g). The filtrate was concentrated to dryness, yielding an additional quantity of less pure title compound (2.0 g). δH(CDCl3) 7.33 (m, 4H), 2.48 (s, 3H). LCMS: MH+ 259.

Intermediate 43 (5.82 g, 31.2 mmol) was dissolved in methanol (250 mL). Triethylamine (4.40 mL, 31.2 mmol) was added and the mixture was stirred at room temperature for 3.5 days. The mixture was pre-adsorbed onto silica (45 g) and subjected to flash chromatography (silica, 120 g, 4% conc. ammonia in acetonitrile, eluted with 2 L volume). Fractions were analysed by TLC, eluting with the foregoing solvent mix, and stained with potassium permanganate solution. Fractions in the middle of the chromatography showed two spots which co-eluted. These fractions were concentrated in vacuo. The resulting damp white solid was azeotroped with toluene (50 mL) to give the title compound (5.46 g, 70%,1H NMR showed 1 equivalent of triethylamine) as a dry white solid. δH(d6-DMSO) 7.50 (br s, 1H), 3.58-3.53 (m, 2H), 3.24-3.19 (m, 2H), 3.20-3.10 (m, 4H), 3.05 (q, Et3N), 1.22 (t, Et3N). LCMS (ES+) 151 (M+H)+.

2-Chloropyrimidin-5-ylboronic acid (1.00 g, 6.32 mmol) and Intermediate 44 (1.75 g, 6.96 mmol) were dissolved in ethanol (25 mL) and heated at reflux overnight. Analysis by LCMS showed the major UV visible component to have the desired mass. The mixture was concentrated in vacuo, re-dissolved in water (20 mL) and acidified with acetic acid (1 mL). The mixture was concentrated in vacuo again and purified by chromatography (silica, 50 g, eluted with 82% DCM, 15% MeOH, 2% AcOH, 1% water) to give the title compound (1.40 g). The product was used in the next step without further purification.

Palladium (II) acetate (1.69 g, 7.53 mmol) and Xantphos (8.71 g, 15.05 mmol) were dissolved/suspended in degassed 1,4-dioxane (1200 mL) in a nitrogen atmosphere. 2-Chloro-4-fluoropyridine (99 g, 753 mmol) and tert-butyl carbamate (97 g, 828 mmol) in 1,4-dioxane (550 mL) were added, followed by sodium hydroxide (45.2 g, 1.12 mol) and water (20 mL). The resulting mixture was heated at 100° C. for 2 h. The mixture was cooled to ambient temperature and filtered over celite. The residue was washed with 1,4-dioxane and the filtrate was concentrated to afford a yellow solid (206 g). The crude material was recrystallized from 2-propanol (400 mL) and dried to afford the title compound (120.8 g) as a white solid. LCMS 213 [M+H], RT 1.96 minutes, purity 94%.

Intermediate 50 (120 g, 565 mmol) was dissolved in DCM (1250 mL) and cooled with an ice bath. Trifluoroacetic acid (250 mL) was added dropwise. The resulting mixture was stirred overnight at ambient temperature. The mixture was concentrated and partitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried with sodium sulphate, filtered and concentrated, to afford the title compound (65.5 g) as a yellow solid. LCMS 113 [M+H], RT 0.17 minutes.

In an aluminium foil-covered flask, Intermediate 51 (62.3 g, 506 mmol) was dissolved in acetonitrile (1500 mL), and NBS (86 g, 481 mmol) was added. The mixture was stirred at ambient temperature for 2 h. The mixture was concentrated to afford a yellow solid. The crude material was dissolved in EtOAc (1000 mL), washed twice with saturated aqueous sodium bicarbonate solution, then with brine, dried with sodium sulphate, filtered and concentrated in vacuo, to afford a light brown solid (71.2 g). The crude material was crystallized from EtOAc (300 mL) and heptane (300 mL) to give the title compound (34.3 g) as brown crystals. LCMS 191 (79Br)/193 (81Br) [M+H], RT 0.79 minutes.

Lithium hexamethyldisilazide in THF/ethylbenzene (1M, 5.55 mL) was added dropwise to a stirred solution of ethyl 4-oxocyclohexanecarboxylate (900 mg, 5.29 mmol) in anhydrous THF (5 mL) under an inert atmosphere at −78° C., and the mixture was stirred for 1 h. 1,1,1-Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (1.98 g, 5.55 mmol) in THF (5 mL) was added over 5 minutes, and the mixture was stirred for 30 minutes. The reaction mixture was then warmed to room temperature and stirred for 12 h. The mixture was quenched with NaHSO4and diluted with ethyl acetate (250 mL), then washed with 0.5M aqueous NaOH solution (2×20 mL), saturated aqueous NH4Cl solution (20 mL) and brine (20 mL). The organic fraction was then dried over MgSO4and concentrated under reduced pressure to afford the intermediate triflate (1.9 g, 83%). This material was dissolved in 1,4-dioxane (30 mL), bis(pinacolato)diboron (1.68 g, 6.6 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (73 mg, 0.13 mmol) were added and the mixture was degassed with N2for 5 minutes. Bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (108 mg, 0.13 mmol) was added and the mixture was heated at 90° C. for 18 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 10-20% ethyl acetate in heptane, to afford the title compound in two batches (440 mg, 26% yield, 73% purity; and 362 mg, 12% yield, 42% purity) as a colourless oil. Method B HPLC-MS: MH+ m/z 281, RT 2.37 minutes (73%).

Prepared from 4-methylpiperidine-4-carboxylic acid methyl ester and (2-chloropyrimidin-5-yl)boronic acid according to the method of Intermediate 45.

To 2-chloropyrimidine-5-boronic acid (4.00 g, 25.3 mmol) were added ethyl 4-methylpiperidine-4-carboxylate hydrochloride (4.09 g, 23.9 mmol), ethanol (40 mL) and triethylamine (9.0 mL, 64.0 mmol). The mixture was heated at 80° C. for 3 h before being concentrated in vacuo. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL), then the aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with brine (100 mL), then dried (Na2SO4). The solvent was then removed under reduced pressure and the crude reaction mixture was purified by flash column chromatography on silica (Biotage SNAP 100 g, Isolera). Gradient elution, with 100% dichloromethane to 30% methanol/dichloromethane, afforded the title compound (4.27 g, 43% yield, 74% purity) as a brown oil. LCMS (pH 10): MH+ m/z 294.1, RT 0.652 minutes.

Example 19 (650 mg, 1.4 mmol) was suspended in 4M HCl in 1,4-dioxane (3.46 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and dried under vacuum to provide the title compound (630 mg, quantitative) as an off-white solid. The crude material was used directly in the next step. Method B HPLC-MS: MH+ m/z 370, RT 1.04 minutes (93%).

(2-Chloropyrimidin-5-yl)boronic acid (250 mg, 1.6 mmol), ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (303 mg, 1.6 mmol) and triethylamine (0.22 mL, 1.6 mmol) were dissolved in ethanol (8 mL) and stirred at 80° C. overnight. The reaction mixture was cooled and concentrated under vacuum. Water (30 mL) was added and the resulting material was filtered and dried to afford the title compound (253 mg, 58%) as a pale brown solid. Method B HPLC-MS: MH+ m/z 278, RT 1.35 minutes (100%).

(2-Chloropyrimidin-5-yl)boronic acid (2 g, 13 mmol) and ethyl piperidine-4-carboxylate (1.94 mL, 13 mmol) were dissolved in 1,4-dioxane (20 mL) and heated to 60° C. under microwave irradiation for 1 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4and concentrated to dryness, to afford the title compound (1.79 g, 51%) as a yellow gum. Method C HPLC-MS: MH+ m/z 280, RT 0.94 minutes (89%).

Ethyl 2-(5-bromopyrimidin-2-yl)acetate (500 mg, 2.04 mmol) was dissolved in THF (8 mL) and the mixture was cooled to −78° C. under nitrogen. LDA in THF/heptane/ethylbenzene (2M, 1.25 mL) was added dropwise, then the mixture was stirred for 15 minutes. Iodomethane (0.22 mL, 3.53 mmol) was added, then the reaction mixture was warmed to room temperature and stirred for a further 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The aqueous layer was acidified to pH ˜5 with 1M HCl, then extracted with additional ethyl acetate (2×20 mL). The combined organic layers were dried over Na2SO4and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate in heptane, to afford the title compound (417 mg, 79%) as a yellow oil. δH(500 MHz, CDCl3) 8.75 (s, 2H), 4.18 (m, 2H), 4.08 (q, J 7.2 Hz, 1H), 1.60 (d, J 7.3 Hz, 3H), 1.22 (t, J 7.1 Hz, 3H).

Prepared from 2(S)-morpholine-2-carboxylic acid and (2-chloropyrimidin-5-yl)boronic acid according to the method of Intermediate 45.

The title compound can be prepared from 5-bromo-4-fluoropyridin-2-amine according to the method of Intermediate 3.

Intermediate 20 (150 mg, 0.39 mmol) and (2-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}pyrimidin-5-yl)boronic acid (133 mg, 0.43 mmol) were dissolved in 1,4-dioxane (1.5 mL) and 2M aqueous potassium carbonate solution (0.69 mL) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (16 mg, 0.02 mmol) was added. The mixture was heated at 90° C. for 3 h in a sealed tube under nitrogen. Further (2-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}pyrimidin-5-yl)boronic acid (61 mg, 0.2 mmol), 2M aqueous potassium carbonate solution (0.3 mL) and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (8 mg, 0.01 mmol) were added. The mixture was degassed, then heated at 90° C. for 2 h in a sealed tube under nitrogen. The mixture was diluted with water (5 mL) and extracted into EtOAc (3×10 mL), then washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography, eluting with 0-10% (7M ammonia in methanol) in DCM followed by 10-50% MeOH in DCM, to afford the title compound (160 mg, 69%). Method C HPLC-MS: MH+ m/z 565, RT 1.18 minutes (90%).

Trifluoroacetic acid (0.21 mL, 2.72 mmol) was added to a solution of Intermediate 69 (96% pure, 160 mg, 0.27 mmol) in DCM (0.5 mL) and the mixture was stirred for 30 minutes. The mixture was loaded onto an SCX cartridge which was washed with MeOH, followed by 7M ammonia in MeOH. Product fractions were concentrated to afford the title compound (109 mg, 86%). Method C HPLC-MS: MH+ m/z 465, RT 0.85 minutes (83%).

(2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at 100° C. under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with methanol and diethyl ether. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. Method B HPLC-MS: MH+ m/z 223, RT 0.25 minutes.

(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 1,4-diazepan-5-one (288.34 mg, 2.53 mmol) were suspended in 1,4-dioxane (3 mL) and the mixture was heated at 100° C. under microwave irradiation for 45 minutes. The resulting slurry was concentrated under vacuum and triturated with MeOH to afford the title compound (145 mg, 30%) as a cream precipitate, which was used without further purification. Method C HPLC-MS: MH+ m/z 237, RT 0.40 minutes.

To a stirred solution of benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (7.3 g, 0.03 mol) and methyl prop-2-ynoate (3.1 mL, 0.04 mol) in dichloromethane (150 mL) at 0° C. under nitrogen was added dropwise a solution of trifluoroacetic acid (0.12 mL, 0.002 mol) in dichloromethane (1 mL). The reaction mixture was allowed to stir at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature for 2 h, then the solvent was evaporated. The residue was purified by FCC, eluting with 0-20% ethyl acetate in heptane, to afford the title compound (2.37 g, 29%) as a yellow oil. δH(250 MHz, CDCl3) 7.35-7.15 (5H, m), 6.70 (1H, s), 3.79 (3H, s), 3.75-3.60 (6H, m).

To a stirred suspension of sodium hydride (60%, 0.71 g, 0.02 mol) in anhydrous DMSO (20 mL) under nitrogen at 0° C. was added portionwise trimethylsulfoxonium iodide (4.16 g, 0.02 mol). The mixture was stirred until gas evolution had ceased, then warmed to 40° C. The mixture was cooled to 0° C., then a solution of Intermediate 74 (1.94 g, 0.01 mol) in DMSO (1 mL) was added dropwise. The mixture was warmed to room temperature, stirred for 10 minutes, then warmed to 50° C. and stirred for 2 h. The mixture was cooled to room temperature, then poured into water (20 mL) and ethyl acetate (20 mL). The phases were separated, and the aqueous phase was extracted twice with ethyl acetate (20 mL). The combined organic extracts were washed with water (2×10 mL) and concentrated under vacuum. The residue was purified by FCC, eluting with 0-25% ethyl acetate in heptane, to afford the title compound (411 mg, 20%) as a colourless oil. δH(500 MHz, CDCl3) 7.26 (5H, m), 3.66 (3H, s), 3.57 (m, 2H), 3.27-2.98 (1H, m), 2.98-2.92 (1H, m), 2.72 (1H, m), 2.42 (1H, m), 1.93 (1H, m), 1.52-1.39 (1H, m), 1.28 (1H, m).

Methyl (triphenylphosphoranylidene)acetate (2.77 g, 8.29 mmol) was added to a mixture of 1-(diphenylmethyl)azetidin-3-one (1.64 g, 6.91 mmol) in THF (24 mL) and the resultant mixture was left to stir overnight. The mixture was concentrated under vacuum, then the residue was dissolved in hot 1:4 EtOAc/heptane (40 mL) and allowed to cool to room temperature. The resultant solid was filtered off and the filtrate was concentrated under vacuum. The crude residue was purified by FCC, eluting with 20% EtOAc in heptane, to afford the title compound (917 mg, 44%) as a pale yellow solid. Method B HPLC-MS: MH+ m/z 294, RT 1.43 minutes.

A mixture of potassium tert-butoxide (1.33 g, 11.9 mmol) and trimethylsulfoxonium iodide (2.78 g, 12.5 mmol) in DMSO (10 mL) was heated at 50° C. until a solution resulted. Then a solution of Intermediate 77 (917 mg, 3.13 mmol) in DMSO (5 mL) was added dropwise. Upon complete addition, the mixture was heated for a further 2 h, then allowed to cool to room temperature. The mixture was diluted with water (90 mL) and extracted with diethyl ether (2×50 mL). The organic phases were combined, washed with water (50 mL) and brine, then dried over sodium sulfate and concentrated under vacuum. The crude product was purified by FCC, eluting with a gradient of 0-20% EtOAc in heptane, to afford the title compound (455 mg, 44%) as a yellow viscous oil. Method B HPLC-MS: MH+ m/z 308, RT 1.44 minutes (93%).

A mixture of Intermediate 78 (570 mg, 1.85 mmol) and palladium(II) dihydroxide (12%, 109 mg, 0.09 mmol) in MeOH (20 mL) was stirred under an atmosphere of hydrogen overnight. A 1M solution of HCl in MeOH (10 mL) was added, and the mixture was filtered through celite. The filtrate was concentrated in vacuo, and the residue was washed with heptane (2×20 mL), to afford the title compound (351 mg, >100%) as a light brown viscous oil. δH(250 MHz, CDCl3) 3.99-4.28 (m, 4H), 3.74-3.87 (m, 5H), 1.75-1.94 (m, 1H), 1.14-1.39 (m, 2H).

A mixture of (2-chloropyrimidin-5-yl)boronic acid (261 mg, 1.65 mmol), Intermediate 79 (351 mg, 1.98 mmol) and triethylamine (0.83 mL, 5.93 mmol) in EtOH (2 mL) were heated under microwave irradiation at 80° C. for 1 h. Intermediate 7 (403 mg, 1.1 mmol), 1,2-dimethoxyethane (18 mL) and 2M aqueous sodium carbonate solution (4 mL) were added and the reaction mixture was thoroughly degassed. Tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.16 mmol) was added and the mixture was heated in a sealed tube at 80° C. under nitrogen overnight. The mixture was allowed to cool to room temperature, then water (10 mL) and EtOAc (15 mL) were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (15 mL). The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-10% MeOH in DCM, to afford the title compound (160 mg, 13%) as a light brown gummy solid. Method B HPLC-MS: MH+ m/z 506, RT 1.52 minutes (80%).

5-Bromo-1-methyl-1H-pyrazol-3-amine (500 mg, 2.84 mmol) and DIPEA (2.47 mL, 14.2 mmol) were stirred in anhydrous 1,2-dichloroethane (8 mL) at room temperature, then mesyl chloride (550 μL, 7.1 mmol) in 1,2-dichloroethane (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 3 h, then partitioned between DCM and water. The organic phases were separated and washed with brine, then dried over sodium sulfate and concentrated. To the resulting orange/brown solid was added 1M tetrabutylammonium fluoride in THF (10.5 mL) and the mixture was heated at reflux for 4 h. The reaction mixture was concentrated and diluted with DCM (40 mL), then washed with water (4×25 mL), followed by brine (25 mL). The organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 35-50% EtOAc in heptane followed by 5-10% MeOH in DCM, to afford the title compound (388 mg, 54%) as a white solid. δH(250 MHz, CDCl3) 6.33 (s, 1H), 3.85 (s, 3H), 3.02 (s, 3H).

Potassium carbonate (422 mg, 3.05 mmol) was added to a solution of Intermediate 82 (388 mg, 1.53 mmol) in anhydrous MeCN (5.5 mL) in a round-bottom flask fitted with a condenser and a potassium hydroxide scrubber. Dimethyl sulfate (290 μL, 3.05 mmol) was added slowly. The reaction mixture was heated at 50° C. and stirred for 17 h. The mixture was concentrated under vacuum and the crude residue was purified by FCC, eluting with 25-50% EtOAc in heptane, to afford the title compound (350 mg, 86%) as a colourless oil. δH(250 MHz, DMSO-d6) 6.35 (s, 1H), 3.80 (s, 3H), 3.29 (s, 3H), 2.90 (s, 3H).

Intermediate 31 (150 mg, 0.45 mmol), 3-chloro-6-iodopyridazine (109 mg, 0.45 mmol), 2M aqueous sodium carbonate solution (677 μL) and anhydrous DMSO (2 mL) were charged to a sealed tube. The mixture was degassed by bubbling with nitrogen for 5 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.023 mmol). The reaction mixture was sealed under nitrogen, then stirred at 90° C. for 2 h. The mixture was diluted with water (2 mL), extracted into EtOAc (3×10 mL) and washed with brine (10 mL), then dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-100% ethyl acetate in heptane followed by 0-10% methanolic ammonia in DCM, to afford the title compound (108 mg, 50%). Method C HPLC-MS: MH+ m/z 401, RT 1.06 minutes.

Intermediate 84 (84%, 108 mg, 0.23 mmol), ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]-hexane-6-carboxylate hydrochloride (43 mg, 0.23 mmol) and triethylamine (32 μL, 0.23 mmol) were stirred in 1,4-dioxane (2 mL) at 90° C. for 2.5 h, then at 120° C. for 1.5 h, then at 130° C. for a total of 9 h. Further ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (43 mg, 0.23 mmol) and triethylamine (63 μL, 0.45 mmol) were added and the reaction mixture was heated for 6 h at 150° C. The mixture was concentrated and diluted with EtOAc (25 mL), then washed with water (2×10 mL) and brine. The aqueous phase was basified with saturated aqueous sodium carbonate solution, then extracted with EtOAc (3×25 mL). The organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum, to afford the title compound (134 mg, 52%), which was used without purification. Method C HPLC-MS: MH+ m/z 520, RT 1.09 minutes.

Intermediate 92 (117 mg, 0.33 mmol), ethyl 4-(methanesulfonyloxy)cyclohexane-1-carboxylate (79 mg, 0.31 mmol), cesium carbonate (151 mg, 0.46 mmol) and anhydrous N,N-dimethylformamide (3 mL) were charged to a sealed tube under nitrogen. The mixture was stirred at 80° C. for 18 h, then at 100° C. for 3 h. Further ethyl 4-(methane-sulfonyloxy)cyclohexane-1-carboxylate (79 mg, 0.31 mmol) and cesium carbonate (102 mg, 0.31 mmol) were added and the mixture was stirred at 100° C. for 6 h. Further ethyl 4-(methanesulfonyloxy)cyclohexane-1-carboxylate (79 mg, 0.31 mmol) and cesium carbonate (102 mg, 0.31 mmol) were added and the mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (3×10 mL) followed by saturated aqueous sodium carbonate solution (10 mL) and brine (10 mL), then dried over sodium sulfate and concentrated. The resulting material was purified by FCC, eluting with 0-2% MeOH in DCM. The residue was then further purified by FCC, eluting with 10-100% EtOAc in heptane, to afford the title compound (60 mg, 29%) as a brown gum. Method D HPLC-MS: MH+ m/z 508, RT 2.57 minutes.

Sodium hydride (60%, 202 mg, 5.06 mmol) was suspended in anhydrous THF (15 mL) and cooled in an ice bath. Ethyl 2-(diethoxyphosphoryl)propanoate (1.2 g, 5.06 mmol) was added dropwise under nitrogen and the mixture was stirred in an ice bath for 1 h. 1-(Diphenylmethyl)azetidin-3-one (1 g, 4.21 mmol) was added in portions as a solid and the mixture was stirred at room temperature for 1 h, then left to stir at room temperature overnight. Water (50 mL) was added and the mixture was extracted with DCM (3×50 mL). Brine was added, and the aqueous and organic layers were separated. The organic layer was dried over sodium sulfate and concentrated. The resulting crude yellow oil was purified by FCC, eluting with 0-50% EtOAc, to afford a clear oil which crystallised upon standing. The solids were sonicated with heptane and the remaining solid was collected by filtration. The filtrate was concentrated and sonicated with heptane to afford a second crop of solid. The filtrate was concentrated and the residue was sonicated with heptane to afford a further crop of solid material. The resultant solids were collected and combined to afford the title compound (892 mg, 66%) as a white solid. δH(250 MHz, CDCl3) 7.56-7.39 (m, 4H), 7.38-7.15 (m, 6H), 4.63-4.45 (m, 1H), 4.24-4.01 (m, 4H), 3.96-3.76 (m, 2H), 1.72-1.58 (m, 3H), 1.27-1.14 (m, 3H).

Intermediate 96 (700 mg, 2.09 mmol) was dissolved in EtOH (20 mL) and palladium dihydroxide (12%, 122 mg, 0.10 mmol) was added. The mixture was purged with nitrogen (×3) followed by hydrogen (×3), then stirred under a hydrogen atmosphere for 2.5 h. The mixture was filtered, then 1M HCl in EtOAc (4 mL) was added to the filtrate and the mixture was concentrated. Further 1M HCl in EtOAc (1 mL) was added and the mixture was concentrated. The resulting clear oil was sonicated in heptane, then concentrated, to afford a white solid with a moist appearance. The residue was then sonicated in diethyl ether, and the resultant solids were collected by filtration, to afford the title compound (393 mg, 92%) as a white solid. δH(500 MHz, DMSO-d6) 9.45 (s, 1H), 9.08 (s, 1H), 4.15-3.97 (m, 5H), 3.97-3.87 (m, 1H), 1.35 (d, J 5.2 Hz, 1H), 1.18 (t, J 7.1 Hz, 3H), 1.15 (s, 3H), 1.09 (d, J 5.2 Hz, 1H). Method B HPLC-MS: MH+ m/z 336, RT 1.48 minutes.

Intermediate 7 (500 mg, 1.36 mmol) and (6-fluoropyridin-3-yl)boronic acid (230 mg, 1.63 mmol) were dissolved in 1,4-dioxane (6 mL) and 2M aqueous potassium carbonate solution (2 mL) was added. The mixture was degassed for 10 minutes with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (55 mg, 0.068 mmol) was added and the mixture was heated at 80° C. for 1 h. Further (6-fluoropyridin-3-yl)boronic acid (40 mg, 0.284 mmol) was added and the mixture was degassed for 10 minutes, then bis[3-(diphenyl-phosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (55 mg, 0.068 mmol) was added and the mixture was heated at 90° C. overnight. The mixture was diluted with EtOAc (20 mL), then washed with water (50 mL) and brine (20 mL), before being dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 90-100% EtOAc in heptane, to afford the title compound (293 mg, 51%) as an off-white solid. Method C HPLC-MS: MH+ m/z 384, RT 1.06 minutes.

Intermediate 101 (300 mg, 0.493 mmol), ethyl 4-methylpiperidine-4-carboxylate (205 mg, 0.986 mmol) and pyridine (3 mL) were charged to a microwave tube and stirred under microwave irradiation at 180° C. for a total of 4 h. After this time, further ethyl 4-methylpiperidine-4-carboxylate (102 mg, 0.493 mmol) was added and the mixture was heated for a total of 3 h at 180° C. under microwave irradiation. Water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL), then washed with more water (2×50 mL) and brine (50 mL). The organic layer was concentrated under vacuum. The resulting brown oil was combined with further crude product (80 mg at 81% purity) for purification. The residue was purified by FCC, eluting with 0-10% methanol in DCM, to afford the title compound (382 mg) as a brown oil. Method C HPLC-MS: MH+ m/z 535, RT 1.16 minutes.

Intermediate 31 (600 mg, 1.807 mmol) and 5-bromo-2-iodopyridine (615 mg, 2.168 mmol) were dissolved in 1,4-dioxane (5 mL) and 2M aqueous potassium carbonate solution (3 mL) was added. The mixture was flushed with nitrogen and tetrakis-(triphenylphosphine)palladium(0) (104 mg, 0.09 mmol) was added. The mixture was heated at 90° C. overnight. 5-Bromo-2-iodopyridine (512 mg, 1.807 mmol) was added and the mixture was degassed for 10 minutes, then tetrakis(triphenylphosphine)palladium(0) (104 mg, 0.09 mmol) was added and the mixture was heated at 90° C. for 2 h. Aqueous potassium carbonate solution (2M, 3 mL) was added and the reaction mixture was heated at 90° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) and washed with brine (100 mL), then dried over sodium sulfate and concentrated. The resulting brown solid (1.3 g) was purified by FCC, eluting with 70-100% EtOAc in heptane, to afford the title compound (363 mg, 43%) as an off-white solid. Method C HPLC-MS: MH+ m/z 444/446, RT 1.15 minutes.

[2′,6′-Bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane (14 mg, 0.031 mmol) and palladium(II) acetate (5.7 mg, 0.026 mmol) were dissolved in degassed 1,4-dioxane (2 mL) and heated at 80° C. for 5 minutes. The mixture was then cooled to room temperature and a solution of Intermediate 103 (363 mg, 0.515 mmol) in 1,4-dioxane (6 mL) was added, followed by ethyl 4-methylpiperidine-4-carboxylate hydrochloride (117 mg, 0.566 mmol) and cesium carbonate (335 mg, 1.03 mmol). The reaction mixture was flushed with nitrogen for 10 minutes, then further [2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane (14 mg, 0.031 mmol) and palladium(II) acetate (5.7 mg, 0.026 mmol) were added and the mixture was heated at 120° C. for 2 h. The reaction mixture was flushed with nitrogen for 10 minutes, then [2′,6′-bis(propan-2-yloxy)-biphenyl-2-yl](dicyclohexyl)phosphane (30 mg, 0.062 mmol) and palladium(II) acetate (10 mg, 0.052 mmol) were added and the mixture was heated at 120° C. for 3 h. Further ethyl 4-methylpiperidine-4-carboxylate hydrochloride (117 mg, 0.566 mmol) and cesium carbonate (335 mg, 1.03 mmol) were added and the mixture was degassed for 10 minutes, before the addition of further [2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)-phosphane (30 mg, 0.062 mmol) and palladium(II) acetate (10 mg, 0.052 mmol), and the mixture was heated at 120° C. for 2.5 h. The crude mixture was filtered through celite and washed with EtOAc (80 mL). The organic phase was washed with water (30 mL) and brine (30 mL), then dried over sodium sulfate and concentrated to dryness under vacuum. The crude material was purified by FCC, then further purified by preparative HPLC, to afford the title compound (139 mg, 51%) as a clear glass. Method C HPLC-MS: MH+ m/z 535, RT 1.25 minutes.

Intermediate 18 (2 g, 5.06 mmol) was dissolved in THF (20 mL) and cooled to 0° C. under nitrogen. Methylmagnesium bromide in THF/toluene (1.4M, 6.51 mL) was added at 0° C. under nitrogen and the reaction mixture was stirred for 1 h at 0° C. under nitrogen. The reaction mixture was then allowed to warm to room temperature and stirred under nitrogen for 1 h. The reaction mixture was cooled to 0° C. under nitrogen and further methylmagnesium bromide in THF/toluene (1.4M, 1.81 mL) was added. The reaction mixture was stirred under nitrogen at 0° C. for 10 minutes, then at room temperature for 1 h. The reaction mixture was carefully quenched by the addition of saturated aqueous ammonium chloride solution (15 mL) at 0° C., and extracted into EtOAc (30 mL). The organic layer was separated, washed with brine (10 mL), dried over sodium sulfate and concentrated to dryness. The residue was triturated with 1:1 DCM/TBME (10 mL), and the solid was washed with TBME, to afford the title compound (1.51 g, 73%) as a pale yellow solid. Method C HPLC-MS: MH+ m/z 411/413, RT 1.00 minutes.

Intermediate 108 (312 mg, 0.73 mmol) and ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]-hexane-6-carboxylate hydrochloride (209 mg, 1.09 mmol) were dissolved in 1-methyl-2-pyrrolidinone (3 mL) and triethylamine (203 μL, 1.46 mmol) was added. The reaction mixture was heated at 150° C. under microwave irradiation for 1 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (3 mL). The resulting organic layer was washed with brine (1 mL), dried over sodium sulfate and concentrated to dryness. Purification was attempted by FCC, to afford the title compound (175 mg, 44%) as a yellow gum, which was used without further purification. Method C HPLC-MS: MH+ m/z 548, RT 1.16 minutes.

Intermediate 29 (0.70 g, 1.46 mmol), {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}boronic acid (0.59 g, 2.62 mmol) and a 2M sodium carbonate solution in water (5.59 mL) were combined in DME (27.5 mL) in a sealed tube and degassed thoroughly under nitrogen for 15 minutes. Pd(PPh3)4(202 mg, 0.17 mmol) was added and the mixture was heated at 90° C. for 120 minutes. The reaction mixture was cooled to r.t., then diluted using DCM (40 mL). The mixture was washed using an aqueous saturated solution of sodium bicarbonate (2×40 mL) and brine (40 mL). The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude residue was successively purified using Biotage (50 g cartridge; eluent: 0-10% MeOH/DCM) and Biotage (50 g cartridge; eluent: 0-7% MeOH/DCM with the gradient held steady at 4% MeOH/DCM), to afford the title compound (1.13 g, 94%) as a pink oil. Method C HPLC-MS: MH+ m/z 548, RT 1.82, 1.88 minutes.

Intermediate 125 (80%, 1.13 g, 1.65 mmol) was dissolved in 1,4-dioxane (10 mL) and 4M HCl in 1,4-dioxane (2.06 mL) was added. The reaction mixture was stirred at r.t. for 2 h. Additional 4M HCl in 1,4 dioxane (5 equivalents) was added and the reaction mixture was stirred at r.t. over the weekend. The solvent was removed under vacuum and the crude residue was triturated using ethyl acetate, to afford the title compound (1.01 g, 94%) as a pale orange solid. Method C HPLC-MS: MH+ m/z 448, RT 0.77 minutes.

Intermediate 132 (3 g, 17.84 mmol) was dissolved in dry toluene (60 mL), then DIPEA (12.5 mL, 71.35 mmol) was added and the reaction mixture was heated at 45° C. Trifluoromethanesulfonic anhydride (12 mL, 71.35 mmol) was added, the temperature rose to 70° C. and the reaction mixture was cooled using an ice bath. The mixture was stirred for 1.5 h at 45° C. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The aqueous washes were extracted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The aqueous washes were extracted (100 mL), then the organic extracts were combined, washed with brine (50 mL), dried over sodium sulfate and concentrated. The crude product was purified by chromatography, eluting with 0-20% ethyl acetate (200 mL), then washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The aqueous washes were extracted in heptane to afford the title compound (2.73 g, 51%). δH(250 MHz, CDCl3) 5.87 (d, J 1.9 Hz, 1H), 4.14 (q, J 7.1 Hz, 2H), 3.00 (dd, J 17.2, 6.2 Hz, 1H), 2.75-2.60 (m, 1H), 2.46-2.31 (m, 1H), 2.23-2.11 (m, 1H), 1.39-1.32 (m, 1H), 1.32-1.16 (m, 3H).

Intermediate 134 (70%, 230 mg, 0.58 mmol) and Intermediate 29 (230 mg, 0.58 mmol) were dissolved in 1,4-dioxane (3 mL). Aqueous potassium carbonate solution (2M, 0.87 mL) was added. The reaction mixture was degassed with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.06 mmol) was added and the reaction mixture was heated under microwave irradiation for 2 h at 120° C. The reaction mixture was allowed to cool, diluted with ethyl acetate (50 mL), washed with aqueous sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated. The resulting black oil was successively purified by column chromatography, using 0-10% methanol in dichloromethane, and preparative HPLC, to afford the title compound (85 mg, 28%) as a white sticky solid. Method B HPLC-MS: MH+ m/z 517, RT 1.70 minutes.

Diisopropylamine (0.35 mL, 2.48 mmol) was added dropwise to 2.5M butyllithium solution (1 mL) in THF (2 mL) at −74° C. The mixture was allowed to warm to r.t. whilst stirring for 1 h. The mixture was re-cooled and Intermediate 136 (478 mg, 1.95 mmol) in THF (5 mL) was added dropwise at −78° C. The reaction mixture was allowed to stir for 1 h, then iodomethane (0.15 mL, 2.41 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was cooled to −78° C. and 2M lithium dipropan-2-ylazanide (10 mL) was added dropwise. The reaction mixture was allowed to stir for 1 h. Iodomethane (0.05 mL, 0.8 mmol) was added dropwise at −78° C. The reaction mixture was allowed to stir at r.t. overnight. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate and concentrated under vacuum. The crude residue was purified onto a 25 g silica cartridge, eluting with a gradient of 0-25% ethyl acetate in heptane, to afford the title compound (110 mg, 22%) as a pale yellow oil. δH(500 MHz, CD3OD) 4.39 (d, J 13.2 Hz, 1H), 3.79-3.70 (m, 6H), 2.99 (s, 1H), 2.85 (d, J 12.3 Hz, 1H), 1.46 (s, 9H), 1.33 (s, 3H).

A 4M solution of hydrogen chloride in 1,4-dioxane (2.07 mL, 8 mmol) was added to a solution of 3-(tert-butyl)6-ethyl 3-azabicyclo[4.1.0]heptane-3,6-dicarboxylate (1 g, 4 mmol) in ethanol (10 mL) at room temperature. The mixture was stirred at room temperature for 2.5 h. Additional ethanol (10 mL) and 4M solution of hydrogen chloride in 1,4-dioxane (4.14 mL) were added and the mixture was heated at 50° C. for 1.5 h. The reaction mixture was cooled and evaporated under vacuum. A second reaction batch was prepared whereby a 4M solution of hydrogen chloride in 1,4-dioxane (10.4 mL, 40 mmol) was added to a solution of 3-(tert-butyl)6-ethyl 3-azabicyclo[4.1.0]heptane-3,6-dicarboxylate (1 g, 4 mmol) in ethanol (40 mL) and the reaction mixture was warmed to 75° C. and stirred at this temperature overnight. The reaction mixture was cooled to r.t. The batches were combined, then concentrated under vacuum, to afford the title compound (3.1 g) as a pale yellow solid. δH(250 MHz, DMSO-d6) 9.07 (d, J 37.9 Hz, 2H), 4.05 (q, J 7.1 Hz, 2H), 3.08 (d, J 13.1 Hz, 1H), 2.83 (s, 2H), 2.61 (dt, J 13.7, 6.5 Hz, 1H), 2.00-1.81 (m, 1H), 1.71 (q, J 7.0 Hz, 1H), 1.36-1.22 (m, 2H), 1.18 (q, J 7.1, 6.4 Hz, 3H).

Intermediate 30 (470 mg, 1.17 mmol), Intermediate 56 (375 mg, 1.41 mmol) and 2M aqueous dipotassium carbonate solution (1.76 mL) were added to 1,4-dioxane (4 mL) in a microwave tube. The mixture was degassed for 10 minutes, then Bedford's catalyst (126 mg, 0.12 mmol) was added. The reaction mixture was heated under microwave irradiation for 30 minutes at 150° C., then filtered through celite. The celite was washed with ethyl acetate. The filtrate was washed with water (50 mL) and brine (25 mL), dried with sodium sulphate and concentrated under vacuum. The crude brown oil was purified on Biotage using 100 g SNAP cartridge (loaded with DCM, eluent: 95% EtOAc/heptane to 100% EtOAc) to afford the title compound (262 mg, 40%) as an off-white solid. Method C HPLC-MS: MH+ m/z 504, RT 1.09 minutes.

To a stirred solution of (1R)-N-(methoxymethyl)-1-phenyl-N-[(trimethylsilyl)-methyl]ethanamine (55.83 mL, 205.62 mmol) and methyl prop-2-ynoate (22.5 mL, 252.9 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added trifluoroacetic acid (800 μL, 10.45 mmol). The reaction mixture was allowed to stir at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was purified by FCC, eluting with 0-70% EtOAc in heptane, to afford the title compound (26.5 g, 56%) as a yellow oil. δH(500 MHz, CDCl3) 7.41-7.29 (m, 4H), 7.28-7.21 (m, 1H), 6.77-6.70 (m, 1H), 3.72 (s, 3H), 3.71-3.65 (m, 1H), 3.65-3.42 (m, 4H), 1.40 (d, J 6.6 Hz, 3H). Method F HPLC-MS: MH+ m/z 232, RT 1.62 minutes.

To a stirred suspension of potassium tert-butoxide (12.86 g, 114.57 mmol) in anhydrous DMSO (80 mL) under nitrogen in a cold water bath (˜5° C.) was added trimethylsulfoxonium iodide (26.72 g, 120.3 mmol) portionwise. The mixture was stirred for 15 minutes, then warmed to 40° C. The mixture was cooled to approximately 5° C. with a cold water bath, then a solution of Intermediate 142 (13.25 g, 57.30 mmol) in DMSO (40 mL) was added portionwise. The mixture was stirred for 1 minute, then warmed to 50° C. and stirred for 1 h. The mixture was cooled to room temperature, then poured into water (120 mL) and ethyl acetate (120 mL). The phases were separated and the organic layer was washed with brine (80 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by FCC, eluting with 0-30% EtOAc in heptane. The procedure was repeated on the same scale as above, and the purified products were combined, to afford the title compound (11.9 g, 42%) as a colourless oil. Method F HPLC-MS: MH+ m/z 246, RT 1.77 minutes.

Intermediate 143 (5 g, 20 mmol) was separated using chiral preparative HPLC (Chiracel OJ column, 20×250 mm, 5 μm; 100% acetonitrile eluent; 20 mL/minute flow rate) and the second-eluting diastereomer was isolated (1.87 g, 7.62 mmol). This was dissolved in methanol (55 mL) and the mixture was degassed with nitrogen, then palladium on carbon (10%, 195 mg, 0.18 mmol) was added. The reaction mixture was stirred under a hydrogen balloon at room temperature for 5 h. The reaction mixture was filtered through celite and the solids were washed with excess methanol. The filtrate was concentrated by evaporation. To the residue was added 4M hydrochloric acid in diethyl ether (10 mL) and the mixture was stirred at room temperature for 10 minutes. The resulting precipitate was filtered, washed with diethyl ether and dried, to afford the title compound (1.21 g, 93%) as an off-white solid. δH(500 MHz, CD3OD) 3.83 (dd, J 11.8, 1.3 Hz, 1H), 3.75 (s, 3H), 3.59-3.52 (m, 2H), 3.44 (d, J 11.7 Hz, 1H), 2.40-2.30 (m, 1H), 1.76-1.69 (m, 1H), 1.17 (t, J 5.9 Hz, 1H).

Ethyl 4-methylidenecyclohexanecarboxylate (50 mg, 0.3 mmol) was stirred with 0.5M 9-borabicyclo[3.3.1]nonane in THF (0.89 mL), which was added slowly under nitrogen. The reaction mixture was stirred at room temperature overnight. The crude mixture was cooled to 0° C. and Intermediate 29 (203 mg, 0.51 mmol) in DMF (3 mL) was added, followed by bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (24 mg, 0.03 mmol) and 2M aqueous potassium carbonate solution (0.22 mL). The reaction mixture was stirred at room temperature over the weekend, then heated at 60° C. for 1.5 h. Further bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (50 mg, 0.061 mmol) was added and the mixture was heated at 80° C. overnight under nitrogen. The reaction mixture was added to cold water and 0.5M aqueous NaOH solution (0.5 mL) was added. The mixture was extracted with DCM (100 mL), dried over sodium sulphate, filtered and concentrated under vacuum. The resulting brown oil was purified twice by FCC, eluting with 0-30% MeOH in DCM. The material was further purified by preparative HPLC (Method C), to afford the title compound (11.4 mg, 7%) as a brown oil. Method B HPLC-MS: MH+ m/z 535, RT 1.72 minutes.

Lithium hexamethyldisilazanide in THF/ethylbenzene (1M, 6.75 mL) was added dropwise to a stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (1 g, 6.41 mmol) in THF (5 mL) at −78° C. The mixture was stirred for 1 h. 1,1,1-Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (2.4 g, 6.75 mmol) in THF (5 mL) was added over 5 minutes and the mixture was stirred for another 30 minutes. The reaction mixture was warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with aqueous sodium hydrogensulphate solution, extracted with ethyl acetate (100 mL) and washed with 0.5M aqueous NaOH solution (50 mL), saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL), then dried over magnesium sulfate and concentrated under reduced pressure, to afford the title compound (2.3 g, 87% yield at 70% purity) as a yellow oil, which was used without further purification. δH(500 MHz, CDCl3) 5.53 (t, J 4.1 Hz, 1H), 3.91-3.80 (m, 4H), 2.46-2.37 (m, 2H), 2.32-2.24 (m, 2H), 1.78 (t, J 6.6 Hz, 2H).

Intermediate 157 (90% pure, 1.57 g, 7.67 mmol) was suspended in water (100 mL), then KMnO4(4.61 g, 29.14 mmol) and 2M aqueous KOH solution (14.6 mL) were added. The mixture was heated under reflux for 2 h. The hot solution was filtered through celite and the solids were washed with water. The filtrate was acidified to pH 2 with 1N HCl, extracted into EtOAc (3×150 mL), dried over sodium sulfate and concentrated. The resulting orange oil (0.84 g) was dissolved in DCM (28 mL) and MeOH (12 mL) under a nitrogen atmosphere. (Diazomethyl)(trimethyl)silane in diethyl ether (2M, 4.22 mL) was added, and the reaction mixture was stirred at room temperature for 16 h. Acetic acid was added to the reaction mixture until the yellow colour disappeared, then the mixture was evaporated to dryness. The residue was dissolved in MeOH (50 mL) and concentrated HCl (4 mL) was added dropwise. The reaction mixture was stirred at 70° C. for 1.5 h before the solvent was removed under vacuum. The residue was partitioned between ethyl acetate (100 mL) and 2M aqueous KOH solution (100 mL). The organic layer was separated and washed with brine (2×50 mL), then dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with 0-100% EtOAc in heptane, to afford the title compound (423 mg, 31%) as a yellow oil. 3.61 (s, 3H), 2.71 (dd, J 18.1, 5.5 Hz, 1H), 2.50 (p, J 1.7 Hz, 1H), 2.42 (dd, J 18.1, 3.1 Hz, 1H), 2.24-2.10 (m, 2H), 2.01 (dt, J 14.0, 5.8 Hz, 1H), 1.68 (dtd, J 9.0, 5.8, 3.2 Hz, 1H), 1.31 (dd, J 9.2, 5.0 Hz, 1H), 1.15-1.10 (m, 1H).

Lithium hexamethyldisilazanide in THF/ethylbenzene (1M, 2.52 mL) was added dropwise to a stirred solution of Intermediate 158 (423 mg, 2.52 mmol) in THF (15 mL) at −78° C. Stirring was continued at this temperature for 1 h, then 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (943 mg, 2.64 mmol) in THF (5 mL) was added over 5 minutes and stirring was continued for another 30 minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic phase was sequentially washed with 0.5M aqueous NaOH solution (2×25 mL), saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and concentrated in vacuo, to afford the title compound (1.27 g, 100% yield at 60% purity) as an orange oil, which was used without further purification. δH(500 MHz, DMSO-d6) 6.25 (dd, J 6.2, 2.0 Hz, 1H), 3.62 (s, 3H), 2.33-2.20 (m, 3H), 2.14 (ddd, J 13.5, 11.3, 7.1 Hz, 1H), 1.91 (dt, J 9.0, 5.9 Hz, 1H), 1.52 (dd, J 9.0, 4.5 Hz, 1H), 1.28-1.25 (m, 1H).

Intermediate 161 (95% pure, 26 mg, 0.05 mmol) was dissolved in ethanol (3 mL) and the reaction vessel was purged and evacuated thrice with nitrogen. Palladium on carbon (10%, 50% wet, 15 mg, 0.01 mmol) was added and the reaction vessel was purged and evacuated thrice with nitrogen gas, then purged and evacuated thrice with hydrogen gas. The reaction was stirred at room temperature under a hydrogen atmosphere for 3 days. The vessel was evacuated and purged with nitrogen gas. The mixture was filtered through a pad of Celite, then the solids were washed with MeOH (50 mL) and the filtrate was evaporated to dryness. The residue was purified by FCC, eluting with 0-100% MeOH in DCM, to afford the title compound (13 mg, 47%) as a yellow oil. Method D HPLC-MS: MH+ m/z 537, RT 2.54-2.55 minutes.

A solution of trimethylsulfoxonium iodide (176 mg, 0.79 mmol) and potassium tert-butoxide (85 mg, 0.75 mmol) in DMSO (2 mL) was stirred at 50° C. for 45 minutes. A solution of methyl 4-[5-(3-{[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-2-yl]cyclohex-3-ene-1-carboxylate (prepared in an analogous manner to that described for Example 39, 100 mg, 0.2 mmol) in DMSO (2 mL) was added and the mixture was stirred at 50° C. for 4 h, then at room temperature for 3 days. The reaction mixture was diluted with DCM (10 mL) and washed with water (3×3 mL). The aqueous washes were combined and further extracted with DCM (2×3 mL). The organic extracts were combined, dried over sodium sulfate and evaporated. The resulting crude brown residue was diluted with DCM (3 mL) and washed with 1N aqueous NaOH solution (3×1 mL). The organic phase was dried over sodium sulfate and evaporated. The resulting pale brown residue was purified by preparative TLC, eluting with 1% MeOH in DCM, to afford the title compound (38.3 mg, 37%) as an off-white solid. Method B HPLC-MS: MH+ m/z 519, RT 1.80 minutes.

To a stirring solution of Intermediate 165 (200 mg, 0.40 mmol) in ethyl acetate (10 mL) and triethylamine (55 μL, 0.4 mmol), degassed and purged with nitrogen, was added palladium on carbon (10%, 42 mg, 0.04 mmol). The reaction mixture was degassed and purged with nitrogen, then stirred under a hydrogen balloon at room temperature until the reduction was complete. The reaction mixture was filtered through celite and the solids were washed with excess 1:1 ethyl acetate/methanol. The filtrate was evaporated. The resulting dark orange residue was purified by FCC, eluting with 50-100% ethyl acetate in heptane followed by 1-20% methanol in ethyl acetate. The material was then further purified to isomeric purity, using SFC (Cellulose-3 column; 10% MeOH/90% CO2eluent), to afford the title compounds as the trans isomer (25 mg, 12%) and the cis isomer (74 mg, 36%).

Intermediate 47 (50 mg, 0.12 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (38 mg, 0.15 mmol) and 2M aqueous potassium carbonate solution (0.19 mL) were added to 1,4-dioxane (1 mL) in a microwave tube, and the mixture was degassed for 10 minutes. Bedford's catalyst (13 mg, 0.01 mmol) was added and reaction mixture was heated under microwave irradiation for 30 minutes at 120° C. The reaction mixture was further heated at 150° C. for 30 minutes under microwave irradiation. Water (5 mL) was added, and the reaction mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with brine (30 mL), dried with sodium sulphate, filtered and concentrated under vacuum. The resulting black oil was purified by chromatography on a Biotage, using 10 g SNAP cartridge (eluent 80% ethyl acetate in heptane to 100% EtOAc), to afford the title compound (110 mg, 41%) as a black oil. Method B HPLC-MS: MH+ m/z 519, RT 1.68 minutes.

Intermediate 176 (76%, 110 mg, 0.16 mmol) and triethylamine (0.03 mL, 0.22 mmol) were dissolved in ethyl acetate (3 mL) and degassed with nitrogen. Palladium (10% on carbon, 18 mg, 0.02 mmol) was added and the reaction mixture was purged with nitrogen (3 times) before replacing nitrogen by hydrogen gas. The reaction mixture was stirred under hydrogen for 3 h at room temperature. The reaction mixture was filtered through celite, washed with ethyl acetate (15 mL) and concentrated to ˜3 mL under vacuum. Additional triethylamine (30 μL) and fresh palladium on carbon (10%, 17.67 mg, 0.02 mmol) were added, and the reaction mixture was stirred at room temperature overnight under hydrogen. The reaction mixture was filtered through celite and washed with ethyl acetate (2 mL). The organic filtrate was washed with water (20 mL) and brine (20 mL), then dried with sodium sulphate, filtered and concentrated under vacuum. The resulting orange oil was purified, using the Biotage system on a 10 g SNAP cartridge (eluent: 25 to 100% EtOAc in heptane), to afford the title compound (45 mg, 53%) as a clear oil (69:31 mixture of cis and trans isomers). Method B HPLC-MS: MH+ m/z 521, RT 1.75 minutes.

Intermediate 178 (680 mg, 2.25 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (855 mg, 3.37 mmol), potassium acetate (660 mg, 6.72 mmol) and 1,1′-bis(diphenylphosphanyl)ferrocene (65 mg, 0.12 mmol) were charged in a tube with anhydrous 1,4-dioxane (5 mL). The mixture was degassed by bubbling nitrogen for 30 minutes. Pd(dppf)Cl2complex with dichloromethane (90 mg, 0.11 mmol) was added and the mixture was sealed under nitrogen. The reaction mixture was stirred at 90° C. for 18 h. The reaction mixture was allowed to cool to room temperature, then diluted with ethyl acetate (50 mL) and water (10 mL). The aqueous phase was separated and the organic phase was washed with saturated aqueous sodium bicarbonate solution (10 mL) and brine (10 mL), then dried over sodium sulphate, filtered and concentrated under vacuum. The crude residue was purified by column chromatography on silica (0 to 100% DCM in heptane, followed by 0 to 2% methanol in DCM), to afford the title compound (259 mg, 29%) as a viscous light brown liquid. 6.46 (s, 1H), 3.65-3.58 (m, 3H), 2.26-2.12 (m, 4H), 2.11-1.96 (m, 2H), 1.81-1.65 (m, 2H), 1.38-1.24 (m, 1H), 1.25-1.14 (m, 12H).

To a cooled solution of diisopropylamine (7.72 mL, 54.62 mmol) in ether (40 mL) at −78° C. was added 2.5M n-butyllithium (21.8 mL) dropwise. The reaction mixture was allowed to warm to −11° C. A solution of cyclohex-2-en-1-one (5.04 mL, 52.01 mmol) in diethyl ether (60 mL) was added over 45 minutes. During the addition, the temperature was maintained between −11° C. and −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl prop-2-enoate (4.68 mL, 52.01 mmol) in THF (40 mL) was added dropwise over 60 minutes. The reaction mixture was stirred at this temperature for 1 h and stored in a freezer overnight. The reaction mixture was poured into saturated ammonium chloride solution (200 mL) and stirred for 15 minutes. A brown sticky polymer was formed and removed using tweezers. The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (Biotage; 0-60% ethyl acetate in heptane) in 2 batches, to afford the title compound (2.98 g, 31%) as the trans isomer as a clear colourless liquid. δH(500 MHz, CDCl3) 3.70 (s, 3H), 2.76 (ddt, J 10.6, 6.4, 1.8 Hz, 1H), 2.53-2.48 (m, 1H), 2.47-2.38 (m, 1H), 2.37-2.31 (m, 1H), 2.22 (ddt, J 14.2, 6.3, 2.5 Hz, 1H), 2.13 (ddd, J 19.1, 2.9, 1.8 Hz, 1H), 2.02 (ddd, J 14.3, 11.0, 3.5 Hz, 1H), 1.89-1.74 (m, 3H), 1.70-1.60 (m, 1H).

Intermediate 183 (1 g, 3.18 mmol) was dissolved in dry 1,4-dioxane (10 mL) and the mixture was degassed for 5 minutes with nitrogen. Bis(pinacolato)diboron (1.21 g, 4.77 mmol), potassium acetate (1 g, 10.19 mmol), 1,1′-bis(diphenylphosphanyl)ferrocene (90 mg, 0.16 mmol) and Pd(dppf)Cl2complex with dichloromethane (130 mg, 0.16 mmol) were added. The mixture was heated at 90° C. and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) was added. The phases were separated. The aqueous phase was washed with ethyl acetate (50 mL), then the organic extracts were washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated. The crude product was purified twice by column chromatography (Biotage, 0-30% ethyl acetate in heptane; then Biotage, 0-100% dichloromethane in heptane). The material thus obtained was added to Intermediate 152 (240 mg, 0.57 mmol) in a microwave vial. Dry 1,4-dioxane (3 mL) and 2M aqueous sodium carbonate solution (900 μL) were added. The mixture was degassed with nitrogen for 2 minutes. Tetrakis(triphenylphosphine) palladium(0) (66 mg, 0.06 mmol) was added and the reaction mixture was heated for 45 minutes under microwave irradiation at 120° C. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2×25 mL), then dried over sodium sulphate, filtered and concentrated. The crude residue was purified by chromatography (0-3% methanol in dichloromethane). The residue (204 mg) was filtered through charcoal, eluting with ethyl acetate. The resulting solution was concentrated and re-dissolved in ethyl acetate (5 mL). Triethylamine (51.32 μL, 0.37 mmol) and palladium on carbon (10%, 50 mg, 0.05 mmol) were added. The mixture was flushed with nitrogen (3 times) and hydrogen (3 times). The mixture was stirred under hydrogen for 20 h. The reaction mixture was filtered through celite and concentrated. The crude residue was purified by column chromatography (0-2% methanol in dichloromethane), to afford the title compound (139 mg, 75%) as a pink oil. Method B HPLC-MS: MH+ m/z 551, RT 1.80 minutes.

Intermediate 152 (190 mg, 0.45 mmol) and Intermediate 134 (75%, 185 mg, 0.5 mmol) were dissolved in 1,4-dioxane (3 mL). Aqueous potassium carbonate solution (2M, 0.7 mL) was added and the reaction mixture was degassed for 5 minutes using nitrogen. Tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.05 mmol) was added and the mixture was heated under microwave irradiation for 2.5 h at 120° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×3 mL). The organic extracts were combined, dried over sodium sulphate, filtered and concentrated. The resulting crude residue was purified by preparative HPLC (Method C), to afford the title compound (120 mg, 45%) as a pink oily solid. Method D HPLC-MS: MH+ m/z 536, RT 2.65 minutes.

A solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5M, 80 mL, 40 mmol) was added dropwise to cyclohexa-1,4-diene (3.2 g, 40 mmol). The solution was stirred overnight at room temperature. An aqueous solution of sodium hydroxide (3M, 12 mL) was added, followed by dropwise addition of hydrogen peroxide (30%, 12 mL). The resulting solution was heated at reflux for 1 h, then allowed to cool. The reaction mixture was poured into brine (200 mL) and extracted with diethyl ether (3×200 mL). The combined ethereal layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography, eluting with 0 to 100% ethyl acetate in heptane, then 0 to 50% methanol in ethyl acetate, to afford the title compound (1.25 g, 32%) as a clear oil. δH(250 MHz, CDCl3) 5.82-5.45 (m, 1H), 4.03-3.74 (m, 1H), 2.60-0.71 (m, 8H).

Intermediate 197 (400 mg, 2.195 mmol) was dissolved in toluene (10 mL), then DIPEA (1.55 mL, 8.90 mmol) was added and the mixture was heated at 45° C. for 10 minutes. 1M trifluoromethanesulfonic anhydride (8.8 mL, 8.8 mmol) was added dropwise and the mixture was heated for 1 h. The reaction mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted with dichloromethane (2×100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then dried over magnesium sulfate and concentrated. The residue was purified by column chromatography, eluting with 10 to 100% ethyl acetate in heptane, to afford the title compound (0.40 g, 56%) as a mixture of double bond isomers as an orange oil. δH(500 MHz, CDCl3) 5.86 (ddd, J 236.4, 5.6, 2.5 Hz, 1H), 4.16 (qd, J 7.1, 3.1 Hz, 2H), 2.95-1.47 (m, 7H), 1.37-1.21 (m, 3H). Method C HPLC-MS: MH+ m/z 315, RT 1.53 minutes.

Intermediate 198 (400 mg, 1.27 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (485 mg, 1.91 mmol), and potassium acetate (375 mg, 3.82 mmol) were suspended in dry 1,4-dioxane (10 mL) and the mixture was degassed for 10 minutes, then 1,1′-bis(diphenylphosphanyl)ferrocene (21 mg, 38 μmol) was added, followed by PdCl2(dppf) complex with dichloromethane (31 mg, 38 μmol). The reaction mixture was heated at 90° C. for 3 h in a microwave reactor. Additional 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane, 1,1′-bis(diphenylphosphanyl)ferrocene and PdCl2(dppf) complex with dichloromethane were added and the mixture was heated at 90° C. in a microwave reactor for a total of 7 h, then at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (80 mL), dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography, eluting with 5 to 50% ethyl acetate in heptanes, to afford the title compound (418 mg, 47% yield at 41% purity) as a yellow solid. δH(500 MHz, CDCl3) 6.87-6.23 (m, 1H), 4.22-3.95 (m, 2H), 2.62-1.40 (m, 7H), 1.18 (d, J 9.2 Hz, 15H). Method C HPLC-MS: MH+ m/z 293, RT 1.59 minutes.

Intermediate 68 (1 g, 2.6 mmol) and (6-chloropyridin-3-yl)boronic acid (368 mg, 2.34 mmol) were dissolved in 1,4-dioxane (6 mL) and 2M aqueous potassium carbonate solution (3.9 mL). The mixture was added to a sealed tube and degassed for 10 minutes with nitrogen. Pd(dppf)Cl2complex with dichloromethane (106 mg, 0.13 mmol) was added and the mixture was heated at 80° C. for 1.5 h. Additional (6-chloropyridin-3-yl)-boronic acid (123 mg, 0.78 mmol) was added, and the reaction mixture was degassed for 10 minutes. Pd(dppf)Cl2complex with dichloromethane (106 mg, 0.13 mmol) was added and the mixture was heated at 80° C. overnight. The mixture was extracted with ethyl acetate (2×25 mL). The organic phase was washed with brine (2×25 mL), dried with sodium sulphate, filtered and concentrated under vacuum. The resulting black oily residue was purified by chromatography using Biotage (100 g SNAP cartridge), eluting with 100% ethyl acetate, then further purified by trituration in ethyl acetate (4 mL), to afford the title compound (173 mg, 15%) as a white solid. Further solid in the filtrate was triturated with ethyl acetate (4 mL) and filtered, to afford an additional quantity of the title compound (145 mg, 13%) as a white solid. Method B HPLC-MS: MH+ m/z 417, RT 1.60 minutes.

Intermediate 202 (350 mg, 0.84 mmol) and Intermediate 134 (75%, 372 mg, 1.00 mmol) were dissolved in 1,4-dioxane (4 mL), then 2M aqueous potassium carbonate solution (1.3 mL) was added and the reaction mixture was degassed for 10 minutes before addition of tetrakis(triphenylphosphine)palladium(0) (484 mg, 0.42 mmol). The reaction mixture was stirred at 120° C. under microwave irradiation for 1.5 h. The reaction mixture was extracted with ethyl acetate (30 mL), and the organic phase was washed with water (2×20 mL) and brine (25 mL). The solid present in the organic phase was filtered and discarded. The organic phase was dried over sodium sulphate, filtered and concentrated under vacuum. The resulting orange residue was purified on the Biotage system (100 g SNAP cartridge used, eluting with 25 to 100% ethyl acetate in heptane), to afford the title compound (92 mg, 20%) as a yellow gum. Method B HPLC-MS: MH+ m/z 534, RT 1.76, 1.87 minutes.

Intermediate 203 (192 mg, 0.17 mmol) was dissolved in ethyl acetate (2 mL), then triethylamine (30 μL, 0.21 mmol) and palladium on carbon (10%, 183 mg, 0.17 mmol) were added. The reaction mixture was purged with nitrogen, then evacuated (3 times), filled with hydrogen and evacuated (3 times). The reaction mixture was stirred at room temperature for 2.5 h under hydrogen. The reaction mixture was filtered through celite and washed with ethyl acetate (25 mL), then the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (Method C) to afford the title compound (47 mg, 51%) as an orange gum. Method B HPLC-MS: MH+ m/z 536, RT 1.78 minutes.

Intermediate 206 (75%, 4.1 g, 12.69 mmol) in a 12N hydrogen chloride solution in water (50 mL) was heated at reflux for 12 h. The solvent was removed in vacuo, then the residue was dissolved in methanol (100 mL) and concentrated sulphuric acid (2 mL) was added. The mixture was heated at reflux for 20 h. Upon cooling, the reaction mixture was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (300 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Biotage Isolera 4, SNAP 100 g), eluting with 0 to 100% methanol in dichloromethane, to afford the title compound (1.67 g, 47%) as a red-brown oil. δH(250 MHz, CDCl3) 7.46-7.10 (m, 5H), 4.15-3.77 (m, 2H), 3.73 (d, J 1.9 Hz, 3H), 3.69-3.49 (m, 3H), 3.48-3.34 (m, 1H), 2.95-2.74 (m, 2H), 2.56-2.09 (m, 5H). Method B HPLC-MS: MH+ m/z 276, RT 1.03 minutes.

Intermediate 207 (98%, 1.3 g, 4.63 mmol) was dissolved in ethyl acetate (15 mL) and the solution was degassed with nitrogen. Palladium on carbon (10%, 500 mg, 0.47 mmol) was added and the mixture was degassed with nitrogen. The reaction mixture was allowed to stir under hydrogen at room temperature for 18 h. Additional palladium on carbon (10%, 250 mg, 0.23 mmol) was added and the mixture was degassed with nitrogen. The reaction mixture was allowed to stir under hydrogen at room temperature for 18 h. Additional palladium on carbon (10%, 250 mg, 0.23 mmol) and 1M hydrogen chloride in ethyl acetate (5 mL) were added and the mixture was degassed with nitrogen. The reaction mixture was allowed to stir under hydrogen at room temperature for 18 h. The reaction mixture was filtered through celite which was washed excessively with ethyl acetate (200 mL) followed by dichloromethane (200 mL). The filtrate was concentrated under vacuum to afford the title compound (1.03 g, 98%) as an orange solid. δH(500 MHz, CD3OD) 4.19 (d, J 11.6 Hz, 1H), 4.01 (d, J 12.0 Hz, 1H), 3.79 (dd, J 25.6, 2.6 Hz, 5H), 3.65 (d, J 12.7 Hz, 1H), 3.49 (d, J 13.3 Hz, 1H), 3.42 (d, J 12.7 Hz, 1H), 3.35-3.31 (m, 1H), 3.09 (s, 1H), 2.36 (d, J 13.3 Hz, 2H).

To a stirred solution of Intermediate 210 (1.05 g, 4.08 mmol) in tetrahydrofuran (70 mL) cooled to −78° C. was added dropwise 1M lithium 1,1,1,3,3,3-hexamethyl-disilazan-2-ide in tetrahydrofuran (4.29 mL). The reaction mixture was stirred at −78° C. for 1 h prior to the addition of 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]-methanesulfonamide (1.53 g, 4.29 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature, and stirred at room temperature over 2 days. The reaction mixture was quenched with aqueous sodium hydrogensulphate solution (50 mL) and extracted with ethyl acetate (70 mL). The organic layer was washed with 0.5M aqueous sodium hydroxide solution (70 mL), saturated aqueous ammonium chloride solution (70 mL) and brine (70 mL), then dried over sodium sulphate, filtered and concentrated under vacuum. The resulting crude yellow oil was purified twice by column chromatography (Biotage Isolera 4, 50 g cartridge), eluting with 0% to 100% tert-butyl methyl ether in heptane for the first column and 0 to 50% tert-butyl methyl ether in heptane for the second column, to afford the title compounds (597 mg, 32%) as a colourless oil. Method B HPLC-MS: [M-BOC]+ m/z 290, RT 2.25 minutes.

A mixture of Intermediate 152 (280 mg, 0.70 mmol), Intermediate 212 (294 mg, 0.80 mmol) and 2M aqueous sodium carbonate solution (1.0 mL) in 1,4-dioxane (5.0 mL) was purged with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.03 mmol) was then added and the reaction mixture was heated at 120° C. under microwave irradiation for 1 h. The cooled reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous layer was separated and extracted into ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulphate, filtered and evaporated. The resulting crude residue was successively purified by column chromatography (Biotage Isolera, 25 g cartridge), eluting with 40% to 100% ethyl acetate in heptane, and by preparative chromatography (Method C), to afford the title compounds (205 mg, 49%) as a pale brown solid. Method B HPLC-MS: MH+ m/z 624, RT 1.92 minutes.

General Method C

Formation of Functionalised Pyrimidine Boronic Acids

To a suspension of (2-chloropyrimidin-5-yl)boronic acid (1.0 eq) in ethanol is added the appropriate amine (0.95 eq). Triethylamine (2.5 eq) is added and the mixture stirred at either ambient temperature or 80° C. until the reaction is complete by TLC or LCMS. If the product precipitates the desired compound is isolated by filtration. For soluble products the reaction mixture is concentrated in vacuo and the crude product mixture is partitioned between aqueous medium and ethyl acetate. The aqueous layer is separated and re-extracted with ethyl acetate. The organic layers are combined and washed with brine, then dried (Na2SO4), filtered and concentrated in vacuo. The product can be further purified if required by column chromatography on silica gel or preparative mass-directed HPLC.

The title compound was prepared from 1,4-oxazepane-7-carboxylic acid and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.

The title compound was prepared from (2R)-morpholine-2-carboxylic acid and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.

The title compound was prepared from 3,6-diazabicyclo[3.2.2]nonan-7-one and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.

The title compound was synthesised from Intermediate 56 in accordance with the method outlined for Intermediate 221.

A stirred mixture of ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (prepared in an analogous manner to Intermediate 273; 70 g, 190 mmol, 80%), 5-bromo-2-iodopyrimidine (54.2 g, 190 mmol) and sodium carbonate (60.5 g, 571 mmol) in 1,2-dimethoxyethane (750 mL) and water (250 mL) was flushed with argon. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride (4.66 g, 5.71 mmol) was added and the resulting mixture was stirred at 100° C. until the reaction was complete by LCMS or TLC. The reaction mixture was quenched into aqueous NaCl solution (˜10 wt %, 1000 mL) and EtOAc (200 mL) with stirring. The layers were separated and the aqueous layer was extracted with EtOAc (3×200 mL). The combined extracts were dried with Na2SO4and concentrated in vacuo. The resulting brown-black tar (95 g) was triturated in diisopropyl ether/heptane (1:1, 400 mL) under slight heating for 1 h. The whole was filtered over kieselguhr and rinsed with diisopropyl ether/heptane (1:1). Upon concentration in vacuo the residue was triturated in warm heptane (1 L) together with Norit® activated charcoal. The whole was again filtered over kieselguhr and concentrated in vacuo. The resulting clear yellow-orange oil (69 g), which solidified upon standing, was purified by gravity column chromatography. The resulting white solid (27 g, 83 mmol) was stirred with bis(pinacolato)diboron (21.08 g, 83 mmol) and potassium acetate (24.4 g, 249 mmol) in 1,4-dioxane (anhydrous, 300 mL) and flushed with argon (3 vacuum-argon cycles) for 5 minutes. 1,1′-Bis(diphenylphosphino)-ferrocenepalladium(II) dichloride (2.034 g, 2.491 mmol) was added, and the resulting mixture was stirred at 90° C. for 3 h. The reaction mixture was cooled to ˜40° C. and filtered over a pad of kieselguhr, which was rinsed with EtOAc (300 mL). The filtrate was concentrated in vacuo. The resulting dark brown solid (51 g) was triturated in heptane/diisopropyl ether (1:1, 400 mL) at ˜50° C., and some scoops of Norit® activated charcoal were added. After 30 minutes the insoluble materials were removed by filtration over kieselguhr. The residue was rinsed with heptane/diisopropyl ether (1:1, 500 mL) at ˜50° C. More insoluble material (sticky dark gum) precipitated from the filtrate. Norit® activated charcoal was added and the resulting suspension was stirred for 30 minutes at room temperature. The residue was filtered over a new pad of kieselguhr and rinsed with warm heptane/diisopropyl ether (1:1, 500 mL). Concentration of the filtrate in vacuo yielded the title compound (38 g) as a beige solid.

General Method B

The appropriate 2-chloropyrimidine (e.g. Intermediate 29 or Intermediate 152; 1 eq), the appropriate amine (1 eq) and triethylamine (1 eq) are dissolved in ethanol and heated at 80° C. until the reaction is complete by TLC or LCMS analysis. The ethanol is removed under vacuum and water added. Depending on solubility, the product is isolated by filtration or extracted into ethyl acetate. Ethyl acetate solutions are subsequently dried over sodium sulphate, filtered and concentrated in vacuo. The crude residue thus obtained is purified by an appropriate technique, typically column chromatography on silica gel or preparative mass-directed HPLC.

A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1 g, 3.89 mmol) in THF (5 mL) was stirred at −78° C. and lithium bis(trimethylsilyl)amide (1M in toluene, 5.8 mL, 29 mmol) was added dropwise, then stirred for 1 h. Paraformaldehyde (0.7370 g, 7.773 mmol) was added and the mixture was stirred for 16 h, allowing the temperature to rise slowly to ambient. The reaction mixture was quenched using saturated aqueous ammonium chloride solution, then partitioned between EtOAc and brine. The aqueous layer was further extracted using EtOAc. The combined organic extracts were dried (MgSO4) and the solvent was removed under vacuum. The resulting material was dissolved and stirred for 1 h in TFA (10 mL), then rotary evaporated to dryness. The crude residue (theoretical 0.7 g, 3.891 mmol) was dissolved in ethanol (12 mL), then sodium carbonate (1.03 g, 9.72 mmol) and (2-chloropyrimidin-5-yl)boronic acid (0.68 g, 4.3 mmol) were added and the reaction mixture was stirred at 60° C. for 2 h. LC/MS showed completion of reaction. The mixture was cooled to ambient temperature and filtered through celite. The solvent was removed to give the crude title compound (1 g, 83%) as a cream solid, which was used without further purification. LCMS (pH 10) MH+ 310, RT 0.95 minutes.

The title compound was synthesized from Intermediate 91 in accordance with General Method C.

TFA (5 mL) was added to 1-tert-butyl 4-ethyl 4-(trifluoromethyl)piperidine-1,4-dicarboxylate (0.42 g, 1.29 mmol). The mixture was stirred for 30 minutes, then rotary evaporated to dryness and left on a high vacuum line for 1 h. The residual syrup was dissolved in ethanol (4 mL), anhydrous sodium carbonate (0.35 g, 3.3 mmol) was added, and the mixture was stirred for 10 minutes. (2-Chloropyrimidin-5-yl)boronic acid (0.23 g, 1.4 mmol) was added and the reaction mixture was stirred at 60° C. for 6 h. The mixture was filtered through celite and concentrated to give the title compound (0.4 g, 89%) as an off-white foam, which was used without further purification. LCMS (pH 10) MH+ 348, RT 1.31 minutes.

A mixture of ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2 g, 9.4491 mmol), (2-chloropyrimidin-5-yl)boronic acid (1.5426 g, 9.4493 mmol) and sodium carbonate decahydrate (2.53 g, 23.6 mmol) in ethanol (15 mL) was stirred at 60° C. for 12 h. The reaction mixture was filtered through celite, the solvent was evaporated and the residue was dried under vacuum to give the title compound (2.7 g, 97%) as a pale yellow gum, which was used without further purification. LCMS (pH 10) MH+ 298, RT 1.19 minutes.

A 2% solution of HCl in MeOH was prepared by adding acetyl chloride (1.1 mL) to MeOH (25 mL). To this solution was added 1-[(tert-butoxy)carbonyl]-4-methoxypiperidine-4-carboxylic acid (1 g, 3.6637 mmol) and the solution was heated under reflux for 6 h. The reaction mixture was evaporated to dryness and left on a vacuum line for 30 minutes. The material thus obtained was dissolved in ethanol (8 mL) and stirred with sodium carbonate (0.96 g, 9.1 mmol) for 10 minutes, then (2-chloropyrimidin-5-yl)-boronic acid (0.57 g, 3.61 mmol) was added and the mixture was stirred at 60° C. for 6 h. The reaction mixture was filtered through celite and the solvents removed in vacuo to give the title compound (0.8 g, 71%) as a white foam, which was used without further purification. LCMS (pH 10) MH+ 296, RT 0.86 minutes.

TFA (8 mL) was added to a stirred solution of 1-tert-butyl 4-methyl 4-ethylpiperidine-1,4-dicarboxylate (0.61 g, 2.25 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred for 2 h, then the volatiles were removed by rotary evaporation and the residue was left on a high vacuum line for 1 h. The syrupy material thus obtained was dissolved in ethanol (8 mL), anhydrous sodium carbonate (0.72 g, 6.79 mmol) was added and the mixture was stirred for 10 minutes. (2-Chloropyrimidin-5-yl)boronic acid (0.37 g, 2.3 mmol) was added and the mixture was stirred at 80° C. for 7 h. The reaction mixture was filtered through celite, then the solvent was removed under vacuum, and water was added. The mixture was decanted and washed again with water, then the residual gum was freeze-dried, to give the title compound (0.4 g, 60%) as a pale yellow lyophilised solid, which was used without further purification. LCMS (pH 10) MH+ 294, RT 1.15 minutes.

(1R,5S)-3-tert-Butoxycarbonyl-3-azabicyclo[3.2.1]octane-8-carboxylic acid (9.0 g, 35.3 mmol) was suspended in HCl solution (2.25M in MeOH) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was allowed to cool to r.t., then concentrated in vacuo. To the resulting white solid was added (2-chloropyrimidin-5-yl)boronic acid (5.58 g, 35.2 mmol) and the mixture was suspended in EtOH (130 mL). Triethylamine (9.90 mL, 70.5 mmol) was added and the reaction mixture was heated at 80° C. for 5 h. The reaction mixture was allowed to cool to r.t., then water (30 mL) was added. The reaction mixture was concentrated to around one-third volume, then more water (100 mL) was added. The resulting off-white solid precipitate was filtered and washed with water (2×30 mL), to afford the title compound (8.9 g, 86%) as an off-white powder. δH(300 MHz, DMSO-d6) 8.59 (2H, s), 8.02 (2H, s), 4.45 (2H, dd, J 13.1, 3.4 Hz), 3.62 (3H, s), 2.98 (2H, br d, J 12.4 Hz), 2.77 (1H, s), 2.59 (2H, br s), 1.66-1.63 (2H, m), 1.38-1.33 (2H, m). HPLC-MS (pH 10): MH+ m/z 292, RT 0.97 minutes.

Intermediate 143 (5 g, 20 mmol) was separated using chiral preparative HPLC (Chiracel OJ column, 20×250 mm, 5 μm; 100% acetonitrile eluent; 20 mL/minute flow rate) and the first-eluting diastereomer was isolated (1.87 g, 7.62 mmol). This was dissolved in methanol (55 mL) and the mixture was degassed with nitrogen, then palladium on carbon (10%, 195 mg, 0.18 mmol) was added. The reaction mixture was stirred under a hydrogen balloon at room temperature for 5 h. The reaction mixture was filtered through celite and the solids were washed with excess methanol. The filtrate was concentrated by evaporation. To the residue was added 4M hydrochloric acid in diethyl ether (10 mL), and the mixture was stirred at room temperature for 10 minutes. The resulting precipitate was filtered, washed with diethyl ether and dried, to afford the title compound as an off-white solid. δH(500 MHz, CD3OD) 3.83 (dd, J 11.8, 1.3 Hz, 1H), 3.75 (s, 3H), 3.59-3.52 (m, 2H), 3.44 (d, J 11.7 Hz, 1H), 2.40-2.30 (m, 1H), 1.76-1.69 (m, 1H), 1.17 (t, J 5.9 Hz, 1H).

To a stirred solution of ethyl 3-oxocyclohexanecarboxylate (0.47 mL, 2.9 mmol) in THF (2.5 mL, 100 mass %) at −78° C. was added lithium bis(trimethylsilyl)amide (3.10 mL, 1M in THF) dropwise. The reaction mixture stirred at −78° C. for 1 h, after which time N-phenyltrifluoromethanesulfonimide (1.10 g, 3.08 mmol) in THF (2.5 mL, 100 mass %) was added to the mixture. The reaction mixture was stirred at −78° C. for a further 1.5 h, after which time the reaction mixture allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with aqueous sodium hydrogensulphate solution (˜10 mL) and diluted with ethyl acetate (50 mL). The layers were separated and organic layers were washed with 5% aqueous NaOH solution (2×30 mL), saturated aqueous ammonium chloride solution (20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentrated in vacuo, to give the title compound (932 mg, quantitative) as a yellow oil. δH(DMSO-d6) 5.89-5.95 (m, 1H), 4.00-4.15 (m, 2H), 2.77-2.91 (m, 1H), 2.16-2.35 (m, 2H), 1.51-1.97 (m, 4H), 1.12-1.24 (m, 3H).

To a stirred solution of Intermediate 238 (350 mg, 0.68 mmol) in EtOH (25 mL) was added 10% palladium on carbon (16 mg, 0.15 mmol) and the reaction mixture was stirred under an atmosphere of hydrogen for 72 h. The reaction mixture was filtered through celite, washed with EtOH and MeOH, and concentrated in vacuo, to give the title compound (300 mg, 85%) as a yellow oil. LCMS (ES+) 521 (M+H)+, RT 2.41, 2.46 minutes.

The title compound was synthesised from methyl 4-(tert-butoxycarbonylamino)-piperidine-4-carboxylate and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.

Intermediate 54 (1.0 g, 2.5 mmol) was cooled (iced bath) and thionyl chloride (10 mL, 137 mmol) was added with stirring. The reaction mixture was stirred for 1 h. The volatiles were removed in vacuo and the residue was separated between DCM and sodium bicarbonate solution. The organic layer was passed through a phase separator, then evaporated in vacuo, to give the title compound (1.0 g, 96%) as an off white solid. LCMS (ES+) 421 (M+H)+, RT 2.5 minutes.

TFA (10 mL) was added to a stirred solution of Intermediate 247 (0.54 g, 1.90 mmol) in 1,4-dioxane (2 mL). The mixture was stirred for 2 h, then the solvent was removed by rotary evaporation and the residue was dried under vacuum for 1 h. The residual syrup was dissolved in ethanol (10 mL), then sodium carbonate (0.5 g, 4.72 mmol) and (2-chloropyrimidin-5-yl)boronic acid (0.37 g, 2.3 mmol) were added and the reaction mixture was stirred at 80° C. for 5 h. The cooled reaction mixture was filtered through celite and concentrated to dryness, to give the title compound as a foam, which was used without further purification. LCMS (pH 10): MH+ 308, RT 1.23 minutes.

Prepared from Intermediate 249 in accordance with General Method C to give the title compound (1.5 g) as an off white solid, which was used without further purification. LCMS (pH 10): MH+ 282, RT 0.23 minutes.

To a stirred solution of 2-amino-4-chloropyridine (1 g) in acetonitrile (8 mL) was added dropwise a solution of N-bromosuccinimide (1.5 g) in acetonitrile (2 mL). The reaction mixture was stirred at 25-28° C. for 1 h. The solvent was evaporated, then the residue was suspended in water and extracted with dichloromethane (2×20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The resulting crude material was purified by column chromatography, using 100-200 mesh size silica and 10-25% EtOAc in hexane as eluent, to give the title compound (1 g) as a yellow solid. δH(400 MHz, CDCl3) 8.16 (s, 1H), 6.62 (s, 1H), 4.55 (br s, 2H). LCMS: m/z 208.9, RT 2.19 minutes.

To a stirred solution of Intermediate 251 (0.1 g) in ethanol (5 mL) was added N,N-dimethylacetamide dimethyl acetal (0.064 g) and the reaction mixture was heated at 90° C. for 1 h. The solvent was evaporated, then the residue was suspended in water and extracted with dichloromethane (3×10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography, using 100-200 mesh size silica and 10-25% EtOAc in hexane as eluent, to give the title compound (0.08 g) as a yellow oil. δH(400 MHz, CDCl3) 8.39 (s, 1H), 6.86 (s, 1H), 3.06 (s, 1H), 3.06 (s, 6H), 2.02 (s, 3H). LCMS m/z 277.95, RT 2.4 minutes.

Sodium borohydride (1.15 g, 0.0305 mol) was added in one portion to a stirred solution of Intermediate 253 (10.6 g, 0.0254 mol) in ethanol (30 mL) at 25-28° C. The reaction mixture was quenched with aqueous ammonium chloride solution (20 mL) and further concentrated under vacuum. The residue was suspended in water and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over anhydrous sodium sulphate and filtered, then concentrated under vacuum and washed with diethyl ether (2×20 mL), to obtain the title compound (10.6 g) as a yellow solid. δH(400 MHz, DMSO-d6) 8.76 (s, 1H), 7.90 (dd, J 4.8, 2.0 Hz, 1H), 7.85 (s, 1H), 7.40-6.91 (m, 4H), 6.40 (s, 1H), 2.10 (s, 3H). LCMS m/z 219.1, RT 2.59 minutes.

A mixture of Intermediate 254 (10.6 g) and sodium iodide (37.9 g) in acetonitrile (40 mL) was heated at 80° C. under nitrogen for 2 h. Chlorotrimethylsilane (8.27 g) was added dropwise over 1 h, and the mixture was stirred for an additional 1 h at 80° C. The reaction mixture was concentrated under vacuum. The residue was suspended in water, extracted with dichloromethane (3×20 mL) and washed with a saturated aqueous solution of sodium bicarbonate (˜20 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The crude material was purified by column chromatography, using 100-200 mesh size silica gel and 10-25% EtOAc in hexane as eluent, to give the title compound (5.2 g) as a brown solid. δH(400 MHz, DMSO-d6) 8.67 (s, 1H), 7.87 (s, 1H), 7.43-6.99 (m, 5H), 4.32 (s, 2H), 2.27 (s, 3H).

The title compound was synthesised from 1-(methylsulfonyl)piperazine in accordance with General Method C. MS: m/z 403.05, RT 3.20 minutes.

To a solution of Intermediate 257 (0.8 g, 0.025 mmol) in THF (10 mL) was added a 2M solution of borane dimethyl sulphide in THF (1.2 mL) at 0° C. The mixture was stirred at r.t. for 30 minutes and heated under reflux for 2 h, then cooled to ambient temperature and hydrolyzed with methanol (3 mL). To the mixture was added 2M aqueous sodium hydroxide solution until pH >8 was reached. The aqueous phases were extracted with EtOAc (4×30 mL), then the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was used without further purification.

(4-Methylpiperidin-4-yl)methanol hydrochloride (2.09 g, 12.63 mmol), (2-chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and triethylamine (1.8 mL, 12.630 mmol) in ethanol (15 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to r.t. and concentrated in vacuo to give the title compound as an orange semi-solid. This material was used without any further purification. HPLC-MS: MH+m/z 252.2, RT 0.34 minutes.

Prepared from piperidine-4-sulfonamide hydrochloride (1.27 g, 6.315 mmol) and (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) in accordance with General Method C to give the title compound as an off-white semi-solid. HPLC-MS: m/z (M−H)+285.1, RT 0.14 minutes.

A solution of Intermediate 68 (15.5 g, 40.2 mmol) and methyl iodide (5.71 g, 40.2 mmol, 2.52 mL) in anhydrous tetrahydrofuran (200 mL) was cooled to between −110° C. and −100° C. under N2and potassium bis(trimethylsilyl)amide solution (1M in THF, 47 mL, 47 mmol) was added dropwise. The reaction mixture was stirred at approximately −110° C. for 1.5 h. The reaction mixture was treated with water (200 mL) and stirred overnight at 5° C. EtOAc (300 mL) was added and the layers were separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude brown oil (17.8 g) was triturated with a 1:1 mixture of heptane and Et2O. The resulting powder was further triturated with diisopropyl ether to give the title compound (8.9 g, 55%) as a pale brown solid. HPLC-MS (pH 3): m/z 399.0 [M+H]+, RT 1.77 minutes.

The title compound can be synthesised from Intermediate 54 by treatment with a suitable oxidant such as Dess Martin Periodinane in dichloromethane and subsequent purification by column chromatography on silica gel.

The following compounds were prepared by reaction of (2-chloropyrimidin-5-yl)boronic acid with the appropriate amine according to General Method C.

A suspension of Example 259 (3.7 g, 7.12 mmol) in DCM (100 mL) was cooled to 0° C. and treated with 1M boron tribromide in DCM (21.35 mL, 21.35 mmol). The resulting solution was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was cooled in an ice bath and quenched by careful addition of MeOH (8 mL). Saturated aqueous NaHCO3solution (50 mL) was added and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with 1M aqueous NaOH solution (80 mL) and brine (80 mL), then dried over Na2SO4and concentrated in vacuo. The resulting crude brown foam was coated onto C18-silica gel (8 g) and purified in 3 batches by C18-reversed phase column chromatography (120 g, eluent: water to 100% acetonitrile+0.1% formic acid). The fractions containing the product were combined and neutralised (pH 7-8) by addition of saturated aqueous NaHCO3solution. The aqueous layer was extracted with DCM (3×75 ml), and the combined DCM layers were concentrated in vacuo, to afford the title compound (1.0 g, 35%) as a brown foam. LCMS (pH 10): m/z 351 [M+H]+, RT 2.09 minutes.

Prepared from 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid and Intermediate 29 in accordance with General Method B to give the title compound (80 mg, 58%) as a solid. HPLC-MS (pH 10): m/z 595.8 [M+H]+, RT 2.09 minutes.

To a stirred solution of Intermediate 272 (1.77 g, 5.86 mmol) in 1,4-dioxane (50 mL) were added bis(pinacolato)diboron (4.46 g, 17.6 mmol), potassium acetate (3.46 g, 35.3 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM adduct (338 mg, 0.41 mmol). The mixture was stirred at 90° C. for 18 h. The reaction mixture was cooled to room temperature, filtered through celite, washed with EtOAc and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with hexane:EtOAc, a gradient from 1:0 to 9:1), to afford the title compound (0.9 g, 55%) as a pale gum.

A solution of Intermediate 273 (340 mg, 1.2 mmol) and Intermediate 152 (335 mg, 0.8 mmol) in 1,4-dioxane (10 mL) was treated with 2N aqueous K2CO3solution (2.5 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg, 0.04 mmol) and heated at 100° C. under N2for 1.5 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water (40 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting crude brown gum was purified by FCC on silica gel (eluting with DCM/EtOAc, a gradient from 1:0 to 0.1) to give the title compound (300 mg, 70%) as a white powder. HPLC-MS (pH 10): m/z 537.2 [M+H]+, RT 1.20 minutes.

General Method A

Aryl bromide (e.g. Intermediate 7 or Intermediate 68) (1 eq), boronic acid or ester (1.2 eq) and 2M aqueous sodium carbonate solution (3 eq) are dissolved in 1,4-dioxane. The mixture is degassed with three cycles of vacuum and nitrogen prior to the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mol %). The reaction mixture is heated for sufficient time (typically 3-5 h) at 100° C. until TLC or LCMS indicates that the reaction is complete. After being allowed to cool to room temperature the solution is filtered through celite, diluted with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered, and the volatiles are removed in vacuo. The crude residue thus obtained is purified by an appropriate technique, typically column chromatography on silica gel or preparative mass-directed HPLC.

Prepared from Intermediate 54 and Intermediate 230 in accordance with General Method A to give the title compound (200 mg, 40%) as a pale solid. LCMS (pH 10) m/z 568.3 [M+H]+, RT 2.08 minutes.

The title compound was synthesised from (2-chloropyrimidin-5-yl)boronic acid and (3R)-piperidine-3-carboxylic acid in accordance with General Method C.

The title compound was synthesised from (2-chloropyrimidin-5-yl)boronic acid and (3S)-piperidine-3-carboxylic acid in accordance with General Method C.

Prepared from (2-chloropyrimidin-5-yl)boronic acid and (2S)-morpholine-2-carboxylic acid in accordance with General Method C to give the title compound as a yellow gum. LCMS (pH 10) MH+(253.5), RT 0.2 minutes.

The title compound was synthesised from (2-chloropyrimidin-5-yl)boronic acid and (2R)-morpholine-2-carboxylic acid in accordance with General Method C.

To a degassed, cold (−78° C.) solution of Intermediate 7 (1.00 g, 2.72 mmol) in THF (10 mL) was added methyl iodide (0.427 g, 2.99 mmol, 0.187 mL). To the mixture was added dropwise a solution of potassium hexamethyldisilylazide (0.5M in toluene, 5.7 mL, 2.9 mmol). The mixture was stirred at this temperature for 1 h. Additional methyl iodide (0.05 mL) and potassium hexamethyldisilylazide (0.5M in toluene, 1 mL) were added at −78° C., and stirring was continued for a further 1 h. The mixture was quenched at −78° C. by the addition of saturated aqueous ammonium chloride solution (5 mL), warmed to room temperature, diluted with EtOAc (20 mL), washed with water (10 mL) and brine (10 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude brown oil was purified by column chromatography (eluent: hexane to 70% EtOAc in hexane) to give the title compound (0.94 g, 91%) as a pale solid.

To a cold (−78° C.) solution of Intermediate 7 (0.6 g, 1.64 mmol) in THF (10 mL) was added benzyl chloroformate (0.58 g, 3.43 mmol, 0.48 mL), followed by KHMDS (0.5M solution in toluene, 6.7 mL, 3.4 mmol). The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (10 mL), and allowed to warm to room temperature. The mixture was diluted with EtOAc (15 mL) and stood at room temperature overnight. The organic layer was separated, and washed with water (5 mL) and brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The resulting brown solid was subjected to column chromatography (eluent: hexane to EtOAc) to give the title compound. LCMS (pH 10): MH+ 503.0, RT 1.613 minutes.

2,5-Dibromopyridine (5 g, 0.021 mol) was dissolved in toluene (100 mL). The mixture was cooled to −78° C. n-Butyllithium (2.5M solution in hexane, 8.44 mL, 0.021 mol) was added dropwise. The mixture was stirred for 30 minutes, followed by the addition of acetone (10 mL). The mixture was stirred for 45 minutes, then allowed to warm to room temperature for 1 h. The mixture was washed with 5% aqueous ammonium chloride solution (100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (0 to 10% ethyl acetate in heptanes) to afford the title compound (2.21 g, 48%) as a yellow oil. δH(500 MHz, CDCl3) 8.57 (d, J 2.1 Hz, 1H), 7.81 (dd, J 8.4, 2.3 Hz, 1H), 7.31 (d, J 8.4 Hz, 1H), 4.41 (s, 1H), 1.53 (s, 6H).

Intermediate 291 (1 g, 4.63 mmol) and imidazole (630 mg, 9.26 mmol) were dissolved in DCM (20 mL) and the solution was cooled in an ice bath prior to addition of chlorotrimethylsilane (553 mg, 5.09 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 0.75 h. Additional chlorotrimethylsilane (1.65 eq) was added, and the reaction mixture was stirred for 45 minutes. The reaction mixture was washed with water (2×20 mL), then dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure to afford the title compound (1.142 g, 82%) as a colourless oil. δH(500 MHz, CDCl3) 8.54 (d, J 2.3 Hz, 1H), 7.76 (dd, J 8.5, 2.4 Hz, 1H), 7.56 (d, J 8.5 Hz, 1H), 1.58 (s, 6H), 0.15 (s, 9H).

A solution of 5-bromo-2-iodopyrimidine (2 g, 7.02 mmol) in anhydrous toluene (25 mL) was cooled to −78° C. with stirring under nitrogen, forming a thick paste. n-Butyllithium (2.5M solution in hexanes, 2.83 mL) was then added dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, then solid tert-butyl 3-oxoazetidine-1-carboxylate (1.33 g, 7.74 mmol) was added portionwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (20 mL). The crude material was extracted into ethyl acetate (2×30 mL). The combined organic phases were dried over sodium sulphate, filtered and concentrated under vacuum. The resulting brown oil (2.66 g) was loaded onto a 50 g KP-silica cartridge, and eluted from a 0-90% ethyl acetate in heptane gradient using a Biotage isolera 4, to afford the title compound (1.083 g, 46%) as a yellow solid. δH(500 MHz, CDCl3) 8.84 (s, 2H), 4.91 (s, 1H), 4.35 (d, J 9.0 Hz, 2H), 4.22 (d, J 9.1 Hz, 2H), 1.48 (s, 9H).

A solution of Intermediate 293 (1.07 g, 3.24 mmol) and imidazole (265 mg, 3.89 mmol) in dichloromethane (20 mL) was treated with chlorotrimethylsilane (0.44 mL, 3.41 mmol) at room temperature and stirred for 1 h under nitrogen. Further imidazole (100 mg) and chlorotrimethylsilane (0.15 mL) were added, and stirring was continued at room temperature for another h. The reaction mixture was washed with water (2×20 mL). The aqueous washes were extracted with dichloromethane (20 mL), and the combined organic extracts were dried over sodium sulphate, then filtered and concentrated under vacuum. The resulting crude brown oil (1.19 g) was loaded onto a 25 g KP-silica cartridge, and eluted from a 0-30% ethyl acetate in heptane gradient using a Biotage isolera 4, to afford the title compound (814 mg, 62.4%) as a pale yellow solid. δH(500 MHz, CDCl3) 8.82 (s, 2H), 4.48 (d, J 9.5 Hz, 2H), 4.17 (d, J 9.5 Hz, 2H), 1.45 (s, 9H), 0.05 (s, 9H).

5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was aged for 30 minutes prior to dropwise addition of oxetan-3-one (0.452 mL, 7.72 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were successively washed with water and brine, then dried over magnesium sulphate and filtered. The solvent was removed under reduced pressure. The resulting crude brown oily solid was absorbed onto a 25 g KP-Sil Biotage column with minimal DCM, and eluted using a Biotage Isolera 4 with 10-100% ethyl acetate in heptanes, to afford the title compound (687 mg, 42%) as a crystalline yellow solid. δH(500 MHz, DMSO-d6) 9.07 (s, 2H), 6.43 (s, 1H), 4.94 (d, J 6.5 Hz, 2H), 4.67 (d, J 6.5 Hz, 2H).

In a pressure tube, a stirring solution of Intermediate 297 (4.88 g, 16.1 mmol) in 1,4-dioxane (50 mL) was treated with bis(pinacolato)diboron (4.90 g, 19.31 mmol) and potassium acetate (4.74 g, 48.28 mmol). The stirring mixture was degassed with nitrogen for 10 minutes, then Pd(dppf)Cl2complex with DCM (657 mg, 0.80 mmol) was added. The pressure tube was sealed and the contents were stirred at 80° C. for 1 h. The reaction mixture was allowed to cool, concentrated in vacuo and redissolved in ethyl acetate (100 mL). The brown solution was washed using water (50 mL) and brine (50 mL), then the organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting brown solid was triturated in 2:1 diethyl ether:heptane (40 mL) and the suspension was filtered, then the filtrate was concentrated in vacuo, to afford the title compound (7.65 g, 68% at 40% purity) as an orange solid. δH(500 MHz, DMSO-d6) 9.00 (d, J 10.6 Hz, 2H), 5.00 (d, J 6.8 Hz, 2H), 4.75 (d, J 6.8 Hz, 2H), 1.33 (s, 12H), −0.06 (s, 9H).

Intermediate 298 (400 mg, 0.8 mmol), Intermediate 68 (277.1 mg, 0.72 mmol) and a 2M solution of potassium carbonate in water (1.2 mL) were combined in 1,4-dioxane (10 mL), and the mixture was degassed thoroughly under nitrogen. Pd(dppf)Cl2complex with DCM (65 mg, 0.08 mmol) was added and the mixture was heated at 90° C. in a sealed tube for 2 h. The reaction mixture was cooled to room temperature, then diluted using ethyl acetate (10 mL) and filtered through a plug of Celite. The mixture was washed using water (10 mL), the aqueous phase was re-extracted using ethyl acetate (2×10 mL) and the combined organics were washed using brine (15 mL). The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The resulting crude dark brown oil was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0 to 5% methanol in dichloromethane, to afford the title compound (379 mg, 30%) as a yellow oil. LC-MS: MH+ m/z 529.5, RT 1.20 minutes.

5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was aged for 15 minutes prior to dropwise addition of tetrahydro-4H-pyran-4-one (0.77 g, 7.72 mmol). The reaction was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over magnesium sulphate and filtered, then the solvent was removed under reduced pressure. The resulting crude orange oil (1.91 g) was absorbed onto a 50 g KP-Sil column, and eluted with 10-100% ethyl acetate in heptanes on a Biotage Isolera 4, to afford the title compound (762 mg, 42%) as a yellow oil. δH(500 MHz, CDCl3) 8.79 (s, 2H), 4.24 (s, 1H), 3.99-3.89 (m, 4H), 2.37 (td, J 12.3, 11.6, 6.3 Hz, 2H), 1.54 (dd, J 13.6, 2.0 Hz, 2H).

2-Bromo-5-chloropyrazine (900 mg, 4.65 mmol) was dissolved in toluene (20 mL). The reaction vessel was flushed with nitrogen and cooled to −78° C. n-Butyllithium (2.5M solution in hexanes, 2.23 mL) was added slowly under stirring and allowed to stir for a further 10 minutes upon complete addition. Acetone (3.42 mL, 46.53 mmol) was added and the reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature and the solvent was removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed using saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The crude brown oil was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (450 mg, 56%) as a yellow oil. Method B HPLC-MS: MH+ m/z 173, RT 1.31 minutes.

5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under nitrogen. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was stirred for 30 minutes before dropwise addition of 1-methylpiperidin-4-one (0.9 mL, 0.01 mol). The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was allowed to warm to room temperature, then diluted with 5% aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulphate, then the solvent removed under reduced pressure. The resulting crude material (1.55 g) was sonicated in ethyl acetate (10 mL) and DCM (1 mL), then heptane was added. The solid that formed was filtered to afford the title compound (580 mg, 29.4%) as a brown solid. LCMS Method F: MH+: m/z 272/274, RT 1.20 minutes.

5-Bromo-2-iodopyrimidine (5 g, 17.55 mmol) was dissolved in dry toluene (90 mL) and cooled to −50 to −60° C. in a dry ice/acetone bath. n-Butyllithium (2.5M solution in hexanes, 7.3 mL) was added dropwise, and the reaction mixture was aged for 20 minutes. A solution of ethyl 4-oxocyclohexanecarboxylate (2.99 g, 17.55 mmol) in toluene (10 mL) was added in one portion, and the reaction mixture was allowed to warm to r.t. and stirred for 30 minutes. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting crude brown oil (6 g) was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with a gradient of 0-50% ethyl acetate in heptanes, to afford a mixture of diastereoisomers of the title compound (2.99 g, 51%) as a yellow oil. Method C HPLC-MS: MH+ m/z 330, RT 1.32, 1.36 minutes.

Intermediate 305 (0.15 g, 0.46 mmol) and Intermediate 290 (50%, 0.4 g, 0.57 mmol) were dissolved in 1,4-dioxane (3 mL) and 2M aqueous K2CO3solution (0.68 mL). The solution was degassed under a stream of nitrogen gas for 15 minutes. Pd(dppf)Cl2complex with DCM (17 mg, 0.02 mmol) was added and the solution was degassed for 5 minutes. The reaction mixture was heated at 100° C. under microwave irradiation for 1 h with stirring. The reaction mixture was cooled and diluted with EtOAc (5 mL), and washed with water (5 mL). The organic phase was dried over MgSO4and the solvent was removed under reduced pressure, to afford the crude title compound (101 mg, 31%) as a brown glassy oil. Method C HPLC-MS: MH+ m/z 555, RT 1.14 minutes.

5-Bromo-2-iodopyrimidine (12.5 g, 43.88 mmol) was suspended in dry toluene (250 mL), then cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 20 mL) was added dropwise, and the reaction mixture was aged for 20 minutes prior to dropwise addition of a solution of cyclobutanone (3.75 g, 53.5 mmol) in dry toluene (10 mL). The reaction mixture was stirred at −78° C. for 45 minutes, then allowed to warm to room temperature. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×300 mL). The combined organic extracts were dried over MgSO4and the solvent removed under reduced pressure. The resulting brown oil was purified by chromatography on silica (Biotage, 340 g cartridge), eluting with a gradient of 0-100% ethyl acetate in heptanes, to afford the title compound (4.76 g) as a bright yellow solid. δH(500 MHz, CD3OD) 8.80 (s, 2H), 2.57 (dddd, J 11.2, 5.2, 4.4, 2.5 Hz, 2H), 2.32-2.23 (m, 2H), 1.93-1.76 (m, 2H). Method C HPLC-MS: MH+ m/z 230, RT 1.06 minutes.

Intermediate 307 (380 mg, 1.66 mmol) was dissolved in acetonitrile (10 mL) and treated with H2SO4(0.5 mL, 9.38 mmol). The mixture was stirred at 65° C. for 18 h. The reaction mixture was cooled to room temperature and poured onto ice/water (50 mL). The pH was adjusted to ˜10 using a 5M aqueous solution of NaOH and the crude material was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4and concentrated under vacuum, to afford the title compound (166 mg, 28%) as a yellow oil, which was used without further purification. δH(500 MHz, CD3OD) 8.62 (s, 2H), 6.65 (s, 1H), 3.64 (d, J 6.2 Hz, 2H), 2.01 (s, 3H), 1.34 (q, J 4.0 Hz, 2H), 1.22-1.16 (m, 2H).

Potassium hydroxide (40 g, 714 mmol) was dissolved in water (100 mL) and acetonitrile (100 mL). The reaction mixture was cooled to −78° C. 1-(5-Fluoro-2-hydroxyphenyl)ethan-1-one (5 g, 32.44 mmol) was added to the reaction mixture and stirred for 5 minutes at −78° C. Diethyl[bromo(difluoro)methyl]phosphonate (11.5 mL, 64.88 mmol) was added dropwise to the mixture. The reaction mixture was stirred at −78° C. for 30 minutes, then warmed to room temperature over 1.5 h. The reaction mixture was diluted using EtOAc (2×100 mL). The mixture was washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude orange oil was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with 0 to 40% ethyl acetate in heptanes, to afford the title compound (4.86 g, 74%) as a clear oil. δH(500 MHz, CDCl3) 7.47 (ddd, J 0.5, 3.0, 8.5 Hz, 1H), 7.24-7.14 (m, 2H), 6.55 (t, J 73.3 Hz, 1H), 2.62 (s, 3H). Method B HPLC-MS: RT 1.84 minutes, no mass ion observed.

To a stirred solution of Intermediate 313 (4.45 g, 21.8 mmol) in acetic acid (210 mL) was added pyridinium tribromide (6.95 g, 21.8 mmol), followed by hydrogen bromide (3.0 mL, 12.31 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was quenched with saturated aqueous NaHCO3solution (50 mL). The aqueous layer was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, washed with water (3×25 mL) and brine (25 mL), then dried over Na2SO4. The solvent was removed under reduced pressure to afford the title compound (5.75 g, 75%) as a red solid. δH(250 MHz, CDCl3) 7.52 (ddd, J 0.5, 2.5, 8.5 Hz, 1H), 7.25-7.15 (m, 2H), 6.59 (t, J 72.5 Hz, 1H), 4.49 (s, 2H). Method B HPLC-MS: RT 1.90 minutes, no mass ion observed.

2,5-Dibromopyrazine (1 g, 4.2 mmol) was dissolved in toluene (20 mL) under nitrogen and cooled to −78° C. n-Butyllithium (2.5M solution in hexanes, 1.77 mL) was added slowly with stirring and allowed to stir for a further 10 minutes upon complete addition. Oxetan-3-one (270 μL, 4.62 mmol) was added, and the reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature and the solvent was removed in vacuo. The residue was taken up in DCM (50 mL) and washed with saturated aqueous sodium bicarbonate solution (40 mL). The aqueous layer was re-extracted with DCM (50 mL). The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The crude brown oil was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (470 mg, 45%) as a yellow solid. Method B HPLC-MS: MH+ m/z 231, RT 1.13 minutes.

5-Bromo-2-iodopyrimidine (10 g, 35.1 mmol) was dissolved in dry toluene (100 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 14.7 mL) was added dropwise and the reaction mixture was aged for 30 minutes prior to dropwise addition of oxolan-3-one (2.97 mL, 38.6 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed successively with water and brine, then dried over magnesium sulphate. The solvent was removed under reduced pressure to afford a dark yellow oil. The crude material was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with 0-100% ethyl acetate in heptanes, to afford the title compound (2.15 g, 25% at 86% purity) as a yellow oil. δH(500 MHz, DMSO-d6) 9.01 (s, 2H), 5.66 (s, 1H), 3.99-3.93 (m, 2H), 3.88-3.77 (m, 2H), 2.46 (dt, J 12.6, 8.9 Hz, 1H), 2.16 (ddd, J 12.6, 6.4, 3.5 Hz, 1H).

Intermediate 7 (1.2 g, 3.27 mmol 1), methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-pent-4-ynoate (891.23 mg, 3.92 mmol) and diethylamine (675 μL, 6.55 mmol) were combined in DMF (20 mL) and the mixture was degassed under nitrogen. CuI (62 mg, 0.33 mmol) and PdCl2(PPh3)2(115 mg, 0.16 mmol) were added and the mixture was heated at 80° C. under nitrogen for 16 h. The mixture was diluted with ethyl acetate (100 mL) and filtered through celite. The solids were washed with further ethyl acetate (30 mL) and the filtrate was washed with water (3×50 mL), followed by brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The resulting dark brown oil (˜3 g) was dissolved in a minimum of DCM and loaded onto a 100 g silica cartridge, eluting with a gradient of 0-10% methanol in DCM. Product fractions were concentrated under vacuum to afford the title compound (1.8 g, 64%) as a brown gum. Method B HPLC-MS: MH+ m/z 514, RT 1.73 minutes.

Intermediate 327 (90%, 720 mg, 1.57 mmol) was dissolved in methanol (10 mL) and cooled to 0° C. under nitrogen. NaBH3CN (148 mg, 2.36 mmol) was added, and the mixture was warmed to room temperature and stirred for 16 h. Further NaBH3CN (200 mg, 3.18 mmol) was added and the mixture was stirred at r.t. for 3 h. Acetic acid (0.11 ml, 1.92 mmol) and further NaBH3CN (200 mg, 3.18 mmol) were added and the mixture was stirred at r.t. for 2 h. The solvent was removed under vacuum, and saturated aqueous ammonium chloride (10 mL) was added to the residue. The mixture was extracted with DCM (3×30 mL), then the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was dissolved in a minimum of DCM and loaded onto a 25 g silica cartridge, eluting with a gradient of 0-10% methanol in DCM, to afford the title compound (482 mg, 74%) as a pale yellow gum. Method D HPLC-MS: MH+ m/z 416, RT 1.21 minutes.

Example 2 (35 mg, 0.09 mmol) was dissolved in 1,4-dioxane (1 mL). Hydrochloric acid (6M, 150 μL) was added and the reaction mixture was heated to reflux at 70° C. for approximately 16 h. The reaction mixture was diluted with ethyl acetate (5 mL) and neutralised with 1M aqueous NaOH solution. Water (5 mL) was added, the organic layer was separated and the aqueous phase was extracted with further ethyl acetate (3×5 mL). The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The resulting white solid was purified by preparative HPLC (Preparative Method A). The product fractions were concentrated under vacuum to afford the title compound (24.5 mg, 72.5%) as a white solid. δH(500 MHz, CD3OD) 8.36 (s, 1H), 7.76-7.65 (m, 3H), 7.57 (d, J 2.3 Hz, 1H), 7.32 (m, 1H), 7.26-7.12 (m, 3H), 7.14-6.62 (m, 1H), 4.43 (s, 2H), 2.48 (s, 3H), 2.18 (s, 3H). Method A HPLC-MS: MH+ m/z 396, RT 2.89 minutes (100%).

To a solution of Intermediate 27 (0.20 g, 0.52 mmol) in ethanol (8 mL) was added sodium borohydride (22 mg) in one portion. After 1.5 h, a second portion of sodium borohydride (10 mg) was added and the mixture was stirred for an additional 1 h. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution (20 mL) and EtOAc (30 mL). The resulting solid was filtered to give a first crop of the title compound (0.14 g, 70%) as a white solid. The ethyl acetate solution was washed with water (10 mL) and brine (10 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The resulting off-white powder was washed with diethyl ether to yield a second crop of the title compound (0.06 g). The two crops were combined to give a total yield in excess of 95%. δH(400 MHz, DMSO-d6) 8.62 (s, 1H), 8.18 (s, 1H), 8.04 (m, 1H), 7.87 (d, 1H, J 0.7 Hz), 7.48 (m, 3H), 7.02 (m, 1H), 6.37 (m, 2H), 3.89 (s, 3H), 1.93 (s, 3H). MH+ 387.

To a suspension of Example 8 (0.10 g) in a mixture of acetic acid (2 mL) and phosphinic acid (0.1 mL) was added iodine (0.05 g). The mixture was heated at 100° C. for 1.5 h before the addition of extra iodine (8 mg) and phosphinic acid (0.02 mL). Heating was continued for 4 h and then the mixture was cooled to room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3solution (20 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (0.025 g) as a white solid. δH(400 MHz, DMSO-d6) 7.21 (t, 1H, J 1.2 Hz), 6.95 (s, 1H), 6.78 (d, 1H, J 0.6 Hz), 6.55 (m, 2H), 6.46 (d, 1H, J 8.5 Hz), 6.27 (dd, 1H, J 8.5, 2.5 Hz), 5.93 (d, 1H, J 2.5 Hz), 3.45 (s, 2H), 2.91 (s, 3H), 1.36 (s, 3H). MH+ 372.

Intermediate 30 (295 mg, 0.74 mmol) was added to morpholine (192 mg, 2.21 mmol) and NMP (5 mL) in a microwave tube. The reaction mixture was heated at 200° C. under microwave irradiation for 90 minutes. The mixture was loaded onto a 10 g SCX cartridge, which was washed with methanol, followed by 7N ammonia in methanol. The ammonia fraction was concentrated under vacuum, and the residue was purified by Preparative Method D, to afford the title compound (70 mg, 21%) as a light brown solid. Method A HPLC-MS: MH+ m/z 451, RT 3.06 minutes (100%).

Intermediate 31 (200 mg, 0.6 mmol) and 3-amino-6-bromopyridine (160 mg, 0.92 mmol) were dissolved in 1,4-dioxane (20 mL) and 2M aqueous potassium carbonate solution (1 mL) was added. The mixture was flushed with nitrogen and bis[3-(diphenyl-phosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (12 mg, 0.01 mmol) was added. The mixture was heated at 90° C. for 16 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (2×10 mL) and then brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with ethyl acetate followed by 1-10% methanol in DCM. The crude product was further purified by flash chromatography, eluting with a gradient of 0-8% methanol in DCM, to afford the title compound (137 mg, 40%) as a light brown solid. Method A HPLC-MS: MH+ m/z 381, RT 2.87 minutes (97%).

Example 20 (100 mg, 0.26 mmol) was dissolved in DCM (6 mL) and triethylamine (45 μL, 0.32 mmol) was added, followed by methanesulfonyl chloride (25 μL, 0.32 mmol), at 0° C. The mixture stirred for 30 minutes at 0° C., then for a further 100 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (5 mL) and neutralised with 1M aqueous sodium hydroxide solution. Water (5 mL) was added, then the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 0-10% methanol in DCM. The resulting crude material was washed with DMSO and the remaining solids were further purified by chromatography, eluting with a gradient of 0-100% ethyl acetate in heptane, to afford the title compound (16 mg, 11%). δH(500 MHz, acetone-d6) 8.86 (s, 1H), 8.71 (t, J 1.7 Hz, 1H), 8.01 (d, J 1.7 Hz, 2H), 7.93 (dd, J 9.4, 1.8 Hz, 1H), 7.56 (d, J 9.4 Hz, 1H), 7.45-6.81 (m, 5H), 4.46 (s, 2H), 3.56 (s, 6H), 2.42 (s, 3H). Method A HPLC-MS: MH+ m/z 537, RT 3.14 minutes (100%).

Intermediate 20 (150 mg, 0.39 mmol) and Intermediate 58 (115 mg, 0.39 mmol) were dissolved in 1,4-dioxane (2 mL) and 2M aqueous K2CO3solution (0.7 mL) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (16 mg, 0.02 mmol) was added. The mixture was heated at 80° C. for 16 h in a sealed tube under nitrogen. Further Intermediate 58 (50 mg, 0.17 mmol), 2M aqueous K2CO3solution (0.24 mL) and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (5 mg, 0.005 mmol) were added and the mixture was heated for a further 2 h. Further Intermediate 58 (50 mg, 0.17 mmol), 2M aqueous K2CO3solution (0.24 mL) and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (5 mg, 0.005 mmol) were added and the mixture was heated for a further 4 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The organic layer was washed with brine (10 mL), dried over MgSO4and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0-100% ethyl acetate in heptane, followed by 0-30% MeOH in DCM. The resulting material was further purified by preparative HPLC (Method B), to afford the title compound (25 mg, 12%). Method A HPLC-MS: MH+ m/z 551, RT 2.75 minutes (95%).

Intermediate 20 (150 mg, 0.39 mmol) and (4-sulfamoylphenyl)boronic acid (109 mg, 0.43 mmol) were dissolved in 1,4-dioxane (2 mL) and 2M aqueous K2CO3solution (0.69 mL) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (16 mg, 0.02 mmol) was added. The reaction mixture was heated at 80° C. for 16 h in a sealed tube under nitrogen. The mixture was diluted with water (5 mL), then extracted with EtOAc (3×10 mL), washed with brine (10 mL), dried over MgSO4and concentrated under vacuum. The crude residue was purified by silica gel chromatography, eluting with a gradient of 0-5% 7M ammonia/methanol in DCM, to afford the title compound (154 mg, 80%) as a yellow solid. Method C HPLC-MS: MH+m/z 458, RT 1.00 minute (94%).

Intermediate 30 (66% pure, 282 mg, 0.46 mmol), ethyl 3-azabicyclo[3.1.0]-hexane-6-carboxylate (216 mg, 1.397 mmol) and triethylamine (0.2 mL, 1.43 mmol) were combined in 1-methyl-2-pyrrolidinone (2 mL) in a microwave tube and the mixture was heated at 200° C. under microwave irradiation with stirring for 1 h. Further triethylamine (2 eq) was added and the mixture was heated for a further 1.5 h. Further triethylamine (3 eq) was added and the mixture was heated for a further 2 h. The mixture was loaded onto an SCX column, flushing with MeOH (70 mL), followed by 7N ammonia in MeOH (100 mL). The methanol fraction was concentrated under vacuum and further purified by SCX. The ammonia fractions were combined and concentrated under vacuum. The crude product fractions were combined. The resulting material was dissolved in THF (3 mL), then 2M aqueous NaOH solution (1.2 mL) was added and the reaction mixture was stirred at 80° C. for 1.5 h. The mixture was concentrated and acidified to pH 4 using 1M HCl, then extracted with isopropanol/chloroform (3×25 mL), dried over sodium sulfate and concentrated under vacuum. The crude material was purified by preparative HPLC (Method D) to afford the title compound (14 mg, 6%) as a yellow solid. δH(500 MHz, DMSO-d6) 8.33 (d, J 2.5 Hz, 1H), 8.25 (s, 1H), 7.76 (dd, J 8.8, 2.5 Hz, 1H), 7.55-6.98 (m, 7H), 6.53 (d, J 8.8 Hz, 1H), 4.36 (s, 2H), 3.76 (d, J 10.7 Hz, 2H), 3.17 (s, 1H), 2.32 (s, 3H), 2.14 (s, 2H), 1.37 (t, J 3.0 Hz, 1H). Method D HPLC-MS: MH+ m/z 491, RT 1.58 minutes.

Intermediate 29 (59%, 200 mg, 0.29 mmol) was dissolved in 1-methyl-2-pyrrolidinone (1.5 mL) and 2-[(2S)-pyrrolidin-2-yl]acetic acid hydrochloride (75 mg, 0.45 mmol) was added, followed by triethylamine (90 μL, 0.65 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 45 minutes. The reaction mixture was diluted with water (2 mL), acidified to pH 6 with 1M HCl and extracted into EtOAc (4 mL). The organic layer was washed with brine (3 mL) and dried over sodium sulphate, then heptane (4 mL) was added. The resultant solid was collected by filtration and combined with a second crop that precipitated in the filtrate. The combined solids were triturated with DCM/heptane, followed by EtOAc/heptane. The resulting material was combined with a precipitate collected from the aqueous layer, to afford the title compound (61.1 mg, 42%) as a white solid. δH(250 MHz, DMSO-d6) 8.65 (s, 2H), 8.37 (s, 1H), 7.59-6.96 (m, 7H), 4.47-4.28 (m, 3H), 3.65-3.48 (m, 2H), 2.89 (dd, J 15.4, 3.0 Hz, 1H), 2.34-2.26 (m, 4H), 2.11-1.79 (m, 4H). Method D HPLC-MS: MH+ m/z 494, RT 2.06 minutes.

Intermediate 29 (59%, 150 mg, 0.22 mmol) was dissolved in 1-methyl-2-pyrrolidinone (1 mL) and 2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochloride (60 mg, 0.33 mmol) was added, followed by triethylamine (70 μL, 0.5 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 45 minutes. Further 2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochloride (60 mg, 0.33 mmol) and triethylamine (70 μL, 0.5 mmol) were added and the mixture was heated at 120° C. under microwave irradiation for a total of 1.5 h. The reaction mixture was diluted with EtOAc (3 mL) and washed with a 1:1 mixture of water and saturated aqueous sodium bicarbonate solution (2 mL). The organic layer was discarded, then the aqueous layer was acidified to pH 6 with 1M HCl and extracted with EtOAc (2×2 mL). During the extraction a solid formed and was collected by filtration. The organic layers were washed with brine (2 mL), dried over sodium sulfate and concentrated to dryness. The residue was triturated with EtOAc/heptane to afford a solid. The aqueous phase was further extracted with 1:1 isopropanol/chloroform (2×3 mL), dried over sodium sulfate and concentrated to dryness. The residue was triturated with EtOAc/heptane to afford a solid. The three crops of solid were combined, and triturated with a minimum of water, to afford the title compound (22 mg, 20%) as a beige solid. δH(500 MHz, DMSO-d6) 8.68 (s, 2H), 8.40 (s, 1H), 7.55 (d, J 9.2 Hz, 1H), 7.48 (dd, J 9.3, 1.7 Hz, 1H), 7.44-7.09 (m, 4H), 7.04 (d, J 7.6 Hz, 1H), 5.04 (s, 1H), 4.36 (s, 2H), 4.01 (d, J 6.1 Hz, 1H), 3.86-3.76 (m, 2H), 3.61 (d, J 10.4 Hz, 1H), 2.31 (s, 3H), 2.25 (d, J 8.2 Hz, 1H), 2.13 (d, J 10.1 Hz, 1H). Method A HPLC-MS: MH+ m/z 508, RT 2.98 minutes.

(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol), methyl 3-azabicyclo-[3.1.1]heptane-6-carboxylate hydrochloride (100 mg, 0.52 mmol) and triethylamine (0.25 mL, 1.79 mmol) were dissolved in ethanol (5 mL) and stirred for 2 h at 80° C. in a sealed tube. To the mixture were added Intermediate 7 (170 mg, 0.46 mmol), 2M aqueous potassium carbonate solution (0.7 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron dichloropalladium dichloromethane complex (40 mg, 0.05 mmol) was added. The mixture was heated at 80° C. in a sealed tube for 4 h. The mixture was diluted with ethyl acetate (20 mL), then washed with water (2×10 mL), followed by brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-10% methanol in DCM. The resulting material (250 mg) was dissolved in 1:1 THF/water (4 mL), then 2M aqueous NaOH solution (0.5 mL) was added and the mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM (20 mL), then extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were extracted with 1:1 isopropanol/chloroform (20 mL), then the organic layer was separated and concentrated under vacuum. The residue was purified by chiral preparative SFC (Method A), eluting with methanol (+0.2% diethylamine) in carbon dioxide to afford the two stereoisomers of the title compound.

Intermediate 98 (115 mg, 0.22 mmol) was dissolved in EtOH (2 mL), then 2M aqueous potassium hydroxide solution (0.11 mL) was added. The mixture was heated at 70° C. for 2.5 h, then left to stand at room temperature over the weekend. The mixture was then heated for 5 h before additional 2M aqueous potassium hydroxide solution (0.005 mL) was added. Heating was continued for 1 h. The mixture was filtered, but only a small amount of solid was collected on the filter paper. The filtrate and solids were recombined using EtOH and diethyl ether, then the mixture was concentrated to an approximate volume of 1.5 mL. The resultant precipitate was filtered, but little solid was recovered. The mixture was recombined and concentrated to dryness. EtOAc (˜5 mL) was added and the mixture was sonicated. The resultant precipitate was collected by filtration to afford the title compound (81 mg, 69%) as a yellow solid. δH(500 MHz, DMSO-d6) 8.62 (s, 2H), 8.38 (s, 1H), 7.56-7.49 (m, 1H), 7.45 (dd, J 9.3, 1.6 Hz, 1H), 7.33-7.25 (m, 2H), 7.22-7.17 (m, 1H), 7.17-7.10 (m, 1H), 7.08-7.01 (m, 1H), 4.35 (s, 2H), 4.10-3.89 (m, 4H), 2.31 (s, 3H), 1.20 (d, J 3.3 Hz, 1H), 1.03 (s, 3H), 0.38 (d, J 3.4 Hz, 1H). Method D HPLC-MS: MH+ m/z 506, RT 2.07 minutes.

Intermediate 109 (175 mg, 0.32 mmol) was dissolved in THF (5 mL) and 4M aqueous sodium hydroxide solution (800 μL) was added. The reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL). The organic layer was discarded and the aqueous layer was acidified to pH 6 with 1M HCl. The resulting aqueous layer was extracted with EtOAc (2×4 mL). The combined organic phases were washed with brine (3 mL), dried over sodium sulfate and concentrated to dryness. A second portion of Intermediate 109 (319 mg, 0.58 mmol) was dissolved in THF (8 mL) and 4M aqueous sodium hydroxide solution (1.5 mL) was added. The reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with water (8 mL) and extracted with EtOAc (8 mL). The organic layer was discarded and the aqueous layer was acidified to pH 6 with 1M HCl. The resulting aqueous layer was extracted with EtOAc (2×5 mL). The combined organic phases were washed with brine (4 mL), dried over sodium sulfate and concentrated to dryness. The two batches were combined, and purified by preparative HPLC, to afford the title compound (56 mg, 12%) as a beige solid. δH(500 MHz, DMSO-d6) 8.32 (s, 2H), 7.96 (s, 1H), 7.45 (d, J 7.3 Hz, 1H), 7.35-7.28 (m, 2H), 7.25-6.93 (m, 3H), 4.84 (q, J 7.2 Hz, 1H), 3.88 (d, J 11.4 Hz, 2H), 3.58 (d, J 10.8 Hz, 2H), 2.84-2.75 (m, 1H), 2.23 (s, 3H), 2.21 (s, 3H), 2.13 (s, 2H), 1.67 (d, J 7.2 Hz, 3H). Method D HPLC-MS: MH+ m/z 519, RT 2.06 minutes.

Intermediate 47 (35 mg, 0.08 mmol) was dissolved in 1-methyl-2-pyrrolidinone (1 mL) and Intermediate 116 (25 mg, 0.13 mmol) was added, followed by triethylamine (27 μL, 0.19 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 45 minutes. A second portion of Intermediate 47 (100 mg, 0.24 mmol) was dissolved in 1-methyl-2-pyrrolidinone (2 mL) and Intermediate 116 (70 mg, 0.36 mmol) was added, followed by triethylamine (76 μL, 0.54 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 45 minutes. The two mixtures were combined, then partitioned between ethyl acetate (5 mL) and water (3 mL). The aqueous layer was separated and extracted into ethyl acetate (5 mL). The combined organic extracts were washed with water (2×10 mL) and brine (10 mL), then dried over sodium sulfate and evaporated. The residue was purified by FCC, eluting with 50-100% ethyl acetate in heptane. The resulting yellow oil was dissolved in ethanol (4 mL) and 2M aqueous potassium hydroxide solution (0.12 mL) was added. The reaction mixture was heated at 80° C. in a sealed tube for a total of 7 h. Further 2M aqueous potassium hydroxide solution (0.24 mL) was added and the reaction mixture was heated at 80° C. in a sealed tube for 2 h. The cooled reaction mixture was acidified with 2M HCl to pH 2, then partitioned between 10% isopropanol/chloroform (10 mL) and water (5 mL). The aqueous layer was separated and further extracted into 10% isopropanol/chloroform (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and evaporated. To the resulting yellow foam were added isopropanol (3 mL), water (1 mL) and 2M aqueous potassium hydroxide solution (0.10 mL). The mixture was brought into solution with a heat gun, then stirred at room temperature for 1 h. The reaction mixture was evaporated to afford the title compound (109 mg, 61%) as a yellow solid. δH(500 MHz, DMSO-d6) 8.31 (s, 2H), 8.00 (s, 1H), 7.43-7.07 (m, 5H), 6.93 (d, J 7.5 Hz, 1H), 4.28 (s, 2H), 4.01 (dd, J 13.5, 2.6 Hz, 1H), 3.87 (dd, J 13.5, 5.1 Hz, 1H), 3.61 (dt, J 12.2, 5.8 Hz, 1H), 2.62 (dt, J 13.7, 5.7 Hz, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.61 (ddd, J 13.9, 8.6, 5.2 Hz, 1H), 1.44-1.35 (m, 1H), 1.00 (dd, J 8.5, 2.8 Hz, 1H), 0.29-0.19 (m, 1H). Method D HPLC-MS: MH+ m/z 520.5, RT 2.13 minutes.

A mixture of Intermediate 101 (150 mg, 0.39 mmol) and Intermediate 117 (150 mg, 0.78 mmol) in pyridine (2 mL) was heated at 180° C. under microwave irradiation for 4 h. The reaction mixture was concentrated under vacuum and the residue was purified by FCC, eluting with 20-100% EtOAc in heptane followed by 20% MeOH in EtOAc. The resulting brown solid (85 mg) was dissolved in methanol (3 mL), then 2M aqueous potassium hydroxide solution (246 μL) was added and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water and washed with EtOAc (3×2 mL). The aqueous phase was acidified with 2M HCl and washed with EtOAc (3×2 mL), followed by 1:1 isopropanol/chloroform (3×2 mL). The aqueous layer was concentrated under vacuum and the residue was triturated with 1:1 isopropanol/chloroform. The mixture was filtered and the filtrate was concentrated under vacuum. The material was suspended in water with potassium hydroxide (1.1 eq), and isopropanol was added. The suspension was heated with a heat gun until all the solid had dissolved, then the mixture was stirred at room temperature for 20 minutes. The mixture was concentrated under vacuum, and the residue was triturated with EtOAc, to afford the title compound (19.7 mg, 9%) as a cream solid. δH(500 MHz, DMSO-d6) 8.32 (d, J 2.5 Hz, 1H), 8.27 (s, 1H), 7.73 (dd, J 8.9, 2.6 Hz, 1H), 7.53-7.11 (m, 6H), 7.04 (d, J 7.7 Hz, 1H), 6.68 (d, J 8.9 Hz, 1H), 4.36 (s, 2H), 3.81-3.76 (m, 2H), 3.22 (td, J 8.1, 4.1 Hz, 1H), 2.59 (d, J 14.1 Hz, 1H), 2.33 (s, 3H), 1.65 (s, 1H), 1.38 (s, 1H), 0.96 (d, J 8.1 Hz, 1H), 0.25 (s, 1H). Method A HPLC-MS: MH+ m/z 505, RT 3.04 minutes.

A mixture of Intermediate 101 (150 mg, 0.39 mmol) and Intermediate 119 (161 mg, 0.78 mmol) in pyridine (2 mL) was heated at 180° C. under microwave irradiation for 4 h. The reaction mixture was concentrated under vacuum and the residue was purified by FCC, eluting with 20-100% EtOAc in heptane followed by 20% MeOH in EtOAc. The resulting material (83.5 mg) was dissolved in methanol (3 mL), then 2M aqueous potassium hydroxide solution (290 μL) was added and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water and washed with EtOAc (3×2 mL). The aqueous phase was acidified with 2M HCl and washed with EtOAc (3×2 mL). The aqueous phase was concentrated under vacuum and the residue was triturated with 1:1 isopropanol/chloroform. The mixture was filtered, and the filtrate was concentrated under vacuum. The material was suspended in water with potassium hydroxide (1.1 eq), and isopropanol was added. The suspension was heated with a heat gun until all the solid had dissolved, then the mixture was stirred at room temperature for 20 minutes. The mixture was concentrated under vacuum, and triturated with EtOAc, to afford the title compound (42.9 mg, 20%) as a cream solid. δH(500 MHz, DMSO-d6) 8.31 (d, J 2.4 Hz, 1H), 8.26 (s, 1H), 7.73 (dd, J 8.9, 2.6 Hz, 1H), 7.53-7.10 (m, 6H), 7.04 (d, J 7.6 Hz, 1H), 6.74 (d, J 8.9 Hz, 1H), 4.36 (s, 2H), 4.20 (d, J 13.6 Hz, 1H), 3.78 (d, J 13.6 Hz, 1H), 2.32 (s, 3H), 1.97 (d, J 6.0 Hz, 1H), 1.77-1.67 (m, 1H), 1.36 (s, 1H), 0.95 (d, J 6.4 Hz, 1H), 0.35 (s, 1H). Method A HPLC-MS: MH+ m/z 505, RT 3.03 minutes.

A mixture of Intermediate 101 (150 mg, 0.39 mmol) and Intermediate 120 (161 mg, 0.78 mmol) in pyridine (2 mL) was heated at 180° C. under microwave irradiation for 4 h. The reaction mixture was concentrated under vacuum and the residue was purified by FCC, eluting with 20-100% EtOAc in heptane followed by 20% MeOH in EtOAc. The resulting material (64 mg) was dissolved in methanol (3 mL), then 2M aqueous potassium hydroxide solution (349 μL) was added and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature and the methanol was removed under vacuum. The residue was diluted with water and washed with EtOAc (3×2 mL). The aqueous phase was acidified with 2M HCl and washed with EtOAc (3×2 mL). The aqueous phase was concentrated under vacuum and the residue was triturated with 1:1 isopropanol/chloroform. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was triturated with several solvents (DCM, water, MeCN, EtOAc) but this failed to increase the purity. The material was suspended in water with potassium hydroxide (1.1 eq), and isopropanol was added. The suspension was heated with a heat gun until all the solid had dissolved, then the mixture was stirred at room temperature for 20 minutes. The mixture was concentrated under vacuum, and triturated with EtOAc, to afford the title compound (35.6 mg, 17%) as a cream solid. δH(500 MHz, DMSO-d6) 8.31 (d, J 2.4 Hz, 1H), 8.26 (s, 1H), 7.73 (dd, J 8.9, 2.5 Hz, 1H), 7.52-7.11 (m, 6H), 7.04 (d, J 7.6 Hz, 1H), 6.75 (d, J 9.0 Hz, 1H), 4.36 (s, 2H), 4.20 (d, J 13.5 Hz, 1H), 3.79 (d, J 13.8 Hz, 1H), 2.32 (s, 3H), 1.98 (d, J 6.6 Hz, 1H), 1.74 (s, 1H), 1.38 (s, 1H), 0.96 (s, 1H), 0.39 (s, 1H). Method A HPLC-MS: MH+ m/z 505, RT 3.05 minutes.

Intermediate 190 (280 mg, 0.52 mmol) was dissolved in ethanol (5 mL) and ethyl acetate (5 mL). Triethylamine (90 μL, 0.65 mmol) was added, followed by palladium hydroxide on carbon (10%, 70 mg, 0.07 mmol). The reaction mixture was flushed with nitrogen (3 times) and hydrogen (3 times). The mixture was stirred under hydrogen overnight. The mixture was filtered through Kieselguhr and washed through with ethyl acetate, then the filtrate was concentrated. The crude residue was purified by column chromatography (0 to 4% methanol in dichloromethane) to afford the title compound (269 mg, 96%). Method D HPLC-MS: MH+ m/z 538, RT 2.59 minutes.

Example 150 (269 mg, 0.5 mmol) was stirred in tetrahydrofuran (5 mL) and 2M aqueous potassium hydroxide solution (5 mL) at 60° C. for 25 h. 1,4-Dioxane (5 mL) was added and the reaction mixture was stirred at 60° C. for a further 18 h. The reaction mixture was allowed to cool, then ethyl acetate (10 mL) and 2M aqueous potassium hydroxide solution (10 mL) were added. The layers were separated. The aqueous phase was washed with ethyl acetate (10 mL) and adjusted to pH 4-5 using 6M hydrogen chloride solution. The resulting solid was collected by filtration, washed with diethyl ether and dried, then dissolved in dimethylsulfoxide (5 mL) and water (2 mL) with heating. Aqueous potassium hydroxide solution (1M, 267 μL) was added and the solution was heated at 60° C. for 30 minutes. The reaction mixture was concentrated in a genevac for 24 h. Water (2 mL) was added to the resulting oil, then the mixture was dried in a genevac for 2 h. Diethyl ether was added to the resulting brown oily solid. The mixture was sonicated, then triturated with a spatula. The resulting grey/light brown solid was collected by filtration, and dried in a vacuum oven at 60° C. for 2 h, to afford the title compound (139 mg, 95%) as a grey/light brown solid. δH(500 MHz, DMSO-d6) 8.86 (d, J 1.4 Hz, 2H), 8.55 (d, J 7.4 Hz, 1H), 7.52 (d, J 11.3 Hz, 1H), 7.42-7.09 (m, 4H), 7.02 (dd, J 7.6, 1.3 Hz, 1H), 4.34 (s, 2H), 3.08-2.96 (m, 1H), 2.27 (s, 3H), 2.16-2.02 (m, 4H), 1.55-1.49 (m, 2H), 1.26-1.20 (m, 1H). Method D HPLC-MS: MH+ m/z 509, RT 1.97 minutes.

Alternative Preparation

A solution of Example 262 (20 mg, 0.046 mmol) in THF (2 mL) and water (2 mL) was treated with conc. HCl (1.5 mL) and heated at 70° C. for 7 h. The reaction mixture was cooled to r.t. and applied to a SCX-2 cartridge, eluting with methanol followed by ammonia (3M in MeOH). The fractions obtained were concentrated in vacuo to give the title compound (11 mg, 45%) as a white solid. LCMS (pH 10) m/z 525.8 [M+H]+, RT 1.62 minutes.

Example 142 (300 mg) was subjected to chiral SFC (carbon dioxide/ethanol+0.1% triethylamine) to afford purified material (84.7 mg, one isomer, unknown stereochemistry). This material (78 mg, 0.14 mmol) was dissolved in 1,4-dioxane (1 mL) and 1M aqueous potassium hydroxide solution (0.71 mL) was added. The reaction mixture was heated at 80° C. in a sealed tube for 3 h, then at 90° C. overnight. The cooled reaction mixture was acidified with 2M hydrochloric acid to pH 2, then partitioned between a 10% solution of isopropanol in chloroform (5 mL) and water (3 mL). The aqueous layer was separated and further extracted into a 10% solution of isopropanol in chloroform (2×5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and evaporated. The resulting yellow solid (80 mg) was purified by preparative HPLC (low pH method).

Example 142 (300 mg) was subjected to chiral SFC (carbon dioxide/ethanol+0.1% triethylamine) to afford purified material (78.9 mg, one isomer, unknown stereochemistry). This material (72 mg, 0.13 mmol) was dissolved in 1,4-dioxane (1 mL) and 1M aqueous potassium hydroxide solution (0.65 mL) was added. The reaction mixture was heated at 80° C. in a sealed tube for 3 h, then at 90° C. overnight. The cooled reaction mixture was acidified with 2M hydrochloric acid to pH 2, then partitioned between a 10% solution of isopropanol in chloroform (5 mL) and water (3 mL). The aqueous layer was separated and further extracted into a 10% solution of isopropanol in chloroform (2×5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and evaporated. The resulting yellow solid was purified by preparative HPLC (low pH method).

Intermediate 204 (75.3 mg, 0.14 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.5 mL), then 2M aqueous potassium hydroxide solution (85 μL) was added and the reaction mixture was heated at 70° C. overnight. Additional 2M aqueous potassium hydroxide solution (0.35 mL) was added and the reaction mixture was stirred at 70° C. for 3.5 h. The reaction mixture was cooled to room temperature and a 3:1 mixture of ethyl acetate:water (10 mL) was added. The organic phase was separated, concentrated and diluted in a 1:1 isopropanol:chloroform mixture (10 mL). The aqueous phase was adjusted to pH 2/3 using 1M hydrogen chloride solution and a saturated aqueous solution of sodium carbonate, then extracted with a 1:1 isopropanol:chloroform mixture (20 mL). The aqueous phase was further adjusted to pH 3 using a saturated aqueous solution of sodium carbonate, then re-extracted with 1:1 isopropanol:chloroform mixture (10 mL). The organic phases were combined, dried over sodium sulphate, and concentrated under vacuum. The resulting gum was dissolved in 1,4-dioxane (1 mL), then water (0.1 mL) and 2M aqueous potassium hydroxide solution (70 μL) were added. The reaction mixture was stirred at room temperature for 1.5 h, then concentrated under vacuum. The residue was triturated in diethyl ether to afford the title compound (46 mg, 56%) as a yellow solid. δH(500 MHz, DMSO-d6) 11.89 (s, 1H), 8.81 (d, J 6.6 Hz, 1H), 8.66 (d, J 15.8 Hz, 1H), 7.90 (t, J 9.4 Hz, 2H), 7.48-7.05 (m, 6H), 4.45 (s, 2H), 3.77-3.65 (m, 1H), 2.43 (t, J 10.1 Hz, 2H), 2.34 (s, 3H), 2.25 (dd, J 13.7, 3.7 Hz, 2H), 1.83 (s, 2H), 1.52 (t, J 2.8 Hz, 1H). Method D HPLC-MS: MH+ m/z 507, RT 2.02, 2.11 minutes.

Example 164 (500 mg, 0.81 mmol) was dissolved in THF (6 mL) and water (6 mL). Lithium hydroxide monohydrate (170 mg, 4.04 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The solution was adjusted to pH 3 with aqueous 1M HCl solution, then extracted with ethyl acetate. The combined organic phase was dried, filtered and concentrated under vacuum. Trituration of the resulting orange foam with acetonitrile yielded the title compound (250 mg, 60%) as a pale yellow solid, consisting of a pair of diastereoisomers in a 3:1 ratio. The constituent diastereoisomers were then separated by preparative HPLC.

Intermediate 239 (250 mg) was separated by preparative HPLC to yield the racemic cis and trans isomers.

To Example 212 (202 mg) were added tetrahydrofuran (4 mL), water (1 mL, 55.51 mmol) and lithium hydroxide monohydrate (76.0 mg, 1.81 mmol). The mixture was stirred at room temperature for 60 h. The reaction mixture was diluted with methanol (2 mL) and heated at 70° C. overnight. The reaction mixture was cooled to room temperature, then acidified to pH 3 with 2M aqueous hydrochloric acid. Ethyl acetate (10 mL) was added and the mixture was stirred for 30 minutes. The mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was discarded and the organic layer was washed with water (20 mL). The aqueous layer was discarded and the organic layer was washed with further water (20 mL). The organic layer was separated, dried (Na2SO4), and filtered under reduced pressure. The solvent was removed in vacuo to yield brown oils/foams. The organic layer was separated, dried (Na2SO4), and filtered under reduced pressure, then the solvent was removed in vacuo. The resulting brown oil was purified by preparative HPLC, and freeze-dried from acetonitrile/water, to afford the title compound (62.4 mg, 47%) as an off-white solid. δH(300 MHz, DMSO-d6) 8.63-8.52 (m, 3H), 8.07-7.96 (m, 1H), 7.48 (q, J 9.3 Hz, 2H), 7.42-7.33 (m, 2H), 7.17-7.07 (m, 1H), 7.10 (m, 1H), 6.44 (s, 1H), 4.35-4.22 (m, 2H), 3.38-3.23 (m, 2H), 2.16 (s, 3H), 2.10-1.97 (m, 2H), 1.39-1.23 (m, 2H), 1.14 (s, 3H). LCMS (pH 3): MH+ m/z 525, RT 1.58 minutes. LCMS (pH 10): MH+ m/z 525, RT 1.21 minutes.

Examples 237 to 242

The following compounds were synthesised from Intermediate 255 and the appropriate boronic acid in accordance with General Method A.

Examples 237 and 242 were prepared from (4-sulfamoylphenyl)boronic acid and (6-methoxy-3-pyridyl)boronic acid respectively.

Example 245 (273 mg, 0.4622 mmol) was mixed with pyridine hydrochloride (0.21 g, 1.85 mmol) and placed on a prewarmed heating block at 160° C. The reaction mixture was heated for 5 minutes, then allowed to cool to room temperature. The solution was adsorbed onto silica, then purified by column chromatography with 5% DCM/MeOH to 10% DCM/MeOH. The resulting solid was washed with water, and dried, to afford the title compound (95 mg, 35%) as a pale solid. LCMS m/z 577.6 (M+H)+, RT 1.81 minutes.

The title compound was prepared from Intermediate 246 and 2-carboxypyridine-5-boronic acid in accordance with General Method A. LCMS m/z 561.7 (M−H)−, RT 1.87 minutes.

Intermediate 245 (387 mg) was dissolved in dimethylsulfoxide (2 mL) and treated with sodium cyanide (0.045 g, 0.92 mmol), then the reaction mixture was stirred at r.t. for 18 h. The solution was diluted into ethyl acetate (50 mL), then washed with water (3×50 mL). The organic layer was separated, dried with sodium sulphate, and filtered, then the solvent was removed under reduced pressure. The resulting clear oil was purified using silica gel chromatography to afford a pale solid (235 mg, 62%). The title compound was then prepared by reacting the material thus obtained with Intermediate 38 in accordance with General Method A. LCMS m/z 495.6 (M+H)+, RT 2.19 minutes.

A mixture of Intermediate 246 (0.2 g, 0.36 mmol), tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-1-carboxylate (170 mg, 0.43 mmol), tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.036 mmol) and potassium carbonate (0.099 g, 0.71 mmol) in 1,4-dioxane (2M) was heated under microwave irradiation for 2 h at 110° C. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and EtOAc. The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 1-10% MeOH in DCM) to give the title compound (75 mg, 28%). LCMS (ES+) 747 (M+H)+, RT 3.0 minutes.

To a suspension of Intermediate 274 (300 mg, 0.56 mmol) in EtOH (25 mL), MeOH (5 mL) and EtOAc (5 mL) was added palladium on carbon (30 mg) and the reaction mixture was heated at 50° C. under H2(1 atm) for 12 h. The reaction mixture was filtered and concentrated in vacuo, then the residue was purified by preparative HPLC.

The title compound was synthesised from Example 261 in accordance with the method of Example 152. HPLC-MS (pH 10): MH+ m/z 525.8 [M+H]+, RT 1.55 minutes.

A solution of Intermediate 270 (90 mg, 0.26 mmol) in pyridine (1 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (59 mg, 0.51 mmol, 0.04 mL). The mixture was allowed to warm to room temperature and stirred for 3 h. Additional methanesulfonyl chloride (22.1 mg, 0.193 mmol) was added. After stirring for 90 minutes, the reaction mixture was concentrated in vacuo and EtOAc was added. The mixture was washed with water and brine, dried over Na2SO4and concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel (eluting with 0.5% to 6% methanol in DCM). The isolated yellowish oil was lyophilised from acetonitrile and water to give the title compound (37.5 mg, 43%) as a white foam. LCMS (pH 10): [M+H]+429, RT 3.351 minutes.

A solution of Example 268 (4 g, 9.697 mmol) in MeOH (150 mL) and acetone (20 mL) at 0° C. was treated with Oxone® (potassium peroxymonosulfate; 11.92 g, 19.39 mmol) in water (100 mL). The resulting suspension was allowed to warm to r.t. and stirred for 18 h. The reaction mixture was treated with water and extracted with DCM (4×300 mL). The combined organic layers were concentrated in vacuo. A portion of the resulting crude yellow solid (4.4 g, 100%) was further purified by preparative HPLC to give the title compound (56 mg was obtained from 130 mg of crude material) as a white solid. HPLC-MS (pH 10): MH+ m/z 445.6 [M+H]+, RT 1.54 minutes.

Prepared from Intermediate 68 and Intermediate 265 in accordance with General Method A. The title compound (380 mg, 39%) was obtained as a white solid. HPLC-MS (pH 10): MH+ m/z 507.8 [M+H]+, RT 2.38 minutes.

Prepared from Intermediate 7 and Intermediate 266 in accordance with General Method A. The title compound (20 mg, 7%) was obtained as a white solid. HPLC-MS (pH 10): MH+ m/z 556.2 [M+H]+, RT 0.70 minutes.

Prepared from Intermediate 267 and Intermediate 7 in accordance with General Method A. The title compound (47 mg, 18%) was obtained as a white solid. HPLC-MS (pH 10): MH+ m/z 493.8 [M+H]+, RT 1.78 minutes.

Prepared from Intermediate 268 and Intermediate 7 in accordance with General Method A. The title compound (46 mg, 17%) was obtained as a white solid. HPLC-MS (pH 10): MH+ m/z 493.8 [M+H]+, RT 1.81 minutes.

A solution of Example 23 (0.138 g, 0.28 mmol) in DCM (6 mL) was treated with methanesulphonamide (0.1 g, 1.0 mmol 1), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.2 g, 1.0 mmol) and 4-(dimethylamino)pyridine (0.033 g, 0.28 mmol) and the mixture was heated to reflux for 3 days. The reaction mixture was concentrated in vacuo and the crude residue was partitioned between DCM (20 mL) and water (10 mL). The organic layer was concentrated in vacuo, and the crude residue purified by FCC on silica gel (eluting with 0-10% MeOH/DCM), to give the title compound (38 mg, 24%) as a white solid. HPLC-MS (pH 10): MH+ m/z 571.7 [M+H]+, RT 1.49 minutes.

Prepared from Intermediate 55 and Intermediate 269 in accordance with General Method A. The title compound (120 mg, 60%) was obtained as a white solid. HPLC-MS (pH 10): m/z 566.8 [M+H]+, RT 1.73 minutes.

A mixture of Intermediate 29 (0.25 g, 0.56 mmol), 3-oxa-8-azabicyclo[3.2.1]-octane hydrochloride (0.126 g, 0.84 mmol) and triethylamine (0.12 g, 1.13 mmol) was dissolved in THF (15 mL) and water (5 mL) and heated at 140° C. for 4 h under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were concentrated in vacuo, and purified by FCC on silica gel (eluting with 0-2% MeOH in EtOAc), to give the title compound (23 mg, 9%) as a white solid. HPLC-MS (pH 10): m/z 478.8 [M+H]+, RT 2.29 minutes.

Prepared from Intermediate 7 and Intermediate 269 in accordance with General Method A. The title compound (32 mg, 11%) was obtained as a white solid. HPLC-MS (pH 10): m/z 518.8 [M+H]+, RT 1.73 minutes.

A solution of Intermediate 29 (0.2 g, 0.45 mmol), (2S,6R)-2,6-dimethyl-morpholine (0.067 g, 0.59 mmol) and triethylamine (0.092 g, 0.90 mmol) in THF (15 mL) and water (5 mL) was heated at 80° C. for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2×50 mL). The combined organic layers were concentrated in vacuo and purified by FCC on silica gel, eluting with 0-10% MeOH in EtOAc, to give the title compound (30 mg, 14%) as a white solid. HPLC-MS (pH10): m/z 480.8 [M+H]+, RT 2.13 minutes.

Prepared from Example 7 and ethyl pyrrolidine-3-carboxylate hydrochloride in accordance with General Method B. The title compound (31 mg, 11%) was obtained as a white solid. HPLC-MS (pH 10): m/z 508.80 [M+H]+, RT 2.47 minutes.

To a solution of Example 280 (0.11 g, 0.22 mmol) in THF (12 mL) and water (4 mL) was added 1M aqueous NaOH solution (0.22 mL). The resulting mixture was stirred for 18 h at r.t. and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the title compound (18 mg, 17%) as a white solid. HPLC-MS (pH 10): m/z 480.8 [M+H]+, RT 1.37 minutes.

Prepared from Intermediate 29 and azetidine-3-carboxylic acid in accordance with General Method B. The title compound (62 mg, 30%) was obtained as a white solid. HPLC-MS (pH 10): MH+ m/z 466.0 [M+H]+, RT 1.24 minutes.

Alternative Method

To a suspension of Intermediate 311 (200 mg, 1 eq) in 2-propanol (10 mL) was added sodium borohydride (1 eq) in one portion and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL), then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulphate and filtered, then the solvents were removed in vacuo. The resultant crude residue was purified by column chromatography on silica (eluent: 0 to 30% isopropanol in DCM), followed by freeze-drying from isopropanol/acetonitrile/water mixture, to give the title compound (82 mg) as an off white solid.

Intermediate 292 (90 mg, 0.30 mmol) and Intermediate 31 (124 mg, 0.36 mmol) were dissolved in 1,4-dioxane (5 mL) and 2M aqueous potassium carbonate solution (0.46 mL) was added. The mixture was degassed thoroughly under nitrogen. Pd(dppf)Cl2complex with dichloromethane (11 mg, 0.015 mmol) was added. The mixture was heated at 105° C. in a sealed tube for 2 h. The reaction mixture was then cooled to room temperature. Ethyl acetate (10 mL) was added and the mixture was filtered through plug of Celite. After further washings with ethyl acetate (3×10 mL), the combined organic layers were washed with brine (15 mL), dried over sodium sulphate and filtered, then the solvent was removed in vacuo. The dark brown oil was purified by chromatography on silica (Biotage, 10 g cartridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford an orange-brown oil (68 mg, 44%). To the foregoing material (112 mg, 0.217 mmol), dissolved in ethyl acetate (5 mL), was added 1M TBAF solution in THF (1 mL), and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed successively with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude brown solid product (123 mg) was dissolved in ethyl acetate and a minimum amount of heptanes was added. The sample was heated until dissolved, then cooled to afford a beige-white precipitate. Slow evaporation of solvents with nitrogen, followed by filtering of the solid and drying in a vacuum oven, afforded the title compound (85 mg, 93%) as a beige solid. δH(500 MHz, DMSO-d6) 8.76 (d, J 2.3 Hz, 1H), 8.49 (s, 1H), 8.04 (dd, J 8.3, 2.4 Hz, 1H), 7.73 (d, J 8.3 Hz, 1H), 7.59 (d, J 9.2 Hz, 1H), 7.55 (dd, J 9.3, 1.6 Hz, 1H), 7.30 (t, J 74.1 Hz, 1H),7.31-7.27 (m, 1H), 7.21 (d, J 8.1 Hz, 1H), 7.17-7.11 (m, 1H), 7.07-7.03 (m, 1H), 5.27 (s, 1H), 4.40 (s, 2H), 2.33 (s, 3H), 1.47 (s, 6H). Method D HPLC-MS: MH+ m/z 424, RT 1.77 minutes.

Intermediate 292 (250 mg, 0.83 mmol) and Intermediate 290 (493.3 mg, 0.92 mmol) were dissolved in 1,4-dioxane (8 mL) and 2M aqueous potassium carbonate solution (1.27 mL) was added. The mixture was degassed thoroughly under nitrogen. Pd(dppf)Cl2complex with dichloromethane (31 mg, 0.042 mmol) was added. The mixture was heated at 105° C. in a sealed tube for 2 h. The reaction mixture was then cooled to room temperature. Ethyl acetate (10 mL) was added and the mixture was filtered through plug of Celite. After further washings with ethyl acetate (3×10 mL), the combined organic layers were washed with brine (15 mL), dried over sodium sulphate and filtered, then the solvent was removed in vacuo. The crude dark brown oil was purified by chromatography on silica (Biotage 10 g cartridge), eluting with 0 to 100% ethyl acetate in heptane, to afford a yellow oil (372 mg, 47%). To a solution of the foregoing material (372 mg, 0.5 mmol) in ethyl acetate (15 mL) was added a 1M solution of TBAF in THF (2.5 mL) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed successively with water (3×5 mL) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude brown oil was purified by preparative HPLC (Method C), followed by trituration from water, to afford the title compound (68 mg, 31%) as a beige solid. δH(500 MHz, CDCl3) 8.54 (s, 1H), 7.80 (ddd, J 6.5, 4.4, 2.2 Hz, 2H), 7.49 (d, J 8.2 Hz, 1H), 7.38 (d, J 10.5 Hz, 1H), 7.34-7.29 (m, 1H), 7.19 (d, J 8.0 Hz, 1H), 7.13 (t, J 7.5 Hz, 1H), 6.92 (d, J 7.7 Hz, 1H), 6.64 (t, J 73.6 Hz, 1H), 4.75 (br s, 1H), 4.31 (s, 2H), 2.53 (s, 3H), 1.60 (s, 6H). Method D HPLC-MS: MH+ m/z 442, RT 1.86 minutes.

2-(5-{3-[(1R or 1S)-1-[2-(Difluoromethoxy)phenyl]ethyl]-2-methylimidazo[1,2-a]-pyridin-6-yl}pyrimidin-2-yl)propan-2-ol (Enantiomers A and B)

A suspension of Intermediate 284 (0.32 g, 0.84 mmol), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (0.23 g, 0.88 mmol) and Pd(dppf)Cl2complex with dichloromethane (0.07 g, 0.08 mmol) in 1,4-dioxane (10 mL) and 2M aqueous K2CO3solution (1.2 mL) was degassed under a stream of N2for 15 minutes. The reaction vessel was sealed and heated at 90° C. for 1 h. The reaction mixture was cooled and diluted with EtOAc (20 mL), then washed with water (20 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by chromatography on silica (Biotage, 10 g cartridge), eluting with 40-100% EtOAc in heptanes, to afford a brown oil (275 mg) (racemic mixture of enantiomers). A sample (100 mg) of the enantiomer mixture was separated on a 25 cm OD-H column, eluting with 90% heptane:10% ethanol, to afford Enantiomer A (23 mg, 6%; RT 19.9 minutes) and Enantiomer B (22 mg, 6%; RT 37.3 minutes).

Example 322 (40 mg, 0.09 mmol) was dissolved in DCM (3 mL) under nitrogen and the solution was cooled to 0° C. using an ice/water bath. BAST (41 mg, 0.17 mmol) was added to the solution, and the cooling bath was removed after the addition was complete. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h before additional BAST (41 mg, 0.17 mmol) was added. After a further 15 minutes of stirring at room temperature, the reaction mixture was quenched with water (5 mL), then basified to pH 8 using saturated aqueous sodium bicarbonate solution with continual stirring. The reaction mixture was partitioned and the aqueous phase was further extracted with DCM (3×5 mL). The combined organic layers were washed with brine (10 mL), then dried over sodium sulfate. The reaction mixture was filtered and concentrated under vacuum. The crude yellow oil was purified by chromatography on silica (Biotage, 10 g catridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (11.4 mg, 28%) as an off-white solid. δH(250 MHz, CDCl3) 8.88 (d, J 1.5 Hz, 2H), 7.84 (d, J 7.0 Hz, 1H), 7.41 (d, J 10.7 Hz, 1H), 7.35-7.27 (m, 1H), 7.22-7.07 (m, 2H), 6.98-6.28 (m, 2H), 5.29-5.04 (m, 4H), 4.30 (s, 2H), 2.53 (s, 3H). Method D HPLC-MS: MH+ m/z 459, RT 1.96 minutes.

A suspension of Intermediate 263 (0.32 g, 0.8 mmol), 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (0.23 g, 0.88 mmol) and PdCl2(dppf) complex with DCM (0.07 g, 0.08 mmol) in 1,4-dioxane (10 mL) and 2M aqueous K2CO3solution (1.2 mL) was degassed under a stream of nitrogen for 15 minutes. The reaction vessel was sealed and heated at 90° C. for 1 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4and concentrated under reduced pressure. The resulting crude material was purified by chromatography on silica (Biotage, 10 g silica), eluting with 1-1.5% MeOH in DCM, to afford a brown oil (280 mg) (mixture of enantiomers). A sample (100 mg) of the enantiomer mixture was separated on chiral SFC (10% isopropanol:90% CO2) on a Chiralcel OD-H 25 cm column to afford Enantiomer A (37 mg; RT 5.72 minutes) and Enantiomer B (32 mg; RT 7.70 minutes).

Prepared from Intermediate 29 and 4,4-difluoropiperidine hydrochloride in accordance with General Method B to give the title compound (52 mg, 37%) as an off-white solid. HPLC-MS (pH 10): MH+ m/z 486.8 [M+H]+, RT 2.70 minutes.

A solution of Intermediate 271 (80 mg, 0.14 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (0.5 mL) and stirred at r.t. for 18 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in aqueous MeCN and freeze-dried, to give the title compound tris(trifluoroacetate) salt (47 mg, 40%) as a brown solid. HPLC-MS (pH 10): MH+ m/z 495.8 [M+H]+, RT 1.40 minutes.

A portion of Example 307 was purified by chiral HPLC (on a Chiracel OD column, with particle size 10 μm, in polar organic mode eluting with 0.1% diethylamine in MeOH at 9 mL/minute at 40° C.). The enantiomer which eluted at 14.4 minutes was collected and concentrated in vacuo to give the title compound as a colourless gum.

A portion of Example 307 was purified by chiral HPLC (on a Chiracel OD column, with particle size 10 μm, in polar organic mode eluting with 0.1% diethylamine in MeOH at 9 mL/minute at 40° C.). The enantiomer which eluted at 15.9 minutes was collected and concentrated in vacuo to give the title compound as a colourless gum.

1-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-a]pyridin-6-yl)-pyrimidin-2-yl]-3-methylpiperidine-3-carboxylic acid (Enantiomers A and B)

Prepared from Intermediate 7 and (4-acetamidomethylphenyl)boronic acid by a method analogous to General Method A, giving the title compound (111 mg, 53%) as a yellow solid. MS: m/z 436.3 [M+H]+. HPLC-MS (Method F): RT 1.38 minutes.