A series of substituted spirocyclic 2-oxoindoline derivatives, and analogues thereof, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national phase of International Application No. PCT/EP2018/065558, filed Jun. 12, 2018, which claims priority from Great Britain Application no. 1709456.6, filed Jun. 14, 2017, the disclosure of each of which is incorporated herein by reference in its entirety.

The present invention relates to heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active spirocyclic oxoindoline derivatives, and analogues thereof. These compounds act as modulators of IL-17 activity, and are accordingly of benefit as pharmaceutical agents for the treatment and/or prevention of pathological conditions, including adverse inflammatory and autoimmune disorders.

IL-17A (originally named CTLA-8 and also known as IL-17) is a pro-inflammatory cytokine and the founder member of the IL-17 family (Rouvier et al.,J. Immunol.,1993, 150, 5445-5456). Subsequently, five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al.,Cytokine Growth Factor Rev.,2003, 14, 155-174). IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, Th17, that also express IL-21 and IL-22 signature cytokines (Korn et al.,Ann. Rev. Immunol.,2009, 27, 485-517). IL-17A and IL-17F are expressed as homodimers, but may also be expressed as the IL-17A/F heterodimer (Wright et al.,J. Immunol.,2008, 181, 2799-2805). IL-17A and F signal through the receptors IL-17R, IL-17RC or an IL-17RA/RC receptor complex (Gaffen,Cytokine,2008, 43, 402-407). Both IL-17A and IL-17F have been associated with a number of autoimmune diseases.

The compounds in accordance with the present invention, being potent modulators of human IL-17 activity, are therefore beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.

Furthermore, 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, the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.

WO 2013/116682 and WO 2014/066726 relate to separate classes of chemical compounds that are stated to modulate the activity of IL-17 and to be useful in the treatment of medical conditions, including inflammatory diseases.

None of the prior art available to date, however, discloses or suggests the precise structural class of spirocyclic oxoindoline derivatives, and analogues thereof, as provided by the present invention.

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

ring A represents C3-9cycloalkyl, C3-7heterocycloalkyl or C4-9heterobicycloalkyl, 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 a pharmaceutically acceptable salt thereof, for use in therapy.

The present invention also provides a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.

The present invention also provides the use of a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.

The present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as depicted above, or a pharmaceutically acceptable salt 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, two or three substituents. Suitably, 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 formula (I) or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, inHandbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P. H. Stahl & C. G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts which may, for example, be formed by mixing a solution of a compound of formula (I) with a solution of a pharmaceutically acceptable acid.

The present invention also includes within its scope co-crystals of the compounds of formula (I) above. 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).

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.

Suitable alkenyl groups which may be present on the compounds of use in the invention include straight-chained and branched C2-7alkenyl groups, for example C2-4alkenyl groups. Typical examples include vinyl, allyl and buten-1-yl.

The term “C3-9cycloalkyl” as used herein refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof. Suitable C3-9cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, tetrahydronaphthalenyl, cycloheptyl, benzocycloheptenyl, cyclooctyl and cyclononanyl.

The term “C3-9cycloalkylidenyl” as used herein refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, optionally comprising benzo-fused analogues thereof, attached to the remainder of the molecule via a C═C double bond. Typically, such groups include cyclobutylidenyl, cyclopentylidenyl, cyclohexylidenyl, cycloheptylidenyl, cyclooctylidenyl and cyclononanylidenyl.

The term “C4-9bicycloalkyl” as used herein refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical bicycloalkyl groups include bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo-[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.0]octanyl and bicyclo[3.2.1]octanyl.

The term “C4-9bicycloalkylidenyl” as used herein refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon, attached to the remainder of the molecule via a C═C double bond. Typically, such groups include bicyclo[3.1.0]hexanylidenyl, bicyclo[2.2.1]heptanylidenyl and bicyclo[3.2.1]octanyliden-yl.

The term “C5-9spirocycloalkyl” as used herein refers to saturated bicyclic ring systems containing 5 to 9 carbon atoms, in which the two rings are linked by a common atom. Suitable spirocycloalkyl groups include spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl and spiro[4.4]nonanyl.

The term “C9-11tricycloalkyl” as used herein refers to monovalent groups of 9 to 11 carbon atoms derived from a saturated tricyclic hydrocarbon. Typical tricycloalkyl groups include adamantanyl.

The term “aryl” as used herein refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

The term “C3-7heterocycloalkylidenyl” as used herein refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, attached to the remainder of the molecule via a C═C double bond. Typically, such groups include tetrahydropyranylidenyl and piperidinylidenyl.

The term “C4-9heterobicycloalkyl” as used herein corresponds to C4-9 bicycloalkyl wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen. Typical heterobicycloalkyl groups include 6-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-azabicyclo-[2.2.2]octanyl, 8-oxabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo-[3.3.1]nonanyl and 3,9-diazabicyclo[4.2.1]nonanyl.

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 in accordance with 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 a first embodiment, ring A represents optionally substituted C3-9cycloalkyl. In one aspect of that embodiment, ring A represents optionally substituted C4-7cycloalkyl.

In a second embodiment, ring A represents optionally substituted C3-7heterocycloalkyl. In one aspect of that embodiment, ring A represents optionally substituted C4-6heterocycloalkyl.

In a third embodiment, ring A represents optionally substituted C4-9heterobicycloalkyl. In one aspect of that embodiment, ring A represents optionally substituted C5-7heterobicycloalkyl.

Appositely, ring A represents pyrrolidinyl, tetrahydropyranyl, tetrahydrothio-pyranyl or piperidinyl, any of which groups may be optionally substituted by one or more substituents.

Suitably, ring A represents tetrahydropyranyl, tetrahydrothiopyranyl or piperidinyl, any of which groups may be optionally substituted by one or more substituents.

In a particular embodiment, ring A represents tetrahydropyranyl, which group may be optionally substituted by one or more substituents.

Suitable examples of optional substituents on ring A include one, two or three substituents independently selected from C1-6alkyl, oxo and imino.

Suitable examples of particular substituents on ring A include one, two or three substituents independently selected from methyl, oxo and imino.

Typical values of ring A include tetrahydropyranyl, tetrahydrothiopyranyl and piperidinyl.

A particular value of ring A is tetrahydropyranyl.

In one embodiment, B represents C—R2. In another embodiment, B represents N.

In one embodiment, D represents C—R3. In another embodiment, D represents N.

In one embodiment, E represents C—R4. In another embodiment, E represents N.

In a first embodiment, B represents C—R2, D represents C—R3and E represents C—R4.

In a second embodiment, B represents C—R2, D represents C—R3and E represents N.

In a third embodiment, B represents C—R2, D represents N and E represents C—R4.

In a fourth embodiment, B represents C—R2, D represents N and E represents N.

In a fifth embodiment, B represents N, D represents C—R3and E represents C—R4.

In a sixth embodiment, B represents N, D represents C—R3and E represents N.

In a seventh embodiment, B represents N, D represents N and E represents C—R4.

In an eighth embodiment, B represents N, D represents N and E represents N.

Suitably, the present invention provides a compound of formula (I-1), (I-2), (I-3), (I-4) or (I-5), or a pharmaceutically acceptable salt thereof:

In a first embodiment, R0represents hydrogen. In a second embodiment, R0represents C1-6alkyl, especially methyl.

In a first embodiment, R2represents hydrogen. In a second embodiment, R2represents halogen. In a first aspect of that embodiment, R2represents fluoro. In a second aspect of that embodiment, R2represents chloro. In a third embodiment, R2represents cyano. In a fourth embodiment, R2represents C1-6alkyl, especially methyl. In a fifth embodiment, R2represents fluoromethyl. In a sixth embodiment, R2represents difluoromethyl. In a seventh embodiment, R2represents trifluoromethyl. In an eighth embodiment, R2represents hydroxy. In a ninth embodiment, R2represents C1-6alkoxy, especially methoxy. In a tenth embodiment, R2represents difluoromethoxy. In an eleventh embodiment, R2represents trifluoromethoxy. In a twelfth embodiment, R2represents C1-6alkylsulphinyl, especially methylsulphinyl. In a thirteenth embodiment, R2represents C1-6alkylsulphonyl, especially methylsulphonyl.

In a first embodiment, R3represents hydrogen. In a second embodiment, R3represents halogen. In a first aspect of that embodiment, R3represents fluoro. In a second aspect of that embodiment, R3represents chloro. In a third embodiment, R3represents cyano. In a fourth embodiment, R3represents C1-6alkyl, especially methyl. In a fifth embodiment, R3represents fluoromethyl. In a sixth embodiment, R3represents difluoromethyl. In a seventh embodiment, R3represents trifluoromethyl. In an eighth embodiment, R3represents hydroxy. In a ninth embodiment, R3represents C1-6alkoxy, especially methoxy. In a tenth embodiment, R3represents difluoromethoxy. In an eleventh embodiment, R3represents trifluoromethoxy. In a twelfth embodiment, R3represents C1-6alkylsulphinyl, especially methylsulphinyl. In a thirteenth embodiment, R3represents C1-6alkylsulphonyl, especially methylsulphonyl.

In a first embodiment, R4represents hydrogen. In a second embodiment, R4represents halogen. In a first aspect of that embodiment, R4represents fluoro. In a second aspect of that embodiment, R4represents chloro. In a third embodiment, R4represents cyano. In a fourth embodiment, R4represents C1-6alkyl, especially methyl. In a fifth embodiment, R4represents fluoromethyl. In a sixth embodiment, R4represents difluoromethyl. In a seventh embodiment, R4represents trifluoromethyl. In an eighth embodiment, R4represents hydroxy. In a ninth embodiment, R4represents C1-6alkoxy, especially methoxy. In a tenth embodiment, R4represents difluoromethoxy. In an eleventh embodiment, R4represents trifluoromethoxy. In a twelfth embodiment, R4represents C1-6alkylsulphinyl, especially methylsulphinyl. In a thirteenth embodiment, R4represents C1-6alkylsulphonyl, especially methylsulphonyl.

Suitably, Rarepresents C1-6alkyl, C3-9cycloalkyl(C1-6)alkyl, C5-9spirocycloalkyl-(C1-6)alkyl or aryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

In a particular embodiment, Rais other than hydrogen.

Suitable values of Rainclude methyl, cyclohexylmethyl, cyclooctylmethyl, spiro[3.3]heptanylmethyl and phenylethyl, any of which groups may be optionally substituted by one or more substituents.

Apposite examples of optional substituents on Rainclude one, two or three substituents independently selected from halogen, amino, C2-6alkylcarbonylamino, (C1-6)alkylheteroarylcarbonylamino, heteroaryl(C1-6)alkylcarbonylamino and aminoheteroaryl(C1-6)alkylcarbonylamino.

Apposite examples of specific substituents on Rainclude one, two or three substituents independently selected from chloro, amino, acetylamino, methylpyrazolyl-carbonylamino, pyridinylmethylcarbonylamino and aminopyridinylmethylcarbonylamino.

Suitably, Rbrepresents C1-6alkyl, C3-9cycloalkyl(C1-6)alkyl, C5-9spirocycloalkyl-(C1-6)alkyl or aryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Suitable values of Rbinclude methyl, cyclohexylmethyl, cyclooctylmethyl, spiro[3.3]heptanylmethyl and phenylethyl, any of which groups may be optionally substituted by one or more substituents.

Apposite examples of optional substituents on Rbinclude one, two or three substituents independently selected from halogen, amino, C2-6alkylcarbonylamino, (C1-6)alkylheteroarylcarbonylamino, heteroaryl(C1-6)alkylcarbonylamino and aminoheteroaryl(C1-6)alkylcarbonylamino.

Apposite examples of specific substituents on Rbinclude one, two or three substituents independently selected from chloro, amino, acetylamino, methylpyrazolyl-carbonylamino, pyridinylmethylcarbonylamino and aminopyridinylmethylcarbonylamino.

A particular sub-class of compounds according to the invention is represented by the compounds of formula (IA), and pharmaceutically acceptable salts thereof:

wherein

R6arepresents hydrogen; or R6arepresents C1-6alkyl, C3-7cycloalkyl, C3-7cyclo-alkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7heterocycloalkyl, C3-7heterocycloalkyl(C1-6)-alkyl, heteroaryl, heteroaryl(C1-6)alkyl or spiro[(C3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one or more substituents;

R6brepresents hydrogen or C1-6alkyl; and

R6crepresents 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.

A second sub-class of compounds according to the invention is represented by the compounds of formula (IB), and pharmaceutically acceptable salts thereof:

wherein

A third sub-class of compounds according to the invention is represented by the compounds of formula (IC), and pharmaceutically acceptable salts thereof:

wherein

R7represents aryl, heteroaryl or spiro[(C3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one or more substituents.

A fourth sub-class of compounds according to the invention is represented by the compounds of formula (ID), and pharmaceutically acceptable salts thereof:

wherein

A fifth sub-class of compounds according to the invention is represented by the compounds of formula (IE), and pharmaceutically acceptable salts thereof:

wherein

A sixth sub-class of compounds according to the invention is represented by the compounds of formula (IF), and pharmaceutically acceptable salts thereof:

wherein

R5arepresents C3-7cycloalkyl, C4-9bicycloalkyl, aryl, C3-7heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and

R5brepresents hydrogen or C1-6alkyl; or

R5aand R5b, when taken together with the carbon atom to which they are both attached, represent C3-7cycloalkyl, C4-9bicycloalkyl or C3-7heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.

Typically, R5represents C1-5alkyl, C3-9cycloalkyl, C3-9cycloalkyl(C1-5)alkyl, C4-9bicycloalkyl, C5-9spirocycloalkyl, C5-9spirocycloalkyl(C1-5)alkyl, C9-11tricycloalkyl, C9-11tricycloalkyl(C1-5)alkyl, aryl, aryl(C1-5)alkyl, C3-7heterocycloalkyl, C3-7heterocyclo-alkyl(C1-5)alkyl, heteroaryl or heteroaryl(C1-5)alkyl, any of which groups may be optionally substituted by one or more substituents. Additionally, R5may represent C4-9bicycloalkyl(C1-5)alkyl, which group may be optionally substituted by one or more substituents.

Appositely, R5represents hydrogen; or R5represents C3-9cycloalkyl, C5-9spiro-cycloalkyl or aryl(C1-5)alkyl, any of which groups may be optionally substituted by one or more substituents.

In a first embodiment, R5represents hydrogen. In a second embodiment, R5represents optionally substituted C1-5alkyl. In a third embodiment, R5represents optionally substituted C3-9cycloalkyl. In a fourth embodiment, R5represents optionally substituted C3-9cycloalkyl(C1-5)alkyl. In a fifth embodiment, R5represents optionally substituted C4-9bicycloalkyl. In a sixth embodiment, R5represents optionally substituted C4-9bicycloalkyl(C1-5)alkyl. In a seventh embodiment, R5represents optionally substituted C5-9spirocycloalkyl. In an eighth embodiment, R5represents optionally substituted C5-9spirocycloalkyl(C1-5)alkyl. In a ninth embodiment, R5represents optionally substituted C9-11tricycloalkyl. In a tenth embodiment, R5represents optionally substituted C9-11tricycloalkyl(C1-5)alkyl. In an eleventh embodiment, R5represents optionally substituted aryl. In a twelfth embodiment, R5represents optionally substituted aryl(C1-5)alkyl. In a thirteenth embodiment, R5represents optionally substituted C3-7heterocycloalkyl. In a fourteenth embodiment, R5represents optionally substituted C3-7heterocycloalkyl(C1-5)alkyl. In a fifteenth embodiment, R5represents optionally substituted heteroaryl. In a sixteenth embodiment, R5represents optionally substituted heteroaryl(C1-5)alkyl.

In a particular embodiment, R5is other than hydrogen.

Suitable values of R5include cyclohexyl, cyclooctyl, spiro[3.3]heptanyl and benzyl, any of which groups may be optionally substituted by one or more substituents.

Suitable examples of optional substituents on R5include one, two or three substituents independently selected from halogen, cyano, C1-6alkyl, trifluoromethyl, phenyl, hydroxy, C1-6alkoxy and aminocarbonyl, especially halogen.

Favoured examples of optional substituents on R5include one, two or three substituents independently selected from halogen, C1-6alkyl, trifluoromethyl, phenyl and C1-6alkoxy, especially halogen.

Favoured examples of specific substituents on R5include one, two or three substituents independently selected from fluoro, chloro, bromo, methyl, trifluoromethyl, phenyl, isopropoxy and tert-butoxy, especially chloro.

Favoured values of R5include cyclohexyl, 4-methylcyclohexyl and cyclooctyl. In a first embodiment, R5represents cyclohexyl. In a second embodiment, R5represents 4-methylcyclohexyl. In a third embodiment, R5represents cyclooctyl.

In a first embodiment, R5arepresents optionally substituted C3-7cycloalkyl. In a second embodiment, R5arepresents optionally substituted C4-9bicycloalkyl. In a third embodiment, R5arepresents optionally substituted aryl. In a fourth embodiment, R5arepresents optionally substituted C3-7heterocycloalkyl. In a fifth embodiment, R5arepresents optionally substituted heteroaryl.

Typical values of R5ainclude cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentanyl, phenyl, dihydrobenzofuranyl and pyrrolyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of optional substituents on R5ainclude C1-6alkyl and halogen.

Selected examples of particular substituents on R5ainclude methyl and chloro.

In a first embodiment, R5brepresents hydrogen. In a second embodiment, R5brepresents C1-6alkyl, especially methyl or ethyl.

Alternatively, R5aand R5b, when taken together with the carbon atom to which they are both attached, may represent C3-7cycloalkyl, C4-9bicycloalkyl or C3-7heterocycloalkyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.

In a first embodiment, R5aand R5b, when taken together with the carbon atom to which they are both attached, may suitably represent optionally substituted C3-7cycloalkyl. Examples include cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, tetrahydronaphthalenyl, cycloheptanyl, benzocycloheptenyl, cyclooctanyl and cyclononanyl, any of which groups may be optionally substituted by one or more substituents.

In a second embodiment, R5aand R5b, when taken together with the carbon atom to which they are both attached, may suitably represent optionally substituted C4-9bicycloalkyl. Examples include bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl and bicyclo[3.2.1]octanyl, any of which groups may be optionally substituted by one or more substituents.

In a third embodiment, R5aand R5b, when taken together with the carbon atom to which they are both attached, may suitably represent optionally substituted C3-7heterocycloalkyl. Examples include tetrahydropyranyl and piperidinyl, either of which groups may be optionally substituted by one or more substituents.

Selected examples of optional substituents on such groups include C1-6alkyl, halogen, trifluoromethyl, trifluoroethyl, phenyl and C1-6alkoxy.

Selected examples of particular substituents on such groups include methyl, chloro, trifluoromethyl, trifluoroethyl, phenyl and methoxy.

Generally, R6represents —NR6aR6b; or R6represents C1-6alkyl, C3-9cycloalkyl, C3-9cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7heterocycloalkyl, C3-7hetero-cycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Favourably, R6represents —NR6aR6bor —OR6c; or R6represents C1-9alkyl, aryl, C3-7heterocycloalkyl, heteroaryl, heteroaryl(C1-6)alkyl or spiro[(C3-7)heterocycloalkyl]-[heteroaryl], any of which groups may be optionally substituted by one or more substituents.

Typically, R6represents —NR6aR6b; or R6represents C1-6alkyl, C3-9cycloalkyl, C3-9cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents. Additionally, R6may represent —OR6c; or R6may represent aryl, C3-7heterocycloalkyl or spiro[(C3-7)-heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one or more substituents.

Suitably, R6represents C1-6alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

In a first embodiment, R6represents optionally substituted C1-6alkyl. In a second embodiment, R6represents optionally substituted C3-9cycloalkyl. In a third embodiment, R6represents optionally substituted C3-9cycloalkyl(C1-6)alkyl. In a fourth embodiment, R6represents optionally substituted aryl. In a fifth embodiment, R6represents optionally substituted aryl(C1-6)alkyl. In a sixth embodiment, R6represents optionally substituted C3-7heterocycloalkyl. In a seventh embodiment, R6represents optionally substituted C3-7heterocycloalkyl(C1-6)alkyl. In an eighth embodiment, R6represents optionally substituted heteroaryl. In a ninth embodiment, R6represents optionally substituted heteroaryl(C1-6)alkyl. In a tenth embodiment, R6represents optionally substituted spiro[(C3-7)heterocycloalkyl][heteroaryl]. In an eleventh embodiment, R6represents —NR6aR6b. In a twelfth embodiment, R6represents —OR6c.

Suitable values of R6include methyl, pyrazolyl and pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.

Illustrative examples of optional substituents on R6include one, two or three substituents independently selected from C1-6alkyl and amino.

Illustrative examples of specific substituents on R6include one, two or three substituents independently selected from methyl and amino.

Favourably, R6arepresents C1-6alkyl, C3-7cycloalkyl, aryl(C1-6)alkyl, C3-7heterocycloalkyl or spiro[(C3-7)heterocycloalkyl][heteroaryl], any of which groups may be optionally substituted by one or more substituents.

In a first embodiment, R6arepresents hydrogen. In a second embodiment, R6arepresents optionally substituted C1-6alkyl. In a first aspect of that embodiment, R6arepresents unsubstituted C1-6alkyl, especially methyl. In a second aspect of that embodiment, R6arepresents monosubstituted, disubstituted or trisubstituted C1-6alkyl. In a third embodiment, R6arepresents optionally substituted C3-7cycloalkyl. In a fourth embodiment, R6arepresents optionally substituted C3-7cycloalkyl(C1-6)alkyl. In a fifth embodiment, R6arepresents optionally substituted aryl. In a sixth embodiment, R6arepresents optionally substituted aryl(C1-6)alkyl. In a seventh embodiment, R6arepresents optionally substituted C3-7heterocycloalkyl. In an eighth embodiment, R6arepresents optionally substituted C3-7heterocycloalkyl(C1-6)alkyl. In a ninth embodiment, R6arepresents optionally substituted heteroaryl. In a tenth embodiment, R6arepresents optionally substituted heteroaryl(C1-6)alkyl. In an eleventh embodiment, R6arepresents optionally substituted spiro[(C3-7)heterocycloalkyl][heteroaryl].

Typical values of R6ainclude methyl, ethyl, n-propyl, isopropyl, 2,2-dimethyl-propyl, cyclohexyl, benzyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl and spiro[tetrahydrofuran][indole], any of which groups may be optionally substituted by one or more substituents.

Selected examples of optional substituents on R6ainclude one, two or three substituents independently selected from trifluoromethyl, oxo and C1-6alkoxy.

Selected examples of specific substituents on R6ainclude one, two or three substituents independently selected from trifluoromethyl, oxo and methoxy.

In a first embodiment, R6brepresents hydrogen. In a second embodiment, R6brepresents C1-6alkyl. In a particular aspect of that embodiment, R6brepresents methyl, ethyl, n-propyl or isopropyl, especially methyl.

Favourably, R6crepresents C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkyl(C1-6)alkyl, C3-7heterocycloalkyl, C3-7heterocycloalkyl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

In a first embodiment, R6crepresents optionally substituted C1-6alkyl. In a second embodiment, R6crepresents optionally substituted C3-7cycloalkyl. In a third embodiment, R6crepresents optionally substituted C3-7cycloalkyl(C1-6)alkyl. In a fourth embodiment, R6crepresents optionally substituted aryl. In a fifth embodiment, R6crepresents optionally substituted aryl(C1-6)alkyl. In a sixth embodiment, R6crepresents optionally substituted C3-7heterocycloalkyl. In a seventh embodiment, R6crepresents optionally substituted C3-7heterocycloalkyl(C1-6)alkyl. In an eighth embodiment, R6crepresents optionally substituted heteroaryl. In a ninth embodiment, R6crepresents optionally substituted heteroaryl(C1-6)alkyl.

Selected examples of optional substituents on R6cinclude one, two or three substituents independently selected from C1-6alkyl, trifluoromethyl, C1-6alkoxy and C2-6alkoxycarbonyl.

Selected examples of specific substituents on R6cinclude one, two or three substituents independently selected from methyl, trifluoromethyl, methoxy and tert-butoxycarbonyl.

In a first embodiment, R7represents aryl, which group may be optionally substituted by one or more substituents. In a second embodiment, R7represents heteroaryl, which group may be optionally substituted by one or more substituents. In a third embodiment, R7represents spiro[(C3-7)heterocycloalkyl][heteroaryl], which group may be optionally substituted by one or more substituents.

Typical values of R7include phenyl, pyrazolo[1,5-a]pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, imidazo[1,2-b]pyridazinyl, purinyl, pyridinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl and spiro[tetrahydropyranyl][indole], any of which groups may be optionally substituted by one or more substituents.

One sub-class of the compounds of formula (IA) above is represented by the compounds of formula (IIA), and pharmaceutically acceptable salts thereof:

wherein

R17represents hydrogen or C1-6alkyl; and

Suitably, W represents O, S or N—R17.

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 S(O)(NH). In a sixth embodiment, W represents N—R17.

In a first embodiment, R17represents hydrogen. In a second embodiment, R17represents C1-6alkyl. In a first aspect of that embodiment, R17represents methyl.

Another sub-class of the compounds of formula (IA) above is represented by the compounds of formula (IIB), and pharmaceutically acceptable salts thereof:

wherein

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.

The compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.

The compounds according to the present invention are useful in the treatment and/or prophylaxis of a pathological disorder that is mediated by a pro-inflammatory IL-17 cytokine or is associated with an increased level of a pro-inflammatory IL-17 cytokine. Generally, the pathological condition is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airways disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's Disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman's disease, ankylosing spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's Disease, coeliac disease, gall bladder disease, Pilonidal disease, peritonitis, psoriasis, atopic dermatitis, vasculitis, surgical adhesions, stroke, autoimmune diabetes, Type I Diabetes, lyme arthritis, meningoencephalitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barr syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrosing disorders including pulmonary fibrosis, liver fibrosis, renal fibrosis, scleroderma or systemic sclerosis, cancer (both solid tumours such as melanomas, hepatoblastomas, sarcomas, squamous cell carcinomas, transitional cell cancers, ovarian cancers and hematologic malignancies and in particular acute myelogenous leukaemia, chronic myelogenous leukemia, chronic lymphatic leukemia, gastric cancer and colon cancer), heart disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydia and pain (particularly pain associated with inflammation).

WO 2009/089036 reveals that modulators of IL-17 activity may be administered to inhibit or reduce the severity of ocular inflammatory disorders, in particular ocular surface inflammatory disorders including Dry Eye Syndrome (DES). Consequently, the compounds in accordance with the present invention are useful in the treatment and/or prevention of an IL-17-mediated ocular inflammatory disorder, in particular an IL-17-mediated ocular surface inflammatory disorder including Dry Eye Syndrome. Ocular surface inflammatory disorders include Dry Eye Syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal ocular surface inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, Pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis. Particular categories of Dry Eye Syndrome include keratoconjunctivitis sicca (KCS), Sjögren syndrome, Sjögren syndrome-associated keratoconjunctivitis sicca, non-Sjögren syndrome-associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.

Illustratively, the compounds of the present invention may be useful in the treatment and/or prophylaxis of a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, scleroderma, systemic sclerosis, lung fibrosis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), ankylosing spondylitis and other spondylo-arthropathies, cancer and pain (particularly pain associated with inflammation).

Suitably, the compounds of the present invention are useful in the treatment and/or prophylaxis of psoriasis, psoriatic arthritis or ankylosing spondylitis.

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 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 according to the present invention 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 according to the present invention 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 according to 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 according to 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 according to 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 the compounds according to the present invention may be formulated in an ointment such as petrolatum.

For rectal administration the compounds according to 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 according to the present 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.

The compounds of formula (I) above wherein R1represents —CORamay be prepared by a process which comprises reacting a carboxylic acid of formula RaCO2H, or a salt thereof, e.g. a lithium salt thereof, with a compound of formula (III):

wherein A, B, D, E and Raare as defined above, and Rpcorresponds to the group R0as defined above, or Rprepresents a N-protecting group; followed, as necessary, by removal of the N-protecting group Rp.

The reaction is conveniently accomplished in the presence of a coupling agent. Suitable coupling agents include 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HATU).

Where compound (III) is reacted with a carboxylic acid of formula RaCO2H, the reaction is generally carried out in the presence of a base. Suitable bases include organic amines, e.g. a trialkylamine such as N,N-diisopropylethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as N,N-dimethylformamide, or a chlorinated solvent such as dichloromethane.

Where compound (III) is reacted with the lithium salt of a carboxylic acid of formula RaCO2H, the reaction is generally carried out at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.

Where the N-protecting group Rpis BOC, the subsequent removal thereof may conveniently be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

Where the N-protecting group Rpis benzyl, the subsequent removal thereof may conveniently be effected by catalytic hydrogenation, typically by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal.

Where the N-protecting group Rpis SEM, the subsequent removal thereof may conveniently be effected by treatment with a fluoride salt, e.g. tetra-n-butylammonium fluoride; or by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

Where Rarepresents —CH(R5)N(H)C(O)R6, the intermediates of formula RaCO2H may be prepared by a two-step procedure which comprises: (i) reacting a carboxylic acid of formula R6—CO2H with a compound of formula (IV):

wherein Alk1represents C1-4alkyl, e.g. methyl, and R5and R6are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula RaCO2H; and (ii) saponification of the resulting material by treatment with a base.

As for the reaction between compound (III) and a carboxylic acid of formula RaCO2H, the coupling agent employed in step (i) may suitably be HATU.

Alternatively, the coupling agent may be 2,4,6-tripropyl-1,3,5,2,4,6-trioxa-triphosphorinane 2,4,6-trioxide, in which case the reaction may generally be carried out in the presence of a base which may suitably include organic amines, e.g. a trialkylamine such as N,N-diisopropylethylamine, or an aromatic base such as pyridine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. an organic ester such as ethyl acetate and/or a cyclic ether such as tetrahydrofuran.

Alternatively, the coupling agent may be a mixture of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, in which case the reaction may generally be carried out in the presence of a base, e.g. an organic amine such as N,N-diisopropylethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethyl-formamide.

The saponification reaction in step (ii) will generally be effected by treatment with a base. Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide. Where lithium hydroxide is employed in step (ii) of the above procedure, the product may be the lithium salt of the carboxylic acid of formula RaCO2H.

Step (ii) is conveniently effected at ambient temperature in water and a suitable organic solvent, e.g. a cyclic ether such as tetrahydrofuran, optionally in admixture with a C1-4alkanol such as methanol.

In another procedure, the compounds of formula (I) above wherein R1represents —SO2Rbmay be prepared by a process which comprises reacting a compound of formula RbSO2C1with a compound of formula (III) as defined above.

The reaction is conveniently accomplished at ambient temperature in the presence of a base, e.g. an organic base such as triethylamine, in a suitable solvent, e.g. a chlorinated hydrocarbon solvent such as dichloromethane.

In another procedure, the compounds of formula (I) above wherein R1represents —CORamay be prepared by a process which comprises reacting an amide of formula RaCONH2with a compound of formula (V):

wherein A, B, D, E, Raand Rpare as defined above, and L1represents a suitable leaving group; in the presence of a transition metal catalyst; followed, as necessary, by removal of the N-protecting group Rp.

The leaving group L1is suitably a halogen atom, e.g. chloro or bromo.

The transition metal catalyst is suitably [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methane-sulfonate (tBuBrettPhos Pd G3), in which case the reaction will generally be performed in the presence of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (tBuBrettPhos). The reaction is conveniently carried out at an elevated temperature in the presence of a base, e.g. an inorganic base such as potassium carbonate, in a suitable solvent, e.g. a lower alkanol such as tert-butanol.

Alternatively, the transition metal catalyst may suitably be tris(dibenzylidene-acetone)dipalladium(0), in which case the reaction will generally be performed in the presence of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos). The reaction is conveniently carried out at an elevated temperature in the presence of a base, e.g. a carbonate salt such as potassium carbonate or cesium carbonate, in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane, or a C1-6alkanol such as tert-butanol.

In another procedure, the compounds of formula (I) above wherein R1is an aryl or heteroaryl moiety may be prepared by a process which comprises reacting a compound of formula R1—NH2with a compound of formula (V) as defined above in the presence of a transition metal catalyst; followed, as necessary, by removal of the N-protecting group Rp.

The transition metal catalyst is suitably tris(dibenzylideneacetone)dipalladium(0), in which case the reaction will generally be performed in the presence of 2-(di-tert-butyl)-phosphino-2′,4′,6′-triisopropylbiphenyl (tert-BuXPhos). The reaction is conveniently carried out at an elevated temperature in the presence of a base, e.g. a tert-butoxide salt such as sodium tert-butoxide, in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane.

The intermediates of formula (V) above may be prepared by reacting the appropriate α,ω-dihaloalkane with a compound of formula (VI):

The reaction is generally performed in the presence of a base, e.g. an inorganic base such as cesium carbonate. The reaction will conveniently be carried out at ambient or elevated temperature, as appropriate, in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, or a carbonyl solvent such as acetone, or a sulfoxide solvent such as dimethyl sulfoxide.

The intermediates of formula (VI) above may be prepared by a two-step procedure from a compound of formula (VII):

(i) treatment of compound (VII) with pyridinium tribromide or N-bromo-succinimide; and

(ii) treatment of the 3,3-dibromo-2-oxoindoline derivative thereby obtained with metallic zinc.

Step (i) is conveniently carried out at ambient temperature in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane, or a C1-4alkanol such as tert-butanol, typically in admixture with water.

Step (ii) is conveniently carried out in the presence of ammonium chloride at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, or a cyclic ether such as tetrahydrofuran. Alternatively, step (ii) may be accomplished in acetic acid at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

Similarly, the intermediates of formula (III) above may be prepared by reacting the appropriate α,ω-dihaloalkane with a compound of formula (VI-A):

wherein B, D, E and Rpare as defined above, and Rqrepresents hydrogen or an N-protecting group; under conditions analogous to those described above for the reaction of an α,ω-dihaloalkane with a compound of formula (VI); followed, as appropriate, by removal of the N-protecting group(s) Rpand/or Rq.

Where the N-protecting group Rqis BOC, the subsequent removal thereof may conveniently be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

In another procedure, the compounds of formula (IA) above may be prepared by a process which comprises reacting a compound of formula (III) as defined above with a compound of formula (VIII):

wherein R5and R6are as defined above; followed, as necessary, by removal of the N-protecting group Rp.

The reaction between compounds (III) and (VIII) will generally be performed in the presence of acetic acid. The reaction is conveniently carried out at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

Similarly, the compounds of formula (IF) above may be prepared by a process which comprises reacting a compound of formula (III) as defined above with a compound of formula (IX):

wherein R5a, R5band R6are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (VIII); followed, as necessary, by removal of the N-protecting group Rp.

Where the respective values of R5, R5aand R5bpermit, an intermediate of formula (VIII) may be obtained from the corresponding intermediate of formula (IX) by conventional catalytic hydrogenation.

The intermediates of formula (IX) above may be prepared by reacting a compound of formula R5aC(O)R5bwith a compound of formula (VIII) as defined above wherein R5represents hydrogen.

The reaction is conveniently effected by treating the reagents with titanium tetrachloride; followed by treatment of the resulting material with pyridine.

In another procedure, the compounds of formula (IA) above may be prepared by a process which comprises reacting a carboxylic acid of formula R6—CO2H with a compound of formula (X):

wherein A, B, D, E, Rp, R5and R6are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula RaCO2H; followed, as necessary, by removal of the N-protecting group Rp.

Similarly, the compounds of formula (IA) above wherein R6represents —NR6aR6bmay be prepared by a process which comprises reacting a carbamate derivative of formula L2-C(O)NR6aR6b, wherein L2represents a suitable leaving group, with a compound of formula (X) as defined above; followed, as necessary, by removal of the N-protecting group Rp.

Where L2is a halogen atom, the reaction is conveniently carried out at ambient temperature in the presence of a base, e.g. an organic amine such as triethylamine, in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.

Where L2is phenoxy, the reaction is conveniently carried out at an elevated temperature in the presence of 4-(dimethylamino)pyridine, in a suitable solvent, e.g. a nitrile solvent such as acetonitrile.

Similarly, the compounds of formula (IA) above wherein R6represents —OR6cmay be prepared by a process which comprises reacting a compound of formula L3-C(O)OR6c, wherein L3represents a suitable leaving group, with a compound of formula (X) as defined above; followed, as necessary, by removal of the N-protecting group Rp.

The leaving group L3is suitably a halogen atom, e.g. chloro.

The reaction is conveniently carried out at ambient temperature in the presence of a base, e.g. an organic amine such as triethylamine, typically in admixture with pyridine, in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

In another procedure, the compounds of formula (IB) above may be prepared by a process which comprises reacting a compound of formula (X) as defined above with a compound of formula L4-S(O)2R6, wherein R6is as defined above, and L4represents a suitable leaving group; followed, as necessary, by removal of the N-protecting group Rp.

The leaving group L4is suitably a halogen atom, e.g. chloro.

The reaction is conveniently carried out at ambient temperature in the presence of a base, e.g. an organic amine such as N,N-diisopropylethylamine, in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.

In another procedure, the compounds of formula (IC) above may be prepared by a process which comprises reacting a compound of formula (X) as defined above with a compound of formula L5-R7, wherein R7is as defined above, and L5represents a suitable leaving group; followed, as necessary, by removal of the N-protecting group Rp.

The leaving group L5is suitably a halogen atom, e.g. chloro or bromo.

The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, e.g. a trialkylamine such as N,N-diisopropylethylamine. The reaction is typically performed at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane.

Alternatively, the reaction may be performed in the presence of a transition metal catalyst. Suitable transition metal catalysts of use in this procedure include [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (tBuBrettPhos Pd G3). The reaction is conveniently carried out at an elevated temperature in the presence of a base, e.g. an inorganic base such as potassium tert-butoxide, in a suitable solvent or solvent mixture. The solvent or solvents may suitably be selected from a cyclic ether such as 1,4-dioxane, and a sulfoxide solvent such as dimethyl sulfoxide.

The intermediates of formula (X) above may be prepared by reacting a compound of formula (III) as defined above with a compound of formula (XI), or a salt thereof, e.g. a lithium salt thereof:

wherein R5and Rqare as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula RaCO2H; followed, as necessary, by removal of the N-protecting group Rq.

In another procedure, the compounds of formula (ID) above may be prepared by a process which comprises reacting a compound of formula R7—NH2with a compound of formula (XII):

wherein A, B, D, E, Rp, R5and R7are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula RaCO2H; followed, as necessary, by removal of the N-protecting group Rp.

The intermediates of formula (XII) above may be prepared by a two-step procedure which comprises: (i) reacting a compound of formula (III) as defined above with a compound of formula (XIII), or a salt thereof, e.g. a lithium salt thereof:

wherein R5and Alk1are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula RaCO2H; and (ii) saponification of the resulting material by treatment with a base.

The saponification reaction in step (ii) will generally be effected by treatment with a base. Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide. Where lithium hydroxide is employed in step (ii) of the above procedure, the product may be the lithium salt of the carboxylic acid of formula (XII).

Step (ii) is conveniently effected at ambient temperature in water and a suitable organic solvent, e.g. a C1-4alkanol such as ethanol.

Where they are not commercially available, the starting materials of formula (IV), (VI-A), (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) comprising a N—BOC moiety (wherein BOC is an abbreviation for tert-butoxycarbonyl) may be converted into the corresponding compound comprising a 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) comprising an amino (—NH2) moiety may be acylated, e.g. acetylated, by treatment with a suitable acyl halide, e.g. acetyl chloride, typically in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine.

A compound which contains an N—H moiety may be alkylated, e.g. methylated, by treatment with the appropriate alkyl halide, e.g. iodomethane, typically at ambient temperature in the presence of a base, e.g. sodium hydride, in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.

A compound of formula (I) wherein R3is hydrogen may be converted into the corresponding compound wherein R3is fluoro by treatment with Selectfluor™.

A compound of formula (I) wherein R3is hydrogen may be converted into the corresponding compound wherein R3is chloro by treatment with N-chlorosuccinimide, typically in the presence of acetic acid.

Where the respective values of R5, R5aand R5bpermit, a compound of formula (IA) may be obtained from the corresponding compound of formula (IF) by conventional catalytic hydrogenation, e.g. by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as palladium on charcoal.

A compound 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 containing the moiety —S— or —S(O)— may be converted into the corresponding compound containing the moiety —S(O)2— by treatment with 3-chloroperoxy-benzoic acid.

A compound containing the moiety —S— may be converted into the corresponding compound containing the moiety —S(O)(NH)— by treatment with ammonium carbamate and (diacetoxyiodo)benzene.

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.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described inGreene's Protective Groups in Organic Synthesis, ed. P. G. M. Wuts, John Wiley & Sons, 5thedition, 2014. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

The compounds in accordance with this invention potently inhibit the ability of IL-17A to bind to IL-17RA. When tested in the IL-17 FRET assay described below, compounds of the present invention exhibit an IC50value of 10 μM or less, generally of 5 μM or less, usually of 1 μM or less, typically of 500 nM or less, suitably of 100 nM or less, ideally of 50 nM or less, and preferably of 25 nM or less (the skilled person will appreciate that a lower IC50figure denotes a more active compound).

Moreover, certain compounds in accordance with this invention potently inhibit IL-17 induced IL-6 release from human dermal fibroblasts. Indeed, when tested in the HDF cell line assay described below, compounds of the present invention exhibit an IC50value of 10 μM or less, generally of 5 μM or less, usually of 1 μM or less, typically of 500 nM or less, suitably of 100 nM or less, ideally of 50 nM or less, and preferably of 25 nM or less (as before, the skilled person will appreciate that a lower IC50figure denotes a more active compound).

The purpose of this assay is to test the ability of compounds to disrupt the interaction between IL-17A and soluble IL-17 Receptor A (IL-17RA). The ability of a compound to inhibit IL-17A binding to IL-17RA is measured in this assay.

An IL-17AA-TEV-Human Fc construct was expressed in a CHO SXE cell system and purified by protein A chromatography and size exclusion. The protein was labelled with an amine reactive AlexaFluor 647 dye (Thermo Fisher # A20006), as per manufacturer's instruction.

Soluble IL-17RA (33-317)-HKH-TEV-Fc was expressed in an Expi HEK293 cell system and purified by protein A chromatography and size exclusion. The Fc tag was cleaved by TEV, producing IL-17RA (33-317)-HKH, and the protein was labelled with amine reactive terbium (Thermo Fisher # PV3581).

For IL-17A assay

Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), to give a 25% DMSO solution.

IL-17A (10 μL) was added to a black low volume assay plate (Costar #4511) and diluted compound (5 μL) was transferred from the aqueous dilution plate. The cytokine and compound were allowed to incubate for 1 h, then IL-17RA (10 μL) was added. The plates were wrapped in foil and incubated at room temperature for 18-20 h with gentle shaking (<400 rpm) before being read on a Perkin Elmer Envision plate reader (Excitation: 330 nm; Emission 615/645 nm).

When tested in the IL-17 FRET assay, the compounds of the accompanying Examples were all found to exhibit IC50values of 10 μM or better.

When tested in the IL-17 FRET assay, compounds of the accompanying Examples exhibit IC50values generally in the range of about 0.01 nM to about 10 μM, usually in the range of about 0.01 nM to about 5 μM, typically in the range of about 0.01 nM to about 1 μM, suitably in the range of about 0.01 nM to about 500 nM, appositely in the range of about 0.01 nM to about 100 nM, ideally in the range of about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM.

Inhibition of IL-17A Induced IL-6 Release from Dermal Fibroblast Cell Line

The purpose of this assay is to test the neutralising ability to IL-17 proteins, in a human primary cell system. Stimulation of normal human dermal fibroblasts (HDF) with IL-17 alone produces only a very weak signal but in combination with certain other cytokines, such as TNFα, a synergistic effect can be seen in the production of inflammatory cytokines, i.e. IL-6.

HDFs were stimulated with IL-17A (50 pM) in combination with TNF-α (25 pM). The resultant IL-6 response was then measured using a homogenous time-resolved FRET kit from Cisbio. The kit utilises two monoclonal antibodies, one labelled with Eu-Cryptate (Donor) and the second with d2 or XL665 (Acceptor). The intensity of the signal is proportional to the concentration of IL-6 present in the sample (Ratio is calculated by 665/620×104).

The ability of a compound to inhibit IL-17 induced IL-6 release from human dermal fibroblasts is measured in this assay.

HDF cells (Sigma #106-05n) were cultured in complete media (DMEM+10% FCS+2 mM L-glutamine) and maintained in a tissue culture flask using standard techniques. Cells were harvested from the tissue culture flask on the morning of the assay using TrypLE (Invitrogen #12605036). The TrypLE was neutralised using complete medium (45 mL) and the cells were centrifuged at 300×g for 3 minutes. The cells were re-suspended in complete media (5 mL) counted and adjusted to a concentration of 3.125×104cells/mL before being added to the 384 well assay plate (Corning #3701) at 40 μL per well. The cells were left for a minimum of three hours, at 37° C./5% CO2, to adhere to the plate.

Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), where 5 μL from the titration plate was transferred to 45 μL of complete media and mixed to give a solution containing 10% DMSO.

Mixtures of TNFα and IL-17 cytokine were prepared in complete media to final concentrations of TNFα 25 pM/IL-17A 50 pM, then 30 μL of the solution was added to a 384 well reagent plate (Greiner #781281).

10 μL from the aqueous dilution plate was transferred to the reagent plate containing 30 μL of the diluted cytokines, to give a 2.5% DMSO solution. The compounds were incubated with the cytokine mixtures for one hour at 37° C. After the incubation, 10 μL was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37° C./5% CO2.

From the Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1:1, as per kit insert. To a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 μL), then supernatant (10 μL) was transferred from the assay plate to Greiner reagent plate. The mixture was incubated at room temperature for 3 h with gentle shaking (<400 rpm) before being read on a Synergy Neo 2 plate reader (Excitation: 330 nm; Emission: 615/645 nm).

When tested in the above assay, compounds of the accompanying Examples were found to exhibit IC50values of 10 μM or better.

When tested in the above assay, compounds of the accompanying Examples exhibit IC50values generally in the range of about 0.01 nM to about 10 μM, usually in the range of about 0.01 nM to about 5 μM, typically in the range of about 0.01 nM to about 1 μM, suitably in the range of about 0.01 nM to about 500 nM, appositely in the range of about 0.01 nM to about 100 nM, ideally in the range of about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM.

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

EXAMPLES

Abbreviations

All reactions involving air-or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

NMR spectra were recorded on a Bruker Avance III HD 500 MHz, 400 MHz, 300 MHz or 250 MHz spectrometer.

Specific Optical Rotations were measured using a Rudolph Research Analytical Autopol 1 polarimeter, S2 Serial 32026.

uPLC-MS was performed on a Waters Acquity UPLC system coupled to a Waters Acquity PDA detector, an ELS detector and an MSD (Scan Positive: 150-850).

Mobile Phase A: 0.1% formic acid in water

Mobile Phase B: 0.1% formic acid in acetonitrile

TimeA %B %0.0070300.55703011.0059513.1059513.317030
Column chromatography separations were performed using a Biotage® Isolera 4 system with Biotage® SNAP KP-Sil pre-packed silica gel columns.
Chiral SFC Analysis
Method 12
Waters Thar 3100 SFC system connected to a Waters 2998 PDA detector
Method 13
Waters UPC2-SQD2 system
Chiral SFC Separation
Method 14
Waters Thar SFC system with a Waters Thar FDM pump, a Waters Thar Alias autoinjector, a Waters Thar fraction collector and a Waters 2998 PDA detector
Method 15
Waters Prep 100-SQD2
HPLC-MS was performed on a Waters ZQ system coupled to Waters 2996 PDA and Waters 2420 detectors.
Method 16
Phenomenex Gemini-NX C18 2.0 mm×50 mm, 3 μm column
Mobile Phase A: 2 mM NH4HCO3modified to pH 10 with NH4OH
Mobile Phase B: acetonitrile
Gradient program: Flow rate 1 mL/minute; column temperature 40° C.

TimeA %B %0.0095.005.004.005.0095.005.005.0095.005.1095.005.00
Automated preparative reverse phase HPLC purification was performed using a Waters FractionLynx Prep system coupled to a SQD2 mass spectrometer and a Waters 2998 PDA detector.
Method 22
Waters XBridge Prep C18 19×100 mm, 5 μm column
Mobile Phase A: 10 mM ammonium bicarbonate in water+0.1% ammonia solution
Mobile Phase B: acetonitrile+5% solvent A+0.1% ammonia solution
Gradient program: Flow rate 20 mL/minute

TimeA %B %0.0098.002.004.005.0095.005.005.0095.005.1098.002.00
Automated preparative reverse phase HPLC purification was performed using a Waters FractionLynx Prep system coupled to a SQD2 mass spectrometer and a Waters 2998 PDA detector.
Method 24
Waters XBridge Prep Phenyl 19×150 mm, 5 μm column
Mobile Phase A: 10 mM ammonium bicarbonate in water+0.1% ammonia solution
Mobile Phase B: acetonitrile+5% solvent A+0.1% ammonia solution
Gradient program: Flow rate 20 mL/minute

TimeA %B %0.009554.4001005.4001005.425956.00595
Automated preparative reverse phase HPLC purification was performed using a Gilson system with a Gilson 306 pump, a Gilson 215 autoinjector, a Gilson 215 fraction collector and a Gilson 156 UV detector.
Method 30
Sunfire C18 Waters 19×100 mm, 5 μm column
Mobile Phase A: water+0.1% formic acid
Mobile Phase B: acetonitrile+0.1% formic acid
Gradient program: Flow rate 20 mL/minute

A solution of potassium tert-butoxide in THF (1M, 48 mL, 48 mmol) was added dropwise to a red solution of methyl isocyanoacetate (4.0 mL, 41.8 mmol) in anhydrous THF (40 mL) at approximately −65° C. under nitrogen. After stirring for 5 minutes, a solution of cyclooctanone (5 g, 39.62 mmol) in anhydrous THF (20 mL) was added slowly at −70° C. The reaction mixture was stirred at −70° C. for 30 minutes, then the cooling bath was removed and the mixture was allowed to warm to 20° C. with stirring under nitrogen for 60 h. The resultant deep red solution was quenched with water (100 mL) and stirred at 20° C. for 1 h. The residue was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude viscous orange oil was separated by flash column chromatography using a gradient of ethyl acetate in heptane (0-90%) to afford the title compound (5.37 g, 58%) as an orange viscous oil, which solidified upon standing. Major rotamer: δH(500 MHz, DMSO-d6) 9.31 (s, 1H), 8.01 (d, J 1.5 Hz, 1H), 3.60 (s, 3H), 2.52-2.47 (m, 2H), 2.31-2.23 (m, 2H), 1.74-1.60 (m, 4H), 1.50-1.31 (m, 6H). HPLC-MS (method 5): MNa+ m/z 248, RT 1.63 minutes.

Magnesium turnings (3.15 g, 129.60 mmol) were added carefully to a stirred solution of Intermediate 9 (2.91 g, 12.95 mmol) in anhydrous methanol (65 mL) at 0° C. under nitrogen. The suspension was stirred at 0° C. for 1 h, then allowed to warm to 20° C. over 2 h. Stirring of the turbid suspension was continued at 20° C. for 16 h. An additional portion of magnesium turnings (1 g, 41.14 mmol) was added, and the suspension was stirred at 20° C. for 3.5 h under nitrogen. The mixture was carefully concentrated in vacuo. The residue was suspended in ethyl acetate (100 mL) and water (200 mL), then cooled to 0° C. Aqueous hydrochloric acid (1M, 100 mL) was cautiously added, then concentrated hydrochloric acid was cautiously added (pH 5) to aid dissolution of the solids. The organic phase was separated, then the aqueous suspension was treated with concentrated hydrochloric acid (pH 4) and the material was extracted with ethyl acetate (100 mL). The aqueous suspension was treated with concentrated hydrochloric acid (pH 2) and the material was extracted with ethyl acetate (100 mL). The aqueous suspension was further treated with concentrated hydrochloric acid (pH 1) and the material was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude orange viscous oil was separated by flash column chromatography, using a gradient of ethyl acetate in heptane (0-80%), to afford the title compound (1.53 g, 52%) as an orange viscous oil. Major rotamer: δH(500 MHz, DMSO-d6) 8.46 (d, J 8.5 Hz, 1H), 8.06 (s, 1H), 4.29 (dd, J 8.6, 6.1 Hz, 1H), 3.64 (s, 3H), 2.04-1.93 (m, 1H), 1.73-1.19 (m, 14H). HPLC-MS (method 4): MH+ m/z 228, RT 3.94 minutes.

A solution of lithium hydroxide monohydrate (74 mg, 1.76 mmol) in water (1.2 mL) was added to a stirred solution of Intermediate 15 (311 mg, 1.17 mmol) in MeOH/THF (1:1; 2.4 mL). The solution was stirred at 20° C. under air for 16 h, then the volatiles were removed in vacuo. The residue was diluted with water (10 mL) and washed with tert-butyl methyl ether (2×5 mL). The combined organic washings were extracted with aqueous sodium hydroxide solution (0.1M, 5 mL). The pH of the aqueous phase was adjusted to pH 5 with 3M aqueous hydrochloric acid and the material was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (20 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo, to afford the title compound (285 mg, 97%) as a white powder. δH(500 MHz, DMSO-d6) 12.49 (br s, 1H), 9.70 (br s, 1H), 8.15 (d, J 5.1 Hz, 1H), 7.73 (s, 1H), 6.92 (dd, J 5.1, 1.4 Hz, 1H), 3.59 (s, 2H), 1.47 (s, 9H). HPLC-MS (method 5): [M+2H-tBu]+ m/z 197, RT 1.36 minutes.

HATU (210 mg, 0.55 mmol) was added to a stirred solution of Intermediate 2 (100 mg, 0.46 mmol) and Intermediate 18 (213 mg, 0.5 mmol) in anhydrous DMF (4 mL) under a nitrogen atmosphere. The mixture was stirred at 20° C. for 15 h, then quenched with saturated aqueous sodium hydrogen carbonate solution (20 mL). Water (20 mL) and ethyl acetate (20 mL) were added, then the resultant white precipitate was filtered and washed with DCM (2×10 mL) and isopropanol/chloroform (1:1; 2×10 mL). The aqueous and organic layers were separated, then the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic washings and extracts were dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was triturated with dichloromethane. The resulting pale yellow precipitate was filtered, then washed with dichloromethane and dried in vacuo, to afford the title compound (160 mg, 56%) as a pale yellow powder. HPLC-MS (method 5): MH+ m/z 620, RT 1.89 minutes.

Lithium hydroxide monohydrate (36 mg, 0.86 mmol) was added to a stirred solution of Intermediate 22 (140 mg, 0.71 mmol) in THF (3 mL) and water (1.5 mL). The reaction mixture was stirred at 20° C. for 64 h, then concentrated and dried in vacuo for 4 h, to afford the title compound (134 mg, quantitative) as a tan foam. HPLC-MS (method 5): MH+ m/z 184, RT 0.12-0.16 minutes.

Trifluoroacetic acid (46 μL, 0.6 mmol) was added to a stirred solution of Intermediate 27 (14 mg, 0.03 mmol) in DCM (0.5 mL). The mixture was stirred under nitrogen at 20° C. for 16 h, then diluted with DCM (2 mL). An additional portion of trifluoroacetic acid (46 μL, 0.6 mmol) was added and stirring was continued at 20° C. for 5 days under nitrogen. The mixture was diluted with DCM (2 mL) and an additional portion of trifluoroacetic acid (92 μL, 1.19 mmol) was added. Stirring was continued for 24 h at 20° C. under nitrogen, then the volatiles were removed in vacuo. The residue was azeotroped three times with dichloromethane, then dissolved in methanol (3 mL). DIPEA (50 μL, 0.3 mmol) was added, then the mixture was heated at 100° C. under nitrogen for 1.5 h. After cooling to room temperature, the mixture was diluted with DCM (20 mL) and partitioned with 0.5M aqueous hydrochloric acid (20 mL). The biphasic mixture was shaken and the phases were separated using a hydrophobic frit. The aqueous phase was washed with DCM/isopropanol (4:1; 20 mL), then adjusted to pH 5-6 with solid sodium hydrogen carbonate. The material was extracted with 4:1 DCM-isopropanol (6×20 mL). The combined organic filtrates were shaken with saturated aqueous sodium hydrogen carbonate solution (10 mL) and the organic phase was separated using a hydrophobic frit. The organic filtrate was concentrated in vacuo to afford the title compound (3.2 mg, 45%) as a tan powder. HPLC-MS (method 5): MH+ m/z 235, RT 1.29 minutes.

A suspension of 6-bromo-1,3-dihydro-2H-indol-2-one (424 mg, 2.00 mmol) in anhydrous THF (20 mL) was purged with nitrogen and sonicated for 10 minutes. The mixture was cooled to −78° C. under nitrogen and 1M sodium bis(trimethylsilyl)amide (10 mL, 10.0 mmol) was added slowly. After stirring for 60 minutes, N-benzylbis(2-chloro-ethyl)amine hydrochloride (590 mg, 2.20 mmol) was added in one portion and the mixture was stirred at −78° C. for 1 h. The cooling bath was removed and the mixture was allowed to warm to 20° C., then heated at 70° C. for 16 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and diluted with water (20 mL). The material was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The resulting crude dark red semi-solid was dissolved in hot DCM (˜20 mL) and allowed to cool to room temperature, then triturated with heptane (˜60 mL). The solids were collected by filtration, washing with heptane (2×20 mL). The filtrate was concentrated in vacuo, and the process was repeated, to afford the title compound (236 mg, 32%) as a light orange powder after drying in vacuo at 50° C. for 16 h. δH(500 MHz, DMSO-d6) 10.50 (br s, 1H), 7.42 (d, J 7.8 Hz, 1H), 7.39-7.30 (m, 4H), 7.29-7.22 (m, 1H), 7.12 (dd, J 8.0, 1.8 Hz, 1H), 6.98 (d, J 1.8 Hz, 1H), 3.61 (s, 2H), 2.91-2.70 (m, 2H), 2.62-2.48 (m, 2H), 1.87-1.74 (m, 2H), 1.72-1.56 (m, 2H). HPLC-MS (method 5): MH+ m/z 371, RT 1.56 minutes.

A sealed tube was charged with Intermediate 29 (326 mg, 0.88 mmol), tert-butyl carbamate (206 mg, 1.76 mmol) and tripotassium phosphate (262 mg, 1.23 mmol). The reagents were suspended in tert-butanol (4.5 mL), then the mixture was purged with nitrogen and sonicated for 5 minutes. The reaction mixture was charged with [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (18.7 mg, 0.02 mmol) and 2-(di-tert-butyl-phosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (10.8 mg, 0.02 mmol), then purged with nitrogen and sonicated for 5 minutes. The mixture was sealed under nitrogen and heated at 110° C. for 16 h. After cooling, the mixture was partitioned between ethyl acetate (30 mL) and water (30 mL), then sonicated. The solids were removed by filtration through a kieselguhr pad, washing with water (20 mL) and ethyl acetate (20 mL). The organic phase was separated, then the aqueous layer was extracted with ethyl acetate (2×30 mL) after the pH had been adjusted to pH 11 with sodium carbonate. The combined organic extracts were washed with brine (20 mL) and dried over magnesium sulfate, then filtered and reduced in vacuo. The residue was dissolved in dichloromethane (8.3 mL), then trifluoroacetic acid (0.65 mL, 8.44 mmol) was added. The solution was stirred at 20° C. under air for 18 h. The volatiles were removed in vacuo and the residue was adsorbed onto an SCX-2 cartridge. The column was washed with DCM (50 mL) and MeOH (50 mL). The material was eluted with 1M ammonia in MeOH (50 mL), then concentrated in vacuo. The resulting purple powder was separated by flash column chromatography (KP-NH column), using a gradient of ethyl acetate in heptane (0-100%) followed by a gradient of MeOH in ethyl acetate (0-10%), to afford the title compound (24 mg, 9%) as a tan viscous oil. HPLC-MS (method 5): MH+ m/z 308, RT 1.07 minutes.

A solution of lithium hydroxide monohydrate (2.02 g, 48.10 mmol) in water (33 mL) was added to a stirred solution of Intermediate 22 (7.3 g, 37.00 mmol) in THF (67 mL). The reaction mixture was stirred at 50° C. for 2 h, then left to cool to ambient temperature. The volatiles were removed in vacuo. The aqueous residue was washed with ethyl acetate (2×100 mL), then acidified to pH 1-2 with 3M hydrochloric acid. The aqueous layer was extracted with a dichloromethane:isopropanol mixture (2:1; 3×120 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo to afford the title compound (6.6 g, 97%) as a white solid. δH(250 MHz, DMSO-d6) 12.66 (s, 1H), 8.81 (t, J 5.9 Hz, 1H), 7.48 (d, J 2.1 Hz, 1H), 6.89 (d, J 2.1 Hz, 1H), 4.05 (s, 3H), 3.90 (d, J 6.0 Hz, 2H). HPLC-MS: MH+ m/z 184, RT 0.174 minutes.

Titanium tetrachloride in DCM (1M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at −10° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of spiro[3.3]heptan-2-one (267 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added portionwise sequentially, and the reaction mixture was stirred at 0° C. for a further 20 minutes. Anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for a further 2 h, then at ambient temperature for 16 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL) and stirring was continued for a further 10 minutes. The solution was extracted with ethyl acetate (2×40 mL). The organic extracts were combined and washed with brine (20 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography, using a gradient of ethyl acetate in heptane (5-40%), to afford the title compound (224 mg, 72%) as a white solid. δH(250 MHz, CDCl3) 7.53 (d, J 2.1 Hz, 1H), 6.86 (d, J 2.1 Hz, 1H), 4.25 (s, 3H), 3.29-3.24 (m, 2H), 3.19-3.15 (m, 2H), 2.19-2.11 (m, 4H), 1.98-1.84 (m, 2H). HPLC-MS (method 5): MH+ m/z 258, RT 1.93 minutes.

To a stirred solution of Intermediate 38 (224 mg, 0.87 mmol) in anhydrous acetonitrile (10 mL) was added 10% palladium on charcoal (50% wet, 44 mg, 20 wt %) in a single portion. The reaction mixture was placed under a hydrogen gas atmosphere and stirring was continued at ambient temperature for 20 h. A second aliquot of 10% palladium on charcoal (50% wet, 22 mg, 10 wt %) was added and the reaction mixture was stirred under hydrogen for a further 43 h. The catalyst was removed by filtration over Kieselguhr, then the filter cake was rinsed with acetonitrile (2×5 mL). The solvent was concentrated in vacuo to afford the title compound (182 mg, 81%) as a grey oil. δH(250 MHz, CDCl3) 7.53 (d, J 2.0 Hz, 1H), 6.81 (d, J 2.0 Hz, 1H), 4.33 (d, J 6.1 Hz, 1H), 4.24 (s, 3H), 2.74 (pd, J 8.4, 6.4 Hz, 1H), 2.23-1.99 (m, 6H), 1.91-1.76 (m, 4H). HPLC-MS (method 6): (M−H)−m/z 258, RT 3.08 minutes.

To a solution of 3-methylisoxazole-4-carboxylic acid (12.9 g, 66.1 mmol) in dry DMF (100 mL) at 0° C. were added with DIPEA (54.9 g, 424.6 mmol), EDCI.HCl (19.5 g, 101.9 mmol) and HOBt (13.8 g, 101.9 mmol). The reaction mixture was stirred for 15 minutes at 0° C., then Intermediate 11 (20.0 g, 84.9 mmol) was added and the reaction mixture was stirred at r.t. for 48 h. The reaction mixture was poured into ice-cold water (500 mL), and extracted with ethyl acetate (2×400 mL). The organic layer was separated, then washed with ice-cold water (2×100 mL) and IN HCl (2×50 mL). The organic layer was dried over anhydrous Na2SO4, then filtered and evaporated in vacuo. The crude residue was purified by silica gel flash column chromatography, using 15% EtOAc in hexane as eluting solvent, to afford the title compound (7.9 g, 41.3%) as a pale yellow viscous oil. LC-MS (method 17): MH+ m/z 309, RT 5.5 minutes.

To a cold (−5° C. to −20° C.) solution of trans-4-methylcyclohexanecarboxylic acid (68.5 g, 0.481 mol) in THF (550 mL) was added a solution of lithium aluminum hydride (2.4M in THF, 200 mL, 0.48 mol) slowly over circa 1 h. The mixture was stirred at −20° C. for 1.5 h, then allowed to warm to ambient temperature. The mixture was re-cooled in an ice-salt bath before water (16 mL), aqueous sodium hydroxide solution (15 wt %, 16 mL), and water (40 mL) were slowly and cautiously added. The resulting viscous mixture was stirred for 10 minutes, then diethyl ether (500 mL) was added. The resulting suspension was filtered through a pad of kieselguhr. The solvents were evaporated under reduced pressure to afford the title compound (63.5 g, 100%) as a clear, colourless mobile oil. δH(500 MHz, CDCl3) 3.44 (d, J 6.3 Hz, 2H), 1.79-1.69 (m, 4H), 1.47-1.23 (m, 3H), 1.04-0.89 (m, 4H), 0.88 (d, J 6.6 Hz, 3H).

To a solution of diethylaluminium cyanide (1M in toluene, 103 mL, 103 mmol) in THF (400 mL) at −78° C. was added anhydrous isopropyl alcohol (5.3 mL, 69 mmol). The mixture was stirred at −78° C. for 30-60 minutes, then canulated into a solution of Intermediate 44 (90% purity, 20.2 g, 69 mmol) in THF (800 mL) at −78° C. over circa 45 minutes. The mixture was allowed to warm to room temperature, then stirred overnight. The mixture was cooled in an ice-water bath, then saturated aqueous ammonium chloride solution (300 mL) was added; some gas was evolved and the internal temperature increased to circa 30° C. After 1 h, the mixture was filtered through a pad of kieselguhr, then the pad was washed with water (300 mL) and ethyl acetate (300 mL). The organic layers were divided, and the aqueous layers were washed with more ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated. The resulting pale yellow oil, which solidified upon standing, was taken up in hot heptane-ethyl acetate, then allowed to crystallise, to afford the title compound (7.78 g, 38%) as a white solid. The residues were evaporated and purified by automated column chromatography to give a clean mixture of the two diastereoisomers. Recrystallisation of this mixture from ethyl acetate-heptane, seeded using some of the first crop, gave a further batch of the title compound (4.05 g, 20%). δH(250 MHz, CDCl3) 7.61 (d, J 8.3 Hz, 2H), 7.36 (d, J 8.2 Hz, 3H), 4.50 (d, J 7.8 Hz, 1H), 3.95 (dd, J 7.9, 5.8 Hz, 1H), 2.43 (s, 3H), 2.25-1.78 (m, 3H), 1.44-0.91 (m, 5H), 0.89 (d, J 6.5 Hz, 3H).

To a stirred solution of Intermediate 54 (44.2 g, 240 mmol) in anhydrous DCM (440 mL) was added EDCI.HCl (59.8 g, 312 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 1.5 h, then diluted with DCM (200 mL) and quenched with water (500 mL). The organic layer was separated and washed with brine (2×500 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo to afford the title compound (34 g, 86%) as a yellow solid, which was utilised without further purification. δH(400 MHz, CDCl3) 8.83 (s, 1H), 4.37 (s, 2H), 2.56 (s, 3H). LC-MS (method 34): [M−H]−m/z 167, RT 0.76 minutes.

Titanium tetrachloride in DCM (1M, 2.7 mL, 2.7 mmol) was added to anhydrous THF (4 mL) at −10° C. A solution of Intermediate 55 (0.146 g, 0.88 mmol) in anhydrous THF (1 mL) and a solution of 5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (0.1 g, 0.67 mmol) in anhydrous THF (1 mL) were added dropwise sequentially. The reaction mixture was stirred at 0° C. for 20 minutes, then anhydrous pyridine (0.44 mL, 14.5 mmol) was added dropwise at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for a further 2 h, then at room temperature for 16 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (12 mL), and stirring was continued for a further 10 minutes. The solution was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (20 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography, using a gradient of ethyl acetate in heptane (0-100%), to afford the title compound (188 mg, 94%) as a yellow solid. δH(500 MHz, DMSO-d6) 9.66 (s, 1H), 7.53 (dd, J 8.5, 7.2 Hz, 1H), 7.09-6.89 (m, 2H), 3.98 (s, 2H), 3.94 (s, 3H), 2.62 (s, 3H). HPLC-MS (method 5): MH+ m/z 297, RT 1.87 minutes.

Titanium tetrachloride in DCM (1M, 3.6 mL, 3.63 mmol) was added to anhydrous THF (6 mL) at −10° C. A solution of Intermediate 37 (150 mg, 0.908 mmol) in anhydrous THF (1.5 mL) and a solution of adamantane-1-carbaldehyde (298 mg, 1.82 mmol) in anhydrous DCM (2 mL) were added portionwise sequentially. The reaction mixture was stirred at 0° C. for 20 minutes, then anhydrous pyridine (0.60 mL, 7.42 mmol) was added at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for 2 h, and at ambient temperature for a further 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (15 mL). Stirring was continued for a further 10 minutes, then the solution was extracted with ethyl acetate (2×30 mL). The organic extracts were combined and washed with brine (10 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography, using a gradient of ethyl acetate in heptane (5-40%), to afford the title compound (24 mg, 8.5%) as a beige solid. δH(250 MHz, CDCl3) 7.55 (d, J 2.1 Hz, 1H), 6.90 (d, J 2.1 Hz, 1H), 6.49 (s, 1H), 4.30 (s, 3H), 2.10-2.03 (m, 3H), 2.03-1.97 (m, 6H), 1.80-1.73 (m, 6H). HPLC-MS (method 4): MH+ m/z 312, RT 3.20 minutes.

To a stirred solution of Intermediate 2 (17 mg, 0.078 mmol) and Intermediate 62 (24 mg, 0.078 mmol) in anhydrous acetonitrile (3 mL) was added acetic acid (0.045 mL, 0.78 mmol). The reaction mixture was stirred at 60° C. for 19 h. The solvent was removed in vacuo and the residue was triturated into DCM (2 mL). The solid was collected by filtration and further dried in vacuo to afford the title compound (20 mg, 42%) as an orange solid. HPLC-MS (method 5): MH+ m/z 530, RT 1.82 minutes (87%) and RT 2.20 minutes (13%).

Titanium tetrachloride in DCM (1M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at −10° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and 1-(bicyclo[1.1.1]pentan-1-yl)ethan-1-one (90%, 297 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added portionwise sequentially. The reaction mixture was stirred at 0° C. for 20 minutes, then anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for 2 h, and at ambient temperature for a further 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for a further 10 minutes, then the solution was extracted with ethyl acetate (2×40 mL). The organic extracts were combined and washed with brine (20 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by automated chromatography, using a gradient of ethyl acetate in heptane (5-40%), to afford the title compound (235 mg, 73%) as a yellow solid. δH(250 MHz, CDCl3) 7.53 (d, J 2.1 Hz, 1H), 6.85 (d, J 2.1 Hz, 1H), 4.29 (s, 3H), 2.60 (s, 1H), 2.30 (s, 3H), 2.22 (s, 6H). HPLC-MS (method 5): MH+ m/z 258, RT 2.13 minutes.

Titanium tetrachloride in DCM (1M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at −10° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of cycloheptanone (272 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added portionwise sequentially. The reaction mixture was stirred at 0° C. for 20 minutes, then anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for 2 h, and at ambient temperature for a further 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for a further 10 minutes, then the solution was extracted with ethyl acetate (2×40 mL). The organic extracts were combined and washed with brine (20 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by chromatography, using a gradient of ethyl acetate in heptane (5-40%), to afford the title compound (201 mg, 64%) as a beige solid. δH(250 MHz, CDCl3) 7.53 (d, J 1.9 Hz, 1H), 6.86 (d, J 1.9 Hz, 1H), 4.28 (s, 3H), 3.12-3.05 (m, 2H), 3.02-2.94 (m, 2H), 1.83-1.73 (m, 4H), 1.65-1.57 (m, 4H). HPLC-MS (method 4): MH+ m/z 260, RT 3.09 minutes.

To a stirred solution of Intermediate 65 (120 mg, 0.52 mmol) in anhydrous THF (6 mL) was added 10% palladium on charcoal (50% wet, 12 mg, 20 wt %) as a single portion. The reaction mixture was placed under a hydrogen gas atmosphere (3 cycles of vacuum/nitrogen gas followed by 3 cycles of vacuum/hydrogen gas). Stirring was continued at ambient temperature for 5 h. Anhydrous acetonitrile (6 mL) was added and stirring under a hydrogen gas atmosphere was continued for a further 16 h. The catalyst was removed by filtration over kieselguhr, rinsing the filter cake with dry THF (2×5 mL). The solvent was concentrated in vacuo to afford the title compound (66 mg, 65%) as a pale grey oil. HPLC-MS (method 4): (M−H)−m/z 260, RT 3.13 minutes.

Titanium tetrachloride in DCM (1M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at −10° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of 5-chlorobicyclo[4.2.0]octa-1,3,5-trien-7-one (369 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added portionwise sequentially. The reaction mixture was stirred at 0° C. for 20 minutes, then anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for 2 h, and at ambient temperature for a further 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for a further 10 minutes, then the solution was extracted with ethyl acetate (2×40 mL). The organic extracts were combined and washed with brine (20 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by automated chromatography, using a gradient of ethyl acetate in heptane (5-50%), to afford the title compound (159 mg, 44%) as a yellow solid. δH(250 MHz, CDCl3) 7.57 (d, J 2.1 Hz, 1H), 7.39 (dd, J 8.2, 6.8 Hz, 1H), 7.33 (d, J 7.5 Hz, 1H), 7.20 (d, J 6.8 Hz, 1H), 6.92 (d, J 2.1 Hz, 1H), 4.38 (s, 3H), 4.09 (s, 2H). HPLC-MS (method 4): MH+ m/z 300, RT 3.18 minutes.

Titanium tetrachloride in DCM (1M, 4.8 mL, 4.80 mmol) was added to anhydrous THF (9 mL) at −10° C. A solution of Intermediate 37 (200 mg, 1.21 mmol) in anhydrous THF (1.5 mL) and a solution of 2,3-dimethylcyclobutan-1-one (238 mg, 2.42 mmol) in anhydrous THF (1.5 mL) were added portionwise sequentially. The reaction mixture was stirred at 0° C. for 20 minutes, then anhydrous pyridine (0.784 mL, 9.69 mmol) was added at 0° C. over 30 minutes. The reaction mixture was stirred at 0° C. for 2 h, and at ambient temperature for a further 16 h, then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). Stirring was continued for a further 10 minutes, then the solution was extracted with ethyl acetate (2×40 mL). The organic extracts were combined and washed with brine (20 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by automated chromatography, using a gradient of ethyl acetate in heptane (5-40%) to afford the title compound (mixture of stereoisomers; 173 mg, 58%) as a yellow solid. HPLC-MS (method 4): MH+ m/z 246, RT 2.90 minutes (49%) and RT 2.95 minutes (51%).

Intermediate 107 (100 mg, 0.18 mmol) was dissolved in anhydrous 1,4-dioxane (0.5 mL) and DIPEA (0.09 mL, 0.53 mmol) and treated with 3-chloro-6-(difluoromethyl)-pyridazine (50 mg, 0.3 mmol). The reaction mixture was stirred at 140° C. for 18 h, then cooled to 20° C. and quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous layer was extracted with DCM (3×20 mL). The organic extracts were combined and washed with brine (10 mL), then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, using a gradient of tert-butyl methyl ether in heptane (0-100%) followed by a gradient of MeOH in tert-butyl methyl ether (0-20%), to afford the title compound (113.3 mg, 33%) as an orange oil. HPLC-MS (method 5): MH+ m/z 631.0, RT 2.16 minutes.

To a solution of Intermediate 88 (10.0 g, 34.6 mmol) in acetic acid (200 mL) was added iron (9.51 g, 173 mmol). The reaction mixture was stirred at 60° C. for 4 h, then diluted with EtOAc (200 mL), stirred for 15 minutes, filtered through a pad of Celite, and washed with EtOAc (3×200 mL). The organic layer was separated, dried over anhydrous Na2SO4and concentrated in vacuo. The crude residue was dissolved in 5% MeOH in EtOAc (30 mL) and adsorbed onto Fluorosil. The resulting slurry was filtered through a Celite pad and washed with 5% MeOH in EtOAc (3×200 mL). The organic layer was dried over anhydrous Na2SO4and concentrated in vacuo, to afford the title compound (5.00 g, 68%) as a brown solid. δH(400 MHz, DMSO-d6) 3.57 (s, 2H), 7.30 (s, 1H), 8.17 (s, 1H), 10.67 (br s, 1H). HPLC-MS (method 6): MH+ m/z 213.0, RT 1.31 minutes.

To a solution of Intermediate 90 (0.40 g, 1.41 mmol) in THF (10 mL) was added NaH (0.05 g, 2.12 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, then SEM-Cl (0.35 g, 2.12 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then diluted with water (50 mL) and extracted with DCM (3×50 mL). The organic layer was separated, washed with H2O (100 mL) and brine (100 mL), then dried over anhydrous Na2SO4and concentrated in vacuo. The crude residue was purified by column chromatography (20% EtOAc in hexanes) to afford the title compound (0.40 g, 43%) as a white solid. HPLC-MS (method 6): MH+ m/z 415.1, RT 2.34 minutes.

To a solution of 2,4-dichloropyrrolo[2,3-d]pyrimidine (10.0 g, 53.2 mmol) in DMF (50 mL) was added NaH (1.91 g, 79.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, then SEM-Cl (9.30 mL, 79.8 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 2 h, then quenched with ice water (200 g) and extracted with diethyl ether (3×150 mL). The organic layer was separated, washed with water (100 mL) and brine (100 mL), then dried over anhydrous Na2SO4and concentrated in vacuo. The crude residue was purified by column chromatography (0-20% EtOAc in hexanes) to afford the title compound (12.0 g, 71%) as a yellow oil. HPLC-MS (method 6): MH+ m/z 317.9, RT 2.47 minutes.

To a solution of Intermediate 95 (2.00 g, 4.37 mmol) in THF (20 mL) and acetic acid (5 mL) was added Zn (1.43 g, 21.9 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h, then filtered through a pad of Celite. The filtrate was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The organic layer was separated, washed with water (30 mL), and brine (30 mL), then dried over anhydrous Na2SO4and concentrated in vacuo. The crude residue was purified by column chromatography (0-20% EtOAc in hexanes) to afford the title compound (0.93 g, 71%) as a red oil. δH(400 MHz, DMSO-d6) −0.04 (s, 9H), 0.85-0.92 (m, 2H), 3.55-3.64 (m, 2H), 3.77 (s, 2H), 5.03 (s, 2H), 8.35 (s, 1H).

Prepared from Intermediate 104 (2.11 g, 4.5 mmol) by a method analogous to that used to prepare Intermediate 50 to give the title compound (1.53 g, 92%) as a white solid. HPLC-MS (Method 7): MH+ m/z 372, RT 1.11 minutes.

Prepared from Intermediate 107 (100 mg, 0.19 mmol) and 3-cyclopropyl-isoxazole-4-carboxylic acid (36 mg, 0.22 mmol) in accordance with Procedure A, and purified by flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes, to give the title compound (100 mg, 85%) as a clear oil, which was utilised without further purification. HPLC-MS (method 7): MH+ m/z 638, RT 1.57 minutes.

A solution of Intermediate 107 (100 mg, 0.19 mmol) in THF (5 mL) was treated with triethylamine (38 mg, 0.37 mmol) and pyridine (22 mg, 0.28 mmol), followed by the slow addition of cyclobutyl chloroformate (25 mg, 0.19 mmol). The reaction mixture was stirred at 20° C. for 18 h, then diluted with water and extracted with DCM, The combined organic layers were passed through a hydrophobic frit phase separator cartridge and concentrated in vacuo. The resulting crude yellow oil was purified by flash column chromatography, using a gradient of 0-100% ethyl acetate in hexanes, to afford the title compound (120 mg, over quant.) as a clear oil, which was utilised without further purification. HPLC-MS (method 7): MH+ m/z 601, RT 1.61 minutes.

Prepared from Intermediate 107 (40 mg, 0.074 mmol) and 1-(3,3,3-trifluoro-propyl)-1H-pyrazole-5-carboxylic acid (19.5 mg, 0.089 mmol) in accordance with Procedure A, and purified by flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes, to give the title compound (50 mg, 97%) as a clear oil. HPLC-MS (method 6): MH+ m/z 693, RT 1.44 minutes.

Prepared from Intermediate 107 (40 mg, 0.074 mmol) and 3-cyclobutylisoxazole-4-carboxylic acid (15 mg, 0.089 mmol) in accordance with Procedure A, and purified by flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes, to give the title compound (45 mg, 93%) as a clear oil. HPLC-MS (method 7): MH+ m/z 652, RT 1.59 minutes.

To a stirred solution of Intermediate 119 (1.00 g, 2.425 mmol) in anhydrous THF (20 mL), previously cooled to −78° C. under nitrogen, was added 2.5M n-butyllithium (0.98 mL, 2.45 mmol) dropwise. The temperature was maintained at −78° C. for 30 minutes, then carbon dioxide (˜4.0 g, as dry ice pellets) was added portionwise. Stirring was continued at −78° C. for a further 20 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 mL) and water (1 mL), then allowed to warm to room temperature and diluted with water (20 mL) and brine (20 mL). The reaction mixture (pH 8) was extracted with ethyl acetate (30 mL), and the aqueous phase was discarded. The organic phase was extracted with 1M aqueous sodium hydroxide solution (2×20 mL). The basic aqueous extracts were combined (pH 12) and the pH was adjusted to pH 4 with 12M hydrochloric acid, then to pH 1-2 with 1M hydrochloric acid. The acidic aqueous phase was extracted with DCM (3×20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to afford the title compound (230 mg, 24%) as a pale orange solid. δH(250 MHz, DMSO-d6) 7.71 (s, 2H), 7.59 (s, 1H), 5.16 (s, 2H), 4.06 (ddd, J 11.6, 8.1, 3.7 Hz, 2H), 3.89-3.79 (m, 2H), 3.50 (t, J 7.7 Hz, 2H), 1.87-1.67 (m, 4H), 0.84 (t, J 8.1 Hz, 2H), −0.09 (s, 9H). HPLC-MS (method 5): [M−H]−m/z 376, RT 1.90 minutes.

Lithium aluminium hydride solution in diethyl ether (4M, 7.3 mL, 29.2 mmol) was added dropwise to a stirred solution of Intermediate 130 (4.57 g, 22.4 mmol) in anhydrous THF (45 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h, then at 20° C. for 16 h. The reaction mixture was cautiously quenched by the dropwise addition of water (0.55 mL), followed by 2M aqueous sodium hydroxide solution (1.32 mL), then water (1.64 mL). The suspension was stirred at room temperature for 30 minutes, then diluted with acetone (50 mL) and filtered through a kieselguhr pad. The residues were washed with acetone (2×50 mL), and the filtrate was concentrated in vacuo. The tan oil was separated by kugelrohr distillation (90-120° C., <1 mbar) to afford the title compound (818 mg, 22%) as a colourless free-flowing oil. δH(500 MHz, CDCl3) 3.77-3.69 (m, 3H), 3.64-3.57 (m, 2H), 3.55-3.45 (m, 2H), 3.25 (br s, 2H), 1.12 (d, J 6.2 Hz, 3H).

Lithium aluminium hydride solution in diethyl ether (4M, 6.8 mL, 27.2 mmol) was added dropwise to a stirred solution of Intermediate 137 (4.26 g, 20.8 mmol) in anhydrous THF (45 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h and at 20° C. for 16 h. The reaction mixture was cautiously quenched by the dropwise addition of water (0.51 mL), followed by 2M aqueous sodium hydroxide solution (1.22 mL), then water (1.53 mL). The suspension was stirred at room temperature for 30 minutes, then diluted with acetone (50 mL) and filtered through a kieselguhr pad. The residues were washed with acetone (2×50 mL) and the filtrate was concentrated in vacuo. The resultant tan oil was separated by kugelrohr distillation (100-120° C., <1 mbar) to afford the title compound (904 mg, 29%) as a colourless free-flowing oil. δH(500 MHz, CDCl3) 3.78-3.67 (m, 3H), 3.67-3.38 (m, 6H), 1.10 (d, J 6.2 Hz, 3H).

To a solution of Intermediate 2 (390 mg, 1.79 mmol) and 2-cyclohexyl-3-ethoxy-3-oxopropanoic acid lithium salt (398 mg, 1.86) in DMF (7 mL, 90.50 mmol) was added HATU (840 mg, 2.14 mmol). The reaction mixture was stirred at 20° C. for 18 h, then partitioned between EtOAc and water. The organic layers were combined, dried and concentrated under vacuum. The residue was separated by flash column chromatography, using a gradient of ethyl acetate in hexane (0-100%), to afford the title compound (623 mg, 84%). HPLC-MS (method 7): MH+ m/z 415, RT 1.24 minutes.

Examples 79 to 143

The title compounds were prepared by a three-step sequence:Step 1: reaction of Intermediate 37 with the appropriate commercially available aldehyde or ketone in accordance with Procedure F.Step 2: reaction of the material thereby obtained in accordance with Procedure H.Step 3: reaction of the material thereby obtained with Intermediate 2 in accordance with Procedure I.

Chiral SFC Analysis (method 12) with the following conditions:

The title compounds were prepared by a three-step sequence:Step 1: reaction of Intermediate 37 with the appropriate commercially available aldehyde or ketone in accordance with Procedure F.Step 2: reaction of the material thereby obtained in accordance with Procedure H.Step 3: reaction of the material thereby obtained with Intermediate 123 in accordance with Procedure I.

Examples 146 to 183

The title compounds were prepared by a two-step sequence:Step 1: reaction of Intermediate 37 with the appropriate commercially available aldehyde or ketone in accordance with Procedure F.Step 2: reaction of the material thereby obtained with Intermediate 2 in accordance with Procedure G.

The title compounds were prepared by a two-step sequence:Step 1: reaction of Intermediate 55 with the appropriate commercially available aldehyde or ketone in accordance with Procedure F.Step 2: reaction of the material thereby obtained with Intermediate 2 in accordance with Procedure G.

Examples 186 to 189

The title compounds were prepared by a three-step sequence:Step 1: reaction of Intermediate 55 or Intermediate 60, as appropriate, with the appropriate commercially available aldehyde or ketone in accordance with Procedure F.Step 2: reaction of the material thereby obtained with Intermediate 57 in accordance with Procedure G.Step 3: reaction of the material thereby obtained in accordance with Procedure C.

Examples 190 to 204

The title compounds were prepared in accordance with Procedure A from Intermediate 78 and the appropriate carboxylic acid.

Examples 205 to 208

The title compounds were prepared in accordance with Procedure D from Intermediate 78 and the appropriate carbamoyl chloride.

Examples 209 to 232

The title compounds were prepared in accordance with Procedure E from Intermediate 78 and the appropriate chloroformate.

Examples 233 to 246

The title compounds were synthesized in accordance with Procedure B from Intermediate 78 and the appropriate halogeno heterocycle.

The title compounds were prepared in accordance with Procedure B from Intermediate 105 and the appropriate halogeno heterocycle.

Examples 249 to 263

The title compounds were prepared in accordance with Procedure A from Intermediate 35 and the appropriate carboxylic acid.

The title compounds were prepared in accordance with Procedure D from Intermediate 35 and the appropriate carbamoyl chloride.

The title compounds were prepared in accordance with Procedure E from Intermediate 35 and the appropriate chloroformate.

Examples 268 to 282

The title compounds were prepared in accordance with Procedure B from Intermediate 35 and the appropriate halogeno heterocycle.

The title compound was prepared from Example 203 in accordance with a procedure analogous to that described for the preparation of Example 12.

Examples 284 to 286

The title compounds were prepared in accordance with Procedure A from Intermediate 151 and the appropriate carboxylic acid.

The title compound was prepared in accordance with Procedure D from Intermediate 151 and the appropriate carbamoyl chloride.

Examples 288 to 336

The title compounds were prepared by a two-step sequence:Step 1: reaction of Intermediate 107 with the appropriate carboxylic acid in accordance with Procedure A.Step 2: reaction of the material thereby obtained in accordance with Procedure C.

Examples 337 to 351

The title compounds were prepared by a two-step sequence:Step 1: reaction of Intermediate 107 with the appropriate carbamoyl chloride in accordance with Procedure D.Step 2: reaction of the material thereby obtained in accordance with Procedure C.

The title compound was prepared by a two-step sequence:Step 1: reaction of Intermediate 107 with tert-butyl chloroformate in accordance with Procedure E.Step 2: reaction of the material thereby obtained in accordance with Procedure C.

Examples 353 to 355

The title compounds were prepared by a two-step sequence:Step 1: reaction of Intermediate 107 with the appropriate halogeno heterocycle in accordance with Procedure B.Step 2: reaction of the material thereby obtained in accordance with Procedure C.