WO2010146351A1

WO2010146351A1 - Indolylmethyl-morpholine derivatives as kinase inhibitors

Info

Publication number: WO2010146351A1
Application number: PCT/GB2010/001171
Authority: WO
Inventors: Mezher Hussein Ali; Julien Alistair Brown; Benjamin Charles De Candole; Brian Woodside Hutchinson; Barry John Langham; Judi Charlotte Neuss; Joanna Rachel Quincey; Graham Peter Trevitt
Original assignee: Ucb Pharma S.A.
Priority date: 2009-06-17
Filing date: 2010-06-15
Publication date: 2010-12-23
Also published as: GB0910493D0

Abstract

A series of morpholine derivatives, substituted in the 4-position by a substituted carbonyl or sulfonyl moiety, and in the 3-position by an optionally substituted indol-3-ylmethyl group, being selective inhibitors of PI3 kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.

Description

INDOLYLMETHYL-MORPHOLINE DERIVATIVES AS KINASE

INHIBITORS

The present invention relates to a class of substituted morpholine derivatives, and to their use in therapy. More particularly, the invention provides a family of morpholine derivatives, substituted in the 4-position by a substituted carbonyl or sulfonyl moiety, and in the 3 -position by an optionally substituted indol-3-ylmethyl group. These compounds are selective inhibitors of phosphoinositide 3-kinase (PI3K) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

The PI3K pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases. Thus, PDKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sci., 2003, 24, 366-376). Aberrant upregulation of the PI3K pathway is implicated in a wide variety of human cancers (cf. S. Brader & S.A. Eccles, Tumori, 2004, 90, 2-8).

The compounds in accordance with the present invention, being potent and selective PI3K inhibitors, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g. during heart failure); neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD).

In addition, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of this invention may be useful as radioligands in assays for detecting compounds capable of binding to human PI3K enzymes.

Various classes of substituted morpholine derivatives are described in WO 2006/114606, WO 2007/141504, WO 2008/001076, WO 2008/047109, WO 2009/001089, WO 2009/071888, WO 2009/071890, WO 2009/071895, and copending international patent application no. PCT/GB2009/000818, published on 8 October 2009 as WO 2009/122148. The compounds described therein are stated to be selective inhibitors of PD kinase enzymes which are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

However, none of those publications describes compounds wherein the substituent at the 4-position of the morpholine ring is linked through a carbonyl or sulfonyl functionality. WO 03/002561 describes a class of cyclic amine derivatives, and includes within its scope substituted morpholine derivatives. The compounds described therein are alleged to be antagonists of human orexin receptors which are of potential use in the treatment of a wide variety of medical conditions, in particular obesity. There is, however, no specific disclosure in that publication of a morpholine derivative substituted by an indol-3-yl- methyl moiety at the 3-position of the morpholine ring.

The compounds in accordance with the present invention are potent and selective PI3K inhibitors having a binding affinity (IC₅₀) for the human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ isoform of 50 μM or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC₅₀ figure denotes a more active compound). The compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ isoform relative to other human kinases. The compounds of the invention possess notable advantages in terms of their high potency and selectivity, and valuable pharmacokinetic properties (including low clearance and high bioavailability).

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

(I)

wherein X represents oxygen, N-R⁵ or a covalent bond;

Y represents C=O or S(O)₂;

R¹ represents Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents;

R² represents hydrogen; or optionally substituted Ci_-6 alkyl; R³ and R⁴ independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR^a, -SR^a, -SOR^a, -SO₂R³, -NR^bR^c, -CH₂NR^bR^c, -NR^cCOR^d, -CH₂NR^cCOR^d, -NR^cCO₂R^d, -NHC0NR^bR^c, -NR^cSO₂R^e, -N(SO₂R^e)₂, -NHS0₂NR^bR^c, -COR^d, -CO₂R^d, -CONR^bR^c, -CON(OR^a)R^b or -SO₂NR^bR^c; or C ,_-6 alkyl, aryl, aryl(Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R⁵ represents hydrogen or Ci_-6 alkyl;

R^a represents Ci_-6 alkyl, aryl, aryl(Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R^b and R^c independently represent hydrogen or trifluoromethyl; or C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(C_1-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(C_1-6)alkyl, heteroaryl or heteroaryl(Cι_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or R^b and R^c, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiρerazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R^d represents hydrogen; or Ci_-6 alkyl, C_3-7 cycloalkyl, aryl, C_3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and

R^e represents C_1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents. The present invention also provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein

Y represents C=O;

R³ and R⁴ independently represent hydrogen, halogen, trifluoromethyl, -OR^a, -SR^a, -SOR\ -SO₂R³, -NR^bR^c, -NR^cC0R^d, -NR^cC0₂R^d, -NR^cSO₂R^e, -COR^d, -CO₂R^d, -CONR^bR^c or -SO₂NR^bR^e; or C_1-6 alkyl, aryl, aryl(C_1-6)alkyl, heteroaryl or heteroaryl- (Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents;

R > b represents hydrogen or trifluoromethyl; or Ci_-6 alkyl, C_3-7 cycloalkyl, C_3- •7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and

R^c represents hydrogen, Ci_-6 alkyl or C_3-7 cycloalkyl; or R^b and R^c, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, isoxazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin- 1 -yl, homopiperidin- 1 -yl, homomorpholin- 4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R^d represents hydrogen; or C]_-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and X, R¹, R², R^a and R^e are as defined above.

Where any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substitutents. Suitably, such groups will be unsubstituted or monosubstituted. 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 the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.

Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched Ci_-6 alkyl groups, for example Ci_-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, H-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, fert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci_-6 alkoxy", "Ci_-6 alkylthio", "Ci_-6 alkylsulphonyl" and "Ci_-6 alkylamino" are to be construed accordingly. Specific C_3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

Suitable aryl(C_1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-δ]pyridinyl, pyrrolyl, indolyl, isoindolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolyl, pyrazolo[l,5-α]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-α]pyridinyl, imidazo[4,5-δ]pyridinyl, imidazo[l,2- α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, 3,4-dihydro-2H-pyrido[3,2- &][l,4]oxazinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, quinoxalinyl and chromenyl groups.

The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.

Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to 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 a ¹H, ²H (deuterium) or ³H (tritium) atom, preferably ¹H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.

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

Y represents C=O;

X represents oxygen or N-R⁵; and R¹, R², R³, R⁴ and R⁵ are as defined above.

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

Y represents C=O;

X represents a covalent bond;

R¹ represents Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl(Ci.₆)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and R², R³ and R⁴ are as defined above.

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

Y represents S(O)₂; and

X, R¹, R², R³ and R⁴ are as defined above.

Typically, X represents oxygen or a covalent bond.

In one embodiment, X represents oxygen. In another embodiment, X represents N-R⁵, in which R⁵ is as defined above. In a further embodiment, X represents a covalent bond.

In a particular embodiment, Y represents C=O. In another embodiment, Y represents S(O)₂. Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IP) and (IQ):

wherein X, R p i , τ R>2 , r R,3 and R are as defined above.

Illustrative sub-classes of the compounds of formula (IP) above are represented by the compounds of formula (IA) and (IB):

(IA)

wherein R¹, R², R³, R⁴ and R⁵ are as defined above.

Another sub-class of the compounds of formula (IP) above is represented by the compounds of formula (IC) :

wherein R^la represents Cj_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl(Ci-₆)alkyl,

C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl or heteroaryl(Ci.₆)alkyl, any of which groups may be optionally substituted by one or more substituents; and R², R³ and R⁴ are as defined above.

In one aspect of the present invention, R¹ represents Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)- alkyl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

In one embodiment of that aspect, R¹ represents Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylmethyl, arylmethyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkylmethyl, C_3-7 heterocycloalkylethyl or heteroarylmethyl, any of which groups may be optionally substituted by one or more substituents. In a first embodiment, R¹ represents optionally substituted Ci_-6 alkyl. In a second embodiment, R¹ represents optionally substituted C_3-7 cycloalkyl. In a third embodiment, R¹ represents optionally substituted C_3-7 cycloalkyl(Ci_-6)alkyl. In one aspect of that embodiment, R¹ represents optionally substituted C_3-7 cycloalkylmethyl. In a fourth embodiment, R¹ represents optionally substituted aryl. In a fifth embodiment, R¹ represents optionally substituted aryl(Ci_-6)alkyl. In one aspect of that embodiment, R¹ represents optionally substituted arylmethyl. In a sixth embodiment, R¹ represents optionally substituted C_3-7 heterocycloalkyl. In a seventh embodiment, R¹ represents optionally substituted C_3-7 heterocycloalkyl(C_1-6)alkyl. In one aspect of that embodiment, R¹ represents optionally substituted C_3-7 heterocycloalkylmethyl. In another aspect of that embodiment, R¹ represents optionally substituted C_3-7 heterocycloalkylethyl. In an eighth embodiment, R¹ represents optionally substituted heteroaryl. In a ninth embodiment, R¹ represents optionally substituted heteroaryl(C_1-6)alkyl. In one aspect of that embodiment, R¹ represents optionally substituted heteroarylmethyl. Selected values of R¹ include methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexylmethyl, phenyl, naphthyl, benzyl, tetrahydrofuryl, oxetanylmethyl, pyrrolidinylethyl, furyl, thienyl, thieno[2,3-ό]pyridinyl, indolyl, pyrrolo[2,3-Z>]pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2- α]pyridinyl, oxadiazolyl, triazolyl, pyridinyl, quinolinyl, 3,4-dihydro-2H-pyrido[3,2- Z)][1, 4]oxazinyl, pyrimidinyl, pyrazinyl, furylmethyl, indolylmethyl, thiazolylmethyl, imidazolylmethyl, imidazo[l,2-α]pyridinylmethyl, triazolylmethyl, benzotriazolylmethyl, tetrazolylmethyl and pyridinyhnethyl, any of which groups may be optionally substituted by one or more substituents.

Typical values of R¹ include methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclohexylmethyl, phenyl, naphthyl, benzyl, tetrahydrofuryl, oxetanylmethyl, pyrrolidinylethyl, furyl, thienyl, pyrrolo[2,3-Z>]pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-α]pyridinyl, oxadiazolyl, triazolyl, pyridinyl, quinolinyl, furylmethyl, indolylmethyl, thiazolylmethyl, imidazolylmethyl, imidazo[l,2-α]pyridinylmethyl, triazolylmethyl, benzotriazolylmethyl, tetrazolylmethyl and pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.

Suitably, R¹ represents phenyl or pyridinyl, either of which groups may be optionally substituted by one or more substituents. Examples of selected substituents on R¹ include halogen, cyano, nitro, C_1-6 alkyl, trifluoromethyl, aryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, aryloxy, hydroxybenzoyloxy, (hydroxy)(methyl)benzoyloxy, Ci_-4 alkylenedioxy, Ci_-6 alkoxy(Ci_-6)alkyl, Ci_-6 alkylthio, Ci_-6 alkylsulphonyl, oxo, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, aryl(Ci_-6)alkoxycarbonylamino, Ci_-6 alkylaminocarbonylamino, arylaminocarbonylamino, Ci_-6 alkylsulphonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylaminocarbonyl, di(Ci_-6)alkylaminocarbonyl, aminosulphonyl, Ci_-6 alkylaminosulphonyl and di(Ci_-6)alkylaminosulphonyl. Examples of typical substituents on R¹ include halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, aryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, Ci_-4 alkylenedioxy, Ci_-6 alkoxy(Ci_-6)alkyl, Ci_-6 alkylthio, Ci_-6 alkylsulphonyl, oxo, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, aryl(Ci_-6)alkoxycarbonylamino, Ci_-6 alkylaminocarbonylamino, arylaminocarbonylamino, Ci_-6 alkylsulphonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylaminocarbonyl, di(Ci-₆)alkylamino- carbonyl, aminosulphonyl, Ci_-6 alkylaminosulphonyl and di(Ci_-6)alkylaminosulphonyl. Definitive examples of selected substituents on R¹ include halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, aryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkoxy, trifluoromethoxy, trifluoroethoxy, hydroxybenzoyloxy, (hydroxy)(methyl)benzoyloxy, Ci_-4 alkylenedioxy, Ci_-6 alkoxy(Ci_-6)alkyl, Ci_-6 alkylthio, Ci_-6 alkylsulphonyl, oxo, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, aryl(Ci_-6)- alkoxycarbonylamino, Ci_-6 alkylaminocarbonylamino, arylaminocarbonylamino, Ci_-6 alkylsulphonylamino, C_2-6 alkoxycarbonyl and Ci_-6 alkylaminosulphonyl. Examples of apposite substituents on R¹ include halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, aryl(Ci_-6)alkyl, Ci_-6 alkoxy, Ci_-4 alkylenedioxy, Ci_-6 alkoxy(Ci_-6)alkyl, oxo, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, aryl(Ci_-6)alkoxycarbonylamino, Ci_-6 alkylaminocarbonylamino, arylaminocarbonylamino and C_2-6 alkoxycarbonyl. Examples of specific substituents on R¹ include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, hydroxybenzoyloxy, (hydroxy)(methyl)benzoyloxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylamino- carbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonyl- amino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylamino- sulphonyl.

Examples of suitable substituents on R¹ include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl. Definitive examples of specific substituents on R¹ include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, hydroxybenzoyloxy, (hydroxy )(methyl)- benzoyloxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxycarbonyl- amino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, methoxycarbonyl and methylaminosulphonyl.

Examples of detailed substituents on R¹ include fluoro, chloro, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, methoxy, ethylenedioxy, methoxy- methyl, oxo, amino, methylamino, dimethylamino, acetylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino and methoxycarbonyl.

Selected values of R¹ include methyl, ethyl, cyanoethyl, oxopropyl, tert-butyl, cyclopropyl, oxocyclohexylmethyl, phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, (fluoro)(nitro)phenyl, methylphenyl, (fiuoro)(methyl)- phenyl, (chloro)(methyl)phenyl, trifluoromethylphenyl, (fluoro)(trifiuoromethyl)phenyl, (chloro)(trifluoromethyl)phenyl, (methyl)(trifluoromethyl)phenyl, hydroxyphenyl, (fluoro)(hydroxy)phenyl, (difluoro)(hydroxy)phenyl, (chloro)(hydroxy)phenyl, (bromo)- (hydroxy)phenyl, (hydroxy)(nitro)phenyl, (hydroxy )(methyl)phenyl, (hydroxy )- (trifluoromethyl)phenyl, methoxyphenyl, (fluoro)(methoxy)phenyl, (difluoro)(methoxy)- phenyl, (chloro)(methoxy)phenyl, (chloro)(fluoro)(methoxy)phenyl, (dichloro)(methoxy)- phenyl, (methoxy)(methyl)phenyl, (methoxy)(trifluoromethyl)phenyl, (hydroxy)- (methoxy)phenyl, dimethoxyphenyl, trifluoromethoxyphenyl, hydroxybenzoyloxyphenyl, (hydroxy)(methyl)benzoyloxyphenyl, methylenedioxyphenyl, ethylenedioxyphenyl, methylthiophenyl, methylsulphonylphenyl, aminophenyl, (dimethylamino)(fluoro)phenyl, (dimethylamino)(trifluoromethyl)phenyl, methylaminosulphonylphenyl, naphthyl, trifluoromethylbenzyl, (dimethyl)(oxo)tetrahydrofuryl, methyloxetanylmethyl, oxopyrrolidinylethyl, dioxopyrrolidinylethyl, furyl, nitrofuryl, methoxymethylthienyl, thieno[2,3-6]pyridinyl, indolyl, pyrrolo[2,3-ό]pyridinyl, pyrazolyl, methylpyrazolyl, (ethyl)(methyl)pyrazolyl, oxazolyl, dimethylisoxazolyl, methoxycarbonylisoxazolyl, chlorothiazolyl, methylthiazolyl, methoxythiazolyl, aminothiazolyl, (amino)(methyl)- thiazolyl, acetylaminothiazolyl, ethylaminocarbonylaminothiazolyl, imidazolyl, methylimidazolyl, (bromo)(methyl)imidazolyl, benzylimidazolyl, dimethylbenzimidazolyl, imidazo[l,2-α]pyridinyl, oxadiazolyl, dimethyltriazolyl, pyridinyl, fluoropyridinyl, chloropyridinyl, (fluoro)(chloro)pyridinyl, dichloropyridinyl, (bromo)(chloro)pyridinyl, cyanopyridinyl, methylpyridinyl, (chloro)(methyl)pyridinyl, (chloro)(cyano)(methyl)- pyridinyl, tert-butylpyridinyl, trifluoromethylpyridinyl, (chloro)(trifluoromethyl)pyridinyl, hydroxypyridinyl, methoxypyridinyl, (fluoro)(methoxy)pyridinyl, (chloro)(methoxy)- pyridinyl, (chloro)(fluoro)(methoxy)pyridinyl, (bromo)(methoxy)pyridinyl, (cyano)- (methoxy)pyridinyl, (methoxy)(nitro)pyridinyl, (methoxy)(methyl)pyridinyl, (cyano)- (methoxy)(methyl)pyridinyl, (methoxy)(trifluoromethyl)pyridinyl, (hydroxy)(methoxy)- pyridinyl, dimethoxypyridinyl, ethoxypyridinyl, (chloro)(ethoxy)pyridinyl, isopropoxy- pyridinyl, trifluoroethoxypyridinyl, methylthiopyridinyl, (chloro)(methylthio)pyridinyl, oxopyridinyl, (chloro)(oxo)pyridinyl, (methyl)(oxo)pyridinyl, (dimethyl)(oxo)pyridinyl, aminopyridinyl, (amino)(chloro)pyridinyl, (amino)(methoxy)pyridinyl, methylamino- pyridinyl, (chloro)(methylamino)pyridinyl, dimethylaminopyridinyl, acetylamino- pyridinyl, (acetylamino)(methoxy)pyridinyl, methoxycarbonylaminopyridinyl, ethoxycarbonylaminopyridinyl, benzyloxycarbonylaminopyridinyl, ethylaminocarbonyl- aminopyridinyl, butylaminocarbonylaminopyridinyl, phenylaminocarbonylamino- pyridinyl, methylsulphonylaminopyridinyl, (chloro)(methylsulphonylamino)pyridinyl, quinolinyl, methyl-3,4-dihydro-2//-pyrido[3,2-ό][l,4]oxazinyl, pyrimidinyl, dimethyl- pyrimidinyl, hydroxypyrimidinyl, methoxypyrimidinyl, (methoxy)(methyl)pyrimidinyl, dimethoxypyrimidinyl, aminopyrimidinyl, chloropyrazinyl, methoxypyrazinyl, furyl- methyl, indolylmethyl, aminothiazolylmethyl, imidazolylmethyl, imidazo[l,2-α]pyridinyl- methyl, methyltriazolylmethyl, benzotriazolylmethyl, tetrazolylmethyl, pyridinylmethyl, oxopyridinylmethyl and aminopyridinylmethyl.

Suitable values of R¹ include methyl, ethyl, cyanoethyl, oxopropyl, tert-butyl, cyclopropyl, oxocyclohexylmethyl, phenyl, chlorophenyl, methylphenyl, (fluoro)- (trifluoromethyl)phenyl, (methyl)(trifluoromethyl)phenyl, methoxyphenyl, (methoxy)- (trifluoromethyl)phenyl, ethylenedioxyphenyl, aminophenyl, naphthyl, trifiuoromethyl- benzyl, (dimethyl)(oxo)tetrahydrofuryl, methyloxetanylmethyl, oxopyrrolidinylethyl, dioxopyrrolidinylethyl, furyl, nitrofuryl, methoxymethylthienyl, pyrrolo[2,3-6]pyridinyl, pyrazolyl, (ethyl)(methyl)pyrazolyl, oxazolyl, dimethylisoxazolyl, methoxycarbonyl- isoxazolyl, methylthiazolyl, aminothiazolyl, (amino)(methyl)thiazolyl, acetylamino- thiazolyl, ethylaminocarbonylaminothiazolyl, methylimidazolyl, benzylimidazolyl, dimethylbenzimidazolyl, imidazo[l,2-α]pyridinyl, oxadiazolyl, dimethyltriazolyl, pyridinyl, chloropyridinyl, cyanopyridinyl, methylpyridinyl, tert-butylpyridinyl, trifiuoro- methylpyridinyl, methoxypyridinyl, oxopyridinyl, aminopyridinyl, methylaminopyridinyl, dimethylaminopyridinyl, acetylaminopyridinyl, ethoxycarbonylaminopyridinyl, benzyloxycarbonylaminopyridinyl, ethylaminocarbonylaminopyridinyl, butylamino- carbonylaminopyridinyl, phenylaminocarbonylaminopyridinyl, quinolinyl, furylmethyl, indolylmethyl, aminothiazolylmethyl, imidazolybnethyl, imidazo[l,2-α]pyridinylmethyl, methyltriazolylmethyl, benzotriazolylmethyl, tetrazolylmethyl, pyridinylmethyl, oxopyridinylmethyl and aminopyridinylmethyl.

A particular value of R¹ is chloropyridinyl, especially 6-chloropyridin-3-yl. A particular value of R¹ is methylpyridinyl, especially 6-methylpyridin-3-yl.

A particular value of R¹ is methoxypyridinyl, especially 6-methoxypyridin-3-yl.

A particular value of R¹ is (chloro)(methoxy)pyridinyl, especially 5-chloro-6- methoxypyridin-3-yl.

A particular value of R¹ is (chloro)(fluoro)(methoxy)pyridinyl, especially 2- chloro-5-fluoro-6-methoxypyridin-3-yl.

Selected values of R² include hydrogen, optionally substituted methyl and optionally substituted ethyl. Examples of suitable substituents on R² include hydroxy, C_1-6 alkoxy, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, aminocarbonyl, Ci_-6 alkylaminocarbonyl and di(Ci _-6)alky laminocarbonyl .

Examples of typical substituents on R² include hydroxy, Ci_-6 alkoxy, aminocarbonyl, C_1-6 alkylaminocarbonyl and di(C_1-6)alky laminocarbonyl.

Examples of selected substituents on R² include hydroxy, di(C_1-6)alkylamino, aminocarbonyl and C_1-6 alkylaminocarbonyl.

Suitable examples of specific substituents on R² include hydroxy, methoxy, amino, methylamino, dimethylamino, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.

Typical examples of specific substituents on R² include hydroxy, methoxy, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.

Selected examples of specific substituents on R² include hydroxy, dimethylamino, aminocarbonyl and methylaminocarbonyl. In one embodiment, R² represents hydrogen. In another embodiment, R² represents optionally substituted C_1-6 alkyl. In one aspect of that embodiment, R² represents unsubstituted C_1-6 alkyl, especially methyl. In another aspect of that embodiment, R² represents substituted Cj_-6 alkyl, especially substituted methyl or substituted ethyl. Specific values of R² include hydrogen, methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, hydroxyethyl and dimethylaminoethyl.

Particular values of R² include hydrogen and methyl.

In a particular aspect, R³ and R⁴ independently represent hydrogen, halogen, trifluoromethyl, -OR^a, -SR^a, -SOR^a, -SO₂R³, -NR^bR^c, -NR^cCOR^d, -NR^cCO₂R^d, -NR^cSO₂R^e, -COR^d, -CO₂R^d, -CONR^bR^c or -SO₂NR^bR^c; or C_-6 alkyl, aryl, aryl-

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

Selected values of R³ include hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR^a, -SO₂R³, -NR^bR^c, -CH₂NR^bR^c, -NR^cCOR^d, -CH₂NR^cCOR^d, -NR^cCO₂R^d, -NHCONR^bR^c, -NR^cSO₂R^e, -N(SO₂R^e)₂, -NHSO₂NR^bR^c, -COR^d, -CO₂R^d, -CONR^bR^c, -CON(OR³)R^b or -SO₂NR^bR^c; or Ci_-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents. Typical values of R³ include hydrogen, -OR^a, -CO₂R^d or -CONR^bR^c; or aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.

In a first embodiment, R³ represents hydrogen. In a second embodiment, R³ represents -OR^a, wherein R^a is as defined above. In a third embodiment, R³ represents -CO₂R^d, wherein R^d is as defined above. In a fourth embodiment, R³ represents -CONR^bR^c, wherein R^b and R^c are as defined above. In a fifth embodiment, R³ represents optionally substituted aryl. In a sixth embodiment, R³ represents optionally substituted heteroaryl. In a seventh embodiment, R³ represents halogen. In one aspect of that embodiment, R³ represents fluoro. In another aspect of that embodiment, R³ represents chloro. In an eighth embodiment, R³ represents cyano. In a ninth embodiment, R³ represents nitro. In a tenth embodiment, R³ represents hydroxy. In an eleventh embodiment, R³ represents trifluoromethyl. In a twelfth embodiment, R³ represents trifluoromethoxy. In a thirteenth embodiment, R³ represents -SO₂R^a, wherein R^a is as defined above. In a fourteenth embodiment, R³ represents -NR^bR^c, wherein R^b and R^c are as defined above. In a fifteenth embodiment, R³ represents -CH₂NR^bR^c, wherein R^b and R^c are as defined above. In a sixteenth embodiment, R³ represents -NR^cCOR^d, wherein R^c and R^d are as defined above. In a seventeenth embodiment, R³ represents -CH₂NR^cCOR^d, wherein R^c and R^d are as defined above. In an eighteenth embodiment, R³ represents -NR^cCO₂R^d, wherein R^c and R^d are as defined above. In a nineteenth embodiment, R³ represents -NHCONR^bR^c, wherein R^b and R^c are as defined above. In a twentieth embodiment, R³ represents -NR^cSO₂R^e, wherein R^c and R^e are as defined above. In a twenty-first embodiment, R³ represents -N(SO₂R^e)₂, wherein R^e is as defined above. In a twenty-second embodiment, R³ represents -NHSO₂NR^bR^c, wherein R^b and R^c are as defined above. In a twenty-third embodiment, R³ represents -COR , wherein R^d is as defined above. In a twenty-fourth embodiment, R³ represents -CON(OR^a)R^b, wherein R^a and R^b are as defined above. In a twenty-fifth embodiment, R³ represents -SO₂NR^bR^c; wherein R^b and R^c are as defined above. In a twenty-sixth embodiment, R³ represents optionally substituted Ci_-6 alkyl. Examples of typical substituents on R³ and/or R⁴ include halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, aryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkoxy, difiuoromethoxy, trifluoromethoxy, aryloxy, C_)-4 alkylenedioxy, Ci_-6 alkoxy(Ci_-6)alkyl, Ci_-6 alkylthio, Ci_-6 alkylsulphonyl, oxo, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, aryl(C_1-6)alkoxycarbonylamino, Ci_-6 alkylaminocarbonyl- amino, arylaminocarbonylamino, Ci_-6 alkylsulphonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylaminocarbonyl, di(Ci_-6)alkyl- aminocarbonyl, aminosulphonyl, Ci_-6 alkylaniinosulphonyl and di(C_1-6)alkylamino- sulphonyl.

Selected examples of typical substituents on R³ and/or R⁴ include halogen, C_]-6 alkyl, Ci_-6 alkoxy and Ci_-4 alkylenedioxy.

Examples of apposite substituents on R³ and/or R⁴ include halogen and Ci_-6 alkyl.

Examples of suitable substituents on R³ and/or R⁴ include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxy- carbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonyl- amino, butylaminocarbonylamino, phenylaminocarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylamino- sulphonyl. An additional example is methylenedioxy.

Selected examples of suitable substituents on R³ and/or R⁴ include fluoro, methyl, methoxy and methylenedioxy. Examples of detailed substituents on R³ and/or R⁴ include fluoro and methyl.

Definitive values of R³ include hydrogen, fluoro, chloro, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR^a, -SO₂R³, -NR^bR^c, -CH₂NR^bR^c, -NR^cCOR^d, -CH₂NR^cCOR^d, -NR^cCO₂R^d, -NHCONR^bR^c, -NR^cSO₂R^e, -N(SO₂R^e)₂, -NHSO₂NR^bR^c, -COR^d, -CO₂R^d, -CONR^bR^c, -CON(OR^a)R^b, -SO₂NR^bR^c, methyl, phenyl, fluorophenyl, methylphenyl, methoxyphenyl, methylenedioxyphenyl, thiazolyl, imidazolyl, methyl- imidazolyl, pyridinyl and methylpyridinyl.

Suitable values of R³ include hydrogen, -OR^a, -CO₂R^d, -CONR^bR^c, phenyl, fluorophenyl, methylphenyl and methylimidazolyl.

Typical values of R⁴ include hydrogen, halogen, -COR^d, -CO₂R^d, -CONR^bR^c and Ci_-6 alkyl, wherein R^b, R^c and R^d are as defined above.

Selected values of R⁴ include hydrogen, halogen, -COR^d, -CO₂R^d and -CONR^bR^c, wherein R^b, R^c and R^d are as defined above.

Suitable values of R include hydrogen and Ci_-6 alkyl. In one embodiment, R represents hydrogen. In another embodiment, R⁴ represents halogen, especially chloro. In another embodiment, R⁴ represents -COR^d, wherein R is as defined above. In another embodiment, R⁴ represents -CO₂R^d, wherein R^d is as defined above. In another embodiment, R⁴ represents -CONR^bR^c, wherein R^b and R^c are as defined above. In another embodiment, R⁴ represents C_1-6 alkyl, especially methyl.

Suitably, R⁵ represents hydrogen or methyl.

In one embodiment, R⁵ represents hydrogen. In another embodiment, R⁵ represents Ci_-6 alkyl, especially methyl. Typical examples of suitable substituents on R^a, R^b, R^c, R^d or R^e, or on the heterocyclic moiety -NR^bR^c, include halogen, Ci_-6 alkyl, C_1-6 alkoxy, difluoromethoxy, trifiuoromethoxy, C_1-6 alkoxy(C_1-6)alkyl, C_1-6 alkylthio, C_1-6 alkylsulphonyl, hydroxy, hydroxy(Ci_-6)alkyl, amino(Ci_-6)alkyl, cyano, trifluoromethyl, oxo, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, phenylamino, pyridinylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxy carbonylamino, aminocarbonyl, Ci_-6 alkylaminocarbonyl and di(Ci_-6)alkylaminocarbonyl. Additional examples include Ci_-6 alkylsulphinyl, C_2-6 alkylcarbonyloxy, C_2-6 alkylcarbonylamino(Ci_-6)alkyl and Ci_-6 alkyl- sulphonylamino.

Selected examples of suitable substituents on R^a, R^b, R^c, R^d or R^e, or on the heterocyclic moiety -NR^bR^c, include halogen, Ci_-6 alkyl, Ci_-6 alkoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, hydroxy, hydroxy(Ci-₆)alkyl, amino(Ci_-6)alkyl, cyano, oxo, C_2-6 alkylcarbonyl, C_2-6 alkylcarbonyloxy, carboxy, C_2-6 alkoxycarbonyl, amino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkylcarbonylamino(Ci_-6)alkyl, C_2-6 alkoxycarbonylamino, Ci_-6 alkylsulphonylamino and aminocarbonyl. Typical examples of specific substituents on R^a, R^b, R^c, R^d or R^e, or on the heterocyclic moiety -NR^bR^c, include fiuoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifiuoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, tert-butoxycarbonylamino, aminocarbonyl, methylamino- carbonyl and dimethylaminocarbonyl. Additional examples include methylsulphinyl, acetoxy, acetylaminomethyl and methylsulphonylamino. Selected examples of specific substituents on R\ R^b, R^c, R^d or R^e, or on the heterocyclic moiety -NR^bR^c, include fluoro, chloro, methyl, methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, acetoxy, carboxy, ethoxycarbonyl, tert-butoxycarbonyl, amino, dimethylamino, acetylamino, acetylaminomethyl, fert-butoxycarbonylamino, methylsulphonylamino and aminocarbonyl.

Suitably, R^a represents Ci_-6 alkyl, aryl(C_1-6)alkyl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

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

Selected examples of suitable substituents on R^a include Ci_-6 alkoxy and oxo.

Selected examples of specific substituents on R^a include methoxy and oxo.

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

Specific values of R^a include methyl, methoxyethyl, benzyl and dioxoisoindolylpropyl. In a particular aspect, R^b represents hydrogen or trifluoromethyl; or Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Selected values of R^b include hydrogen; or Ci_-6 alkyl, aryl(Ci.₆)alkyl, C_3-7 heterocycloalkyl or C_3-7 heterocycloalkyl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Typical values of R^b include hydrogen and Ci_-6 alkyl. Illustratively, R^b represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylmethyl, morpholinylethyl, moφholinylpropyl, pyridinyl, indolyhnethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.

Representative values of R^b include hydrogen; or methyl, ethyl, w-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^b include Ci_-6 alkoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, hydroxy, cyano, C_2-6 alkoxycarbonyl, di- (Ci_-6)alkylamino and C_2-6 alkoxycarbonylamino.

Selected examples of specific substituents on R^b include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.

Specific values of R include hydrogen, methyl, methoxyethyl, methylthioethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino- ethyl, fert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert- butoxycarbonylpyrrolidinyl and morpholinylpropyl.

In one embodiment, R represents hydrogen. In another embodiment, R^b represents Ci_-6 alkyl, especially methyl.

Selected values of R^c include hydrogen; or Ci_-6 alkyl, C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.

In a particular aspect, R^c represents hydrogen, Ci_-6 alkyl or C_3-7 cycloalkyl. Representative values of R^c include hydrogen; or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^c include C_2-6 alkylcarbonyl and C_2-6 alkoxycarbonyl.

Selected examples of specific substituents on R^c include acetyl and tert- butoxy carbony 1.

Specific values of R^c include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl, Suitably, R^c represents hydrogen or C_1-6 alkyl. In one embodiment, R^c is hydrogen.

In another embodiment, R^c represents Ci_-6 alkyl, especially methyl or ethyl, particularly methyl. In a further embodiment, R^c represents C_3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Alternatively, the moiety -NR^bR^c may suitably represent azetidin-1-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomoφholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.

In a particular aspect, the moiety -NR^bR^c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, isoxazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.

Selected values for the moiety -NR^bR^c suitably include azetidin-1-yl, pyrrolidin-1- yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl and homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on the heterocyclic moiety -NR^bR^c include Ci_-6 alkyl, Ci_-6 alkylsulphonyl, hydroxy, hydroxy(Ci-₆)alkyl, amino(Ci_-6)alkyl, cyano, oxo, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, amino, C_2-6 alkylcarbonyl- amino, C_2-6 alkylcarbonylamino(Ci_-6)alkyl, C_2-6 alkoxycarbonylamino, Ci_-6 alkyl- sulphonylamino and aminocarbonyl.

Selected examples of specific substituents on the heterocyclic moiety -NR^bR^c include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulphonylamino and aminocarbonyl.

Specific values of the moiety -NR^bR^c include azetidin-1-yl, hydroxyazetidin-1-yl, hydroxymethylazetidin- 1 -yl, (hydroxy)(hydroxymethyl)azetidin- 1 -yl, aminomethyl- azetidin- 1 -yl, cyanoazetidin- 1 -yl, carboxyazetidin- 1 -yl, aminoazetidin- 1 -y 1, aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl, oxopyrrolidin-1- yl, acetylaminomethylpyrrolidin-1-yl, tert-butoxycarbonylaminopyrrolidin-l-yl, oxo- oxazolidin-3-yl, hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3-yl, dioxo- isothiazolidin-2-yl, piperidin-1-yl, hydroxypiperidin-1-yl, hydroxymethylpiperidin-1-yl, aminopiperidin- 1 -yl, acetylaminopiperidin- 1 -yl, tert-butoxycarbonylaminopiperidin- 1 -yl, methylsulphonylaminopiperidin-1-yl, morpholin-4-yl, piperazin-1-yl, methylpiperazin-1- yl, methylsulphonylpiperazin-1-yl, oxopiperazin-1-yl, acetylpiperazin-1-yl, ethoxycarbonylpiperazin-1-yl and oxohomopiperazin-1-yl.

Suitably, R^d represents hydrogen; or Ci_-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable values for R^d include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents. Selected examples of suitable substituents on R^d include halogen, C_1-6 alkyl, Ci_-6 alkoxy, oxo, C_2-6 alkylcarbonyloxy and di(Ci_-6)alkylamino.

Selected examples of particular substituents on R^d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.

In one embodiment, R^d represents hydrogen. In another embodiment, R^d represents optionally substituted Ci_-6 alkyl. In one aspect of that embodiment, R^d ideally represents unsubstituted Ci_-6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl. In another aspect of that embodiment, R^d ideally represents substituted Ci_-6 alkyl, e.g. substituted methyl or substituted ethyl, including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. In another embodiment, R^d represents optionally substituted aryl. In one aspect of that embodiment, R^d represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R^d represents monosubstituted aryl, especially methylphenyl. In a further aspect of that embodiment, R^d represents disubstituted aryl, e.g. dimethoxyphenyl. In a further embodiment, R^d represents optionally substituted heteroaryl,,e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl. In another embodiment, R^d represents optionally substituted C_3-7 cycloalkyl, e.g. cyclopropyl or cyclobutyl. In a further embodiment, R^d represents optionally substituted C_3-7 heterocycloalkyl, e.g. thiazolidinyl or oxo- thiazolidinyl.

Selected examples of specific values for R^d include hydrogen, methyl, acetoxy- methyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl. Suitably, R^e represents C]_-6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^e include Cj_-6 alkyl, especially methyl.

In one embodiment, R^e represents optionally substituted Ci_-6 alkyl, ideally unsubstituted Ci_-6 alkyl, e.g. methyl or propyl, especially methyl. In another embodiment, R^e represents optionally substituted aryl. In one aspect of that embodiment, R^e represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, R^e represents monosubstituted aryl, especially methylphenyl. In a further embodiment, R^e represents optionally substituted heteroaryl. Selected values of R^e include methyl, propyl and methylphenyl.

Suitably, the substituent at the 3 -position of the morpholine ring in the compounds of formula (I) as depicted above is in the (S) configuration.

One sub-class of compounds according to the invention is represented by the compounds of formula (HA) and iV-oxides thereof, and pharmaceutically acceptable salts and solvates thereof:

wherein X, R¹, R² and R³ are as defined above.

One subset of the compounds of formula (HA) above is represented by the compounds of formula (HB) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof:

wherein

R^z and R^J are as defined above; R¹¹ represents hydrogen, halogen, Ci_-6 alkyl, trifluoromethyl, hydroxy, Ci_-6 alkoxy, trifluoromethoxy or Ci_-6 alkylaminosulphonyl;

R¹² represents hydrogen, halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, hydroxy, Ci_-6 alkoxy, trifluoromethoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphonyl, amino or di(Ci_-6)alkylamino; and

R¹³ represents hydrogen, halogen, trifluoromethyl or Ci_-6 alkoxy. Suitable values of R¹¹ include hydrogen, fluoro, chloro, methyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy and methylaminosulphonyl. A particular value of R¹ ' is hydroxy. Suitable values of R¹² include hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, methylthio, methyl- sulphonyl, amino and dimethylamino.

A particular value of R¹² is methoxy.

Suitable values of R¹³ include hydrogen, fluoro, chloro, bromo, trifluoromethyl and methoxy.

In a particular embodiment, R¹³ represents hydrogen. In another embodiment, R¹³ represents halogen. In one aspect of that embodiment, R¹³ represents fluoro. In another aspect of that embodiment, R¹³ represents chloro. In a further aspect of that embodiment, R¹³ represents bromo. In another embodiment, R¹³ represents trifluoromethyl. In a further embodiment, R¹³ represents C_1-6 alkoxy, especially methoxy.

Another subset of the compounds of formula (HA) above is represented by the compounds of formula (HC) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof:

wherein

R² and R³ are as defined above; R²¹ represents hydrogen, halogen, cyano, Ci_-6 alkyl, Ci_-6 alkoxy, trifluoroethoxy,

Ci_-6 alkylthio, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, aryl(Ci_-6)alkoxycarbonylamino, Ci_-6 alkylaminocarbonylamino, arylaminocarbonylamino or Ci_-6 alkylsulphonylamino;

R²² represents hydrogen, halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, hydroxy, Ci_-6 alkoxy, amino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino or Cj_-6 alkylsulphonylamino; and R²³ represents hydrogen, halogen, cyano, C_1-6 alkyl, C_1-6 alkoxy or amino.

Suitable values of R²¹ include hydrogen, chloro, cyano, methyl, tert-butyl, methoxy, ethoxy, isopropoxy, trifluoroethoxy, methylthio, amino, methylamino, dimethylamino, acetylamino, ethoxycarbonylamino, benzyloxycarbonylamino, ethylaminocarbonylamino, butylaminocarbonylamino, phenylaminocarbonylamino and methylsulphonylamino .

Particular values of R²¹ include halogen, C_1-6 alkyl, Cj_-6 alkoxy and amino.

In one embodiment, R²¹ represents hydrogen. In another embodiment, R²¹ represents halogen, especially chloro. In another embodiment, R²¹ represents Ci_-6 alkyl, especially methyl. In a particular embodiment, R²¹ represents Ci_-6 alkoxy, especially methoxy. In a further embodiment, R²¹ represents amino.

Suitable values of R²² include hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, methoxycarbonylamino and methylsulphonylamino. Particular values of R²² include hydrogen, halogen, cyano and Ci_-6 alkyl.

In one embodiment, R²² represents hydrogen. In another embodiment, R²² represents halogen, especially fluoro or chloro. In one aspect of that embodiment, R²² represents fluoro. In one aspect of that embodiment, R²² represents chloro. In a further embodiment, R represents cyano. In another embodiment, R represents Ci_-6 alkyl, especially methyl.

Suitable values of R²³ include hydrogen, chloro, cyano, methyl, methoxy and amino.

Particular values of R²³ include hydrogen and halogen.

In one embodiment, R²³ represents hydrogen. In another embodiment, R²³ represents halogen, especially chloro.

Suitably, R²¹ is chloro, and R²² and R²³ are both hydrogen.

Suitably, R²¹ is methyl, and R²² and R²³ are both hydrogen.

Suitably, R²¹ is methoxy, and R²² and R²³ are both hydrogen.

Suitably, R²¹ is methoxy, R²² is chloro and R²³ is hydrogen. Suitably, R²¹ is methoxy, R²² is fluoro and R²³ is chloro.

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 present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.

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

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

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

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

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

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

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

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

The compounds of formula (I) above wherein X represents a covalent bond may be prepared by a process which comprises reacting a compound of formula R¹ -Y-Cl with a compound of formula (III):

(III)

wherein Y, R¹, R², R³ and R⁴ are as defined above.

The reaction is conveniently effected in a suitable solvent, typically under basic conditions, e.g. in the presence of an organic base such as triethylamine or N,N- diisopropylethylamine. Suitable solvents include chlorinated solvents such as dichloromethane, cyclic ether solvents such as tetrahydrofuran, and dipolar aprotic solvents such as N, ./V-dimethylformamide.

Alternatively, the compounds of formula (I) above wherein X represents a covalent bond and Y represents C=O may be prepared by a process which comprises reacting a compound of formula R¹ -CO₂H, wherein R¹ is as defined above, with a compound of formula (III) as defined above; in the presence of a coupling reagent. The coupling agent of use in the above reaction is suitably l-(3-dimethylamino- propyl)-3-ethylcarbodiimide (EDC), in which case the reaction is conveniently effected in the presence of an additive such as 1-hydroxybenzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic base such as ΛζN-diisopropyl- ethylamine.

Alternatively, the coupling agent employed may be polymer-supported Mukaiyama resin, in which case the reaction is conveniently effected under basic conditions, e.g. in the presence of an organic base such as N,N-diisopropylethylamine.

In another alternative, the coupling agent employed may be polymer-supported carbodiimide (PS-CDI), in which case the reactants may be brought together in the presence of the coupling agent and the material thereby obtained may then be treated with polymer-supported isocyanate (PS-NCO) in the presence of a base, typically an organic base such as triethylamine.

The compounds of formula (I) above wherein X represents oxygen and Y represents C=O may be prepared by a two-stage process which comprises (i) reacting a compound of formula R¹ -OH, wherein R¹ is as defined above, with a condensing agent such as 4-nitrophenyl chloroformate; then (ii) reacting the resulting product with a compound of formula (III) as defined above.

Both stages of the above process may conveniently be performed in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, typically under basic conditions, e.g. in the presence of an organic base such as Λf,N-diisopropylethylamine. The compounds of formula (I) above wherein X represents N-H and Y represents

C=O may be prepared by a process which comprises reacting an isocyanate derivative of formula R¹ -N=C=O, wherein R¹ is as defined above, with a compound of formula (III) as defined above.

The reaction may conveniently be performed in a suitable solvent, e.g. a cyclic ether solvent such as tetrahydrofuran, typically in the presence of iV,iV-dimethylacetamide.

In an additional procedure, the compounds of formula (I) wherein R² is hydrogen may be prepared by a process which comprises reacting a compound of formula (IV) with a compound of formula (V):

(IV)

wherein X, Y, R¹, R³ and R⁴ are as defined above; in the presence of a transition metal catalyst; followed by removal of the trimethylsilyl moiety from the 2-position of the resulting cycloaddition product.

The transition metal catalyst of use in the reaction between compounds (IV) and (V) is suitably palladium(II) acetate, in which case the reaction may conveniently be effected at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as jV,N-dimethylformamide, in the presence of lithium chloride and a base, typically an inorganic base, e.g. an alkaline earth metal carbonate such as sodium carbonate.

Removal of the trimethylsilyl moiety from the resulting cycloaddition product may be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid.

The intermediates of formula (IV) above wherein X represents a covalent bond may be prepared by reacting a compound of formula R'-Y-Cl with the compound of formula (VI):

(VI)

wherein Y and R¹ are as defined above; under conditions analogous to those described above for the reaction between a compound of formula R¹ -Y-Cl and compound (III). The intermediates of formula (III) above may be prepared by the methods described in prior art publications, including WO 2006/114606, WO 2007/141504, WO 2008/001076, WO 2008/047109, WO 2009/001089, WO 2009/071888, WO 2009/071890, WO 2009/071895, and copending international patent application no. PCT/GB2009/000818, published on 8 October 2009 as WO 2009/122148.

Where they are not commercially available, the starting materials of formula R'-Y-Cl, R'-CO₂H, R'-OH, R'-N=C=O, (V) and (VI) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of example, a compound of formula (I) wherein R¹ contains an amino (-NH₂) group may be converted into the corresponding compound wherein R¹ contains a C_2-6 alkoxycarbonylamino or aryl(C_1-6)alkoxycarbonylamino moiety by treatment with the appropriate alkyl or aryl- (Ci_-6)alkyl chloroformate respectively. Moreover, a compound of formula (I) wherein R¹ contains an amino (-NH₂) group may be converted into the corresponding compound wherein R¹ contains a Ci_-6 alkylaminocarbonylamino or arylaminocarbonylamino moiety by treatment with the appropriate alkyl or aryl isocyanate respectively. A compound of formula (I) wherein R¹ contains an amino (-NH₂) group may be converted into the corresponding compound wherein R¹ contains a Ci_-6 alkylsulphonylamino moiety by treatment with the appropriate alkyl sulphonyl chloride, typically in the presence of a base, e.g. an organic base such as triethylamine.

A compound of formula (I) wherein R¹ contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein R¹ contains a Ci_-6 alkoxy moiety, e.g. methoxy or ethoxy, by treatment with an alkali metal alkoxide, e.g. sodium methoxide; or by treatment with a Ci_-6 alkanol, e.g. methanol or ethanol, in the presence of a base, e.g. an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide. Moreover, a compound of formula (I) wherein R¹ contains a halogen atom, e.g. fluoro or chloro, may be converted into the corresponding compound wherein R¹ contains a Ci_-6 alkylamino or di(Ci_-6)alkylamino moiety, e.g. methylamino or dimethylamino, by treatment with the appropriate alkylamine or dialkylamine, e.g. methylamine or dimethyl- amine respectively, optionally in the presence of a base, typically an inorganic base, e.g. an alkali metal carbonate such as potassium carbonate. A compound of formula (I) wherein R¹ contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein R¹ contains a C_1-6 alkylthio moiety, e.g. methylthio, by treatment with an alkali metal thioalkoxide, e.g. sodium thiomethoxide. A compound of formula (I) wherein R¹ contains a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein R¹ contains a C_1-6 alkylsulphonyl- amino moiety, e.g. methylsulphonylamino, by treatment with the appropriate alkyl sulphonamide, e.g. methanesulphonamide, generally in the presence of a transition metal catalyst. A suitable transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), in which case the reaction is conveniently effected in the presence of 4,5-bis(diphenyl- phosphino)-9,9-dimethylxanthene (Xantphos) and a base, typically an inorganic base, e.g. an alkali metal carbonate such as caesium carbonate.

A compound of formula (I) wherein R¹ contains a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein R¹ contains a hydroxy (-OH) group by treatment with a hydroxide salt, e.g. an alkali metal hydroxide such as potassium hydroxide, generally in the presence of a transition metal catalyst. A suitable transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), in which case the reaction is conveniently effected in the presence of a reagent such as 2-di-tert-butylphosphino- 3,4,5,6-tetramethyl-2',4',6'-triisopropyl-l,l'-biphenyl. A compound of formula (I) wherein R¹ contains a nitro (-NO₂) group may be converted into the corresponding compound wherein R¹ contains an amino (-NH₂) group by treatment with a reducing agent, which may typically be elemental zinc in the presence of an acid, e.g. an organic acid such as acetic acid, or a mineral acid such as hydrochloric acid. A compound of formula (I) wherein R¹ contains a N-H moiety may be converted into the corresponding compound wherein R¹ contains a N-methyl moiety by treatment with a methylating agent, e.g. iodomethane, typically under basic conditions, e.g. in the presence of sodium hydride.

A compound of formula (I) wherein R² represents hydrogen may be converted into the corresponding compound wherein R² represents optionally substituted C_1-6 alkyl, e.g. methyl or 2-(dimethylamino)ethyl, by treatment with an appropriate alkylating agent, e.g. iodomethane, methyl carbonate or 7V-(2-chloroethyl)dimethylamine, typically under basic conditions, e.g. in the presence of sodium hydride, l,4-diazabicyclo[2.2.2]octane (DABCO) or lithium bis(trimethylsilyl)amide.

A compound of formula (I) wherein R³ represents nitro (-NO₂) may be converted into the corresponding compound wherein R³ represents amino (-NH₂) by treatment with a reducing agent, which may typically be elemental zinc in the presence of an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as acetic acid.

A compound of formula (I) wherein R³ represents amino (-NH₂) may be converted into the corresponding compound wherein R³ represents -NHC0R^d by treatment with the appropriate compound of formula Cl-COR^d, typically in the presence of a base, e.g. an organic base such as triethylamine, or an alkali metal carbonate such as potassium carbonate. A compound of formula (I) wherein R³ represents -NHCO(CH₂)₃C1 may be cyclised to the corresponding compound wherein R³ represents 2-oxopyrrolidin-l-yl by treatment with a base such as lithium bis(trimethylsilyl)amide or potassium carbonate.

A compound of formula (I) wherein R³ represents amino (-NH₂) may be converted into the corresponding compound wherein R³ represents -NHCO₂R^d by treatment with the appropriate compound of formula Cl-CO₂R^d, typically in the presence of a base, e.g. an organic base such as triethylamine. A compound of formula (I) wherein R³ represents -NHCO₂(CH₂)₂C1 may be cyclised to the corresponding compound wherein R³ represents 2-oxooxazolidin-3-yl by treatment with a base, e.g. an alkali metal carbonate such as potassium carbonate.

A compound of formula (I) wherein R³ contains an amino (-NH₂) group may be converted into the corresponding compound wherein R³ contains a -NHSO₂R⁶ or -N(SO₂R^e)₂ moiety by treatment with the appropriate compound of formula Cl-SO₂R⁶, typically in the presence of a base, e.g. an organic base such as triethylamine. A compound of formula (I) wherein R³ represents -NHSO₂(CH₂)₃C1 may be cyclised to the corresponding compound wherein R³ represents l,l-dioxoisothiazolidin-2-yl by treatment with a base, e.g. an alkali metal carbonate such as potassium carbonate.

A compound of formula (I) wherein R³ represents -NHC0₂R^d or -NHSO₂R⁶ may be converted into the corresponding compound wherein R³ represents -NR^cCO₂R^d or -NR⁰SO₂R⁶ in which R^c is Ci_-6 alkyl, e.g. methyl, by treatment with an appropriate alkylating agent, e.g. iodomethane, typically under basic conditions, e.g. in the presence of sodium hydride. A compound of formula (I) wherein R³ contains a N-H moiety may be converted into the corresponding compound wherein R³ contains a N-COCH₃ moiety by treatment with an acetylating agent, which may suitably be acetic anhydride and optionally acetic acid, typically under basic conditions, e.g. in the presence of an organic base such as triethylamine or 4-(dimethylamino)pyridine.

A compound of formula (I) wherein R³ represents an ester moiety -CO₂R^d (wherein R^d is other than hydrogen) may be converted into the corresponding compound wherein R³ represents a carboxy moiety -CO₂H by standard saponification methodology, generally by treatment with a base, typically an inorganic base, e.g. an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide.

A compound of formula (I) wherein R³ represents a carboxy moiety -CO₂H may be converted into the corresponding compound wherein R³ represents an ester moiety -CO₂R^d (wherein R^d is other than hydrogen) by treatment with the appropriate compound of formula R^d-OH in the presence of a coupling reagent, which will suitably be l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and an additive such as 1-hydroxy- benzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic base such as N,iV-diisopropylethylamine. A compound of formula (I) wherein R³ represents -CO₂H may be converted into the corresponding compound wherein R³ represents tert-butoxycarbonyl by treatment with ΛfΛf-dimethylformamide di-tert-buty\ acetal.

A compound of formula (I) wherein R³ represents -CO₂H may be converted into the corresponding compound wherein R³ represents -CONR^bR^c by treatment with the appropriate compound of formula H-NR^bR^c in the presence of a coupling reagent, which will suitably be l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and an additive such as 1-hydroxybenzotriazole hydrate (HOBT), typically under basic conditions, e.g. in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine. Alternatively, the coupling agent may be 2-(lH-7-azabenzotriazol-l-yl)-l, 1,3,3- tetramethyl uronium hexafluorophosphate (ΗATU), in which case the reaction will conveniently be performed in the presence of an organic base such as N,./V-diisopropyl- ethylamine.

A compound of formula (I) wherein R³ represents pentafluorophenoxycarbonyl may be converted into the corresponding compound wherein R³ represents -CONR R^c by treatment with the appropriate compound of formula H-NR^bR^c, typically under basic conditions, e.g. in the presence of an organic base such as ΛζN-diisopropylethylamine.

A compound of formula (I) wherein R³ represents -CO₂H may be converted into the corresponding compound wherein R³ represents -C0N(0R^a)R^b by treatment with the appropriate compound of formula H-N(0R^a)R^b, typically in the presence of 2-chloro-4,6- dimethoxy [l,3,5]triazine and an organic base such as AζjV-diisopropylethylamine.

A compound of formula (I) wherein R³ represents -CON(OR^a)R^b may be converted into the corresponding compound wherein R³ represents -COR^d, in which R^d is optionally substituted aryl or optionally substituted heteroaryl, by treatment with the appropriate arylmagnesium bromide or heteroarylmagnesium bromide. Moreover, a compound of formula (I) wherein R³ represents -CON(OR^a)R^b may be converted into the corresponding compound wherein R³ represents -COR^d, in which R^d is optionally substituted heteroaryl, by treatment with the appropriate heteroaromatic compound, e.g. thiazole or 1 -methyl- IH- imidazole, in the presence of a base such as n-butyllithium. A compound of formula (I) wherein R³ represents halogen, e.g. chloro, may be converted into the corresponding compound wherein R³ represents hydrogen by treatment with a hydrogenation catalyst, e.g. 10% palladium on charcoal, ideally under transfer hydrogenation conditions, e.g. in the presence of ammonium formate.

A compound of formula (I) wherein R³ represents halogen, e.g. chloro, may be converted into the corresponding compound wherein R³ represents optionally substituted aryl or optionally substituted heteroaryl by treatment with the appropriate arylboronic acid or heteroarylboronic acid, in the presence of a transition metal catalyst. A suitable transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), in which case the reaction is conveniently effected in the presence of 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (XPhos) and a base, typically an inorganic base, e.g. an alkali metal phosphate such as potassium phosphate.

Moreover, a compound of formula (I) wherein R³ represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R³ represents optionally substituted heteroaryl by treatment with the appropriate tri-rø-butyltin(IV)-substituted heteroaromatic compound, e.g. 2-(tributylstannanyl)thiazole, in the presence of a transition metal catalyst. A suitable transition metal catalyst is tetrakis(triphenylphosphine)- palladium(O), in which case the reaction is conveniently effected in the presence of lithium chloride. A compound of formula (I) wherein R³ represents benzyloxy may be converted into the corresponding compound wherein R³ represents hydroxy by treatment with a hydrogenation catalyst, e.g. 10% palladium on charcoal, ideally under transfer hydrogenation conditions, e.g. in the presence of ammonium formate. A compound of formula (I) wherein R³ represents hydroxy may be converted into the corresponding compound wherein R³ represents an optionally substituted Ci_-6 alkoxy, aryl(Ci_-6)alkoxy or heteroaryl(Ci_-6)alkoxy moiety, e.g. 2-methoxyethoxy or 3-(l,3-dioxo- isoindol-2-yl)propoxy, by treatment with the appropriate alkylating agent, e.g. an alkyl halide, typically an alkyl bromide, such as l-bromo-2-methoxyethane or 2-(3-bromo- propyl)isoindole- 1 ,3 -dione, typically in the presence of a base, e.g. an alkali metal carbonate such as caesium carbonate.

A compound of formula (I) wherein R³ represents hydroxymethyl may be converted into the corresponding compound wherein R³ represents formyl (-CHO) by treatment with an oxidising agent, which may suitably be manganese dioxide. A compound of formula (I) wherein R³ represents -CHO may be converted into the corresponding compound wherein R³ represents -CH₂NR^bR^c by treatment with the appropriate compound of formula H-NR^bR^c in the presence of a reducing agent, which may suitably be polymer-supported cyanoborohydride (PS-BH₃CN). A compound of formula (I) wherein R³ represents -CHO may be converted into the corresponding compound wherein R³ represents lH-imidazol-2-yl by treatment with glyoxal and ammonia.

A compound of formula (I) wherein R³ represents -COCH₃ may be converted into the corresponding compound wherein R³ represents isopropylcarbonyl or tert-butyl- carbonyl by treatment with iodomethane in the presence of lithium bis(trimethylsilyl)- amide.

A compound of formula (I) wherein R³ contains a -S- moiety may be converted into the corresponding compound wherein R³ contains a -S(O)- (sulfinyl) moiety by treatment with 3-chloroperoxybenzoic acid (MCPBA). In the appropriate circumstances, prolonged treatment with MCPBA may give rise to the corresponding compound wherein R³ contains a -S(O)₂- (sulfonyl) moiety.

A compound of formula (I) wherein R³ contains a cyano moiety may be converted into the corresponding compound wherein R³ contains an aminocarbonyl or carboxy moiety by treatment with hydrogen peroxide and a base, e.g. an inorganic base which may suitably be an alkali metal hydroxide, e.g. sodium hydroxide.

A compound of formula (I) wherein R⁵ represents hydrogen may be converted into the corresponding compound wherein R⁵ represents C_1-6 alkyl, e.g. methyl, by standard alkylation procedures, e.g. by treatment with an alkylating agent such as iodomethane in the presence of a base such as sodium hydride; or by treatment with a carbonyl compound such as formaldehyde in the presence of a reducing agent such as sodium cyano- borohydride.

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 in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3^rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds according to the invention. The compounds in accordance with this invention potently inhibit the activity of human PDKα and/or PDKβ and/or PDKγ and/or POKδ.

Enzyme Inhibition Assays

Measurement of the ability of compounds to inhibit the lipid kinase activity of the four class 1 PI3 kinase isoforms (α, β, γ and δ) was performed using a commercially available homogeneous time-resolved fluorescence assay as described by Gray et al., Anal. Biochem., 2003, 313, 234-245, according to the manufacturer's instructions (Upstate). All assays were performed at 2 μM ATP and a concentration of purified class 1 PI3 kinase known to generate product within the linear range of the assay. Dilutions of inhibitor in DMSO were added to the assay and compared with assays run in the presence of 2% (v/v) DMSO alone (100% activity). The concentration of inhibitor required to inhibit the enzyme activity by 50% is quoted as the ICs₀.

When tested in the above assay, the compounds of the accompanying Examples were all found to possess IC₅₀ values for inhibition of activity of human PI3Kα and/or PDKβ and/or PDKγ and/or PDKδ of 50 μM or better.

EXAMPLES

Abbreviations

DCM: dichloromethane EtOAc: ethyl acetate

DMF: N,jV-dimethylformamide Et₂O: diethyl ether

DMSO: dimethylsulphoxide MeOH: methanol THF: tetrahydrofuran MeCN: acetonitrile

DMAP: 4-(dimethylamino)pyridine TEA: triethylamine

DABCO: l,4-diazabicyclo[2.2.2]octane Pd(OAc)₂: palladium(II) acetate

DIPEA: Λζ JV-diisopropylethylamine EtOH: ethanol «-BuOH: n-butanol AcOH: acetic acid

HOBT: 1-hydroxybenzotriazole hydrate LiHMDS: lithium bis(trimethylsilyl)amide

TBME: ter t-buty\ methyl ether TBAF: tetrabutylammonium fluoride

PS-CDI: polymer-supported carbodiimide PS-NCO: polymer-supported isocyanate

SiO₂: silica r.t: room temperature br: broad h: hour

M: mass brine: saturated aqueous sodium chloride solution

DMF. DBA: ΛζiV-dimethylfbrmamide di-tert-butyl acetal

EDC : 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide HATU : 2-( 1 H-7-azabenzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyl uronium hexafluorophosphate

XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Pd₂(dba)₃ : tris(dibeπzylideneacetone)dipalladium(0)

PS-BH₃CN: polymer-supported cyanoborohydride HPLC: High Performance Liquid Chromatography

LCMS: Liquid Chromatography Mass Spectrometry

ES+: Electrospray Positive Ionisation

Analytical Conditions All NMRs were obtained either at 300 MHz or 400 MHz.

Compounds were named with the aid of MDL ISIS™/Draw version 2.5 SP 2. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

Compound purities were determined by LCMS using Method 1 or 2 below. Preparative HPLC for compounds that required it was performed using Method 3 or 4 below.

Method 1: Waters XBridge, C 18, 2.1 x 20 mm, 2.5 μm column. Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% mobile phase A + 0.1% formic acid Gradient program (flow rate 1.0 niL/min, column temperature 4O⁰C):

Time A% B% 0.00 95.0 5.0

4.00 5.0 95.0

5.00 5.0 95.0

5.10 95.0 5.0

Method 2: Waters XBridge, C 18, 2.1 x 20 mm, 2.5 μm column.

Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% solvent A2 + 0.1% ammonia solution Gradient Program (flow rate 1.0 mL/min, column temperature 4O⁰C):

Time A% B% 0.00 95.0 4.9

4.00 5.0 95.0 5.00 5.0 95.0 5.10 95.0 4.9

Method 3: Luna C18, 21.2 mm, 5 mm column, pH 2.5. Mobile phase A: 99.92% water and 0.08% formic acid. Mobile phase B: 99.92% MeCN and 0.08% formic acid. Gradient program (flow rate 25 mL/min, column temperature ambient): variable gradient.

Method 4: Waters XBridge Prep MS Cl 8 ODB, 30 x 50 mm, 5 μm column. Mobile phase A: water. Mobile phase B: MeCN. Mobile Phase C: NH₄HCO₃ in water (40g/5L). Gradient program (flow rate 35 mL/min -→ 60 mL/min):

Time A% B% C% flow rate

0.00 85.0 5.0 10.0 35

1.00 85.0 5.0 10.0 35 7.00 80.0 20.0 0.0 35

7.50 5.0 95.0 0.0 35

9.00 5.0 95.0 0.0 35

9.10 5.0 95.0 0.0 60 12..00 5.C ) 95.0 0.0 60

12. .50 90 .0 10.0 0.0 35

13.00 85 .0 5.0 10. 0 35

16. .00 85. .0 5.0 10. 0 35

INTERMEDIATE 1

(5^-3-[5-(DiniethylcarbamoylV2-(trimethylsilanylVlH-indol-3-ylmethyllmorpholine-4- carboxylic acid tert-butγl ester To a stirred solution of 4-amino-3-iodo-Λ^7V-dimethylbenzamide (6.70 g, 23.10 mmol) in DMF (100 mL) was added (S)-3-[3-(trimethylsilanyl)prop-2-ynyl]morpholine- 4-carboxylic acid tert-butyl ester (6.86 g, 23.10 mmol), LiCl (0.97 g, 23.10 mmol) and Na₂CO₃ (4.90 g, 46.21 mmol). The reaction mixture was then degassed before Pd(OAc)₂ (0.26 g, 2.31 mmol) was added and the mixture further degassed. The solution was heated to 100⁰C for 16 h. After cooling to room temperature, the solids were removed by filtration through celite and the remaining solution was diluted with DCM (250 mL), washed with brine (2 x 250 mL), dried (sodium sulphate), filtered and concentrated in vacuo to give a crude oil. Purification by column chromatography (SiO₂, 20-60% EtOAc/hexanes) gave the title compound (7.53 g, 71%) as an orange solid. 6_Η (CDCl₃) 8.02 (s, 1Η), 7.92 (s, 1Η), 7.35 (d, J 8.3 Hz, IH), 7.32-7.27 (m, IH), 4.33-4.23 (m, IH), 3.99-3.79 (m, 2H), 3.69-3.60 (m, IH), 3.52-3.39 (m, 2H), 3.38-3.26 (m, 2H), 3.07 (s, 6H), 2.96 (s, IH), 1.45 (s, 9H), 0.43 (s, 9H). LCMS (ES+) 460 (M+H)⁺.

INTERMEDIATE 2

(^-3-r5-(Dimethylcarbamoyl)-l-methyl-2-(trimethylsilanylVlH-indol-3-ylmethyll- morpholine-4-carboxylic acid fert-butyl ester

Intermediate 1 (7.53 g, 16.41 mmol) was dissolved in THF (100 mL), cooled to -78°C and treated with methyl iodide (3.49 g, 24.62 mmol). LiHMDS (IM in THF, 18 mL, 18.00 mmol) was added and the reaction mixture was stirred at -78⁰C for 30 minutes. After warming to room temperature the mixture was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride solution (2 x 100 mL), the organic phase dried (sodium sulphate) and concentrated in vacuo. Purification by column chromatography (SiO₂, 20-60% EtOAc/hexanes) yielded the title compound (5.60 g, 72%) as a pale brown foam. δ_H (CDCl₃) 8.01-7.96 (m, IH), 7.44-7.38 (m, IH), 7.32 (s, IH), 4.28-4.21 (m, IH), 3.97 (dd, J 10.9, 2.0 Hz, IH), 3.90 (s, 3H), 3.69-3.46 (m, 2H), 3.40-3.31 (m, 2H), 3.15 (s, 6H), 3.00 (dd, J 13.6, 3.3 Hz, 2H), 1.86 (s, IH), 1.52 (s, 9H), 0.56 (s, 9H). LCMS (ES+) 474 (M+H)⁺.

INTERMEDIATE 3

l-Methyl-S-rffl-moφholin-S-ylmethyll-lH-indole-S-carboxylic acid dimethylamide Intermediate 2 (5.60 g, 11.84 mmol) was dissolved in MeOH (20 niL) and treated with 4M HCl in 1,4-dioxane (50 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and then partitioned between ethyl acetate (100 mL) and sodium hydrogencarbonate solution (100 mL). The aqueous layer was washed with DCM (3 x 100 mL). The combined organic layers were dried (sodium sulphate) and concentrated in vacuo yielding the title compound (3.58 g, 100%) as a brown oil. δ_Η (CDCl₃) 7.74 (s, IH), 7.33 (m, 2H), 6.97 (s, IH), 4.15-4.07 (m, IH), 3.89 (dd, J 10.9, 2.5 Hz, IH), 3.85-3.77 (m, 4H), 3.55 (td, J 10.6, 3.5 Hz, IH), 3.30 (t, J 9.9 Hz, IH), 3.12 (s, 6H), 2.90-2.79 (m, 3H), 2.63 (dd, J 14.1, 9.1 Hz, IH). LCMS (ES+) 302 (M+H)⁺.

INTERMEDIATE 4

ό-CAcetylaminoinicotinic acid

6-Aminonicotinic acid (1 g, 7.24 mmol) was dissolved in pyridine (30 mL) and treated with acetic anhydride (0.81 mL, 7.96 mmol). The reaction mixture was heated at 13O⁰C for 16 h. After cooling, the mixture was stirred at room temperature for 2 h. A precipitate was formed, which was filtered and dried on a freeze drier, yielding the title compound (641 mg, 49%) as a white solid. δ_H (d₆-DMSO) 13.08 (br s, IH), 10.82 (s, IH), 8.82-8.80 (m, IH), 8.24 (dd, J8.6, 2.3 Hz, IH), 8.17 (d, J8.6 Hz, IH), 2.13 (s, 3H). LCMS (ES+) 181 (M+H)⁺. INTERMEDIATE 5

2-(Acetylamino)thiazole-5-carboxylic acid

2-Amino-l,3-thiazole-5-carboxylic acid (1 g, 6.94 mmol) was dissolved in pyridine (30 mL) and treated with acetic anhydride (722 mg, 7.63 mmol). The reaction mixture was heated at 13O⁰C for 16 h. After cooling, the mixture was stirred at room temperature for 2 h. A precipitate was formed, which was filtered and dried on a freeze drier, yielding the title compound (920 mg, 71%) as a white solid. δ_H (αVDMSO) 13.04 (br s, IH), 12.45 (s, IH), 8.04 (s, IH), 2.19 (s, 3H). LCMS (ES+) 187 (M+H)⁺.

INTERMEDIATE 6

(S)-3 - \5 -Chloro-2-(trimethylsilanvD- 1 H-indol-3 - ylmethyllmoφholine-4-carboxylic acid terf-butyl ester Prepared from 4-chloro-2-iodoaniline and (5)-3-[3-(trimethylsilanyl)prop-2- ynyl]morpholine-4-carboxylic acid tert-butyl ester using the procedure described for Intermediate 1 and the method described in WO 2008/001076.

INTERMEDIATE 7

(yt-S-fS-fo-TolvD^-ftrimethylsilanvD-lH-indol-S-ylmethyllmorpholine^-carboxylic acid tgrt-butyl ester

To a stirred solution of Intermediate 6 (224 mg, 530 μmol) in rc-butanol (4 mL) were added ø-tolylboronic acid (108 mg, 795 μmol), potassium phosphate (225 mg, 1.06 mmol), XPhos (10 mg, 21 μmol) and tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.3 μmol). The reaction mixture was degassed, heated at reflux overnight, cooled and partitioned between DCM and water. The organic layer was separated, dried (magnesium sulphate), and concentrated in vacuo to afford a yellow oil which was chromatographed on silica gel to afford the title compound (223 mg, 88%) as a colourless oil. 6_Η (CDCl₃) 8.16-7.95 (m, 1Η), 7.97-7.57 (m, 1Η), 7.52-6.98 (m, 6Η), 4.48-4.28 (m, IH), 4.27-4.05 (m, IH), 4.05-3.85 (m, 2H), 3.84-3.64 (m, IH), 3.61-3.24 (m, 4H), 3.13-2.91 (m, IH), 2.31 (m, 2H), 1.35-1.25 (m, 9H), 0.47 (m, 9H). LCMS (ES+) 479.2 (M+H)⁺. INTERMEDIATE 8

(^-3-ri-Methyl-5-ro-tolylV2-(trimethylsilanylVlH-indol-3-ylmethyl1morpholine-4- carboxylic acid tgrt-butyl ester To a stirred solution of Intermediate 7 (223 mg, 466 μmol) in THF (5 mL) at -

78°C were added iodomethane (87 μL, 1.40 mmol) and LiHMDS (1.0M, 700 μL). The reaction mixture was stirred at r.t. for 1 h and partitioned between brine and Et₂O. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo, to afford the title compound (265 mg, 100%) as a colourless oil which was used without further purification in the next reaction. LCMS (ES+) 493.2 (M+H)⁺.

INTERMEDIATE 9

(5^r)-3-[5-(4-Fluorophenyl)-2-(trimethylsilanyl)-lH-indol-3-ylmethyllmorpholine-4- carboxylic acid tert-butyl ester

To a stirred solution of Intermediate 6 (322 mg, 762 μmol) in w-butanol (6 mL) were added 4-fluoroboronic acid (160 mg, 1.14 mmol), potassium phosphate (323 mg, 1.52 mmol), XPhos (14.5 mg, 30 μmol) and tris(dibenzylideneacetone)dipalladium(0) (7 mg, 7.6 μmol). The reaction mixture was degassed, heated at reflux for 4 h, cooled and partitioned between diisopropyl ether and water. The organic layer was separated, washed with brine, dried (magnesium sulphate) and concentrated in vacuo to afford the title compound (574 mg, 100%) as a yellow oil which was used without further purification in the next reaction. LCMS (ES+) 479.2 (M+H)⁺.

INTERMEDIATE 10

5 -(4-FluorophenylV3 - [CSVinorpholin-S -ylmethyl] - 1 H-indole

Intermediate 9 (574 mg, 760 μmol) was dissolved in HCl (4M solution in 1,4- dioxane). After 3 h the solution was concentrated in vacuo, the residue dissolved in DCM (5 mL) and shaken with aqueous sodium carbonate. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo to afford the title compound (275 mg, 100%) as a yellow oil which was used without further purification in the next reaction. LCMS (ES+) 311.2 (M+H)⁺. INTERMEDIATES 11 TO 13

Prepared using the procedures described for Intermediates 1 to 3 and the methods described in WO 2008/001076.

Intermediate 11: l-Methyl-3-[(S)-moφholin-3-ylmethyl]-5-phenyl-lH-indole Intermediate 12: l-Methyl-5-(2-methylimidazol-l-yl)-3-[(5)-morpholin-3-ylmethyl]-lH- indole

Intermediate 13: (5)-3-(5-Benzyloxy-l-methyl-lH-indol-3-ylmethyl)morpholine-4- carboxylic acid tert-butyl ester

INTERMEDIATE 14

(6-Chloropyridin-3-yl)-{(5^-3-r3-(^'trimethylsilanyl)prop-2-vnyl]morpholin-4-vU- methanone

To a stirred solution of (5)-3-[3-(trimethylsilanyl)prop-2-ynyl]morpholine (2.9 g, 12.4 mmol) and 6-chloronicotinoyl chloride (2.18 g, 12.4 mmol) in DCM (30 niL) at 0- 5°C was added triethylamine (1.8 mL, 24.8 mmol). The reaction was stirred at r.t. for 2 h and then partitioned between ethyl acetate (50 mL) and brine (50 mL). The organic layer was separated, dried (MgSO₄) and concentrated in vacuo. The resulting oil was chromatographed (SiO₂, 0-50% EtOAc/hexanes), yielding the title compound (830 mg, 100%) as a colourless oil. LCMS (ES⁺) 337 (M+Η)⁺.

INTERMEDIATE 15

(6-Methoxypyridin-3-yl)-{(5^f)-3-[3-(trimethylsilanyl)prop-2-vnyl1morpholin-4-vU- methanone

To a stirred solution of (5)-3-[3-(trimethylsilanyl)prop-2-ynyl]morpholine (500 mg, 2.5 mmol) and 6-methoxynicotinoyl chloride (572 mg, 2.75 mmol) in DCM (10 mL) at 0-5⁰C was added triethylamine (1.1 mL, 7.5 mmol). The reaction was stirred at r.t. for

1 h and then partitioned between ethyl acetate (20 mL) and brine (20 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting oil was chromatographed (SiO₂, 0-50% EtOAc/hexanes), yielding the title compound (755 mg, 91%) as a yellow oil. LCMS (ES⁺) 333 (M+H)⁺.

INTERMEDIATE 16

(S)-3 - \5 -(DimethylaminomethylV 1 -methyl- 1 H-indol-3 - ylmethyl] morpholine-4- carboxylic acid tert-butyl ester

To a stirred solution of (5)-3-[5-(dimethylcarbamoyl)-l-methyl-lH-indol-3- ylmethyl]morpholine-4-carboxylic acid tert-butyl ester (250 mg, 0.63 mmol) in TΗF (10 mL) at 0⁰C was added lithium aluminium hydride (125 mg, 3.1 mmol). The reaction mixture was stirred at r.t. for 3 h, then quenched with water (625 μL) and stirred for 15 minutes. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the title compound (402 mg) as a brown oil. LCMS (ES⁺) 388 (M+Η)⁺.

INTERMEDIATE 17

( 1 -Methyl-3 - r(35Vmorpholin-3 -ylmethyll- 1 H-indol-5 -yl } methanol

To a stirred solution of methyl l-methyl-3-[(35)-morpholin-3-ylmethyl]-lH- indole-5-carboxylate (WO 2008/001076, Intermediate 77; 200 mg, 0.69 mmol) in TΗF (10 mL) at 0⁰C was added lithium aluminium hydride (130 mg, 3.45 mmol). The reaction mixture was stirred at r.t. for 16 h, then quenched with water (600 μL) and stirred for 30 minutes. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the title compound (260 mg) as a colourless oil. LCMS (ES⁺) 261 (M+Η)⁺.

INTERMEDIATE 18

[(y)-3-(5-Hvdroxymethyl-l-methyl-lH-indol-3-ylmethvπmorphoUn-4-yl]-(6-methoxy- pyridin-3 - yl)-methanone

To a stirred solution of Intermediate 17 (260 mg, 1.0 mmol) in DCM (5 mL) at O⁰C were added triethylamine (285 μL, 2.0 mmol) and 6-methoxynicotinoyl chloride (120 mg, 0.7 mmol). The reaction mixture was stirred at r.t. for 1 h. The mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was dried (phase separator), concentrated in vacuo and chromatographed (SiO₂, 2:1 EtOAc: hexanes), yielding the title compound (210 mg, 76%) as a colourless oil. LCMS (ES⁺) 396 (M+H)⁺.

INTERMEDIATE 19

3 - [6SV4-f 6-Methoxypyridine-3-carbonyl)morpholin-3 -ylmethyll - 1 -methyl- 1 H-indole-5- carbaldehyde To a stirred solution of Intermediate 18 (1.03 g, 2.6 mmol) in DCM (20 mL) was added activated MnO₂ (2.26 g, 26 mmol). The reaction mixture was stirred for 18 h.

More MnO₂ (226 mg, 2.6 mmol) was added and the reaction stirred for 1 h. The reaction mixture was filtered through celite and concentrated in vacuo to give the title compound

(919 mg, 90%) as a colourless oil. LCMS (ES⁺) 394 (M+Η)⁺.

INTERMEDIATE 20

l-Methyl-3-r(3,y)-morDholin-3-ylmethyl1-5-nitro-lH-indole

Prepared using the method described in WO2008/001076.

INTERMEDIATE 21

IY5V3 -(5 -Amino- 1 -methyl- lH-indol-3 -ylmethyl)morpholin-4-yl]-(6-methoxypyridin-3- yl)-methanone To a stirred solution of Example 306 (3.1 g, 7.56 mmol) in MeOH (200 mL) was added zinc (3.0 g, 4.59 mol) and cone. HCl (3 mL). The reaction mixture was heated at 5O⁰C for 30 minutes until a clear solution was obtained. The excess zinc was removed by filtration and the solution was concentrated in vacuo. The residue was partitioned between saturated sodium carbonate solution (200 mL) and DCM (200 mL). The aqueous layer was washed with DCM (2 x 100 mL). The organic layers were combined, dried (sodium sulphate), filtered and concentrated in vacuo to yield the title compound (3.0 g, 100%) as a pale pink foam. δ_H (d₆-DMSO at 110⁰C) 8.05 (d, J 2.3 Hz, IH), 7.43 (dd, J8.6, 2.3 Hz, IH), 7.05 (d, J8.6 Hz, IH), 6.82 (s, IH), 6.71 (d, J8.6 Hz, IH), 6.57 (dd, J8.6, 2.0 Hz, IH), 6.51 (s, IH), 4.25-4.18 (m, IH), 4.12-4.03 (m, 2H), 3.95-3.89 (m, 4H), 3.85-3.75 (m, 2H), 3.63 (s, 3H), 3.57 (dd, J 11.4, 3.0 Hz, IH), 3.50-3.43 (m, 2H), 3.10 (dd, J 14.4, 8.3 Hz, IH), 2.99-2.93 (m, IH). LCMS (ES⁺) 381 (M+H)⁺.

INTERMEDIATE 22

1 - { 3 - [(^-4-(6-Methoxypyridine-3 -carbonvDmorpholin-S - ylmethyll -2-(trimethylsilanvD- 1 H-indol-5- yl } ethanone

To a stirred degassed solution of Intermediate 15 (2.0 g, 6.0 mmol) in DMF (25 mL) were added l-(4-amino-3-iodophenyl)ethanone (1.6 g, 6.0 mmol), Pd(OAc)₂ (67 mg, 0.3 mmol), LiCl (253 mg, 6.0 mmol) and sodium carbonate (1.28 g, 12.0 mmol). The reaction mixture was heated at 90⁰C for 21 h, then filtered and partitioned between water (50 mL) and ethyl acetate (150 mL). The organic layer was washed with water (5 x 40 mL) and brine (40 mL), dried (sodium sulphate), concentrated in vacuo and chromatographed (SiO₂, 0-25% ethyl acetate/hexanes) to give the title compound (1.15 g, 41%) as a white solid. δ_Η (d₆-DMSO at 110⁰C) 10.41 (d, J0.8 Hz, IH), 8.08 (d, J0.8 Hz, IH), 7.76 (m, IH), 7.48 (dd, J8.6, 1.5 Hz, IH), 7.21 (d, J8.6 Hz, IH), 7.19-7.15 (m, IH), 6.46 (d, J8.6 Hz, IH), 4.28-4.19 (m, IH), 3.73 (dd, J 10.9, 2.8 Hz, IH), 3.67 (s, 3H), 3.61-3.54 (m, IH), 3.50 (m, IH), 3.44-3.25 (m, 3H), 3.18 (dd, J 14.1, 8.8 Hz, IH), 2.96 (dd, J 14.1, 6.3 Hz, IH), 2.33 (s, 3H), 0.16 (m, 9H). LCMS (ES⁺) 466 (M+H)⁺.

INTERMEDIATE 23

(6-Methylpyridin-3-yl)-{(5^-3-r3-(trimethylsilanyl^')prop-2-vnyl1morpholin-4-yU- methanone

To a stirred solution of (5)-3-[3-(trimethylsilanyl)prop-2-ynyl]morpholine (6.11 g, 31 mmol), 6-methylnicotinic acid (4.25 g, 31 mmol), HOBT (4.74 g, 31 mmol) and 4- methylmorpholine (6.8 mL, 62 mmol) in DMF (5OmL) was added EDC (5.95 g, 31 mmol). The reaction mixture was stirred at r.t. for 16 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic layer was washed with brine (3 x 100 mL), separated, dried (sodium sulphate) and concentrated in vacuo. The residue was chromatographed (SiO₂, 50-100% EtOAc/ hexanes), yielding a mixture of product and HOBT. This was dissolved in EtOAc (50 mL), washed with 2M sodium carbonate solution (3 x 50 mL) and brine (5OmL), dried (sodium sulphate) and concentrated in vacuo to yield the title compound (9.16 g, 93%) as a brown oil. δ_H (CDCl₃) 8.46 (d, J 1.9 Hz, IH), 7.57 (dd, J7.9, 1.9 Hz, IH), 7.09 (d, J7.9 Hz, IH), 3.77 (m, 3H), 3.48 (dd, J 11.7, 2.8 Hz, IH), 3.40-3.32 (IH, m), 3.21 (br s, 2H), 2.70 (dd, J 17.0, 7.9 Hz, IH), 2.57 (dd, J 16.8, 7.9 Hz, IH), 2.47 (s, 3H), 0.00 (m, 9H). LCMS (ES⁺) 317 (M+H)⁺.

INTERMEDIATE 24

S-Chloropropanesulfonic acid {3-r(»SV4-(6-methoxypyridine-3-carbonyl)morpholin-3- ylmethyl] - 1 -methyl- 1 H-indol-5 -yl } amide

To a stirred solution of Intermediate 21 (150 mg, 0.395 mmol) in DCM (5 mL) was added TEA (83 μL, 0.593 mmol) followed by 3-chloropropanesulfonyl chloride (48 μL, 0.395 mmol). The reaction mixture was stirred at r.t. for 2 h, then diluted with DCM (5 mL) and washed with brine (2 x 1OmL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was chromatographed (SiO₂, 60-100% EtOAc/hexanes), yielding the title compound (142 mg, 69%) as a white solid. δ_Η (d₆-DMSO at 110⁰C) 9.03 (s, IH), 7.94-7.91 (m, IH), 7.41-7.38 (m, IH), 7.37-7.30 (m, 2H), 7.08 (dd, J8.6, 1.5 Hz, IH), 7.03 (s, IH), 6.68 (d, J 8.3 Hz, IH), 4.34-4.26 (m, IH), 3.94-3.87 (m, 4H), 3.84-3.74 (m, 2H), 3.73 (s, 3H), 3.72-3.68 (m, 2H), 3.61 (dd, J 11.6, 3.3 Hz, IH), 3.56-3.47 (m, 2H), 3.19-3.10 (m, 4H), 2.24-2.16 (m, 2H). LCMS (ES⁺) 521 (M+H)⁺.

INTERMEDIATE 25

7-Acetyl-3 - [(5^-4-(6-methylpyridine-3 -carbonyl)morpholin-3 -ylmethyl] -2- (ttimethylsilanviyiH-indole-5-carboxylic acid methyl ester

To a stirred degassed solution of Intermediate 23 (500 mg, 1.58 mmol), 3-acetyl- 4-amino-5-iodobenzoic acid methyl ester (506 mg, 1.58 mmol), LiCl (67 mg, 1.58 mmol) and sodium carbonate (335 mg, 3.16 mmol) in DMF (20 mL) was added Pd(OAc)₂ (18 mg, 0.08 mmol). The reaction mixture was further degassed, then heated at 9O⁰C for 16 h. The reaction mixture was cooled and partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with water (3 x 50 mL), dried (sodium sulphate), concentrated in vacuo and chromatographed (SiO₂, 60-100% ethyl acetate/ hexanes), to give the title compound (130 mg, 30%) as an off-white solid. LCMS (ES⁺) 505 (M+H)⁺.

INTERMEDIATE 26

7- Acetyl-3 -[(S)-4-(6-methylpyridine-3 -carbonyl)morpholin-3 -ylmethyll - 1 H-indole-5- carboxylic acid methyl ester

To a stirred solution of Intermediate 25 (130 mg, 0.299 mmol) in MeOH (5 mL) was added HCl (4M in 1,4-dioxane, 5 mL). The reaction mixture was stirred at r.t. for 4 h, then concentrated in vacuo. The residue was partitioned between 2M sodium carbonate solution (10 mL) and DCM (10 mL). The organic layer was dried (phase separator) and concentrated in vacuo, yielding the title compound (100 mg, 77%) as a brown foam. LCMS (ES⁺) 436 (M+Η)⁺.

INTERMEDIATE 27

7- Acetyl-3- [(5^f)-4-(6-methylpyridine-3 -carbonyl^')morpholin-3 -ylmethyll - 1 H-indole-5 - carboxylic acid To a stirred solution of Intermediate 26 (100 mg, 0.229 mmol) in MeOH (5 mL) and TΗF (5 mL) was added 2M NaOH solution (5 mL). The reaction mixture was heated at 50⁰C for 30 minutes, then concentrated in vacuo and passed down a Biotage 103 resin to remove any inorganic salts. The resin was washed with MeOH (25 mL). The resulting filtrate was concentrated in vacuo, yielding the title compound (-100 mg, 100%) as a colourless oil. LCMS (ES⁺) 422 (M+Η)⁺.

INTERMEDIATE 28

(4-Amino-3-iodophenyl)-phenyl-methanone To a stirred solution of (4-aminophenyl)-phenyl-methanone (3 g, 15 mmol) and calcium carbonate (2.4 g, 15 mmol) in methanol (50 mL) and water (10 mL) was added ICl (3.4 g, 15 mmol). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. The brown residue was partitioned between EtOAc (100 mL) and saturated sodium bisulphite solution (100 mL). The organic layer was dried (sodium sulphate), filtered and concentrated in vacuo. The residue was washed with DCM (50 mL), yielding the title compound (1.1 g, 23%) as a pale grey solid. δ_H (d₆-DMSO) 7.99 (d, J 2.1 Hz, IH), 7.67-7.58 (m, 4H), 7.57-7.44 (m, 3H), 6.80 (d, J8.7 Hz, IH), 6.24-6.16 (m, 2H). LCMS (ES⁺) 324 (M+H)⁺.

INTERMEDIATE 29

{(S)-3 - r5-Benzoyl-2-(trimethylsilanylV 1 H-indol-3 -ylmethylimorpholin-4-yl } -(6- methox yp yridin-3 -yl)-methanone

To a stirred solution of Intermediate 28 (179 mg, 0.5 mmol) in DMF (3 mL) were added Intermediate 15 (170 mg, 0.5 mmol), LiCl (20 mg, 0.5 mmol) and sodium carbonate (150 mg, 1.0 mmol). The reaction mixture was then degassed before Pd(OAc)₂ (7 mg, 0.025 mmol) was added and the mixture further degassed. The solution was heated to 9O⁰C for 16 h. After cooling to r.t., the reaction mixture was partitioned between DCM (50 mL) and water (20 mL). The organic layer was separated and washed with water (4 x 20 mL), dried (sodium sulphate), filtered and concentrated in vacuo. The dark oil was purified by column chromatography (SiO₂, 0-100% EtOAc/hexanes) to give the title compound (208 mg, 78%) as a colourless oil. LCMS (ES⁺) 528 (M+Η)⁺.

INTERMEDIATE 30

yl)-methanone Intermediate 13 (975 mg, 2.24 mmol) was dissolved in 4M HCl in 1,4-dioxane

(15 mL). After 1 h the solution was concentrated in vacuo and the residue partitioned between DCM (10 mL) and sodium carbonate solution (20 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. To the brown oil in DCM (10 mL) were added 6-methylnicotinic acid (337 mg, 2.46 mmol), ΗOBT (342 mg, 2.24 mmol), DIPEA (795 μL, 4.5 mmol) and EDC (688 mg, 3.6 mmol). The reaction mixture was stirred at r.t. for 16 h, then shaken with water (20 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo, yielding the title compound (1.0 g, 98%) as a brown oil. The crude product was elaborated further without additional purification. LCMS (ES⁺) 456 (M+H)⁺.

INTERMEDIATE 31

{(^-β-rS-dVlethanesulfonvD-Σ-faimethylsilanylVlH-indol-S-ylmethylimorpholin^-vU- (6-methoxypyridin-3-yl^*)-methanone

To a stirred solution of 2-iodo-4-(methanesulfonyl)phenylamine (158 mg, 0.53 mmol) in DMF (3 mL) were added Intermediate 15 (175 mg, 0.53 mmol), LiCl (22 mg, 0.53 mmol) and sodium carbonate (112 mg, 1.6 mmol). The reaction mixture was then degassed before Pd(OAc)₂ (6 mg, 0.025 mmol) was added and the mixture further degassed. The solution was heated to 100⁰C for 2 h. After cooling to r.t., the reaction mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated and washed with water (4 x 1OmL), dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-

100% EtOAc/hexanes) to give the title compound (107 mg, 40%) as a white solid. LCMS (ES⁺) 502 (M+H)⁺.

INTERMEDIATE 32

3-[(_>S^r)-4-(6-Methoxypyridine-3-carbonyl)morpholin-3-ylmethyl]-2-(trimethylsilanylVl//- indole-5 -sulfonic acid dimethylamide

To a stirred solution of 4-amino-iV,N-dimethyl-3-iodobenzenesulfonamide (173 mg, 0.53 mmol) in DMF (3 mL) were added Intermediate 15 (175 mg, 0.53 mmol), LiCl (22 mg, 0.53 mmol) and sodium carbonate (112 mg, 1.6 mmol). The reaction mixture was then degassed before Pd(OAc)₂ (6 mg, 0.025 mmol) was added and the mixture further degassed. The solution was heated to 100⁰C for 2 h. After cooling to r.t., the reaction mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated and washed with water (4 x 10 mL), dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-100% EtOAc/hexanes) to give the title compound (142 mg, 51%) as a white solid. LCMS (ES⁺) 530 (M+H)⁺. INTERMEDIATE 33

1 -Methyl-3 -[(S)-4-(6-methylpyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 H-indole-5- carboxylic acid To a stirred solution of Example 280 (2.86 g, 7.04 mmol) in MeOH (50 niL) was added 10% NaOH solution (2.5M, 10 mL). The reaction mixture was heated to reflux and stirred for 5 h. The reaction mixture was cooled to r.t., acidified with IM HCl and then concentrated in vacuo. The residue was washed with DCM to give a precipitate, which was washed with water and filtered. The resulting solid was washed with DCM (3 x 50 mL) and the combined organic layers were dried (sodium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-20% MeOH/ EtOAc) to give the title compound (2.52 mg, 91%) as a white solid. δ_Η (d₆-DMSO at 110⁰C) 8.18-8.13 (m, IH), 8.09-8.05 (m, IH), 7.77 (dd, J8.8, 1.5 Hz, IH), 7.40 (d, J8.6 Hz, IH), 7.27-7.21 (m, IH), 7.13 (s, IH), 7.07-7.01 (m, IH), 4.35-4.27 (m, IH), 3.97-3.91 (m, IH), 3.87-3.81 (m, 2H), 3.81-3.75 (m, 3H), 3.64 (dd, J 11.4, 3.0 Hz, IH), 3.50 (m, 2H), 3.19 (d, J7.6 Hz, 2H), 2.43 (s, 3H). LCMS (ES⁺) 394 (M+H)⁺.

INTERMEDIATE 34

{(^-3-[5-Bromo-2-(trimethylsilanyl)-lH-indol-3-ylmethyl1moφholin-4-yl|-(6-methoxy- pyridin-3 -ylVmethanone

To a stirred degassed solution of Intermediate 15 (332 mg, 1.0 mmol) in DMF (5 mL) were added 4-bromo-2-iodoaniline (298 mg, 1.0 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), LiCl (42 mg, 1.0 mmol) and sodium carbonate (212 mg, 2.0 mmol). The reaction mixture was heated at 100⁰C for 2 h, then filtered and partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was washed with water (5 x 40 mL) and brine (40 mL), dried (sodium sulphate) and concentrated in vacuo to give the title compound (282 mg, 56%) as a brown solid. LCMS (ES⁺) 503 (M+H)⁺. INTERMEDIATE 35

[(5^-3-(5-Bromo-l//-indol-3-ylmethyl^')morpholin-4-yll-(6-methoxypyridin-3-yl)- methanone To a stirred solution of Intermediate 34 (282 mg, 0.56 mmol) in MeOH (5 mL) was added HCl (4M in 1 ,4-dioxane, 5 mL). The reaction mixture was stirred at r.t. for 4 h, then concentrated in vacuo. The residue was partitioned between 2M sodium carbonate solution (10 mL) and DCM (10 mL). The organic layer was dried (phase separator) and concentrated in vacuo, yielding the title compound (104 mg, 43%) as an off-white foam. LCMS (ES⁺) 431 (M+H)⁺.

INTERMEDIATE 36

\(S)-3 -(5 -Hydroxymethyl- 1 -methyl- 1 H-indol-3 - ylmethyl)morpholin-4- yll -(6-methyl- pyridin-3 -yl)-methanone

To a stirred solution of Intermediate 17 (3.33 g, 12.8 mmol) in DCM (50 mL) at 0⁰C were added triethylamine (7.4 mL, 51.2 mmol) and 6-methylnicotinoyl chloride (3.07 mg, 12.8 mmol). The reaction mixture was stirred at r.t. for 30 minutes. The mixture was partitioned between DCM (50 mL) and water (100 mL). The organic layer was dried (phase separator), concentrated in vacuo and chromatographed (SiO₂, 5% MeOΗ/EtOAc), yielding the title compound (2.78 g, 57%) as a yellow solid. LCMS (ES⁺) 380 (M+Η)⁺.

INTERMEDIATE 37

l-Methyl-3-r(S^r)-4-(6-methylpyridine-3-carbonyl^>)morpholin-3-ylmethyll-lH-indole-5- carbaldehyde

To a stirred solution of Intermediate 36 (2.78 g, 7.34 mmol) in DCM (50 mL) was added activated MnO₂ (6.44 g, 73.4 mmol). The reaction mixture was stirred for 2 h, then filtered through celite and concentrated in vacuo to give the title compound (3.66 g, 100%) as a yellow oil. LCMS (ES⁺) 378 (M+Η)⁺. INTERMEDIATE 38

[(yi-S-CS-Amino-lH-indol-S-ylmethvDmorpholin^-yll-fό-methoxypyridin-S-yl)- methanone To a stirred solution of Example 372 (200 mg, 0.51 mmol) and zinc (300 mg, 4.59 mmol) in MeOH (13 mL) was added cone, hydrochloric acid (33 drops). The reaction mixture was stirred at 5O⁰C for 10 minutes and then allowed to cool to r.t. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was partitioned between DCM (25 mL) and saturated sodium carbonate solution (25 mL). A white precipitate began to form. NaOH pellets (4) were added and the reaction was stirred for 30 minutes. The aqueous layer was separated, then washed with DCM (2 x 50 mL) and 10% MeOH in DCM (2 x 50 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo, yielding the title compound (200 mg, 100%) as a beige foam. LCMS (ES⁺) 367 (M+H)⁺.

INTERMEDIATE 39

3-Chloropropanesulfonic acid {3-[(5^r)-4-(6-methoxypyridine-3-carbonyl)morpholin-3- ylmethyll - 1 H-indol-5 -yl } amide To a stirred solution of Intermediate 38 (428 mg, 1.17 mmol) in DCM (15 mL) was added triethylamine (0.25 mL, 1.76 mmol), followed by 3-chloropropanesulphonyl chloride (207 mg, 1.17 mmol). The reaction mixture was stirred at r.t. for 16 h. Additional 3-chloropropanesulphonyl chloride (62 mg, 0.35 mmol) was added and the reaction mixture stirred for 3 h. The reaction was not complete, so additional 3-chloro- propanesulphonyl chloride (41 mg, 0.23 mmol) and triethylamine (0.08 mL, 0.59 mmol) were added and the reaction mixture stirred for 40 minutes. The reaction was still not complete, so additional 3-chloropropanesulphonyl chloride (31 mg, 0.18 mmol) was added and the reaction mixture stirred for 40 minutes. The reaction mixture was partitioned between DCM (25 mL) and brine (2 x 40 mL). The combined aqueous layers were extracted with DCM (2 x 40 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 60-100% EtOAc/hexanes), yielding the title compound (291 mg, 49%) as a beige foam. δ_Η (d₆-DMSO at HO⁰C) 10.63-10.54 (m, IH), 8.98 (s, IH), 7.95 (d, J2.3 Hz, IH), 7.38 (s, IH), 7.35-7.29 (m, 2H), 7.08 (d, J2.0 Hz, IH), 7.02 (dd, J8.6, 2.0 Hz, IH), 6.66 (d, J8.3 Hz, IH), 4.36-4.29 (m, IH), 3.91 (d, J7.1 Hz, IH), 3.89 (s, 3H), 3.81 (m, IH), 3.78-3.73 (m, IH), 3.71 (t, J6.8 Hz, 2H), 3.61 (dd, J 11.4, 3.0 Hz, IH), 3.54-3.47 (m, 2H), 3.19-3.12 (m, 4H), 2.24-2.15 (m, 2H). LCMS (ES⁺) 507 (M+H)⁺.

INTERMEDIATE 40

lH-indol-5-vUbutyr amide

To a stirred solution of Intermediate 21 (150 mg, 0.39 mmol) in MeCN (5 mL) was added potassium carbonate (136 mg, 0.99 mmol), followed by 4-chlorobutyryl chloride (56 mg, 0.39 mmol). The reaction mixture was stirred at r.t. for 2 h, then partitioned between DCM (15 mL) and water (15 mL). The combined aqueous layers were extracted with DCM (2 x 15 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-0.5% MeOΗ/EtOAc), yielding the title compound (111 mg, 58%) as a white solid. δ_Η (d₆-DMSO at HO⁰C) 9.35-9.25 (m, IH), 7.95 (d, J2.0 Hz, IH), 7.61 (m, IH), 7.35-7.28 (m, 2H), 7.27-7.24 (m, IH), 6.98 (s, IH), 6.64 (d, J 8.3 Hz, IH), 4.32-4.26 (m, IH), 3.94-3.89 (m, IH), 3.89 (m, 3H), 3.85-3.76 (m, 2H), 3.75-3.72 (m, IH), 3.72-3.66 (m, 5H), 3.62 (dd, J 11.4, 3.0 Hz, IH), 3.49 (d, J9.1 Hz, 2H), 3.11 (d, J 7.6 Hz, 2H), 2.47 (d, J 7.3 Hz, IH), 2.15-2.06 (m, 2H). LCMS (ES⁺) 485 (M+H)⁺.

INTERMEDIATE 41

6-(2,2,2-Trifluoroethoxy)nicotinic acid

To a stirred solution of 2,2,2-trifluoroethanol (1.0 mL, 14 mmol) in THF (25 mL) was added sodium hydride (60% dispersion in oil, 0.56 g, 14 mmol). The reaction mixture was stirred at r.t. for 30 minutes prior to the addition of 6-chloronicotinic acid methyl ester (1.71 g, 10 mmol) in MeCN (5 mL). The reaction mixture was heated at 7O⁰C for 1.5 h, then partitioned between EtOAc (50 mL) and saturated ammonium chloride solution (50 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The resulting white solid was dissolved in THF (5 mL) and water (5 niL). Lithium hydroxide (200 mg) was added and the reaction mixture was stirred at r.t. for 2 h, then taken to pH 6 with HCl (2M aqueous). The reaction mixture was concentrated in vacuo, yielding the title compound (0.7 g, 32%) as a white solid. δ_H (de-DMSO) 8.62 (d, J 2.0 Hz, IH), 8.17 (dd, J8.6, 2.3 Hz, IH), 6.86 (d, J8.3 Hz, IH), 5.00 (q, J9.1 Hz, 2H). LCMS (ES⁺) 222 (M+H)⁺.

INTERMEDIATE 42

3 - [(35^-Morpholin-3 -ylmethyl]- 1 H-indole-5 -carboxylic acid dimethylamide Prepared using the method described in WO2008/001076.

INTERMEDIATE 43

(S)-3 - { 5 - rN-(2-Methoxyethyl)-N-methylcarbamoyll -2-(trimethylsilanyl)- 1 H-indol-3 - ylmethvUmorpholine-4-carboxylic acid tert-butγ\ ester

Methyl 3- { [(35)-4-(tert-butoxycarbonyl)morpholin-3-yl]methyl}-2- (trimethylsilyl)-lH-indole-5-carboxylate (WO 2008/001076, Intermediate 41; 446 mg, 1.0 mmol) was added portionwise to a solution of iV-(2-methoxyethyl)-iV-methylamine (356 μL, 4.0 mmol) and trimethylaluminium (1 mL, 2.0M in toluene) at O⁰C. The mixture was then warmed to r.t. and heated to reflux for 18 h. The reaction mixture was quenched with water and partitioned between TBME (10 mL) and 2M NaOH (10 mL, aqueous). The aqueous layer was extracted with TBME (2 x 10 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo to give the title compound (440 mg, 82%) as a yellow oil. LCMS (ES⁺) 504 (M+Η)⁺.

INTERMEDIATE 44

3 -[(35^r)-Morpholin-3-ylmethvn-l H-indole-5 -carboxylic acid N-(2-methoxyethyl)-iV- methylamide

The title compound was prepared from Intermediate 43 according to Method J and was isolated as a yellow oil. LCMS (ES⁺) 332 (M+Η)⁺. INTERMEDIATE 45

(5-Chloro-6-methoxypyridin-3 -vD- \(S)-3 -(5-hvdroxymethyl- 1 -methyl- 1 H-indol-3 - ylmethyl)morpholin-4- yli -methanone The title compound was prepared from Intermediate 17 according to Method F and was isolated as a colourless oil. LCMS (ES⁺) 412.

INTERMEDIATE 46

(iS^r)-3-r5-Amino-2-(trimethylsilanyl)-lH-indol-3-ylmethyl]morpholine-4-carboxylic acid tert-butyl ester

Prepared using the method described in WO2008/001076.

INTERMEDIATE 47

(5^-3-[5-(AcetylaminoV2-(trimethylsilanyl)-lH-indol-3-ylmethyl]morpholine-4- carboxylic acid tert-butyl ester

The title compound was prepared from Intermediate 46 and acetyl chloride according to Method D and was isolated as a colourless oil. LCMS (ES⁺) 446 (M+Η)⁺.

INTERMEDIATE 48

The title compound was prepared from Intermediate 47 according to Method J and was isolated as a colourless oil. LCMS (ES⁺) 274 (M+H)⁺.

INTERMEDIATE 49

(S)-3 - [5-(Methoxycarbonylamino)-2-(trimethylsilanylV 1 H-indol-3 -ylmethyl]morpholine- 4-carboxylic acid fert-butyl ester

The title compound was prepared from Intermediate 46 and methyl chloroformate according to Method D and was isolated as a colourless oil. LCMS (ES⁺) 462 (M+Η)⁺. INTERMEDIATE 50

{3-[(35^-Morpholin-3-ylmethyll-l//-indol-5-vUcarbamic acid methyl ester

The title compound was prepared from Intermediate 49 according to Method J and was isolated as a colourless oil. LCMS (ES⁺) 290 (M+H)⁺.

INTERMEDIATE 51

(S)-3- \5 -(Cyclopropanecarbonylamino)-2-(^'trimethylsilanylV 1 H-indol-3 -ylmethyl] - morpholine-4-carboxylic acid fert-butyl ester

The title compound was prepared from Intermediate 46 and cyclopropanecarbonyl chloride according to Method D and was isolated as a colourless oil. LCMS (ES⁺) 472 (M+H)⁺.

INTERMEDIATE 52

Cyclopropanecarboxylic acid {3-r(3.S^r)-morpholin-3-ylmethyl]-lH-indol-5-vUamide

The title compound was prepared from Intermediate 51 according to Method J and was isolated as a colourless oil. LCMS (ES⁺) 300 (M+H)⁺.

INTERMEDIATE 53

CSV3 - [5 -( 1.1 -Dioxo- 1 Λ6-isothiazolidin-2-ylV2-(trimethylsilanvn- 1 H-indol-3 -ylmethyll - morpholine-4-carboxylic acid fert-butyl ester To a stirred solution of Intermediate 46 (400 mg, 1.0 mmol) in DCM (5 mL) at

O⁰C were added triethylamine (276 μL, 2.0 mmol) and 3-chloropropanesulfonyl chloride (145 μL, 1.2 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting material was dissolved in MeCN (5 mL), potassium carbonate (350 mg, 2.5 mmol) was added and the reaction was heated at 8O⁰C for 1.5 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-1% MeOH/DCM), yielding a colourless oil. LCMS (ES⁺) 509 (M+H)⁺.

INTERMEDIATE 54

5-(l,l-Dioxo-lΛ6-isothiazolidin-2-ylV3-rGS)-morpholin-3-ylmethyl1-lH-indole

The title compound was prepared from Intermediate 53 according to Method J and was isolated as a colourless oil. LCMS (ES⁺) 336 (M+Η)⁺.

INTERMEDIATE 55

(5-Chloro-6-methoxypyridin-3-yl)-r(5^f)-3-(l-methyl-5-nitro-lH-indol-3-ylmethyl)- morpholin-4-yl] -methanone

The title compound was prepared from Intermediate 20 and 5-chloro-6-methoxy- nicotinic acid at r.t. according to Method A and was isolated as a yellow solid. LCMS (ES⁺) 445 (M+Η)⁺.

INTERMEDIATE 56

[(5^-3-(5-AmUiO-I -methyl- lH-indol-3-ylmethyl)morpholin-4-yl]-(5-chloro-6-methoxy- pyridin-3 -ylVmethanone

To a stirred solution of Intermediate 55 (1.1 g, 5.65 mmol) in AcOH (3 mL) was added zinc powder (1.1 g, 16.8 mmol). The reaction mixture was heated at 8O⁰C for 1 h.

The reaction mixture was cooled, quenched with water (50 mL) and saturated sodium carbonate solution (100 mL) and partitioned with EtOAc. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 1% TEA/EtOAc), yielding a red oil. LCMS

(ES⁺) 415 (M+Η)⁺. INTERMEDIATE 57

3-[(S)-4-(3-HvdroxybenzovDmorpholin-3-ylmethyll-l-methyl-l//-indole-5-carboxylic acid methyl ester The title compound was prepared from methyl 1 -methyl-3-[(3S)-morpholin-3- ylmethyl]-lH-indole-5-carboxylate (WO 2008/001076, Intermediate 77) and 3-hydroxy- benzoic acid at r.t. according to Method A and was isolated as a white solid. LCMS (ES⁺) 409 (M+Η)⁺.

INTERMEDIATE 58

3 -IY5V 4-f 3 -Hydroxybenzoyl)morpholin-3 -ylmethyll - 1 -methyl- 1 H-indole-5-carboxylic acid

To a stirred solution of Intermediate 57 (0.87 mg, 2.13 mmol) in MeOH (15 mL) was added aqueous sodium hydroxide solution (2M, 4.0 mL). The reaction was heated at reflux for 1 h. The reaction mixture was cooled and concentrated in vacuo. The aqueous residue was acidified using HCl (2M, 25 mL) to pΗ 2, and extracted with DCM (30 mL). The organic layer was dried (magnesium sulphate) and concentrated in vacuo, yielding the title compound (820 mg, 97%) as a white foam. LCMS (ES⁺) 395 (M+Η)⁺.

INTERMEDIATE 59

(1-13 -FCSV 4-(3 -HvdroxybenzovDmorpholin-S -ylmethyll - 1 -methyl- 1 H-indole-5- carbonyUazetidin-3-yDcarbamic acid terf-butyl ester The title compound was prepared from Intermediate 58 and azetidin-3-ylcarbamic acid tert-butyl ester at r.t. according to Method F and was isolated as a white solid. LCMS (ES⁺) 549 (M+Η)⁺.

INTERMEDIATE 60

5-Chloro-6-methoxynicotinic acid

To a stirred solution of S-chloro-ό-methoxynicotinic acid methyl ester (1.0 g, 4.96 mmol) in THF (4 mL) and water (4 mL) was added lithium hydroxide (0.6 g, 14.3 mmol). The reaction mixture was stirred at r.t. for 2.5 h, then neutralised with acetic acid and extracted with DCM. The organics were combined, dried (sodium sulphate) and concentrated in vacuo, yielding the title compound (0.4 g, 43%) as a white solid, δπ (CDCl₃) 13.30 (br s, IH), 8.65 (d, J2.0 Hz, IH), 8.22 (d, J2.0 Hz, IH), 4.02 (s, 3H).

INTERMEDIATE 61

3-|^"(5)-4-(5-Chloro-6-methoxypyridine-3-carbonyl)moφholin-3-ylmethyll-l-methyl-lH- indole-5-carboxylic acid methyl ester The title compound was prepared from methyl l-methyl-3-[(35)-morpholin-3- ylmethyl]-lH-indole-5-carboxylate (WO 2008/001076, Intermediate 77) and Intermediate 60 at r.t. according to Method F and was isolated as a white solid. LCMS (ES⁺) 458 (M+Η)⁺.

INTERMEDIATE 62

3 -r(^-4-(5-Chloro-6-methoxypyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 -methyl- 1 H- indole-5-carboxylic acid

To a stirred solution of Intermediate 61 (0.7 g, 1.53 mmol) in THF (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.2 g, 4.76 mmol). The reaction mixture was heated to 75°C for 18 h, then cooled and neutralised with 2M HCl. The precipitate was filtered, washed with water and dried in vacuo, yielding the title compound (0.47 g, 69%) as a white solid. LCMS (ES⁺) 444 (M+H)⁺.

INTERMEDIATE 63

3 - F(»y)-4-(4-Chloro-3 -hvdroxybenzoyl)morpholin-3 -ylmethyl] - 1 -methyl- 1 H-indole-5- carboxylic acid methyl ester

The title compound was prepared from methyl l-methyl-3-[(3S)-morpholin-3- ylmethyl]- lH-indole-5-carboxylate (WO 2008/001076, Intermediate 77) and 4-chloro-3- hydroxybenzoic acid at r.t. according to Method F and was isolated as a yellow solid. LCMS (ES⁺) 443 (M+Η)⁺. INTERMEDIATE 64

3 - [(S)-4-(4-Claϊoro-3 -hydroxybenzoyl)morpholin-3 -ylmethyl]- 1 -methyl- 1 H-indole-5- carboxylic acid To a stirred solution of Intermediate 63 (0.7 g, 1.58 mmol) in TΗF (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.25 g, 5.95 mmol). The reaction mixture was heated to 75⁰C for 3 h, then cooled and neutralised with 2M HCl. The precipitate was filtered, washed with water and dried in vacuo, yielding the title compound (0.5 g, 74%) as a white solid. LCMS (ES⁺) 429 (M+Η)⁺.

INTERMEDIATE 65

carboxylic acid methyl ester The title compound was prepared from methyl l-methyl-3-[(35)-morpholin-3- ylmethyl]-lH-indole-5-carboxylate (WO 2008/001076, Intermediate 77) and 3-fluoro-5- hydroxybenzoic acid at r.t. according to Method F and was isolated as a yellow solid. LCMS (ES⁺) 427 (M+Η)⁺.

INTERMEDIATE 66

3 - \(S)-4-(3 -Fluoro-5 -hydroxybenzoyl)morpholin-3 -ylmethyl] - 1 -methyl- 1 H-indole-5 - carboxylic acid

To a stirred solution of Intermediate 65 (0.9 g, 2.11 mmol) in THF (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.25 g, 5.95 mmol). The reaction mixture was heated to 75⁰C for 3 h, then cooled and neutralised with 2M HCl. The precipitate was filtered, washed with water and dried in vacuo, yielding the title compound (0.84 g, 96%) as a yellow solid. LCMS (ES⁺) 413 (M+H)⁺. INTERMEDIATE 67

(5^r)-3-r5-(2-OxopynOlidin-l-yl)-2-(trimethylsilanyl)-lH-indol-3-ylmethyl]morpholine-4- carboxylic acid fert-butyl ester To a stirred solution of Intermediate 46 (400 mg, 1.0 mmol) in DCM (5 mL) at

O⁰C were added triethylamine (276 μL, 2.0 mmol) and 4-chlorobutyryl chloride (133 μL, 1.2 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting material was dissolved in MeCN (5 mL), potassium carbonate (350 mg, 2.5 mmol) was added and the reaction heated at 80⁰C for 1.5 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-1% MeOH/DCM), yielding a colourless oil. LCMS (ES⁺) 472 (M+H)⁺.

INTERMEDIATE 68

1-13- r(3<S^r)-Moφholin-3 -ylmethyl] - 1 H-indol-5-vUpyrrolidin-2-one

The title compound was prepared from Intermediate 67 according to Method J and was isolated as a colourless oil. LCMS (ES⁺) 300 (M+Η)⁺.

INTERMEDIATE 69

(2-Chloro-5-fluoro-6-methoxypyridin-3 - vD- \(S)-3-( 1 -methyl-5 -nitro- 1 //-indol-3 - ylrnethyDmorpholin-4-yll-methanone The title compound was prepared from Intermediate 20 and 2-chloro-5-fluoro-6- methoxynicotinic acid at r.t. according to Method A and was isolated as a yellow solid. LCMS (ES⁺) 463 (M+H)⁺. INTERMEDIATE 70

[(S)-3-(5-Amino-l-methyl-lH-indol-3-ylmethyl^')morpholin-4-yl]-(2-chloro-5-fluoro-6- methoxypyridin-3 - ylVmethanone To a stirred solution of Intermediate 69 (1.5 g, 3.24 mmol) in AcOH (4 mL) was added zinc powder (1.5 g, 23.0 mmol). The reaction mixture was heated at 8O⁰C for 1 h, then cooled and quenched with water (50 mL) and saturated sodium carbonate solution (100 mL), and partitioned with EtOAc. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 1% TEA/EtOAc), yielding a red solid. LCMS (ES⁺) 433 (M+H)⁺.

INTERMEDIATE 71

l-(Carboxymethyl)-3-[(5^-4-(5-chloro-6-methoxypyridine-3-carbonyl)morpholin-3- ylmethyll-lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 99 (550 mg, 1.2 mmol) in DMF (10 mL) at O⁰C was added sodium hydride (60% dispersion in oil, 58 mg, 1.44 mmol). The reaction mixture was stirred at r.t. for 1 h and then cooled to O⁰C prior to the addition of bromo- acetic acid methyl ester (138 μL, 1.44 mmol). The reaction mixture was stirred at r.t. for 2 h, then partitioned between DCM (20 mL) and water (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was dissolved in TΗF (5 mL) and water (5 mL), and lithium hydroxide monohydrate (152 mg, 3.6 mmol) was added. The reaction mixture was stirred at r.t for 1.5 h, then neutralised with 2M HCl. The precipitate was filtered, washed with water and dried in vacuo, yielding the title compound (412 mg, 66%) as a white solid. LCMS (ES⁺) 515 (M+Η)⁺.

INTERMEDIATE 72

3 - [(y>-4-(5 -Cyano-o-methoxypyridine-S-carbonyllmorpholin-S -y lmethyl] - 1 -methyl- 1 H- indole-5-carboxylic acid

To a stirred solution of methyl l-methyl-3-[(35)-morpholin-3-ylmethyl]-lH- indole-5-carboxylate (WO 2008/001076, Intermediate 77; 150 mg, 0.52 mmol) in DCM (5 mL) at 0⁰C were added DIPEA (427 μL, 2.6 mmol) and 5-cyano-6-methoxynicotinoyl chloride hydrochloride (120 mg, 0.52 mmol). The reaction mixture was stirred at r.t. for 1 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 75-100% EtOAc/isohexane), yielding a white solid. LCMS (ES⁺) 449 (M+H)⁺. This material was dissolved in THF (5 mL) and water (5 mL), and lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added. The reaction mixture was heated to reflux for 1.5 h, then cooled and neutralised with 2M HCl. The precipitate was filtered, washed with water and dried in vacuo, yielding the title compound (87 mg, 22%) as a white solid. LCMS (ES⁺) 435 (M+H)⁺.

INTERMEDIATE 73

3-r(5^-4-(tert-Butoxycarbonyl)morpholin-3-ylmethyl1- 1 -methyl-2-(trimethylsilanylV IH- indole-5-carboxylic acid Methyl 3-{[(35)-4-(tert-butoxycarbonyl)morpholin-3-yl]methyl}-2-(trimethyl- silyl)-lH-indole-5-carboxylate (WO 2008/001076, Intermediate 77; 4.7 g, 10.0 mmol) was dissolved in TΗF (75 mL), cooled to -78⁰C and treated with methyl iodide (1.6 mL, 25.0 mmol). LiΗMDS (IM in TΗF, 20 mL, 20.0 mmol) was added and the reaction mixture was stirred at -78°C for 30 minutes. After warming to r.t., the mixture was diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride solution (2 x 100 mL). The organic phase was dried (sodium sulphate) and concentrated in vacuo, yielding a colourless oil. The resulting material was dissolved in EtOH (100 mL) and water (50 mL), and sodium hydroxide (1 g, 25.0 mmol) was added. The reaction mixture was heated to reflux for 2.5 h, then cooled and concentrated in vacuo. The resulting residue was acidified with citric acid (10% aqueous solution) and extracted with EtOAc. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo, yielding a white solid. δ_Η (CDCl₃) 8.47-8.37 (m, IH), 7.83 (dd, J 8.6, 1.3 Hz, IH), 7.14 (d, J8.8 Hz, IH), 7.10 (s, IH), 4.12-4.05 (m, IH), 3.79 (dd, J 10.9, 2.5 Hz, IH), 3.70 (s, 4H), 3.45-3.42 (m, IH), 3.38-3.32 (m, 2H), 3.23-3.14 (m, 2H), 2.91-2.88 (m, IH), 1.31 (s, 9H), 0.36 (s, 9H). INTERMEDIATE 74

3 -[(iSy4-(fert-Butoxycarbonyl)morpholin-3 -ylmethyl] - 1 -methyl-2-(trimethylsilanvπ- 1 H- indole-5-carboxylic acid pentafluorophenyl ester To a stirred solution of Intermediate 73 (4.46 g, 10.0 mmol), EDC (3.0 g, 12.0 mmol) and ΗOBT (1.35 g, 10.0 mmol) in DCM (50 mL) were added DIPEA (4.2 mL, 30.0 mmol) and pentafluorophenol (2.2 g, 12.0 mmol). The reaction mixture was stirred at r.t. for 5 h, then quenched with water (10 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and purified by column chromatography (SiO₂, 5-15% EtOAc/isohexane), yielding the title compound (4 g, 65%) as a white solid. δ_Η (CDCl₃) 8.70 (s, IH), 8.06 (dd, J8.6, 1.3 Hz, IH), 7.37 (d, J8.8 Hz, IH), 4.30-4.22 (m, IH), 3.93-3.90 (m, IH), 3.91 (s, 4H), 3.61-3.59 (m, IH), 3.57-3.45 (m, 2H), 3.35 (dd, J 10.9, 3.0 Hz, 2H), 3.08 (dd, J 13.9, 5.1 Hz, IH), 1.43 (s, 9H), 0.55 (s, 9H). LCMS (ES⁺) 613 (M+H)⁺.

INTERMEDIATE 75

l-Methyl-3-[(3^-morpholin-3-ylmethyll-lH-indole-5-carboxylic acid pentafluorophenyl ester hydrochloride The title compound was prepared from Intermediate 74 at r.t. according to Method

J and the hydrochloride salt was isolated as a yellow solid. 5_Η (d_ό-DMSO) 9.59 (s, 1Η), 9.14 (s, 1Η), 8.61 (d, J 1.3 Hz, IH), 7.98 (dd, J8.8, 1.5 Hz, IH), 7.69 (d, J 8.6 Hz, IH), 7.50 (s, IH), 3.94-3.91 (m, IH), 3.86 (s, 4H), 3.73-3.70 (m, IH), 3.68-3.57 (m, IH), 3.54- 3.46 (m, IH), 3.24-3.21 (m, IH), 3.17-3.03 (m, 3H). LCMS (ES⁺) 441 (M+H)⁺.

INTERMEDIATE 76

3-fdS^-4-(5-Chloro-6-methoxypyridine-3-carbonyl)morpholin-3-ylmethyll-l-methyl-lH- indole-5-carboxylic acid pentafluorophenyl ester To a stirred solution of Intermediate 61 (2.3 g, 5.0 mmol) in TΗF (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.850 g, 20.0 mmol). The reaction mixture was heated to 75°C for 17 h, then cooled and neutralised with 2M HCl. The precipitate was filtered, washed with water and dried in vacuo, yielding a white solid. The resulting material was dissolved in DCM (50 mL), and EDC (1.5 g, 6.0 mmol), HOBT (0.68 g, 5.0 mmol), DIPEA (2.1 mL, 15.0 mmol) and pentafluorophenol (1.1 g, 6.0 mmol) were added. The reaction mixture was stirred at r.t. for 5 h, then quenched with water (10 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and purified by column chromatography (SiO₂, 5-15% EtOAc/ isohexane), yielding a colourless oil (1.3 g, 43%). LCMS (ES⁺) 610 (M+H)⁺.

INTERMEDIATE 77

2-(Methylsulfanyl^N)ethylamine hydrochloride

To a stirred solution of 2-hydroxyethylcarbamic acid tert-butyl ester (5.0 g, 31.0 mmol) in pyridine (10 mL) at O⁰C was added methanesulfonyl chloride (3.1 mL, 31.0 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo and the residue partitioned in EtOAc (50 mL) and water (50 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and purified by column chromatography (SiO₂, 30% EtOAc/isohexane). The resulting material was dissolved in DMF (10 mL) and sodium methanethiolate (345 mg, 5.0 mmol) was added. The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo and the residue partitioned in EtOAc (50 mL) and water (50 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was treated with HCl in 1 ,4-dioxane (5 mL, 4M solution) and stirred at r.t. for 4 h. The reaction mixture was concentrated in vacuo, yielding the title compound as a yellow solid. 5_H (d₆-DMSO) 8.15 (dd, J l.l, 0.8 Hz, 3H), 3.04-2.91 (m, 2H), 2.74-2.69 (m, 2H), 2.10 (s, 3H).

INTERMEDIATE 78

3-[(^-4-(2-Chloro-5-fluoro-6-methoxypyridine-3-carbonyl)morpholin-3-ylmethyl1-l- methyl-lH-indole-5-carboxylic acid methyl ester

The title compound was prepared from methyl l-methyl-3-[(3.S)-morpholin-3- ylmethyl]-lH-indole-5-carboxylate (WO 2008/001076, Intermediate 77) and 2-chloro-5- fluoro-6-methoxynicotinic acid at r.t. according to Method A and was isolated as a white solid. LCMS (ES⁺) 476 (M+Η)⁺. INTERMEDIATE 79

3 - [6Sy4-(2-Chloro-5-fluoro-6-methoxypyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 - methyl- 1 H-indole-5-carboxylic acid To a stirred solution of Intermediate 78 (0.7 g, 1.47 mmol) in THF (15 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.62 g, 14.7 mmol). The reaction mixture was heated to 75°C for 18 h, then cooled and neutralised with 2M HCl. The precipitate was filtered, washed with water and dried in vacuo, yielding the title compound as a white solid. LCMS (ES⁺) 462 (M+H)⁺.

INTERMEDIATE 80

3-[(iS^-4-(5,6-Dichloropyridine-3-carbonyl)morpholin-3-ylmethyl]- 1 -methyl- lH-indole-5- carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and 5,6-dichloronicotinic acid according to Method A and was isolated as a white solid (224 mg) after purification by preparative ΗPLC. LCMS (ES⁺) 475 (M+Η)⁺.

EXAMPLE 1 (METHOD A)

3-[(iS^r)-4-(4-Aminobenzoyl)morpholin-3-ylmethyl]-l-methyl-lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Intermediate 3 (150 mg, 0.50 mmol), 4-aminobenzoic acid (68 mg, 0.50 mmol), EDC (144 mg, 0.75 mmol) and ΗOBT (76 mg, 0.50 mmol) in DMF (10 mL) was added DIPEA (0.11 mL, 0.10 mmol). The reaction mixture was heated at 90⁰C for 2 h. After cooling, the mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with water (3 x 10 mL), dried (phase separator filters), concentrated in vacuo and chromatographed (SiO₂, 20-60% EtOAc/ hexanes) to yield an off-white solid which was purified further using preparative ΗPLC, yielding the title compound (22 mg, 100%) as a white solid. δ_Η (d₆-DMSO) 7.58 (d, J 0.8 Hz, IH), 7.39 (d, ./ 8.6 Hz, IH), 7.19 (dd, J8.3, 1.5 Hz, IH), 7.11 (s, IH), 6.95 (d, J8.6 Hz, 2H), 6.50 (d, J8.3 Hz, 2H), 5.15 (br s, 2H), 4.40-4.30 (m, IH), 3.92-3.85 (m, IH), 3.79-3.71 (m, 5H), 3.52-3.39 (m, 3H), 3.25 (dd, J 14.4, 8.8 Hz, IH), 3.03-3.01 (m, IH), 2.99 (s, 6H). LCMS (ES+) 421 (M+H)⁺.

EXAMPLE 2

3 - { (S)-4- \6-( Acetylamino)pyridine-3 -carbonyll morpholin-3 - ylmethyl } - 1 -methyl- 1 H- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and Intermediate 4 according to Method A and was isolated as a white solid (39 mg) after purification by preparative HPLC. δ_H (d₆-DMSO) 10.25 (s, IH), 8.02 (dd, J 1.8, 0.8 Hz, IH), 7.91 (d, J 8.3 Hz, IH), 7.54 (s, IH), 7.47-7.41 (m, IH), 7.39 (d, J8.6 Hz, IH), 7.19 (dd, J8.6, 1.5 Hz, IH), 7.12 (s, IH), 4.28 (d, J2.0 Hz, IH), 3.90-3.96 (m, IH), 3.82 (d, J 11.6 Hz, IH), 3.77 (s, 4H), 3.57-3.64 (m, IH), 3.45-3.56 (m, 2H), 3.12-3.20 (m, 2H), 2.97 (s, 6H), 2.11 (s, 3H). LCMS (ES+) 464 (M+H)⁺.

EXAMPLE 3

3-[(5^r)-4-(2-Amino-l,3-thiazole-5-carbonyl^')morpholin-3-ylmethyl]-l -methyl- lH-indole- 5-carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and 2-amino- 1 ,3-thiazole-

5-carboxylic acid according to Method A and was isolated as an off-white solid (12 mg) after purification by preparative ΗPLC. δ_Η (d₆-DMSO) 7.67 (d, J 1.0 Hz, IH), 7.39 (d, J 8.3 Hz, IH), 7.23-7.19 (m, 2H), 7.17 (s, IH), 7.09 (s, 2H), 4.52-4.46 (m, IH), 4.02-3.90 (m, 2H), 3.80-3.74 (m, 4H), 3.61-3.42 (m, 3H), 3.28 (dd, J 14.1, 9.1 Hz, IH), 3.00 (s, 6H), 2.99-2.96 (m, IH). LCMS (ES+) 428 (M+H)⁺.

EXAMPLE 4

3 - { (S)-4- \2-( Acetylamino)- 1 ,3 -thiazole-S-carbonyllmorpholin-S-ylmethyl 1-1 -methyl- 1 H- indole-5-carboxylic acid diethylamide

The title compound was prepared from Intermediate 3 and Intermediate 5 according to Method A and was isolated as a white solid (98 mg) after purification by preparative HPLC. δ_H (d₆-DMSO) 7.65 (s, IH), 7.56 (s, IH), 7.41 (d, J 8.4 Hz, IH), 7.21 (d, J 8.4 Hz, IH), 7.20 (s, IH), 4.56-4.52 (m, IH), 4.05-3.99 (m, 2H), 3.88 (d, J 11.5 Hz, IH), 3.80 (s, 3H), 3.68-3.49 (m, 3H), 3.27 (dd, J8.0, 14.3 Hz, IH), 3.12 (dd, J8.0, 14.2 Hz, IH), 3.04 (s, 6H), 2.21 (s, 3H). LCMS (ES+) 470 (M+H)⁺.

EXAMPLE 5

(6- Aminopyridin-3 -vD- |Yff)-3-( 1 H-indol-3-ylmethv0morpholin-4-yl] -methanone

The title compound was prepared from (iS)-3-(lH-indol-3-ylmethyl)morpholine and 6-aminonicotinic acid according to Method A and was isolated as a white solid (205 mg). δ_Η (d₆-DMSO at 100⁰C) 10.61 (s, IH), 7.90 (d, J2.2 Hz, IH), 7.35-7.31 (m, 2H), 7.22 (dd, J8.5, 2.4 Hz, IH), 7.07-7.03 (m, 2H), 6.94-6.90 (m, IH), 6.38 (d, J8.5 Hz, IH), 6.02 (s, 2H), 4.38-4.30 (m, IH), 3.90 (d, J7.8 Hz, IH), 3.80-3.71 (m, 2H), 3.52-3.44 (m, 3H), 3.29-3.20 (m, IH), 2.98 (dd, J 13.1, 7.2 Hz, IH). LCMS (ES+) 337 (M+H)⁺.

EXAMPLE 6

3 - [CSV 4-(6-Chlorop yridine-3 -carbonyl^')morpholin-3 - ylmethyl] - 1 -methyl- 1 H-indole-5 - carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 6-chloronicotinic acid according to Method A and was isolated as a white solid (100 mg). δ_Η (d₆-DMSO at

100⁰C) 8.09 (s, IH), 7.52-7.33 (m, 4H), 7.20 (d, J 8.6 Hz, IH), 7.12 (s, IH), 4.25-4.10 (m, IH), 3.95-3.93 (m, IH), 3.83 (d, J 11.6 Hz, IH), 3.78 (s, 3H), 3.64-3.62 (m, IH), 3.52 (d, J 9.0 Hz, 2H), 3.16 (d, J 7.3 Hz, 2H), 2.99-2.97 (m, 7H). LCMS (ES+) 441 (M+H)⁺.

EXAMPLE 7

1 -Methyl-3 - [CSV 4-(6-methylpyridine-3 -carbonyl)morpholin-3 -ylmethyll - 1 H-indole-5- carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 6-methylnicotinic acid according to Method A and was isolated as a white solid (164 mg). 5_Η (d₆-DMSO at

100⁰C) 8.19 (s, 1Η), 7.48 (s, 1Η), 7.39 (d, J8.3 Hz, IH), 7.30 (s, IH), 7.19 (d, J8.2 Hz, IH), 7.11 (s, 2H), 4.28-4.15 (m, IH), 3.93 (d, J6.8 Hz, IH), 3.82-3.76 (m, 5H), 3.69 (d, J 11.4 Hz, IH), 3.49 (d, J8.3 Hz, 2H), 3.18-3.13 (m, 2H), 2.99 (s, 6H), 2.45 (s, 3H). LCMS (ES+) 421 (M+H)⁺.

EXAMPLE 8

3-[(5^-4-(2-Amino-4-methyl-l,3-thiazole-5-carbonyl)morpholin-3-ylmethyll-l-methyl- l//-indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 2-amino-4-methyl-l,3- thiazole-5-carboxylic acid according to Method A and was isolated as a white solid (20 mg). δ_H (d₆-DMSO at 9O⁰C) 7.62 (s, IH), 7.39 (d, J8.4 Hz, IH), 7.19 (dd, J8.4, 1.5 Hz, IH), 7.16 (s, IH), 6.92 (s, 2H), 4.50-4.35 (m, IH), 3.93-3.85 (m, IH), 3.79-3.72 (m, 4H), 3.49-3.37 (m, 4H), 3.23 (dd, J8.5, 8.2 Hz, IH), 3.04-2.98 (m, 7H), 1.93 (s, 3H). LCMS (ES+) 442 (M+H)⁺.

EXAMPLE 9

3-|^"(5^-4-Acetylmorpholin-3-ylmethyll-l-methyl-lH-indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 2-amino-4-methyl-l,3- thiazole-5-carboxylic acid sodium acetate salt according to Method A and was isolated as a white solid (53 mg). δ_Η (d₆-DMSO) 7.82 (s, 0.5H), 7.70 (s, 0.5H), 7.43 (t, J 8.1 Hz, IH), 7.26-7.18 (m, 2H), 4.47-4.41 (m, 0.5H), 4.18-4.10 (m, 0.5H), 3.97-3.85 (m, 2H), 3.76 (s, 3H), 3.62 (m, IH), 3.54-3.04 (m, 4H), 3.01 (s, 3H), 2.98 (s, 3H), 2.72-2.64 (m, IH), 2.03 (s, 1.5H), 1.62 (s, 1.5H). LCMS (ES+) 344 (M+H)⁺.

EXAMPLE 10

3- {(S)-4-[2-(6-Aminopyridin-2-yl)acetyl]morpholin-3-ylmethvU - 1 -methyl- lH-indole-5- carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and [6-(tert-butoxy- carbonylamino)pyridin-2-yl] acetic acid according to Method A and was isolated as a white solid (17 mg). δ_Η (d₆-DMSO) 7.81 (s, 0.5H), 7.70 (s, 0.5H), 7.43 (t, J8.6 Hz, IH), 7.27 (m, IH), 7.21 (d, J 10.6 Hz, 2H), 6.30 (m, IH), 6.21 (m, IH), 5.80 (dd, J2.5, 1.5 Hz, 2H), 4.53-4.47 (m, IH), 4.21-4.10 (m, IH), 3.95-3.82 (m, IH), 3.77 (d, J6.6 Hz, 3H), 3.60-3.70 (m, 2H), 3.50-3.09 (m, 5H), 2.99 (s, 3H), 2.95 (s, 3H), 2.75 (dd, J 13.6, 4.3 Hz, IH). LCMS (ES+) 436 (M+H)⁺.

EXAMPLE 11

3 - { (S)-4- F2-C3 -Ethylureido)- 1 ,3 -thiazole-5 -carbonyl] morpholin-3 - ylmethyl 1-1 -methyl- lH-indole-5-carboxylic acid dimethylamide

Example 3 (150 mg, 0.35 mmol) was dissolved in ethyl isocyanate (2 mL). The reaction mixture was heated at 6O⁰C for 1 h. After cooling, the solution was concentrated in vacuo and purified using preparative ΗPLC to yield the title compound (111 mg, 64%) as a white solid. δ_Η (d₆-DMSO) 7.66 (s, IH), 7.47(s, IH), 7.42 (d, J 8.3 Hz, IH), 7.23 (d, J 8.3 Hz, IH), 7.22 (s, IH), 6.66 (t, J 5.5 Hz, IH), 4.58-4.52 (m, IH), 4.06-3.99 (m, 2H), 3.86 (d, J 11.5 Hz, IH), 3.80 (s, 3H), 3.67-3.48 (m, 4H), 3.35-3.22 (m, 3H), 3.19-3.06 (m, IH), 3.04 (s, 6H), 1.16 (t, J 7.2 Hz, 3H). LCMS (ES+) 499 (M+H)⁺.

EXAMPLE 12

3 - [(S)-4-(6- Aminopyridine-3 -carbonvQmorpholin-3 -ylmethyl] - 1 -methyl- 1 H-indole-5- carboxylic acid dimethylamide

To a stirred solution of Intermediate 3 (200 mg, 0.66 mmol) in DCM (5 mL) were added 6-aminonicotinic acid (101 mg, 0.73 mmol), ΗOBT (100 mg, 0.66 mmol), DIPEA (233 μL, 1.32 mmol) and EDC (192 mg, 0.99 mmol). The mixture was stirred overnight, diluted with DCM (10 mL) and shaken with water (15 mL). The organic layer was separated and concentrated in vacuo to afford a white gum which was purified by preparative ΗPLC to afford the title compound (36 mg, 13%) as a white solid. 6_Η (d₆- DMSO at 110⁰C) 7.84 (d, J 1.8 Hz, IH), 7.59 (s, IH), 7.38 (d, J 8.6 Hz, IH), 7.25-7.14 (m, 2H), 7.09 (s, IH), 6.38 (d, J8.6 Hz, IH), 5.81 (s, 2H), 4.41-4.30 (m, IH), 3.96-3.87 (m, IH), 3.83-3.69 (m, 5H), 3.59-3.43 (m, 3H), 3.30-3.18 (m, IH), 3.13-3.03 (m, IH), 3.00 (s, 6H). LCMS (ES+) 422 (M+H)⁺. EXAMPLE 13

l-Methyl-3-[(iS^-4-(pyridine-3-carbonyl^')morpholin-3-ylmethyll-l//-indole-5-carboxylic acid dimethylamide To a stirred solution of Intermediate 5 (210 mg, 700 μmol) in DCM (5 mL) were added nicotinic acid (94 mg, 0.77 mmol), HOBT (107 mg, 700 μmol), DIPEA (250 μL, 1.40 mmol) and EDC (202 mg, 1.05 mmol). The reaction mixture was stirred overnight, diluted with DCM (10 mL) and shaken with water (15 mL). The organic layer was separated and concentrated in vacuo to afford a white gum which was purified by preparative HPLC to afford the title compound (160 mg, 56%) as a white solid. 6_H (d₆- DMSO at 120⁰C) 8.50-8.52 (m, IH), 8.33 (s, IH), 8.21 (br s, IH), 7.44 (br s, IH), 7.39 (d, J8.5 Hz, IH), 7.28-7.24 (m, IH), 7.20-7.17 (m, IH), 7.09 (m, IH), 4.22 (br s, IH), 3.97- 3.88 (m, IH), 3.82-3.71 (m, 5H), 3.60 (dd, J 11.6, 3.1 Hz, IH), 3.58-3.40 (m, 2H), 3.27- 3.10 (m, 2H), 2.99 (s, 6H). LCMS (ES+) 407 (M+H)⁺.

EXAMPLE 14

3-[(5^f)-4-(6-Aminopyridine-3-carbonyl^')morpholin-3-ylmethyl]-l-methyl-lH-indole-5- carboxylic acid methyl ester To a stirred solution of l-methyl-3-[(5)-morpholin-3-ylmethyl]-lH-indole-5- carboxylic acid methyl ester (500 mg, 1.74 mmol) and 6-aminonicotinic acid (263 mg, 1.91 mmol) in DMF (10 mL) were added EDC (501 mg, 2.61 mmol), ΗOBT (266 mg, 1.74 mmol) and DIPEA (576 μL, 3.5 mmol). The reaction mixture was stirred at 6O⁰C for 2 h, cooled and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the title compound (465 mg, 56%) as a white solid. 5_Η (d₆-DMSO at 80⁰C) 8.20 (s, 1Η), 7.79-7.75 (m, 2Η), 7.44 (d, J8.7 Hz, IH), 7.19 (s, IH), 7.12 (d, J7.1 Hz, IH), 6.30 (d, J 8.5 Hz, IH), 5.99 (br s, 2H), 4.43-4.35 (m, IH), 3.93-3.70 (m, 9H), 3.61-3.40 (m, 3H), 3.26-3.05 (m, 2H). LCMS (ES+) 409 (M+H)⁺. EXAMPLE 15

r6-Aminopyridin-3-yl)-[(.S^-3-(^'l-methyl-lH-indol-3-ylmethyl)morpholin-4-yl1- methanone To a stirred solution of Example 5 (157 mg, 0.45 mmol) in DMF (3 mL) in a sealed tube were added methyl carbonate (60 μL, 0.67 mmol) and DABCO (5 mg, 45 μmol). The reaction mixture was heated in a microwave at 160⁰C for 20 minutes. Additional methyl carbonate (40 μL) was added, and the mixture was heated for a further 20 minutes. The cooled solution containing the crude product was purified by preparative ΗPLC to afford the title compound (28 mg, 18%) as a white solid. δ_Η (de-DMSO) 8.37 (br s, IH), 7.89 (s, IH), 7.35 (d, J 8.3 Hz, IH), 7.30-7.17 (m, IH), 7.16-7.07 (m, 2H), 7.00-6.87 (m, IH), 6.35 (s, 3H), 3.90 (m, IH), 3.72 (s, 3H), 3.68 (s, IH), 3.53-3.10 (m, 6H), 2.89 (dd, J 13.9, 5.6 Hz, IH). LCMS (ES+) 409 (M+H)⁺.

EXAMPLE 16

3 - { (S)-A- r6-(3-Ethylureido)pyridine-3 -carbonyllmoφholin-3 -ylmethyl } - 1 -methyl- 1 H- indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 12 (200 mg, 475 μmol) in ethyl isocyanate (3 mL) was added DMAP (3 mg). The reaction mixture was heated at reflux for 30 minutes and concentrated in vacuo to give an oil, which was purified by preparative HPLC to afford the title compound (28 mg, 12%) as a yellow solid. δ_H (d₆-DMSO) 9.01 (s, IH), 7.90 (s, IH), 7.70 (s, IH), 7.52 (s, IH), 7.39 (d, J 8.7 Hz, IH), 7.35-7.30 (m, 2H), 7.18 (d, J8.7 Hz, IH), 7.12 (s, IH), 4.30-4.20 (m, IH), 3.93-3.87 (m, IH), 3.83-3.72 (m, 5H), 3.63-3.42 (m, 3H), 3.25-3.02 (m, 4H), 2.96 (s, 6H), 1.12 (t, J 6.5 Hz, 3H). LCMS (ES+) 493 (M+H)⁺.

EXAMPLE 17

3-{(S)-4-\6-(3 -Butylureido)pyridine-3 -carbonyl] morpholin-3 - ylmethy 1 } - 1 -methyl- 1 H- indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 12 (93 mg, 221 μmol) in «-butyl isocyanate (2 mL) was added DMAP (2 mg). The mixture was heated at 8O⁰C for 1 h and concentrated in vacuo to give an oil, which was purified by preparative HPLC to afford the title compound (28 mg, 24%) as a white solid. δ_H (d₆-DMSO) 9.33-9.11 (m, IH), 7.96-7.02 (m, 8H), 4.07-3.84 (m, IH), 3.79 (m, 4H), 3.69-3.40 (m, 2H), 3.30 (s, 6H), 3.20-2.80 (m, 7H), 1.62-1.17 (m, 4H), 1.03-0.82 (t, J7.2 Hz, 3H). LCMS (ES+) 521 (M+H)⁺.

EXAMPLE 18

l-Methyl-3-{(5^r)-4-r6-(3-phenylureido)pyridine-3-carbonyl1morpholin-3-ylmethyl}-lH- indole-5-carboxylic acid dimethylamide To a stirred solution of Example 72 (105 mg, 250 μmol) in pyridine (1 mL) was added phenyl isocyanate (500 μL). The mixture was heated at 60⁰C for 30 minutes, cooled and concentrated in vacuo. The residue was purified by preparative ΗPLC to afford the title compound (50 mg, 37%) as a white solid. δ_Η (d₆-DMSO at 8O⁰C) 10.07 (s, IH), 9.30 (s, IH), 7.98 (s, IH), 7.52-7.50 (m, 3H), 7.42-7.30 (m, 5H), 7.18-7.13 (m, 2H), 7.07-7.02 (m, IH), 4.33-4.20 (m, IH), 3.95-3.91 (m, IH), 3.95-3.81 (m, 2H), 3.77 (s, 3H), 3.63-3.61 (m, IH), 3.54-3.47 (m, 2H), 3.18-3.16 (m, 2H), 2.95 (s, 6H). LCMS (ES+) 556 (M+H)⁺.

EXAMPLE 19

US)-J¹ -(5-Benzyloxy- 1 -methyl- 1 H-indol-3 -ylmethyl)morpholin-4-yll -(6-chloropyridin-3 - yl)-methanone

Intermediate 13 (194 mg, 445 μmol) was dissolved in HCl (4M solution in 1,4- dioxane, 5 mL). After 1 h the solution was concentrated in vacuo and the residue dissolved in DCM (5 mL). The stirred solution was cooled to 0⁰C and TEA (285 μL, 2 mmol) and 6-chloronicotinoyl chloride (78 mg, 445 μmol) were added. The reaction mixture was stirred at r.t. for 1 h, shaken with water (10 mL) and the organic layer separated, dried (magnesium sulphate) and chromatographed on silica gel to afford the title compound (170 mg, 80%) as a white solid. δ_Η (d₆-DMSO at 8O⁰C) 8.06 (m, IH), 7.51-7.44 (m, 2H), 7.43-7.35 (m, 2H), 7.26 (m, 4H), 7.05-6.96 (m, IH), 6.90-6.83 (m, 2H), 5.09-4.96 (m, 2H), 3.99-3.90 (m, IH), 3.82 (m, 2H), 3.75-3.61 (m, 5H), 3.49 (m, 2H), 3.19-3.07 (m, 2H). LCMS (ES+) 476 (M+H)⁺. EXAMPLE 20

(5 - ( (ff)^ - [5 -(Dimethylcarbamoyl)- 1 -methyl- 1 H-indol-3 - ylmethvHmorpholine-4- carbonvUpyridin-2-yl^')carbamic acid benzyl ester To a stirred solution of Example 12 (102 mg, 242 μmol) in DCM at 0⁰C was added TEA (70 μL, 484 μmol) and benzyl chloroformate (51 μL, 363 μmol). The reaction mixture was stirred at r.t. for 30 minutes, and shaken with water (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo to afford a yellow oil which was purified by preparative HPLC to afford the title compound (48 mg, 36%) as a white solid. δ_H (Cl₆-DMSO at 80⁰C) 8.01 (d, J 1.1 Hz, IH), 7.67 (d, J 8.9 Hz, IH), 7.52 (m, IH), 7.47-7.30 (m, 8H), 7.21-7.14 (m, IH), 7.11 (s, IH), 5.21 (s, 2H), 4.34-4.17 (m, IH), 3.97-3.88 (m, IH), 3.85-3.70 (m, 6H), 3.64-3.55 (m, IH), 3.55- 3.45 (m, 2H), 3.19-3.01 (m, 7H). LCMS (ES+) 556 (M+H)⁺.

EXAMPLE 21

(5-(CSV3-r5-(DimethylcarbamoylVl -methyl- lH-indol-3-ylmethvHmorpholine-4- carbonyUpyridin-2-yl)carbamic acid ethyl ester

To a stirred solution of Example 12 (170 mg, 403 μmol) in DCM at 0⁰C was added TEA (115 μL, 810 μmol) and ethyl chloroformate (42 μL, 440 μmol). The reaction mixture was stirred at r.t. for 30 minutes, and shaken with water (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo to afford a yellow oil which was purified by preparative ΗPLC to afford the title compound (49 mg, 25%) as a white solid. δ_Η (d₆-DMSO at 80⁰C) 9.78 (br s, IH), 8.01 (s, IH), 7.72-7.64 (m, IH), 7.53 (s, IH), 7.47-7.35 (m, 2H), 7.22-7.14 (m, IH), 7.11 (s, IH), 4.27 (m, IH), 4.18 (q, J7.2 Hz, 2H), 3.97-3.88 (m, IH), 3.83 (s, IH), 3.80-3.77 (m, IH), 3.65-3.55 (m, IH), 3.46-3.44 (m, 2H), 3.24-3.05 (m, 1 IH), 1.27 (t, J 7.2 Hz, 3H). LCMS (ES+) 494 (M+H)⁺. EXAMPLE 22

(6-Chloropyridin-3 -ylV ( CSV3 -IT -methyl-5-fo-tolyl V 1 H-indol-3 -ylmethylimorpholin-4- vU-methanone Intermediate 8 (265 mg, 460 μmol) was dissolved in HCl (4M solution in 1,4- dioxane, 5 mL). After 1 h the solution was concentrated in vacuo, and the residue was dissolved in DCM (5 mL) and shaken with aqueous sodium carbonate. The organic layer was separated, dried (magnesium sulphate) and cooled at O⁰C. TEA (285 μL, 2 mmol) and 6-chloronicotinoyl chloride (78 mg, 445 μmol) were added to the stirred solution. The reaction mixture was stirred at r.t. for 1 h, shaken with water (10 mL) and the organic layer separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative ΗPLC to afford the title compound (16 mg, 8%) as a white solid. δ_Η (d₆-DMSO at 9O⁰C) 8.05 (m, IH), 7.44-7.38 (m, IH), 7.37-7.15 (m, 7H), 7.12- 7.05 (m, 2H), 3.96-3.90 (m, IH), 3.83 (m, 5H), 3.69-3.60 (m, IH), 3.57-3.46 (m, 2H), 3.23-3.09 (m, 3H), 2.22 (s, 3H). LCMS (ES+) 460 (M+H)⁺.

EXAMPLE 23

(6-Chloropyridin-3 - vD- { (S)-3 - \5 -(4-fluorophenyl)- 1 H-indol-3 -ylmethyllmorpholin-4-yl } - methanone

To a stirred solution of Intermediate 10 (236 mg, 760 μmol) in DCM (5 mL) at O⁰C was added TEA (164 μL, 1.14 mmol) and 6-chloronicotinoyl chloride (78 mg, 445 μmol). The reaction mixture was stirred at r.t. for 1 h, shaken with water (10 mL) and the organic layer separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford a yellow oil, which was purified further by preparative ΗPLC to afford the title compound (50 mg, 38%) as a white solid. δ_Η (d₆-DMSO at 9O⁰C) 10.71 (br s, IH), 8.04 (br s, IH), 7.64-7.49 (m, 3H), 7.45-7.38 (m, IH), 7.35-7.28 (m, IH), 7.26-7.16 (m, 3H), 7.15-7.08 (m, 2H), 4.23 (br s, IH), 4.00-3.91 (m, IH), 3.91-3.78 (m, 2H), 3.75-3.68 (m, IH), 3.56-3.46 (m, 2H), 3.33- 3.05 (m, 2H). LCMS (ES+) 450 (M+H)⁺. EXAMPLE 24

(6-Chloropyridin-3-ylV((5)-3-r5-r4-fluorophenylVl-methyl-lH-indol-3-ylmethyll- morpholin-4- yl } -methanone To a stirred solution of Example 23 (200 mg 445 μmol) in DMF (4 mL) at 0⁰C were added iodomethane (81 μL, 1.3 mmol) and sodium hydride (27 mg, 668 μmol). The reaction mixture was stirred at r.t. for 10 minutes, quenched by the addition of water (20 mL) and extracted with EtOAc (20 mL). The organic extract was washed with brine (20 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (55 mg, 27%) as a white solid, δπ (d₆-

DMSO at 90⁰C) 8.04 (br s, IH), 7.66-7.49 (m, 3H), 7.48-7.34 (m, 2H), 7.30-7.13 (m, 4H), 7.09 (s, IH), 4.24 (br s, IH), 4.01-3.92 (m, IH), 3.90-3.81 (m, 3H), 3.78 (s, 3H), 3.73- 3.64 (m, IH), 3.60-3.44 (m, 3H). LCMS (ES+) 450 (M+H)⁺.

EXAMPLE 25

3-[(5V4-Benzoylmoφholin-3-ylmethyl^"|- 1 -methyl- lH-indole-5-carboxylic acid dimethyamide

To a stirred solution of Intermediate 3 (200 mg, 0.7 mmol) and DIPEA (141 μL, 0.84 mmol) in DCM (5 mL) was added a solution of benzoyl chloride (85 μL, 0.77 mmol) in DCM (2 mL) dropwise. The reaction mixture was stirred overnight at room temperature. After quenching with water (10 mL), the organic solution was dried (phase separator filters) and concentrated in vacuo. Purification by column chromatography (SiO₂, 100% EtOAc) yielded the title compound (123 mg, 43%) as a white solid. δ_Η (d₆- DMSO at 12O⁰C) 7.43 (s, IH), 7.39-7.29 (m, 4H), 7.19-7.15 (m, 3H), 7.08 (s, IH), 4.30- 4.23 (m, IH), 3.91 (d, J7.7 Hz, IH), 3.78-3.75 (m, 5H), 3.54 (dd, J 11.7, 3.1 Hz, IH), 3.49-3.46 (m, 2H), 3.25 (dd, J 14.3, 8.5 Hz, IH), 3.06 (dd, J 14.3, 6.5 Hz, IH), 2.98 (s, 6H). LCMS (ES+) 406 (M+H)⁺. EXAMPLE 26

l-Methyl-3-[(iS^-4-(pyridine-4-carbonyl^')morpholin-3-ylmethyll-lH-indole-5-carboxylic acid dimethyamide To a stirred solution of Intermediate 3 (200 mg, 0.7 mmol) and DIPEA (420 μL,

2.45 mmol) in DCM (10 mL) was added a solution of isonicotinoyl chloride mono- hydrochloride (130 μL, 0.77 mmol) in DCM (2 mL) dropwise. The reaction mixture was stirred overnight at room temperature. After quenching with water (10 mL), the organic solution was dried (phase separator) and concentrated in vacuo. Purification by column chromatography (SiO₂, 5- 10% MeOΗ/EtOAc) yielded the title compound ( 110 mg, 39%) as a white solid. δ_Η (de-DMSO at 12O⁰C) 8.49 (d, J5.1 Hz, 2H), 7.48 (s, IH), 7.40 (d, J 8.4 Hz, IH), 7.20 (dd, J8.4, 1.5 Hz, IH), 7.11 (s, IH), 7.03 (d, J3.7 Hz, 2H), 4.20-4.10 (m, IH), 3.93 (d, J7.0 Hz, IH), 3.82-3.77 (m, 5H), 3.59 (dd, J 11.6, 3.1 Hz, IH), 3.50 (d, J8.9 Hz, 2H), 3.22 (dd, J 14.3, 7.8 Hz, IH), 3.13 (dd, J 14.3, 7.2 Hz, IH), 2.98 (s, 6H). LCMS (ES+) 407 (M+H)⁺.

EXAMPLE 27 (METHOD B)

3 - { CSV4- [6-(Dimethylamino^')pyridine-3 -carbonyπmorpholin-3 -ylmethvU - 1 -methyl- 1 H- indole-5-carboxylic acid dimethylamide

Dimethylamine (3 mL) at O⁰C was added to Example 6 (20 mg, 0.045 mmol) in a microwave vial. The reaction mixture was then heated to 100⁰C for 3 h. The experiment was repeated four more times. The products were combined, dissolved in EtOAc, concentrated in vacuo and the residue was purified by preparative HPLC to yield the title compound (75 mg, 93%) as a white solid. δ_H (d₆-DMSO at 8O⁰C) 7.96 (s, IH), 7.56 (s, IH), 7.39 (d, J8.5 Hz, IH), 7.21-7.17 (m, 2H), 7.12 (s, IH), 6.45 (d, J8.8 Hz, IH), 4.35- 4.27 (m, IH), 3.91 (d, J7.5 Hz, IH), 3.80-3.75 (m, 5H), 3.58-3.47 (m, 3H), 3.22-3.08 (m, 2H), 3.03 (s, 6H), 2.97 (s, 6H). LCMS (ES+) 450 (M+H)⁺. EXAMPLE 28

1 -Methyl-3 - { (S)-4- [6-(methylamino)pyridine-3 -carbonyl]morpholin-3 - ylmethyl }-\H- indole-5-carboxylic acid dimethylamide The title compound was prepared from Example 6 and methylamine (2N in THF,

2 mL) according to Method B and was isolated as a white solid (75 mg). 8_H (d₆-DMSO at 8O⁰C) 7.91 (s, IH), 7.57 (s, IH), 7.39 (d, J8.4 Hz, IH), 7.20-7.12 (m, 3H), 6.53 (s, IH), 6.31 (d, J8.6 Hz, IH), 4.35-4.30 (m, IH), 3.91 (d, J8.4 Hz, IH), 3.79-3.76 (m, 5H), 3.55- 3.42 (m, 3H), 3.21 (dd, J 14.2, 8.3 Hz, IH), 3.06 (dd, J 14.2, 6.8 Hz, IH), 2.98 (s, 6H), 2.79 (d, J3.2 Hz, 3H). LCMS (ES+) 436 (M+H)⁺.

EXAMPLE 29

3-[(5^f)-4-(6-Methoxypyridine-3-carbonyl^')moφholin-3-ylmethyl1-l -methyl- lH-indole-5- carboxylic acid dimethylamide

To a stirred solution of Example 6 (100 mg, 0.227 mmol) in MeOH (2 mL) was added sodium methoxide (120 mg, 2.27 mmol). The resulting solution was heated in a microwave at 100⁰C for 1 h. The reaction mixture was quenched with water (0.5 mL) and concentrated in vacuo after stirring for 2 minutes. The residue was dissolved in DCM (5 mL), washed with water (5 mL), dried (MgSO₄) and concentrated in vacuo. The crude product was purified by preparative ΗPLC to yield the title compound (43 mg, 43%) as a white solid. δ_Η (d₆-DMSO at 8O⁰C) 7.95 (s, IH), 7.48 (s, IH), 7.40-7.32 (m, 2H), 7.18 (dd, J 8.4, 1.2 Hz, IH), 7.12 (s, IH), 6.64 (d, J 8.4 Hz, IH), 4.32-4.24 (m, IH), 3.93 (d, J 7.6 Hz, IH), 3.86 (s, 3H), 3.81 (d, J 11.5 Hz, 2H), 3.77 (s, 3H), 3.59 (dd, J 11.5, 2.9 Hz, IH), 3.51-3.48 (m, 2H), 3.16-3.08 (m, 2H), 2.97 (s, 6H). LCMS (ES+) 437 (M+H)⁺.

EXAMPLE 30

1 -Methyl-3 -|Y,SV4-(6-oxo- 1 ,6-dihydropyridine-3 -carbonylimoφholin-3 -ylmethyl] - 1 H- indole-5-carboxylic acid dimethylamide

Example 29 (200 mg, 0.475 mmol) was dissolved in a solution OfH₂SO₄ (1 mL; 600 μL cone. H₂SO₄ and 400 μL water) and stirred at r.t. for 5 minutes. A solution of sodium nitrite (36 mg, 0.523 mmol) in water (0.5 mL) was added dropwise to the reaction mixture whilst the temperature was maintained between 0 and 5⁰C. On complete addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was neutralized with cone, sodium hydroxide solution and extracted with DCM (3 x 10 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The crude product was purified by preparative HPLC to yield the title compound (10 mg, 5%) as a white solid. δ_H (de-DMSO at 80⁰C) 11.40 (s, IH), 7.58 (s, IH), 7.38 (d, J8.4 Hz, IH), 7.25 (s, IH), 7.19-7.13 (m, 3H), 6.16 (d, J9.4 Hz, IH), 4.32-4.22 (m, IH), 3.91 (d, J7.7 Hz, IH), 3.80-3.73 (m, 5H), 3.55 (dd, J 11.6, 2.7 Hz, IH), 3.50-3.42 (m, 2H), 3.18 (dd, J 14.3, 7.8 Hz, IH), 3.10-3.05 (m, IH), 2.98 (s, 6H). LCMS (ES+) 423 (M+H)⁺.

EXAMPLE 31 (METHOD C)

1 -Methyl-3-[(_lSy4-propionylmorpholin-3-ylmethyll- lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Intermediate 3 (200 mg, 0.67 mmol) in DCM (5 mL) at 0-5⁰C were added triethylamine (143 μL, 1.0 mmol) and propionyl chloride (69 μL, 0.80 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was quenched with water (5 mL), then the organic layer was separated, dried (MgSO₄) and concentrated in vacuo. The residue was chromatographed (SiO₂, 50% EtOAc/hexanes), yielding the title compound (120 mg, 50%) as a white solid. δ_Η (d₆-DMSO) 7.81 (s, 0.5H), 7.70 (s, 0.5H), 7.42 (d, J8.3 Hz, IH), 7.21 (m, 2H), 4.51- 4.40 (m, IH), 4.16-3.84 (m, 2H), 3.76 (s, 3H), 3.63 (d, J 11.7 Hz, IH), 3.51-3.05 (m, 4H), 3.00 (s, 6H), 2.81-2.60 (m, IH), 2.46-2.06 (m, 2H), 1.85-1.66 (m, IH), 1.00 (t, J7.3 Hz, IH), 0.70 (t, J 7.2 Hz, IH). LCMS (ES+) 358 (M+H)⁺.

EXAMPLE 32

3-[(5^r)-4-(2,2-Dimethylpropionyl^')morpholin-3-ylmethyll- 1 -methyl- 1 H-indole-5- carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and pivaloyl chloride according to Method C and was isolated as a white solid (140 mg, 54%). 6_Η (d₆-DMSO) 7.79 (s, 1Η), 7.42 (d, J8.3 Hz, IH), 7.23 (s, IH), 7.21 (dd, J8.3, 1.3 Hz, IH), 4.49-4.40 (m, IH), 3.97 (d, J 13.1 Hz, IH), 3.87 (d, J9.6 Hz, IH), 3.76 (s, 3H), 3.65 (d, J 11.4 Hz, IH), 3.51-3.31 (m, 4H), 3.00 (s, 6H), 2.73 (dd, J 14.1, 4.8 Hz, IH), 1.18 (s, 9H). LCMS (ES+) 386 (M+H)⁺.

EXAMPLE 33

3 - IYS¹M-(C vclopropanecarbonyl)morpholin-3 - ylmethyl] - 1 -methyl- 1 H-indole-5 - carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and cyclopropanecarbonyl chloride according to Method C and was isolated as a white solid (140 mg, 57%). δ_Η (d₆- DMSO) 7.73 (m, IH), 7.41 (d, J8.3 Hz, IH), 7.23-7.17 (m, 2H), 4.49-4.29 (m, IH), 4.12- 4.00 (m, IH), 3.95-3.89 (m, IH), 3.87-3.80 (m, IH), 3.75 (s, 3H), 3.63-3.32 (m, 2H), 3.22-3.06 (m, 2H), 2.97 (d, J 5.6 Hz, 6H), 1.46 (m, IH), 0.83-0.57 (m, 2H), 0.44 (ddd, J 4.3, 1.5, 0.8 Hz, IH), 0.17-0.10 (m, IH), -0.15 to -0.06 (m, IH). LCMS (ES+) 370 (M+H)⁺.

EXAMPLE 34 (METHOD D)

(6-Chloropyridin-3 -vD- \(S)-3 -( 1 -methyl-5-phenyl- 1 H-indol-3 -ylmethyl)morpholin-4-yl1- methanone

To a stirred solution of Intermediate 11 (70 mg, 0.23 tnmol) in DCM (5 mL) at 0⁰C were added triethylamine (72 μL, 0.46 mmol) and 6-chloronicotinoyl chloride (230 μL, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 h, then quenched with water. The organic layer was separated, dried (MgSO₄) and concentrated in vacuo to yield an oil which was purified by preparative ΗPLC to give title compound (22 mg, 21%) as a yellow solid. δ_Η (d₆-DMSO at 9O⁰C) 8.06 (s, IH), 7.60 (d, J7.3 Hz, 3H), 7.43 (dd, J7.6, 7.6 Hz, 4H), 7.31-7.26 (m, 2H), 7.25-7.10 (m, IH), 7.09 (s, IH), 4.30-4.12 (m, IH), 3.95 (d, J6.7 Hz, IH), 3.86 (d, J 11.5 Hz, 2H), 3.78 (s, 3H), 3.69-3.67 (m, IH), 3.52 (d, J 9.0 Hz, 2H), 3.22-3.15 (m, 2H). LCMS (ES+) 446 (M+H)⁺. EXAMPLE 35

l-Methyl-3-[(5^f)-4-(3-methylbenzoyl)morpholin-3-ylmethyl1-l//-indole-5-carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and /w-toluoyl chloride according to Method D and was isolated as a white solid (70 mg) after purification by preparative HPLC. δ_H (d₆-DMSO at HO⁰C) 7.42 (s, IH), 7.38 (d, J 8.5 Hz, IH), 7.22- 7.14 (m, 3H), 7.09 (s, IH), 6.96 (d, J 7.1 Hz, IH), 6.91 (s, IH), 4.26-4.24 (m, IH), 3.91 (d, J7.7 Hz, IH), 3.79-3.75 (m, 5H), 3.53 (dd, J 11.4, 3.1 Hz, IH), 3.48-3.45 (m, 2H), 3.23 (dd, J 14.2, 8.3 Hz, IH), 3.06 (dd, J 14.2, 6.7 Hz, IH), 2.97 (s, 6H), 2.25 (s, 3H). LCMS (ES+) 420 (M+H)⁺.

EXAMPLE 36

1 -Methyl-3-[(S^r)-4-(4-methylbenzoyl)moφholin-3-ylmethyll- lH-indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and^-toluoyl chloride according to Method D and was isolated as a white solid (70 mg) after purification by preparative ΗPLC. δ_Η (d₆-DMSO at 110⁰C) 7.49 (s, IH), 7.38 (d, J8.4 Hz, IH), 7.19 (dd, J8.4, 1.2 Hz, IH), 7.13-7.04 (m, 5H), 4.28-4.19 (m, IH), 3.90 (d, J7.5 Hz, IH), 3.79- 3.60 (m, 5H), 3.52 (dd, J 11.5, 3.2 Hz, IH), 3.46 (d, J 8.9 Hz, 2H), 3.24 (dd, J 14.3, 8.4 Hz, IH), 3.06 (dd, J 14.3, 6.7 Hz, IH), 2.98 (s, 6H), 2.31 (s, 3H). LCMS (ES+) 420 (M+H)⁺.

EXAMPLE 37

3-[(iSy4-(3-Chlorobenzoyl)morpholin-3-ylmethyl]- 1 -methyl- lH-indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and /w-chlorobenzoyl chloride according to Method D and was isolated as a white solid (70 mg) after purification by preparative ΗPLC. δ_Η (d₆-DMSO at HO⁰C) 7.45-7.26 (m, 4H), 7.18 (d, J 8.4 Hz, IH), 7.10-7.05 (m, 3H), 4.25-4.19 (m, IH), 3.92 (d, J 7.5 Hz, IH), 3.82-3.76 (m, 5H), 3.58 (dd, J 11.6, 3.1 Hz, IH), 3.49 (d, J 8.9 Hz, 2H), 3.21 (dd, J 14.4, 7.7 Hz, IH), 3.12 (dd, J 14.4, 7.3 Hz, IH), 2.98 (s, 6H). LCMS (ES+) 440 (M+H)⁺.

EXAMPLE 38

3-[(5V4-(4-Chlorobenzoyl)morpholin-3-ylmethyll- 1 -methyl- lH-indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and/>-chlorobenzoyl chloride according to Method D and was isolated as a white solid (70 mg) after purification by preparative HPLC. δ_H (d₆-DMSO at 110⁰C) 7.52 (s, 1 H), 7.39 (d, J 8.4 Hz, IH), 7.31 (d, J8.3 Hz, 2H), 7.20 (dd, J8.4, 1.3 Hz, IH), 7.13-7.10 (m, 3H), 4.23-4.19 (m, IH), 3.92 (d, J7.6 Hz, IH), 3.82-3.75 (m, 5H), 3.56 (dd, J 11.6, 3.1 Hz, IH), 3.48 (d, J8.9 Hz, 2H), 3.22 (dd, J 14.3, 7.9 Hz, IH), 3.11 (d, J 14.3, 7.1 Hz, IH), 2.99 (s, 6H). LCMS (ES+) 440 (M+H)⁺.

EXAMPLE 39

1 -Methyl-3 - [(5^r)-4-(naphthalene- 1 -carbonvDmorpholin-3 -ylmethyl] - 1 H-indole-5- carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and 1-naphthoyl chloride according to Method D and was isolated as a white solid (70 mg) after purification by preparative ΗPLC. δ_Η (d₆-DMSO at 13O⁰C) 7.92-7.87 (m, 2H), 7.70-7.60 (m, IH), 7.53- 7.37 (m, 5H), 7.19-7.16 (m, 2H), 7.15-7.01 (m, IH), 3.90-3.85 (m, IH), 3.77-3.72 (m, 4H), 3.60-3.42 (m, 4H), 3.30 (dd, J 14.4, 8.4 Hz, IH), 3.20-3.02 (m, IH), 2.96 (s, 6H), 2.86-2.70 (m, IH). LCMS (ES+) 456 (M+H)⁺.

EXAMPLE 40

l-Methyl-3-[(5)-4-(naphthalene-2-carbonvπmorpholin-3-ylmethyll-lH-indole-5- carboxylic acid diethylamide

The title compound was prepared from Intermediate 3 and 2-naphthoyl chloride according to Method D and was isolated as a white solid (70 mg) after purification by preparative ΗPLC. δ_Η (d₆-DMSO at HO⁰C) 7.89-7.80 (m, 3H), 7.61 (s, IH), 7.56-7.49 (m, 3H), 7.38 (d, J8.4 Hz, IH), 7.23 (dd, J8.4, 1.5 Hz, IH), 7.16 (dd, J8.4, 1.5 Hz, IH), 7.10 (s, IH), 4.36-4.30 (m, IH), 3.94-3.79 (m, 3H), 3.76 (s, 3H), 3.61 (dd, J 11.6, 3.2 Hz, IH), 3.56-3.52 (m, 2H), 3.29-3.13 (m, 2H), 2.88 (s, 6H). LCMS (ES+) 456 (M+H)⁺.

EXAMPLE 41

3 - \(S)-4-(3 -MethoxybenzovDmorpholin-3 - ylmethyll - 1 -methyl- 1 H-indole-5 -carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 3-methoxybenzoyl chloride according to Method D and was isolated as a white solid (70 mg) after purification by preparative ΗPLC. δ_Η (de-DMSO at 90⁰C) 7.44 (br s, IH), 7.39 (d, J 8.4 Hz, IH), 7.25-7.17 (m, 2H), 7.11 (s, IH), 6.91 (dd, J8.2, 2.1 Hz, IH), 6.72 (d, J7.4 Hz, IH), 6.68 (s, IH), 4.30-4.15 (m, IH), 3.92-3.90 (m, IH), 3.76 (s, 4H), 3.74, (s, 3H), 3.53 (dd, J 15.3, 3.0 Hz, IH), 3.47-3.45 (m, 2H), 3.24 (dd, J 14.2, 8.5 Hz, 2H), 3.05 (dd, J 14.2, 6.7 Hz, IH), 2.98 (s, 6H). LCMS (ES+) 436 (M+H)⁺.

EXAMPLE 42

l-Methyl-3-{(S)-4-r4-methyl-3-(trifluoromethyl)benzoyl1morpholin-3-ylmethvU-lH- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 4-methyl-3- (trifluoromethyl)benzoyl chloride according to Method D and was isolated as a white solid (80 mg). δ_Η (d₆-DMSO at 110⁰C) 7.49 (s, IH), 7.37 (d, J 8.4 Hz, IH), 7.30 (s, 2H), 7.25 (d, J7.7 Hz, IH), 7.18 (d, J8.4 Hz, IH), 7.10 (s, IH), 4.26-4.20 (m, IH), 3.92 (d, J 7.4 Hz, IH), 3.82 (d, J 11.6 Hz, IH), 3.75-3.70 (m, 4H), 3.60 (dd, J 11.6, 3.1 Hz, IH), 3.55-3.46 (m, 2H), 3.17 (dd, J7.5, 2.7 Hz, 2H), 2.91 (s, 6H), 2.43 (s, 3H). LCMS (ES+) 488 (M+H)⁺. EXAMPLE 43

3 - { (S)-4- r4-Fluoro-3 -(trifluoromethyl)benzoyllmorpholin-3 -ylmethyl) - 1 -methyl- 1 H- indole-5-carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and 4-fluoro-3-(trifluoro- methyl)benzoyl chloride according to Method D and was isolated as a white solid (75 mg). δ_H Cd₆-DMSO at HO⁰C) 7.48-7.29 (m, 5H), 7.18 (dd, J 7.4, 1.5 Hz, IH), 7.11 (s, IH), 4.25-4.20 (m, IH), 3.93 (d, J7.2 Hz, IH), 3.83 (d, J 11.5 Hz, IH), 3.77 (s, 4H), 3.64 (dd, J 11.5, 3.1 Hz, IH), 3.52 (d, J8.8 Hz, 2H), 3.17 (d, J7.5 Hz, 2H), 2.91 (s, 6H). LCMS (ES+) 492 (M+H)⁺. The title compound was also prepared by Method F.

EXAMPLE 44

l-Methyl-3-(r^-4-(2-r3-(trifluoromethyl^')phenyllacetvUmorpholin-3-ylmethyl)-lH- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 3-(trifluoromethyl)- phenylacetyl chloride according to Method D and was isolated as a white solid (47 mg). δ_Η (d₆-DMSO at 110⁰C) 7.78 (d, J 0.8 Hz, IH), 7.62-7.36 (m, 4H), 7.29-7.18 (m, 2H),

7.00-6.92 (m, IH), 4.53-4.46 (m, IH), 4.15 (d, J 11.4 Hz, IH), 3.97-3.80 (m, 3H), 3.76 (d, J7.3 Hz, 3H), 3.70-3.64 (m, IH), 3.58-3.33 (m, 3H), 3.25-3.14 (m, 2H), 3.04 (d, J 16.2

Hz, IH), 2.97 (s, 3H), 2.91 (s, 2H). LCMS (ES+) 488 (M+H)⁺.

EXAMPLE 45

3 - { (Sy4-[4-Methoxy-3-(trifluoromethvDbenzoyl]morpholm-3 -ylmethvU - 1 -methyl- 1 H- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 4-methoxy-3-(trifluoro- methyl)benzoyl chloride according to Method D and was isolated as a white solid (76 mg). δ_H (dβ-DMSO at 9O⁰C) 7.49 (s, IH), 7.39-7.33 (m, 2H), 7.25 (s, IH), 7.17 (d, J8.4 Hz, IH), 7.11-7.09 (m, 2H), 4.25-4.20 (m, IH), 3.92 (d, J7.7 Hz, IH), 3.89 (s, 3H), 3.81 (d, J 11.5 Hz, IH), 3.77 (s, 3H), 3.60 (dd, J 11.6, 3.0 Hz, IH), 3.50 (d, J9.0 Hz, 2H), 3.16 (J 7.5 Hz, 2H), 2.99-2.97 (m, IH), 2.96 (s, 6H). LCMS (ES+) 504 (M+H)⁺. EXAMPLE 46 (METHOD E)

3 - { (S)-4- r6-(fert-Butyl)pyridine-3 -carbonyl]morpholin-3 - ylmethyl } - 1 -methyl- 1 H-indole- 5-carboxylic acid dimethylamide To a solution of Intermediate 3 (250 mg, 0.83 mmol), tert-butylcarboxylic acid

(89 mg, 0.88 mmol), 6-(tert-butyl)pyridine-3-carboxylic acid (158 mg, 0.88 mmol), EDC (270 mg, 1.25 mmol) and HOBT (150 mg, 0.83 mmol) in DCM (5 mL) was added DIPEA (250 μL, 1.66 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL). The organic layer was separated, dried (MgSO₄), concentrated in vacuo and chromatographed (SiO₂, 20: 1 EtOAc/MeOH), yielding the title compound (140 mg, 34%) as a white solid after freeze-drying with 1 : 1 MeCN-water. δ_H (d₆-DMSO) 8.30 (s, IH), 7.61 (s, IH), 7.41-7.37 (m, 2H), 7.32 (d, J 8.1 Hz, IH), 7.21 (dd, J8.4, 1.4 Hz, IH), 7.07 (s, IH), 4.30-4.18 (m, IH), 3.93-3.90 (m, IH), 3.82 (d, J 11.6 Hz, IH), 3.78-3.75 (m, 4H), 3.59 (dd, J 11.7, 3.2 Hz, IH), 3.57-3.50 (m, 2H), 3.22-3.14 (m, 2H), 2.99 (s, 6H), 1.33 (s, 9H). LCMS (ES+) 463 (M+H)⁺.

EXAMPLE 47

1 -Methyl-3 - { (S)-4- [5-(trifluoromethyl)pyridine-3 -carbonylimorpholin-3 -ylmethyl } - 1 H- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 5-(trifluoromethyl)- nicotinic acid according to Method E and was isolated as a white solid (85 mg). 5_H (d₆- DMSO at 11O⁰C) 8.84 (s, IH), 8.54 (s, IH), 7.76 (s, IH), 7.48 (s, IH), 7.38 (d, J 8.4 Hz, IH), 7.18 (dd, J8.4, 1.4 Hz, IH), 7.12 (s, IH), 4.30-4.15 (m, IH), 3.94 (d, J7.3 Hz, IH), 3.84 (d, J 11.6 Hz, IH), 3.77-3.75 (m, 4H), 3.69 (dd, J 11.6, 2.9 Hz, IH), 3.61-3.52 (m, 2H), 3.21-3.18 (m, 2H), 2.97 (s, 6H). LCMS (ES+) 475 (M+H)⁺.

EXAMPLE 48

1 -Methyl-3 - \(S)-4-( 1 ,3 -oxazole-5 -carbonvDmorpholin-3 -ylmethyll - 1 H-indole-5- carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and l,3-oxazole-5- carboxylic acid according to Method E and was isolated as an off-white solid (86 mg). 5_Η (4-DMSO at 8O⁰C) 8.27 (s, IH), 7.64 (s, IH), 7.39-7.36 (m, 2H), 7.21-7.15 (m, 2H), 4.50-4.42 (m, IH), 4.04-3.96 (m, 2H), 3.83 (d, J 11.7 Hz, IH), 3.75 (s, 3H), 3.59-3.46 (m, 3H), 3.27 (dd, J 14.2, 8.1 Hz, IH), 3.08 (dd, J 14.2, 6.8 Hz, IH), 3.01 (s, 6H). LCMS (ES+) 397 (M+H)⁺.

EXAMPLE 49

1 -Methyl-3 - [(^-4-(I H-pyrazole-3 -carbonylimoφholin-3 - y lmethyll - 1 H-indole-5 - carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and 1 H-pyrazole-3 - carboxylic acid according to Method E and was isolated as an off-white solid (53 mg). δπ (de-DMSO at 90⁰C) 7.66 (br s, 2Η), 7.38 (d, J 8.4 Hz, IH), 7.20 (dd, J 8.4, 1.4 Hz, IH), 7.14 (s, IH), 6.45 (s, IH), 4.75-4.71 (m, IH), 4.45-4.30 (m, IH), 3.94 (d, J7.4 Hz, IH), 3.76-3.73 (m, 4H), 3.48-3.44 (m, 3H), 3.34 (dd, J 14.1, 9.6 Hz, IH), 3.12-3.00 (m, 7H). LCMS (ES+) 396 (M+H)⁺.

EXAMPLE 50

3 - ( (S)-A- \2-( 1 H-Indol-3 -vnacetyllmorpholin-3 -ylmethyl) - 1 -methyl- 1 H-indole-5 - carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and indole-3 -acetic acid according to Method E and was isolated as an off-white solid (78 mg). δ_Η (d₆-DMSO) 10.50 (br s, IH), 7.75 (s, IH), 7.43 (br s, IH), 7.39 (d, J8.3 Hz, IH), 7.34 (d, J8.1 Hz, IH), 7.22 (dd, J8.3, 1.5 Hz, IH), 7.10-7.03 (m, 3H), 6.95 (t, J7.3 Hz, IH), 4.46-4.32 (m, IH), 4.07-3.94 (m, IH), 3.86 (d, J7.3 Hz, IH), 3.77-3.66 (m, 6H), 3.63-3.53 (m, IH),

3.37-3.28 (m, 3H), 3.20 (dd, J 14.1, 8.6 Hz, IH), 2.99 (s, 6H). LCMS (ES+) 459 (M+H)⁺.

EXAMPLE 51

3-U5)-4-r2-r2-Amino-1.3-thiazol-5-yl)acetyl1morpholin-3-ylmethyU-l-methyl-lH- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 2-amino-l,3-thiazole- 5-acetic acid according to Method E and was isolated as an off-white solid (29 mg). 6_Η Cd₆-DMSO at HO⁰C) 7.75 (s, IH), 7.40 (d, J8.6 Hz, IH), 7.22 (dd, J8.3, 1.3 Hz, IH), 7.17 (s, IH), 6.43 (br s, 2H), 6.13 (s, IH), 4.45-4.32 (m, IH), 4.03-3.85 (m, 2H), 3.77 (s, 3H), 3.72 (d, J 11.6 Hz, IH), 3.52-3.25 (m, 6H), 3.00 (s, 6H), 2.98-2.87 (m, IH). LCMS (ES+) 442 (M+H)⁺.

EXAMPLE 52

1 -Methyl-3 - { (S)A- \2-( 1 H-tetrazol-5-vnacetyllmoφholin-3 -ylmethyll - 1 H-indole-5- carboxylic acid dimethylamide The title compound was prepared from Intermediate 3 and lH-tetrazole-5-acetic acid according to Method E and was isolated as a white solid (60 mg). δπ (d^-DMSO at HO⁰C) 7.74 (s, 1Η), 7.39 (d, 78.4 Hz, IH), 7.21 (dd, J8.4, 1.5 Hz, IH), 7.18 (s, IH), 4.45-4.40 (m, IH), 4.10-3.98 (m, IH), 3.86-3.82 (m, 2H), 3.77 (s, 3H), 3.71 (d, J 11.5 Hz, 2H), 3.38-3.27 (m, 3H), 3.24 (dd, J 14.1, 9.3 Hz, IH), 2.99 (s, 6H), 2.98-2.89 (m, IH). LCMS (ES+) 412 (M+H)⁺.

EXAMPLE 53

1 -Methyl-3 - { (S)A- F2-(5 -methyl-2H- [ 1.2.41triazol-3 -yliacetyll morpholin-3-ylmethyl } - lH-indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and 2-(3 -methyl- IH- [l,2,4]triazol-5-yl)acetic acid according to Method E and was isolated as a white solid (47 mg). δ_Η (d₆-DMSO at 110⁰C) 7.74 (s, IH), 7.40 (d, J8.3 Hz, IH), 7.21 (dd, J8.3, 1.3 Hz, IH), 7.18 (s, IH), 4.44-4.33 (m, IH), 4.03-3.93 (m, IH), 3.90 (d, J7.3 Hz, IH), 3.77 (s, 3H), 3.74 (d, J 11.6 Hz, 2H), 3.68-3.50 (m, 2H), 3.44-3.34 (m, 3H), 3.26 (dd, J 14.4, 9.3 Hz, IH), 2.99 (s, 6H), 2.27 (s, 3H). LCMS (ES+) 425 (M+H)⁺.

EXAMPLE 54

3-(r5^r)-4-r2-(3H-Imidazol-4-yl)acetyllmorpholin-3-ylmethvU-l-methyl-lH-indole-5- carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and imidazole-4-acetic acid hydrochloride salt according to Method E and was isolated as a white solid (7 mg). 6_Η Cd₆-DMSO at 110⁰C) 7.74 (s, IH), 7.46 (s, IH), 7.40 (d, J8.6 Hz, IH), 7.22 (dd, J8.3, 1.3 Hz, IH), 7.16 (s, IH), 6.75 (s, IH), 4.46-4.37 (m, IH), 4.05-3.96 (m, IH), 3.88 (d, J7.6 Hz, IH), 3.76 (s, 3H), 3.73 (d, J 11.6 Hz, IH), 3.58-3.50 (m, IH), 3.48-3.43 (m, IH), 3.36 (dd, J 10.9, 3.0 Hz, 3H), 3.24 (dd, J 14.1, 9.1 Hz, IH), 3.01 (m, 6H), 2.98-2.90 (m, IH). LCMS (ES+) 410 (M+H)⁺.

EXAMPLE 55

3-(C5)-4-r2-(Imidazori.2-αlpyridin-2-vnacetvnmorpholin-3-ylmethvU-l-methyl-lH- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and imidazo[l,2-α]- pyridine-2 -acetic acid hydrochloride salt according to Method E and was isolated as a white solid (60 mg). δ_H (d₆-DMSO at HO⁰C) 8.40 (d, J 6.6 Hz, IH), 7.76 (s, IH), 7.64 (s, IH), 7.42 (d, J9.1 Hz, IH), 7.39 (d, J8.3 Hz, IH), 7.21 (dd, J8.3, 1.5 Hz, IH), 7.16 (m, 2H), 6.80 (t, J6.8 Hz, IH), 4.49-4.41 (m, IH), 4.10-4.01 (m, IH), 3.90 (d, J7.3 Hz, 2H), 3.77-3.71 (m, 5H), 3.45-3.34 (m, 3H), 3.25 (dd, J 14.1, 8.8 Hz, IH), 3.01-2.98 (s, 6H), 2.96-2.92 (m, IH). LCMS (ES+) 460 (M+H)⁺.

EXAMPLE 56

1 -Methyl-3 -\ (S)A-(I H-pyrrolo [23 -bλ p yridine-5 -carbonvnmorpholin-3 - ylmethyli - 1 H- indole-5-carboxylic acid dimethylamide

The title compound was prepared from Intermediate 3 and lH-pyrrolo[2,3-Z>]- pyridine-5-carboxylic acid according to Method E and was isolated as a white solid (15 mg). δ_Η (d₆-DMSO at 8O⁰C) 11.51 (s, IH), 8.01 (s, IH), 7.66 (s, IH), 7.52 (s, IH), 7.45

(t, J3.0 Hz, IH), 7.39 (d, J8.4 Hz, IH), 7.16 (dd, J 1.4, 8.4 Hz, IH), 7.11 (s, IH), 6.41

(dd, J 1.7, 3.3 Hz, IH), 4.36 (br s, IH), 3.92 (d, J 8.2 Hz, IH), 3.82-3.76 (m, 4H), 3.60

(dd, J3.0, 11.4 Hz, IH), 3.56-3.47 (m, 2H), 3.25-2.95 (m, 3H), 2.91 (s, 6H). LCMS

(ES+) 446 (M+H)⁺. EXAMPLE 57

1 -Methyl-3 - { (S)-4- β-f Pyridin-2-vnacetyl]morpholin-3 -ylmethyl } - 1 H-indole-5- carboxylic acid dimethylamide To a solution of Intermediate 3 (150 mg, 0.50 mmol), 2-pyridylacetic acid (86 mg,

0.50 mmol), EDC (142 mg, 0.75 mmol) and HOBT (75 mg, 0.50 mmol) in DCM (5 mL) was added DIPEA (177 μL, 1.00 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water (5 mL) and stirred for a further 30 minutes. The organic layer was separated, dried (phase separator), concentrated in vacuo and purified by preparative HPLC, yielding the title compound (42 mg, 20%) as a white solid. δ_H (de-DMSO at 100⁰C) 8.45-8.43 (m, IH), 7.74 (s, IH), 7.67 (t, J7.6 Hz, IH), 7.40 (d, J8.4 Hz, IH), 7.22-7.13 (m, 4H), 4.50-4.35 (m, IH), 4.10-3.92 (m, IH), 3.89 (d, J7.2 Hz, IH), 3.77-3.70 (m, 6H), 3.39-3.34 (m, 4H), 3.24 (dd, J 14.2, 8.9 Hz, IH), 2.98 (s, 6H). LCMS (ES+) 421(M+H)⁺.

EXAMPLE 58

3-{6Sy4-r2-(2-Amino- 1.3-thiazol-4-vnacetyllmorpholin-3-ylmethvU - 1 -methyl- IH- indole-5-carboxylic acid dimethylamide To a stirred solution of (2-amino-l,3-thiazol-4-yl)acetic acid ethyl ester (500 mg,

2.70 mmol) in TΗF (3 mL) was added a solution of LiOH (130 mg, 3.10 mmol) in water (1 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and treated with DMF (10 mL), followed by EDC (I g, 6.44 mmol), ΗOBT (500 mg, 3.70 mmol) and DIPEA (1 mL, 5.74 mmol). After stirring for 30 minutes at r.t. the reaction mixture was treated with a solution of Intermediate 3 (200 mg, 0.66 mmol) in DMF (1 mL) and heated to 7O⁰C for 2 h. The reaction mixture was partitioned between water (30 mL) and DCM (30 mL). The aqueous was washed with DCM (2 x 2OmL) and the combined organics were dried (Na₂SO₄ and phase separator), filtered and concentrated in vacuo. The residue was chromatographed (SiO₂, 0-20% MeOΗ/EtOAc) yielding an off-white solid, which was further purified by preparative ΗPLC to yield the title compound (70 mg, 6%) as a white solid. δ_Η (d₆-DMSO) 7.81 (s, 0.5H), 7.70 (s, 0.5H), 7.43 (t, J8.3 Hz, IH), 7.21 (s, 2H), 6.82 (d, J 13.6 Hz, 2H), 6.12 (d, J 13.1 Hz, IH), 4.52-4.45 (m, IH), 4.20-4.11 (m, IH), 3.95-3.82 (m, IH), 3.79-3.74 (m, 4H), 3.67 (dd, J24.0, 11.1 Hz, IH), 3.53 (s, IH), 3.29-3.12 (m, 3H), 3.02-2.94 (m, 7H), 2.78-2.70 (m, IH). LCMS (ES+) 442 (M+H)⁺.

EXAMPLE 59

3 - \(S)-4-(2- Aminopyridine-3 -carbonyl)morpholin-3 - ylmethyl] - 1 -methyl- 1 H-indole-5 - carboxylic acid dimethylamide

To a stirred solution of 2-aminonicotinic acid (45 mg, 0.33 mmol) in DMF (3 mL) was added EDC (150 mg, 0.96 mmol), ΗOBT (80 mg, 0.59 mmol) and DIPEA (180 μL, 1.03 mmol). The reaction mixture was stirred at 50⁰C for 2 h. To the resulting pale yellow solution was added Intermediate 3 (100 mg, 0.33 mmol) in DMF (3 mL) and the mixture was heated to 8O⁰C for 2 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous was washed with DCM (2 x 15 mL) and the combined organics were dried (Na₂SO₄ and phase separator), filtered, concentrated in vacuo and azeotroped with heptane (3 x 15 mL). The residue was purified by preparative ΗPLC, yielding the title compound (65 mg, 47%) as an off-white solid. δ_Η (d_δ-DMSO at 9O⁰C) 7.94 (d, J4.8 Hz, IH), 7.44 (s, IH), 7.39 (d, J8.5 Hz, IH), 7.18 (d, J 8.4 Hz, IH), 7.12 (s, IH), 7.08 (d, J7.3 Hz, IH), 6.46 (dd, J7.1, 5.1 Hz, IH), 5.56 (br s, 2H), 4.25- 4.18 (m, IH), 3.90 (d, J 10.8 Hz, IH), 3.76-3.70 (m, 4H), 3.59-3.42 (m, 4H), 3.24 (dd, J 14.2, 8.8 Hz, IH), 3.04 (dd, J 14.2, 6.5 Hz, IH), 2.99 (s, 6H). LCMS (ES+) 422 (M+H)⁺.

EXAMPLE 60

(6-Chloropyridin-3-vn-((5^f)-3-ri-methyl-5-r2-methylimidazol-l-yl)-lH-indol-3- ylmethyll morpholin-4-y 1 } -methanone

To a stirred solution of Intermediate 12 (155 mg, 0.50 mmol) in DCM (5 mL) at 0⁰C was added triethylamine (144 μL, 0.10 mmol) and 6-chloronicotinoyl chloride (97 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with water. The organic layer was separated, dried (MgSO₄) and concentrated in vacuo to yield an oil which was purified by preparative HPLC to give the title compound (32 mg, 14%) as an off-white solid. δ_H (d₆-DMSO at 9O⁰C) 7.98 (br s, IH), 7.49 (d, J 8.6 Hz, IH), 7.43-7.18 (m, 4H), 7.12-7.09 (m, 2H), 6.88 (d, J 1.2 Hz, IH), 4.20-4.13 (m, IH), 3.94-3.92 (m, IH), 3.86-3.81 (m, 5H), 3.67 (d, J 10.8 Hz, IH), 3.51 (d, J9.0 Hz, 2H), 3.21 (dd, J 14.1, 8.2 Hz, IH), 3.12-3.06 (m, IH), 2.22 (s, 3H). LCMS (ES+) 450 (M+H)⁺.

EXAMPLES 61 TO 75

General Procedure

To a stirred solution of the relevant carboxylic acid (0.036 mmol), Mukaiyama resin supported reagent from Polymer Labs (44 mg, 0.046 mmol, CPT004, 1.04 mmol/g) and Intermediate 3 (9.3 mg, 0.03 mmol) in DMF (1 mL) was added DIPEA (26.8 μL, 0.153 mmol). The reaction mixture was shaken for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC {Method 4), yielding the title compound.

EXAMPLES 76 TO 90

General Procedure

To a stirred solution of the relevant alcohol (0.05 mmol) in DCM (300 μL) at O⁰C were successively added a solution of 4-nitrophenyl chloro formate (12 mg, 0.06 mmol) in DCM (200 μL) and a solution of DIPEA (9.5 mg, 0.07 mmol) in DCM (100 μL). The mixture was stirred for 1 h at 0⁰C and 4 h at r.t. The reaction mixture was cooled to O⁰C prior to the successive addition of a solution of Intermediate 3 (30 mg, 0.1 mmol) in DCM (200 μL) and a solution of DIPEA (19 mg, 0.14 mmol) in DCM (100 μL). The reaction mixture was stirred at r.t. overnight. The reaction was then concentrated in vacuo (Genevac, EZ2) and the residue was purified by preparative HPLC {Method 4), yielding the title compound.

EXAMPLES 91 TO 97

The following compounds were prepared from the relevant carboxylic acid and the appropriate amine according to Method A, with heating to 45°C.

EXAMPLES 98 TO 132

The following compounds were prepared from the relevant amine and the appropriate carboxylic acid according to Method A.

EXAMPLES 133 TO 250 (METHOD F)

To a stirred solution of the appropriate amine (0.72 mmol), EDC (1.14 mmol) and HOBT (0.76 mmol) in DCM (5 mL) were added DIPEA (1.52 mmol) and the relevant carboxylic acid (0.76 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water (10 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and purified using preparative HPLC, to yield the title compound.

"%

EXAMPLES 251 TO 261

The following compounds were prepared from the relevant carboxylic acid and the appropriate amine according to Method F, heating the reaction mixture to 4O⁰C.

EXAMPLE 262 (METHOD G)

3-|^"(5^-4-(2-Chloro-6-methylpyridine-3 -carbon vDmorpholin-3-ylmethyl] - 1 -methyl- 1 H- indole-5-carboxylic acid dimethylamide To a stirred solution of Intermediate 3 (684 mg, 2.3 mmol) and DIPEA (494 μL,

3.0 mmol) in THF (25 mL) was added 2-chloro-6-methylnicotinoyl chloride (2.53 mmol). The reaction mixture was stirred at r.t. for 3 h. The reaction was partitioned between water (25 mL) and DCM (25 mL). The organic layer was washed with brine, separated, dried (magnesium sulphate) and concentrated in vacuo. The crude mixture was chromatographed (SiO₂, DCM→ 10% MeOH/DCM), yielding the title compound. δ_H (d₆- DMSO) 7.85-7.77 (m, 0.7H), 7.49-6.98 (m, 4.3H), 6.52 (d, J 7.8 Hz, 0.5H), 6.14 (d, J 7.8 Hz, 0.5H), 4.69-4.63 (m, 0.5H), 4.35-4.25 (m, 0.6H), 4.05-3.96 (m, 0.6H), 3.88-3.68 (m, 4.8H), 3.62-3.18 (m, 4.9H), 3.08-2.86 (m, 7.3H), 2.50-2.45 (m, 0.9H), 2.35-2.26 (m, 1.4H). LCMS (ES⁺) 455 (M+H)⁺.

EXAMPLE 263

3-[(5^r)-4-(6-Methoxypyridine-3-carbonyl)moφholin-3-ylmethyl]- 1 -methyl- lH-indole-5- carboxylic acid methyl ester Prepared from the relevant acyl chloride and the appropriate amine according to

Method G. δ_H (d₆-DMSO) 7.91 (d, J 8.3 Hz, IH), 7.87-7.75 (m, IH), 7.34-7.25 (m, 3H), 7.01-6.89 (m, IH), 6.50-6.33 (m, IH), 4.19-4.10 (m, IH), 4.10-4.02 (m, IH), 3.97-3.86 (m, 6H), 3.80 (m, 3H), 3.76-3.69 (m, IH), 3.66-3.55 (m, IH), 3.54-3.44 (m, IH), 3.43- 3.31 (m, IH), 3.23-3.02 (m, IH), 2.09-2.05 (m, IH), 1.33-1.22 (m, IH). LCMS (ES⁺) 424 (M+H)⁺.

EXAMPLES 264 TO 270 (METHOD H)

To a stirred solution of Intermediate 14 (300 mg, 0.76 mmol) in DMF (5 mL) were added the relevant substituted 2-iodoaniline (0.76 mmol), Pd(OAc)₂ (9 mg, 0.038 mmol), LiCl (32 mg, 0.76 mmol) and sodium carbonate (160 mg, 1.52 mmol). The reaction mixture was heated at 100⁰C for 2 h and then partitioned between brine (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and chromatographed (SiO₂, 25% EtOAc/hexanes). To the resulting solid was added HCl (4M in 1,4-dioxane, 10 niL) and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated sodium hydrogencarbonate solution (10 mL) and ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was chromatographed (SiO₂, 50% EtOAc/hexanes), yielding the title compound.

EXAMPLES 271 TO 275

The following compounds were prepared from the relevant substituted {(5)-3-[3- (trimethylsilanyl)prop-2-ynyl]morpholin-4-yl} methanone (1.00 mmol) and the appropriate substituted 2-iodoaniline according to Method H.

PREPARATIVE EXAMPLES 276 TO 278 (METHOD I)

To the relevant substituted {(S)-3-[3-(trimethylsilanyl)prop-2-ynyl]morpholin-4- yl}methanone (l.OOmmol) and the appropriate substituted 2-iodoaniline (1.00 mmol) in DMF (5 mL) were added Pd(OAc)₂ (0.05 mmol), LiCl (1.00 mmol) and sodium carbonate (2.00 mmol). The reaction mixture was heated at 100⁰C for 2 h and then partitioned between brine (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and chromatographed (SiO₂, 75% EtOAc/ hexanes), yielding the title compound.

EXAMPLES 279 TO 287 (METHOD j>

To the relevant precursor compound was added HCl (4M in 1,4-dioxane, 10 mL) and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated sodium hydrogencarbonate solution (10 mL) and ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was chromatographed (SiO₂, 50% EtOAc/hexanes), yielding the title compound.

EXAMPLE 288 (METHOD K)

(6-Methoxypyridin-3-ylV { (S)-3 - [ 1 -methyl-5 -(piperidin- 1 -ylmethyl)- 1 H-indol-3- ylmethvnmoφholin-4-yl } -methanone

To a stirred solution of Intermediate 19 (200 mg, 0.50 mmol) in 10:1 DCM: AcOH (4 mL) were added piperidine (99 μL, 1.00 mmol) and PS-BH₃CN (428 mg, 1.50 mmol). The reaction mixture was stirred for 16 h, then the resin was filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by preparative HPLC to afford the title compound (45 mg, 16%) as an off-white solid. δ_H (de-DMSO at 110⁰C) 7.98 (d, J 2.0 Hz, IH), 7.37 (dd, J8.3, 2.0 Hz, IH), 7.27 (d, J8.3 Hz, IH), 7.19 (s, IH), 7.10 (d, J 8.6 Hz, IH), 6.98 (s, IH), 6.65 (d, J8.6 Hz, IH), 4.29-4.21 (m, IH), 3.96-3.91 (m, IH), 3.89 (s, 3H), 3.85-3.77 (m, 2H), 3.72 (s, 3H), 3.60 (dd, J 11.4, 3.0 Hz, IH), 3.52-3.43 (m, 4H), 3.18 (dd, J 14.1, 7.8 Hz, IH), 3.07 (dd, J 14.1, 7.1 Hz, IH), 2.40-2.33 (m, 4H), 1.56- 1.48 (m, 4H), 1.46-1.38 (m, 2H). LCMS (ES⁺) 463 (M+H)⁺.

EXAMPLES 289 TO 291

The following compounds were prepared from the relevant aldehyde and the appropriate amine according to Method K.

EXAMPLE 292 (METHOD L)

3-[(_lS^r)-4-(4-Cyanobenzoyl)moφholin-3-ylmethyl]-l-methyl-lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of 4-cyanobenzoic acid (63 mg, 0.4 mmol) and Intermediate 3 (151 mg, 0.5 mmol) in DCM was added PS-CDI (1 g, 1 mmol). The reaction mixture was stirred at r.t. for 16 h prior to filtration. The resin was washed with MeOH (5 mL) then DCM (5 mL) and the filtrate was concentrated in vacuo to yield a yellow oil. To a solution of the yellow oil in DCM (5 mL) were added PS-NCO (0.5 g, 1.5 mmol) and TEA (one drop). The reaction mixture was stirred for 5 h, then filtered and concentrated in vacuo. The resulting oil was partitioned between EtOAc (5 mL) and water (5 mL). The organic layer was separated, dried (phase separator) and concentrated in vacuo. The residue was purified by preparative HPLC to yield the title compound (90 mg, 52%) as a white solid. δ_H (d₆-DMSO at 11O⁰C) 7.65 (d, J 7.6 Hz, 2H), 7.47-7.37 (m, 2H), 7.25-7.17 (m, 3H), 7.11 (s, IH), 4.20-4.09 (m, IH), 3.96-3.90 (m, IH), 3.83-3.73 (m, 5H), 3.63-3.57 (m, IH), 3.55-3.43 (m, 2H), 3.23-3.09 (m, 2H), 2.99 (s, 6H). LCMS (ES⁺) 431 (M+H)⁺.

EXAMPLES 293 TO 305

The following compounds were prepared from Intermediate 3 and the appropriate substituted carboxylic acid according to Method L.

EXAMPLES 306 TO 322

The following compounds were prepared from the relevant precursor amine and the appropriate acyl chloride according to Method D.

EXAMPLE 323 (METHOD M)

{(Sl-S-rS-K-MethoxyphenylVl-methyl-lH-indol-S-ylmethyllmorpholin^-yll-Cό- methoxypyridin-3 -ylVmethanone

To a stirred solution of Example 365 (193 mg, 0.48 mmol) in «-BuOΗ (4 mL) were added 4-methoxybenzeneboronic acid (109 mg, 0.72 mmol), potassium phosphate (212 mg, 1.0 mmol), XPhos (9 mg, 0.019 mmol) and Pd₂(dba)₃ (4.4 mg, 0.005 mmol). The reaction mixture was heated to reflux for 4 h, then partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting brown oil was purified by preparative HPLC, yielding the title compound (40 mg, 18%) as an off-white solid. δ_H (de-DMSO at 110⁰C) 7.95 (d, J2.0 Hz, IH), 7.56 (s, IH), 7.51 (d, J 8.6 Hz, 2H), 7.42-7.34 (m, 2H), 7.30 (dd, J 8.1, 1.3 Hz, IH), 7.05 (s, IH), 7.01 (d, J8.6 Hz, 2H), 6.57 (d, J8.6 Hz, IH), 4.38-4.30 (m, IH), 3.97-3.92 (m, IH), 3.88-3.81 (m, 5H), 3.80 (s, 3H), 3.76 (s, 3H), 3.63 (dd, J 11.6, 3.0 Hz, IH), 3.51 (d, J 8.8 Hz, 2H), 3.22-3.15 (m, 2H). LCMS (ES⁺) 472 (M+H)⁺.

EXAMPLES 324 TO 326

The following compounds were prepared from Example 365 and the appropriate boronic acid according to Method M.

EXAMPLE 327 (METHOD N)

Di( 1 -propanesulfonic acid) (3 - r(5y4-(6-methoxypyridine-3 -carbonyl)morpholin-3 - ylmethyll- 1 -methyl-lH-indol-5-vU amide

To a stirred solution of Intermediate 21 (100 mg, 0.26 mmol) in DCM (3 mL) was added TEA (54 μL, 0.39 mmol), followed by 1-propanesulfonyl chloride (29 μL, 0.26 mmol). The reaction mixture was stirred at r.t. for 2 h, then diluted with DCM (10 mL) and washed with brine (2 x 10 mL). The aqueous layer was extracted with DCM (20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by preparative ΗPLC, yielding the title compound (4 mg, 3%) as an off-white solid. δ_Η (d₆-DMSO at HO⁰C) 8.03 (d, J2.0 Hz, IH), 7.66 (d, J 1.8 Hz, IH), 7.46-7.41 (m, 2H), 7.18-7.14 (m, 2H), 6.71 (d, J8.6 Hz, IH), 4.38-4.29 (m, IH), 3.94-3.87 (m, 4H), 3.83-3.78 (m, IH), 3.78 (s, 3H), 3.75-3.68 (m, IH), 3.64-3.57 (m, 5H), 3.57-3.48 (m, 2H), 3.29-3.21 (m, IH), 3.15-3.07 (m, IH), 1.94-1.83 (m, 4H), 1.04 (t, J 7.6 Hz, 6H). LCMS (ES⁺) 593 (M+H)⁺.

EXAMPLES 328 TO 333

The following compouinds were prepared from the relevant precursor amine and the appropriate sulfonyl chloride according to Method N.

EXAMPLES 334 TO 337 (METHOD O)

To a stirred solution of the relevant amine precursor (0.07 mmol) and TEA (0.14 mmol) in DCM (5 mL) was added acetic anhydride (0.14 mmol). The reaction mixture was stirred at r.t. for 1 h, then partitioned between DCM (10 mL) and water (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL) and the combined organic layers were dried (sodium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 20-50% MeOH/EtOAc), yielding the title compound.

EXAMPLE 338 (METHOD P)

iV-Methyl-N-{l-methyl-3-fffl-4-(6-methylpyridine-3-carbonyl)moφholin-3-ylmethyl1- 1 H-indol-5 - ylmethyl } acetamide

To a stirred solution of Intermediate 37 (240 mg, 0.64 mmol) in 10:1 DCM:AcOΗ (10 mL) were added methylamine (33% in EtOH; 0.15 mL, 1.28 mmol) and PS-BH₃CN (428 mg, 1.5 mmol). The reaction mixture was stirred for 72 h, then filtered. The filtrate was concentrated in vacuo. The residue was treated with acetic anhydride (0.5 mL, 6.4 mmol) and DMAP (10 mg). The reaction mixture was stirred at r.t. for 30 minutes, then partitioned between DCM (25 mL) and water (50 mL). The organic layer was dried (phase separator) and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (81 mg, 29%) as a white solid. δ_H (d₆-DMSO at HO⁰C) 8.19 (s, IH), 7.33-7.25 (m, 3H), 7.11 (d, J7.9 Hz, IH), 7.02-7.00 (m, 2H), 4.54 (s, 2H), 4.28-4.24 (m, IH), 3.94-3.91 (m, IH), 3.81-3.79 (m, 2H), 3.72 (s, 3H), 3.60 (dd, J 11.5, 3.2 Hz, IH), 3.54-3.47 (m, 2H), 3.20-3.07 (m, 2H), 2.84 (s, 3H), 2.46 (s, 3H), 2.08 (s, 3H). LCMS (ES⁺) 435 (M+H)⁺.

EXAMPLES 339 TO 343

The following compounds were prepared from Intermediate 37 and the appropriate amine according to Method P.

EXAMPLE 344 (METHOD O)

(6-Methylpyridin-3-ylV((5)-3-ri-methyl-5-(thiophene-2-carbonyl)-lH-indol-3-ylmethyll- morpholin-4-vU -methanone

To a stirred solution of Example 376 (190 mg, 0.44 mmol) in TΗF (1 mL) at -7O⁰C under nitrogen was added 2-thienylmagnesium bromide (IM solution in TΗF; 874 μL, 0.087 mmol) dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 16 h, then partitioned between DCM (10 mL) and brine (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-3% MeOΗ/DCM), and further purified by preparative ΗPLC, yielding the title compound (145 mg, 72%) as a yellow solid. δ_Η (d₆-DMSO at HO⁰C) 8.14 (s, IH), 8.02 (s, IH), 7.96 (dd, J5.1, 0.8 Hz, IH), 7.73 (dd, J3.5, 0.8 Hz, IH), 7.70 (dd, J8.6, 1.5 Hz, IH), 7.52 (d, J 8.6 Hz, IH), 7.28-7.18 (m, 3H), 7.02 (d, J 7.8 Hz, IH), 4.33-4.26 (m, IH), 3.96-3.90 (m, IH), 3.87-3.77 (m, 5H), 3.65 (dd, J 11.6, 3.3 Hz, IH), 3.53-3.47 (m, 2H), 3.21 (d, J7.6 Hz, 2H), 2.38 (s, 3H). LCMS (ES⁺) 460 (M+H)⁺.

EXAMPLES 345 TO 347

The following compounds were prepared from Example 376 and the appropriate Grignard reagent according to Method Q.

EXAMPLE 348

S-lffl^-rό-Methoxy-S-faifluoromethyπpyridine-S-carbonyiimorpholin-S-ylmethvU-l- methyl- lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 133 (200 mg, 0.4 mmol) in DCM (5 mL) was added a solution of sodium hydroxide (500 mg) in MeOH (5 mL). The resulting mixture was stirred for 0.5 h at r.t. prior to the addition of water (10 mL) and DCM (10 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and chromatographed (SiO₂, 75% EtOAc/hexanes + 1% MeOH), yielding the title compound (95 mg, 50%) as a white solid after freeze-drying with 1:1 MeCN-water. 5_Η (d₆-DMSO at HO⁰C) 8.16 (s, 1Η), 7.58-7.49 (m, 2Η), 7.37 (d, J 8.6 Hz, IH), 7.18 (dd, 78.3, 1.3 Hz, IH), 7.11 (s, IH), 4.31-4.23 (m, IH), 4.00 (s, 3H), 3.95 (d, J7.8 Hz, IH), 3.89-3.84 (m, IH), 3.82-3.78 (m, IH), 3.76 (s, 3H), 3.69 (dd, J 11.4, 3.0 Hz, IH), 3.60 -3.49 (m, 2H), 3.27-3.18 (m, IH), 3.17-3.10 (m, IH), 2.96 (s, 6H). LCMS (ES+) 505 (M+H)⁺. EXAMPLE 349

3-[(5)-4-(6-Methoxypyridine-3-carbonyl)morpholin-3-ylmethyl1-l -methyl- lH-indole-5- carboxylic acid To a stirred solution of Example 263 (1.19 g, 2.0 mmol) in MeOH (30 niL) was added sodium hydroxide solution (2M, 2.0 mL, 4.0 mmol). The reaction mixture was heated at reflux for 15minutes. A further excess of sodium hydroxide solution (2M, 20 mL) was added and the reaction heated under reflux for 0.5 h. The reaction mixture was cooled and concentrated in vacuo. The aqueous residue was acidified using HCl (2M, 25 mL) to pH 2. The gummy solid was dissolved in DCM, dried (magnesium sulphate) and concentrated in vacuo, yielding the title compound (690 mg, 84%) as a brown oil. 5_H (d₆- DMSO at HO⁰C) 11.79-11.34 (m, IH), 8.10 (s, IH), 7.89 (s, IH), 7.76 (d, J8.6 Hz, IH), 7.41 (d, J8.6 Hz, IH), 7.31 (d, J8.1 Hz, IH), 7.14 (s, IH), 6.59 (d, J8.6 Hz, IH), 4.37- 4.30 (m, IH), 3.94 (d, J7.6 Hz, IH), 3.88-3.77 (m, 8H), 3.65 (dd, J 11.4, 2.8 Hz, IH), 3.50 (d, J8.6 Hz, 2H), 3.23-3.16 (m, 2H). LCMS (ES⁺) 408 (M+H)⁺.

EXAMPLE 350

3-[(5^-4-(6-Methoxypyridine-3-carbonyl)morpholin-3-ylmethyl1-lH-indole-7-carboxylic acid methyl ester

To a stirred solution of Intermediate 15 (332 mg, 1.00 mmol) in DMF (5 mL) were added 2-amino-5-chloro-3-iodobenzoic acid methyl ester (311 mg, 1.00 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), LiCl (42 mg, 1.00 mmol) and sodium carbonate (212 mg, 2.00 mmol). The reaction mixture was heated at 100⁰C for 2 h and then partitioned between brine (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried (magnesium sulphate), concentrated in vacuo and chromatographed (SiO₂, 75% EtOAc/ hexanes). To the resulting solid (290 mg, 0.56 mmol) was added HCl (4M in 1,4- dioxane, 10 mL) and the reaction mixture was stirred at r.t. for 1 h, then concentrated in vacuo. The residue was partitioned between aqueous sodium hydrogencarbonate solution (10 mL) and ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), dried (magnesium sulphate) and concentrated in vacuo. To the resulting residue (200 mg, 0.45 mmol) in EtOH (4 mL) were added ammonium formate (150 mg, 2.3 mmol) and 10% Pd/C (20 mg). The reaction mixture was heated under microwave irradiation at 16O⁰C for 2 h, then filtered through celite. The residue was concentrated in vacuo, then chromatographed (SiO₂, 50% EtOAc/hexanes), yielding the title compound (70 mg, 17%) as an off-white solid. δ_H (d₆-DMSO at 110⁰C) 10.61 (s, IH), 7.97 (s, IH), 7.75 (d, J 7.6 Hz, IH), 7.64 (d, J7.6 Hz, IH), 7.37 (m, IH), 7.19 (s, IH), 7.02 (t, J7.6 Hz, IH), 6.62 (d, J8.6 Hz, IH), 4.35-4.27 (m, IH), 3.98-3.92 (m, 4H), 3.88 (s, 3H), 3.84-3.76 (m, 2H), 3.62 (dd, J 11.6, 3.0 Hz, IH), 3.50 (d, J 8.8 Hz, 2H), 3.26-3.13 (m, 2H). LCMS (ES⁺) 410 (M+H)⁺.

EXAMPLE 351

{ (S)-3 -[5-(DimethylaminomethylV 1 -methyl- 1 H-indol-3 -ylmethylimorpholin-4-vU -(6- methoxypyridin-3 -yl)-methanone

Intermediate 16 (402 mg, 1.04 mmol) was dissolved in 4M HCl in 1,4-dioxane (10 mL). After 2 h the solution was concentrated in vacuo, and the residue was dissolved in ethyl acetate (10 mL) and shaken with aqueous sodium carbonate solution (10 mL). The organic layer was separated, dried (magnesium sulphate) and cooled at 0⁰C. TEA (285 μL, 2 mmol) and 6-methoxynicotinoyl chloride (240 mg, 0.84 mmol) were added to the stirred solution. The reaction mixture was stirred at r.t. for 30 minutes, shaken with water (10 mL) and the organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting oil was purified by preparative ΗPLC to afford the title compound (120 mg, 27%) as an off-white solid. δ_Η (d₆-DMSO at 110⁰C) 7.97 (s, IH), 7.36 (d, J8.3 Hz, IH), 7.28 (d, J8.3 Hz, IH), 7.20 (s, IH), 7.09 (d, J 8.3 Hz, IH), 6.99 (s, IH), 6.64 (d, J 8.3 Hz, IH), 4.29-4.22 (m, IH), 3.97-3.92 (m, IH), 3.90-3.77 (m, 5H), 3.72 (s, 3H), 3.60 (dd, J 11.4, 3.0 Hz, IH), 3.49 (m, 2H), 3.44 (s, 2H), 3.17 (dd, J 14.4, 7.8 Hz, IH), 3.08 (dd, J 14.4, 7.3 Hz, IH), 2.18 (s, 6H). LCMS (ES⁺) 423 (M+H)⁺.

EXAMPLE 352

3 - [(5^r)-4-(6-Methoxypyridine-3 -carbon yl)morpholin-3 -ylmethyl]- 1 -methyl- 1 H-indole-5- carboxylic acid ferf-butyl ester

To Example 349 (95 mg, 0.23 mmol) was added DMF.DBA (0.5mL). The reaction mixture was heated at 100-130⁰C for 20 minutes. The excess reagent was removed in vacuo and the residue was chromatographed (SiO₂, 75% EtOAc/hexanes), yielding the title compound (74 mg, 69%) as an off-white solid. δ_H Cd₆-DMSO at HO⁰C) 8.08 (s, IH), 7.89 (s, IH), 7.71 (d, J8.6 Hz, IH), 7.39 (d, J8.6 Hz, IH), 7.32 (d, J8.1 Hz, IH), 7.14 (s, IH), 6.61 (d, J8.3 Hz, IH), 4.38-4.28 (m, IH), 3.94 (d, J7.6 Hz, IH), 3.88- 3.76 (m, 8H), 3.65 (dd, J 11.6, 3.0 Hz, IH), 3.57-3.45 (m, 2H), 3.24-3.13 (m, 2H), 1.59 (s, 9H). LCMS (ES⁺) 466 (M+H)⁺.

EXAMPLE 353

[(5^f)-3-(5-Chloro-lH-indol-3-ylmethyl^')moφholin-4-yll-(6-methoxypyridin-3-yl^')- methanone

Intermediate 5 (100 mg, 237 μmol) was dissolved in 4M HCl in 1,4-dioxane (4 mL). After 1 h the solution was concentrated in vacuo, and the residue was dissolved in DCM (5 mL) and shaken with aqueous sodium carbonate solution (5 mL). The organic layer was separated, dried (magnesium sulphate) and cooled at O⁰C. TEA (70 μL, 0.47 mmol) and 6-methoxynicotinoyl chloride (45 mg, 261 μmol) were added to the stirred solution. The reaction mixture was stirred at r.t. for 18 h, shaken with water (10 mL) and the organic layer was separated, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by preparative ΗPLC to afford the title compound (11 mg, 84%) as a white solid. δ_Η (d₆-DMSO at HO⁰C) 10.75 (m, IH), 7.96 (s, IH), 7.38- 7.27 (m, 3H), 7.16-7.13 (m, IH), 7.02 (d, J8.6 Hz, IH), 6.63 (d, J8.3 Hz, IH), 4.31-4.24 (m, IH), 3.94 (m, IH), 3.90 (s, 3H), 3.85-3.75 (m, 2H), 3.62 (dd, J 11.6, 3.0 Hz, IH), 3.55-3.42 (m, 2H), 3.18-3.07 (m, 2H). LCMS (ES⁺) 386 (M+H)⁺.

EXAMPLES 354 & 355

l-{3-r(5^f)-4-(6-Methoxypyridine-3-carbonyl^')morpholin-3-ylmethyll-l-methyl-lH-indol- 5-vU -2-methylpropan- 1 -one and 2,2-Dimethyl- 1 - {3-[T.Sy4-(6-methoxypyridine-3- carbonyl)morpholin-3 -ylmethyll - 1 -methyl- 1 //-indol-5 -yll propan- 1 -one

To a stirred solution of Intermediate 22 (1.1 g, 2.4 mmol) in THF (21 mL) at -78⁰C was added methyl iodide (3 mL) followed by a solution of LiHMDS (IM solution in hexanes, 10 mL). The reaction mixture was stirred for 20 minutes at -78⁰C, then allowed to warm to r.t. and stirred for 16 h. The reaction mixture was partitioned between ammonium chloride solution (100 mL) and EtOAc (100 mL). The organic layer was separated, dried (sodium sulphate), filtered (phase separator) and concentrated in vacuo. The residue was treated with DCM (2 mL) and 4M HCl in 1,4-dioxane (10 mL) and stirred for 10 minutes. The reaction mixture was then partitioned between saturated sodium carbonate solution (100 mL) and EtOAc (100 mL). The organic layer was separated, dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-100% EtOAc/hexanes), yielding l-{3-[(S)-4-(6- methoxypyridine-3-carbonyl)morpholin-3-ylmethyl]-l-methyl-lH-indol-5-yl}-2- methylpropan-1-one (241 mg, 23%) as a white solid. δ_H (d₆-DMSO at HO⁰C) 8.12 (s, IH), 7.89 (d, J 1.8 Hz, IH), 7.76 (dd, J 8.8, 1.8 Hz, IH), 7.44 (d, J 8.6 Hz, IH), 7.28 (d, J 7.6 Hz, IH), 7.15 (s, IH), 6.58 (d, J8.6 Hz, IH), 4.38-4.29 (m, IH), 3.95 (d, J7.3 Hz, IH), 3.89-3.77 (m, 8H), 3.72-3.63 (m, 2H), 3.57-3.47 (m, 2H), 3.28-3.14 (m, 2H), 1.16 (dd, J 6.6, 4.8 Hz, 6H). LCMS (ES⁺) 436 (M+H)⁺. Further purification by preparative HPLC yielded 2, 2-dimethyl-l-{3-[(S)-4-(6-methoxypyridine-3-carbonyl)morpholin-3- ylmethylj-l -methyl- lH-indol-5-yljpropan-l -one (12 mg, 1%) as a white solid. 5_H (d₆- DMSO at 11O⁰C) 7.95 (m, 2H), 7.59 (dd, J8.6, 1.8 Hz, IH), 7.40 (d, J8.6 Hz, IH), 7.34 (dd, J8.3, 1.8 Hz, IH), 7.13 (s, IH), 6.62 (d, J8.3 Hz, IH), 4.35-4.27 (m, IH), 3.93 (d, J 7.6 Hz, IH), 3.89-3.75 (m, 8H), 3.62 (dd, J 11.6, 3.3 Hz, IH), 3.55-3.49 (m, 2H), 3.12- 3.26 (m, 2H), 1.36 (s, 9H). LCMS (ES⁺) 450 (M+H)⁺.

PREPARATIVE EXAMPLE 356

1 -Methyl-3 -[(^-4-(6-methylpyridine-3 -carbonyl)morpholin-3 -ylmethyll -2- (trimethylsilanyl)-lH-indole-5-carboxylic acid methyl ester

To a stirred solution of Example 277 (3.71 g, 8.0 mmol) in TΗF (50 mL) at -78⁰C was added methyl iodide (1.5 mL, 24 mmol) followed by a solution of LiΗMDS (1.06M solution in TΗF; 15 mL, 16 mmol). The reaction mixture was stirred for 2 h at -78°C, then allowed to warm to r.t. and stirred for 2 h. The reaction mixture was partitioned between brine (100 mL) and EtOAc (100 mL). The organic layer was separated, dried (sodium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 80- 100% EtOAc/hexanes to 5% MeOΗ/EtOAc), yielding the title compound (3.489 g, 91%) as an off-white solid. δ_Η (d₆-DMSO at 110⁰C) 8.25 (s, IH), 8.11 (s, IH), 7.79-7.77 (m, IH), 7.44 (dd, J8.8, 2.3 Hz, IH), 7.27 (m, IH), 7.13 (d, J7.6 Hz, IH), 4.35 (s, IH), 3.94 (d, J 10.9 Hz, IH), 3.84 (s, 3H), 3.76-3.73 (m, IH), 3.70 (d, J 11.6 Hz, IH), 3.59-3.45 (m, 3H), 3.39 (dd, J 14.4, 8.3 Hz, IH), 3.23 (dd, J 14.4, 7.1 Hz, IH), 2.90 (s, 3H), 2.46 (s, 3H), 0.44 (s, 9H). LCMS (ES⁺) 480 (M+H)⁺.

EXAMPLE 357

3 -[(S)-4-(6-Methylpyridine-3 -carbonyl)morpholin-3 - ylmethyll - 1 H-indole-5-carboxylic acid methyl ester

To a stirred solution of Example 277 (1 g, 2.15 mmol) in TΗF (12 mL) was added HCl (4M in 1,4-dioxane, 12 mL). The reaction mixture was stirred at r.t. for 5 h, then partitioned between 2M sodium carbonate solution (50 mL) and EtOAc (50 mL). The aqueous layer was washed with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried (sodium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-20% MeOΗ/EtOAc), yielding the title compound (779 mg, 92%) as a yellow solid. δ_Η (d₆-DMSO at HO⁰C) 10.90 (s, IH), 8.14 (s, IH), 8.07 (s, IH), 7.71 (dd, J8.6, 1.5 Hz, IH), 7.41 (d, J8.6 Hz, IH), 7.21- 7.18 (m, 2H), 7.01 (d, J7.8 Hz, IH), 4.32 (s, IH), 3.97-3.89 (m, IH), 3.86 (s, 3H), 3.83- 3.81 (m, IH), 3.79-3.77 (m, IH), 3.65 (dd, J 11.6, 3.3 Hz, IH), 3.54-3.45 (m, 2H), 3.24 (dd, J 14.4, 7.8 Hz, IH), 3.18 (dd, J 14.7, 7.3 Hz, IH), 2.41 (s, 3H). LCMS (ES⁺) 394 (M+H)⁺.

EXAMPLE 358

3 - [(iSy4-(6-Methylpyridine-3-carbonyl)morpholin-3 - ylmethyll - 1 H-indole-5 -carboxylic acid To a stirred solution of Example 357 (769 mg, 1.94 mmol) in MeOH (20 mL) was added 10% NaOH solution (2.5M, 4 mL). The reaction mixture was heated to reflux and stirred for 5 h. The reaction mixture was cooled to r.t., acidified with IM HCl and then concentrated in vacuo. The residue was washed with DCM to give a precipitate, which was washed with water, then filtered. The resulting solid was washed with DCM (10 mL) and hexane (10 mL) and dried in a vacuum oven, yielding the title compound (642 mg, 87%) as a brown glassy solid. δ_Η (d₆-DMSO at HO⁰C) 11.76 (br s, IH), 10.91 (s, IH), 8.16 (s, IH), 8.05 (s, IH), 7.71 (dd, J8.3, 1.3 Hz, IH), 7.39 (d, J8.6 Hz, IH), 7.22 (d, J 5.1 Hz, IH), 7.16 (s, IH), 7.02 (d, J7.6 Hz, IH), 4.31 (s, IH), 3.94 (d, J7.6 Hz, IH), 3.83 (d, J 11.4 Hz, IH), 3.80-3.78 (m, IH), 3.64 (dd, J 11.4, 2.8 Hz, IH), 3.51-3.49 (m, 2H), 3.25-3.15 (m, 2H), 2.42 (s, 3H). LCMS (ES⁺) 380 (M+H)⁺.

EXAMPLE 359

((5)-3-[5-(lJ-Dioxidoisothiazolidin-2-ylVl-methyl-lH-indol-3-ylmethyl1morpholin-4- yl 1 -(6-methoxypyridin-3 -ylVmethanone

To a stirred solution of Intermediate 24 (140 mg, 0.209 mmol) in MeCN (5 mL) was added potassium carbonate (93 mg, 0.673 mmol). The reaction mixture was heated at 8O⁰C for 3 h. The reaction mixture was allowed to cool to r.t. and then concentrated in vacuo. The residue was diluted with DCM (15 mL), then washed with brine (2 x 15 mL). The aqueous layer was extracted with DCM (15 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 2% MeOH:EtOAc), yielding the title compound (103 mg, 79%) as a pale pink solid. δ_H (de-DMSO at HO⁰C) 7.97 (d, J2.3 Hz, IH), 7.38-7.33 (m, 2H),

7.31-7.28 (m, IH), 7.18 (dd, J8.6, 2.0 Hz, IH), 7.07 (s, IH), 6.66 (d, J8.6 Hz, IH), 4.34- 4.26 (m, IH), 3.93 (d, J 7.6 Hz, IH), 3.89 (s, 3H), 3.84-3.76 (m, 2H), 3.74 (s, 3H), 3.70 (t, J6.6 Hz, 2H), 3.61 (dd, J 11.4, 3.0 Hz, IH), 3.50 (d, J9.1 Hz, 2H), 3.41-3.36 (m, 2H), 3.20-3.08 (m, 2H), 2.49-2.40 (m, 2H). LCMS (ES⁺) 485 (M+H)⁺.

EXAMPLE 360

7-Acetyl-3-[(5^r)-4-(6-methylpyridine-3-carbonyl^')morpholin-3-ylmethyll-lH-indole-5- carboxylic acid dimethylamide To a stirred solution of Intermediate 27 (100 mg, 0.24 mmol), ΗATU (108 mg,

0.29 mmol) and dimethylamine hydrochloride (25 mg, 0.29 mmol) in DCM (10 mL) was added DIPEA (166 μL, 0.96 mmol). The reaction mixture was stirred at r.t. for 3 h and then partitioned between water (10 mL) and DCM (5 mL). The organic layer was washed with water (2 x 10 mL), dried (phase separator) and concentrated in vacuo. The residue was purified by preparative ΗPLC, yielding the title compound (27 mg, 25%) as a white solid. δ_Η (d₆-DMSO at HO⁰C) 11.02 (s, IH), 8.19 (s, IH), 7.88-7.78 (m, 2H), 7.34-7.23 (m, 2H), 7.06 (d, J7.8 Hz, IH), 4.31-4.21 (m, IH), 3.95-3.89 (m, IH), 3.84-3.72 (m, 2H), 3.61 (dd, J 11.6, 2.8 Hz, IH), 3.57-3.45 (m, 2H), 3.22 (d, J7.6 Hz, 2H), 3.05 (s, 6H), 2.68 (s, 3H), 2.44 (s, 3H). LCMS (ES⁺) 449 (M+H)⁺.

EXAMPLE 361

\(S)-3 -(5 -Benzoyl- 1 -methyl- 1 H-indol-3 - ylmethyl)morpholin-4- y 11 -(6-methoxypyridin-3 - vQ-methanone

To a stirred solution of Intermediate 29 (190 mg, 0.36 mmol) in TΗF (3 mL) at O⁰C were added LiΗMDS (IM solution; 0.5 mL, 0.50 mmol) and MeI (0.05 mL, 0.70 mmol). The solution was warmed to r.t. and stirred for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated ammonium chloride solution (10 mL). The aqueous layer was separated and extracted with EtOAc (10 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo to give a pale yellow oil, which was dissolved in DCM (1 mL) and treated with HCl (4M in 1,4- dioxane, 3 mL). The reaction mixture was stirred at r.t. for 20 minutes prior to being partitioned between EtOAc (50 mL) and saturated sodium carbonate solution (20 mL). The aqueous layer was separated and extracted with EtOAc (10 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-100% EtOAc/hexanes to 2% MeOΗ/EtOAc) to give the title compound (107 mg, 63%) as a white solid. δ_Η (d₆-DMSO at 110⁰C) 7.91 (s, IH), 7.85 (d, J2.0 Hz, IH), 7.71 (m, 2H), 7.62 (m, 2H), 7.56-7.47 (m, 3H), 7.25 (dd, J8.6, 2.0 Hz, IH), 7.18 (s, IH), 6.58 (d, J8.3 Hz, IH), 4.32-4.24 (m, IH), 3.94-3.89 (m, IH), 3.86-3.77 (m, 8H), 3.65 (dd, J 11.4, 3.0 Hz, IH), 3.53-3.43 (m, 2H), 3.21 (m, IH), 3.12 (m, IH). LCMS (ES⁺) 470 (M+H)⁺.

EXAMPLE 362

[(_l$^-3-(5-Hydroxy-l-methyl-lH-indol-3-ylmethyl^')morpholin-4-yll-(6-methylpyridin-3- ylVmethanone To a stirred solution of Intermediate 30 (1.0 g, 2.24 mmol) in EtOH (40 mL) were added NH₄HCO₂ (1.39 g, 22 mmol) and 10% Pd/C (100 mg, 0.11 mmol). The reaction mixture was heated to reflux for 2 h, then cooled and filtered though celite. The filtrate was concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (5OmL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The brown foam was purified using preparative HPLC, yielding the title compound (32 mg, 4%) as a white solid. δ_H (d₆-DMSO at 11O⁰C) 8.25 (s, IH), 7.33 (d, J7.6 Hz, IH), 7.12 (d, J8.6 Hz, 2H), 6.89 (s, IH), 6.73-6.64 (m, 2H), 4.28-4.19 (m, IH), 3.95-3.88 (m, IH), 3.83-3.74 (m, 2H), 3.66 (s, 3H), 3.57 (dd, J 11.6, 3.0 Hz, IH), 3.52-3.41 (m, 2H), 3.16-2.91 (m, 2H), 2.48 (s, 3H). LCMS (ES⁺) 366 (M+H)⁺.

EXAMPLE 363

{(5')-3-r5-(2-Methoxyethoxy)-l-methyl-lH-indol-3-ylmethyllmort>holin-4-vU-(^'6-methyl- pyridin-3 - vD-methanone

To a stirred solution of Example 362 (100 mg, 0.27 mmol) and l-bromo-2- methoxyethane (52 μL, 0.55 mmol) in TΗF (10 mL) was added caesium carbonate (62 mg, 0.19 mmol). The reaction mixture was heated to 9O⁰C for 2 h, then cooled and partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The brown oil was purified using preparative ΗPLC, yielding the title compound (25 mg, 22%) as a white solid. 6_Η ((h- DMSO at 110⁰C) 8.21 (s, 1Η), 7.28-7.21 (m, 2Η), 7.08 (d, J7.8 Hz, IH), 6.97 (s, IH), 6.89 (s, IH), 6.80 (dd, J 8.8, 1.3 Hz, IH), 4.28-4.20 (m, IH), 4.10-4.02 (m, 2H), 3.96-3.90 (m, IH), 3.80 (d, J 11.6 Hz, 2H), 3.73-3.66 (m, 5H), 3.60 (dd, J 11.4, 3.0 Hz, IH), 3.53- 3.45 (m, 2H), 3.37 (s, 3H), 3.11 (m, 2H), 2.46 (s, 3H). LCMS (ES⁺) 424 (M+H)⁺.

EXAMPLE 364

2-(3 - { 1 -Methyl-3 -\ (ιS^r)-4-(6-methylpyridine-3 -carbonvDmorpholi n-3 -ylmethyl] - 1 H-indol- 5-yloxy}propyl)isoindole-l,3-dione

To a stirred solution of Example 362 (100 mg, 0.27 mmol) and 2-(3-bromo- propyl)isoindole-l,3-dione (147 mL, 0.55 mmol) in TΗF (10 mL) was added caesium carbonate (62 mg, 0.19 mmol). The reaction mixture was heated to 90⁰C for 2 h, then cooled and partitioned between DCM (10 mL) and water (1OmL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The brown oil was purified using preparative ΗPLC, yielding the title compound (50 mg, 33%) as a white solid. δ_Η (d₆-DMSO at 11O⁰C) 8.18 (s, IH), 7.88-7.79 (m, 4H), 7.28-7.16 (m, 2H), 7.06 (d, J7.8 Hz, IH), 6.95 (s, IH), 6.83 (s, IH), 6.69 (d, J8.6 Hz, IH), 4.26-4.17 (m, IH), 4.05-3.98 (m, 2H), 3.95-3.91 (m, IH), 3.86-3.76 (m, 4H), 3.68 (s, 3H), 3.60 (dd, J 11.6, 3.0 Hz, IH), 3.52-3.44 (m, 2H), 3.10-3.01 (m, 2H), 2.44 (s, 3H), 2.17-2.05 (m, 2H). LCMS (ES⁺) 553 (M+H)⁺.

EXAMPLE 365

[(^-S-CS-Chloro-l-methyl-lH-indol-S-ylmethvπmorpholin^-yll-rό-methoxypyridin-S- ylVmethanone To a stirred solution of Example 353 (1.91 g, 4.95 mmol) in TΗF (100 mL) at

-78⁰C were added methyl iodide (623 μL, 10 mmol) and LiΗMDS (IM solution; 6 mL, 6 mmol). The reaction mixture was allowed to warm to r.t. prior to quenching with water. The reaction mixture was partitioned between TBME (50 mL) and brine (50 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo, yielding the title compound (1.77 g, 90%) as a yellow oil. δ_Η (dβ-DMSO at HO⁰C) 7.95 (d, J 1.8 Hz, IH), 7.38-7.30 (m, 3H), 7.11 (s, IH), 7.09 (dd, J8.8, 2.0 Hz, IH), 6.65 (d, J 8.3 Hz, IH), 4.27 (m, IH), 3.97-3.92 (m, IH), 3.90 (s, 3H), 3.85-3.77 (m, 2H), 3.74 (s, 3H), 3.62 (dd, J 11.4, 3.0 Hz, IH), 3.48 (m, 2H), 3.11 (m, 2H). LCMS (ES⁺) 400 (M+H)⁺.

PREPARATIVE EXAMPLE 366

{(^-3-r5-Chloro-l-methyl-2-αrimethylsilanylVlH-indol-3-ylmethyllmorpholin-4-vU-(6- methylpyridin-3 - yl)-methanone To a stirred solution of Example 278 (218 mg, 0.49 mmol) and methyl iodide

(0.09 mL, 1.48 mmol) in TΗF (5 mL) at -78⁰C was added LiΗMDS (IM solution; 0.93 mL, 0.98 mmol). The reaction mixture was stirred at -78°C before being allowed to warm to r.t. The reaction mixture was partitioned between EtOAc (20 mL) and brine (20 mL). The organic layer was separated, dried (sodium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 50-100% EtOAc/hexanes), yielding the title compound (180 mg, 93%) as a cream powder. δ_Η (d₆-DMSO at HO⁰C) 8.26 (d, J 1.0 Hz, IH), 7.47-7.35 (m, 3H), 7.21 (d, J7.8 Hz, IH), 7.12 (dd, J8.8, 2.0 Hz, IH), 4.34-4.25 (m, IH), 3.97-3.90 (m, IH), 3.83-3.75 (m, 4H), 3.64 (m, IH), 3.56-3.48 (m, 3H), 3.42 (dd, J 14.1, 9.1 Hz, IH), 3.05 (dd, J 14.1, 5.8 Hz, IH), 2.51 (s, 3H), 0.45 (s, 9H). LCMS (ES⁺) 456 (M+H)⁺.

EXAMPLE 367

N- { 3 -[(5)-4-(6-Methoxypyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 -methyl- 1 H-indol- 5-vU-N-methylcarbamic acid methyl ester

To a stirred solution of Example 311 (114 mg, 0.26 mmol) in THF (5 mL) at O⁰C was added sodium hydride (16 mg, 0.39 mmol). The reaction mixture was stirred at 0⁰C for 20 minutes prior to the addition of methyl iodide (41 mg, 0.29 mmol). The reaction mixture was allowed to warm to r.t and stirred for 2 h, then partitioned between DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, EtOAc) to yield the title compound (77 mg, 66%) as a white solid. δ_H (d₆-DMSO at 110⁰C) 7.99-7.97 (m, IH), 7.36 (dd, J 8.6, 2.3 Hz, IH), 7.32 (d, J8.6 Hz, IH), 7.23-7.21 (m, IH), 7.06 (s, IH), 7.00 (dd, J8.6, 2.0 Hz, IH), 6.64 (d, J8.3 Hz, IH), 4.27-4.20 (m, IH), 3.95-3.91 (m, IH), 3.88 (s, 3H), 3.84-3.78 (m, 2H), 3.74 (s, 3H), 3.62-3.57 (m, 4H), 3.52-3.47 (m, 2H), 3.21 (s, 3H), 3.17 (dd, J 14.4, 7.8 Hz, IH), 3.07 (dd, J 14.4, 7.1 Hz, IH). LCMS (ES⁺) 453 (M+H)⁺.

EXAMPLE 368

N- 13 - [(5^f)-4-(6-Methoxypyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 -methyl- 1 H-indol- 5-vU -iV-methylmethanesulfonamide

To a stirred solution of Example 328 (119 mg, 0.26 mmol) in TΗF (5 mL) at O⁰C was added sodium hydride (16 mg, 0.39 mmol). The reaction mixture was stirred at O⁰C for 20 minutes prior to the addition of methyl iodide (41 mg, 0.29 mmol). The reaction mixture was allowed to warm to r.t and stirred for 2 h, then partitioned between DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 90% EtOAc/hexanes), followed by preparative ΗPLC, to yield the title compound (50 mg, 41%) as a white solid. 6_Η (d₆- DMSO at 11O⁰C) 7.92 (d, J2.3 Hz, IH), 7.47 (s, IH), 7.37 (d, J8.8 Hz, IH), 7.33-7.27 (m, IH), 7.17 (dd, J 8.8, 2.0 Hz, IH), 7.09 (s, IH), 6.63 (d, J 8.6 Hz, IH), 4.22-4.32 (m, IH), 3.96-3.91 (m, IH), 3.88 (s, 3H), 3.81 (m, 2H), 3.75 (s, 3H), 3.63 (dd, J 11.6, 3.3 Hz, IH), 3.53-3.48 (m, 2H), 3.25 (s, 3H)₅ 3.14 (d, J 7.6 Hz, 2H). LCMS (ES⁺) 473 (M+H)⁺.

EXAMPLE 369

{(5^f)-3-r5-(lH-Imidazol-2-yl)-l-methyl-lH-indol-3-ylmethyl1morpholin-4-vU-(6- methoxyp yridin-3 - vQ-methanone To a stirred solution of Intermediate 19 (159 mg, 0.40 mmol) in EtOH (4 mL) at

O⁰C were added glyoxal (40% wt in water; 27 mg, 0.48 mmol) and cone, ammonia (1 mL). The reaction mixture was stirred at r.t. for 72 h prior to the addition of further glyoxal (27 mg) and ammonia (1 mL). The reaction mixture was stirred at r.t for a further 16 h, then concentrated in vacuo, dissolved in MeOH and captured on a SCX cartridge. The crude product was released using methanolic ammonia. The solution was concentrated in vacuo to give a brown solid which was purified by preparative ΗPLC to yield the title compound (12 mg, 7%) as a white solid. δ_Η (d₆-DMSO at 110⁰C) 7.99-7.88 (m, 2H), 7.75 (dd, J8.6, 1.3 Hz, IH), 7.39 (d, J8.6 Hz, IH), 7.29-7.24 (m, IH), 7.04 (s, 3H), 6.55 (d, J8.3 Hz, IH), 4.41-4.34 (m, IH), 3.95 (d, J7.8 Hz, IH), 3.88 (m, IH), 3.82 (dd, J 10.1, 0.8 Hz, IH), 3.78 (s, 3H), 3.76 (s, 3H), 3.68 (dd, J 11.6, 3.3 Hz, IH), 3.56- 3.46 (m, 2H), 3.25 (dd, J 14.7, 8.3 Hz, IH), 3.19-3.09 (m, IH). LCMS (ES⁺) 432 (M+H)⁺.

EXAMPLE 370

f6-Methoxypyridin-3-vD-((^-3-r5-(thiazol-2-yl)-lH-indol-3-ylmethyllmorpholin-4-vU- methanone

To a degassed stirred solution of Intermediate 35 (81 mg, 0.19 mmol), 2-(tributyl- stannanyl)thiazole (88 μL, 0.28 mmol) and lithium chloride (10 mg, 0.23 mmol) in 1,4- dioxane (3 mL) was added Pd(PPh₃ )₄ (11 mg, 0.01 mmol). The reaction mixture was further degassed and then heated to reflux for 8 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The residue was purified by column chromatography (SiO₂,

60-100% EtOAc/hexanes), and further purified by preparative ΗPLC, to yield the title compound (8 mg, 10%) as an off-white solid. δ_H Cd₆-DMSO at 110⁰C) 7.97 (s, IH), 7.92 (d, J 1.8 Hz, IH), 7.81 (d, J3.3 Hz, IH), 7.69 (dd, J8.6, 1.8 Hz, IH), 7.54 (d, J3.3 Hz, IH), 7.43 (dd, J8.3, 0.5 Hz, IH), 7.33-7.28 (m, IH), 7.16 (d, J 1.5 Hz, IH), 6.56 (d, J8.6 Hz, IH), 4.41-4.33 (m, IH), 3.95 (d, J7.6 Hz, IH), 3.86 (m, IH), 3.82 (d, J9.6 Hz, IH), 3.78 (s, 3H), 3.66 (dd, J 11.6, 3.3 Hz, IH), 3.51 (m, 2H), 3.28-3.15 (m, 2H). LCMS (ES⁺) 435 (M+H)⁺.

EXAMPLE 371

N-( 1 - Acetylpiperidin-4-ylV./V- { 1 -methy 1-3- [(5^f)-4-(6-methylpyridine-3 -carbonyl^")- morpholin-3 - ylmethyl] - 1 H-indol-5 -ylmethyl 1 acetamide

To a stirred solution of Example 339 (200 mg, 0.33 mmol) in MeOH (2 mL) was added 4M HCl in 1,4-dioxane (4 mL). The reaction mixture was stirred at r.t. for 16 h prior to being concentrated in vacuo. The reaction mixture was partitioned between DCM (25 mL) and sodium carbonate solution (25 mL). The organic layer was dried (phase separator) and concentrated in vacuo. To a stirred solution of the residue in acetic acid (2 mL) and acetic anhydride (400 μL) was added DMAP (5 mg). The reaction mixture was heated at 90⁰C for 1 h, then allowed to cool and concentrated in vacuo. The residue was purified by preparative ΗPLC, yielding the title compound (88 mg, 49%) as a white solid. δ_Η (de-DMSO at 110⁰C) 8.23-8.17 (m, IH), 7.36-7.26 (m, 3H), 7.14 (d, J8.1 Hz, IH), 7.04 (dd, J 8.6, 1.3 Hz, IH), 6.99 (s, IH), 4.55 (d, J 2.5 Hz, 2H), 4.32-4.03 (m, 4H), 3.92 (d, J7.3 Hz, IH), 3.83-3.74 (m, 2H), 3.72 (s, 3H), 3.58 (dd, J 11.6, 3.3 Hz, IH), 3.49 (d, J 8.8 Hz, 2H), 3.47-3.41 (m, IH), 3.18 (m, IH), 3.09 (m, IH), 2.88-2.64 (m, IH), 2.48 (s, 3H), 2.08 (s, 3H), 1.94 (s, 3H), 1.70-1.54 (m, 4H). LCMS (ES⁺) 546 (M+H)⁺.

EXAMPLE 372

(6-Methoxypyridin-3 -yl)- \(S)-3 -(5-nitro- 1 H-indol-3 -ylmethyl)morpholin-4-yl] - tnethanone To a stirred solution of 3-[(35)-morpholin-3-ylmethyl]-5-nitro-l//-indole (WO

2008/001076, Intermediate 39; 1.20 g, 4.61 mmol) in DCM (30 mL) and DMF (15 mL) was added triethylamine (560 mg, 5.53 mmol) followed by 6-methoxynicotinoyl chloride (867 mg, 5.07 mmol). The reaction mixture was stirred at r.t. for 16 h and then concentrated in vacuo. The residue was partitioned between DCM (25 niL) and water (25 mL). The organic layer was washed with brine (2 x 25 mL), dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 20- 100% EtOAc/hexanes), yielding the title compound (1.49 g, 81%) as a yellow foam, δπ (d₆-DMSO at 11O⁰C) 8.31 (s, IH), 8.08 (s, IH), 8.00 (dd, J 9.1, 2.3 Hz, IH), 7.55 (d, J 8.8 Hz, IH), 7.32 (s, IH), 7.26-7.20 (m, IH), 7.03 (d, J7.6 Hz, IH), 4.37-4.29 (m, IH), 3.98- 3.91 (m, IH), 3.88-3.78 (m, 5H), 3.68 (dd, 711.6, 3.0 Hz, IH), 3.57-3.46 (m, 2H), 3.26 (dd, 714.7, 8.3 Hz, IH), 3.18 (dd, 714.4, 6.8 Hz, IH), 2.40 (s, 3H). LCMS (ES⁺) 397 (M+H)⁺.

EXAMPLE 373

{(^-3-r5-(l.l-Dioxo-lΛ6-isothiazolidin-2-vn-lH-indol-3-ylmethyllmorpholin-4-vU-(6- methox ypyridin-3 - yl)-methanone To a stirred solution of Intermediate 39 (388 mg, 0.77 mmol) in MeCN (10 mL) was added potassium carbonate (266 mg, 1.93 mmol). The reaction mixture was stirred at 80⁰C for 2 h, then partitioned between DCM (20 mL) and brine (2 x 20 mL). The combined aqueous layers were extracted with DCM (2 x 30 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 70-100% EtOAc/hexanes), and further purified by preparative HPLC, to yield the title compound (96 mg, 26%) as a white solid, δπ (d₆- DMSO at HO⁰C) 10.47 (d, J 1.0 Hz, IH), 7.81 (d, J2.0 Hz, IH), 7.21-7.10 (m, 3H), 6.98- 6.93 (m, 2H), 6.48 (d, 78.6 Hz, IH), 4.19-4.12 (m, IH), 3.77 (d, J7.6 Hz, IH), 3.73 (s, 3H), 3.68-3.60 (m, 2H), 3.53 (t, J6.6 Hz, 2H), 3.46 (dd, J 11.6, 3.3 Hz, IH), 3.36-3.31 (m, 2H), 3.22 (t, J7.6 Hz, 2H), 2.99 (dd, J7.3, 1.3 Hz, 2H), 2.32-2.23 (m, 2H). LCMS (ES⁺) 471 (M+H)⁺.

EXAMPLE 374

1 - (3 -[(^-4-(6-Methoxypyridine-3 -carbonyDmorpholin-3 -ylmethyll - 1 -methyl- 1 H-indol- 5 - vU pyrrolidin-2-one

To a stirred solution of Intermediate 40 (102 mg, 0.21 mmol) in TΗF (7 mL) at -1O⁰C was added lithium bis(trimethylsilyl)amide (0.50 mL, 0.53 mmol). The reaction mixture was stirred for 1.5 h, then allowed to warm to r.t. and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 5-20% MeOH/EtOAc), and further purified by preparative HPLC, yielding the title compound (30 mg, 32%) as an off-white solid. δ_H (Cl₆-DMSO at 11O⁰C) 7.95 (d, J2.3 Hz, IH), 7.49 (dd, J 8.8, 2.0 Hz, IH), 7.40 (s, IH), 7.35-7.27 (m, 2H), 7.03 (s, IH), 6.63 (d, J 8.3 Hz, IH), 4.32-4.24 (m, IH), 3.96-3.90 (m, IH), 3.88 (s, 3H), 3.84-3.77 (m, 4H), 3.73 (s, 3H), 3.62 (dd, J 11.6, 3.3 Hz, IH), 3.53-3.46 (m, 2H), 3.13 (d, J7.6 Hz, 2H), 2.47 (d, J8.3 Hz, 2H), 2.18-2.06 (m, 2H). LCMS (ES⁺) 449 (M+H)⁺.

EXAMPLE 375

3-[(5^r)-4-(2-Methoxythiazole-5-carbonyl)morpholin-3-ylmethyll- 1 -methyl- lH-indole-5- carboxylic acid dimethylamide

To a stirred solution of Example 157 (90 mg, 0.2 mmol) in MeOH (1 mL) was added sodium methoxide (12 mg, 0.22 mmol). The reaction mixture was stirred at r.t. for 30 minutes. Sodium methoxide (5 mg, 0.10 mmol) was added and the reaction mixture was heated at 50⁰C for 1.5 h. The reaction mixture was concentrated in vacuo and then partitioned between DCM (5 mL) and saturated ammonium chloride solution (2 mL). The aqueous layer was extracted with DCM (1 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The white foam was purified using preparative ΗPLC, yielding the title compound (38 mg, 43%) as a white solid. δ_Η (d₆- DMSO at HO⁰C) 7.61 (s, IH), 7.38 (d, J8.3 Hz, IH), 7.30 (s, IH), 7.20 (dd, J8.3, 1.5 Hz, IH), 7.14 (s, IH), 4.52-4.45 (m, IH), 4.03-3.93 (m, 5H), 3.84 (d, J 11.6 Hz, IH), 3.75 (s, 3H), 3.59 (dd, J 11.6, 3.0 Hz, IH), 3.56-3.44 (m, 2H), 3.24 (dd, J 14.4, 7.8 Hz, IH), 3.15-3.10 (m, IH), 3.00 (s, 6H). LCMS (ES+) 443 (M+H)⁺.

EXAMPLE 376

l-Methyl-3-[(y)-4-(6-methylpyridine-3-carbonyl)morpholin-3-ylmethyl]-lH-indole-5- carboxylic acid N-methoxy-N-methylamide

To a stirred solution of Intermediate 33 (3.1 g, 7.89 mmol) in TΗF (30 mL) were added 2-chloro-4,6-dimethoxy-[l,3,5]triazine (1.66 g, 9.46 mmol) and DIPEA (3.9 mL, 23.64 mmol). The reaction mixture was stirred at r.t. for 1 h. N,O-Dimethylhydroxyl- amine hydrochloride (0.77 g, 7.9 mmol) was added and the reaction mixture was stirred for 18 h. The reaction was not complete, so further DIPEA (1 mL, 6.1 mmol) and N,O- dimethylhydroxylamine hydrochloride (0.29 g, 2.97 mmol) were added and the reaction mixture was stirred for a further 18 h prior to pouring over ice- water. The solution was extracted with EtOAc (100 mL) and DCM (2 x 100 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-3% MeOH/DCM), yielding the title compound (2.6 g, 76%) as a white solid. δ_H (dό-DMSO at 110⁰C) 8.21 (d, J 1.5 Hz, IH), 7.77 (s, IH), 7.45 (dd, J 8.3, 1.5 Hz, IH), 7.42-7.37 (m, IH), 7.31 (d, J7.3 Hz, IH), 7.13- 7.08 (m, 2H), 4.33-4.24 (m, IH), 3.93 (d, J7.6 Hz, IH), 3.82 (d, J 11.4 Hz, IH), 3.77 (s, 4H), 3.64-3.56 (m, 5H), 3.27 (s, 3H), 3.22 (dd, J 14.4, 7.6 Hz, IH), 3.14 (dd, J 14.4, 7.3 Hz, IH), 2.45 (s, 3H). LCMS (ES⁺) 437 (M+H)⁺.

EXAMPLE 377 (METHOD R)

(6-Methylpyridin-3-ylVI(5)-3-ri-methyl-5-rthiazole-2-carbonvn-lH-indol-3-ylmethvπ- morpholin-4-yl } -methanone

To a stirred solution of Example 376 (200 mg, 0.46 mmol) and thiazole (40 μL, 0.56 mmol) in TΗF (0.2 mL) at -78°C was added w-butyllithium (2.5M; 62 μL, 0.16 mmol) dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 16 h, then partitioned between DCM (10 mL) and water (10 mL). The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-3% MeOΗ/DCM), and further purified by preparative ΗPLC, yielding the title compound (44 mg, 21%) as a yellow solid. δ_Η (d₆-DMSO at 110⁰C) 8.66 (s, IH), 8.29 (dd, J8.8, 1.5 Hz, IH), 8.17 (d, J3.3 Hz, IH), 8.11 (d, J2.8 Hz, 2H), 7.52 (d, J8.8 Hz, IH), 7.23-7.18 (m, 2H), 6.99 (d, J7.8 Hz, IH), 4.38-4.29 (m, IH), 3.95 (d, J 7.6 Hz, IH), 3.87 (m, IH), 3.81 (s, 4H), 3.67 (dd, J 11.6, 3.0 Hz, IH), 3.56-3.46 (m, 2H), 3.27 (dd, J 14.7, 8.1 Hz, IH), 3.18 (dd, J 14.4, 6.8 Hz, IH), 2.35 (s, 3H). LCMS (ES⁺) 461 (M+H)⁺. EXAMPLE 378

{(5^r)-3-ri-Methyl-5-(l-methyl-lH-imidazole-2-carbonylVlH-indol-3-ylmethyll- morpholin-4-yl } -(6-methylpyridin-3 - vD-methanone The title compound was prepared from Example 376 and 1 -methyl- lH-imidazole according to Method R and was isolated as an off-white solid (14 mg). δ_Η Cd₆-DMSO at HO⁰C) 8.49 (s, IH), 8.19 (dd, J8.6, 1.5 Hz, IH), 8.15 (s, IH), 7.46-7.41 (m, 2H), 7.23 (d, J7.6 Hz, IH), 7.15 (m, 2H), 7.02 (d, J7.8 Hz, IH), 4.36-4.27 (m, IH), 4.02 (s, 3H), 3.97- 3.90 (m, IH), 3.85 (m, IH), 3.80 (s, 4H), 3.65 (dd, J 11.6, 3.3 Hz, IH), 3.54-3.45 (m, 2H), 3.27-3.12 (m, 2H), 2.39 (s, 3H). LCMS (ES⁺) 457 (M+H)⁺.

EXAMPLE 379

(5-Chloro-6-methoxypyridin-3 - vD- ( (S)-3 - \5 -( 1 H-imidazol-2-ylV 1 -methyl- 1 H-indol-3- ylmethyllmorpholin-4-vU-methanone

To a stirred solution of Intermediate 45 (443 mg, 1.03 mmol) in DCM (10 mL) was added manganese dioxide (1.0 g, 12.36 mmol). The reaction mixture was stirred at r.t. for 18 h, then filtered through celite and concentrated in vacuo, yielding a colourless oil. LCMS (ES⁺) 428 (M+Η)⁺. The resulting material was dissolved in glyoxal (40% aqueous solution; 260 μL) and THF (2 mL) and cooled to O⁰C. Concentrated ammonia (2 mL) was added to the reaction mixture, which was stirred at O⁰C for 1 h. Repeated addition of glyoxal and ammonia was carried out and the reaction mixture was stirred at r.t. for 72 h, then concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-5% MeOH/DCM), and further purified by preparative HPLC, yielding the title compound (86 mg, 19%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 8.19 (s, IH), 7.94 (s, IH), 7.79 (d, J 1.8 Hz, IH), 7.74 (dd, J 8.6, 1.5 Hz, IH), 7.38 (d, J8.6 Hz, IH), 7.23 (s, IH), 7.02 (s, 3H), 4.43-4.36 (m, IH), 3.99-3.89 (m, 2H), 3.85-3.80 (m, 4H), 3.77-3.73 (m, 4H), 3.55-3.49 (m, 2H), 3.30 (dd, J 14.7, 8.8 Hz, 2H). LCMS (ES⁺) 466 (M+H)⁺. EXAMPLE 380

(5-Chloro-6-methoxypyridin-3 -ylV US)-3 - [5 -(1.1 -dioxo- 1 Λ6-isothiazolidin-2- yl)- 1 - methyl-lH-indol-3-ylmethyl]morpholin-4-vU-methanone To a stirred solution of Intermediate 56 (150 mg, 0.4 mmol) in DCM (5 mL) at

O⁰C were added triethylamine (276 μL, 0.6 mmol) and 3-chloropropanesulfonyl chloride (58 μL, 0.5 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting material was dissolved in MeCN (5 mL), potassium carbonate (125 mg, 1.0 mmol) was added and the reaction mixture heated at 8O⁰C for 4 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (45 mg, 22%) as a yellow solid. δ_H (de-DMSO at 100⁰C) 7.85 (d, J2.0 Hz, IH), 7.36-7.34 (m, 2H), 7.29 (s, IH), 7.17 (dd, J8.8, 2.3 Hz, IH), 7.06 (s, IH), 4.33-4.26 (m, IH), 3.97 (s, 3H), 3.94 (d, J 8.6 Hz, IH), 3.87-3.77 (m, IH), 3.75 (s, 3H), 3.72-3.68 (m, 2H), 3.65 (d, J3.0 Hz, IH), 3.54-3.48 (m, 2H), 3.39-3.35 (m, 2H), 3.20-3.07 (m, 2H), 2.48-2.40 (m, 3H). LCMS (ES⁺) 519 (M+H)⁺.

EXAMPLE 381

3-(3-r(iS^l)-4-(5-Chloro-6-methoxypyridine-3-carbonyl)morpholin-3-ylmethyll-l-methyl- lH-indol-5-yl}oxazolidin-2-one

To a stirred solution of Intermediate 56 (150 mg, 0.4 mmol) in DCM (5 mL) at O⁰C were added triethylamine (276 μL, 0.6 mmol) and 2-chloroethyl chloroformate (49 μL, 0.5 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting material was dissolved in MeCN (5 mL), potassium carbonate (125 mg, 1.0 mmol) was added and the reaction mixture heated at 8O⁰C for 4 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative ΗPLC to afford the title compound (82 mg, 42%) as a white solid. δ_Η (d_ό-DMSO at 100⁰C) 7.82 (d, J 1.8 Hz, IH), 7.45-7.39 (m, 2H), 7.37-7.34 (m, IH), 7.29 (d, J 0.8 Hz, IH), 7.05 (s, IH), 4.44 (t, J 7.8 Hz, 2H), 4.33-4.25 (m, IH), 4.05-4.00 (m, 2H), 3.95 (s, 3H), 3.95-3.94 (m, IH), 3.86-3.81 (m, 2H), 3.75 (s, 3H), 3.69 (dd, J 11.6, 3.3 Hz, IH), 3.54-3.49 (m, 2H), 3.20 (dd, J 14.7, 8.1 Hz, IH), 3.07 (dd, J 14.4, 6.6 Hz, IH). LCMS (ES⁺) 485 (M+H)⁺.

EXAMPLE 382

3-{3-r(iS^r)-4-(2-Chloro-5-fluoro-6-methoxypyridine-3-carbonyl)niorpholin-3-ylmethyl]-l- methyl- l//-indol-5-vUoxazolidin-2-one

To a stirred solution of Intermediate 70 (150 mg, 0.3 mmol) in DCM (5 mL) at O⁰C were added triethylamine (76 μL, 0.45 mmol) and 2-chloroethyl chloroformate (34 μL, 0.36 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting material was dissolved in MeCN (5 mL), potassium carbonate (250 mg, 1.8 mmol) was added and the reaction mixture heated at 8O⁰C for 4 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (3 mg) as a white solid. δ_H (d₆-DMSO at 100⁰C) 7.45- 7.43 (m, 2H), 7.39-7.37 (m, 2H), 7.11 (br s, IH), 4.44 (t, J8.1 Hz, 3H), 4.09-4.02 (m, 2H), 3.96-3.94 (m, 5H), 3.85 (d, J 11.4 Hz, 2H), 3.75 (s, 3H), 3.70-3.59 (m, IH), 3.51- 3.49 (m, 2H), 3.23-3.09 (m, IH). LCMS (ES⁺) 503 (M+H)⁺.

EXAMPLE 383

(2-Chloro-5-fluoro-6-methoxypyridin-3 -vD- i(S)-3 - [5 -( 1 , 1 -dioxo- 1 Λ6-isothiazolidin-2- ylVl-methyl-lH-indol-3-ylmethyl^"|morpholin-4-vU-methanone

To a stirred solution of Intermediate 70 (150 mg, 0.3 mmol) in DCM (5 mL) at 0⁰C were added triethylamine (76 μL, 0.45 mmol) and 3 -chloropropanesulfonyl chloride (53 μL, 0.36 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting material was dissolved in MeCN (5 mL), potassium carbonate (250 mg, 1.8 mmol) was added and the reaction mixture heated at 80⁰C for 4 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (12 mg) as an off-white solid. δ_H Cd₆-DMSO at 100⁰C) 7.63-7.44 (m, IH), 7.38 (d, J8.8 Hz, IH), 7.19 (dd, J8.8, 1.5 Hz, IH), 7.12 (br s, 2H), 4.01-3.90 (m, 4H), 3.84 (d, J 11.4 Hz, IH), 3.78-3.69 (m, 6H), 3.67-3.60 (m, IH), 3.50 (d, J7.6 Hz, 2H), 3.39-3.36 (m, 2H), 3.15-3.13 (m, 2H), 2.48-2.41 (m, 3H). LCMS (ES⁺) 537 (M+H)⁺.

EXAMPLE 384

l-{3-r(5)-4-(2-Chloro-5-fluoro-6-methoxypyridine-3-carbonyl)morpholin-3-ylmethyl]-l- methyl- 1 H- indol-5-vUpyrrolidin-2-one

To a stirred solution of Intermediate 70 (150 mg, 0.3 mmol) in DCM (5 mL) at O⁰C were added triethylamine (76 μL, 0.45 mmol) and 4-chlorobutyryl chloride (43 μL, 0.36 mmol). The reaction mixture was stirred at r.t. for 18 h, then quenched with water. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The resulting material was dissolved in MeCN (5 mL), potassium carbonate (250 mg, 1.8 mmol) was added and the reaction mixture heated at 8O⁰C for 1.5 h. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-1% MeOH/DCM), yielding the title compound (3 mg) as a white solid. δ_H (d₆- DMSO at 100⁰C) 7.50-7.47 (m, 2H), 7.35 (d, J9.1 Hz, IH), 7.09 (br s, IH), 3.97 (s, 3H), 3.86-3.81 (m, 2H), 3.75 (s, 3H), 3.70-3.63 (m, IH), 3.51-3.49 (m, 2H), 3.20-3.10 (m, 2H), 2.95-2.84 (m, 5H), 2.49-2.25 (m, 2H), 2.15-2.08 (m, 2H). LCMS (ES⁺) 501 (M+H)⁺.

EXAMPLE 385

3 - [(■Sy4-(5-Chloro-6-methoxypyridine-3 -carbonyl)moipholin-3 -ylmethyl] - 1 - [2- (dimethylamino^')ethyl^'|-lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 99 (150 mg, 0.30 mmol) in DMF (5 mL) at O⁰C was added sodium hydride (60% dispersion in oil; 32 mg, 0.78 mmol). The reaction mixture was stirred at r.t. for 1 h and then cooled to O⁰C prior to the addition ofN-(2- chloroethyl)dimethylamine hydrochloride (50 mg, 0.46 mmol). The reaction mixture was heated at 5O⁰C for 18 h, then partitioned between DCM (20 mL) and water (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-10% MeOH/EtOAc), yielding the title compound (40 mg, 25%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 7.88 (d, J2.0 Hz, IH), 7.48 (s, IH), 7.43 (d, J8.3 Hz, IH), 7.39 (s, IH), 7.19 (s, IH), 7.17 (dd, J8.6, 1.3 Hz, IH), 4.26-4.19 (m, 3H), 3.96 (s, 3H), 3.93-3.89 (m, IH), 3.85-3.80 (m, 2H), 3.66 (dd, J 11.4, 3.0 Hz, IH), 3.52 (d, J9.1 Hz, 2H), 3.17 (m, 2H), 2.97 (s, 6H), 2.68 (t, J 6.6 Hz, 2H), 2.24 (s, 6H). LCMS (ES⁺) 528 (M+H)⁺.

EXAMPLE 386

3-[^"(^-4-(5-Chloro-6-methoxypyridine-3-carbonyl)moφholin-3-ylmethyl1-l-(2-hydroxy- ethyl)-lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 99 (150 mg, 0.30 mmol) in DMF (5 mL) at 0⁰C was added sodium hydride (60% dispersion in oil; 32 mg, 0.78 mmol). The reaction mixture was stirred at r.t. for 1 h and then cooled to O⁰C prior to the addition of (2-bromo- ethoxy)-fert-butyldimethylsilane (94 μL, 0.46 mmol). The reaction mixture was heated at 50⁰C for 18 h, then partitioned between EtOAc (20 mL) and 10% aqueous NH₄Cl solution (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 70- 100% EtOAc/isohexane), yielding a clear oil. The residue was dissolved in THF (5 mL) and TBAF (5 mL, IM solution in THF) was added. The reaction mixture was stirred at r.t. for 18 h, then partitioned between EtOAc (2OmL) and 10% aqueous NH₄Cl solution (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0- 10% MeOH/EtOAc), yielding the title compound (71 mg, 47%) as a white solid. δ_H (d₆- DMSO at 100⁰C) 7.89 (d, J 1.8 Hz, IH), 7.49 (s, IH), 7.44-7.42 (m, 2H), 7.18 (s, IH),

7.16 (dd, J8.6, 1.5 Hz, IH), 4.47 (t, J 5.1 Hz, IH), 4.30-4.23 (m, IH), 4.21-4.16 (m, 2H), 3.97 (s, 3H), 3.94 (d, J7.8 Hz, IH), 3.86-3.81 (m, IH), 3.79-3.76 (m, 3H), 3.65 (dd, J 11.6, 3.3 Hz, IH), 3.52 (d, J8.8 Hz, 2H), 3.17 (dd, J7.6, 1.3 Hz, 2H), 2.98 (s, 6H). LCMS (ES⁺) 501 (M+H)⁺. EXAMPLE 387

5-US)-3-\5-(3 - Aminoazetidine- 1 -carbonyl)- 1 -methyl- 1 H-indol-3 - ylmethyll morpholine-4- carbonyU-2-methoxynicotinonitrile To a stirred solution of Intermediate 72 (87 mg, 0.20 mmol), azetidin-3-yl- carbamic acid fert-butyl ester hydrochloride (42 mg, 0.20 mmol), EDC (58 mg, OJOmmol) and ΗOBT (27 mg, 0.20 mmol) in DMF (5 mL) was added DIPEA (1.10 mL, 1.0 mmol). The reaction mixture was heated at 6O⁰C for 2 h. After cooling, the mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with water (3 x 10 mL), dried (phase separator), concentrated in vacuo and chromatographed (SiO₂, 0-10% MeOΗ/EtOAc), yielding an off-white solid. This material was dissolved in DCM (4 mL), trifluoroacetic acid (4 mL) was slowly added dropwise, and the reaction mixture was stirred at r.t. for 2 h, then concentrated in vacuo. The residue was purified using preparative ΗPLC, yielding the title compound (7 mg, 7%) as a white solid. δ_Η (d₆-DMSO at 100⁰C) 8.09 (d, J 1.5 Hz, IH), 7.69 (s, IH), 7.66 (d, J 0.8 Hz, IH), 7.45-7.43 (m, IH), 7.39-7.37 (m, IH), 7.12 (s, IH), 4.37-4.29 (m, 2H), 4.29- 4.22 (m, IH), 4.01 (s, 3H), 3.96 (d, J7.8 Hz, IH), 3.89-3.81 (m, IH), 3.79-3.76 (m, 8H), 3.73 (dd, J 11.6, 3.0 Hz, IH), 3.56-3.50 (m, 2H), 3.25-3.22 (m, 2H), 3.11 (dd, J 14.4, 6.6 Hz, IH). LCMS (ES⁺) 489 (M+H)⁺.

EXAMPLE 388

3 -|Y5')-4-(6-Methoxy-5-methylpyridine-3 -carbonyPmorpholin-3 -ylmethyll - 1 -methyl- 1 H- indole-5-carboxylic acid N-(2-hydroxyethyl)-_J/V-methylamide To a stirred solution of Intermediate 75 (200 mg, 0.40 mmol), 6-methoxy-5- methylnicotinic acid (70 mg, 0.40 mmol), EDC (120 mg, 0.60 mmol) and HOBT (56 mg, 0.40 mmol) in DCM (5 mL) was added DIPEA (233 μL, 1.60 mmol). The reaction mixture was stirred at r.t. for 18 h, then partitioned between DCM (10 mL) and water (10 mL). The organic layer was washed with water (3 x 10 mL), dried (phase separator) and concentrated in vacuo. The resulting material was dissolved in THF (4 mL), 2-(methyl- amino)ethanol (70 μL, 0.80 mmol) and DIPEA (215 μL, 1.60 mmol) were added and the reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (140 mg, 87%) as a white solid. δ_H (d₆-DMS0 at 100⁰C) 7.82 (d, J2.0 Hz, IH), 7.53 (s, IH), 7.38 (d, J8.6 Hz, IH), 7.19 (dd, J8.6, 1.5 Hz, IH), 7.11 (s, IH), 7.09 (s, IH), 4.35-4.26 (m, 2H), 3.95-3.88 (m, 3H), 3.84-3.81 (m, 2H), 3.79-3.73 (m, 3H), 3.65-3.58 (m, 3H), 3.52-3.43 (m, 5H), 3.17 (dd, J 7.6, 4.0 Hz, 2H), 3.00 (s, 3H), 2.06 (s, 3H). LCMS (ES⁺) 481 (M+H)⁺.

EXAMPLE 389

3 - \(S)-4-(5 -Cyano-ό-methoxypyridine-S -carbonyl)morpholin-3 - ylmethyl] - 1 -methyl- 1 H- indole-5-carboxylic acid 7V-(2-hydroxyethyl)-N-methylamide To a stirred solution of Intermediate 75 (200 mg, 0.40 mmol), 5-cyano-6- methoxynicotinic acid (89 mg, 0.50 mmol), EDC (120 mg, 0.60 mmol) and HOBT (56 mg, 0.40 mmol) in DCM (5 mL) was added DIPEA (233 μL, 1.60 mmol). The reaction mixture was stirred at r.t. for 18 h, then partitioned between DCM (10 mL) and water (10 mL). The organic layer was washed with water (3 x 10 mL), dried (phase separator) and concentrated in vacuo. The resulting material was dissolved in THF (4 mL), 2-(methyl- amino)ethanol (70 μL, 0.80 mmol) and DIPEA (215 μL, 1.60 mmol) were added and the reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (60 mg, 30%) as a white solid. δ_H (de-DMSO at 100⁰C) 8.07 (d, J 2.0 Hz, IH), 7.66 (d, J 0.5 Hz, IH), 7.46 (s, IH), 7.36 (dd, J8.6, 0.5 Hz, IH), 7.17 (dd, J8.3, 1.5 Hz, IH), 7.07 (s, IH), 4.24-4.20 (m, IH), 4.21-4.19 (m, IH), 3.99 (s, 3H), 3.95-3.90 (m, IH), 3.85-3.82 (m, 2H), 3.81-3.75 (m, 5H), 3.68 (dd, J 11.6, 3.3 Hz, IH), 3.52-3.48 (m, 2H), 3.46-3.41 (m, 2H), 3.21-3.10 (m, IH), 3.08-3.05 (m, IH), 2.98 (s, 3H). LCMS (ES⁺) 492 (M+H)⁺.

EXAMPLE 390

3 - \(S)-4-(5 -Chloro-6-methoxypyridine-3 -carbonyDmorpholin-3 -ylmethyll - 1 -methyl- 1 H- indole-5-carboxylic acid 2-(methylsulfanyl)ethylamide

To a stirred solution of Intermediate 76 (250 mg, 0.4 mmol) in THF (5 mL) and Intermediate 77 (126 mg, 0.8 mmol) was added DIPEA (106 μL, 0.8 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (60 mg, 29%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 7.97 (s, IH), 7.84 (s, IH), 7.79 (d, J 2.0 Hz, IH), 7.66 (dd, J8.6, 1.5 Hz, IH), 7.38-7.36 (m, IH), 7.25 (s, IH), 7.10 (s, IH), 4.39-4.31 (m, IH), 3.97- 3.92 (m, 4H), 3.89-3.86 (m, IH), 3.83-3.81 (m, IH), 3.77 (s, 3H), 3.73 (dd, J 11.6, 3.3 Hz, IH), 3.56-3.47 (m, 4H), 3.29 (dd, J 14.7, 8.6 Hz, IH), 3.10 (dd, J 14.7, 6.3 Hz, IH), 2.73 (t, J 7.3 Hz, 2H), 2.15 (s, 3H). LCMS (ES⁺) 517 (M+H)⁺.

EXAMPLE 391

3 - [(5^r)-4-(5-Chloro-6-methoxypyridine-3 -carbonyl)morpholin-3-ylmethyl1 - 1 -methyl- 1 H- indole-5-carboxylic acid 2-(methanesulfinyl)ethylamide To a stirred solution of Example 390 (110 mg, 0.2 mmol) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (58 mg, 0.24 mmol). The reaction mixture was stirred at r.t. for 2 h, then partitioned between DCM (10 mL) and saturated sodium bicarbonate solution (10 mL). The organics were separated, dried (sodium sulphate) and concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (31 mg, 29%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 8.02 (s, IH), 7.97 (s, IH), 7.78 (s, IH), 7.65 (dd, J8.6, 1.8 Hz, IH), 7.39 (d, J8.6 Hz, IH), 7.24 (s, IH), 7.10 (s, IH), 4.40- 4.31 (m, IH), 3.95-3.94 (m, IH), 3.94 (s, 3H), 3.88-3.86 (m, 2H), 3.85-3.81 (m, IH), 3.78 (s, 3H), 3.76-3.70 (m, 2H), 3.55-3.50 (m, 2H), 3.29 (dd, J 14.7, 8.6 Hz, IH), 3.10-3.04 (m, 2H), 2.95-2.89 (m, IH), 2.61 (s, 3H). LCMS (ES⁺) 533 (M+H)⁺.

EXAMPLE 392

3-r(^)-4-(5-Chloro-6-methoxypyridine-3-carbonyl)morpholin-3-ylmethyl1-l-methyl-lH- indole-5-carboxylic acid 2-(methanesulfonyl)ethylamide To a stirred solution of Example 390 (110 mg, 0.2 mmol) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (58 mg, 0.24 mmol). The reaction mixture was stirred at r.t. for 2 h, then partitioned between DCM (10 mL) and saturated sodium bicarbonate solution (10 mL). The organics were separated, dried (sodium sulphate) and concentrated in vacuo. The residue was purified using preparative ΗPLC, yielding the title compound (28 mg, 26%) as a white solid. δ_Η (d₆-DMSO at 100⁰C) 7.99 (s, IH), 7.96 (s, IH), 7.76 (d, J 1.8 Hz, IH), 7.65 (dd, J8.6, 1.8 Hz, IH), 7.39 (d, J8.6 Hz, IH), 7.24 (s, IH), 7.10 (s, IH), 4.40-4.35 (m, IH), 3.96-3.94 (m, IH), 3.94 (s, 3H), 3.87 (d, J 11.5 Hz, IH), 3.84- 3.81 (m, IH), 3.78 (s, 3H), 3.77-3.71 (m, 3H), 3.57-3.50 (m, 2H), 3.40 (t, J6.8 Hz, 2H), 3.29 (dd, J 14.7, 8.6 Hz, IH), 3.09 (dd, J 14.5, 6.2 Hz, IH), 3.01 (s, 3H). LCMS (ES⁺) 549 (M+H)⁺.

EXAMPLE 393

3-[(ιS)-4-(5-Chloro-6-methoxypyridine-3-carbonyl)moφholin-3-ylmethyl1-l-methyl-lH- indole-5-carboxylic acid N- r2-(methanesulfonyl)ethyl] -N-methylamide

To a stirred solution of Intermediate 76 (110 mg, 0.2 mmol) in THF (5 mL) and N-[2-(methanesulfonyl)ethyl]-N-methylamine (50 mg, 0.4 mmol) was added DIPEA (60 μL, 0.4 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (40 mg, 36%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 7.88 (d, J 1.8 Hz, IH), 7.55 (s, IH), 7.41 (d, J8.4 Hz, IH), 7.38 (s, IH), 7.22 (dd, J8.3, 1.5 Hz, IH), 7.11 (s, IH), 4.33-4.25 (m, IH), 3.97 (s, 3H), 3.94 (d, J7.6 Hz, IH), 3.86-3.81 (m, 3H), 3.78 (s, 4H), 3.65 (dd, J 11.6, 3.0 Hz, IH), 3.56-3.51 (m, 2H), 3.48-3.45 (m, 2H), 3.19-3.15 (m, 2H), 2.99 (d, J7.8 Hz, 6H). LCMS (ES⁺) 563 (M+H)⁺.

EXAMPLE 394

{3-f(5^r)-4-(5-Chloro-6-methoxypyridine-3-carbonyl)morpholin-3-ylmethyl1-l-methyl-lH- indol-5-yl>-(thiazolidin-3-yl)-methanone

To a stirred solution of Intermediate 76 (360 mg, 0.7 mmol) in THF (5 mL) and thiazolidine (106 μL, 1.4 mmol) was added DIPEA (170 μL, 1.4 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (170 mg, 47%) as a white solid. 5_H (d₆-DMSO at 100⁰C) 7.84 (d, J 1.8 Hz, IH), 7.67 (s, IH), 7.43-7.41 (m, IH), 7.35-7.30 (m, 2H), 7.13 (s, IH), 4.62 (s, 2H), 4.31-4.24 (m, IH), 3.96 (s, 3H), 3.94 (s, IH), 3.87 (s, IH), 3.84-3.81 (m, 3H), 3.79 (s, 3H), 3.67 (dd, J 11.4, 3.0 Hz, IH), 3.56-3.51 (m, 2H), 3.25-3.11 (m, 2H), 3.03 (t, J 6.3 Hz, 2H). LCMS (ES⁺) 515 (M+H)⁺. EXAMPLE 395

(3 - [(S)-4-(5-Chloro-6-methoxypyridine-3 -carbonyl)morpholin-3 -ylmethyl] - 1 -methyl- 1 H- indol-5-vU -(I -oxo- 1 Λ4-thiazolidin-3-yl)-methanone To a stirred solution of Example 394 (130 mg, 0.25 mmol) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (57 mg, 0.25 mmol). The reaction mixture was stirred at r.t. for 18 h, then partitioned between DCM (10 mL) and saturated sodium bicarbonate solution (10 mL). The organics were separated, dried (sodium sulphate) and concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (51 mg, 39%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 7.84 (d, J 1.8 Hz, IH), 7.71 (d, J 4.8 Hz, IH), 7.45-7.42 (m, IH), 7.37-7.30 (m, 2H), 7.14 (d, J2.3 Hz, IH), 4.60-4.59 (m, 2H), 4.33-4.24 (m, 2H), 4.03-3.97 (m, IH), 3.96 (d, J2.3 Hz, 3H), 3.96-3.93 (m, 2H), 3.86-3.84 (m, IH), 3.79 (s, 3H), 3.69-3.66 (m, IH), 3.53-3.48 (m, 2H), 3.25-3.20 (m, IH), 3.17-3.14 (m, IH), 3.10-3.08 (m, IH), 3.07-3.00 (m, IH). LCMS (ES⁺) 531 (M+H)⁺.

EXAMPLE 396

\(S)-3 - ( 1 - r2-f Dimethylaminokthyll -5 -(T .1 -dioxo- 1 Λ6-isothiazolidin-2- ylV 1 H-indol-3 - ylmethyl}morpholin-4-yll-(6-methoxypyridin-3-yl)-methanone To a stirred solution of Example 373 (100 mg, 0.21 mmol) in DMF (5 mL) at O⁰C was added sodium hydride (60% dispersion in oil; 51 mg, 2.13 mmol). The reaction mixture was stirred at r.t. for 1 h and then cooled to O⁰C prior to the addition of N-(2- chloroethyl)dimethylamine hydrochloride (92 mg, 0.64 mmol). The reaction mixture was heated at 50⁰C for 18 h, then partitioned between DCM (20 mL) and water (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-10% MeOΗ/EtOAc), yielding the title compound (32 mg, 28%) as a yellow solid. δ_Η (d₆-DMSO at 100⁰C) 7.98 (d, J2.3 Hz, IH), 7.40 (d, J8.8 Hz, IH), 7.35 (dd, J8.6, 2.3 Hz, IH), 7.28 (s, IH), 7.18- 7.14 (m, 2H), 6.64 (d, J8.6 Hz, IH), 4.34-4.27 (m, IH), 4.17 (t, J6.6 Hz, 2H)₅ 3.94-3.90 (m, IH), 3.89 (s, 3H), 3.83-3.76 (m, 2H), 3.70 (t, J6.6 Hz, 2H), 3.61 (dd, J 11.6, 3.3 Hz, IH), 3.52-3.47 (m, 2H), 3.41-3.35 (m, 2H), 3.14 (dd, J7.6, 1.0 Hz, 2H), 2.64 (t, J6.6 Hz, 2H), 2.47-2.41 (m, 2H), 2.21 (s, 6H). LCMS (ES⁺) 542 (M+H)⁺. EXAMPLE 397

3 - \(S)A-( 1 ,6-Dimethyl-2-oxo- 1 ,2-dihydropyridine-4-carbonyl)niorpholin-3 - ylmethyli - 1 - methyl- li/-indole-5-carboxylic acid dimethylamide To a stirred solution of Example 187 (120 mg, 0.27 mmol) in DMF (5 niL) at O⁰C were added iodomethane (17 μL, 0.27 mmol) and sodium hydride (11 mg, 0.27 mol). The reaction mixture was stirred at r.t. for 3 h, quenched by the addition of water (20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (18 mg, 15%) as a white solid. 6_H (d₆- DMSO at HO⁰C) 7.59 7.50 (m, IH), 7.40 (d, J8.3 Hz, IH), 7.19 (dd, J8.6, 1.5 Hz, IH), 7.13 (s, IH), 5.95 (s, IH), 5.64-5.53 (m, IH), 4.32-4.19 (m, IH), 3.97-3.90 (m, IH), 3.85- 3.75 (m, 5H), 3.56 (dd, J 11.6, 3.0 Hz, IH), 3.50-3.42 (m, 2H), 3.37 (s, 3H), 3.18-3.07 (m, 2H), 3.00 (s, 6H), 2.23 (s, 3H). LCMS (ES⁺) 451(M+H)⁺.

EXAMPLE 398

3 - \(S)-A-C5 -Chloro -6-methoxypyridine-3 -carbonyl)morpholin-3 - ylmethyl] - 1 -methyl- 1 H- indole-5-carboxylic acid N-(2-cvanoethyl)-7V-methylamide To a stirred solution of Intermediate 76 (120 mg, 0.2 mmol) in THF (5 mL) and 3-

(methylamino)propionitrile (33 mg, 0.4 mmol) was added DIPEA (60 μL, 0.4 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (64 mg, 63%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 7.86 (d, J 2.0 Hz, IH), 7.54 (s, IH), 7.42 (dd, J 8.6, 0.5 Hz, IH), 7.35 (s, IH), 7.21 (dd, J 8.3, 1.5 Hz, IH), 7.11 (s, IH), 4.34-4.20 (m, IH), 3.99-3.88 (m, 4H), 3.88-3.71 (m, 6H), 3.73-3.62 (m, 3H), 3.57-3.47 (m, 2H), 3.17 (dd, J 14.4, 7.6 Hz, 2H), 3.02 (s, 3H), 2.93-2.76 (m, IH). LCMS (ES⁺) 510 (M+H)⁺. EXAMPLE 399

3 - { (S)-4- [4-(Dimethylamino)-3 -(trifluoromethvπbenzoylimorpholin-3-ylmethyl } - 1 - methyl- lH-indole-5-carboxylic acid dimethylamide Dimethylamine hydrochloride (12 mg, 0.15 mmol) was added to a solution of

Example 210 (60 mg, 0.12 mmol) in DMSO (1 mL) in a microwave vial. Potassium carbonate (35 mg, 0.26 mmol) was added and the reaction mixture was then heated to 100⁰C for 0.5 h. Water (5 mL) was added and the mixture was extracted with DCM (2 x 10 mL). The combined organics were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by preparative ΗPLC to yield the title compound as a white solid. δ_Η ((J₆-DMSO at 8O⁰C) 7.58 (s, IH), 7.38 (d, J8.3Hz, IH), 7.31-7.24 (m, 3H), 7.20 (dd, J8.3, 1.5 Hz, IH), 7.09 (s, IH), 4.29-4.27 (m, IH), 3.93-3.90 (m, IH), 3.82 (d, J 11.6 Hz, IH), 3.76 (s, 3H), 3.74-3.71 (m, IH), 3.59 (dd, J 11.6, 3.3 Hz, IH), 3.56- 3.45 (m, 2H), 3.21 (dd, J 14.4, 7.3 Hz, IH), 3.15 (dd, J 14.7, 7.6 Hz, IH), 2.98 (s, 6H), 2.73 (s, 6H). LCMS (ES+) 517 (M+H)⁺.

EXAMPLE 400

1 -Methyl-3 -\(S)-4-( 1 -methyl-6-oxo- 1.6-dihydropyridine-3 -carbonyl)morpholin-3 - ylmethyn-lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 30 (102 mg, 0.24 mmol) in DMF (5 mL) at 0⁰C was added sodium hydride (12 mg, 0.20 mmol). The reaction mixture was stirred at O⁰C for 20 minutes prior to the addition of methyl iodide (20 μL, 0.36 mmol). The reaction mixture was allowed to warm to r.t and stirred for 18 h, then partitioned between DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by preparative ΗPLC to yield the title compound as a white solid. δ_Η (d₆-DMSO at 110⁰C) 7.58 (d, J0.8 Hz, IH), 7.46 (d, J2.3 Hz, IH), 7.39 (d, J 8.3 Hz, IH), 7.20 (dd, 78.3, 1.5 Hz, IH), 7.15 (dd, J9.3, 2.5 Hz, IH), 7.12 (s, IH), 6.21 (d, J9.3 Hz, IH), 4.29-4.26 (m, IH), 3.96-3.89 (m, IH), 3.82 (d, J 11.6 Hz, IH), 3.82 (d, J 10.9 Hz, IH), 3.77 (s, 3H), 3.59 (dd, J 11.6, 3.3 Hz, IH), 3.55-3.45 (m, 2H), 3.34 (s, 3H), 3.20 (dd, J 14.4, 7.6 Hz, IH), 3.12 (dd, J 14.4, 7.3 Hz, IH), 2.98 (s, 6H). LCMS (ES⁺) 437 (M+H)⁺. EXAMPLE 401

1 -Methyl-3 - { (SV4-r6-(methylsulfanyl)pyridine-3 -carbonyllmorpholin-3 -ylmethyl) - 1 H- indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 6 (100 mg, 0.23 mmol) in TΗF (10 mL) was added sodium thiomethoxide (16 mg, 0.23 mmol). The reaction mixture was heated to reflux for 18 h, then partitioned between DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by preparative

ΗPLC to yield the title compound (12 mg, 11%) as a white solid. δ_Η (d₆-DMSO at HO⁰C) 8.18 (d, J 1.8 Hz, IH), 7.55 (s, IH), 7.39 (dd, J8.3, 0.5 Hz, IH), 7.28 (dd, J8.1, 2.0 Hz, IH), 7.20 (dd, J8.3, 1.5 Hz, IH), 7.15 (d, J8.1 Hz, IH), 7.09 (s, IH), 4.26-4.23 (m, IH), 3.96-3.89 (m, IH), 3.83 (d, J 11.6 Hz, IH), 3.79-3.76 (m, IH), 3.76 (s, 3H), 3.61 (dd, J 11.6, 3.3 Hz, IH), 3.56-3.46 (m, 2H), 3.21 (dd, J 14.7, 7.8 Hz, IH), 3.15 (dd, J 14.7, 7.6 Hz, IH), 2.99 (s, 6H), 2.52 (s, 3H). LCMS (ES⁺) 453 (M+H)⁺.

EXAMPLE 402

3-[(5^-4-(5-Bromo-6-methoxypyridine-3-carbonyl)morpholin-3-ylmethyll- 1 -methyl- IH- indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 233 (149 mg, 0.29 mmol) in MeOH (10 mL) was added lithium hydroxide monohydrate (36 mg, 0.86 mmol). The reaction mixture was heated to reflux for 4.5 h, then cooled and neutralised with 2M HCl. The residue was partitioned with DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0- 10% MeOΗ/EtOAc), yielding the title compound (129 mg, 87%) as a white solid. δ_Η (d₆- DMSO at HO⁰C) 7.91 (d, J2.0 Hz, IH), 7.53-7.50 (m, 2H), 7.39 (d, J8.3 Hz, IH), 7.19 (dd, J8.3, 1.5 Hz, IH), 7.09 (s, IH), 4.26-4.23 (m, IH), 3.95 (s, 3H), 3.95-3.90 (m, IH), 3.85 (d, J 11.6 Hz, IH), 3.83-3.79 (m, IH), 3.78 (s, 3H), 3.65 (dd, J 11.6, 3.3 Hz, IH), 3.56-3.48 (m, 2H), 3.19 (dd, J 14.4, 7.6 Hz, IH), 3.15 (dd, J 14.4, 7.6 Hz, IH), 2.97 (s, 6H). LCMS (ES⁺) 517 (M+H)⁺. EXAMPLE 403

S-^^^-Cό-Ethoxypyridine-S-carbonvπmorpholin-S-ylmethyll-l-methyl-lH-indole-S- carboxylic acid dimethylamide

To a solution of Example 6 (119 mg, 0.27 mmol) in EtOH (5 niL) in a microwave vial was added lithium hydroxide monohydrate (34 mg, 0.81 mmol). The reaction mixture was heated to 18O⁰C for 1 h, then cooled and neutralised with 2M HCl. The residue was partitioned with DCM (20 mL) and water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by preparative HPLC to yield the title compound (5 mg, 11%) as a pink solid. δ_H (d₆-DMSO at 11O⁰C) 7.96 (d, J 2.3 Hz, IH), 7.53 (d, J0.8 Hz, IH), 7.39-7.37 (m, 2H), 7.19 (dd, J 8.3, 1.3 Hz, IH), 7.09 (s, IH), 6.63 (d, J8.6 Hz, IH), 4.34 (q, J6.8 Hz, 2H), 4.30-4.27 (m, IH), 3.93-3.89 (m, IH), 3.82 (d, J 11.4 Hz, IH), 3.78-3.76 (m, IH), 3.76 (s, 3H), 3.60 (dd, J 11.6, 3.Hz, IH), 3.56-3.48 (m, 2H), 3.21 (dd, J 14.1, 7.8 Hz, IH), 3.13 (dd, J 14.7, 7.3 Hz, IH), 2.98 (s, 6H), 1.33 (t, J 7.1 Hz, 3H). LCMS (ES⁺) 451 (M+H)⁺.

EXAMPLE 404

3-[(iS^r)-4-(5-Amino-6-methoxypyridine-3-carbonvπmorpholin-3-ylmethyll-l-methyl-lH- indole-5-carboxylic acid dimethylamide

To a stirred solution of Example 237 (112 mg, 0.23 mmol) in AcOH (5 mL) was added zinc powder (46 mg, 0.70 mmol). The reaction mixture was heated at 80⁰C for 1 h, then cooled, quenched with water (50 mL) and saturated sodium carbonate solution (100 mL), and partitioned with EtOAc. The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 2-30% MeOH/EtOAc), yielding the title compound as a white solid (17 mg, 16%). δ_H (dβ-DMSO at HO⁰C) 7.55 (s, IH), 7.39 (d, J8.6 Hz, IH), 7.27 (d, J2.0 Hz, IH), 7.19 (dd, J8.3, 1.5 Hz, IH), 7.09 (s, IH), 6.72 (d, J2.0 Hz, IH), 4.67 (s, 2H), 4.37-4.34 (m, IH), 3.91 (s, 3H), 3.91-3.87 (m, IH), 3.80-3.75 (m, 2H), 3.76 (s, 3H), 3.53 (dd, J 11.6, 3.0 Hz, IH), 3.49-3.42 (m, 2H), 3.25 (dd, J 14.1, 8.3 Hz, IH), 3.07 (dd, J 14.1, 6.6 Hz, IH), 2.98 (s, 6H). LCMS (ES⁺) 452 (M+H)⁺. EXAMPLE 405

3-[(^'5^r)-4-(5-Hvdroxy-6-methoxypyridine-3-carbonyπmorpholin-3-ylmethyll-l-methyl- lH-indole-5-carboxylic acid dimethylamide

To a degassed solution of Example 402 (150 mg, 0.29 mmol) in 1,4-dioxane (0.5 mL), under nitrogen, were added 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-tri- isopropyl-l,l'-biphenyl (3 mg, 0.0058 mmol), potassium hydroxide (49 mg, 0.87 mmol) and Pd₂(dba)₃ (2 mg, 0.0015 mmol). The reaction mixture was heated to reflux for 18 h, then neutralized with HCl, and partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by preparative ΗPLC, yielding the title compound (75 mg, 57%) as an off-white solid. δ_Η (d₆-DMSO at HO⁰C) 9.10 (br s, IH), 7.54 (s, IH), 7.46 (d, J 2.0 Hz, IH), 7.38 (d, J8.3 Hz, IH), 7.19 (dd, J8.6, 1.5 Hz, IH), 7.09 (s, IH), 6.86 (d, J2.0 Hz, IH), 4.36-4.33 (m, IH), 3.95-3.88 (m, IH), 3.91 (s, 3H), 3.80 (d, J 11.4 Hz, IH), 3.81-3.76 (m, IH), 3.76 (s, 3H), 3.56 (dd, J 11.4, 3.0 Hz, IH), 3.51-3.43 (m, 2H), 3.23 (dd, J 14.1, 8.1 Hz, IH), 3.09 (dd, J 14.4, 7.1 Hz, IH), 2.98 (s, 6H). LCMS (ES⁺) 453 (M+H)⁺.

EXAMPLE 406

3-[(5^r)-4-(5-Chloro-6-methoxypyridine-3-carbonyl^')morpholin-3-ylmethyll- 1 -methyl- IH- indole-5-carboxylic acid N-r2-(dimethylamino)ethyl]-N-methylamide

To a stirred solution of Intermediate 76 (120 mg, 0.2 mmol) in THF (5 mL) and iV,N,iV-trimethylethylenediamine (52 μL, 0.4 mmol)was added DIPEA (60 μL, 0.4 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. The residue was purified using preparative HPLC, yielding the title compound (43 mg, 40%) as a white solid. δ_H (d₆-DMSO at 100⁰C) 7.90 (d, J2.0 Hz, IH), 7.51 (s, IH), 7.42-7.37 (m, 2H), 7.17 (dd, J8.6, 1.5 Hz, IH), 7.09 (s, IH), 4.34-4.25 (m, IH), 4.01-3.90 (m, 5H), 3.87-3.74 (m, 6H), 3.64 (dd, J 11.4, 3.0 Hz, IH), 3.52 (d, J 8.8 Hz, 2H), 3.46 (t, J6.8 Hz, 2H), 3.18 (d, J 7.3 Hz, 2H), 2.97 (s, 3H), 2.16 (s, 6H). LCMS (ES⁺) 528 (M+H)⁺. EXAMPLE 407

pyridin-3-vUcarbamic acid methyl ester To a stirred solution of Example 193 (140 mg, 0.3 mmol) in DCM (5 mL) and methyl chloroformate (26 μL, 0.3 mmol) was added TEA (93 μL, 0.6 mmol). The reaction mixture was stirred at r.t. for 18 h, then partitioned between DCM (20 mL) and saturated brine (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried (phase separator) and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 5-20% MeOH/EtOAc) to yield the title compound (41 mg, 26%) as a yellow solid. δ_H (Cl₆-DMSO at 100⁰C) 9.47-9.39 (m, IH), 8.57 (d, J2.3 Hz, IH), 7.97 (s, IH), 7.63 (s, IH), 7.47 (s, IH), 7.36 (d, J8.3 Hz, IH), 7.17 (dd, J8.3, 1.3 Hz, IH), 7.09 (s, IH), 4.37-4.20 (s, IH), 3.99-3.89 (m, IH), 3.85- 3.79 (m, 2H), 3.77 (s, 3H), 3.74 (s, 3H), 3.60 (dd, J 11.6, 3.0 Hz, IH), 3.55-3.47 (m, 2H), 3.26-3.18 (m, IH), 3.17-3.08 (m, IH), 2.98 (s, 6H). LCMS (ES⁺) 480 (M+H)⁺.

EXAMPLE 408

\(S)-3-{ 5 - \(R)-3 -( AminomethyDpyrrolidine- 1 -carbonyl]- 1 -methyl- 1 H-indol-3 -ylmethyl } - morpholin-4-yll-(2-chloro-5-fluoro-6-methoxypyridin-3-yl)-methanone

To a stirred solution of Intermediate 79 (108 mg, 0.23 mmol), (i?)-pyrrolidin-3-yl- methylcarbamic acid tert-butyl ester (46 mg, 0.23 mmol), EDC (45 mg, 0.35 mmol) and ΗOBT (31 mg, 0.23 mmol) in DMF (5 mL) was added TEA (0.10 mL, 0.71 mmol). The reaction mixture was stirred at r.t. for 18 h, then partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with water (3 x 10 mL), dried (phase separator), concentrated in vacuo and chromatographed (SiO₂, 20-60% EtOAc/ hexanes), yielding an off-white solid. This material was dissolved in DCM (5 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at r.t. for 2 h, quenched by the addition of sodium carbonate solution (20 mL) and extracted with DCM (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0- 10% MeOΗ/EtOAc), yielding the title compound (63 mg, 50%) as a white solid. δ_Η (d₆- DMSO at 100⁰C) 7.78-7.60 (m, 2H), 7.40-7.38 (m, IH), 7.33-7.31 (m, IH), 7.15 (s, IH), 4.23 (br s, IH), 3.98 (s, 3H), 3.95-3.92 (m, 2H), 3.86-3.83 (m, IH), 3.78 (s, 3H), 3.63 (dd, J 11.6, 7.6 Hz, 2H), 3.57-3.47 (m, 4H), 3.30-3.11 (m, 3H), 2.64 (dd, J6.6, 4.3 Hz, 2H), 2.24-2.20 (m, IH), 2.00-1.96 (m, 2H), 1.94-1.87 (m, IH), 1.70-1.57 (m, IH). LCMS (ES⁺) 544 (M+H)⁺.

EXAMPLE 409

(CS)-3 - [5-(3 - Aminoazetidine- 1 -carbonvO- 1 -methyl- 1 H-indol-3 - ylmethyl]morpholin-4- yl|-(2-chloro-5-fluoro-6-methoxypyridin-3-yl)-methanone To a stirred solution of Intermediate 79 (108 mg, 0.23 mmol), azetidin-3-yl- carbamic acid tert-butyl ester (46 mg, 0.23 mmol), EDC (45 mg, 0.35 mmol) and ΗOBT (31 mg, 0.23 mmol) in DMF (5 mL) was added TEA (0.10 mL, 0.71 mmol). The reaction mixture was stirred at r.t. for 18 h, then partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with water (3 x 10 mL), dried (phase separator), concentrated in vacuo and chromatographed (SiO₂, 20-60% EtOAc/hexanes), yielding an off-white solid. This material was dissolved in DCM (5 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at r.t. for 2 h, quenched by the addition of sodium carbonate solution (20 mL) and extracted with DCM (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0- 10% MeOΗ/EtOAc), yielding the title compound (63 mg, 50%) as a white solid. δ_Η (d₆- DMSO at 100⁰C) 7.92-7.71 (m, 2H), 7.46-7.44 (m, IH), 7.41-7.38 (m, IH), 7.17 (br s, IH), 4.38-4.26 (m, 3H), 4.01-3.89 (m, 4H), 3.85 (d, J 11.6 Hz, IH), 3.82-3.74 (m, 6H), 3.70-3.60 (m, 2H), 3.56-3.47 (m, 2H), 3.29-3.12 (m, 2H), 1.97-1.86 (m, 2H). LCMS (ES⁺) 516 (M+H)⁺.

EXAMPLE 410

(3 - Aminoazetidin- 1 - vD- { 3 - [(._>)-4-(3 -hydroxybenzo yl)morpholin-3 - ylmethyll - 1 -methyl- 1 H-indol-5-vU -methanone

To a stirred solution of Intermediate 59 (210 mg, 0.38 mmol) in DCM (5 mL) at O⁰C was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at r.t. for 2 h, quenched by the addition of sodium carbonate (20 mL) and extracted with DCM (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0-10% MeOH/ EtOAc), yielding the title compound (IS mg, 10%) as a white solid, δπ (d₆-DMSO at 100⁰C) 8.19 (s, IH), 7.80 (s, IH), 7.45-7.43 (m, IH), 7.39-7.37 (m, IH), 7.16-7.07 (m, 2H), 6.81-6.78 (m, IH), 6.66-6.64 (m, IH), 6.59 (d, J7.6 Hz, IH), 4.38-4.27 (m, 3H), 3.91 (d, J7.6 Hz, IH), 3.82-3.69 (m, 8H), 3.52 (dd, J 11.6, 3.3 Hz, IH), 3.46-3.41 (m, 2H), 3.32-2.96 (m, 4H). LCMS (ES⁺) 449 (M+H)⁺.

EXAMPLE 411

1 - { 3 - r(S)-4-(4-Chloro-3 -hydroxybenzoyr)morpholin-3 -ylmethyl] - 1 -methyl- 1 H-indole-5- carbonvUazetidine-3-carboxylic acid amide

To a stirred solution of Example 248 (0.32 mg, 0.65 mmol) in EtOH (5 mL) was added sodium hydroxide (5.0 mL, IM solution) and the reaction mixture was cooled to O⁰C. Hydrogen peroxide (1.0 mL, 35% solution) was added and the reaction mixture was stirred at r.t. for 18 h. The reaction mixture was diluted with water (10 mL) and neutralised with Dowex, filtered and the resin washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified using preparative HPLC, yielding the title compound (5 mg, 1%) as a white solid. δ_H (de-DMSO at HO⁰C) 8.22 (s, IH), 7.84 (d, J0.5 Hz, IH), 7.49 (dd, J8.6, 1.3 Hz, IH), 7.40-7.38 (m, IH), 7.21 (d, J8.1 Hz, IH), 7.13 (s, IH), 6.99 (d, J 1.8 Hz, 2H), 6.58 (dd, J 8.1, 1.8 Hz, IH), 4.37-4.19 (m, 6H), 3.92- 3.90 (m, IH), 3.85-3.76 (m, 5H), 3.56 (dd, J 11.4, 3.0 Hz, IH), 3.51-3.42 (m, 3H), 3.31- 3.28 (m, 2H). LCMS (ES⁺) 510 (M-H)⁺.

EXAMPLE 412

l-{3-r(5^r)-4-(3-Fluoro-5-hydroxybenzoyl^')moφholin-3-ylmethyll-l-methyl-lH-indole-5- carbonvUazetidine-3-carboxylic acid

To a stirred solution of Example 128 (0.40 mg, 0.84 mmol) in EtOH (5 mL) was added sodium hydroxide (5.0 mL, IM solution) and the reaction mixture was cooled to 0⁰C. Hydrogen peroxide (1.0 mL, 35% solution) was added and the reaction mixture was stirred at r.t. for 18 h. The reaction mixture was diluted with water (10 mL) and neutralised with Dowex, filtered and the resin washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified using preparative HPLC, yielding the title compound (19 mg, 4%) as a white solid. δ_H Cd₆-DMSO at HO⁰C) 8.22 (s, IH), 7.75 (s, IH), 7.46-7.35 (m, 2H), 7.11 (s, IH), 6.54 (dt, J 10.9, 2.0 Hz, IH), 6.46 (s, IH), 6.25 (d, J8.6 Hz, IH), 4.35-4.18 (m, 5H), 3.92-3.89 (m, IH), 3.82-3.68 (m, 5H), 3.56 (dd, J 11.6, 3.0 Hz, 2H), 3.49-3.43 (m, 2H), 3.37-3.32 (m, IH), 3.24 (dd, J 14.4, 8.1 Hz, 2H). LCMS (ES⁺) 496 (M+H)⁺.

EXAMPLE 413

{ffl-3-r5-(3-Aminoazetidine-l-carbonyl)-l-methyl-lH-indol-3-ylmethyl1morpholin-4- yl ) -(5 -chloro-6-methoxypyridin-3 -vD-methanone

To a stirred solution of Intermediate 62 (140 mg, 0.23 mmol), azetidin-3-yl- carbamic acid tert-butyl ester (48 mg, 0.23 mmol), EDC (68 mg, 0.35 mmol) and HOBT (32 mg, 0.23 mmol) in DMF (5 mL) was added TEA (0.07 mL, 0.71 mmol). The reaction mixture was stirred at r.t. for 18 h, then partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with water (3 x 10 mL), dried (phase separator), concentrated in vacuo and chromatographed (SiO₂, 20-60% EtOAc/hexanes), yielding an off-white solid. This material was dissolved in DCM (5 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at r.t. for 2 h, quenched by the addition of sodium carbonate solution (20 mL) and extracted with DCM (20 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 0- 10% MeOH/EtOAc), yielding the title compound (64 mg, 38%) as a white solid. δ_H (αV DMSO at 100⁰C) 7.90 (d, J2.0 Hz, IH), 7.82 (s, IH), 7.48-7.41 (m, 2H), 7.39 (d, J0.5 Hz, IH), 7.15 (s, IH), 4.47-4.45 (m, 2H), 4.38-4.32 (m, IH), 4.21-4.18 (m, 2H), 4.14-4.07 (m, IH), 3.98 (s, 3H), 3.94 (d, J 8.6 Hz, IH), 3.85-3.83 (m, IH), 3.78 (s, 4H), 3.65 (dd, J 11.6, 3.0 Hz, IH), 3.57-3.49 (m, 2H), 3.19-3.15 (m, 4H). LCMS (ES⁺) 498 (M+H)⁺. EXAMPLE 414

S-lffl^-fS-Chloro-ό-Cmethylamino^pyridine-B-carbonyllmorpholin-S-ylmethvU-l- methyl-lH-indole-5-carboxylic acid dimethylamide The title compound was prepared from Intermediate 80 and methylamine according to Method B and was isolated as a white solid (53 mg, 47%). 5_Η (d₆-DMSO at 11O⁰C) 7.87 (d, J 2.0 Hz, IH), 7.55 (d, J 0.5 Hz, IH), 7.38 (d, J 8.6 Hz, IH), 7.19-7.16 (m, 2H), 7.09 (s, IH), 6.32 (s, IH), 4.35-4.30 (m, IH), 3.93-3.91 (m, IH), 3.84-3.81 (m, 2H), 3.77 (s, 3H), 3.61 (dd, J 11.6, 3.3 Hz, IH), 3.54-3.48 (m, 2H), 3.16 (t, J6.8 Hz, 2H), 2.98 (s, 6H), 2.92 (d, J4.8 Hz, 3H). LCMS (ES⁺) 469 (M+H)⁺.

EXAMPLE 415

3-|(5^f)-4-r5-Chloro-6-(niethanesulfonylamino)pyridine-3-carbonyl]niorpholin-3- ylmethvU-l-methyl-lH-indole-5-carboxylic acid dimethylamide

To a stirred solution of Intermediate 80 (200 mg, 0.42 mmol) in 1,4-dioxane (4 mL) were added methanesulfonamide (48 mg, 0.51 mmol), cesium carbonate (192 mg, 0.59 mmol), Xantphos (8 mg, 0.013 mmol) and Pd₂(dba)₃ (3.9 mg, 0.004 mmol). The reaction mixture was heated to 100⁰C for 1 h, then partitioned between EtOAc (10 mL) and brine (10 mL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by preparative ΗPLC, yielding the title compound (2 mg, 1%) as a white solid. δ_Η (d₆-DMSO at HO⁰C) 7.89 (d, J2.3 Hz, IH), 7.61 (s, IH), 7.39 (d, J8.3 Hz, IH), 7.27 (d, J2.0 Hz, IH), 7.20 (dd, J 8.6, 1.5 Hz, IH), 7.10 (s, IH), 4.37-4.30 (m, IH), 3.92 (d, J8.1 Hz, IH), 3.82-3.80 (m, 2H), 3.77 (s, 4H), 3.60 (dd, J 11.6, 3.3 Hz, IH), 3.54-3.51 (m, 2H), 3.24-3.11 (m, 2H), 3.09 (s, 3H), 2.99 (s, 6H). LCMS (ES⁺) 534(M+H)⁺.

EXAMPLE 416

3-[(>SV4-(5-Methoxypyrazine-2-carbonyl)morpholin-3-ylmethyl]- 1 -methyl- lH-indole-5- carboxylic acid diethylamide

To a stirred solution of Example 250 (47 mg, 0.10 mmol) in methanol (1 mL) was added sodium methoxide (6 mg, 0.11 mmol) and the reaction mixture was heated to 5O⁰C for 2 h, then partitioned between EtOAc (10 mL) and brine (10 niL). The organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by preparative HPLC, yielding the title compound (19 mg, 44%) as a white solid. δ_H (d₆-DMSO at 110⁰C) 8.08 (s, IH), 8.02 (s, IH), 7.51 (s, IH), 7.34 (d, J8.4 Hz, IH), 7.17 (d, J8.4 Hz, IH), 7.06 (s, IH), 4.56-4.54 (m, IH), 4.03-4.00 (m, IH), 3.97 (d, J7.6 Hz, IH), 3.94 (s, 3H), 3.83 (d, J 11.5 Hz, IH), 3.75 (s, 3H), 3.60 (dd, J 11.5, 3.1 Hz, IH), 3.55-3.48 (m, 2H), 3.23-3.15 (m, 2H), 2.99 (s, 6H). LCMS (ES⁺) 438(M+H)⁺.

Claims

Claims: *>

1. A compound of formula (I) or an TV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

(D

wherein

X represents oxygen, N-R⁵ or a covalent bond; Y represents C=O or S(O)₂;

R¹ represents C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(C_1-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R² represents hydrogen; or optionally substituted Ci_-6 alkyl;

R³ and R⁴ independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR^a, -SR^a, -SOR^a, -SO₂R^a, -NR^bR^c, -CH₂NR^bR^c, -NR^cC0R^d, -CH₂NR^cC0R^d, -NR^cCO₂R^d, -NHCONR^bR^c, -NR⁰SO₂R⁶, -N(SO₂R^e)₂, -NHS0₂NR^bR^c, -COR^d, -C0₂R^d, -CONR^bR^c, -C0N(0R^a)R^b or -SO₂NR^bR^c; or Ci_-6 alkyl, aryl, aryl(Ci.₆)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R⁵ represents hydrogen or Ci_-6 alkyl;

R^a# represents Ci_-6 alkyl, aryl, aryl(Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R^b and R^c independently represent hydrogen or trifluoromethyl; or Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or

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

R^d represents hydrogen; or C_1-6 alkyl, C_3-7 cycloalkyl, aryl, C_3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and

R^e represents C_1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

2. A compound as claimed in claim 1 wherein the substituent at the 3 -position of the morpholine ring is in the (S) configuration.

3. A compound as claimed in claim 1 represented by formula (HA) or an TV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

(^IIA>

wherein X, R¹, R² and R³ are as defined in claim 1.

4. A compound as claimed in any one of the preceding claims wherein X represents oxygen or a covalent bond.

5. A compound as claimed in any one of the preceding claims wherein R¹ represents methyl, ethyl, propyl, ter/-butyl, cyclopropyl, cyclohexylmethyl, phenyl, naphthyl, benzyl, tetrahydrofuryl, oxetanylmethyl, pyrrolidinylethyl, furyl, thienyl, thieno[2,3-ό]pyridinyl, indolyl, pyrrolo[2,3-&]pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-α]pyridinyl, oxadiazolyl, triazolyl, pyridinyl, quinolinyl, 3,4-dihydro-2H-pyrido[3,2-Z>][l,4]oxazinyl, pyrimidinyl, pyrazinyl, furylmethyl, indolylmethyl, thiazolylmethyl, imidazolylmethyl, imidazo[l,2-α]pyridinyl- methyl, triazolylmethyl, benzotriazolylmethyl, tetrazolylmethyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents independently selected from halogen, cyano, nitro, C_1-6 alkyl, trifluoromethyl, aryl(C_1-6)alkyl, hydroxy, C_1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, aryloxy, hydroxy- benzoyloxy, (hydroxy)(methyl)benzoyloxy, Ci_-4 alkylenedioxy, Ci_-6 alkoxy(C_1-6)alkyl, Ci_-6 alkylthio, Ci_-6 alkylsulphonyl, oxo, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, aryl(Ci_-6)alkoxycarbonylamino, Ci_-6 alkylaminocarbonylamino, arylaminocarbonylamino, Ci_-6 alkylsulphonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxy carbonyl, aminocarbonyl, Ci_-6 alkylamino- carbonyl, di(Ci_-6)alkylaminocarbonyl, aminosulphonyl, Ci_-6 alkylaminosulphonyl and di(C i_-6)alkylaminosulphonyl.

6. A compound as claimed in claim 3 represented by formula (HB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

wherein

R and R are as defined in claim 1 ; R¹¹ represents hydrogen, halogen, C_1-6 alkyl, trifluoromethyl, hydroxy, C_1-6 alkoxy, trifluoromethoxy or Ci_-6 alkylaminosulphonyl;

R¹² represents hydrogen, halogen, cyano, nitro, C_1-6 alkyl, trifluoromethyl, hydroxy, C_1-6 alkoxy, trifluoromethoxy, C_1-6 alkylthio, C_1-6 alkylsulphonyl, amino or di(C i _-6)alky lamino; and

R¹³ represents hydrogen, halogen, trifluoromethyl or C_1-6 alkoxy.

7. A compound as claimed in claim 3 represented by formula (IIC) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

(IIC)

wherein

R² and R³ are as defined in claim 1 ; R²¹ represents hydrogen, halogen, cyano, Ci_-6 alkyl, Ci_-6 alkoxy, trifluoroethoxy,

Ci-₆ alkylthio, amino, Ci_-6 alkylamino, di(Ci_-6)alky lamino, C_2-6 alky lcarbony lamino, C_2-6 alkoxycarbonylamino, aryl(Ci_-6)alkoxycarbonylamino, Ci_-6 alkylaminocarbonylamino, arylaminocarbonylamino or Ci_-6 alky lsulphony lamino;

R²² represents hydrogen, halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, hydroxy, Ci_-6 alkoxy, amino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino or Ci_-6 alky lsulphony lamino; and

R²³ represents hydrogen, halogen, cyano, Ci_-6 alkyl, Ci_-6 alkoxy or amino.

8. A compound as claimed in any one of the preceding claims wherein R² represents hydrogen or methyl.

9. A compound as claimed in any one of the preceding claims wherein R³ represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR^a, -SO₂R^a, -NR^bR^c, -CH₂NR^bR^c, -NR^cCOR^d, -CH₂NR^cCOR^d, -NR^cC0₂R^d, -NHC0NR^bR^c, -NR^cSO₂R^e, -N(SO₂R^e)₂, -NHSO₂NR^bR^c, -COR^d, -CO₂R^d, -CONR^bR^c, -CON(OR^a)R^b or -SO₂NR^bR^c, wherein R^a, R^b, R^c, R^d and R^e are as defined in claim 1 ; or C_1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents independently selected from halogen, Ci_-6 alkyl, Ci_-6 alkoxy and C_1-4 alkylenedioxy.

10. A compound as claimed in any one of the preceding claims wherein R⁴ represents hydrogen, halogen, -COR^d, -CO₂R^d or -CONR^bR^c, wherein R^b, R^c and R^d are as defined in claim 1.

11. A compound as herein specifically disclosed in any one of the Examples.

12. A compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

13. A compound of formula (I) as defined in claim 1 or an iV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and/or prevention of a disorder for which the administration of a selective PBK inhibitor is indicated.

14. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an iV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier.

15. The use of a compound of formula (I) as defined in claim 1 or an TV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of a disorder for which the administration of a selective PI3K inhibitor is indicated.

16. A method for the treatment and/or prevention of a disorder for which the administration of a selective PBK inhibitor is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 or an iV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof.