WO2010001126A1

WO2010001126A1 - Thiophene derivatives as kinase inhibitors

Info

Publication number: WO2010001126A1
Application number: PCT/GB2009/001659
Authority: WO
Inventors: Rikki Peter Alexander; Stuart Bailey; Daniel Christopher Brookings; Julien Alistair Brown; Sacha Callaghan; Faye Charlotte Pollard
Original assignee: Ucb Pharma S.A.
Priority date: 2008-07-03
Filing date: 2009-07-02
Publication date: 2010-01-07
Also published as: GB0812309D0

Abstract

A series of thiophene derivatives which are substituted in the 2 -position by a morphoIin-4-yl substituent, and in the 3 -position by a substituted ethynyl moiety, 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

THIOPHENE DERIVATIVES AS KINASE INHIBITORS

The present invention relates to a class of substituted thiophene derivatives, and to their use in therapy. More particularly, the invention provides a family of thiophene derivatives which are substituted in the 2-position by a morpholine ring, and in the 3- position by a substituted ethynyl moiety. 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, PI3Ks 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 ah, 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 ah, 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.

A class of PI3K inhibitors comprising a fused bicyclic thiophene ring is described in WO 2007/141504. A class of monocyclic thiazole-containing PBK inhibitors is described in WO 2008/047109. Nowhere in the prior art published to date, however, is there the precise disclosure of a class of compounds whose structure corresponds to those of the present invention.

The compounds in accordance with the present invention are potent and selective PDK inhibitors having a binding affinity (IC₅₀) for the human PB Ka and/or PBKβ and/or PBKγ and/or PBKδ 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 PBKα and/or PBKβ and/or PBKγ and/or PBKδ isoform relative to other human kinases. The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein

R » 1¹ represents cyano, -C(=X)R^a, -CH(OH)R^a, -CO₂R" or -C(=X)NR^cR^d; or R¹ represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or

R¹ represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;

X represents oxygen, sulphur or N-OH;

R^a represents hydrogen, C_1-6 alkyl or optionally substituted aryl;

R represents hydrogen or Ci_-6 alkyl;

R^c represents hydrogen; 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(Ci_-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and

R represents hydrogen or C_1-6 alkyl; or

R^c and R^d, when taken together with the nitrogen atom to which they are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, homomorpholinyl or homopiperazinyl, any of which groups may be optionally substituted by one or more substituents;

R represents hydrogen, C_1-6 alkyl, halogen, cyano or trifloromethyl; and

R³ represents C_3-7 cycloalkyl, aryl, C_3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

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; ammonium 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 C_1-4 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, ^-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "Ci -₆ alkoxy", "Ci_-6 alkylthio", "C]_-6 alkylsulphonyl" and "C_1-6 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(Ci_-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthy lmethyl .

Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, pyrrolidinyl, indolinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, 1,2,3,4-tetrahydroqumolinyl, 1,2,3,4-tetrahydro- isoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, morpholinyl and thiomorpholinyl.

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazo[l,2-α]pyridinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl and pyrazinyl 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 embodiment, R¹ represents cyano. In another embodiment, R¹ represents -C(=X)R^a. In another embodiment, R¹ represents -CH(OH)R^a. In another embodiment, R¹ represents -CO₂R^b. In an additional embodiment, R¹ represents -C(=X)NR^cR^d. In a further embodiment, R represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl. In a still further embodiment, R¹ represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

In one embodiment, X is O. In another embodiment, X is S. In a further embodiment, X is N-OH.

In one embodiment, R^a represents hydrogen. In another embodiment, R^a represents Ci_-6 alkyl, especially methyl. In a further embodiment, R^a represents optionally substituted aryl. Where R^a represents optionally substituted aryl, examples of typical substituents include C_!-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(C_]-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl, lieteroaryl, heteroaryl(Ci_-6)alkyl, hydroxy, C_1-6 alkoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, halogen, cyano and trifluoromethyl. Examples of suitable substituents include halogen, especially chloro. Suitable values of R^a include hydrogen, methyl and chlorophenyl. In one embodiment, R^b represents hydrogen. In another embodiment, R^b represents C_J-6 alkyl. In one aspect of the latter embodiment, R represents methyl. In another aspect of the latter embodiment, R^b represents ethyl.

Suitable values of R^b include hydrogen, methyl and ethyl. Suitably, R^c represents hydrogen; or Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl- (Ci.₆)alkyl or aryl(Ci.₆)alkyl, any of which groups may be optionally substituted by one or more substituents. Suitably, the group R^c, or the cyclic moiety -NR^cR^d, may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In one embodiment, the group R^c, or the cyclic moiety -NR^cR^d, is unsubstituted. In another embodiment, the group R^c, or the cyclic moiety -NR^cR^d, is monosubstituted. In a further embodiment, the group R^c, or the cyclic moiety -NR^cR^d, is disubstituted. Examples of typical substituents on R^c, or on the cyclic moiety -NR^cR^d, include

Ci_-6 alkyl, Cj_-6 alkoxy, Ci_-6 alkoxy(C[_-6)alkyl, hydroxy, hydroxy(Ci_-6)alkyl, amino(Ci_-6)- alkyl, (amino)(hydroxy)(Ci_-6)alkyl, halogen, oxo, C_2-6 alkylcarbonyl, carboxy, carboxy- (Ci_-6)alkyl, C_2-6 alkoxycarbonyl, C_2-6 alkoxy carbonyl(Ci_-6)alkyl, di(Ci_-6)alkylhydrazinyl- carbonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_2-6 alkoxycarbonylamino(Ci_-6)alkyl, aminocarbonylamino, aminocarbonyl, Cj_-6 alkylaminocarbonyl, di(Ci-₆)alkylaminocarbonyl, aminosulfonyl, Ci_-6 alkylsulfonyl and Ci_-6 alkylaminocarbonyl(Ci_-6)alkyl.

Examples of particular substituents on R^c, or on the cyclic moiety -NR^cR^d, include methyl, methoxy, methoxymethyl, hydroxy, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-amino-3-hydroxyρropyl, fluoro, oxo, acetyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, ført-butoxycarbonyl, ethoxycarbonylmethyl, dimethylhydrazinylcarbonyl, amino, methylamino, 1,3-dimethylbutylamino, dimethylamino, acetylamino, føY-butoxycarbonylamino, fert-butoxycarbonylaminomethyl, aminocarbonylamino, aminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, aminosulfonyl, methylsulfonyl and methylaminocarbonylmethyl.

Examples of suitable substituents on R°, or on the cyclic moiety -NR^cR^d, include Ci_-6 alkyl, Ci_-6 alkoxy and di(C_1-6)alkylamino. Examples of specific substituents on R^c, or on the cyclic moiety -NR^cR^d, include methyl, methoxy and dimethylamino.

Suitable values of R^c include hydrogen, methyl, ethyl, cyclopropyl, cyclopropylmethyl and benzyl, any of which groups may be optionally substituted by one or more substituents. Particular values of R^c include hydrogen, methyl, ethyl, methoxyethyl, dimethylaminoethyl, cyclopropyl, cyclopropylmethyl and benzyl.

In one embodiment, R^d is hydrogen. In another embodiment, R^d represents C_1-6 alkyl, especially methyl.

Alternatively, the moiety -NR^cR^d may suitably represent azetidin-1-yl, pyrrolidin- 1 -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.

Suitable values for the cyclic moiety -NR^cR^d include piperidin- 1-yl and piperazin- 1-yl, either of which groups may be optionally substituted by one or more substituents. Suitably, the cyclic moiety -NR⁰R may be substituted by Ci-₆ alkyl, especially methyl. Particular values of the cyclic moiety -NR^cR^d include piperidin- 1-yl and 4- methylpiperazin- 1 -yl.

Where R¹ in the compounds of formula (I) above represents an optionally substituted five-membered or six-membered heteroaromatic ring, this ring may be unsubstituted, or may suitably be substituted, where possible, by one or more, typically by one or two, substituents. In one embodiment, this ring is unsubstituted. In another embodiment, this ring is monosubstituted. In a further embodiment, this ring is disubstituted.

Suitable values for the optionally substituted five-membered or six-membered heteroaromatic ring R¹ include pyrazolyl, oxazolyl, isoxazolyl and pyrimidinyl, any of which rings may be substituted, where possible, by one or more substituents.

Examples of typical substituents on the five-membered or six-membered heteroaromatic ring as specified for R¹ include 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- (C]_-6)alkyl, heteroaryl, heteroaryl(C_{) -6})alkyl, hydroxy, C]_-6 alkoxy, C_1-6 alkylthio, Cj_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, amino, Ci_-6 alkylamino, di(C_1-6)alkylamino, halogen, cyano and trifluoromethyl. Examples of suitable substituents include Ci_-6 alkyl, especially methyl.

Particular values for the optionally substituted five-membered or six-membered heteroaromatic ring R¹ include methylpyrazolyl, oxazolyl, isoxazolyl and pyrimidinyl.

In one embodiment, R² represents hydrogen. In another embodiment, R² represents Ci_-6 alkyl, especially methyl. In a further embodiment, R² represents halogen. In a still further embodiment, R represents cyano. In an additional embodiment, R² represents trifloromethyl.

Suitably, R² represents hydrogen or Ci_-6 alkyl.

Typically, R³ represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents. Suitable values of R³ include cyclopropyl, cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, indolyl, pyrazolyl, imidazolyl, imidazo[l,2-α]pyridinyl, pyridinyl and pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.

Typical values of R³ include phenyl and imidazolyl, either of which groups may be optionally substituted by one or more substituents.

Examples of suitable substituents on R³ include Cj_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, hydroxy(Ci_-6)alkyl- (C_3-7)heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl, heteroaryl, heteroaryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, amino, Cj_-6 alkylamino, di(Ci_-6)alkylamino, di(Ci-₆)alkylamino(Ci_-6)alkyl, di(Ci_-6)alkylamino(C_1-6)alkylamino, halogen, cyano, nitro and trifluoromethyl.

Examples of typical substituents on R³ include Ci_-6 alkyl, hydroxy(Ci_-6)alkyl- (C_3-7)heterocycloalkyl_J hydroxy, Ci_-6 alkoxy, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, C_2-6 alkoxycarbonyl, amino, di(Ci.6)alkylamino, di(Ci_-6)alkylammo(Ci_-6)alkyl, di(Ci_-6)alkyl- amino(Ci.₆)alkylamino, halogen and nitro.

Examples of representative substituents on R³ include methyl, hydroxymethyl- pyrrolidinyl, hydroxy, methoxy, methylsulphonyl, acetyl, /erf-butoxycarbonyl, amino, dimethylamino, dimethylaminomethyl, dimethylaminoethylamino, fluoro, chloro and nitro.

One example of a particular substituent on R³ is Ci_-6 alkyl, especially methyl.

Suitable values of R include cyclopropyl, hydroxycyclohexyl, aminocyclohexyl, phenyl, hydroxyphenyl, methoxyphenyl, dimethylaminophenyl, fluorophenyl, nitrophenyl, pyrrolidinyl, tert-butoxycarbonylpyrrolidinyl, piperidinyl, lnethylsulphonylpiperidinyl, acetylpiperidinyl, tert-butoxycarbonylpiperidinyl, indolyl, methylindolyl, pyrazolyl, methylpyrazolyl, methylimidazolyl, dimethylimidazolyl, imidazo[l,2-α]pyridinyl, dimethylaminomethylimidazo[l ,2-α]pyridinyl, pyridinyl, hydroxymethylpyrrolidinyl- pyridinyl, aminopyridinyl, dimethylaminoethylaminopyridinyl, chloropyridinyl and aminopyrimidinyl.

Particular values of R³ include phenyl and methylimidazolyl.

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

(IIA)

wherein

R¹ and R² are as defined above; and R¹³ and R¹⁴ independently represent hydrogen, 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, heteroaryl(C_1-6)alkyl, hydroxy, Cj_-6 alkoxy, Ci_-6 alkylthio, C_!-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, halogen, cyano, nitro or trifluoromethyl. Suitable values of R¹³ and/or R¹⁴ include hydrogen, hydroxy, Ci_-6 alkoxy, di(Ci_-6)alkylamino, halogen and nitro.

Typical values of R¹³ and/or R¹⁴ include hydrogen, hydroxy, methoxy, dimethylamino, fluoro and nitro.

A particular value of R¹³ is hydrogen.

A particular value of R¹⁴ is hydrogen.

Another sub-class of compounds according to the invention is represented by the compounds of formula (IIB), and pharmaceutically acceptable salts and solvates thereof:

wherein

R¹ and R² are as defined above; and

R²³ represents hydrogen, 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, heteroaryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl or trifluoromethyl.

Suitably, R²³ represents hydrogen or Ci_-6 alkyl.

In one embodiment, R represents hydrogen. In another embodiment, R represents Cj_-6 alkyl, especially methyl.

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 may be prepared by a process which comprises reacting a compound of formula H-C≡C-R³ with a compound of formula (III):

(III)

wherein R¹, R² and R³ are as defined above, and L¹ represents a readily displaceable group; in the presence of a transition metal catalyst.

The readily displaceable group L¹ is typically a halogen atom, e.g. iodo.

The transition metal catalyst is suitably dichlorobis(triphenylphosphine)- palladium(II), in which case the reaction is conveniently effected at an elevated temperature in the presence of copper(I) iodide and an organic base such as diisopropy lamine .

The intermediates of formula (III) above wherein L¹ represents iodo may be prepared by a process which comprises reacting a compound of formula (IV):

(IV)

wherein R¹ and R² are as defined above; with an iodinating agent.

The iodinating agent is suitably iV-iodosuccinimide or elemental iodine, in which case the reaction is conveniently effected in a suitable organic solvent, e.g. tetrahydrofuran or dichloromethane. Where they are not commercially available, the starting materials of formula (IV) 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 represents -CO₂R¹³, in which R^b is other than hydrogen, may be converted into the corresponding compound wherein R¹ represents carboxy (-CO₂H) by treatment with a base such as lithium hydroxide. A compound of formula (I) wherein R¹ represents -CO₂H may be converted into the corresponding compound wherein R¹ represents -CONR^cR^d by treatment with an amine of formula H-NR^cR^d and a condensing agent, e.g. l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCHCl) and 1-hydroxybenzotriazole hydrate, or O- (benzotriazol-l-yl)-N,N,N'^V'-tetramethyluronium hexafluorophosphate (HBTU), typically in the presence of an organic base such as triethylamine or Aζλf-diisopropylethylamine.

A compound of formula (I) wherein R¹ represents foπnyl (-CHO) may be converted into the corresponding compound wherein R¹ represents oxazol-5-yl by treatment with tosylmethyl isocyanide (TosMIC) in the presence of a base such as potassium carbonate. A compound of formula (I) wherein R¹ represents -C(=X)R^a and X represents oxygen may be converted into the corresponding compound wherein X represents N-OH by treatment with hydroxylamine hydrochloride.

A compound of formula (I) wherein R^! represents -C(=X)H and X represents N-OH may be converted into the corresponding compound wherein R¹ represents cyano by treatment with trichloroacetyl chloride, typically in the presence of an organic base such as triethylamine.

A compound of formula (I) wherein R¹ represents cyano may be converted into the corresponding compound wherein R¹ represents -C(=X)NH₂ and X represents sulphur by treatment with a hydrosulfide salt, e.g. sodium hydrosulfide hydrate. A compound of formula (I) wherein R¹ represents cyano may be converted into the corresponding compound wherein R¹ represents -C(=X)NH₂ and X represents N-OH by treatment with hydroxylamine. A compound of formula (I) wherein R¹ represents -C(=X)R^a and X represents oxygen may be converted into the corresponding compound wherein R¹ represents -CH(OH)R^a by treatment with a reducing agent, e.g. sodium borohydride.

A compound of formula (I) wherein R represents acetyl (-COCH₃) may be converted into the corresponding compound wherein R¹ represents an optionally substituted pyrazolyl moiety by a two-stage procedure which comprises (i) reaction with iV,Λ?-dimethylformarnide dimethyl acetal; and (ii) reaction of the 3-(dimethylamino)prop- 2-en-l-on-l-yl derivative thereby obtained with hydrazine hydrate or an appropriately substituted hydrazine derivative. Similarly, the enamine derivative obtained from stage (i) of the foregoing procedure may be reacted with hydroxylamine hydrochloride or formamidine acetate to provide the corresponding compound wherein R¹ represents isoxazol-5-yl or pyrimidin-4-yl respectively.

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. Cliromatography, 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 PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PI3Kδ.

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 ah, 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 IC₅₀.

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 PI3Kβ and/or PI3Kγ and/or PI3Kδ of 50 μM or better. EXAMPLES

Abbreviations

DCM: dichloromethane EtOAc: ethyl acetate

DMF: iV,N-dimethylformamide MeOH: methanol

DMSO: dimethylsulfoxide EtOH: ethanol

Et₂O: diethyl ether THF: tetrahydrofuran

MeCN: acetonitrile NIS: iV-iodosuccinimide Et₃N: triethylamine TosMlC: tosylmethyl isocyanide

NaOAc: sodium acetate NaOEt: sodium ethoxide

DIPEA: iV,iV-diisopropylethylamine HOBT: 1-hydroxybenzotriazole hydrate

DMF. DMA: N^-dimethylformamide dimethyl acetal

EDCHCl: 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HBTU: O-(benzotriazol-l-yl)-iV,7V,iV'^V'-tetramethyluronium hexafluorophosphate r.t.: room temperature sat.: saturated

RT: retention time Ph: phenyl h: hour SiO₂: silica br.: broad w: weight M: mass brine: saturated aqueous sodium chloride solution

HPLC: High Performance Liquid Chromatography

LCMS: Liquid Chromatography Mass Spectrometry

ES+: Electrospray Positive Ionisation

Analytical Conditions

All ΝMRs were obtained either at 300 MHz or 400 MHz.

Compounds were named with the aid of ACD Labs Name (v. 9.0) supplied by

Advanced Chemical Development, Toronto, Canada. AU reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

All compound purities and retention times were determined by LCMS using one of Methods 1-2 below. Method 1: Gemini Cl 8 50 x 4.6 mm, 5 μm column. Mobile phase A: 99.9% ammonium formate, 0.1% formic acid. Mobile phase B: 94.9% MeCN, 0.1% formic acid, 5% mobile phase A. Gradient program (flow rate 0.9 mL/min, column temperature 40°C):

Time A % B % 0.00 95.0 5.0 2.00 5.0 95.0 4.00 5.0 95.0

Method 2: Luna Cl 8(2) 100 x 4.6 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid. Gradient program (flow rate 3.0 mL/min, column temperature 35°C): Time A % B % 0.00 95.0 5.0

4.40 5.0 95.0 5.30 5.0 95.0 5.32 95.0 5.0 6.50 95.0 5.0

Preparative HPLC for all compounds that required it was performed at pH 2.5 using a Luna C18, 21.2 mm, 5 μm column. 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.

INTERMEDIATE 1 (METHOD A)

Ethyl 4-iodo-5-(morpholin-4-yl)thiophene-2-carboxylate

To a stirred solution of ethyl 5-(morpholin-4-yl)thiophene-2-carboxylate (0.18 g, 0.75 mmol) in THF (10 mL) was added NIS (0.18 g, 0.82 mmol). The reaction mixture was stirred at r.t. for 10 minutes. Aqueous sat. NaHCO₃ solution (15 mL) and EtOAc (20 mL) were added, and the layers separated. The aqueous fraction was extracted with EtOAc (2 x 15 mL). The combined organic fractions were dried (Na₂SO₄), filtered and concentrated in vacuo to give the title compound (0.21 g, 76%) as a brown oil that was used without further purification. δ_H (DMSOd₆) 7.66 (IH, s), 4.25 (2H, q, J7.1 Hz), 3.79-3.75 (4H, m), 3.13-3.09 (4H, m), 1.27 (3H, t, J7.1 Hz). MS (ES+) 369.0 (M+H)⁺ (Method 1).

INTERMEDIATE 2

4-Iodo-5-(morpholin.-4-yl)thiophene-2-carbaldehyde

The title compound was prepared from 5-(morpholin-4-yl)thiophene-2- carbaldehyde according to Method A and was isolated as a green solid (57%) that was used without further purification. δ_H (DMSO-d₆) 9.67 (IH, s), 7.99 (IH, s), 3.79-3.74 (4H, m), 3.24-3.19 (4H, m). LCMS (ES+) 324.0 (M+H)⁺, RT 3.24 minutes (Method 1).

INTERMEDIATE 3 (METHOD B)

ferZ-Butyl 2-amino-5 -carbamoyM-methylthiophene-S -carboxylate

To a stirred suspension of sulfur (3.2 g, 100.0 mmol), acetoacetamide (10.1 g, 100.0 mmol) and tert-butyl cyanoacetate (14.1 g, 100.0 mmol) in EtOH (50 mL) at 45⁰C was added morpholine (8.7 mL, 100.0 mmol) dropwise over 15 minutes. The reaction mixture was stirred at 45⁰C for 5 h, then cooled to r.t. and the precipitate filtered. Water (50 mL) was added to the filtrate and more precipitate was filtered off. The combined solids were washed with EtOH/water (1:1 ratio) and dried to give the title compound (20 g, 79%) as a white solid. δ_H (DMSOd₆) 7.57 (2H, br. s), 7.03 (2H, br. s), 2.45 (3H, s), 1.51 (9H, s). LCMS (ES+) 256.9 (M+H)⁺, RT 2.81 minutes (Method 1).

INTERMEDIATE 4 (METHOD C)

/er/-Butyl 2-bromo-5-carbamoyl-4-methylthiophene-3-carboxylate

To a stirred solution of Intermediate 3 (0.30 g, 1.17 mmol) in MeCN (10 mL) was added copper(II) bromide (0.37 g, 1.64 mmol). The reaction mixture was cooled to O⁰C, and tert-biityl nitrite (0.15 mL, 1.29 mmol) was added dropwise. The reaction mixture was stirred at O⁰C for 15 minutes, then at r.t. for 2 h. Aqueous HCl (2M; 10 mL) and DCM (10 mL) were added, and the layers separated. The aqueous fraction was extracted with DCM (3 x 10 mL). The combined organic fractions were dried (Na₂SO₄), filtered and concentrated in vacuo. The resulting solid was triturated with DCM/hexanes, then with hexanes, and air-dried to give the title compound (0.23 g, 61%) as an orange solid. δ_H (DMSOd₆) 7.63 (2H, br. s), 2.43 (3H, s), 1.55 (9H₅ s). LCMS (ES+) 321.7 (M+H)⁺, RT 3.14 minutes {Method 1).

INTERMEDIATE 5 (METHOD D)

tert-Butyl 5-carbamoyl-4-methyl-2-(moipholin-4-yl)thiophene-3-carboxylate To a stirred solution of Intermediate 4 (0.23 g, 0.72 mmol) in DMSO (3 mL) was added morpholine (0.16 mL, 1.87 mmol). The reaction mixture was heated to 100⁰C for 16 h. Upon cooling to r.t. and the addition of water (5 mL) a precipitate formed. It was filtered, washed with water (5 mL), then Et₂O (3 x 10 mL), and air dried to give the title compound (0.14 g, 62%) as an off-white solid. δ_H (DMSO-d₆) 7.27 (2H, br. s), 3.74-3.71 (4H, m), 3.05-3.03 (4H, m), 2.36 (3H, s), 1.51 (9H, s). LCMS (ES+) 326.9 (M+H)⁺, RT 2.79 minutes {Method I).

INTERMEDIATE 6 (METHOD E)

3 -Methyl-5 -(morpholin-4-yl)thiophene-2-carboxamide

To a stirred solution of Intermediate 5 (0.14 g, 0.44 mmol) in DCM (2.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at r.t. for 1 h, and then partitioned between DCM (5 mL) and aqueous sat. NaHCO₃ solution (5 mL). The organic fraction was washed with aqueous sat. NaHCO₃ solution (2 x 5 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The resulting solid was triturated with

DCM/Et2θ, then with Et₂O, and air-dried to give the title compound (0.065 g, 65%) as a white solid. δ_H (DMSO-d₆) 6.89 (2H, br. s), 6.02 (IH, s), 3.72-3.70 (4H, m), 3.10-3.07 (4H, m), 2.32 (3H, s). LCMS (ES+) 226.9 (M+H)⁺, RT 2.37 minutes {Method I). INTERMEDIATE 7

4-Iodo-3-methyl-5-(morpholin-4-yl)thiophene-2-carboxaniide

To a stirred solution of Intermediate 6 (0.2 g, 0.89 mmol) in THF (5 mL) at O⁰C was added iodine (0.23 g, 0.89 mmol). The reaction mixture was stirred for 10 minutes, and then partitioned between aqueous sat. NaHCO₃ solution (10 mL) and EtOAc (10 mL). The aqueous fraction was extracted with EtOAc (3 x 10 mL). The combined organic fractions were dried (Na₂SO₄), filtered and concentrated in vacuo to give the title compound (0.3 g, 97%) as a brown solid that was used without further purification, δπ (DMSO-d₆) 7.37 (2H, br. s), 3.77-3.73 (4H, m), 3.01-2.98 (4H, m), 2.41 (3H, s). LCMS (ES+) 352.8 (M+H)⁺, RT 2.77 minutes (Method 1).

INTERMEDIATE 8

4-tøt-Butyl 2-methyl 5-amino-3-methylthiophene-2,4-dicarboxylate

The title compound was prepared from methyl acetoacetate and tert-bv&yl cyanoacetate according to Method B and was isolated as an orange solid (78%) that was used without further purification. δ_H (DMSO-d₆) 7.90 (2H, br. s), 3.69 (3H, s), 2.58 (3H, s), 1.51 (9H, s). LCMS (ES+) 272.0 (M+H)⁺, RT 3.63 minutes (Method 1).

INTERMEDIATE 9

4-ferf-Butyl 2-methyl 5-bromo-3-methylthioρhene-2,4-dicarboxylate

The title compound was prepared from Intermediate 8 according to Method C and was isolated as a brown oil (85%) that was used without further purification. 5_H (DMSO- dβ ) 3.81 (3H₅ s), 2.55 (3H, s), 1.55 (9H, s). LCMS (ES+) 279.0 (M-¹Bu)⁺, RT 4.13 minutes (Method 1).

INTERMEDIATE 10

4-fert-Butyl 2-methyl 3-methyl-5-fmorpholin-4-yl)thiophene-2,4-dicarboxylate

The title compound was prepared from Intermediate 9 according to Method D and was isolated as a pink oil (50%) that was used without further purification. 5_H (DMSO- d₆) 3.74 (3H, s), 3.73-3.71 (4H, m), 3.15-3.12 (4H, m), 2.46 (3H, s), 1.51 (9H, s). LCMS (ES+) 342.1 (M+H)⁺, RT 3.67 minutes {Method 1).

INTERMEDIATE 11

Methyl 3 -methyl-5 -(morpholm-4-yl)thiophene-2-carboxylate

The title compound was prepared from Intermediate 10 according to Method E and was isolated as a pale pink solid (65%) that was used without further purification. 6_H (DMSOd₆) 6.51 (IH, s), 3.73-3.68 (4H, m), 3.69 (3H, s), 3.18-3.15 (4H, m), 2.37 (3H, s). LCMS (ES+) 242.1 (M+H)⁺, RT 3.17 minutes {Method 1).

INTERMEDIATE 12

Methyl 4-iodo-3-methyl-5-(morpholin-4-yl)thiophene-2-carboxylate The title compound was prepared from Intermediate 11 according to Method A and was isolated as a pale brown solid (75%) that was used without further purification. δ_H (DMSOd₆) 3.77 (3H₅ s), 3.90-3.88 (4H, m), 3.17-3.14 (4H, m), 2.51 (3H, s). LCMS (ES+) 368.0 (M+H)⁺, RT 3.75 minutes {Method 1).

INTERMEDIATE 13

tert-Butyl 5-acetyl-2-amino-4-methy lthiophene-3 -carboxylate

The title compound was prepared from pentane-2,4-dione and fe7*t-butyl cyanoacetate according to Method B and was isolated as an off-white solid (76%) that was used without further purification. δ_H (DMSOd₆) 7.96 (2H₅ br. s), 2.58 (3H, s), 2.35 (3H, s), 1.52 (9H, s). MS (ES+) 256.1 (M+H)⁺ (Method 1).

INTERMEDIATE 14

ferf-Butyl 5-acetyl-2-bromo-4-methylthiophene-3 -carboxylate

The title compound was prepared from Intermediate 13 according to Method C and was isolated as a brown oil (99%) that was used without further purification. 5H (DMSO-d₆) 2.53 (3H, s), 2.51 (3H₅ s), 1.56 (9H₅ s). LCMS (ES+) 319.0 (M+H)⁺, RT 3.88 minutes (Method 1).

INTERMEDIATE 15

tert-Butyl 5-acetyl-4-methyl-2-fmorpholin-4-vπthiophene-3-carboxylate

The title compound was prepared from Intermediate 14 according to Method D and was isolated as a pale brown solid (33%) after purification by column chromatography (SiO₂, 10% EtOAc/hexanes). δ_H (DMSOd₆) 3.75-3.71 (4H₅ m), 3.18- 3.14 (4H, m), 2.43 (3H₅ s), 2.40 (3H₅ s), 1.51 (9H, s). LCMS (ES+) 326.1 (M+H)⁺, RT 3.44 minutes (Method 1).

INTERMEDIATE 16

l-[3-Methyl-5-(morpholin-4-yl)-2-thienyl]ethanone

The title compound was prepared from Intermediate 15 according to Method E and was isolated as a brown solid (98%) that was used without further purification. 6_H (CD₃OD) 5.33 (IH₅ s), 3.01-2.99 (4H₅ m), 2.51-2.47 (4H₅ m), 1.65 (3H₅ s), 1.60 (3H₅ s). LCMS (ES+) 226.1 (M+H)⁺, RT 2.91 minutes (Method 1).

INTERMEDIATE 17

l-[4-Iodo-3-methyl-5-(morpholin-4-yl)-2-thienyl]ethanone

The title compound was, prepared from Intermediate 16 according to Method A and was isolated as a pale brown solid (77%) that was used without further purification. δ_H (DMSO-d₆) 3.78-3.75 (4H, m), 3.12-3.09 (4H, m), 2.52 (3H₅ s), 2.46 (3H₅ s). LCMS (ES+) 351.9 (M+H)⁺, RT 3.51 minutes (Method 1). INTERMEDIATE 18 (METHOD F)

( 22D-3-( Dimethylamino)- 1 - [3 -methyl-5 -f morpholin-4-viy4-φhenylethvnyl)-2- thienyl]prop-2-en- 1 -one A stirred solution of Example 22 (1.00 g, 3.08 mmol) in DMF.DMA (10 mL) was heated at HO⁰C for 3 days, then cooled to r.t. and concentrated in vacuo. The residue was triturated in hot Et₂O and filtered to give the title compound (0.66 g, 56%) as an orange solid. δ_H (DMSO-d₆) 7.60 (IH, d, J 12 Hz), 7.49-7.46 (2H, m), 7.43-7.36 (3H, m), 5.37 (IH, d, J 12.1 Hz), 3.81-3.78 (4H, m), 3.48-3.45 (4H, m), 2.53 (3H, s), 2.51 (6H, s). LCMS (ES+) 381.1 (M+H)⁺, RT 2.80 minutes (Method 1).

INTERMEDIATE 19

l-[5-(Morpholin-4-yl)-2-thienyl]ethanone To a stirred solution of 1 -(5-chloro-2-thienyl)ethanone ( 1.6 g, 0.01 mol) in DMSO

(10 mL) was added morpholine (1 mL). The reaction mixture was heated at 110⁰C for 2 days, then cooled to r.t. and partitioned between EtOAc (50 mL) and water (50 mL). The organic fraction was washed with water (3 x 40 mL), then brine (40 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to give the title compound (1.2 g, 57%) as a pale solid that was used without further purification. δ_H (DMSO-d₆) 7.69 (1 H, d, J 4.4 Hz), 6.28 (IH, d, J4.4 Hz), 3.74-3.71 (4H, m), 3.26-3.23 (4H, m), 2.35 (3H, s). LCMS (ES+) 212.1 (M+H)⁺, RT 2.80 minutes {Method 1).

INTERMEDIATE 20

l-r4-Iodo-5-fmorpholin-4-yl)-2-thienyl]ethanone

The title compound was prepared from Intermediate 19 according to Method A and was isolated as a pale yellow solid (90%) after purification by column chromatography (SiO₂, 20% EtOAc/hexanes). δ_H (DMSO-d₆) 7.92 (IH, s), 3.79-3.72 (4H, m), 3.17-3.13 (4H, m), 2.45 (3H, s). LCMS (ES+) 338.0 (M+H)⁺, RT 3.33 minutes

{Method 1). INTERMEDIATE 21

(2E)-3-fDimethylamino)-l-[5-rmorpholin-4-yl)-4-(phenylethynyl)-2-thienyl]ρrop-2-en-l- one The title compound was prepared from Example 26 according to Method F and was isolated as a beige solid (50%) after trituration in Et₂O. δ_H (DMSO-d₆) 7.73 (IH₅ s), 7.56 (IH, d, J 12.3 Hz), 7.47-7.36 (5H, m), 5.76 (IH, d, J 12.3 Hz), 3.81-3.77 (4H, m), 3.50-3.47 (4H, m), 3.11 (3H, br. s), 2.89 (3H, br. s). LCMS (ES+) 367.1 (M+H)⁺, RT 3.43 minutes (Method 1).

INTERMEDIATE 22

(2-Chlorophenyl)[5-(morpholin-4-yl)-2-thienyl]methanone

To a stirred solution of (lE)-iV,iV-dimethyl-3-(morpholin-4-yl)-3-thioxoprop-l-en- 1-amine (0.07 g, 0.35 mmol) in a mixture of acetonitrile (1 mL) and THF (0.5 mL) were added 2-bromo-l-(2-chlorophenyl)ethanone (0.09 g, 0.385 mmol) and sodium carbonate (0.08 g, 0.77 mmol). The reaction mixture was heated to 100⁰C under microwave irradiation, in a sealed tube, for 10 minutes, and then partitioned between water (5 mL) and EtOAc (5 mL). The organic fraction was dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.085 g, 79%) as a pale brown solid. δ_H (CDCl₃) 7.29-7 '.47 (4H, m), 7.11 (IH, d, J4.5 Hz), 6.05 (IH, d, J 4.5 Hz), 3.88-3.82 (4H, m), 3.37-3.31 (4H, m). LCMS (ES+) 308.1 (M+H)⁺, RT 3.37 minutes {Method 2).

INTERMEDIATE 23

(2-Chlorophenvπ[^"4-iodo-5-(morpholin-4-yl)-2-thienyl]methanone

To a stirred solution of Intermediate 22 (0.23 g, 0.75 mmol) in DCM (10 mL) was added NIS (0.177 g, 0.78 mmol). The reaction mixture was stirred at r.t. for 1 h, then concentrated in vacuo. Purification by column chromatography (SiO₂, 50-100%

EtO Ac/heptane) gave the title compound (0.195 g, 60%) as a cream solid. 5_H (CDCl₃) 7.50-7.32 (4H, m), 7.25 (IH, s), 3.92-3.83 (4H, m), 3.31-3.24 (4H, m). LCMS (ES+) 434.0 (M+H)⁺, RT 4.23 minutes (Method 2). INTERMEDIATE 24

3-Methyl-5-(morpholin-4-yl)thiophene-2-carboxylic acid To a stirred solution of Intermediate 11 (0.64 g, 2.66 mmol) in a mixture of THF

(1.5 niL) and MeOH (1.5 mL) was added a solution of LiOH (0.127 g, 5.31 mmol) in water (0.5 mL). The reaction mixture was stirred at r.t. for 16 h. An additional portion of LiOH (0.1 g) was added. The reaction mixture was stirred for 3 days, then diluted with water (50 mL) and extracted with EtOAc (50 mL). The aqueous fraction was neutralised with IM aqueous HCl. The precipitate formed was filtered and dried in vacuo to give the title compound (0.31 g, 51%) as an off-white solid. δ_H (DMSO-d₆) 12.11 (IH, br. s), 6.11 (IH, s), 3.75-3.66 (4H, m), 3.18-3.10 (4H, m), 2.35 (3H, s). LCMS (ES+) 228.1 (M+H)⁺, RT 2.46 minutes {Method!).

INTERMEDIATE 25

N-Cyclopropyl-3-methyl-5-(morpholin-4-yDthiophene-2-carboxamide

To a stirred suspension of Intermediate 24 (0.30 g, 0.132 mmol) in DMF (6 mL) was added HBTU (0.055 g, 0.145 mmol), followed by DIPEA (0.037 g, 0.291 mmol). The reaction mixture was stirred for 2 minutes prior to addition of cyclopropylamine (1 mL) and then THF (1 mL). The reaction mixture was stirred at r.t. for 30 minutes, then concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.027 g, 77%) as a pale blue solid. δ_H (DMSO-d₆) 5.87 (IH₅ s), 5.66 (IH, br. s), 3.86-3.78 (4H, m), 3.19-3.11 (4H, m), 2.86-2.78 (IH, m), 2.41 (3H, s), 0.87-0.77 (2H, m), 0.61-0.52 (2H, m). LCMS (ES+) 267.0 (M+H)⁺, RT 2.56 minutes {Method 2).

INTERMEDIATE 26

4-[3-Iodo-5-(l,3-oxazol-5-ylV2-thienyl1morpholine To a stirred solution of Intermediate 2 (0.48 g, 0.15 mmol) in MeOH (5 mL) was added K₂CO₃ (0.032 g, 0.23 mmol) followed by TosMIC (0.045 g, 0.23 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to r.t. and concentrated in vacuo. The residue was dissolved in DCM (100 mL), washed with water (2 x 40 mL), dried (MgSO₄), filtered and concentrated in vacuo to give the title compound (0.057 g, 100%) as an orange solid that was used without further purification. 5_H (CDCl₃) 7.83 (IH, s), 7.16 (IH, s), 7.13 (IH, s), 3.93-3.85 (4H, m), 3.12-3.04 (4H, m). LCMS (ES+) 363.0 (M+H)⁺, RT 3.63 minutes (Method 2).

EXAMPLE 1 (METHOD G)

Ethyl 5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylate

To a stirred solution of Intermediate 1 (0.81 g, 2.21 mmol) in a mixture of THF (10 mL) and diisopropylamine (10 mL) were added, in turn, phenylacetylene (0.25 g, 2.43 mmol), copper(I) iodide (0.04 g, 0.22 mmol) and Pd(PPh₃)₂Cl₂ (0.08 g, 0.11 mmol). The reaction mixture was heated to 7O⁰C for 2 h, then cooled to r.t. The solids were removed by filtration. The filtrate was diluted with EtOAc (15 mL), washed with brine (10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by column chromatography (SiO₂, 20-60% EtOAc/hexanes), followed by trituration with

Et₂O/hexanes, gave the title compound (0.40 g, 53%) as a yellow solid. 5_H (DMSO-d₆) 7.63 (IH, s), 7.50-7.43 (2H, m), 7.43-7.35 (3H, m), 4.23 (2H, q, J 6.9 Hz), 3.84-3.75 (4H, m), 3.56-3.48 (4H, m), 1.27 (3H, t, J6.9 Hz). LCMS (ES+) 342.0 (M+H)⁺, RT 3.91 minutes (Method 1).

EXAMPLE 2

5-fMorpholin-4-yl)-4-(phenylethynyπthiophene-2-carboxylic acid

To a stirred solution of Example 1 (0.40 g, 1.17 mmol) in a mixture of THF (15 mL) and water (5 mL) was added LiOH (0.14 g, 5.85 mmol). The reaction mixture was stirred at 7O⁰C for 3 days, then cooled to r.t. Aqueous HCl (2M; 25 mL) and EtOAc (25 mL) were added, and the layers separated. The aqueous fraction was extracted with EtOAc (2 x 20 mL). The combined organic fractions were dried (Na₂SO₄), filtered and concentrated in vacuo. Trituration in EtOAc/hexanes gave the title compound (0.31 g, 85%) as a yellow solid. δ_H (DMSO-d₆) 12.76 (IH, br. s), 7.55 (IH, s), 7.50-7.43 (2H, m), 7.43-7.35 (3H, m), 3.86-3.73 (4H, m), 3.57-3.46 (4H, m). LCMS (ES+) 314.0 (M+H)⁺, RT 3.30 minutes (Method 1). EXAMPLE 3

5-(Morpholin-4-yl)-4-(ρhenylethvnyl)thiophene-2-carbaldehyde

The title compound was prepared from Intermediate 2 according to Method G and was isolated as a yellow solid (81 %) after purification by column chromatography (SiO₂, 10% EtOAc/hexanes), followed by trituration with EtOAc/hexanes. δ_H (DMSOd₆) 9.58 (IH, s), 7.92 (IH, s), 7.51-7.45 (2H₅ m), 7.46-7.37 (3H, m), 3.84-3.78 (4H, m), 3.72-3.66 (4H, m). LCMS (ES+) 298.0 (M+H)⁺, RT 3.53 minutes {Method 1).

EXAMPLE 4

4-[5-(L3-Oxazol-5-yl)-3-(phenylethynyl)-2-thienyl]morpholine

To a stirred solution of Example 3 (0.25 g, 0.84 mmol) in MeOH (15 mL) was added K₂CO₃ (0.17 g, 1.26 mmol), followed by TosMIC (0.25 g, 1.26 mmol). The reaction mixture was heated to 7O⁰C for 12 h, then cooled to r.t. and partitioned between EtOAc (20 mL) and water (15 mL). The aqueous fraction was extracted with EtOAc (2 x 20 mL). The combined organic fractions were washed with brine (15 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by column chromatography (SiO₂, 15% EtOAc/hexanes) gave the title compound (0.03 g, 11%) as a beige solid. 6_H (DMSO-dg) 8.36 (IH, s), 7.50-7.45 (2H, m), 7.45-7.38 (4H, m), 7.35 (IH, s), 3.85-3.77 (4H, m), 3.43-3.37 (4H, m). LCMS (ES+) 337.0 (M+H)⁺, RT 3.72 minutes (Method 1).

EXAMPLE 5

5-(Morpholin-4-yl)-4-(phenylethvnyDthiophene-2-carbaldehyde oxime

To a stirred solution of Example 3 (0.50 g, 1.68 mmol) in EtOH (10 mL) were added NH₂ORHCl (1.13 g, 1.85 mmol) and NaOAc (0.15 g, 1.85 mmol). The reaction mixture was heated to reflux for 3 h, then cooled to r.t. and concentrated in vacuo. The residue was triturated with Et₂O, filtered, washed with water then Et₂O and air-dried to give the title compound (mixture of two regioisomers, ratio 1 :4) (0.25 g, 47%) as a white solid. 5_H (DMSO-d₆) 11.62 (IH, s, major regioisomer), 10.97 (IH, s, minor regioisomer), 8.13 (IH, s, minor regioisomer), 7.59 (IH, s, major regioisomer), 7.50-7.35 (5H, m), 7.33 (IH, s, major regioisomer), 7.14 (IH, s, minor regioisomer), 3.86-3.74 (4H, m), 3.51-3.39 (4H, m). LCMS (ES+) 313.0 (M+H)⁺, RT 3.35 minutes {Method 1).

EXAMPLE 6

5-fMorpholin-4-yl)-4-(phenylethynyl^>)thiophene-2-carbonitrile

To a stirred solution of Example 5 (0.1 g, 0.32 mmol) in DCM (10 mL) was added Et₃N (0.03 g, 0.05 mL, 0.32 mmol), followed by trichloroacetyl chloride (0.06 g, 0.04 mL, 0.32 mmol) dropwise. The reaction mixture was stirred at r.t. for 1 h, then partitioned between water (10 mL) and DCM (10 mL). The organic fraction was washed with water (10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by column chromatography (SiO₂, 10% EtOAc/hexanes), followed by trituration in EtOAc/hexanes, gave the title compound (0.04 g, 42%) as a white solid, δπ (DMSO-d₆) 7.86 (IH, s), 7.51-7.44 (2H, m), 7.45-7.39 (3H, m), 3.85-3.75 (4H, m), 3.60-3.50 (4H, m). LCMS (ES+) 295.0 (M+H)⁺ _s RT 3.69 minutes (Method 1).

EXAMPLE 7

5-(Morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carbothioamide To a stirred solution of Example 6 (0.16 g, 0.54 mmol) in 1,4-dioxane (5 mL) was added NaSRH₂O (0.037 g, 0.65 mmol). The reaction mixture was heated at 5O⁰C for 2 days, and then concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 20% EtOAc/hexanes) to give the title compound (0.019 g, 11%) as a yellow solid. δ_H (DMSO-d₆) 9.23 (IH, s), 9.10 (IH, s), 7.66 (IH, s), 7.48-7.36 (5H, m), 3.83-3.75 (4H, m), 3.58-3.51 (4H, m). LCMS (ES+) 329.0 (M+H)⁺, RT 3.35 minutes (Method 1).

EXAMPLE 8

N'-Hydroxy-5-(morpholin-4-yl)-4-(phenylethynyπthiophene-2-carboximidamide

To a stirred solution of Example 6 (0.2 g, 0.7 mmol) in EtOH (15 mL) was added hydroxylamine (0.05 g, 50 w/w % in water, 0.7 mmol). The reaction mixture was stirred at r.t. for 30 minutes, then concentrated in vacuo to give the title compound (0.17 g, 74%) as beige crystals. δ_H (DMSO-d₆) 9.51 (IH, s), 7.46-7.37 (5H, br. m), 7.34 (IH, s), 5.83 (2H, s), 3.82-3.75 (4H, m), 3.40-3.33 (4H, m). LCMS (ES+) 328.0 (M+H)⁺, RT 2.79 minutes (Method 1).

EXAMPLE 9

3-Methyl-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxamide

To a stirred solution of Intermediate 7 (0.31 g, 0.88 mmol) in diisopropylamine (5 mL) were added, in turn, phenylacetylene (0.11 mL, 0.97 mmol), Pd(PPh₃)₂Cl₂ (0.08 g, 0.11 mmol) and copper(I) iodide (0.017 g, 0.09 mmol). The reaction mixture was heated to 7O⁰C for 2 h, then cooled to r.t. The precipitate formed was filtered, washed with water (2 mL), then DCM (2 mL), and triturated in hot MeOH to give the title compound (0.008 g, 3%) as a pale yellow solid. δ_H (DMSOd₆) 7.49-7.45 (2H, m), 7.44-7.40 (3H, m), 7.20 (2H, br. s), 3.82-3.78 (4H, m), 3.43-3.40 (4H, m), 2.45 (3H, s). LCMS (ES+) 327.0 (M+H)⁺, RT 3.07 minutes (Method 1).

EXAMPLE 10

Methyl 3 -methyl-5 -(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylate The title compound was prepared from Intermediate 12 according to Method G and was isolated as an off-white solid (85%) after purification by column chromatography (SiO₂, DCM). δ_H (DMSO-d₆) 7.51-7.46 (2H, m), 7.44-7.36 (3H, m), 3.80-3.77 (4H, m), 3.75 (3H, s), 3.56-3.53 (4H, m), 2.52 (3H, s). LCMS (ES+) 342.0 (M+H)⁺, RT 3.98 minutes (Method I).

EXAMPLE 11

3-Methyl-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylic acid

To a stirred solution of Example 10 (3.2 g, 9.35 mmol) in THF (30 mL) was added a solution of LiOH (1.12 g, 46.75 mmol) in water (6 mL) . The reaction mixture was stirred at 70⁰C for 16 h, then cooled to r.t. Aqueous HCl (2M; 50 mL) was added. The precipitate formed was filtered, then washed with Et₂O (30 mL), to give the title compound (2.68 g, 88%) as a white solid. δ_H (DMSO-d₆) 12.64 (IH, br. s), 7.49-7.46 (2H, m), 7.43-7.40 (3H, m), 3.80-3.78 (4H₅ m), 3.52-3.49 (4H, m), 2.51 (3H, s). LCMS (ES+) 328.0 (M+H)⁺, RT 3.45 minutes {Method 1).

EXAMPLE 12 (METHOD H)

N- [2-(Dimethylamino)ethyl] -3 -methyl-5 -(morpholin-4-yiy4-φhenylethynyl)thiophene-2- carboxamide

To a stirred solution of Example 11 (0.2 g, 0.61 mmol) in DCM (5 mL) were added HOBT (0.083 g, 0.61 mmol), EDCHCl (0.176 g, 0.92 mmol), NEt₃ (0.21 mL, 1.53 mmol) and 2-(dimethylamino)ethylamine (0.054 g, 0.61 mmol). The reaction mixture was stirred for 2 days at r.t. EtOAc (10 mL) and water (10 mL) were added and the layers separated. The organic fraction was washed with water (3 x 10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by column chromatography (SiO₂, 50% EtOAc/hexane) gave the title compound (0.012 g, 5%) as an off-white solid. 5_H (CDCI₃) 7.48-7.44 (2H, m), 7.39-7.34 (3H, m), 6.61 (IH, br. s), 3.91-3.88 (4H, m), 3.55-3.53 (2H, m), 3.53-3.48 (4H, m), 2.61-2.56 (2H, m), 2.57 (3H, s), 2.35 (6H, s). LCMS (ES+) 398.0 (M+H)⁺, RT 2.49 minutes {Method 1).

EXAMPLE 13

4-{4-Methyl-5-[(4-methylpiperazin-l-yl)carbonyl]-3-(phenylethynyl)-2- thienyl } morpholine

The title compound was prepared from Example 11 and 1-methylpiperazine according to Method H and was isolated as a yellow foam (41%) after purification by column chromatography (SiO₂, EtOAc). δ_H (CDCl₃) 7.47-7.44 (2H, m), 7.39-7.33 (3H₅ m), 3.91-3.89 (4H₅ m), 3.72-3.68 (4H₅ m), 3.46-3.43 (4H₅ m), 2.50-2.45 (4H₅ m), 2.37

(3H₅ s), 2.31 (3H₅ s). LCMS (ES+) 410.0 (M+H)⁺, RT 2.47 minutes {Method 1).

EXAMPLE 14

N-Cyclopropyl-3-methyl-5-(morpholm-4-yl)-4-rphenylethvnyl)thiophene-2-carboxamide

The title compound was prepared from Example 11 and cyclopropylamine according to Method H and was isolated as an off-white solid (33%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 7.80 (IH, d, J3.7 Hz), 7.49-7.35 (5H, m), 3.81-3.77 (4H, m), 3.42-3.38 (4H, m), 2.79-2.70 (IH, m), 2.41 (3H, s), 0.69-0.60 (2H, m), 0.59-0.50 (IH, m). LCMS (ES+) 367.0 (M+H)⁺, RT 3.51 minutes (Method 1).

EXAMPLE 15

iV,3-Dimethyl-5-(morρholin-4-ylV4-(phenylethynyl)thiophene-2-carboxamide

The title compound was prepared from Example 11 and methylamine according to Method H and was isolated as a white solid (35%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 7.67 (IH, d, J4.4 Hz), 7.49-7.41 (2H, m), 7.40-7.36 (3H, m), 3.81-3.78 (4H, m), 3.42-3.39 (4H, m), 2.72 (3H, d, J4.4 Hz), 2.44 (3H, s). LCMS (ES+) 341.0 (M+H)⁺, RT 3.39 minutes (Method 1).

EXAMPLE 16

4-[4-Methyl-3-(phenylethynyl)-5-(piperidin-l-ylcarbonvπ-2-thienyl]morpholine

The title compound was prepared from Example 11 and piperidine according to

Method H and was isolated as a white solid (15%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 7.49-7.47 (2H, m), 7.46-7.36 (3H, m), 3.80-3.77 (4H, m), 3.48-3.44 (4H, m), 3.39-3.32 (4H, m), 2.19 (3H, s), 1.62-1.60 (2H, m),

1.53-1.49 (4H, m). LCMS (ES+) 395.0 (M+H)⁺, RT 3.88 minutes (Method 1).

EXAMPLE 17

iV,N,3-Trimethyl-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxamide

The title compound was prepared from Example 11 and dimethylamine according to Method H and was isolated as a yellow oil (28%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 7.49-7.44 (2H, m), 7.43-7.38 (3H, m), 3.80-3.78 (4H, m), 3.40-3.35 (4H, m), 2.98 (6H, s), 2.19 (3H, s). LCMS (ES+) 355.0 (M+H)⁺, RT 3.52 minutes (Method 1). EXAMPLE 18

N-(Cvclopropylmethyl)-3-methyl-5-(morpholin-4-ylV4-fphenylethvnyl)thiophene-2- carboxamide The title compound was, prepared from Example 11 and (cyclopropylmethyl)amine according to Method Hand was isolated as a white solid (29%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 8.05 (IH, t, J5.7 Hz), 7.51-7.39 (5H, m), 3.83-3.79 (4H, m), 3.42-3.40 (4H₅ m), 3.09 (2H₅1, J6.3 Hz), 2.55 (3H, s), 1.05- 1.00 (IH, m), 0.45-0.40 (2H, m), 0.24-0.00 (2H, m). LCMS (ES+) 381.0 (M+H)⁺, RT 3.68 minutes (Method 1).

EXAMPLE 19

N-(2-Methoxyethyl)-N,3-dimethyl-5-(morpholin-4-ylV4-(phenylethvnyl)thiophene-2- carboxamide

The title compound was prepared from Example 11 and JV-(2-methoxyethyl)-iV- methylamine according to Method H ^'and was isolated as a yellow oil (27%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 7.49-7.43 (2H, m), 7.42-4.38 (3H, m), 3.81-3.77 (4H, m), 3.58-3.53 (2H, m), 3.51-3.47 (2H, m), 3.40- 3.35 (4H, m), 3.24 (3H₅ s), 2.99 (3H, s), 2.17 (3H, s). LCMS (ES+) 399.0 (M+H)⁺, RT 3.55 minutes (Method 1).

EXAMPLE 20

N-Ethyl-3-methyl-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxamide

The title compound was prepared from Example 11 and ethylamine according to Method H and was isolated as a white solid (24%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 7.56 (IH, t, J5.5 Hz), 7.49-7.47 (2H, m), 7.47-7.37 (3H, m), 3.81-3.78 (4H, m), 3.41-3.39 (4H, m), 3.26-3.18 (2H, m), 2.44 (3H₅ s), 1.09 (3H, t, J7.1 Hz). LCMS (ES+) 355.0 (M+H)⁺, RT 3.52 minutes (Method 1). EXAMPLE 21

7^-Benzyl-3-methyl-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxaniide

The title compound was prepared from Example 11 and benzylamine according to Method H and was isolated as a white solid (23%) after purification by column chromatography (SiO₂, EtOAc). δ_H (DMSO-d₆) 8.32 (IH, t, J6.0 Hz), 7.50-7.47 (2H, m), 7.47-7.38 (3H, m), 7.36-7.30 (4H, m), 7.30-7.22 (IH, m), 4.41 (2H, d, J6.0 Hz), 3.81- 3.79 (4H, m), 3.44-3.41 (4H, m), 2.47 (3H, s). LCMS (ES+) 417.0 (M+H)⁺, RT 3.75 minutes {Method 1).

EXAMPLE 22

l-[3-Methyl-5-(morpholin-4-yl)-4-rphenylethynyl)-2-thienyl]ethanone

The title compound was prepared from Intermediate 17 according to Method G and was isolated as an off-white solid (36%) after purification by column chromatography (SiO₂, 25% EtOAc/hexanes). δ_H (DMSO-d₆) 7.50-7.47 (2H, m), 7.45-7.38 (3H, m), 3.82- 3.78 (4H, m), 3.59-3.31 (4H, m), 2.54 (3H, s), 2.43 (3H, s). LCMS (ES+) 326.0 (M+H)⁺, RT 3.71 minutes {Method 1).

EXAMPLE 23 (METHOD D

4-[4-Methyl-3 -( phenylethynyl)-5-f 1 H-pyrazol-3 -vD-2-thienyl]morpholine

To a stirred solution of Intermediate 18 (0.20 g, 0.53 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.029 g, 0.58 mmol). The reaction mixture was heated at 6O⁰C for 7 h, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO₂, 20% EtOAc/hexanes) gave the title compound (0.054 g, 29%) as a pale yellow solid. δ_H (CD₃OD) 7.71 (IH, br. s), 7.48-7.44 (2H, m), 7.40-7.33 (3H, m), 6.49 (IH, br. s), 3.91-3.88 (4H, m), 3.42-3.39 (4H, m), 2.42 (3H, s). Exchangeable proton was not observed. LCMS (ES+) 350.1 (M+H)⁺, RT 3.53 minutes {Method 1). EXAMPLE 24 (METHOD J)

4-[4-Methyl-5-fl-methyl-l//^'-pyrazol-5-yl)-3-fphenylethvnyl)-2-thienyl]morpholine

To a stirred solution of Intermediate 18 (0.20 g, 0.53 mmol) in EtOH (5 mL) was added methylhydrazine (0.027 g, 0.58 mmol). The reaction mixture was heated at 6O⁰C for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO₂, 20% EtOAc/hexanes) gave the title compound (0.076 g, 40%) as a yellow foam. δ_H (DMSO-d₆) 7.52-7.46 (3H, m), 7.45-7.36 (3H, m), 6.36 (IH, d, J 1.8 Hz), 3.85-3.77 (4H, m), 3.73 (3H, s), 3.41-3.34 (4H, m), 2.11 (3H, s). LCMS (ES+) 364.0 (M+H)⁺, RT 3.83 minutes (Method 1).

EXAMPLE 25

4-[5-(Isoxazol-5-yl)-4-methyl-3-fphenylethynyl)-2-thienyl]morpholine To a stirred solution of Intermediate 18 (0.20 g, 0.53 mmol) in EtOH (5 mL) was added hydroxylamine hydrochloride (0.040 g, 0.58 mmol). The reaction mixture was heated at 6O⁰C for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by column chromatography (SiO₂, 20% EtOAc/hexanes) gave the title compound (0.024 g, 13%) as a yellow solid. δ_H (DMSO-d₆) 8.63 (IH, d, J2.0 Hz), 7.53-7.48 (2H, m), 7.46- 7.38 (3H, m), 6.61 (IH, d, J2.0 Hz), 3.86-3.77 (4H, m), 3.52-3.44 (4H, m), 2.44 (3H, s). LCMS (ES+) 351.0 (M+H)⁺, RT 3.89 minutes (Method 1).

EXAMPLE 26

l-[5-(Morpholin-4-yl)-4-(phenylethynyl)-2-thienyl]ethanone

The title compound was prepared from Intermediate 20 according to Method G and was isolated as an off-white solid (74%) after purification by column chromatography (SiO₂, 10% EtOAc/hexanes). δ_H (DMSO-d₆) 7.88 (IH, s), 7.49-7.45 (2H, m), 7.43-7.40 (3H, m), 3.82-3.78 (4H, m), 3.62-3.59 (4H, m), 2.41 (3H, s). LCMS (ES+) 312.0 (M+H)⁺, RT 3.60 minutes (Method 1). EXAMPLE 27

πjE/Z)-l-[5-(Morpholin-4-yl)-4-(phenylethynyl)-2-thienyl]ethanone oxime

To a stirred solution of Example 26 (0.50 g, 1.61 mmol) in EtOH (20 mL) were added hydroxylamine hydrochloride (0.278 g, 4.02 mmol) and pyridine (2 mL). The reaction mixture was heated under reflux for 4 h, then cooled to r.t. and concentrated in vacuo. Water (20 mL) was added and the mixture stirred for 16 h at r.t. The precipitate formed was filtered and washed with cold water (2 x 5 mL). Purification by column chromatography (SiO₂, 20% EtOAc/hexanes) gave the separate syn and anti title compounds as yellow solids. First eluting compound (0.007 g, 1%). 5_H (DMSO-d₆)

10.98 (IH, s), 7.45-7.35 (5H, m), 7.19 (IH, s), 3.80-3.77 (4H, m), 3.42-3.39 (4H, m), 2.09 (3 H, s). LCMS (ES+) 327.0 (M+H)⁺, RT 3.52 minutes {Method 1). Second eluting compound (0.006 g, 1%). δ_H (DMSO-d₆) 11.38 (IH, s), 7.48-7.36 (5H, m), 7.34 (IH, s), 3.81-3.78 (4H, m), 3.47-3.43 (4H, m), 2.17 (3H, s). LCMS (ES+) 327.0 (M+H)⁺, RT 3.40 minutes {Method 1).

EXAMPLE 28

3 -Methyl-4-[( 1 -methyl- 1 H-imidazol-5 -yl)ethynyl1 -5-(morpholin-4-yl)thiophene-2- carboxamide

The title compound was prepared from Intermediate 7 according to Method G and was isolated as a pale brown solid (2%) after purification by column chromatography (SiO₂, 10% EtOAc/hexanes). δ_Η (CD₃OD) 7.73 (IH, s), 7.24 (IH, s), 3.87-3.84 (4H, m), 3.77 (3H, s), 3.50-3.47 (4H, m), 2.42 (3H, s). Exchangeable protons were not observed. LCMS (ES+) 331.0 (M+H)⁺, RT 2.14 minutes {Method 1).

EXAMPLE 29

l-[5-(Morpholin-4-yl)-4-(phenylethynyl)-2-thienyl]ethanol To a stirred solution of Example 26 (0.20 g, 0.64 mmol) in THF (5 mL) at O⁰C was added sodium borohydride (0.024 g, 0.64 mmol). The reaction mixture was stirred at this temperature for 3 h. MeOH (2 mL) was added and the reaction mixture was stirred at r.t. for 16 h before being concentrated in vacuo. The residue was dissolved in DCM (10 mL), _,

- 37 -

and the solution washed with aqueous sat. NH₄Cl (10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to give the title compound (0.139 g, 44%) as a yellow foam. 6H (DMSOd₆) 7.46-7.35 (5H, m), 6.75 (IH, d, J0.8 Hz), 5.47 (IH, d, J4.8 Hz), 4.82-4.75 (IH, m), 3.80-3.76 (4H, m), 3.27-3.21 (4H, m), 1.38 (3H, d, J 6.6 Hz). LCMS (ES+) 314.0 (M+H)⁺, RT 3.42 minutes (Method 1).

EXAMPLE 30

4- [3 -(Phenyl eth vnyl)-5 -( 1 /i-pyrazol-3 -yl)-2-thienyl]morpholine The title compound was prepared from Intermediate 21 according to Method I and was isolated as an off-white solid (66%) after trituration in Et₂O. δ_H (DMSO-d₆) 12.77 (IH, br. s), 7.74 (IH, s), 7.48-7.29 (5H, m), 7.25 (IH, s), 6.60 (IH, s), 3.82-3.78 (4H, m), 3.37-3.32 (4H, m). LCMS (ES+) 336.1 (M+H)⁺, RT 3.45 minutes (Method 1).

EXAMPLE 31

4-[5-(l-Methyl-lH-pyrazol-5-ylV3-(phenylethynyl)-2-thienyl]morpholine

The title compound was prepared from Intermediate 21 according to Method J ^'and was isolated as a pale solid (32%) after purification by column chromatography (SiO₂, 50% EtOAc/hexanes). δ_H (CDCl₃) 7.49-7.45 (3H, m), 7.40-7.33 (3H, m), 7.01 (IH, s), 6.32 (IH, d, J 1.9 Hz), 4.00 (3H, s), 3.94-3.91 (4H, m), 3.46-3.43 (4H, m). LCMS (ES+) 350.1 (M+H)⁺, RT 3.67 minutes (Method 1).

EXAMPLE 32

4-[3-(Phenylethvnyl)-5-fpyrimidin-4-yl)-2-tliienyl]morpholine

To a stirred solution of Intermediate 21 (0.44 g, 1.20 mmol) in EtOH (10 mL) was added formamidine acetate (0.374 g, 3.60 mmol). The reaction mixture was heated at 9O⁰C for 10 minutes. A freshly prepared solution of NaOEt in EtOH [Na (0.082 g, 3.60 mmol) dissolved in EtOH (5 mL)] was added. The reaction mixture was heated to reflux for 7 days, then cooled to r.t. and partitioned between EtOAc (50 mL) and water (25 mL). The organic fraction was washed with water (10 mL), then brine (10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by column chromatography (SiO₂, 50% EtOAc/hexanes) gave the title compound (0.12 g, 29%) as a pale yellow solid. δ_H (DMSO-de) 8.96 (IH, d, J 1.3 Hz), 8.64 (IH, d, J5.5 Hz), 8.03 (IH, s), 7.89 (IH, dd, J 5.5, 1.4 Hz), 7.50-7.38 (5H, m), 3.84-3.80 (4H, m), 3.58-3.54 (4H, m). LCMS (ES+) 347.9 (M+H)⁺, RT 3.66 minutes {Method 1).

EXAMPLE 33

N^'-Cyclopropyl-3-methyl-4-[(l-methyl-l/i-imidazol-5-yl)ethynyl]-5-(morpholin-4- yl)thiophene-2-carboxamide To a stirred solution of Intermediate 25 (0.048 g, 0.18 mmol) in THF (2 mL) was added ΝIS (0.041 g, 0.18 mmol). The reaction mixture was stirred at r.t. for 2 h, then concentrated in vacuo onto silica. Purification by column chromatography (SiO₂, 0-100% EtO Ac/heptane) gave a cream solid. To a stirred solution of this intermediate (0.035 g, 0.09 mmol) in diisopropylamine (3 mL) were added 5 -ethynyl-1 -methyl- lH-imidazole (0.01 mL, 1.34 mmol), PdCl₂(PPh₃)₂ (0.004 g, 0.006 mmol) and copper(I) iodide (0.001 g, 0.005 mmol). The reaction mixture was heated at 100⁰C under microwave irradiation, in a sealed tube, for 10 minutes, and then concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.008 g, 12% over two steps) as a yellow glass. δ_H (CD₃OD) 7.65 (IH, d, J0.7 Hz), 7.15 (IH, d, J0.7 Hz), 3.82-3.71 (4H, m), 3.67 (3H, s), 3.42-3.31 (4H, m), 2.73-2.62 (IH, m), 2.38 (3H, s), 0.77-0.66 (2H, m), 0.57-0.47 (2H, m). Exchangeable proton was not observed. LCMS (ES+) 371.3 (M+H)⁺, RT 1.70 minutes (Method 2).

EXAMPLE 34

f2-ChloiOphenvn(4-[a-methyl-lH-imidazol-5-yl^N)ethvnyl]-5-rmorpholin-4-yl)-2- thienyl 1 methanone

To a stirred solution of Intermediate 23 (0.043 g, 0.1 mmol) in THF (0.1 mL) were added 5-ethynyl-l -methyl- 1/i-imidazole (0.016 g, 0.1 mmol), PdCl₂(PPh₃)₂ (0.007 g, 0.01 mmol), copper(I) iodide (0.002 g, 0.01 mmol) and diisopropylamine (1 mL). The reaction mixture was heated to 100⁰C under microwave irradiation, in a sealed tube, for 10 minutes, and then concentrated in vacuo. Purification by column chromatography (SiO₂, 0-10% MeOH/DCM) gave the title compound (0.021 g, 51%) as a yellow gum. δ_H (CDCl₃) 7.60-7.31 (6H₃ m), 7.17 (IH₅ s), 3.90-3.82 (4H₅ m), 3.73-3.66 (4H₅ m), 3.64 (3H, s). LCMS (ES+) 412.2 (M+H)⁺, RT 2.29 minutes {Method!).

EXAMPLE 35

4- { 3 -f ( 1 -Methyl- 1 ff-imidazol-5-vDethvnyli -5-( 1.3 -oxazol-5 -ylV2-thienyl> morpholine

To a stirred solution of Intermediate 26 (0.057 g, 0.16 mmol) in diisopropylamine (6 mL) were added, in turn, 5 -ethynyl-1 -methyl- lH-imidazole (0.02 mL, 0.24 mmol), PdCl₂(PPh₃)₂ (0.008 g, 0.01 mmol) and copper® iodide (0.002 g, 0.01 mmol). The reaction mixture was stirred at 6O⁰C for 16 h, and then concentrated in vacuo. EtOAc

(100 mL) was added and the solution washed with aqueous sat. NaHCO₃ solution (3 x 50 mL), dried (MgSO₄), filtered and concentrated in vacuo. Purification by preparative HPLC gave the title compound (0.02 g, 40%) as a yellow solid. δ_H (CDCl₃) 7.82 (IH, s), 7.49 (IH, s), 7.29 (IH₅ dd, J0.8, 0.4 Hz), 7.14 (IH₅ s), 7.09 (IH₅ s), 3.91-3.84 (4H, m), 3.71 (3H₅ s), 3.45-3.38 (4H, m). LCMS (ES+) 341.2 (M+H)⁺, RT 1.89 minutes (Method 2).

Claims

Claims:

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

wherein

R¹ represents cyano, -C(=X)R^a, -CH(OH)R^a, -CO₂R^b or -C(=X)NR^cR^d; or R¹ represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or

R¹ represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; X represents oxygen, sulphur or N-OH;

R^a represents hydrogen, Ci_-6 alkyl or optionally substituted aryl;

R^b represents hydrogen or Ci_-6 alkyl;

R^c represents hydrogen; or Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(C]_-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^d represents hydrogen or Ci_-6 alkyl; or

R represents hydrogen, Ci_-6 alkyl, halogen, cyano or trifloromethyl; and R³ represents C_3-7 cycloalkyl, aryl, C_3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

2. A compound as claimed in claim 1 represented by formula (HA), or a pharmaceutically acceptable salt or solvate thereof:

(HA)

wherein R and R are as defined in claim 1 ; and

R and R¹ independently represent hydrogen, Cj_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(Cj_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (Ci_-6)alkyl, heteroaryl, heteroaryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, amino, Ci_-6 alkylamino, di(Ci-₆)alkylamino, halogen, cyano, nitro or trifluoromethyl.

3. A compound as claimed in claim 2 wherein R¹³ and R¹⁴ independently represent hydrogen, hydroxy, C_1-6 alkoxy, di(Ci_-6)alkylamino, halogen and nitro.

4. A compound as claimed in claim 1 represented by formula (HB), or a pharmaceutically acceptable salt or solvate thereof:

(IIB)

wherein

R¹ and R² are as defined in claim 1; and

R²³ represents hydrogen, Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(C_1-6)alkyl, heteroaryl, heteroaryl(C_1-6)alkyl, hydroxy, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl or trifluoromethyl.

5. A compound as claimed in claim 4 wherein R represents hydrogen or Ci_-6 alkyl.

6. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.

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

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

9. A compound of formula (I) as defined in claim 1, 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.

10. The use of a compound of formula (I) as defined in claim 1, 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 PD K inhibitor is indicated.

11. A method for the treatment and/or prevention of a disorder for which the administration of a selective PI3K 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 a pharmaceutically acceptable salt or solvate thereof.