WO2011058109A1 - Fused bicyclic pyrrole and imidazole derivatives as kinase inhibitors - Google Patents

Abstract

A series of substituted pyrrolo[2,1-ƒ][1,2,4]triazine and imidazo[2,1-ƒ]-[1,2,4]triazine derivatives, and fused pyridazine analogues thereof, 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 (Formula (I)).

Description

FUSED BICYCLIC PYRROLE AND IMIDAZOLE DERIVATIVES AS

KINASE INHIBITORS

The present invention relates to a class of fused bicyclic pyrrole and imidazole derivatives, and to their use in therapy. More particularly, the compounds in accordance with the present invention are substituted pyrrolo[2,l- J[l,2,4]triazine and imidazo[2,l-/j- [l,2,4]triazine derivatives, and fused pyridazine analogues thereof. 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.

WO 2008/118454, WO 2008/118455 and WO 2008/118468 describe various series of quinoline and quinoxaline derivatives that are structurally related to each other and are stated to be useful to inhibit the biological activity of human PI3K5 and to be of use in treating PI3K-mediated conditions or disorders.

WO 2009/081105, copending international application PCT/GB2009/002504, published on 29 April 2010 as WO 2010/046639 (claiming priority from United Kingdom patent application 0819593.5), copending international application PCT/GB2010/000243, published on 19 August 2010 as WO 2010/092340 (claiming priority from United

Kingdom patent applications 0902450.6 and 0914533.5), copending international application PCT/GB2010/000361, published on 10 September 2010 as WO 2010/100405 (claiming priority from United Kingdom patent applications 0903949.6 and 0915586.2), and copending international application PCT/GB2010/001000 (claiming priority from United Kingdom patent application 0908957.4) describe separate classes of fused bicyclic heteroaryl derivatives as selective inhibitors of PI3K enzymes that are of benefit in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

Copending international patent application PCT/US2009/005380, published on 1 April 2010 as WO 2010/036380, describes a family of pyridine and pyrazine derivatives that are stated to be selective inhibitors of type I PI3 kinases and to be of use in treating a medical condition mediated by a type I PI3 kinase.

None of the prior art available to date, however, discloses or suggests the precise structural class of fused bicyclic pyrrole and imidazole derivatives as provided by the present invention.

The compounds of the present invention are potent and selective PI3K inhibitors having a binding affinity (IC₅₀) for the human PI3Ka and/or ΡΙ3Κβ and/or ΡΙ3Κγ and/or PI3K6 isoform of 50 μΜ or less, generally of 20 μΜ or less, usually of 5 μΜ or less, typically of 1 μΜ 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 PI3Ka and/or ΡΙ3Κβ and/or ΡΙ3Κγ and/or PI3K5 isoform relative to other human kinases.

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

(I) wherein

Y represents N or C-R⁷;

X represents N or C-R⁸;

E represents an optionally substituted straight or branched C_1-4 alkylene chain; Q represents oxygen, sulfur, N-R⁹ or a covalent bond;

M represents the residue of an optionally substituted saturated five-, six- or seven- membered monocyclic ring containing one nitrogen atom and 0, 1 , 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom;

W represents C-R¹⁰ or N;

R¹, R² and R³ independently represent hydrogen, halogen, cyano, nitro, C_1- alkyl, trifluoromethyl, aryl(C_1-6)alkyl, hydroxy, C_1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, amino, C_1-6 alkylamino, di(C_1-6)alkyl- amino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, Ci_-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6

alkylaminocarbonyl, di(C_1-6)alkylaminocarbonyl, aminosulfonyl, Cj_-6 alkylaminosulfonyl or di(C_1-6)alkylaminosulfonyl;

R⁴, R⁵, R⁶, R⁷ and R⁸ independently represent C_1-6 alkyl, aryl, aryl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or hydrogen, halogen, trifluoromethyl, -OR , -SR^a, -SOR^a, -S0₂R^a, -NR^bR°, -NR^cCOR^d, -NR^cC0₂R^d, -NR^cS0₂R^e, -COR^d, -C0₂R^d, -CONR^bR^c or -S0₂NR^bR^c;

R⁹ represents hydrogen or C_1-6 alkyl;

R¹⁰ represents hydrogen, halogen, Ci_-6 alkyl or Ci_-6 alkoxy;

R^a represents Ci_-6 alkyl, difluoromethyl or trifluoromethyl;

R^b represents hydrogen or trifluoromethyl; or C_1-6 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_1-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;

R^c represents hydrogen, C_1-6 alkyl or C_3-7 cycloalkyl;

R^d represents hydrogen or C_1-6 alkyl; and

R^e represents C_1-6 alkyl.

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

For use in medicine, the salts of the compounds of formula (I) will be

pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of 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 C_1-6 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, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "C_1-6 alkoxy", "C_1- alkylthio", "C_1-6 alkylsulphonyl" and "C_1-6 alkylamino" are to be construed accordingly.

The expression "C_1-3 alkylene chain" refers to a divalent straight or branched alkylene chain containing 1 to 3 carbon atoms. Typical examples include methylene, ethylene, methylmethylene, ethylmethylene and dimethylmethylene.

Specific C_3- 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 azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2- cjpyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4-if|pyrimidinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, imidazo[4,5-£]pyridinyl, purinyl, imidazo[l,2- <z]pyrimidinyl, imidazo[l,2- ]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl,

benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups.

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

Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of 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=0)<→enol (CH=CHOH) tautomers or amide (NHC=0)<→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 'Η. 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 C atom, preferably C.

In one embodiment, Y represents N. In another embodiment, Y represents C-R . In one embodiment, X represents N. In another embodiment, X represents C-R . In one embodiment, W represents C-R¹⁰. In another embodiment, W represents N. Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA), (IB), (IC) and (ID), particularly (IA) and (IC), especially (IA):

 wherein Y, E, Q, M, R¹, R², R³, R⁴, R⁵, R⁶, R⁸ and R¹⁰ are as defined above.

Typical values of E include methylene (-CH₂-), (methyl)methylene, ethylene (-CH₂CH₂-), (ethyl)methylene, (dimethyl)methylene, (methyl)ethylene, (propyl)methylene and (dimethyl)ethylene, any of which chains may be optionally substituted by one or more substituents. Suitably, such chains are unsubstituted, monosubstituted or disubstituted. Preferably, such chains are unsubstituted or monosubstituted. In one embodiment, such chains are unsubstituted. In another embodiment, such chains are monosubstituted.

Examples of suitable substituents on the alkylene chain represented by E include trifluoromethyl, C_3-7 heterocycloalkyl, aryl, oxo, hydroxy, C]_-6 alkoxy, C_2-6 alkoxy- carbonyl(C_1- )alkoxy, aminocarbonyl(Ci_-6)alkoxy, trifluoromethoxy, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, aminocarbonyl, C_1-6 alkylaminocarbonyl and

di(C_1-6)alkylaminocarbonyl.

Examples of particular substituents on the alkylene chain represented by E include trifluoromethyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, oxo, hydroxy, ethoxy, ethoxycarbonylmethoxy, aminocarbonylmethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, aminocarbonyl, methylaminocarbonyl and dimethylamino- carbonyl.

Suitable values of E include methylene (-CH₂-) and (methyl)methylene.

A particular value of E is (methyl)methylene, i.e. -CH(CH₃)-.

Another value of E is methylene, i.e. -CH₂-.

Suitable values of Q include oxygen and N-R⁹.

In one embodiment, Q represents oxygen. In another embodiment, Q represents sulfur. In a further embodiment, Q represents N-R⁹. In a still further embodiment, Q represents a covalent bond.

In one embodiment, M represents the residue of an optionally substituted saturated five-membered monocyclic ring. In another embodiment, M represents the residue of an optionally substituted saturated six-membered monocyclic ring. In a further embodiment, M represents the residue of an optionally substituted saturated seven-membered monocyclic ring.

In one embodiment, the monocyclic ring of which M is the residue contains one nitrogen atom and no additional heteroatoms (i.e. it is an optionally substituted pyrrolidin- 1-yl, piperidin-l-yl or hexahydroazepin-l-yl ring). In another embodiment, the monocyclic ring of which M is the residue contains one nitrogen atom and one additional heteroatom selected from N, O and S. In a further embodiment, the monocyclic ring of which M is the residue contains one nitrogen atom and two additional heteroatoms selected from N, O and S, of which not more than one is O or S. In a still further embodiment, the monocyclic ring of which M is the residue contains one nitrogen atom and three additional heteroatoms selected from N, O and S, of which not more than one is O or S.

Suitable values of the monocyclic ring of which M is the residue include pyrrolidin-l-yl, imidazolidin-l-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl and [l,4]diazepan-l-yl, any of which rings may be optionally substituted by one or more substituents.

Selected values of the monocyclic ring of which M is the residue include pyrrolidin-l-yl, piperidin-l-yl and piperazin-l-yl, any of which rings may be optionally substituted by one or more substituents.

A particular value of the monocyclic ring of which M is the residue is optionally substituted piperazin- 1 -yl.

In one embodiment, the monocyclic ring of which M is the residue is

unsubstituted. In another embodiment, the monocyclic ring of which M is the residue is substituted by one or more substituents. In one subset of that embodiment, the

monocyclic ring of which M is the residue is monosubstituted. In another subset of that embodiment, the monocyclic ring of which M is the residue is disubstituted.

Typical examples of suitable substituents on the monocyclic ring of which M is the residue include halogen, C_1-6 alkyl, heteroaryl, C_1-6 alkoxy, difluoromethoxy,

trifluoromethoxy, C_1-6 alkoxy(C_1- )alkyl, C_1-6 alkylthio, C_1-6 alkylsulphonyl, hydroxy, hydroxy(C_1-6)alkyl, cyano, trifluoromethyl, oxo, C_2-6 alkylcarbonyl, (C_3-7)cycloalkyl- carbonyl, (C3_-7)heterocycloalkylcarbonyl(C_1-6)alkyl, carboxy, carboxy(C_1-6)alkyl, C_2-6 alkoxycarbonyl, C_2-6 alkoxycarbonyl(C_1-6)alkyl, amino, amino(C_1- )alkyl, C_1-6 alkylamino, di(C_1-6)alkylamino, phenylamino, pyridinylamino, C_2-6 alkylcarbonylamino, hydroxy- (C_1-6)alkylcarbonylamino, (C_3-7)cycloalkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulphonylamino, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(C_1-6)alkylamino- carbonyl and di(C_1-6)alkylaminocarbonyl(C_1-6)alkyl. Additional examples include C_1-3 alkylenedioxy, trifluoroethyl, hydroxy(C_1-6)alkylcarbonyl, di(C_1-6)alkylamino(C_1-6)alkyl- carbonyl, heteroarylcarbonyl, (C_1-6)alkylcarbonylamino(Ci_-6)alkyl, aminocarbonyl- (C_1-6)alkyl and (C_1-6)alkylaminocarbonyl(C_1-6)alkyl. Selected examples of suitable substituents on the monocyclic ring of which M is the residue include C_1-6 alkyl, heteroaryl, C_1-3 alkylenedioxy, Ci_-6 alkylsulphonyl, hydroxy, hydroxy(C_1-6)alkyl, trifluoroethyl, oxo, C_2-6 alkylcarbonyl, hydroxy(C_1-6)alkylcarbonyl, di(C_1-6)alkylamino(Ci_-6)alkylcarbonyl, heteroarylcarbonyl, carboxy, carboxy(C_1-6)alkyl, C_2-6 alkoxycarbonyl(Ci_-6)alkyl, hydroxy(C_1-6)alkylcarbonylamino, (C_1-6)alkylcarbonyl- amino(C_1-6)alkyl, (C_3-7)cycloalkylcarbonylamino, aminocarbonyl, aminocarbonyl- (C_1-6)alkyl, C_1-6 alkylaminocarbonyl and (C_1-6)alkylammocarbonyl(C_1-6)alkyl.

Illustrative examples of suitable substituents on the monocyclic ring of which M is the residue include hydroxy(C_1-6)alkyl, oxo, carboxy(C_1-6)alkyl and C_2-6 alkoxycarbonyl- (C_1-6)alkyl.

Typical examples of specific substituents on the monocyclic ring of which M is the residue include fluoro, chloro, bromo, methyl, ethyl, isopropyl, pyridinyl, pyrazinyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, cyano,

trifluoromethyl, oxo, acetyl, ethylcarbonyl, tert-butylcarbonyl, cyclopropylcarbonyl, morpholinylcarbonylmethyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino,

aminomethyl, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, hydroxyacetylamino, cyclopropylcarbonylamino, tert-butoxycarbonylamino, methylsulphonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and dimethylaminocarbonylmethyl. Additional examples include thiazolyl, ethylenedioxy, trifluoroethyl, hydroxyacetyl, dimethylaminoacetyl, pyridinylcarbonyl, acetylamino- methyl, aminocarbonylmethyl and methylaminocarbonylmethyl.

Selected examples of specific substituents on the monocyclic ring of which M is the residue include methyl, isopropyl, thiazolyl, pyridinyl, ethylenedioxy, methylsulphonyl, hydroxy, hydroxyethyl, trifluoroethyl, oxo, acetyl, hydroxyacetyl, dimethylaminoacetyl, pyridinylcarbonyl, carboxy, carboxymethyl, ethoxycarbonylmethyl, hydroxyacetylamino, acetylaminomethyl, cyclopropylcarbonylamino, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl and methylaminocarbonylmethyl.

Illustrative examples of specific substituents on the monocyclic ring of which M is the residue include hydroxyethyl (especially 2-hydroxyethyl), oxo, carboxymethyl and ethoxycarbonylmethyl .

A particular substituent on the monocyclic ring of which M is the residue is oxo. Typical values of the monocyclic ring of which M is the residue include pyrrolidin-l-yl, 3-hydroxypyrrolidin-l-yl, 3-(acetylamino)pyrrolidin-l-yl, 3-(hydroxy- acetylamino)pyrrolidin- 1 -yl, 3 -(cyclopropylcarbonylamino)pyrrolidin- 1 -yl, imidazolidin- 1-yl, 4-(acetylamino)piperidin-l-yl, 4-(methylsulphonylamino)piperidin-l-yl, morpholin- 4-yl, 3 -methylmorpholin-4-yl, thiomorpholin-4-yl, 1 , 1 -dioxothiomorpholin-4-yl, piperazin-l-yl, 4-(pyridin-2-yl)piperazin-l-yl, 4-(pyrazin-2-yl)piperazin-l-yl, 4- (methylsulphonyl)piperazin- 1 -yl, 4-(2-hydroxyethyl)piperazin- 1 -yl, 3 -oxopiperazin- 1 -yl, 4-methyl-3-oxopiperazin-l-yl, 4-acetylpiperazin-l-yl, 4-(ethylcarbonyl)piperazin-l-yl, 4- (tert-butylcarbonyl)piperazin- 1 -yl, 4-(cyclopropylcarbonyl)piperazin- 1 -yl, 4-(morpholin- 4-ylcarbonylmethyl)piperazin- 1 -yl, 4 -(carboxymethy l)piperazin- 1 -y 1, 4-

(methoxycarbonyl)piperazin- 1 -yl, 4-(ethoxycarbonylmethyl)piperazin- 1 -yl, 4- (dimethylaminocarbonylmethyl)piperazin-l-yl and 5-oxo-[l,4]diazepan-l-yl. Additional values include 3-(acetylaminomethyl)pyrrolidin-l-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl, 4-hydroxypiperidin-l-yl, 4-carboxypiperidin-l-yl, 4-(aminocarbonyl)piperidin-l-yl, 4- (methylaminocarbonyl)piperidin-l-yl, 3,5-dimethylpiperazin-l-yl, 4-(isopropyl)piperazin- 1 -yl, 4-(thiazol-2-yl)piperazin- 1 -yl, 4-(pyridin-3 -yl)piperazin- 1 -yl, 4-(2,2,2-trifluoro- ethyl)piperazin- 1 -yl, 4-(hydroxyacetyl)piperazin- 1 -yl, 4-(dimethylaminoacetyl)- piperazin- 1 -yl, 4-(pyridin-4-ylcarbonyl)piperazin- 1 -yl, 3 -(aminocarbonyl)piperazin- 1 -yl, 4-(aminocarbonyl)piperazin- 1 -yl, 4-(aminocarbonylmethyl)piperazin- 1 -yl, 4-(methyl- aminocarbonyl)piperazin- 1 -yl and 4-(methylaminocarbonylmethyl)piperazin- 1 -yl.

Selected values of the monocyclic ring of which M is the residue include 3- (hydroxyacetylamino)pyrrolidin- 1 -yl, 3 -(cyclopropylcarbonylamino)pyrrolidin- 1 -yl, 3 - (acetylaminomethyl)pyrrolidin- 1 -yl, 1 ,4-dioxa- 8 -azaspiro [4.5] dec-8 -yl, 4-hydroxypiperidin-l-yl, 4-carboxypiperidin-l-yl, 4-(aminocarbonyl)piperidin-l-yl, 4-(methyl- aminocarbonyl)piperidin- 1 -yl, piperazin- 1 -yl, 3 ,5 -dimethylpiperazin- 1 -yl, 4-(isopropy 1)- piperazin-l-yl, 4-(thiazol-2-yl)piperazin-l-yl, 4-(pyridin-3-yl)piperazin-l-yl, 4-(methyl- sulphonyl)piperazin- 1 -yl, 4-(2-hydroxyethyl)piperazin- 1 -yl, 4-(2,2,2-trifluoroethyl)- piperazin-l-yl, 3 -oxopiperazin- 1-yl, 4-acetylpiperazin-l-yl, 4-(hydroxyacetyl)piperazin- 1-yl, 4-(dimethylaminoacetyl)piperazin-l-yl, 4-(pyridin-4-ylcarbonyl)piperazin-l-yl, 4- (carboxymethy l)piperazin- 1-yl, 4-(ethoxycarbonylmethyl)piperazin-l-yl, 3-(amino- carbonyl)piperazin- 1 -yl, 4-(aminocarbonyl)piperazin- 1 -yl, 4-(aminocarbonylmethyl)- piperazin-l-yl, 4-(methylaminocarbonyl)piperazin-l-yl and 4-(methylaminocarbonyl- methyl)piperazin- 1 -yl. Particular values of the monocyclic ring of which M is the residue include 4-(2- hydroxyethyl)piperazin-l-yl, 3-oxopiperazin-l-yl, 4-(carboxymethyl)piperazin-l-yl and 4-(ethoxycarbonylmethyl)piperazin- 1 -yl.

A favoured value of the monocyclic ring of which M is the residue is 3-oxo- piperazin-l-yl.

Typical values of R¹, R² and/or R³ include hydrogen, halogen, C_1-6 alkyl, aryl(C_1-6)alkyl and C_1-6 alkoxy.

Suitably, R¹, R² and R³ independently represent hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, mefhylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, mefhoxycarbonyl, aminocarbonyl, methylaminocarbonyl,

dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl or dimethylaminosulfonyl.

Typically, R¹ represents hydrogen, halogen, C_1-6 alkyl, aryl(Ci_-6)alkyl or C_1-6 alkoxy.

Illustrative values of R¹ include hydrogen, halogen and C_1-6 alkyl.

In one embodiment, R¹ represents hydrogen. In another embodiment, R¹ represents halogen, particularly fluoro or chloro. In one aspect of that embodiment, R¹ represents fluoro. In another aspect of that embodiment, R¹ represents chloro. In a further embodiment, R¹ represents C_1-6 alkyl, particularly methyl or ethyl. In one aspect of that embodiment, R¹ represents methyl. In another aspect of that embodiment, R¹ represents ethyl. In a still further embodiment, R¹ represents aryl(C_1-6)alkyl, especially benzyl. In an additional embodiment, R¹ represents Ci- alkoxy, especially methoxy.

Typically, R² represents hydrogen or halogen.

In one embodiment, R 2 represents hydrogen. In another embodiment, R 2

represents halogen, particularly fluoro or chloro. In one aspect of that embodiment, R represents fluoro. In another aspect of that embodiment, R² represents chloro.

Typically, R³ represents hydrogen.

In a particular embodiment, R² and R³ both represent hydrogen.

Typical examples of suitable substituents on R⁴ and/or R⁵ and/or R⁶ and/or R⁷ and/or R⁸ include halogen, C_]-6 alkyl, C).₆ alkoxy, difluoromethoxy, trifluoromethoxy, Ci_-6 alkoxy(C_1-6)alkyl, Ci- 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, C_1-6 alkylamino, di(C_1-6)alkylamino, phenylamino,

pyridinylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino and aminocarbonyl.

Typical examples of specific substituents on R⁴ and/or R⁵ and/or R⁶ and/or R⁷ o

and/or R include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 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 and aminocarbonyl.

Illustrative values of R⁴ include hydrogen, halogen, C_1-6 alkyl, -SR^a, -S0₂R^a and -NR^bR°.

Typical values of R⁴ include hydrogen, C_1-6 alkyl, -SR^a, -S0₂R^a and -NR^bR^c.

Suitable values of R⁴ include hydrogen, -SR^a and -S0₂R .

Selected values of R⁴ include hydrogen and halogen.

In one embodiment, R⁴ represents hydrogen. In another embodiment, R⁴ represents halogen, particularly fluoro or chloro. In one aspect of that embodiment, R⁴ represents fluoro. In another aspect of that embodiment, R⁴ represents chloro. In another embodiment, R⁴ represents C_1-6 alkyl, especially methyl. In a further embodiment, R⁴ represents -SR^a. In a further embodiment, R⁴ represents -S0₂R^a. In an additional embodiment, R⁴ represents -NR^bR^c.

Suitable values of R⁵ include hydrogen, C_1-6 alkyl and -NR^bR^c.

In one embodiment, R⁵ represents hydrogen. In another embodiment, R⁵ represents C_1-6 alkyl, especially methyl. In a further embodiment, R⁵ represents -NR^bR°.

Suitable values of R⁶ include hydrogen, Ci_-6 alkyl and -NR^bR^c.

In one embodiment, R⁶ represents hydrogen. In another embodiment, R⁶ represents C_1-6 alkyl, especially methyl. In a further embodiment, R⁶ represents -NR^bR°.

Suitable values of R⁷ include hydrogen, C_1-6 alkyl and -NR^bR°.

In one embodiment, R⁷ represents hydrogen. In another embodiment, R⁷ represents C_1- alkyl, especially methyl. In a further embodiment, R⁷ represents -NR^bR^c.

Suitable values of R⁸ include hydrogen and C_1-6 alkyl.

In one embodi *ment, R 8 represents hydrogen. In another embodiment, R 8

represents C_1-6 alkyl, especially methyl. In one embodiment, R⁹ represents hydrogen. In another embodiment, R⁹ represents C_1-6 alkyl, especially methyl.

Suitable values of the group R⁹ include hydrogen and methyl.

Typically, R¹⁰ represents hydrogen or Ci_-6 alkyl.

In one embodiment, R¹⁰ represents hydrogen. In another embodiment, R¹⁰ represents halogen, particularly fluoro or chloro. In one aspect of that embodiment, R¹⁰ represents fluoro. In another aspect of that embodiment, R¹⁰ represents chloro. In a further embodiment, R¹⁰ represents Ci_-6 alkyl, especially methyl. In an additional embodiment, R¹⁰ represents C_1-6 alkoxy, especially methoxy.

Suitable values of the group R¹⁰ include hydrogen, fluoro, chloro, bromo, methyl and methoxy. Suitably, R¹⁰ represents hydrogen or methyl. Typically, R¹⁰ represents hydrogen.

In one embodiment, R^a represents C_1-6 alkyl, especially methyl. In another embodiment, R^a represents difluoromethyl. In a further embodiment, R^a represents trifluoromethyl.

Suitably, R represents hydrogen; or C_1-6 alkyl or aryl(C_1-6)alkyl, either of which groups may be optionally substituted by one or more substituents.

Typical values of R include hydrogen and Ci_-6 alkyl.

Illustratively, R represents hydrogen or trifluoromethyl; or methyl, ethyl, ^-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, morpholinylpropyl, pyridinyl, indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.

Typical examples of suitable substituents on R^b include halogen, C_1-6 alkyl, C_1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C_1-6 alkoxy(C_1- )alkyl, C_1-6 alkylthio, Ci_-6 alkylsulphonyl, hydroxy, hydroxy(C_1-6)alkyl, amino(C_1-6)alkyl, cyano, trifluoromethyl, oxo, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, amino, C_1-6 alkylamino, di(Ci_-6)- alkylamino, phenylamino, pyridinylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonyl- amino and aminocarbonyl.

Typical examples of specific substituents on R include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy,

methoxycarbonyl, ethoxycarbonyl, fert-butoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, tert-butoxycarbonylamino and aminocarbonyl.

In one embodiment, R^b represents hydrogen. In another embodiment, R^b represents C_1-6 alkyl, especially methyl. In a further embodiment, R^b represents optionally substituted aryl(C_1-6)alkyl. In one aspect of that embodiment, R^b represents methoxy- benzyl.

Suitably, R^c represents hydrogen or C_1-6 alkyl. In one embodiment, R° is hydrogen.

In another embodiment, R^c represents C_1-6 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.

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

Suitably, R^e represents methyl.

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

(IIA) wherein E, Q, M, R¹, R² and R⁴ are as defined above.

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

(IIB) wherein E, Q, M, R¹, R² and R⁴ are as defined above.

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

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

Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum.

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

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

The compounds of formula (I) above wherein Q represents oxygen, sulphur or N-R⁹ may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):

wherein Q¹ represents oxygen, sulphur or N-R⁹, L¹ represents a suitable leaving group, and Y, X, E, M, W, R¹, R², R³, R⁴, R⁵, R⁶ and R⁹ are as defined above.

The leaving group L¹ is typically a halogen atom, e.g. bromo or iodo.

The reaction is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. N, N-dimethylformamide or acetonitrile. The reaction may be performed in the presence of a suitable base, e.g. an inorganic base such as potassium carbonate, cesium carbonate, sodium hydride or aqueous sodium hydroxide.

The intermediates of formula (III) above wherein L¹ is bromo or iodo may be prepared from a compound of formula (V):

(V) wherein E, M, W, R¹, R² and R³ are as defined above; by bromination or iodination.

The bromination reaction is conveniently effected by stirring compound (V) with an appropriate brominating agent, e.g. phosphorus tribromide, in a suitable solvent, e.g. a halogenated hydrocarbon such as dichloromethane.

The iodination reaction is conveniently effected by stirring compound (V) with an appropriate iodinating agent, e.g. elemental iodine, in a suitable solvent, e.g. a halogenated hydrocarbon such as dichloromethane, typically in the presence of triphenylphosphine and imidazole.

Alternatively, the intermediates of formula (III) above wherein E represents methylene and L¹ is bromo may be prepared from a compound of formula (VI):

(VI) wherein M, W, R¹, R² and R³ are as defined above; by bromination.

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a halogenated solvent such as carbon tetrachloride, in the presence of a suitable brominating agent, e.g. N-bromosuccinimide, typically in the presence of a catalyst such as benzoyl peroxide.

In another procedure, the compounds of formula (I) wherein Q represents oxygen may be prepared by a process which comprises reacting a compound of formula (V) as defined above with a compound of formula (VII):

wherein Y, X, R⁴, R⁵ and R⁶ are as defined above, and L² represents a suitable leaving group.

The leaving group L² is typically a halogen atom, e.g. chloro or bromo.

The reaction is conveniently effected by stirring compounds (V) and (VII) at an elevated temperature in a suitable solvent, e.g. N,N-dimethylformamide or 1,4-dioxane, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium hydride.

In another procedure, the compounds of formula (I) wherein Q represents sulfur may be prepared by a process which comprises reacting a compound of formula (VII) as defined above with a compound of formula (VIII):

(VIII) wherein E, M, W, R¹, R² and R³ are as defined above.

The reaction is conveniently effected by stirring compounds (VII) and (VIII) in a suitable solvent, e.g. a lower alkanol such as methanol, typically under basic conditions, e.g. in the presence of an alkali metal alkoxide such as sodium methoxide.

The intermediates of formula (VIII) may typically be prepared by treating a suitable compound of formula (III) above with thiolacetic acid; followed by treatment of the resulting compound with a base, e.g. an alkali metal alkoxide such as sodium methoxide.

In another procedure, the compounds of formula (I) wherein Q represents N-R⁹ may be prepared by a process which comprises reacting a compound of formula (VII) as defined above with a compound of formula (IX):

wherein E, M, W, R¹, R², R³ and R⁹ are as defined above.

The reaction is conveniently effected at a suitable temperature, e.g. at ambient or an elevated temperature, in a suitable solvent, e.g. tetrahydrofuran, rc-butanol, l-methyl-2- pyrrolidinone (NMP), 1,4-dioxane or isopropanol. The reaction may be performed in the presence of a suitable base, e.g. an organic base such as N,N-diisopropylethylamine.

The intermediates of formula (IX) wherein R⁹ represents hydrogen may be prepared by treating a suitable compound of formula (III) above with potassium

phthalimide; followed by treatment of the resulting compound with hydrazine.

Alternatively, they may be prepared by treating a suitable compound of formula (III) above with sodium azide; followed by treatment of the resulting compound with triphenylphosphine.

In an additional procedure, the compounds of formula (I) wherein E represents methylene and Q represents N-R⁹ may be prepared by a process which comprises reacting a compound of formula (IV) wherein Q¹ represents N-R⁹ with a compound of formula (X):

(X) wherein M, W, R¹, R² and R³ are as defined above; under reducing conditions.

The reaction is conveniently effected by stirring the reactants at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, in the presence of a reducing agent. A suitable reducing agent comprises a mixture of di-n- butyltin dichloride and phenylsilane.

The intermediates of formula (IX) wherein E represents methylene and R⁹ represents C_1-6 alkyl, e.g. methyl, may be prepared by treating a suitable compound of formula (X) above with a C_1-6 alkylamine, e.g. methylamine, in the presence of titanium(IV) n-propoxide and a base, e.g. an organic base such as N,N-diisopropylamine; followed by treatment of the resulting compound with a reducing agent, e.g. sodium triacetoxyborohydride.

The intermediates of formula (V) wherein E represents methylene may be prepared from the corresponding compound of formula (X) by treatment with a reducing agent, e.g. sodium borohydride.

The intermediates of formula (V), (VIII) and (IX) may be prepared by reacting a compound of formula (XI) with a compound of formula (XII):

(XI) (XII) wherein E, Q¹, M, W, R¹, R² and R³ are as defined above, and L³ represents a suitable leaving group. The leaving group L³ is typically a halogen atom, e.g. chloro.

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. tetrahydrofuran, rc-butanol, l-methyl-2-pyrrolidinone (NMP) or ethylene glycol dimethyl ether (DME). The reaction may be performed in the presence of a suitable base, e.g. an organic base such as N,N-diisopropylethylamine.

The intermediates of formula (XI) wherein E represents (methyl)methylene and Q¹ represents NH may be prepared by a three-step procedure which comprises: (i) treating a suitable compound of formula (XIII):

(XIII) wherein W, R¹, R², R³ and L³ are as defined above; with 2-methyl-2-propanesulfinamide in the presence of titanium(IV) isopropoxide; (ii) reaction of the resulting compound with a Grignard reagent, e.g. methylmagnesium bromide; and (iii) treatment of the resulting compound with a mineral acid, e.g. hydrochloric acid.

Similarly, the intermediates of formula (XI) wherein E represents methylene and Q¹ represents NH may be prepared by a three-step procedure which comprises: (i) treating a suitable compound of formula (XIII) above with 2-methyl-2-propanesulfinamide in the presence of titanium(IV) isopropoxide; (ii) reaction of the resulting compound with a reducing reagent, e.g. sodium borohydride; and (iii) treatment of the resulting compound with a mineral acid, e.g. hydrochloric acid.

In a further procedure, the compounds of formula (I) may be prepared by a process which comprises reacting a compound of formula (XII) as defined above with a compound of formula (XIV):

(XIV) wherein Y, X, E, Q, W, R¹, R², R³, R⁴, R⁵, R⁶ and L³ are as defined above.

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. l-methyl-2-pyrrolidinone (NMP).

The intermediates of formula (XIV) above may be prepared by reacting a compound of formula (VII) as defined above with a compound of formula (XI) as defined above; under conditions analogous to those described above for the reaction between compound (VII) and compound (V), (VIII) or (IX).

Where they are not commercially available, the starting materials of formula (IV),

(VI), (VII), (X), (XII) and (XIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of illustration, a compound of formula (I) wherein the monocyclic ring of which M is the residue is substituted by C_2-6 alkoxycarbonyl or C_2-6 alkoxycarbonyl(C_1- )alkyl may be converted into the corresponding compound wherein the monocyclic ring of which M is the residue is substituted by carboxy or carboxy(C_1-6)alkyl respectively by treatment with a base, e.g. an aqueous solution of an inorganic base, which will typically be an alkali metal hydroxide such as sodium hydroxide. A compound of formula (I) wherein M represents the residue of a piperazin-l-yl moiety may be converted into the corresponding compound wherein M represents the residue of a 4-(aminocarbonyl)piperazin-l-yl moiety by treatment with trimethylsilyl isocyanate. A compound of formula (I) wherein R¹ or R⁴ represents a halogen atom, e.g.

chloro, may be converted into the corresponding compound wherein R¹ or R⁴ represents hydrogen by treatment with hydrogen gas or a hydrogen donor, e.g. hydrazine hydrate, in the presence of a hydrogenation catalyst, e.g. palladium on carbon.

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^r 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 PI3Ka and/or ΡΒΚβ and/or ΡΙ3Κγ and/or PI3K5.

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 μΜ 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 IC₅o.

When tested in the above assay, the compounds of the accompanying Examples were all found to possess IC ₀ values for inhibition of activity of human PI3Kct and/or ΡΙ3Κβ and/or ΡΙ3Κγ and/or PI3K5 of 50 μΜ or better.

EXAMPLES

Abbreviations

DCM: dichloromethane Et₂0: diethyl ether

DIPEA: N,N-diisopropylethylamine EtOAc: ethyl acetate

MeOH: methanol EtOH: ethanol

ft-BuOH: -butanol NMP : 1 -methyl-2 -pyrrolidinone

THF: tetrahydrofuran TFA: trifluoroacetic acid

Me: methyl MeCN: acetonitrile

DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide

r.t: room temperature RT: retention time Si0₂: silica h: hour

br: broad M: mass

HPLC: High Performance Liquid Chromatography

LCMS: Liquid Chromatography Mass Spectrometry

ES+: Electrospray Positive Ionisation

Analytical Conditions

All NMRs were obtained at 400 MHz.

Compounds were named with the aid of the Cambridgesoft Chemistry Cartridge (v. 9.0.0.182) software.

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

Analytical Condition Method Description

Solvents: Acetonitrile (far UV grade)

Water (high purity via PureLab Option unit) with 10 mM ammonium hydrogencarbonate

10cm_ESCI_AmmBicarb_ Column: Waters Xterra MS 5 μιη CI 8, 100 MeCN x 4.6 mm (Plus guard cartridge)

10cm_ESCI_Bicarb_ Flow Rate: 2 mL/min

MeCN Gradient: A: Water/Bicarb

10cm_ESI_Bicarb B: MeCN

10cm_ESI_Bicarb_MeCN Time A% B%

10cm APCI Formic 0.00 95 5

0.50 95 5

4.00 5 95

5.50 5 95

5.60 95 5

6.50 95 5

Solvents: Acetonitrile (far UV grade) with

0.1% (v/v) formic acid

1 Ocm ESI Formic Water (high purity via PureLab 1 Ocm ESI Formic Option unit) with 0.1% formic MeCN acid

Column: Phenomenex Luna 5 μηι CI 8 (2),

100 x 4.6 mm (Plus guard cartridge) Flow Rate: 2 mL/min Gradient: A: Water/formic acid

B: MeCN/formic acid

Time B%

0.00 5

3.50 95

5.50 95

5.60 5

6.50

INTERMEDIATE 1

(i?,E)-N-[(2,8-Dichloroquinolin-3-vDmethylidenel-2-methylpropane-2-sulfinamide

To a solution of 2,8-dichloroquinoline-3-carboxaldehyde (43.0 g, 0.19 mol) in anhydrous THF (500 mL) was added titanium(IV) isopropoxide (114 mL, 0.38 mol) at r.t. After stirring for 15 minutes, (i?)-2-methyl-2-propanesulfinamide (23.0 g, 0.19 mol) was added and stirring was continued for 17 h at r.t. Water (1 L) was added to the reaction mixture and the resulting precipitate was filtered and washed with DCM. The organic layer was dried (Na₂S0₄) and concentrated in vacuo to give the title compound (61 g,

97%) as a pale yellow solid. δ_Η (CDC1₃) 9.11 (1H, s), 8.83 (1H, s), 7.93 (1H, dd, J7.54, 1.31 Hz), 7.88 (1H, dd, J 8.22, 1.31 Hz), 7.55 (1H, t, J 7.88 Hz), 1.33 (9H, s).

INTERMEDIATE 2

(i? -iV-[(S)-l-(2,8-Dichloroquinolin-3-yl ethyll-2-methylpropane-2-sulfinamide

To a solution of Intermediate 1 (61 g, 0.18 mol) in DCM (1.5 L) was added dropwise methylmagnesium bromide (123.5 mL, 0.37 mol; 3M in Et₂0) over 50 minutes at -70°C under nitrogen. The reaction mixture was allowed to reach r.t. with stirring overnight. The mixture was cooled in an ice-salt bath and saturated aqueous NH₄C1 (500 mL) was slowly added. The aqueous layer was extracted with DCM (2 x 500 mL). The combined organic layers were dried (MgS0₄) and concentrated in vacuo. The residue was triturated with Et₂0 and the solid filtered, washed with Et₂0 and dried under reduced pressure to give the title compound (32 g, 50%) as a pale pink solid. 5H (CDC1₃) 8.26

(1H, s), 7.83 (1H, dd, J7.52, 1.32 Hz), 7.74 (1H, dd, J 8.19, 1.32 Hz), 7.49 (1H, t, J7.86 Hz), 5.16-5.07 (1H, m), 3.47 (1H, d, J4.63 Hz), 1.71 (3H, d, J6.75 Hz), 1.25 (9H, s). INTERMEDIATE 3

(S)- 1 -(2,8-Dichloroquinolin-3 -vDethanamine

To a solution of Intermediate 2 (3 '.7 g, 0.11 mol) in MeOH (370 mL) was added 4M hydrogen chloride in 1,4-dioxane (58 mL) at r.t. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was partitioned between 5M HC1 (300 mL) and DCM (300 mL). The organic layer was extracted with 5M aqueous HC1 (100 mL) and the combined aqueous layers basified with aqueous NaOH and extracted with DCM (3 x 500 mL) and chloroform (3 x 500 mL). The organic layers were dried (MgS0₄) and concentrated in vacuo to afford the title compound (23.7 g, 90%) as an amber oil. 5H (CDC1₃) 8.40 (IH, s), 7.80 (IH, dd, J7.51, 1.33 Hz), 7.75 (IH, dd, J8.19, 1.33 Hz), 7.46 (IH, t, J 7.86 Hz), 4.67 (IH, q, J 6.52 Hz), 1.50 (3H, d, J 6.53 Hz).

INTERMEDIATE 4

CSVfe -Butyl 1 -(2,8-dichloroquinolin-3-yl ethylcarbamate

To a stirred solution of Intermediate 3 (23.7 g, 98 mmol) and DIPEA (51 mL, 0.3 mol) in DCM (1 L) was added di-tert-butyl dicarbonate (25.7 g, 118 mmol). The reaction mixture was allowed to stand at r.t. overnight and concentrated in vacuo. The residue was triturated with 40-60 petroleum ether, filtered, washed with 40-60 petroleum ether and dried under reduced pressure to give the title compound (28.4 g, 85%) as a colourless solid. 6_H (CDC1₃) 8.13 (IH, s), 7.80 (IH, dd, J7.51, 1.32 Hz), 7.72 (IH, dd, J 8.18, 1.31 Hz), 7.46 (IH, t, J 7.85 Hz), 5.23-5.16 (IH, m), 5.10 (IH, br s), 1.55 (3H, br d, J 7.18 Hz), 1.42 (9H, br s).

INTERMEDIATE 5

A mixture of Intermediate 4 (0.53 g, 1.56 mmol), 2-oxopiperazine (0.78 g, 7.78 mmol) and DIPEA (1.35 mL, 7.78 mmol) in NMP (10 mL) was heated at 140°C for 16 h. After cooling, Et₂0 (250 mL) was added and the mixture washed with water (3 x 100 mL) and brine (100 mL). The organic layer was separated, dried (MgS0₄), concentrated in vacuo and the residue purified by column chromatography on silica, eluting with 0-100% EtOAc in isohexane, to afford the title compound (0.34 g, 53%) as a pale yellow solid. 5H (CDC1₃) 8.03 (IH, s), 7.72 (IH, dd, J 7.5, 1.3 Hz), 7.63 (IH, dd, J 8.0, 1.3 Hz), 7.32 (IH, t, J7.8 Hz), 6.32 (IH, br s), 5.15-4.93 (2H, m), 4.36 (IH, d, J 17.7 Hz), 4.13-3.84 (2H, m), 3.77-3.68 (IH, m), 3.45 (2H, m), 1.48-1.42 (12H, m).

INTERMEDIATE 6

(S)-4-[3-(l-Aminoethvn-8-chloroquinolin-2-yl]piperazin-2-one

TFA (1 mL) was added to a stirred solution of Intermediate 5 (0.34 g, 0.83 mmol) in DCM (5 mL) and the mixture was allowed to stand at r.t. for 16 h before being concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with 0.1M NaOH solution. 15% aqueous NaOH solution was added to the aqueous layer which was extracted with EtOAc (20 mL) and DCM (2 x 20 mL). The combined organics were dried (MgS0₄) and concentrated in vacuo to afford the title compound (0.24 g, 95%) as a pale orange-yellow solid. δ_Η (CDC1₃) 8.41 (IH, s), 7.73-7.66 (2H, m), 7.38-7.27 (IH, m), 4.81 (IH, m), 4.02 (IH, d, J 17.5 Hz), 3.88 (IH, d, J 17.5 Hz), 3.59- 3.38 (4H, m), 2.93 (3H, br s), 1.69 (3H, d, J 6.7 Hz).

INTERMEDIATE 7

(E)-N-[(2-Chloro-7-fluoro-8-methylquinolin-3-yl)methylidene]-(j? -2-methylpropane-2- sulfinamide

Following the procedure described for Intermediate I, 2-chloro-7-fluoro-8- methylquinoline-3-carbaldehyde (6.6 g, 29.5 mmol), titanium(IV) isopropoxide (17 g, 60 mmol) and (i?)-(+)-2-methyl-2-propanesulfmamide (3.6 g, 29.5 mmol) afforded the title compound (S3 g, 86%) as a yellow solid. δ_Η (CDC1₃) 9.12 (IH, s), 8.73 (IH, s), 7.71 (IH, dd, J 6.0 Hz), 7.40 (IH, t, J 8.2 Hz), 2.69 (3H, s), 1.32 (9H, s). INTERMEDIATE 8

N-r(Syi-i2-Chloro-7-fluoro-8-methv^

sulfanamide

Following the procedure described for Intermediate 2, Intermediate 7 (8.3 g, 25.4 mmol) and methylmagnesium bromide (16.0 mL, 48 mmol; 3.0M in Et 0) afforded, after crystallisation from 40-60 petroleum ether, the title compound (4.2 g, 48%) as a yellow solid. δ_Η (CDC1₃) 8.17 (1H, s), 7.63 (1H, dd, J 6.0 Hz), 7.32 (1H, t, J 8.8 Hz), 5.16 (1H, q, J6.8 Hz), 3.45 (1H, d, J 6.8 Hz), 2.66 (3H, s), 1.70 (3H, d, J6.8 Hz), 1.26 (9H, s).

INTERMEDIATE 9

CSVtert-Butyl l-(2-chloro-7-fluoro-8-methylquinolin-3-yl ethylcarbamate

To a solution of Intermediate 8 (4.2 g, 12.2 mmol) in MeOH (20 mL) was added cone. HC1 (1 mL) and the mixture was stirred at r.t. for 2 h. The reaction mixture was partitioned between DCM (100 mL) and 2M NaOH solution (50 mL). The organic layer was dried (MgS0₄) and filtered. To this filtrate was added DIPEA (1.6 g, 12.2 mmol) followed by a solution of di-fert-butyl dicarbonate (2.7 g, 12.2 mmol) in DCM (10 mL) dropwise. The reaction mixture was stirred at r.t. for 3 h, then diluted with DCM (10 mL) and washed with saturated NaHC0₃ solution (15 mL) and brine (15 mL). The organic layer was dried (MgS0₄), concentrated in vacuo and purified by column chromatography (Si0₂, 0-30% EtOAc in 40-60 petroleum ether) to give the title compound (4.38 g, 90%) as a yellow solid. δ_Η (CDC1₃) 8.07 (1H, s), 7.62 (1H, dd, J6.0 Hz), 7.30 (1H, t, J 8.8 Hz), 5.17 (1H, m), 5.07 (1H, br s), 2.65 (3H, s) 1.54 (3H, d, J6.4 Hz), 1.42 (9H, s).

INTERMEDIATE 10

(E)-N-|Y2-Chloro-5 J-difluoroquinolin-3-yl)methylidene]-(i?)-2-methylpropane-2- sulfinamide

To a solution of 2-chloro-5,7-difluoroquinoline-3-carboxaldehyde (7.9 g, 34.7 mmol) in dry THF (200 mL) under nitrogen was added titanium(IV) isopropoxide (20 g, 70 mmol). The mixture was stirred at r.t. for 10 minutes and treated with (i?)-(+)-2- methyl-2-propanesulfmamide (4.3 g, 34.7 mmol). The reaction mixture was stirred at r.t. for 72 h. The mixture was treated with water (60 mL), and the resulting precipitate was filtered through Kieselguhr and washed extensively with DCM. The filtrate was extracted with DCM (2 x 150 mL). The combined organic layers were dried (MgS0₄) and concentrated, to afford the title compound (9.35 g, 82%) as a pale yellow solid. 5_H

(CDC1₃) 9.09 (IH, s), 9.02 (IH, s), 7.55 (IH, d, J 9.6 Hz), 7.14 (IH, t, J 9.6 Hz), 1.32 (9H, s).

INTERMEDIATE 11

N-[(S)-l-(2-Chloro-5,7-difluoroquinolin-3-yl ethyll-(i? -2-methylpropane-2-sulfinamide

To a solution of Intermediate 10 (9.35 g, 28.3 mmol) in toluene (40 mL) at r.t. was added dropwise over 30 minutes a solution of methylmagnesium bromide (12.0 mL, 36 mmol; 3.0M in Et₂0). The reaction mixture was stirred for 18 h. Saturated NH₄C1 solution (50 mL) was added. The solids were filtered off through Kieselguhr and the filtrate was extracted with DCM (2 x 100 mL). The combined organic layers were dried (MgS0₄) and concentrated, to give a pale yellow solid. This was crystallised from 40-60 petroleum ether to afford the title compound (6.7 g, 68%) as a pale yellow solid. 8_H (CDCI3) 8.35 (IH, s), 7.49 (IH, d, J 9.6 Hz), 7.08 (IH, t, J 9.6 Hz), 5.19 (IH, q, J 6.8 Hz), 5.05 (IH, d, J 6.8 Hz), 1.59 (9H, s), 1.43 (3H, d, J 6.8 Hz).

INTERMEDIATE 12

(S)-tert- vX \ l -(2-chloro-5,7-difluoroquinolin-3-yl)ethylcarbamate

To a solution of Intermediate 11 (6.7 g, 19.3 mmol) in MeOH (20 mL) was added cone. HC1 (1 mL). The mixture was stirred at r.t. for 2 h, poured into DCM (100 mL) and washed with 2M NaOH solution (50 mL). The organic layer was separated, dried (MgS0₄) and concentrated in vacuo. The crude product was dissolved in dry DCM (40 mL) and treated with di-tert-butyl dicarbonate (4.3 g, 19.3 mmol) and DIPEA (3.0 mL, 15.0 mmol). The reaction mixture was stirred at r.t. for 16 h, diluted with DCM (10 mL) and washed with saturated aqueous NaHC0₃ solution (15 mL) and brine (15 mL). The organic layer was separated, dried (MgS0₄) and concentrated in vacuo. Purification by column chromatography (Si0₂, 0-30% EtOAc in 40-60 petroleum ether) afforded the title compound (5.2 g, 78%) as a white solid. δ_Η (CDC1₃) 8.45 (IH, s), 7.48 (IH, d, J 9.6 Hz), 7.10 (IH, t, J 9.6 Hz), 5.05 (IH, q, J 6.4 Hz), 3.77 (IH, d, J 6.4 Hz), 1.68 (3H, d, J 6.4 Hz), 1.26 (9H, s).

INTERMEDIATE 13

(S)-tert-Buty\ 1 - [7-fluoro-8-methyl-2-(3 -oxopiperazin- 1 -yl)quinolin-3 - yl] ethylcarbamate

Following the procedure described for Intermediate 5, Intermediate 9 (280 mg, 0.83 mmol), 2-oxopiperazine (86 mg, 1.0 mmol) and DIPEA (0.5 mL, 3.8 mmol) in n- BuOH (2.0 mL) gave the title compound (270 mg, 81 %) as a purple oil. δ_Η (CDC1₃) 7.99 (IH, s), 7.54 (IH, dd, J 8.9, 6.0 Hz), 7.17 (IH, t, J9.0 Hz), 6.73 (IH, br s), 5.10 (2H, br s), 4.28 (IH, d, J 17.5 Hz), 3.95 (IH, d, J 17.5 Hz), 3.89-3.77 (IH, m), 3.70-3.51 (IH, m), 3.44-3.35 (2H, m), 2.58 (3H, d, J2.4 Hz), 1.50-1.30 (12H, m).

INTERMEDIATE 14 r5 -4-|^"3-(l-Aminoethyl -5,7-difluoroquinolin-2-yllpiperazin-2-one

To a solution of Intermediate 12 (600 mg, 1.75 mmol) in rc-BuOH (6 mL) were added 2-oxopiperazine (200 mg, 2.0 mmol) and DIPEA (0.3 g, 2.3 mmol), and the resulting solution was heated at 120°C for 48 h. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (2 x 5 mL). The organic phase was separated and dried (MgS0₄), and the solvent was removed in vacuo. To a solution of the resulting material in DCM (10 mL) was added TFA (3 mL) and the resulting solution was stirred at r.t. for 1 h. The mixture was washed with 2M aqueous NaOH solution (2 x 5 mL) and water (2 x 5 mL). The organic phase was separated and dried (MgS0₄), and the solvent was removed in vacuo, to afford the title compound (180 mg, 34%) as a yellow gum. 6H (CDC1₃) 8.42 (IH, s), 7.40 (IH, d, J 9.6 Hz), 6.95 (IH, t, J7.2 Hz), 6.60 (IH, s), 5.40 (2H, br s), 5.15 (IH, q, J6.8 Hz), 4.15 (IH, d, J 17.2 Hz), 4.05 (IH, d, J 17.2 Hz), 3.10- 3.28 (2H, m), 2.83-3.08 (2H, m), 1.50 (3H, d, J 7.6 Hz). INTERMEDIATE 15

( S)-ter f -Butyl 1 - |^"2-(4-acetylpiperazin- 1 - ylV 8 -chloroquinolin-3 -yl] ethylcarbamate

Following the procedure described for Intermediate 5, Intermediate 4 (300 mg, 0.88 mmol), 1 -acetylpiperazine (564 mg, 4.40 mmol), NMP (3 mL) and DIPEA (1.53 mL, 8.80 mmol) gave the title compound (250 mg, 65%) as a clear glass. 6H (CDC1₃) 8.01 (1H, s), 7.71 (lH, dd, J7.5, 1.4 Hz), 7.62 (1H, dd, J 8.0, 1.4 Hz), 7.31 (1H, t, J7.8 Hz), 5.08 (1H, m), 3.94-3.71 (3H, m), 3.67-3.52 (3H, m), 3.39-3.15 (2H, m), 2.16 (3H, s), 1.76 (1H, d, J2.5 Hz), 1.48-1.43 (12H, m).

INTERMEDIATE 16

CSV 1 - {4- [^"3 -( 1 - Aminoethyl)-5 ,7-difluoroquinolin-2-yllpiperazin- 1 -yl> ethanone

To a solution of Intermediate 12 (500 mg, 1.46 mmol) in «-BuOH (5 mL) were added 1 -acetylpiperazine (200 mg, 1.6 mmol) and DIPEA (0.36 mL, 2.8 mmol), and the resulting solution was heated at 100°C for 72 h. The mixture was taken up in EtOAc (15 mL) and washed with water (2 5 mL). The organic phase was separated and dried (MgS0₄), and the solvent was removed in vacuo. To a solution of the resulting material in DCM (10 mL) was added TFA (3 mL) and the resulting solution was stirred at r.t. for 1 h. The reaction mixture was washed with 2M NaOH solution (2 x 5 mL) and water (2 x 5 mL). The organic phase was separated and dried (MgS0₄), and the solvent removed in vacuo, to afford the title compound (430 mg, 88%) as an orange oil. 5R (CDC1₃) 8.35 (1H, s), 7.32 (1H, d, J 8.8 Hz), 6.88 (1H, t, J 8.8 Hz), 4.70 (2H, br s), 4.45 (1H, q, J 6.4 Hz), 3.78-3.82 (2H, m), 3.64-3.68 (2H, m), 3.20-3.42 (4H, br m), 2.20 (3H, s), 1.49 (3H, d, J 6.8 Hz).

INTERMEDIATE 17

(S)- 1 - {4- [3 -( 1 - Aminoethyl)quinolin-2-yl]piperazin- 1 -yl j ethanone

To a solution of Intermediate 15 (500 mg, 1.15 mmol) in EtOH (10 mL) were added hydrazine hydrate (200 mg, 4.0 mmol) and 10% palladium on carbon (0.05 g). The reaction mixture was heated at 80°C for 72 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue obtained was purified by column chromatography (Si0₂, 3% MeOH in DCM) to give an orange oil (300 mg, 66%). To a solution of this material in DCM (5 mL) was added TFA (1 mL) and the resulting solution was stirred at r.t. for 1 h. The reaction mixture was washed with 2M NaOH solution (2 x 5 mL) and water (2 x 5 mL). The organic phase was separated and dried (MgS0₄), and the solvent was removed in vacuo, to afford the title compound (210 mg, 91%) as a yellow oil. δ_Η (CDC1₃) 8.10 (1H, s), 7.89 (1H, d, J8.8 Hz), 7.72 (1H, d, J 8.8 Hz), 7.66 (1H, t, J 8.8 Hz), 7.63 (1H, t, J 8.8 Hz), 5.17-5.23 (1H, m), 4.75 (2H, br s), 3.92-3.95 (1H, m), 3.79-3.83 (2H, m), 3.64-3.68 (1H, m), 3.35-3.38 (2H, m), 3.18-3.22 (2H, m), 2.22 (3H, s), 1.84 (3H, d, J 6.8 Hz).

INTERMEDIATE 18

N- \(RY 1 -(2, 8-Dichloroquinolin-3 -vDethyl] - R)-2-methylpropane-2-sulfinamide

Purification by column chromatography (Si0₂, 0-50% EtOAc in isohexane) of the ether filtrate from Intermediate 2 afforded the title compound (1.9 g, 14%) as a colourless solid. δ_Η (CDC1₃) 8.28 (1H, s), 7.86-7.73 (2H, m), 7.53-7.45 (1H, m), 5.10-5.01 (1H, m), 3.81 (1H, d, J5.32 Hz), 1.66 (3H, d, J6.66 Hz), 1.26 (9H, s).

INTERMEDIATE 19

(R)-tert-BvXy\ 1 -(2,8-dichloroquinolin-3-yl)ethylcarbamate

To a stirred solution of Intermediate 18 (1.9 g, 5.5 mmol) in MeOH (12.6 mL) was added 4N HC1 in 1 ,4-dioxane (2.9 mL, 11.6 mmol) and the reaction mixture was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure to give a pale yellow gum (1.8 g). To this gum dissolved in DCM (85 mL) were added di-tert-butyl dicarbonate (2.55 g, 11.7 mmol) and DIPEA (5.1 mL, 29.1 mmol). The resulting mixture was stirred at r.t. for 24 h. The mixture was washed with saturated aqueous NaHC0₃ solution (20 mL), then the organic layer was separated and dried (MgS0₄), and the solvent was removed in vacuo. Crystallisation from 40-60 petroleum ether afforded the title compound (1.1 g, 59%) as a white solid. δ_Η (CDC1₃) 8.13 (1H, s), 7.81 (1H, d, J7.51 Hz), 7.73 (1H, dd, J 8.17, 1.32 Hz), 7.51-7.42 (1H, m), 5.28-5.04 (2H, m), 1.72-1.28 (12H, m). INTERMEDIATE 20

(i?)-fert-Butyl 1 - |^"8-chloro-2-(3 -oxopiperazin- 1 -yl quinolin-3 -yl] ethylcarbamate

Following the procedure described for Intermediate 5, Intermediate 19 (1.1 g, 3.43 mmol) and 2-oxopiperazine (1.73 g, 17.3 mmol) gave the title compound (850 mg, 59%) as a white solid. δ_Η (CDC1₃) 8.03 (IH, s), 7.72 (IH, dd, J7.52, 1.32 Hz), 7.63 (IH, dd, J 8.09, 1.32 Hz), 7.32 (IH, t, J7.81 Hz), 6.11 (IH, s), 5.19-4.88 (2H, m), 4.43-4.29 (IH, m), 4.10-3.87 (2H, m), 3.79-3.69 (IH, m), 3.56-3.35 (2H, m), 1.47-1.38 (12H, m). INTERMEDIATE 21

(S)- 1 - (4- [3 -( 1 - Aminoethyl)-7-fluoro-8-methy lquinolin-2-yllpiperazin- 1 -yl > ethanone To a solution of Intermediate 9 (280 mg, 0.83 mmol) in «-BuOH (3 mL) were added 1-acetylpiperazine (128 mg, 1.0 mmol) and DIPEA (0.3 g, 2.3 mmol), and the resulting solution was heated at 120°C for 16 h. The reaction mixture was taken up in

EtOAc (15 mL) and washed with water (2 x 5 mL). The organic phase was separated and dried (MgS0₄), and the solvent was removed in vacuo. To a solution of the resulting material in DCM (10 mL) was added TFA (3 mL) and the resulting solution was stirred at r.t. for 1 h. The reaction mixture was washed with 2M NaOH solution (2 x 5 mL) and water (2 x 5 mL). The organic phase was separated and dried (MgSC ), and the solvent was removed in vacuo, to afford the title compound (140 mg, 52%) as an orange oil. δπ (CDC1₃) 7.66 (IH, s), 7.38 (IH, dd, J6.4 Hz), 6.93 (IH, t, J 8.8 Hz), 4.90 (2H, br s), 4.55 (IH, br q, J6.4 Hz), 3.83-3.90 (2H, m), 3.75-3.83 (2H, m), 3.64-3.72 (4H, m), 3.42 (3H, s), 2.50 (3H, s), 1.61 (3H, d, J6.8 Hz).

INTERMEDIATE 22

(S)-l-(2-Chloro-7-fluoro-8-methylquinolin-3-yl ethanamine

Intermediate 9 (8.0 g, 0.024 mol) in DCM (20 mL) at r.t. was treated with TFA (10 mL) and stirred for 15 minutes. The mixture was concentrated in vacuo and the residue was taken up in DCM (100 mL) and basified with NaHC0₃ solution. The organic layer was washed with brine (20 mL), separated, dried (phase separation cartridge) and concentrated in vacuo to give the title compound (5.5 g, 96%) as a cream foam. 5H (CDCI3) 8.31 (1H, s), 7.65 (1H, dd, J8.98, 5.95 Hz), 7.33-7.24 (1H, m), 4.64 (1H, q, J 6.54 Hz), 2.66 (3H, s), 1.44 (3H, d, J 6.80 Hz).

INTERMEDIATE 23

(S)-N-ri-(2-Chloro-7-fluoro-8-met^

amine

Intermediate 22 (800 mg, 3.4 mmol) in NMP (10 mL) was cooled to 10°C and treated with 4-bromopyrrolo[2,l- J[l,2,4]triazine (800 mg, 4.0 mmol) followed by the dropwise addition of DIPEA (1.7 g, 13.0 mmol). The mixture was allowed to warm to r.t. and stirred for 64 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (25 mL). The organic layer was washed with water (25 mL) and brine (25 mL), then separated, dried (phase separation cartridge) and concentrated in vacuo. The residue was purified by column chromatography (Si0₂, 20-30% EtOAc in isohexane) to give the title compound (1.16 g, 96%) as a cream foam. δ_Η (CDC1₃) 8.10 (1H, s), 7.86 (1H, s), 7.61-7.53 (2H, m), 7.33-7.24 (1H, m), 6.68-6.61 (2H, m), 5.84 (1H, m), 5.69 (1H, d, J 7.06 Hz), 2.66 (3H, s), 1.77 (3H, d, J 6.89 Hz).

EXAMPLE 1 r^-4-i8-Chloro-3-ri-(pyrrolor2J- irL2^1triazin-4-ylamino)ethyl1quinolin-2- yl I piperazin-2-one

Intermediate 6 (100 mg, 0.33 mmol), 4-bromopyrrolo[2,l-/][l,2,4]triazine (91 mg, 0.46 mmol) and DIPEA (0.29 mL, 1.65 mmol) in NMP (1.5 mL) were combined and treated under microwave conditions at 140°C for 1 h. The crude mixture was purified by preparative HPLC to yield the title compound (32 mg, 25%) as a beige solid. δ_Η (DMSO- d₆) 8.69 (1H, d, J 6.9 Hz), 8.38 (1H, s), 7.99 (1H, s), 7.89-7.83 (3H, m), 7.68 (1H, dd, J 2.6, 1.6 Hz), 7.43 (1H, t, J 7.8 Hz), 7.13 (1H, dd, J4.4, 1.6 Hz), 6.70 (1H, dd, J4.4, 2.6 Hz), 5.75-5.67 (1H, m), 4.19 (1H, d, J 17.2 Hz), 4.13-4.04 (1H, m), 3.92 (1H, d, J 17.2 Hz), 3.62 (1H, d, J9.9 Hz), 3.41 (1H, ddd, J 13.1, 8.4, 3.8 Hz), 3.34-3.28 (1H, m), 1.58 (3H, d, J 6.7 Hz). LCMS (ES+) 422 (M+H)⁺. EXAMPLE 2

(S)-2-f4-{8-Chloro-3-ri-rpyrrolor2J- l i ^ltriazin-4-ylamino)ethyl1quinolin-2- yl Ipiperazin- 1 -vDethanol

Intermediate 4 (0.7 g, 2.05 mmol), 2-(piperazin-l-yl)ethanol (1 n L, 8.15 mmol), rc-butanol (6 mL) and DIPEA (1 mL, 5.74 mmol) were combined in a sealed tube and heated to 120-130°C for 7 days. Reaction progression was followed by LCMS. Upon completion, the mixture was evaporated to dryness on silica and purified by flash chromatography. The resulting crude product was treated at r.t. with MeOH (5 mL) and 2M HC1 in diethyl ether (5 mL). When LCMS analysis of the reaction mixture indicated complete conversion of the starting material, the mixture was evaporated to dryness. The resulting amine intermediate (HC1 salt, 50 mg) was combined with 4-bromopyrrolo[2,l- |[l,2,4]triazine (50 mg) in «-butanol (5 mL) and DIPEA (1 mL). The reaction mixture was heated in a sealed tube under microwave irradiation to 140°C for 1 h. When LCMS analysis of the reaction mixture indicated completion, the mixture was evaporated to dryness and purified by preparative HPLC to give the title compound (20 mg) as an off- white solid. δ_Η (DMSO-d₆) 8.62 (IH, d, J7.2 Hz), 8.33 (IH, s), 7.88 (IH, s), 7.87-7.79 (2H, m), 7.67 (IH, dd, J2.6, 1.6 Hz), 7.40 (IH, t, J7.8 Hz), 7.12 (IH, dd, J4.4, 1.6 Hz), 6.69 (IH, dd, J4.4, 2.6 Hz), 5.82-5.73 (IH, m), 4.48-4.41 (IH, m), 3.75-3.62 (2H, m), 3.58 (2H, q, J5.6 Hz), 3.23-3.11 (2H, m), 2.78-2.69 (3H, m), 2.68-2.57 (2H, m), 2.11

(IH, s), 1.59 (3H, d, J 6.7 Hz). LCMS (ES+) 452 (M+H)⁺, RT 2.24 minutes {Method 2).

EXAMPLE 3

yl } piperazin- 1 - vDacetate

Prepared by a method analogous to that described in Example 2. 6R (DMSO-d₆)

8.64 (IH, d, J7.2 Hz), 8.34 (IH, s), 7.88 (IH, s), 7.88-7.80 (2H, m), 7.67 (IH, dd, J2.6,

1.6 Hz), 7.41 (IH, t, J7.8 Hz), 7.12 (IH, dd, J4.4, 1.6 Hz), 6.69 (IH, dd, J4.4, 2.6 Hz), 5.81-5.73 (IH, m), 4.15 (2H, q, J7.1 Hz), 3.74-3.68 (2H, m), 3.27-3.10 (4H, m), 2.89-

2.82 (2H, m), 2.79-2.70 (2H, m), 1.59 (3H, d, J 6.7 Hz), 1.25 (3H, t, J 7.1 Hz). LCMS

(ES+) 494 (M+H)⁺, RT 2.51 minutes {Method 2). EXAMPLE 4

(S)-2-r4-(8-Chloro-3-ri-(pyrrolor2J- iri.2^1triazin-4-ylamino ethyllquinolin-2- yl } piperazin- 1 - vDacetic acid

A solution of Example 3 (ca. 50 mg; crude reaction mixture) in ethanol (4 mL) and water (2 mL) was treated at room temperature with 15% aqueous NaOH solution (0.1 mL). The mixture was stirred at room temperature for 24 h. When LCMS analysis of the reaction mixture indicated completion, the mixture was evaporated to dryness and purified by preparative HPLC to give the title compound (34 mg) as a tan glass. δ_Η (DMSO-d₆) 8.65 (1H, d, J 7.2 Hz), 8.35 (1H, s), 7.88 (1H, s), 7.89-7.79 (2H, m), 7.67 (1H, t, J 1.9 Hz), 7.41 (1H, t, J7.8 Hz), 7.13-7.10 (1H, m), 6.69 (1H, dd, J4.4, 2.6 Hz), 5.77 (1H, m), 3.80-3.65 (3H, m), 3.27-3.20 (3H, m), 2.95-2.87 (2H, m), 2.85-2.75 (2H, m), 1.59 (3H, d, J 6.6 Hz). LCMS (ES+) 466 (M+H)⁺, RT 2.45 minutes (Method 1).

EXAMPLE 5

N-{r(3i?)-l-i8-Chloro-3-rri^-l-rpyrrolor2J- iri,2,41triazin-4-ylamino)ethyllquinolin-2- yl lpyrrolidin-3 -yl^"|methyl} acetamide

Intermediate 4 (700 mg, 2.05 mmol), (5)-l-[3-(aminomethyl)pyrrolidin-l-yl]- ethanone (710 mg, 4.02 mmol), «-BuOH (6 mL) and DIPEA (1 mL) were combined in a sealed tube and heated to 130°C for 10 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0 , 0-100% EtOAc in isohexane) to give [(5)-l-(2-{(i?)-3-[(acetylamino)methyl]pyrrolidin-l-yl}-8-chloro- quinolin-3-yl)ethyl]carbamic acid fert-butyl ester (258 mg) as a white solid (from rearrangement of amine in situ) and [(5)-l-(2-{[(5)-l-acetylpyrrolidin-3-ylmethyl]- amino}-8-chloroquinolin-3-yl)ethyl]carbamic acid tert-butyl ester (189 mg) as a clear glass. [(S)- 1 -(2- { (R)-3 - [( Acetylamino)methyl]pyrrolidin- 1 -yl} -8-chloro-quinolin-3 - yl)ethyl]carbamic acid tert-butyl ester (240 mg), MeOH (5 mL) and 2M HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 1 day. The reaction mixture was then concentrated in vacuo to give a yellow solid (250 mg). A portion of this solid (50 mg, 0.15 mmol), rc-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l-/][l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (19.3 mg, 28%) as a tan glass. δ_Η (DMSO-d₆) 8.61 (IH, dd, J 13.78, 7.17 Hz), 8.13 (IH, s), 8.04-7.98 (IH, m), 7.85 (IH, s), 7.69-7.61 (3H, m), 7.18-7.07 (2H, m), 6.68-6.64 (IH, m), 6.01-5.92 (IH, m), 3.96-3.80 (2H, m), 3.76-3.67 (IH, m), 3.56-3.48 (IH, m), 3.14-3.09 (2H, m), 2.49-2.40 (IH, m), 2.11-1.99 (IH, m), 1.86-1.75 (4H, m), 1.54 (3H, d, J6.6 Hz). LCMS (ES+) 464/466 (M+H)⁺, RT 3.25 minutes {Method 1).

EXAMPLE 6 1 - ( 7-Fluoro-8-methyl-3- IT 1 S)- 1 -ίρνιτοΐοβ, 1-/ 1 ,2,41triazin-4-ylamino^')ethyl1quinolin-2- yl)piperidine-4-carboxamide

Intermediate 9 (700 mg, 2.06 mmol), 4-piperidinecarboxamide (0.5 g, 3.90 mmol), «-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 130°C for 12 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a clear gum (823 mg). This material, MeOH (10 mL) and 2N HC1 in Et₂0 (7 mL) were combined and stirred at r.t. for 24 h. The mixture was concentrated to give a yellow solid. A portion of this material (60 mg), rc-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo [2,1 1,2,4] - triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (14.8 mg) as a white solid. 6H (DMSO-d₆) 8.59 (IH, d, J 7.22 Hz), 8.27 (IH, s), 7.87 (IH, s), 7.75 (IH, dd, J 8.92, 6.31 Hz), 7.66 (IH, dd, J2.59, 1.56 Hz), 7.32-7.25 (2H, m), 7.12 (IH, dd, J4.36, 1.57 Hz), 6.82 (IH, s), 6.68 (IH, dd, J4.35, 2.61 Hz), 5.75 (IH, m), 4.16-4.07 (IH, m), 3.70-3.61 (IH, m), 3.22-3.12 (IH, m), 2.73-2.65 (IH, m), 2.57 (3H, s), 2.41-2.31 (IH, m), 1.99-1.89 (2H, m), 1.86-1.75 (2H, m), 1.58 (3H, d, J6.70 Hz). LCMS (ES+) 448 (M+H)⁺, RT 3.19 minutes (Method 2). EXAMPLE 7

quinolin-2-yl}pyrrolidin-3-yllcyclopropanecarboxamide

(5)-(-)-3 -Amino- l-(fert-butoxycarbonyl)pyrrolidine (500 mg, 2.68 mmol), DCM

(30 mL), DIPEA (2 mL) and cyclopropanecarbonyl chloride (0.28 mL, 3 mmol) were combined at r.t. under a nitrogen atmosphere. The reaction mixture was stirred for 1 day, then diluted with DCM (50 mL) and washed with water (50 mL). The organic layer was separated, dried (MgS0₄) and concentrated in vacuo to give a brown oil. This oil, MeOH (10 mL) and 2N HC1 in Et₂0 (5 mL) were stirred at r.t. for 3 days. The reaction mixture was concentrated in vacuo. The resulting crude material (51 1 mg, 2.68 mmol),

Intermediate 9 (500 mg, 1.48 mmol), rc-BuOH (16 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 130°C for 15 days. The mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-100% EtOAc in isohexane) to give a tan solid (779 mg). This solid, MeOH (10 mL) and 2N HC1 in Et₂0 (7 mL) were combined and stirred at r.t. for 24 h. The mixture was concentrated in vacuo to give a brown glass. A portion of this material (50 mg, 0.127 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (25.5 mg, 42%») as an off-white solid. δ_Η (DMSO-d₆) 8.63 (1H, d, J7.14 Hz), 8.41 (1H, d, J6.93 Hz), 8.10 (1H, s), 7.88 (1H, s), 7.69-7.59 (2H, m), 7.16- 7.07 (2H, m), 6.69 (1H, dd, J4.35, 2.60 Hz), 5.98-3.89 (1H, m), 4.48-4.37 (1H, m), 3.97- 3.80 (3H, m), 3.68 (1H, dd, J 10.36, 7.38 Hz), 2.50 (3H, s), 2.31-2.21 (1H, m), 1.98-1.86 (1H, m), 1.64-1.54 (4H, m), 0.75-0.66 (4H, m). LCMS (ES+) 474 (M+H)⁺, RT 2.96 minutes {Method 2).

EXAMPLE 8 N-r(3ig)-l-{8-Chloro-3-rri^-l-(pyrrolor2J- irL2^1triazin-4-ylamino)ethyllquinolin-2- yl }pyrrolidin-3 -yl] -2-hydroxyacetamide

(i?)-(+)-3 -Amino- l-(tert-butoxycarbonyl)pyrrolidine (400 mg, 2.15 mmol), (30 mL), DIPEA (2 mL) and acetoxyacetyl chloride (0.247 mL, 2.3 mmol) were combined at r.t. under a nitrogen atmosphere. The reaction mixture was stirred for 7 days, then diluted with DCM (50 mL) and washed with water (30 mL). The organic layer was separated, dried (MgS0₄) and concentrated in vacuo to give a tan oil (747 mg). This oil, MeOH (10 mL) and 2N HC1 in Et₂0 (4 mL) were stirred at r.t. for 1 day. The reaction mixture was concentrated in vacuo. The resulting crude material, Intermediate 4 (400 mg, 1.17 mmol), «-BuOH (14 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 130°C for 13 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-100% EtOAc in isohexane, then 10% MeOH in EtOAc) to give an off-white foam. This material, MeOH (10 mL) and 2M HC1 in Et₂0 (6 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow solid. A portion of this material (50 mg, 0.13 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (10.3 mg, 9%) as an off-white solid. 6H (DMSO-d₆) 8.63 (IH, d, J7.l l Hz), 8.17 (IH, s), 7.96 (IH, d, J6.83 Hz), 7.87 (IH, s), 7.73-7.65 (3H, m), 7.20 (IH, t, J 7.76 Hz), 7.13 (IH, dd, J4.34, 1.60 Hz), 6.69 (IH, dd, J 4.36, 2.60 Hz), 6.01-5.93 (IH, m), 5.40 (IH, t, J5.89 Hz), 4.52-4.43 (IH, m), 4.10-3.98 (2H, m), 3.87-3.72 (4H, m), 2.24-2.15 (IH, m), 2.14-2.06 (IH, m), 1.60 (3H, d, J6.67 Hz). LCMS (ES+) 466/468 (M+H)⁺, RT 3.46 minutes {Method 2).

EXAMPLE 9

(A- (7-Fluoro-8-methyl-3 -IT 1 S)- 1 -fpyrrolo [2.1 -f] Π .2.41triazin-4-ylamino ethyl1quinolin-2- vUpiperazin- 1 -vDacetic acid

Intermediate 9 (700 mg, 2.06 mmol), ethyl 1-piperazineacetate (0.5 g), rc-BuOH (10 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 130°C for 12 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-100% EtOAc in isohexane). The resulting material, EtOH (7 mL) and 2N HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 3 days. The reaction mixture was concentrated to give a pale yellow solid. A portion of this material (50 mg), rc-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l-/J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. 15% NaOH solution (0.2 mL) was then added to the reaction mixture, which was stirred at r.t. for 3 days. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (25.2 mg) as a tan solid. δ_Η (DMSO-d₆) 8.61 (IH, d, J7.22 Hz), 8.30 (IH, s), 7.88 (IH, s), 7.77 (IH, dd, J 8.90, 6.25 Hz), 7.66 (IH, t, J 1.96 Hz), 7.31 (IH, t, J9.10 Hz), 7.11 (IH, d, J4.30 Hz), 6.68 (IH, dd, J4.36, 2.60 Hz), 5.81-5.71 (IH, m), 3.73-3.64 (2H, m), 3.25 (2H, s), 3.23- 3.14 (2H, m), 2.95-2.87 (2H, m), 2.84-2.74 (2H, m), 2.58 (3H, s), 1.57 (3H, d, J6.61 Hz) LCMS (ES+) 464 (M+H)⁺, RT 2.58 minutes {Method 1).

EXAMPLE 10 l-(4-(8-Chloro-3-rfiy)-l-(pyrrolor2.1- irL2.41triazin-4-ylamino)ethyllquinolin-2- yl}piperazin-l-yl)-2-hvdroxyethanone

Intermediate 4 (700 mg, 2.05 mmol), 2-hydroxy-l-(piperazin-l-yl)ethanone hydrochloride (1.5 g, 8.30 mmol), rc-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 130°C for 7 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a yellow gum (318 mg). This material, MeOH (5 mL) and 2N HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow glass. A portion of this material (50 mg, 0.13 mmol), n- BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l-/][l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (8.6 mg, 7%) as a brown solid. 6H (DMSO-d ) 8.65 (IH, d, J7.22 Hz), 8.36 (IH, s), 7.88-7.77 (3H, m), 7.65 (IH, dd, J2.60, 1.55 Hz), 7.40 (IH, t, J7.82 Hz), 7.09 (IH, dd, J4.36, 1.58 Hz), 6.66 (IH, dd, J4.35, 2.61 Hz), 5.81- 5.72 (IH, m), 4.60 (IH, br s), 4.23-4.10 (2H, m), 3.83-3.10 (8H, m), 1.57 (3H, d, J6.69 Hz). LCMS (ES+) 466/468 (M+H)⁺, RT 3.23 minutes (Method 2). EXAMPLE 11

1-Γ4- { 8-Chloro-3 -|Y1S)-1 -(pyrrolo Γ2,1- 1Γ1 ,2,41triazin-4-ylamino ethyll quinolin-2- yl jpiperazin- 1 -yl -2-(dimethylamino)ethanone

Intermediate 4 (700 mg, 2.05 mmol), 2-(dimethylamino)-l-(piperazin-l-yl)- ethanone (500 mg), «-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 130°C for 10 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a cream solid (610 mg). This material, MeOH (6 mL) and 2N HC1 in Et₂0 (6 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a yellow foam. A portion of this material (50 mg, 0.12 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (7.3 mg, 6%) as an off-white solid. δ_Η (DMSO-d₆) 8.65 (1H, d, J7.17 Hz), 8.35 (1H, s), 7.88-7.79 (3H, m), 7.65 (1H, dd, J2.61, 1.56 Hz), 7.40 (1H, t, J7.82 Hz), 7.09 (1H, dd, J4.36, 1.58 Hz), 6.66 (1H, dd, J4.37, 2.60 Hz), 5.80-5.72 (1H, m), 3.92- 3.83 (1H, m), 3.72-3.55 (5H, m), 3.25-3.17 (1H, m), 3.16-3.08 (3H, m), 2.21 (6H, s), 1.58 (3H, d, J 6.68 Hz). LCMS (ES+) 493/495 (M+H)⁺, RT 3.40 minutes {Method I).

EXAMPLE 12

1 -{7-Fluoro-8-methyl-3-[(lS)-l -(pyrrolo[2, 1 - ] [1 ,2,4]triazin-4-ylamino)ethyl]quinolin-2- yl}piperidine-4-carboxylic acid

Intermediate 9 (700 mg, 2.06 mmol), methyl 4-piperidinecarboxylate

hydrochloride (500 mg, 2.78 mmol), «-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 130°C for 12 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc). The resulting material, MeOH (10 mL) and 2M HC1 in Et₂0 (6 mL) were combined and stirred at r.t. for 24 h. The reaction mixture was concentrated to give a tan foam. A portion of this material (50 mg), rc-BuOH (6 mL), DIPEA (1 mL) and 4- bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated under microwave irradiation to 160°C for 2 h. 15% NaOH solution (0.2 mL) was added to the reaction mixture, which was stirred at r.t. for 3 days. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give the title compound (27.9 mg) as a green glass. δ_Η (DMSO-d₆) 8.58 (IH, d, J7.25 Hz), 8.29-8.25 (IH, m), 7.87 (IH, s), 7.76 (IH, t, J 7.60 Hz), 7.66 (IH, s), 7.30 (IH, t, J 9.12 Hz), 7.12 (IH, d, J4.26 Hz), 6.68 (IH, dd, J4.32, 2.62 Hz), 5.79-5.71 (IH, m), 4.06-3.98 (IH, m), 3.63-3.55 (IH, m), 3.28-3.21 (2H, m), 2.83-2.73 (IH, m), 2.57 (3H, s), 2.53-2.45 (IH, m), 2.11-2.02 (lH, m), 1.97-1.88 (IH, m), 1.86-1.74 (IH, m), 1.58 (3H, d, J 6.65 Hz). LCMS (ES+) 449 (M+H)⁺, RT 2.77 minutes {Method 1).

EXAMPLE 13

2-(Dimethylamino -l-(4-{7-fluoro-8-methyl-3-r(^'lS)-l-rpyrrolor2J- irL2,41triazin-4- ylamino)ethyl1quinolin-2-yl}piperazin- 1 -vDethanone

Intermediate 9 (700 mg, 2.06 mmol), 2-(dimethylammo)-l-(piperazin-l-yl)- ethanone (500 mg), «-BuOH (10 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 130°C for 13 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a white solid. This material, MeOH (8 mL) and 2N HC1 in Et₂0 (4 mL) were combined and stirred at r.t. for 2 days. The reaction mixture was concentrated to give a yellow foam. A portion of this material (50 mg, 0.12 mmol), rc-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l-/j[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and stirred at r.t. for 2 days. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (5.1 mg, 4%) as an off-white solid. δ_Η (DMSO-d₆) 8.64 (IH, d, J 7.26 Hz), 8.34 (IH, s), 7.90 (IH, s), 7.79 (IH, t, J 7.60 Hz), 7.67 (IH, s), 7.33 (IH, t, J9.11 Hz), 7.1 1 (IH, d, J4.35 Hz), 6.68 (IH, t, J3.38 Hz), 5.85-5.77 (IH, m), 3.93-3.85 (IH, m), 3.77-3.56 (4H, m), 3.23-3.05 (5H, m), 2.57 (3H, s), 2.24 (6H, s), 1.60 (3H, d, J6.68 Hz). LCMS (ES+) 491 (M+H)⁺, RT 3.58 minutes {Method 1). EXAMPLE 14

1 - { 7-Fluoro-8-methyl-3 - |Y 1 S)- 1 -(pyrrolo \2, 1 -f] \ 1 ,2,41triazin-4-ylamino ethyll quinolin-2- yll-N-methylpiperidine-4-carboxamide

Intermediate 9 (700 mg, 2.06 mmol), piperidine-4-carboxylic acid methylamide

(426 mg, 3 mmol), «-BuOH (10 mL) and DIPEA (3 mL) were combined in a sealed tube and heated to 130°C for 20 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a white solid. This material, MeOH (10 mL) and 2N HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 4 days. The reaction mixture was concentrated to give a yellow solid. A portion of this material (50 mg, 0.12 mmol), ra-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 130°C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (33.2 mg, 11%) as a tan solid. δ_Η (DMSO-d₆) 8.59 (IH, d, J7.27 Hz), 8.27 (IH, s), 7.87 (IH, s), 7.81-7.72 (2H, m), 7.66 (IH, d, J2.14 Hz), 7.29 (IH, t, J9.13 Hz), 7.12 (IH, d, J4.29 Hz), 6.68 (IH, dd, J4.34, 2.61 Hz), 5.80-5.71 (IH, m), 4.16-4.08 (IH, m), 3.71-3.63 (IH, m), 3.20-3.09 (IH, m), 2.73-2.67 (IH, m), 2.63 (3H, d, J4.50 Hz), 2.56 (3H, s), 2.40-2.30 (IH, m), 2.01-1.74 (4H, m), 1.58 (3H, d, J6.68 Hz). LCMS (ES+) 462 (M+H)⁺, RT 3.40 minutes {Method I).

EXAMPLE 15 l-i8-Chloro-3- lS -l-(Pyrrolor2a- iri,2,41triazin-4-ylamino)ethyllquinolin-2-vn-N- methylpiperidine-4-carboxamide

Intermediate 4 (700 mg, 2.06 mmol), piperidine-4-carboxylic acid methylamide (426 mg, 3 mmol), ra-BuOH (10 mL) and DIPEA (3 mL) were combined in a sealed tube and heated to 130°C for 10 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10%) MeOH in EtOAc) to give a white solid. This material, MeOH (10 mL) and 2N HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 3 days. The reaction mixture was concentrated to give a yellow solid. A portion of this material (50 mg, 0.12 mmol), ra-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l-/][l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and stirred at r.t. for 2 days. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (39.9 mg, 72%) as a tan glass. δ_Η (DMSO-d₆) 8.62 (IH, d, J7.15 Hz), 8.32 (IH, s), 7.88-7.75 (4H, m), 7.67 (IH, dd, J2.62, 1.57 Hz), 7.39 (IH, t, J7.81 Hz), 7.13 (IH, dd, J4.35, 1.57 Hz), 6.69 (IH, dd, J4.36, 2.62 Hz), 5.79-5.71 (IH, m), 4.21-4.13 (IH, m), 3.75-3.67 (IH, m), 3.21-3.13 (IH, m), 2.78-2.68 (IH, m), 2.63 (3H, d, J4.49 Hz), 2.42-2.32 (IH, m), 2.02-1.76 (4H, m), 1.59 (3H, d, J 6.64 Hz). LCMS (ES+) 464/466 (M+H)⁺, RT 3.39 minutes {Method 1).

EXAMPLE 16

1 -(8-Chloro-3- (iy>-l -ίτ>νιτο1οΓ2 ,1 -f\\\ .2,41triazin-4-ylamino ethyllquinolin-2- yl}piperidin-4-ol

Intermediate 4 (700 mg, 2.06 mmol), 4-hydroxypiperidine (300 mg, 3 mmol), n- BuOH (10 mL) and DIPEA (3 mL) were combined in a sealed tube and heated to 130°C for 7 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a clear oil. This material, MeOH (10 mL) and 2N HC1 in Et₂0 (4 mL) were combined and stirred at r.t. for

2 days. The reaction mixture was concentrated to give a yellow foam. A portion of this material (50 mg, 0.12 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- /][l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 130°C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (56.8 mg, 54%) as a tan solid. 6H (DMSO- d₆) 8.60 (IH, d, J7.11 Hz), 8.31 (IH, s), 7.87-7.76 (3H, m), 7.67 (IH, dd, J2.58, 1.56 Hz), 7.38 (IH, t, J7.80 Hz), 7.12 (IH, dd, J4.35, 1.57 Hz), 6.69 (IH, dd, J4.34, 2.62 Hz), 5.80-5.71 (IH, m), 4.73 (IH, d, J4.22 Hz), 4.01-3.92 (IH, m), 3.76-3.69 (IH, m), 3.59-3.50 (IH, m), 3.35-3.28 (IH, m), 2.89 (IH, t, J 11.21 Hz), 2.05-1.96 (IH, m), 1.93- 1.85 (IH, m), 1.80-1.69 (IH, m), 1.65-1.57 (4H, m). LCMS (ES+) 423/425 (M+H)⁺, RT 3.39 minutes {Method 2). EXAMPLE 17

1- {7-Fluoro-8-methyl-3-raSH-ipyrro^

yl}piperidin-4-ol

Intermediate 9 (700 mg, 2.06 mmol), 4-hydroxypiperidine (300 mg, 3 mmol), n-

BuOH (10 mL) and DIPEA (3 mL) were combined in a sealed tube and heated to 130°C for 14 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a clear gum. This material, MeOH (6 mL) and 2N HC1 in Et₂0 (6 mL) were combined and stirred at r.t. for 1 day. The reaction mixture was concentrated to give a yellow foam. A portion of this material (50 mg, 0.12 mmol), n-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- /J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 130°C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (51.6 mg, 49%) as a tan glass. δ_Η (DMSO- d₆) 8.57 (IH, d, J 7.31 Hz), 8.26 (IH, s), 7.88 (IH, s), 7.75 (IH, dd, J8.94, 6.35 Hz), 7.66 (IH, dd, J2.59, 1.57 Hz), 7.29 (IH, t, J9.14 Hz), 7.12 (IH, dd, J4.34, 1.60 Hz), 6.68 (IH, dd, J4.35, 2.61 Hz), 5.80-5.72 (IH, m), 4.72 (IH, br s), 3.96-3.87 (IH, m), 3.77- 3.68 (IH, m), 3.54-3.46 (IH, m), 3.34-3.25 (IH, m), 2.84 (IH, t, J 11.17 Hz), 2.56 (3H, s), 2.04-1.96 (IH, m), 1.92-1.84 (IH, m), 1.79-1.68 (IH, m), 1.66-1.56 (4H, m). LCMS (ES+) 421 (M+H)⁺, RT 4.00 minutes {Method 2).

EXAMPLE 18

2- (4-i7-Fluoro-8-methyl-3-r(lS -l-(pyrrolor2a- iri.2^1triazin-4-ylaminokthyllquinolin- 2-yl}piperazin- 1 -vDacetamide

Intermediate 9 (700 mg, 2.06 mmol), 2-(piperazin-l-yl)acetamide hydrochloride (500 mg), ?2-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 130°C for 30 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a clear gum. This material, MeOH (5 mL) and 2N HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 1 day. The reaction mixture was concentrated to give a beige solid. A portion of this material (50 mg, 0.12 mmol), «-BuOH (6 mL), DIPEA (1 mL) and 4- bromopyrrolo[2,l-/][l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 130°C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (38.6 mg, 33%) as an off-white solid. δ_Η (DMSO-d₆) 8.59 (1H, d, J 7.32 Hz), 8.29 (1H, s), 7.88 (1H, s), 7.77 (1H, dd, J 8.91 , 6.33 Hz), 7.66 (1H, t, J 1.96 Hz), 7.35-7.25 (2H, m), 7.17 (1H, s), 7.1 1 (1H, dd, J 4.37, 1.54 Hz), 6.68 (1H, dd, J4.35, 2.63 Hz), 5.81-5.73 (1H, m), 3.75-3.66 (2H, m),

3.23-3.15 (2H, m), 3.03-2.93 (2H, m), 2.80-2.72 (2H, m), 2.69-2.61 (2H, m), 2.58 (3H, s), 1.58 (3H, d, J 6.68 Hz). LCMS (ES+) 463 (M+H)⁺, RT 2.24 minutes {Method 2).

EXAMPLE 19

2-(4-l7-Fluoro-8-methyl-3-r(l^

2-vUpiperazin- 1 -yl -N-methylacetamide

Intermediate 9 (700 mg, 2.06 mmol), N-methyl-2-(piperazin-l-yl)acetamide bis(hydrochloride) (500 mg), rc-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 130°C for 30 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give a clear gum. This material, MeOH (5 mL) and 2N HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 3 days. The reaction mixture was concentrated to give a beige solid. A portion of this material (50 mg, 0.12 mmol), n-BuOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 120°C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (22.5 mg, 19%) as a beige solid. δ_Η (DMSO-d₆) 8.59 (1H, d, J 7.30 Hz), 8.30 (1H, s), 7.88 (1H, s), 7.78 (2H, t, J 7.17 Hz), 7.66 (1H, dd, J2.59, 1.54 Hz), 7.31 (1H, t, J 9.12 Hz), 7.1 1 (lH, dd, J4.33, 1.57 Hz), 6.68 (1H, dd, J4.35, 2.61 Hz), 5.81-5.73 (1H, m), 3.75-3.66 (2H, m), 3.23-3.15 (2H, m), 3.07-2.97 (2H, m), 2.79-2.71 (2H, m), 2.69-2.60 (5H, m), 2.58 (3H, s), 1.57 (3H, d, J 6.67 Hz). LCMS (ES+) 477 (M+H)⁺, RT 4.03 minutes {Method 1). EXAMPLE 20

2-(4- 18-Chloro-3 -IT 1 S)- 1 -(pyrrolo^, 1 - I \ L2,41triazin-4-ylamino)ethyllquinolin-2- yl Ipiperazin- 1 -vD-N-niethylacetamide

Intermediate 4 (700 mg, 2.06 mmol), N-methyl-2-(piperazin-l-yl)acetamide bis(hydrochloride) (500 mg), «-BuOH (10 mL) and DIPEA (4 mL) were combined in a sealed tube and heated to 130°C for 30 days. The reaction mixture was cooled, concentrated onto silica and purified by column chromatography (Si0₂, 0-10% MeOH in EtOAc) to give an off-white foam. This material, MeOH (5 mL) and 2N HC1 in Et₂0 (5 mL) were combined and stirred at r.t. for 3 days. The reaction mixture was concentrated to give a beige solid. A portion of this material (50 mg, 0.12 mmol), A-BUOH (6 mL), DIPEA (1 mL) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) were combined in a sealed tube and heated to 130°C for 16 h. The reaction mixture was then concentrated to dryness and purified by preparative HPLC to give the title compound (38.1 mg, 66%) as a tan solid. δ_Η (DMSO-d₆) 8.62 (IH, d, J7.23 Hz), 8.35 (IH, s), 7.89- 7.77 (4H, m), 7.67 (IH, dd, J2.60, 1.56 Hz), 7.41 (IH, t, J7.81 Hz), 7.11 (IH, dd, J4.37, 1.57 Hz), 6.69 (IH, dd, J4.36, 2.61 Hz), 5.81-5.73 (IH, m), 3.79-3.70 (2H, m), 3.27-3.18 (2H, m), 3.06-2.98 (2H, m), 2.80-2.71 (2H, m), 2.69-2.60 (5H, m), 1.59 (3H, d, J6.69 Hz). LCMS (ES+) 479/481 (M+H)⁺, RT 3.35 minutes {Method 1).

EXAMPLE 21

4- (5 J-Difluoro-3-IYlS)- 1 -(pyrrolo Γ2, 1 -f] ri.2.41triazin-4-ylamino ethyllquinolin-2- yl > piperazin-2-one

A solution of Intermediate 14 (100 mg, 0.32 mmol), 4-bromopyrrolo[2,l- J-

[l,2,4]triazine (70 mg, 0.36 mmol) and DIPEA (76.0 mg, 0.60 mmol) in «-BuOH (3 mL) was heated at 120°C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (86 mg, 62%) as a cream solid. 6H (CDC1₃) 8.28 (IH, s), 7.85 (IH, s), 7.57 (IH, d, J4.4 Hz), 7.48 (IH, d, J 8.8 Hz), 6.91 (IH, t, J 7.2 Hz), 6.68 (2H, s), 6.16 (IH, s), 5.74 (IH, br s), 5.70 (IH, q, J 6.8 Hz), 4.38 (IH d, J 17.2 Hz), 4.01-4.11 (IH m), 3.99 (IH d, J 17.2 Hz), 3.68-3.78 (IH, m), 3.38-3.55 (2H, m), 1.62 (3H, d, J 7.6 Hz). LCMS (ES+) 424 (M+H)⁺, RT 3.06 minutes {Method 1). EXAMPLE 22

1 -C4- { 8-Chloro-3 - lYlSH -( pyrrolo Γ2.1-/ΊΓ1 ,2,41triazin-4-ylamino ethyllquinolin-2- yllpiperazin-l-vDethanone

To a solution of Intermediate 15 (130 mg, 0.3 mmol) in 1,4-dioxane (1 mL) was added HC1 (2.25 mL; 4M in 1,4-dioxane). The mixture was stirred at r.t. for 1 h and the solvent was removed in vacuo. The resulting material was dissolved in TJ-BUOH (2.5 mL), then DIPEA (0.78 mg, 0.6 mmol) and 4-bromopyrrolo[2,l-/][l,2,4]triazine (66 mg, 0.33 mmol) were added. The mixture was heated at 120°C for 16 h and the solvent was removed in vacuo. The residue was purified by preparative HPLC to afford the title compound (43.8 mg, 33%) as a cream solid. δ_Η (DMSO-d₆) 8.69 (IH, d, J 7.2 Hz), 8.39 (IH, s), 7.92 (IH, s), 7.89 (IH, d, J 8.8 Hz), 7.85 (IH, d, J 8.8 Hz), 7.68 (IH, s), 7.43 (IH, t, J 8.8 Hz), 7.12 (IH, d, J5.2 Hz), 6.69 (IH, d, J5.2 Hz), 5.72-5.80 (IH, m), 3.75-3.82 (2H, m), 3.64-3.72 (4H, m), 3.18-3.26 (IH, m), 3.08-3.16 (IH, m), 2.14 (3H, s), 1.62 (3H, d, J 6.8 Hz). LCMS (ES+) 450/452 (M+H)⁺, RT 3.38 minutes {Method 1).

EXAMPLE 23

1 -(4- ( 5.7-Difluoro-3 - ITISH -( pyrrolo \2Λ-Ά\\ ,2,41triazin-4-ylamino)ethyl1quinolin-2- yl > piperazin- 1 - vDethanone

A solution of Intermediate 16 (70 mg, 0.21 mmol), 4-bromopyrrolo[2,l- J- [l,2,4]triazine (48 mg, 0.24 mmol) and DIPEA (50 mg, 0.40 mmol) in «-BuOH (3 mL) was heated at 120°C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (75 mg, 79%) as a cream solid. δ_Η (CDC1₃) 8.33 (IH, s), 7.89 (IH, s), 7.58 (IH, d, J6.4 Hz), 7.35 (IH, d, J 8.8 Hz), 6.90 (IH, t, J 8.8 Hz), 6.75 (IH, d, J6.4 Hz), 6.65 (IH, d, J6.4 Hz), 6.38 (IH, br s), 5.78-5.90 (IH, m), 3.90-4.05 (IH, m), 3.72-3.82 (2H, m), 3.62-3.72 (3H, m), 3.12-3.31 (2H, m), 2.19 (3H, s), 1.65 (3H, d, J6.8 Hz). LCMS (ES+) 452 (M+H)⁺, RT 3.35 minutes

{Method 1). EXAMPLE 24

1 -(4- 13 - Γ(Ί S)- 1 -(Pyrrolo Γ2 J -/! Γ 1 ,2,41triazin-4-ylamino)ethyl1 quinolin-2-yl Ipiperazin- 1 - vDethanone

A solution of Intermediate 17 (70 mg, 0.23 mmol), 4-bromopyrrolo[2,l- J-

[l ,2,4]triazine (50 mg, 0.26 mmol) and DIPEA (60 mg, 0.46 mmol) in «-BuOH (3 mL) was heated at 120°C for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound (20 mg, 22%) as a cream solid. 5H (CDC1₃) 8.09 (1H, s), 7.89 (1H, d, J4.4 Hz), 7.88 (1H, s), 7.68 (1H, d, J 8.8 Hz), 7.62 (1H, t, J 8.8 Hz), 7.56 (1H, d, J4.4 Hz), 7.42 (1H, t, J 8.8 Hz), 6.67 (2H, d, J4.4 Hz), 5.80-5.91 (2H, m), 3.88-3.98 (1H, m), 3.68-3.78 (2H, m), 3.55-3.65 (3H, m), 3.12-3.21 (2H, m), 2.19 (3H, s), 1.68 (3H, d, J 6.8 Hz). LCMS (ES+) 416 (M+H)⁺, RT 2.72 minutes {Method 2).

EXAMPLE 25

4- j7-Fluoro-8-methyl-3-IY \S)-\ -(ρνιτο1οΓ2, 1 -f] Π ,2,41triazin-4-ylamino ethyllquinolin-2- y 11 piperazin-2-one

To a solution of Intermediate 13 (800 mg, 2 mmol) in DCM (20 mL) was added TFA (5 mL). The reaction mixture was stirred at r.t. for 3 h and the excess solvent was removed in vacuo. The oil obtained was basified with 2M NaOH solution (40 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried (MgS0₄), filtered and concentrated in vacuo to give a colourless oil (606 mg, 100%). A solution of this oil (120 mg, 0.40 mmol), 4-bromopyrrolo[2,l- J[l ,2,4]triazine (87 mg, 0.44 mmol) and DIPEA (0.11 mL, 0.48 mmol) in «-BuOH (2.2 mL) was heated to 130°C overnight. After cooling, the solvents were removed in vacuo. The residue was redissolved in DCM (20 mL) and washed with water (2 xlO mL). The organic layer was dried (MgS0₄), and the solvent was removed in vacuo. Purification by column chromatography (Si0₂, 0-5% MeOH in DCM) afforded the title compound (90 mg, 18%) as a white solid. δ_Η (CDC1₃) 8.10 (1H, s), 7.87 (1H, s), 7.61-7.51 (2H, m), 7.19 (1H, t, J 8.97 Hz), 6.73-6.68 (2H, m), 5.98 (1H, s), 5.82-5.74 (1H, m), 4.42-4.34 (1H, m), 4.10-3.98 (2H, m), 3.79-3.69 (2H, m), 3.57-3.48 (1H, m), 3.47-3.40 (1H, m), 2.62 (3H, d, J2.37 Hz), 1.63 (3H, s). LCMS (ES+) 420 (M+H)⁺, RT 2.34 minutes (Method 2). EXAMPLE 26

4 3-ra5Vl-(2-CMoropynolor2g -/iri.2^

quinolin-2-yl) piperazin-2-one

To a solution of Intermediate 13 (300 mg, 0.75 mmol) in DCM (5 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t. for 3 h and the excess solvent was removed in vacuo. The oil obtained was basified with 2M NaOH solution (40 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried (MgS0₄), filtered and concentrated in vacuo to give a colourless oil (606 mg, 100%). A solution of this oil (226 mg, 0.75 mmol), 2,4-dichloropyrrolo[2,l-/J[l,2,4]triazine (211 mg, 1.12 mmol) and DIPEA (0.39 mL, 2.25 mmol) in isopropanol (3 mL) was heated to 130°C overnight. After cooling, the solvents were removed in vacuo. The residue was redissolved in DCM (20 mL) and washed with water (2 xlO mL). The organic layer was dried (MgS0₄), and the solvent was removed in vacuo. Purification by preparative HPLC afforded the title compound (211 mg, 62%) as a white solid. 6H (CDC1₃) 8.02 (1H, s), 7.57-7.46 (2H, m), 7.16 (1H, t, J 8.96 Hz), 6.76 (1H, d, J4.46 Hz), 6.67 (1H, dd, J4.49, 2.65 Hz), 6.19-6.09 (2H, m), 5.81-5.71 (1H, m), 4.35 (1H, d, J 17.33 Hz), 4.11-3.99 (1H, m), 3.95 (1H, d, J 17.35 Hz), 3.76-3.63 (2H, m), 3.49-3.38 (1H, m), 2.59 (3H, d, J2.35 Hz), 1.62 (3H, d, J 6.73 Hz). LCMS (ES+) 454/456 (M+H)⁺, RT 2.99 minutes {Method 2).

EXAMPLE 27

4-( 8-Chloro-3-rf -(ρνπΌΐοΓ2, 1 -f] rL2,41triazin-4-ylamino ethyl1quinolin-2- yl}piperazin-2-one

To a solution of Intermediate 20 (700 mg, 1.73 mmol) in DCM (10 mL) was added TFA (4 mL). The reaction mixture was stirred at r.t. for 3 h and the excess solvent was removed in vacuo. The oil obtained was basified with 2M NaOH solution (40 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried (MgS0₄), filtered and concentrated in vacuo to give a colourless oil (525 mg, 100%). A solution of this oil (175 mg, 0.57 mmol), 4-bromopyrrolo[2,l-/][l,2,4]triazine (175 mg, 0.86 mmol) and DIPEA (0.3 mL, 1.73 mmol) in fl-BuOH (2 mL) was heated to 130°C overnight. After cooling, the solvents were removed in vacuo. The residue was redissolved in DCM (20 mL) and washed with water (2 xl O mL). The organic layer was dried (MgS0₄) and the solvent was removed in vacuo. Purification by preparative HPLC afforded the title compound (132 mg, 55%) as a white solid. δ_Η (CDC1₃) 8.14-8.06 (IH, m), 7.84 (IH, s), 7.70 (IH, dd, J 7.53, 1.31 Hz), 7.59-7.56 (2H, m), 6.73-6.65 (2H, m), 6.62 (IH, s), 6.05- 5.85 (IH, m), 5.75-5.68 (IH, m), 4.44 (IH, d, J 17.67 Hz), 4.18-4.05 (2H, m), 3.84-3.75 (IH, m), 3.52-3.42 (2H, m), 2.00 (IH, s), 1.62 (3H, d, J 6.68 Hz). LCMS (ES+) 422/424 (M+H)⁺, RT 2.74 minutes (Method !).

EXAMPLE 28

4- { 7-Fluoro-8-methyl-3 - [Y 1 S)- 1 -fpyrrolo [2, 1 -f] 1 ,2,4]triazin-4-ylamino)ethyll quinolin-2- yl } -N-methylpiperazine- 1 -carboxamide

A solution of Intermediate 9 (500 mg, 1.476 mmol), N-methylpiperazine-1- carboxamide (677 mg, 4.73 mmol) and DIPEA (1.54 mL, 8.85 mmol) in NMP (3.5 mL) was heated under microwave irradiation at 150°C for 3.5 h. After cooling, the mixture was dissolved in a 1 : 1 mixture of EtOAc and Et₂0 (250 mL) and washed with saturated brine (3 x 50 mL). The organic layer was separated, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (Si0₂, 2% EtOAc in DCM) gave a pale yellow solid (214 mg, 33%). LCMS (ES+) 446 (M+H)⁺. To this solid (214 mg, 0.48 mmol) dissolved in DCM (12 mL) was added TFA (2.2 mL). The reaction mixture was stirred at r.t. for 1.5 h and the excess solvent was removed in vacuo. The oil obtained was basified with 0.5M NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS0₄), filtered and concentrated in vacuo to give a pale yellow glass (179 mg, 100%). LCMS (ES+) 346 (M+H)⁺. This glass (44.7 mg, 0.129 mmol), 4-bromopyrrolo[2,l-/J[l ,2,4]triazine (38.4 mg, 0.194 mmol), DIPEA (0.068 mL, 0.388 mmol) and n-BuOH (1 mL) were combined and heated under microwave irradiation at 130°C for 1 h. Purification by preparative HPLC gave the title compound (2.0 mg, 3%) as a cream solid. δ_Η (DMSO-d₆) 8.63 (IH, d, J 7.35 Hz), 8.34 (IH, s), 7.90 (IH, s), 7.79 (IH, dd, J 8.91, 6.32 Hz), 7.67 (IH, dd, J2.60, 1.56 Hz), 7.33 (IH, t, J 9.1 1 Hz), 7.1 1 (IH, dd, J4.36, 1.58 Hz), 6.68 (IH, dd, J4.35, 2.61 Hz), 6.56- 6.50 (IH, m), 5.84-5.75 (IH, m), 3.64-3.53 (4H, m), 3.49-3.40 (2H, m), 3.12-3.04 (2H, m), 2.62 (3H, d, J 4.23 Hz), 2.57 (3H, d, J 2.24 Hz), 1.58 (3H, d, J 6.68 Hz). LCMS (ES+) 463 (M+H)⁺, RT 3.40 minutes (Method 1).

EXAMPLE 29

1- (4-j7-Fluoro-8-methyl-3-rQ

2- yl } piperazin- 1 -vDethanone

A solution of Intermediate 21 (70 mg, 0.21 mmol), 4-bromopyrrolo[2,l-/J- [l,2,4]triazine (50 mg, 0.25 mmol) and DIPEA (0.184 mL, 1.1 mmol) in NMP (1.5 mL) was heated at 150°C for 1 h under microwave irradiation. The reaction mixture was purified by preparative HPLC to afford the title compound (46.9 mg, 80%) as a white solid. δ_Η (DMSO-d₆) 8.63 (IH, d, J7.32 Hz), 8.34 (IH, s), 7.91 (IH, s), 7.80 (IH, dd, J 8.94, 6.28 Hz), 7.67 (IH, d, J2.61 Hz), 7.34 (IH, t, J9.12 Hz), 7.11 (IH, dd, J4.36, 1.59 Hz), 6.68 (IH, d, J4.36 Hz), 5.86-5.77 (IH, m), 3.81-3.72 (2H, m), 3.67-3.57 (4H, m), 3.20-3.02 (2H, m), 2.52 (3H, s), 2.06 (3H, s), 1.59 (3H, d, J6.68 Hz). LCMS (ES+) 448 (M+H)⁺, RT 3.06 minutes (Method 2).

EXAMPLE 30

( 4- {7-Fluoro-8-methyl-3 -ITISH -fpyrrolo Γ2,1-/1Γ1 ,2,41triazin-4-ylamino)ethyl1 quinolin-2- yl|piperazin-l-ylXpyridin-4-vDmethanone

To a solution of Intermediate 9 (500 mg, 1.48 mmol) in NMP (6 mL) were added (piperazin- l-yl)(pyridin-4-yl)methanone (778 mg, 3.00 mmol) and DIPEA (1.3 mL), and the resulting mixture was heated at 140°C for 16 h. The reaction mixture was taken up in

EtOAc (150 mL) and water (50 mL) and the organic layer was washed with water (2 x 50 mL) and brine (50 mL). The organic layer was separated and dried (phase separation cartridge), and the solvent was removed in vacuo. Purification by column

chromatography (Si0₂, 10-20% EtOAc in isohexane) gave a beige solid (400 mg, 55%). To a solution of this material (400 mg, 0.81mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting solution was stirred at r.t. for 15 minutes. The solvents were removed in vacuo. The residue was dissolved in MeOH (5 mL) and placed on an SCX cartridge, washed (MeOH), eluted (7M NH₃ in MeOH) and concentrated in vacuo to afford a white solid (318 mg, 100%). To a portion of this material (60 mg, 0.15 mmol) in NMP (1.2 mL) were added DIPEA (0.14 mL) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (36 mg, 0.18 mmol), and the resulting solution was heated under microwave irradiation at 150°C for 1 h. Purification by preparative HPLC afforded the title compound (15.1 mg, 20%) as a pink solid. δ_Η (DMSO-d₆) 8.73 (2H, d, J4.44 Hz), 8.63 (IH, d, J 7.33 Hz), 8.33 (IH, s), 7.88 (IH, s), 7.80 (IH, dd, J 8.93, 6.16 Hz), 7.66 (IH, d, J2.62 Hz), 7.50 (2H, d, J4.42 Hz), 7.34 (IH, t, J 9.09 Hz), 7.10 (IH, d, J4.34 Hz), 6.68 (IH, d, J4.34 Hz), 5.84-5.76 (IH, m), 3.95-3.30 (8H, m), 2.57 (3H, d, J2.26 Hz), 1.59 (3H, d, J 6.68 Hz). LCMS (ES+) 51 1 (M+H)⁺, RT 3.84 minutes (Method 2).

EXAMPLE 31

N- IY 1 S)- 1 - { 7-Fluoro- 8 -methyl-2- |^"4-(pyridin-3 - vDpiperazin- 1 -yl] quinolin-3 - yl > ethyll - pyrrolo [2, 1 -f] \ 1 ,2,4^~|triazin-4-amine

Following the procedure describedfor Example 30, Intermediate 9 (500 mg, 1.48 mmol) and l-(pyridin-3-yl)piperazine (482 mg, 2.95 mmol) gave the corresponding amine intermediate (220 mg, 41%). A portion of this intermediate (60 mg, 0.16 mmol) and 4-bromopyrrolo[2,l-/][l,2,4]triazine (38 mg, 0.19 mmol) afforded the title compound (7.5 mg, 10%) as a brown solid. δ_Η (DMSO-d₆) 8.64 (IH, d, J 7.27 Hz), 8.42 (IH, d, J 2.92 Hz), 8.34 (IH, s), 8.06 (IH, d, J4.53 Hz), 7.91 (IH, s), 7.79 (IH, dd, J 8.94, 6.27 Hz), 7.67 (IH, s), 7.43 (IH, dd, J 8.48, 2.83 Hz), 7.37-7.22 (2H, m), 7.13 (IH, s), 6.69 (IH, dd, J4.36, 2.61 Hz), 5.91-5.77 (IH, m), 3.87-3.79 (2H, m), 3.54-3.30 (6H, m), 2.59 (3H, d, J 2.24 Hz), 1.60 (3H, d, J 6.66 Hz). LCMS (ES+) 483 (M+H)⁺, RT 4.15 minutes (Method 1).

EXAMPLE 32

N- \(\S)-\ - {7-Fluoro-8-methyl-2- \4-( 1 ,3 -thiazol -2 -vDpiperazin- 1 -yl] quinolin-3 - yl } ethyl]pyrrolo [2, 1 - [ 1 ,2,4]triazin-4-amine

Following the procedure described for Example 30, Intermediate 9 (500 mg, 1.48 mmol) and 2-(piperazin-l-yl)thiazole (500 mg, 2.95 mmol) gave the corresponding amine intermediate (330 mg, 47%). A portion of this intermediate (60 mg, 0.16 mmol) and 4- bromopyrrolo[2,l-/] [l ,2,4]triazine (38 mg, 0.19 mmol) afforded the title compound (27 mg, 34%) as a beige solid. δ_Η (DMSO-d₆) 8.65 (IH, d, J7.24 Hz), 8.34 (IH, s), 7.91 (IH, s), 7.80 (IH, dd, J 8.94, 6.27 Hz), 7.67 (IH, d, J2.62 Hz), 7.34 (IH, t, J 9.1 1 Hz), 7.25 (IH, d, J3.61 Hz), 7.12 (IH, dd, J4.37, 1.60 Hz), 6.93 (IH, d, J3.61 Hz), 6.69 (IH, dd, J 4.35, 2.61 Hz), 5.87-5.78 (IH, m), 3.82-3.69 (4H, m), 3.65-3.57 (2H, m), 3.34- 3.26 (2H, m), 2.58 (3H, d, J 2.26 Hz), 1.60 (3H, d, J 6.67 Hz). LCMS (ES+) 489 (M+H)⁺, RT 4.34 minutes {Method I).

EXAMPLE 33

4-{7-Fluoro-8-methyl-3- fl^-l-(pyrrolor2 - iri,2^1triazin-4-ylamino ethyl1quinolin-2- yl)piperazine-2-carboxamide

Following the procedure for Example 30, Intermediate 9 (500 mg, 1.48 mmol) and piperazine-2-carboxamide (388 mg, 3.0 mmol) gave the corresponding amine

intermediate (270 mg, 55%) as a 1 :1 mixture of diastereoisomers. This intermediate (270 mg, 0.81 mmol) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (160 mg, 0.81 mmol) afforded the title compound (11 mg, 3%) as a beige solid. δ_Η (CDC1₃) 8.11 (IH, s), 7.88 (IH, d, J 5.23 Hz), 7.55-7.51 (2H, m), 7.19-7.12 (2H, m), 6.65-6.80 (2H, m), 6.00-5.45 (2H, m), 3.67-2.97 (7H, m), 2.61 (3H, s), 1.70 (3H, t, J 6.52 Hz). LCMS (ES+) 449 (M+H)⁺, RT 2.85 minutes (Method I).

EXAMPLE 34

N- IY 1 SD- 1 - { 7-Fluoro-8-methyl-2- r4-(methylsulfonyl piperazin- 1 -yl] quinolin-3 -yl} ethyl]- pyrrolo[2,l- ][L2,41triazin-4-amine

Following the procedure described for Example 30, Intermediate 9 (500 mg, 1.48 mmol) and l-(methylsulfonyl)piperazine (500 mg, 3.0 mmol) gave the corresponding amine intermediate (54 mg, 10%). This intermediate (54 mg, 0.15 mmol) and 4-bromo- pyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) afforded the title compound (36 mg, 50%) as a beige solid. δ_Η (DMSO-d₆) 8.65 (IH, d, J7.34 Hz), 8.34 (IH, s), 7.93 (IH, s), 7.80 (IH, dd, J8.91, 6.31 Hz), 7.66 (IH, t, J 1.91 Hz), 7.34 (IH, t, J9.12 Hz), 7.11 (IH, dd, J4.36, 1.53 Hz), 6.68 (IH, dd, J4.32, 2.64 Hz), 5.82-5.74 (IH, m), 3.77 (2H, t, J 8.60 Hz), 3.48-3.41 (2H, m), 3.35-3.20 (4H, m), 2.99 (3H, s), 2.58 (3H, d, J2.17 Hz), 1.58 (3H, d, J 6.70 Hz). LCMS (ES+) 484 (M+H)⁺, RT 3.75 minutes (Method I). EXAMPLE 35

N-IYISVI- ί 7-Fluoro-8-methyl-2- r4-r2,2,2-trifluoroethyl)piperazin- 1 -yll quinolin-3 -yl I - ethyllpyrrolo [2, 1 -f] \ 1 ,2,4]triazin-4-amine

Following the procedure described for Example 30, Intermediate 9 (500 mg, 1.48 mmol) and l-(2,2,2-trifluoroethyl)piperazine (500 mg, 2.95 mmol) gave the

corresponding amine intermediate (170 mg, 31%). A portion of this intermediate (77 mg, 0.21 mmol) and 4-bromopyrrolo[2,l-/J[l,2,4]triazine (50 mg, 0.25 mmol) afforded the title compound (43 mg, 42%) as an off-white solid. δ_Η (DMSO-d₆) 8.61 (IH, d, J7.24 Hz), 8.30 (IH, s), 7.88 (IH, s), 7.77 (IH, dd, J 8.92, 6.31 Hz), 7.66 (IH, d, J2.58 Hz), 7.31 (IH, t, J9.12 Hz), 7.1 1 (IH, dd, J4.36, 1.56 Hz), 6.68 (IH, dd, J4.35, 2.61 Hz), 5.81-5.72 (IH, m), 3.71-3.63 (2H, m), 3.33-3.22 (2H, m), 3.19-3.11 (2H, m), 2.99-2.92 (2H, m), 2.87-2.80 (2H, m), 2.58 (3H, s), 1.58 (3H, d, J 6.70 Hz). LCMS (ES+) 488 (M+H)⁺, RT 4.39 minutes {Method 1).

EXAMPLE 36

N- \( 1 S)- 1 - {7-Fluoro-8-methyl-2- |^"4-(prop-2-yl)piperazin- 1 -yl] quinolin-3 -yl ) ethyll - pyrrolo [2, 1 -f] \ 1 ,2,41triazin-4-amine

Following the procedure described for Example 30, Intermediate 9 (500 mg, 1.48 mmol) and 1 -isopropylpiperazine (379 mg, 3.0 mmol) gave the corresponding amine intermediate (345 mg, 71%). A portion of this intermediate (70 mg, 0.21 mmol) and 4- bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) afforded the title compound (33 mg, 35%) as an off-white solid. δ_Η (DMSO-d₆) 8.57 (IH, d, J 7.28 Hz), 8.28 (IH, s), 7.88 (IH, s), 7.77 (IH, dd, J 8.90, 6.34 Hz), 7.66 (IH, d, J2.57 Hz), 7.30 (IH, t, J9.13 Hz), 7.11 (IH, d, J4.35 Hz), 6.67 (IH, dd, J4.34, 2.62 Hz), 5.84-5.75 (IH, m), 3.67-3.59 (2H, m), 3.17-3.09 (2H, m), 2.77-2.69 (3H, m), 2.66-2.59 (2H, m), 2.58 (3H, s), 1.58 (3H, d, J 6.69 Hz), 1.05 (6H, d, J 6.49 Hz). LCMS (ES+) 448 (M+H)⁺, RT 2.35 minutes {Method 2). EXAMPLE 37

N-r(lS -l-l2-r(^,3i?,5S)-3.5-Dimethylpiperazin-l-yll-7-fluoro-8-methylquinoU^ ethyllpyrrolol 1 -f] [1 ,2,41triazin-4-amine

Following the procedure described for Example 30, Intermediate 9 (500 mg, 1.48 mmol) and (2S,6i?)-2,6-dimethylpiperazine (340 mg, 3.0 mmol) gave the corresponding amine intermediate (402 mg, 86%). A portion of this intermediate (66 mg, 0.21 mmol) and 4-bromopyrrolo[2,l- J[l,2,4]triazine (50 mg, 0.25 mmol) afforded the title compound (19 mg, 21%) as an off-white solid. δ_Η (DMSO-d₆) 8.62 (IH, d, J7.44 Hz), 8.33 (IH, d, J 3.75 Hz), 7.88 (IH, s), 7.77 (IH, dd, J 8.91, 6.35 Hz), 7.67 (IH, dd, J2.58, 1.57 Hz), 7.30 (IH, t, J9.13 Hz), 7.11 (IH, dd, J4.36, 1.55 Hz), 6.68 (IH, dd, J4.35, 2.62 Hz), 5.82- 5.74 (IH, m), 3.96 (IH, d, J 12.08 Hz), 3.55-3.48 (2H, m), 3.19-3.10 (IH, m), 3.06-2.96 (IH, m), 2.79-2.69 (IH, m), 2.56 (3H, d, J2.29 Hz), 2.22 (IH, t, J 11.12 Hz), 1.56 (3H, d, J 6.67 Hz), 1.10 (3H, d, J 6.26 Hz), 0.90 (3H, d, J 6.27 Hz). LCMS (ES+) 434 (M+H)⁺, RT 2.34 minutes {Method 2).

EXAMPLE 38

N-{(lS)-l-[7-Fluoro-8-methyl-2-(piperazin-l-yl)quinolin-3-yllethyl)pyrrolor2,l- ]- Γ1 ,2,4]triazin-4-amine

Intermediate 23 (540 mg, 1.5 mmol) in NMP (4 niL) was treated with piperazine (1.3 g, 15.0 mmol) and heated in a sealed tube at 110°C for 16 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (150 mL). The organic layer was washed with water (2 x 30 mL) and brine (30 mL), then dried (phase separation cartridge) and concentrated in vacuo to give the title compound (600 mg, 97%) as a beige solid, δκ (CDC1₃) 8.56 (IH, s), 8.04 (IH, s), 7.86 (IH, s), 7.57 (IH, t, J 1.91 Hz), 7.51 (IH, dd, J 8.89, 5.96 Hz), 7.17 (IH, t, J 8.96 Hz), 6.69-6.63 (2H, m), 5.73 (IH, t, J 6.71 Hz), 5.63 (IH, br s), 3.87 (2H, t, J 11.42 Hz), 3.50-3.39 (4H, m), 3.33-3.24 (2H, m), 2.61 (3H, d, J 2.30 Hz), 1.60 (3H, s). LCMS (ES+) 406 (M+H)⁺, RT 2.32 minutes (Method 2). EXAMPLE 39

N-((lS -l-r2-(l^-Dioxa-8-azaspiror4.51dec-8-ylV7-fluoro-8-methylquinolin-3-yllethv^ pyrrolo|^"2, 1 -/] Γ1 ,2,41triazin-4-amine

Intermediate 23 (480 mg, 1.3 mmol) and l,4-dioxa-8-azaspiro[4.5]decane (780 mg, 5.2 mmol) in NMP (4 mL) were heated in a sealed tube at 130°C for 16 h. The reaction mixture was purified by column chromatography (Si0₂, 10-30% EtOAc in isohexane) to give the title compound (280 mg, 45%) as an off-white solid, δκ (CDC1₃) 7.99 (IH, s), 7.90 (IH, s), 7.56 (IH, dd, J2.62, 1.48 Hz), 7.49 (IH, dd, J 8.87, 6.10 Hz), 7.13 (IH, t, J 8.99 Hz), 6.67-6.59 (2H, m), 5.84-5.71 (2H, m), 4.02 (4H, s), 3.70-3.62 (2H, m), 3.37-3.29 (2H, m), 2.60 (3H, d, J2.38 Hz), 2.06-1.98 (2H, m), 1.94-1.86 (2H, m), 1.62 (3H, s). LCMS (ES+) 463 (M+H)⁺, RT 4.90 minutes (Method 2).

EXAMPLE 40

4-{7-Ρ1ηοΓθ-8^6Φν1-3-Γ(Ί^ -1- ρνιτο1οΓ2, 1 -f] rL2,41triazin-4-ylamino ethvnquinolin-2- yl Ipiperazine- 1 -carboxamide

Example 38 (100 mg, 0.25 mmol), trimethylsilyl isocyanate (37 mg, 0.32 mmol) and triethylamine (75 mg, 0.75 mmol) in DCM were stirred at r.t. for 16 h. The solid precipitate which formed was filtered, washed with Et₂0 and dried to give the title compound (60 mg, 54%) as a white solid. δ_Η (DMSO-d₆) 8.61 (IH, d, J7.33 Hz), 8.33 (IH, s), 7.90 (IH, s), 7.79 (IH, dd, J 8.94, 6.31 Hz), 7.67 (IH, dd, J2.59, 1.57 Hz), 7.33 (IH, t, J9.12 Hz), 7.11 (IH, dd, J4.36, 1.56 Hz), 6.68 (IH, dd, J4.36, 2.61 Hz), 6.06 (2H, s), 5.83-5.77 (IH, m), 3.66-3.54 (4H, m), 3.50-3.42 (2H, m), 3.08 (2H, t, J 8.70 Hz), 2.58 (3H, s), 1.59 (3H, d, J 6.69 Hz). LCMS (ES+) 449 (M+H)⁺, RT 3.79 minutes (Method 2).

EXAMPLE 41 1 -(4- { 3 - IY 1 S)- 1 -( 6-Chloroimidazo Γ 1 ,2-blpyridazin-8-ylamino ethyl1 -7-fluoro-8-methyl- quinolin-2-yl)piperazin-l-yl)ethanone

Intermediate 21 (800 mg, 2.42 mmol) and 8-bromo-6-chloroimidazo[l,2- >]- pyridazine (670 mg, 2.8 mmol) in NMP (8 mL) were treated with DIPEA (1.4 g, 11 mmol) and heated at 120°C under microwave irradiation for 1 h. The reaction mixture was partitioned between water (25 mL) and EtOAc (150 mL). The organic layer was washed with water (25 mL) and brine (25 mL), then dried (phase separation cartridge) and concentrated in vacuo. Purification by column chromatography (Si0₂, 20% EtOAc in isohexane) gave the title compound (400 mg, 38%) as a white solid, δπ (CDC1₃) 8.13 (IH, s), 7.69 (IH, s), 7.52 (IH, dd, J8.92, 6.04 Hz), 7.46 (IH, s), 7.17 (IH, t, J9.01 Hz), 6.48 (IH, d, J6.64 Hz), 6.28 (IH, s), 5.08-5.00 (IH, m), 4.10-4.02 (IH, m), 3.95-3.70 (3H, m), 3.46-3.18 (4H, m), 2.61 (3H, d, J2.34 Hz), 2.21 (3H, s), 1.83 (3H, d, J6.80 Hz). LCMS (ES+) 482/484 (M+H)⁺, RT 4.22 minutes {Method 2).

EXAMPLE 42

1 -(4- { 7-Fluoro-3 - 1^"( 1 S)- 1 -(imidazo |^" 1 ,2-&1pyridazin-8-ylamino ethyll -8-methylquinolin-2- yl Ipiperazin- 1 -vDethanone

Example 41 (100 mg, 0.2 mol) in EtOH (20 mL) was treated with 10% palladium on carbon (100 mg) and the mixture was shaken under a 20 psi pressure of hydrogen gas for 20 h. The catalyst was removed by filtration and a further 100 mg of 10% palladium on carbon added. The mixture was hydrogenated for a further 16 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (2.8 mg, 3%) as a white solid. 5H (DMSO- d₆) 8.56 (IH, s), 8.01-7.96 (2H, m), 7.94-7.85 (IH, m), 7.72 (IH, dd, J 8.92, 6.29 Hz), 7.53 (IH, s), 7.31 (IH, t, J9.13 Hz), 6.17 (IH, d, J 5.64 Hz), 5.10 (IH, br s), 3.83-3.67 (4H, m), 3.35-3.20 (4H, m), 2.56 (3H, s), 2.12 (3H, s), 1.81 (3H, d, J6.66 Hz). LCMS (ES+) 448 (M+H)⁺, RT 3.23 minutes {Method 1).

Claims

Claims:

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

(I) wherein

Y represents Ν or C-R⁷;

X represents Ν or C-R⁸ ;

E represents an optionally substituted straight or branched C_1-4 alkylene chain; Q represents oxygen, sulfur, N-R⁹ or a covalent bond;

M represents the residue of an optionally substituted saturated five-, six- or seven- membered monocyclic ring containing one nitrogen atom and 0, 1 , 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom;

W represents C-R¹⁰ or N;

R , R and R independently represent hydrogen, halogen, cyano, nitro, C_1- alkyl, trifluoromethyl, aryl(C_1-6)alkyl, hydroxy, C_1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, amino, C_1-6 alkylamino, di(C_1-6)alkyl- amino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxy carbonyl, aminocarbonyl, C_1-6

alkylaminocarbonyl, di(C_1-6)alkylaminocarbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl or di(Ci_-6)alkylaminosulfonyl; R⁴, R⁵, R⁶, R⁷ and R⁸ independently represent C_1-6 alkyl, aryl, aryl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1- )alkyl, any of which groups may be optionally substituted by one or more substituents; or hydrogen, halogen, trifluoromethyl, -OR^a, -SR^a, -SOR^a, -S0₂R^a, -NR^bR^c, -NR^cCOR^d, -NR^cC0₂R^d, -NR^cS0₂R^e, -COR^d, -C0₂R^d, -CONR^bR° or -S0₂NR^bR^c;

R⁹ represents hydrogen or C_1-6 alkyl;

R¹⁰ represents hydrogen, halogen, C_1-6 alkyl or C_1-6 alkoxy;

R^a represents C_1-6 alkyl, difluoromethyl or trifluoromethyl;

R^b represents hydrogen or trifluoromethyl; or C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(C_1-6)alkyl, C_3- 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;

R^c represents hydrogen, C_1-6 alkyl or C_3-7 cycloalkyl;

R^d represents hydrogen or C_1-6 alkyl; and

R^e represents C_1-6 alkyl.

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

(HA) wherein E, Q, M, R¹, R² and R⁴ are as defined in claim 1.

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

(IB) wherein E, Q, M, R¹, R² and R⁴ are as defined in claim 1.

4. A compound as claimed in any one of the preceding claims wherein M represents the residue of a monocyclic ring selected from pyrrolidin-l-yl, piperidin-l-yl and piperazin-l-yl, any of which rings may be optionally substituted by one or more substituents independently selected from C_1-6 alkyl, heteroaryl, C_1-3 alkylenedioxy, Ci_-6 alkylsulphonyl, hydroxy, hydroxy(C_1-6)alkyl, trifluoroethyl, oxo, C_2-6 alkylcarbonyl, hydroxy(C_1- )alkylcarbonyl, di(C_1-6)alkylamino(C_1-6)alkylcarbonyl, heteroarylcarbonyl, carboxy, carboxy(Ci_-6)alkyl, C_2-6 alkoxycarbonyl(Ci_-6)alkyl, hydroxy(Ci_-6)alkylcarbonyl- amino, (C_1-6)alkylcarbonylamino(C_1-6)alkyl, (C_3-7)cycloalkylcarbonylamino,

aminocarbonyl, aminocarbonyl(C_1-6)alkyl, C_1-6 alkylaminocarbonyl and (C_1-6)alkyl- aminocarbonyl(C_1- )alkyl.

5. A compound as claimed in any one of claims 1 to 3 wherein the moiety of which M is the residue is selected from 3-(hydroxyacetylamino)pyrrolidin-l-yl, 3- (cyclopropylcarbonylamino)pyrrolidin- 1 -yl, 3 -(acetylaminomethyl)pyrrolidin- 1 -yl, 1 ,4- dioxa- 8 -azaspiro [4.5 ] dec- 8 -yl, 4-hydroxypiperidin- 1 -y 1, 4-carboxypiperidin- 1-yl, 4-

(aminocarbonyl)piperidin- 1 -yl, 4-(methylaminocarbonyl)piperidin- 1 -yl, piperazin- 1 -yl, 3,5-dimethylpiperazin-l-yl, 4-(isopropyl)piperazin-l-yl, 4-(thiazol-2-yl)piperazin-l-yl, 4- (pyridin-3-yl)piperazin- 1 -yl, 4-(methylsulphonyl)piperazin- 1 -yl, 4-(2-hydroxyethyl)- piperazin-l-yl, 4-(2,2,2-trifluoroethyl)piperazin-l-yl, 3-oxopiperazin-l-yl, 4-acetyl- piperazin- 1 -yl, 4-(hydroxyacetyl)piperazin- 1 -yl, 4-(dimethylaminoacetyl)piperazin- 1 -yl, 4-(pyridin-4-ylcarbonyl)piperazin- 1 -yl, 4-(carboxymethyl)piperazin- 1 -yl, 4-(ethoxy- carbonylmethyl)piperazin- 1 -yl, 3 -(aminocarbonyl)piperazin- 1 -yl, 4-(aminocarbonyl)- piperazin- 1 -yl, 4-(aminocarbonylmethyl)piperazin- 1 -yl, 4-(methylaminocarbonyl)- piperazin-l-yl and 4-(methylaminocarbonylmethyl)piperazin-l-yl.

6. A compound as claimed in any one of the preceding claims wherein E represents methylene or (methyl)methylene.

7. A compound as claimed in any one of the preceding claims wherein Q represents N-R⁹, in which R⁹ is as defined in claim 1.

8. A compound as claimed in any one of the preceding claims wherein R¹ represents hydrogen, halogen or C_1-6 alkyl.

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

10. A compound as claimed in any one of the preceding claims wherein R⁴ represents hydrogen, halogen, C_1-6 alkyl, -SR^a, -S0₂R^a or -NR^bR^c, in which R^a, R^b and R° 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 iV-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 N-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 PI3K inhibitor is indicated.

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