WO2009063240A1

WO2009063240A1 - 2,4-diaminopyrimidine derivatives useful as inhibitors of aurora kinase

Info

Publication number: WO2009063240A1
Application number: PCT/GB2008/051058
Authority: WO
Inventors: Richard Martyn Angell; Robert Alan Harris; Richard Kelsey; James Lumley; Andrew Slatter
Original assignee: Arrow Therapeutics Limited
Priority date: 2007-11-16
Filing date: 2008-11-13
Publication date: 2009-05-22

Abstract

A 2,4-diaminopyrimidine derivative of the formula (I), or a pharmaceutically acceptable salt thereof, formula (I) wherein R1, R2, R3, R4, X and Y are as defined in the specification; together with processes for their preparation; pharmaceutical compositions containing them; and their use in therapy. The compounds are inhibitors of Aurora kinase.

Description

2,4-DIAMINOPYRIMIDINE DERIVATIVES USEFUL AS INHIBITORS OF AURORA KINASE

The present invention relates to a series of 2,4-diaminopyrimidine derivatives which are active in inhibiting Aurora kinase, such as Aurora A kinase.

Aurora kinase proteins are key mitiotic regulators required for genome stability. Aurora-A is known to have an important role in tumour formation or progression, and is an established target for anticancer drug development. The compounds of the present invention are therefore therapeutically useful in the treatment or prevention of proliferative disease such as cancer.

The present invention therefore provides a 2,4-diaminopyrimidine derivative of the formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

R¹ represents hydrogen, C₁-C₆ alkyl, Ci-C₄ haloalkyl, C₆-CiO aryl, 5- to 10- membered heteroaryl, hydroxy, -NR⁷R⁷⁷ or -CO₂R⁷ wherein each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl;

R represents hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or -(Ci-C₄ alkylene)-X, wherein X represents cyano, nitro, -CO₂R⁷, -CO-NR⁷R⁷⁷, C₆-Ci₀ aryl, 5- to 10- membered heteroaryl, -CO-(Co-CiO aryl) or -CO-(5- to 10- membered heteroaryl) wherein each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl; R³ represents hydrogen, C₁-C₆ alkyl, C₁-C₄ haloalkyl, halogen, nitro, cyano, hydroxy, C₁-C₄ alkoxy or -NR⁷R⁷⁷ wherein each R¹ and R¹¹ is the same or different and represents hydrogen or Ci-C₄ alkyl; R⁴ represents hydrogen or Ci-C₄ alkyl; and - either X is CH and Y is N, or Y is CH and X is N; the aryl and heteroaryl moieties in R¹ and R² being unsubstituted or substituted by 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C₁-C₆ alkyl, C₁-C₆ alkoxy, and Ci-C₄ haloalkyl substituents.

As used herein, a C₁-C₆ alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example 1 to 4 carbon atoms.

Examples Of C₁-C₆ alkyl groups and moieties include Ci-C₄ alkyl groups and moieties, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl, preferably methyl. For the avoidance of doubt, where two alkyl moieties are present in a group, the alkyl moieties may be the same or different. As used herein, a Ci-C₄ alkylene group or moiety is a linear or branched alkylene group or moiety. Examples include methylene, n-ethylene and n-propylene groups and moieties. Methylene and n-propylene groups are preferred.

As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine. As used herein, a Ci-C₄ alkoxy group is typically a said Ci-C₄ alkyl group attached to an oxygen atom.

A haloalkyl group is typically a said alkyl substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl groups are -(Ci-C₄ alkylene)-CF₃ groups. Other preferred haloalkyl groups are perhaloalkyl groups such as -CX₃ wherein X is a said halogen atom, for example chlorine and fluorine. A particularly preferred haloalkyl group is -CF₃.

As used herein, a 5- to 10- membered heteroaryl group or moiety is a 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl and pyrazolyl groups. Pyridyl groups are preferred. For the avoidance of doubt, although the above definition of heteroaryl groups refers to an "N" moiety which can be present in the ring, as will be evident to a skilled chemist the N atom will be protonated (or will carry a substitutent as defined above) if it is attached to each of the adjacent ring atoms via a single bond. As used herein, a Cβ-Cio aryl group is preferably a phenyl or naphthyl group.

Preferably, it is a phenyl group.

Typically, the aryl and heteroaryl moieties in R*and R² are unsubstituted or substituted by 1 or 2 unsubstituted Ci-C₄ alkyl substituents which are the same or different. Preferably, the aryl and heteroaryl moieties in R¹ and R² are unsubstituted or substituted with a single unsubstituted methyl or ethyl group.

For the avoidance of doubt, R¹ can be attached to the benzimidazole/indazole moiety at any position. Typically, however, it is attached on the 5-membered ring. Preferably, R¹ is attached at the 1- or 2- position of the benzimidazole/indazole moiety.

Typically, when R¹ is attached to a N atom in the benzimidazole/indazole ring, it is other than hydroxy and -NR⁷R⁷⁷. Preferably, when R¹ is attached to a N atom in the benzimidazole/indazole ring, it is other than hydroxy, -NR⁷R⁷⁷ and Ci-C₄ haloalkyl. Most preferably, when R¹ is attached to a N atom in the benzimidazole/indazole ring, it is Cβ-Cio aryl or -CO₂R⁷.

Typically, R¹ represents hydrogen, Ci-C₄ haloalkyl, C₁-C₆ alkyl, phenyl, hydroxy or -CO₂-R⁷, wherein R⁷ is Ci-C₄ alkyl.

Preferably, R¹ is hydrogen, C₁-C₂ haloalkyl, Ci-C₂ alkyl, phenyl, hydroxy or -CO₂-(Ci-C₄ alkyl). Most preferably, R¹ is hydrogen, -CF₃, phenyl, hydroxy or -CO₂-(Ci-C₂ alkyl).

Preferably, when R¹ is a phenyl group it is unsubstituted or substituted by a methyl group.

Typically, R² represents hydrogen, C₁-C₆ alkyl or -(Ci-C₄ alkylene)-X⁷, wherein X⁷ represents -CF₃, cyano, -CO₂R⁷, -CO-NR⁷R⁷⁷, phenyl, 5- to 6- membered heteroaryl, -CO-phenyl or -C0-(5- to 6- membered heteroaryl), wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or Ci-C₄ alkyl. Preferably, R² represents hydrogen, Ci-C₄ alkyl or -(Ci-C₄ alkylene)-X⁷, wherein X⁷ represents -CF₃, cyano, -CO₂-(Ci-C₄ alkyl), -CO-NR⁷R⁷⁷, phenyl, pyridyl, -CO-phenyl or -CO-pyridyl, wherein R¹ and R¹¹ are the same or different and each represent hydrogen or Ci-C₄ alkyl.

Most preferably, R² represents hydrogen, Ci-C₄ alkyl or -(Ci-C₄ alkylene)-X^/, wherein X¹ represents -CF₃, cyano, -CO₂-(Ci-Ci alkyl), -CO-NH₂, -CO-phenyl or pyridyl.

Typically, the aryl and heteroaryl moieties in R² are unsubstituted.

Preferably, R³ is attached at the 5- position of the pyrimidine ring (i.e. at the carbon atom adjacent to the -NR²- moiety).

Typically, R > 3 i ^•s hydrogen, Ci-C₄ alkyl, Ci-C₂ haloalkyl, halogen, nitro, hydroxy or

-NH₉.

Preferably, R³ is hydrogen, bromine, Ci-C₂ alkyl, -CF₃, nitro or -NH₂. Preferably, R⁴ is hydrogen.

Within the present invention it is to be understood that a compound of formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric forms or mixtures thereof which has Aurora kinase inhibitory activity such as Aurora-A kinase inhibitory activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.

For example, where X is CH, Y is N and R¹ is a hydroxy group at the 2-position of the benzimidazole moiety, the compounds of the invention can adopt the following tautomeric form:

wherein R², R³ and R⁴ are as defined above. Similarly, when X is CH, Y is N and the nitrogen atoms of the benzimidazole moiety are unsubstituted, the compounds of the invention can adopt the following tautomeric form:

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

Preferably, in the formula (I⁷⁷), R¹ is Ci-C₂ haloalkyl, more preferably -CF₃. Preferred compounds of the invention are the 2,4-diaminopyrimidines of formula (I), the tautomers thereof and the pharmaceutically acceptable salts thereof, in which: R¹ is hydrogen, Ci-C₄ haloalkyl, C₁-C₆ alkyl, phenyl, hydroxy or

-CO₂-R⁷, wherein R⁷ is Ci-C₄ alkyl, provided that when R¹ is attached via a N atom it is other than hydroxy;

R² is hydrogen, C₁-C₆ alkyl or -(Ci-C₄ alkylene)-X', wherein X' represents -CF₃, cyano, -CO₂R⁷, -CO-NR⁷R⁷⁷, phenyl, 5- to 6- membered heteroaryl, -CO-phenyl or -CO-(5- to 6- membered heteroaryl), wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or Ci-C₄ alkyl; R³ is hydrogen, C₁-C₄ alkyl, Ci-C₂ haloalkyl, halogen, nitro, hydroxy or -NH₂; R⁴ is hydrogen; and - either X is CH and Y is N, or Y is CH and X is N, the phenyl and heteroaryl groups in R¹ and R² being unsubstituted or substituted with 1 or 2 unsubstituted C₁-C₄ alkyl substituents which are the same or different.

Further preferred compounds of the invention are the 2,4-diaminopyrimidine derivatives of formula (Ia), the tautomers thereof and the pharmaceutically acceptable salts thereof

wherein:

R¹ is attached at the 1- or 2- position of the benzimidazole/indazole ring, and is hydrogen, -CF₃, phenyl, hydroxy or -CO₂-(Ci-C₂ alkyl), the phenyl group being unsubstituted or substituted by a methyl group, provided that when R¹ is attached to a N atom it is other than hydroxy and -CF₃;

R² is hydrogen, Ci-C₄ alkyl or -(Ci-C₄ alkylene)-X^/, wherein X¹ represents -CF₃, cyano, -CO₂-(Ci-C₂ alkyl), -CO-NH₂, -CO-phenyl or pyridyl, the phenyl and pyridyl groups in R² being unsubstituted; R³ is hydrogen, bromine, Ci-C₂ alkyl, -CF₃, nitro or -NH₂; and; - either X is CH and Y is N, or Y is CH and X is N.

Typically, said tautomers of the compounds of formula (Ia) are compounds of formula (Ia⁷) or (Ia^/A)

wherein R¹, R² and R³ are as defined in the formula (Ia). Particular compounds of formula (I) include: 5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-(2- trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-(lH-indazol-

5-yl)-pyrimidine-2,4-diamine; N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-fluoro-N*4*-

( 1 H-indazol- 5 -y 1) -pyrimidine-2,4- diamine ;

5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-

( 1 H-indazol- 5 -y 1) -pyrimidine-2,4- diamine ;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-(2- trifluoromethyl- lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*4*-(lH-Benzoimidazol-5-yl)-5-bromo-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*- benzo[c]thiophen-5-yl)-pyrimidine-2,4-diamine;

5-[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-5-nitro- pyrimidin-4-ylamino]-l,3-dihydro-benzoimidazol-2-one; N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-nitro-N*4*-(2- trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

4-tert-Butyl-N-{5-[2-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-lH-indazol-3-yl}-benzamide;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-methyl-N*4*-(2- trifluoromethyl- lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-propyl-N*4*-(2- trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-thiophen-2-yl-

N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine; 5-Chloro-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-(2- trifluoromethyl-3H-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-fluoro-N*4*-(2- trifluoromethyl-3H-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

4-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-pyrimidin-4- yl]-(lH-indazol-5-yl)-amino]-butyric acid;

4-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-pyrimidin-4- yl]-(lH-indazol-5-yl)-amino]-butyric acid methyl ester; 4-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-pyrimidin-4- yl]-(lH-indazol-5-yl)-amino]-butyronitrile;

5-yl)-N*4*-(4,4,4-trifluoro-butyl)-pyrimidine-2,4-diamine; 2-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-pyrimidin-4- yl]-(lH-indazol-5-yl)-amino]-l-phenyl-ethanone;

[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-pyrimidin-4- yl]-(lH-indazol-5-yl)-amino]-acetic acid methyl ester;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-(lH-indazol- 5-yl)-N*4*-methyl-pyrimidine-2,4-diamine;

5-yl)-N*4*-prop-2-ynyl-pyrimidine-2,4-diamine;

5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-

(lH-indazol-5-yl)-N*4*-methyl-pyrimidine-2,4-diamine; 5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*- ethyl-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-fluoro-N*4*-

(lH-indazol-5-yl)-N*4*-methyl-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-ethyl-5- fluoro-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine;

[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-5-fluoro- pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-acetonitrile;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-ethyl-N*4*-

( 1 H-indazol- 5 -y 1) -pyrimidine-2,4- diamine ; [[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-pyrimidin-4- yl]-(lH-indazol-5-yl)-amino]-acetonitrile;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-fluoro-N*4*- methyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-fluoro-N*4*- isopropyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-fluoro-N*4*- isobutyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine; N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-(lH-indazol-

5-yl)-N*4*-pyridin-2-ylmethyl-pyrimidine-2,4-diamine;

N*4*-Benzyl-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-

N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine; 2-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)-pyrimidin-4- yl]-(lH-indazol-5-yl)-amino]-acetamide;

5-[5-Amino-2-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)- pyrimidin-4-ylamino]-indazole-l-carboxylic acid methyl ester;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-trifluoromethyl- N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine;

N*4*-(6,7-Difluoro-2-trifluoromethyl-lH-benzoimidazol-5-yl)-N*2*-(2,2-dioxo-2,3- dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-trifluoromethyl-pyrimidine-2,4- diamine;

N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-N*4*-(6-fluoro-2- trifluoromethyl-lH-benzoimidazol-5-yl)-5-trifluoromethyl-pyrimidine-2,4-diamine; and pharmaceutically acceptable salts of any one thereof.

Compounds were named using the software Autonom Standard Name, ISIS Draw version 2.4, MDL Information Services Inc. Corresponding molecular structures are included in the Examples section of the specification. Compounds of formula (I) containing one or more chiral centres may be used in enantiomeric ally or diastereoisomerically pure form, or in the form of a mixture of isomers. For the avoidance of doubt, the compounds of formula (I) can, if desired, be used in the form of solvates.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines. The compounds of the invention can, for example, be prepared by routes such as those outlined in Scheme 1.

For example, POCl₃, H₃PO₄, 1Pr₉EtN

VII For example,

BoC₂O, 0 1 eq DMAP

Scheme 1 The substituents in Scheme 1 have the same meaning as the substituents defined for formula I, although for the particular reagents exemplified, R represents Boc and L and

2 L each represent chloro. Compounds of general formula II can be purchased from commercial suppliers or synthesized using literature methods that will be readily apparent to the man skilled in the art.

The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises:

(a) reacting a compound of formula (V)

2 3 4 wherein L represents a leaving group (such as halogen) and R and R are as defined in formula (I), with an amine of formula (VI)

VI wherein X, Y, R , R and R are as defined in formula (I); or

(b) reacting a compound of formula (IV)

1 1 3 wherein L represents a leaving group and X, Y, R and R are as defined in formula (I), with an amine of formula (VII)

VII

4 wherein R is as defined in formula (I); or

(c) reacting a compound of formula (IX)

wherein L is a leaving group, R is a protecting group, and X, Y, R , R and R are as defined in formula (I), with an amine of formula (VII)

VII

4 wherein R is as defined in formula (I); ; and optionally after (a), (b) or (c) carrying out one or more of the following: • converting the compound obtained to a further compound of the invention • forming a pharmaceutically acceptable salt of the compound.

In processes (a), (b) and (c), the reagents may be stirred in the presence of an inorganic base exemplified but not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, or a non nucleophilic organic base exemplified by but not limited to pyridine, triethylamine, or sodium hydride, or an acid exemplified but not limited to hydrochloric acid, hydrobromic acid, /?-toluene sulfonic acid, acetic acid, triethylammonium hydrochloride, in an appropriate solvent or solvent mixture exemplified but not limited to methanol, ethanol, tetrahydrofuran, water and acetone. Alternative methodologies for achieving such aryl amination processes are described in the literature and will be readily understood by a person skilled in the art (see Hartwig, J. F., Angew. Chem. Int. Ed., 1998; 37; Buchwald, S. L., et al, Ace. Chem. Res., 1998, 31; Buchwald, S. L., et al., J. Org. Chem., 2000, 65; Buchwald, S. L., et al., Topics in Current Chemistry, 2002 and references sited therein). The reaction is normally continued until LCMS analysis indicates that the reaction is complete. Typical reaction temperatures for the reaction vary from 0 to 150 ⁰C, length of reaction time may vary from

5 minutes to 48 hours and heating may be either from a thermal or microwave source.

1 2

Suitable leaving groups L and L may be independently selected from S-alk, S-aryl, SO- alk, SO-aryl, SO₂-alk, SO₂-aryl, halogen, and triflate. In one embodiment, the leaving group is Cl.

Processes (a), (b) and (c), wherein X=Cl, are achieved, for example, by heating the appropriate reagents in a mixture of acetone, water and cone. HCl (150:100:1 v/v) at 85 ⁰C for 48 hours. Specific processes for the preparation of compounds of Formula (I) are disclosed within the Examples section of the present specification. Such processes form an aspect of the present invention.

Compounds of general formula V may be prepared by treating compounds of

1 2 general formula III wherein L and L represent leaving groups such as chloro, with an amine of general formula VII in the presence of a Lewis acid exemplified by but not limited to halide salts of zinc, titanium, iron, magnesium, tin or copper, in the presence of a suitable solvent or solvents, exemplified by but not limited to THF, 1,4-dioxane, tert- butanol, ¹PrOH, 1,2-dichloroethane and dichloromethane and a suitable base, including but not limited to non-nucleophilic organic bases, e.g. triethylamine or di-isopropylamine or inorganic bases such as potassium carbonate or cesium carbonate or resin bound bases such as MP-carbonate. In one embodiment, a compound of general formula III may be treated with an amine of general formula VII in the presence of ZnCl₂, triethylamine using tert-butanol and 1,2-dichloroethane as solvents at 0 ⁰C and allowing the reaction to warm to room temperature over 18 hours.

Compounds of general formula III are either commercially available or may be prepared from uracils of formula II using chlorinating methodologies exemplified by but not limited to oxalyl chloride, thionyl chloride, N-chlorosuccinimide/triphenylphosphine, phosphorous pentachloride, phosphorous oxychloride and oxalyl chloride/dimethyl formamide.

Compounds of general formula IV may be prepared by treating compounds of general formula III with amines of general formula VI in the presence of an inorganic base exemplified but not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium hydride and sodium hydride or non nucleophilic organic base exemplified by but not limited to pyridine, triethylamine, sodium hydride in an appropriate solvent exemplified but not limited to methanol, ethanol,

1 2 tetrahydrofuran, water and acetone. In one embodiment both L and L represent chloro and the base used is 5 eq. of sodium carbonate using ethanol as a solvent at room temperature for 18 hours. Compounds of general formula IX may be made by treating compounds of general formula VIII with suitable electrophiles in the presence of an inorganic or non-nucleophilic organic base; an aldehyde or its equivalent in the presence of acid, then reduction of the intermediate imine with an appropriate reducing group ('reductive animation'); an alcohol in the presence of triphenylphosphine and azadicarboxylate diester ('Mitsunobu reaction'). In one embodiment, an amine of general formula VIII is treated with excess alkyl bromide in the presence of cesium carbonate using dimethyl formamide as a solvent at 50 ⁰C for 5 days.

Compounds of general formula VIII may themselves be made from compounds of general formula IV by the addition of a suitable protecting group. In one embodiment, installation of a /-butoxycarbonyl (Boc) group using 1 equivalent of di-tert-butyl carbonate in dichloromethane in the presence of triethylamine and catalytic quantities of dimethylaminopyridine. In another embodiment, the methyl carbamate may be formed by treating a compound of general formula IV with methyl chloroformate in dichloromethane in the presence of triethylamine and dimethylaminopyridine.

Amines of general formula VI and VII are either commercially available or may be prepared by a person skilled in the art by methods that are well known in the literature.

The necessary starting materials are either commercially available, are known in the literature or may be prepared using known techniques. Specific processes for the preparation of certain key starting materials are disclosed within the Examples section of the present specification and such processes form an aspect of the present invention. Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.

Certain intermediates may be novel. Such novel intermediates form another aspect of the invention.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition and/or removal of one or more protecting groups.

The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 4th edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (2007). The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate orp-toluenesulphonate. The compounds of the present invention are therapeutically useful. The present invention therefore provides a 2,4-diaminopyrimidine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy. Also provided is a pharmaceutical composition comprising a 2,4-diaminopyrimidine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

Further provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound of formula (I), or a pharmaceutically acceptable salt thereof, is also provided for use in the treatment of a disease where the inhibition of one or more Aurora kinase is beneficial. In particular it is envisaged that inhibition of Aurora-A kinase may be beneficial. A compound of formula (I), or a pharmaceutically acceptable salt thereof, has further use in the treatment of hyperproliferative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic or bladder and renal cancer or leukemias or lymphomas.

Additionally a compound of formula (I), or a pharmaceutically acceptable salt thereof is provided for use in a method of treatment of a warm-blooded animal such as man by therapy. According to this aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the method of treating a human suffering from a disease in which the inhibition of one or more Aurora kinases is beneficial, comprising the steps of administering to a person in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular it is envisaged that inhibition of Aurora-A kinase may be beneficial. Further provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the method of treating a human suffering from a hyperproliferative disease such as cancer and in particular colorectal, breast, lung, prostate, pancreatic or bladder and renal cancer or leukemias or lymphomas, comprising the steps of administering to a person in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease where the inhibition of one or more Aurora kinase is beneficial. In particular it is envisaged that inhibition of Aurora-A kinase may be beneficial. In another aspect of the invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of hyperproliferative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic or bladder and renal cancer or leukemias or lymphomas. For the above mentioned therapeutic uses the dose administered will vary with the compound employed, the mode of administration, the treatment desired, the disorder indicated and the age and sex of the animal or patient. The size of the dose would thus be calculated according to well known principles of medicine.

In using a compound of formula (I) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.05 mg/kg to 50 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used.

The treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents :- (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine-threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), ./V-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-./V-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet- derived growth factor family and for example inhibitors of the hepatocyte growth factor family;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti- vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example, linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WOO 1/92224, WO02/04434 and WO02/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. In addition a compound of the invention may be used in combination with one or more cell cycle inhibitors. In particular with cell cycle inhibitors which inhibit bubl, bubRl or CDK.

Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically active agent within its approved dosage range.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 1-100 mg/kg, preferably 0.51-50 mg/kg is envisaged. In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.

Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free. Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer. The compounds of the invention have efficacy in alleviating or reducing the incidence of cancer. They are active against leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas. They can therefore be used to treat or prevent leukaemia, breast cancer, lung cancer, liver cancer, cancer of the colon, rectal cancer, stomach cancer, prostate cancer, cancer of the bladder, pancreatic cancer and ovarian cancer.

The present invention therefore provides the use of a compound of the invention in the manufacture of a medicament for use in the treatment or prevention of cancer. Also provided is a method of alleviating or reducing the incidence of cancer, which method comprises administering to a patient suffering from or susceptible to cancer a compound of the invention.

The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories. Preferably, they are administered parenterally.

The compounds of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.01 to 100 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the cancer and the frequency and route of administration. Preferably, daily dosage levels are from 0.05 to 16 mg per kg of body weight, more preferably, from 0.05 to 1.25 mg per kg of body weight. The following Examples illustrate the invention. They do not however, limit the invention in any way. In this regard, it is important to understand that the particular assay used in the Examples section is designed only to provide an indication of anti- Aurora A activity. There are many assays available to determine such activity, and a negative result in any one particular assay is therefore not determinative.

General Methods

1 13

H NMR and C NMR spectra were recorded on a Bruker Avance spectrometer at 250

MHz, and chemical shifts are reported in ppm relative to dg-DMSO or CDCI3. The central peaks of chloroform-d (dH 7.27 ppm), dimethylsulfoxide-d6 (dH 2.50 ppm), acetonitrile- d3 (dH 1.95 ppm) or methanol-d4 (dH 3.31 ppm) were used as internal references.

LC-MS Conditions. Samples were run on a Micromass ZMD, using electrospray with simultaneous positive-negative ion detection: column, YMC-PACK FL-ODS AQ, 50 x 4.6 mm LD S-5 m; gradient, 95:5 to 5:95 v/v H2O/CH3CN + 0.05% formic acid over 4.0 min, hold 3 min, return to 95:5 v/v H2O/CH3CN + 0.05% formic acid over 0.2 min, and hold at 95:5 v/v H2O/CH3CN + 0.05% formic acid over 3 min; detection, PDA 250-340 nm; flow rate, 1.5 mL/min.

Solid-phase extraction (SPE) chromatography was carried out using Jones chromatography (Si) cartridges under 15 mmHg vacuum with stepped gradient elution. All chemicals were purchased from commercial suppliers and used directly without further purification. Column chromatography was carried out using silica gel (0.040-0.063 mm, Merck).

The names of compounds were generated using the software Autonom Standard Name, ISIS Draw version 2.4, MDL Information Services Inc.

Example 1 5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro- lH-21ambda*6*-benzo[c]thiophen- 5-yl)-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

(5-Bromo-2-chloro-pyrimidin-4-yl)-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-amine (Intermediate 40; 1.00 g, 2.56 mmol) and 5-amino-2,2-dioxo-2,3-dihydro-lH-21ambda*6*- benzo[c]thiophene (0.47 g, 2.56 mmol) were stirred in refluxing water:acetone:conc. HCl (150:100:1, 50 mL) for 48 hours. After this time, the resultant solid was filtered off, dissolved in the minimum amount of hot dimethylformamide and allowed to cool. Sufficient diethyl ether was then added to the solution to produce a dense white solid, which was filtered off. The resultant solid was then dissolved in 5% methanol/dichloromethane and all the solvent then removed in vacuo. The resultant white powder was then dried over a stream of air for 24 hours to remove all traces of dimethylformamide, 0.97 g, 70%.

¹H NMR (de-DMSO) 10.50 (IH, bs), 9.80 (IH, bs), 8.45 (IH, s), 7.85 (IH, s), 7.80 (IH, d), 7.50 (2H, m), 7.25 (IH, d), 7.10 (IH, d), 4.35 (2H, s), 3.90 (2H, s); LC/MS RT 2.12 min, M+H 539.3.

The compounds of Examples 2 to 36 were produced using the stated 4-anilino-2- chloropyrimidine and 5-amino-2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophene. Subject to any Note, the synthesis was achieved following an analogous procedure to that described in Example 1.

Notes [1] The product formed as a precipitate in the reaction mixture and was isolated by filtering off, washing with acetonitrile and drying.

[2] The final product was purified, either by HPLC or flash column chromatography (SiO₂, dichloromethane:ethanol:ammonia, 200:8: 1).

Example 2 N*2*-(2,2-Dioxo-2,3-dihydro- lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 46. Note 1.

¹H NMR (d₆-DMSO) 9.55, 9.50 (2H, 2bs), 8.40 (IH, bs), 8.15 (2H, d & s), 8.00 (IH, s), 7.80 (IH, d), 7.75 (IH, d), 7.60 (IH, d), 7.35 (IH, d), 6.35 (IH, d), 4.50 (2H, s), 4.40 (2H, s); LC/MS RT 1.91 min, M+H 393.

Example 3 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- fluoro-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 51. Note 1.

¹H NMR (d₆-DMSO) 9.15 (IH, s), 9.10 (2H, 2s), 7.85 (3H, d & s), 7.55 (IH, s), 7.40 (2H, s), 7.30 (IH, d), 6.95 (IH, d), 4.15 (2H, bs), 3.90 (2H, bs); LC/MS RT 2.19 min, M+H 411.

Example 4 5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro- lH-21ambda*6*-benzo[c]thiophen- 5-yl)-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 52. Note 1.

¹H NMR (d₆-DMSO) 9.55 (IH, s), 8.85 (IH, s), 8.20 (IH, s), 8.05 (IH, s), 7.90 (IH, s),

7.60 (2H, m), 7.40 (2H, 2d), 7.00 (IH, d), 4.35 (2H, s), 3.85 (2H, s); LC/MS RT 2.38 min, M+H 473.

Example 5 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 53. Note 1.

¹H NMR (de-DMSO) 11.10 (IH, s), 10.85 (IH, s), 7.95 (2H, d), 7.70 (IH, d), 7.60 (IH, s), 7.45 (IH, d), 7.25 (2H, m), 6.45 (IH, d), 4.35, 4.25 (4H, 2d); LC/MS RT 2.07 min, M+H 461.

Example 6 N*4*-(lH-Benzoimidazol-5-yl)-5-bromo-N*2*-(2,2-dioxo-2,3-dihydro-lH- 21ambda*6*-benzo[c]thiophen-5-yl)-pyrimidine-2,4-diamine

From Intermediate 54. Note 1.

¹H NMR (de-DMSO) 9.35 (IH, s), 8.70 (IH, s), 8.35 (IH, bs), 8.10 (IH, s), 7.60 (2H, bs), 7.50 (IH, s), 7.25 (2H, d), 6.90 (IH, d), 4.25 (2H, d), 3.85(2H, s); LC/MS RT 2.09 min, M+H 473. Example 7 5-[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-5-nitro-pyrimidin-4-ylamino]-l,3-dihydro-benzoimidazol-2-one

From Intermediate 50. Note 1. 1H NMR (de-DMSO) 10.68 (IH, bs), 10.57 (IH, bs), 10.34 (IH, bs), 10.10 (IH, bs), 8.91 (IH, bs), 7.78 (IH, bs), 7.44 (IH, bs), 7.30-7.23 (IH, m), 7.00-6.77 (3H, m), 4.2 (2H, bs), 3.81 (2H, bs); LC/MS RT 2.18 min, M+H 454.5.

Example 8 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- nitro-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 49. Note 1.

¹H NMR (de-DMSO) 10.63 (IH, bs), 10.57 (IH, bs); 8.06-7.81 (2H, m), 7.70-7.38 (3H, m), 7.2-7.08 (IH, m), 4.4 (2H, bs), 3.77 (2H, bs); LC/MS RT 2.5 min, M+H 506.5.

Example 9 4-tert-Butyl-N-{5-[2-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*- benzo[c]thiophen-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-lH-indazol-3-yl}- benzamide

1H NMR (de-DMSO) 10.20 (IH, bs), 9.45 (IH, bs), 8.40 (2H, 2s), 7.95-7.85 (3H, m), 7.60 (IH, d), 7.50 (2H, d), 7.45 (IH, app s), 7.25 (IH, m), 7.05 (IH, d), 4.30 (2H, s), 3.80 (2H, s), 1.30 (9H, s); LC/MS RT 3.10 min, M+H 636. Example 10 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- methyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 42. Note 1. 1H NMR (de-DMSO) 13.69 (IH, bs), 9.16 (IH, s), 8.51 (IH, s), 8.0-7.85 (2H, m), 7.82- 7.77 (IH, m), 7.75-7.67 (IH, m), 7.59 (IH, dd, J=2.0, 8.0), 7.45 (IH, d, J=8), 7.09 (IH, d, J=9), 4.3 (2H, s), 4.07 (2H, s), 2.14 (3H, s); LC/MS RT 1.72 min, M+H 475.5.

Example 11 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- propyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 41. Note 1.

¹H NMR (de-DMSO) 13.79 (IH, bs), 9.12 (IH, s), 8.52 (IH, s), 7.95-7.58 (m, 4H), 7.5 (IH, dd, J=1.5, 8.5), 7.31 (IH, d, J=7.6), 7.03 (IH, d, J=8.2), 4.27 (s, 2H), 3.98 (s, 2H), 2.49-2.45 (2H, m), 1.55 (2H, m, 1.65-1.49), 0.94 (3H, t, J=7.5); LC/MS RT 1.83 min, M+H 503.5.

Example 12 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- thiophen-2-yl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 43. Note 1. ¹U NMR (de-DMSO) 13.85 (IH, bs), 9.53 (IH, s), 8.60 (IH, s), 8.12 (IH, s), 7.86 (IH, bs), 7.80-7.58 (3H, m), 7.55-7.40 (2H, m), 7.36 (IH, dm, J=3) 7.21 (IH, dd, J=4.0, 5.0), 7.08 (IH, d, J=8.0), 4.31 (2H, s), 3.98 (2H, s); LC/MS RT 2.19 min, M+H 543.5.

Example 13 5-Chloro-N*2*-(2,2-dioxo-2,3-dihydro- lH-21ambda*6*-benzo[c]thiophen- 5-yl)-N*4*-(2-trifluoromethyl-3H-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 44. Note 1.

IH NMR (de-DMSO) 9.55 (IH, s), 9.16 (IH, s), 8.19 (IH, s), 7.91 (IH, m), 7.70 (2H, m), 7.58 (IH, m), 7.42 (IH, m), 7.11 (IH, m), 4.33 (2H, s), 4.01 (2H, m); LC/MS RT 2.46 min, M+H 495.54.

Example 14 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- fluoro-N*4*-(2-trifluoromethyl-3H-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 45. Note 1.

IH NMR (de-DMSO) 9.50 (IH, s), 9.38 (IH, s), 8.29 (IH, s), 8.12 (IH, m), 7.66 (2H, m), 7.55 (IH, m), 7. ,43 (IH, m), 7.13 (IH, m), 4.31 (2H, s), 4.19 (2H, m) ; LC/MS RT 2.34 min, M+H 477.48.

Example 15 4-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-butyric acid

From Intermediate 66. Note 2.

¹H NMR (de-DMSO) 13.29 (IH, bs), 9.31 (IH, s), 8.12 (IH, s), 7.89-7.50 (4H, m), 7.29- 7.08 (2H, m), 5.79-5.56 (IH, m), 4.35 (2H, s), 4.29-4.02 (2H, m), 3.91 (2H, s), 2.33-2.21 (2H, m), 1.92-1.72 (2H, m); LC/MS RT 1.62 min, M+H 479.5.

Example 16 4-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-butyric acid methyl ester

From Intermediate 66. Note 2. 1H NMR (de-DMSO) 13.28 (IH, bs), 9.31 (IH, s), 8.11 (IH, s), 7.91-7.47 (4H, m), 7.30- 7.06 (2H, m), 5.83-5.55 (IH, m), 4.55-3.82 (6H, m), 3.52 (3H, s), 2.4 (2H, t, J=7.5), 1.87 (2H, Q, J=7.5); LC/MS RT 2.06 min, M+H 493.5.

Example 17 4-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-butyronitrile

From Intermediate 67. Note 2.

¹H NMR (de-DMSO) 13.29 (IH, bs), 9.33 (IH, s), 8.13 (IH, s), 7.95 (IH, s), 7.86 (IH, d, J=6.5), 7.81-7.53 (3H, m), 7.29 (IH, dm, J=IO), 7.25-7.12 (IH, m), 5.81-5.51 (IH, m), 4.42-4.15 (4H, m), 3.97 (2H, t, J=7.5), 2.59 (2H, t, J=7.5), 1.93 (2H, Q, J=7.5); LC/MS RT 1.98 min, M+H 460.5.

Example 18 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-(lH-indazol-5-yl)-N*4*-(4,4,4-trifluoro-butyl)-pyrimidine-2,4-diamine

From Intermediate 68. Note 2.

¹H NMR (de-DMSO) 13.28 (IH, s), 9.33 (IH, s), 8.13 (IH, s), 7.85 (IH, d, J=6), 7.74-7.56 (IH, m), 7.73-7.57 (2H, m), 7.26 (IH, dd, J=2, 9), 7.22-7.07 (IH, m), 5.67 (IH, bs), 4.36 (2H, s), 4.32-4.13 (2H, m), 4.04-3.93 (2H, m), 2.45-2.24 (2H, m), 1.91-1.75 (2H, m); LC/MS RT 2.21 min, M+H 503.

Example 19 2-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-l-phenyl-ethanone

From Intermediate 69. Note 2.

¹H NMR (de-DMSO) 13.25 (IH, bs), 9.33 (IH, bs), 8.15-8.04 (3H, m), 7.95 (2H, s), 7.89 (IH, d, J=5.5), 7.82 (IH, bs), 7.76-7.54 (5H, 7.42-7.38 (2H, m), 6.76 (IH, d, J=8), 5.8-5.69 (IH, m), 5.89 (2H, s), 4.24 (2H, s), 3.8 (2H, bs) ; LC/MS RT 2.15 min, MH+ 511.

Example 20 [[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)- pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-acetic acid methyl ester

From Intermediate 70. Note 2.

¹H NMR (de-DMSO) 13.26 (IH, bs), 9.42 (IH, s), 8.14 (IH, s), 7.95 (IH, s), 7.89 (IH, d, J=6.5), 7.82-7.76 (2H, m), 7.66 (IH, d, J=9), 7.62-7.51 (IH, m), 7.35 (IH, d, J=9), 7.19 (IH, d, J=6.5), 5.74-5.65 (IH, m), 4.80 (2H, bs), 4.48 (2H, bs), 3.63 (3H, s); LC/MS RT 2.01 min, M+H 465. Example 21 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-(lH-indazol-5-yl)-N*4*-methyl-pyrimidine-2,4-diamine

From Intermediate 65. Note 2.

¹H NMR (de-DMSO) 13.26 (IH, s), 9.53 (IH, s), 7.95 (IH, s), 7.88 (IH, d, J=6.5), 7.80-

7.70 (2H, m), 7.65 (IH, d, J=8), 7.60-7.51 (IH, m), 7.28 (IH, dd, J=1.5, 9.0), 7.13 (IH, m),

5.85-5.77 (IH, m), 4.34 (2H, s), 4.15 (2H, bs), 3.44 (3H, s); LC/MS RT 1.95 min, M+H

407.5.

Example 22 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-(lH-indazol-5-yl)-N*4*-prop-2-ynyl-pyrimidine-2,4-diamine

From Intermediate 64. Note 2.

¹H NMR (de-DMSO) 13.29 (IH, s), 9.45 (IH, s), 8.15 (IH, s), 7.99-7.84 (2H, m), 7.78 (IH, s), 7.73-7.52 (2H, m), 7.3 (IH, d, J=8.0), 7.17 (IH, dm, J=9.5); 5.76 (IH, bs), 4.71 (2H, s), 4.37 (2H, s), 4.24 (IH, bs), 3.27 (2H, s); LC/MS RT 2.04 min, M+H 432.

Example 23 5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen- 5-yl)-N*4*-(lH-indazol-5-yl)-N*4*-methyl-pyrimidine-2,4-diamine

From Intermediate 57. Note 2. ¹H NMR (de-DMSO) 13.13 (IH, s), 9.65 (IH, s), 8.11 (IH, s), 8.03 (IH, s), 7.33 (IH, s), 7.66 (IH, dd, J=2, 8.5), 7.57-7.54 (2H, m), 7.24 (2H, dd, J=2, 9), 4.42 (2H, s), 4.39 (2H, s), 3.47 (3H, s); LC/MS RT 2.14 min, M+H 485.

Example 24 5-Bromo-N*2*-(2,2-dioxo-2,3-dihydro- lH-21ambda*6*-benzo[c]thiophen- 5-yl)-N*4*-ethyl-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 59. Note 2.

¹H NMR (de-DMSO) 13.14 (IH, s), 9.62 (IH, s), 8.09-8.02 (2H, m), 7.85 (IH, s), 7.66- 7.48 (3H, m), 7.30-7.19 (2H, m), 4.42 (2H, s), 4.40 (2H, s), 4.01 (2H, q, J=7.0), 1.19 (3H, t, J=7.0); LC/MS RT 2.24 min, MH+ 499.5.

Example 25 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- fluoro-N*4*-(lH-indazol-5-yl)-N*4*-methyl-pyrimidine-2,4-diamine

From Intermediate 60. Note 2.

¹H NMR (de-DMSO) 13.12 (IH, bs), 9.41 (IH, s), 8.30 (IH, s), 8.07 (IH, s); 7.95 (IH, d, J=6.5), 7.76-7.69 (IH, m), 7.61-7.51 (IH, m), 7.32 (IH, dd, J=2, 9), 7.15 (IH, dd, J=8), 4.35 (2H, s), 4.26 (2H, s), 3.49 (3H, s) LC/MS RT 2.0 min, M+H 425.5.

Example 26 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-ethyl-5-fluoro-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 61. Note 2.

¹H NMR (de-DMSO) 13.18 (IH, s), 9.38 (IH, s), 8.07 (IH, s), 7.93 (IH, d, J=6.0), 7.77- 7.72 (IH, m), 7.71-7.66 (IH, m), 7.59-7.56 (2H, m), 7.28 (IH, dd, J=2.0, 9.0), 7.14 (IH, d, J=8.0), 4.36 (2H, s), 4.25 (2H, s), 3.99 (2H, q, J=7), 1.21 (3H t, J=7); LC/MS RT 2.12 min, M+H 439.5.

Example 27 [[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)- 5-fluoro-pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-acetonitrile

From Intermediate 62. Note 2.

¹H NMR (de-DMSO) 13.30 (IH, s), 13.26 (IH, s), 8.31 (IH, d, J=5), 8.15-8.08 (2H, m), 7.9-7.84 (IH, m), 7.67-7.59 (2H, m), 7.44-7.33 (IH, m), 4.98 (2H, s), 4.96 (2H, s), 4.4 (2H, s); LC/MS RT 1.99 min, M+H 450.5.

Example 28 N*2*-(2,2-Dioxo-2,3-dihydro- lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-ethyl-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 63. Note 2.

¹H NMR (de-DMSO) 13.24 (IH, bs), 9.28 (IH, s), 8.12 (IH, s), 7.90-7.45 (5H, m), 7.23 (IH, dd, J=1.5, 8.0), 7.14 (IH, dm J=9.0), 5.68 (IH, bs), 4.34 (2H, s), 4.18 (2H, bs), 3.95 (2H, q, J=7.0), 1.20 (3H, t, J=7.0); LC/MS RT 1.73 min, M+H 421.5.

Example 29 [[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-ylamino)- pyrimidin-4-yl] - ( 1 H-indazol- 5 -yl) - amino] - acetonitrile

From Intermediate 58. Note 2.

¹H NMR (de-DMSO) 13.32 (IH, bs), 9.56 (IH, bs), 8.17 (IH, s), 7.99 (IH, d, J=5.5), 7.89 (IH, s) 7.82 (IH, s), 7.72 (IH, d, J=9), 7.62 (IH, d, J=7.5), 7.31 (IH, dd, J=2, 9), 7.28 (IH, d, J=9), 5.76 (IH, d, J=6.5), 4.99 (2H, s), 4.39 (2H, s), 4.35 (2H, bs); LC/MS RT 1.79 min, M+H 432.5.

Example 30 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- fluoro-N*4*-methyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4- diamine

From Intermediate 78. Note 2.

¹H NMR (de-DMSO) 14.09 (IH, bs), 9.46 (IH, s), 8.00 (IH, d, J=6), 7.74 (3H, m), 7.58 (IH, dd, J=2.9), 7.38 (IH, dd, J=2.8), 7.19 (IH, d, J=9), 4.36 (2H, s), 4.28 (2H, s), 3.52 (3H, s); LC/MS RT 2.12 min, M+H 515.

Example 31 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- fluoro-N*4*-isopropyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4- diamine

From Intermediate 76. Note 2. ¹U NMR (de-DMSO) 9.53 (IH, d, J=14), 9.40 (IH, d, J=15), 8.17 (IH, m), 8.00 (2H, m), 7.87 (IH, m), 7.71 (IH, m), 7.49 (IH, m), 7.20 (IH, m), 4.89 (IH, m), 4.37 (2H, s), 4.32 (IH, s), 4.24 (IH, s), 1.64 (9H, dd, J=7, 17); LC/MS RT 2.28 min, M+H 543.

Example 32 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- fluoro-N*4*-isobutyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4- diamine

From Intermediate 79. Note 2. 1H NMR (de-DMSO) 9.51 (2H, m), 8.14 (2H, m), 7.82 (3H, m), 7.52 (IH, m), 7.20 (IH, d, J=8), 4.25 (6H, m), 2.23 (IH, m), 0.84 (9H, dd, J=7, 17); LC/MS RT 2.40 min, M+H 557.

Example 33 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-(lH-indazol-5-yl)-N*4*-pyridin-2-ylmethyl-pyrimidine-2,4-diamine

From Intermediate 71. Note 2.

¹H NMR (de-DMSO) 9.33 (IH, s), 8.55 (IH, dd, J=5), 8.06 (IH, s), 8.99-8.85 (2H, m), 8.84-8.55 (4H, m), 8.52-8.33 (3H, m), 7.26 (IH, dd, J=6, 6.5), 7.04 (IH, d, J=8.5), 5.82 (IH, bs), 5.28 (2H, s), 4.33 (2H, s), 4.11 (2H, bs); LC/MS RT 2.01 min, M+H 484.5.

Example 34 N*4*-Benzyl-N*2*-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*- benzo[c]thiophen-5-yl)-N*4*-(lH-indazol-5-yl)-pyrimidine-2,4-diamine

From Intermediate 72. Note 2.

¹H NMR (de-DMSO) 9.38 (IH, s), 8.08 (IH, s), 7.99-7.87 (2H, m), 7.75-7.65 (IH, m), 7.62 (IH, d, J=8.5), 7.3 (IH, dm, J=8.5), 7.37-7.19 (6H, m), 7.06 (IH, d, J=8), 5.77 (IH, bs), 5.26 (2H, s), 4.33 (2H, s), 3.99 (IH, bs); LC/MS RT 2.20 min, M+H 483.5.

Example 35 2-[[2-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-pyrimidin-4-yl]-(lH-indazol-5-yl)-amino]-acetamide

From Intermediate 58. Note 2. 1H NMR (de-DMSO) 9.37 (IH, s), 8.11 (IH, s), 8.05 (IH, s), 7.84 (IH, s), 7.66-7.13 (6H, m), 5.64 (IH, bs), 4.47-4.37 (6H, m); LC/MS RT 1.78 min, M+H 450.5.

Example 36 5-[5-Amino-2-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5- ylamino)-pyrimidin-4-ylamino]-indazole-l-carboxylic acid methyl ester

From Intermediate 55. Note 2.

¹H NMR (de-DMSO) 8.89-8.95 (IH, m), 8.55-7.5 (1OH, m), 7.19-7.08 (IH, m), 4.35 (2H, s), 4.26 (2H, s), 4.06 (3H, s); LC/MS RT 2.19 min, M+H 466.5.

Example 37 N*2*-(2,2-Dioxo-2,3-dihydro- lH-21ambda*6*-benzo[c]thiophen-5-yl)-5- trifluoromethyl-N*4*-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-pyrimidine-2,4-diamine

(4-Chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*- benzo[c]thiophen-5-yl)-amine (1.00 g, 2.77 mmol) and 5-amino-2-trifluoromethyl-lH- benzoimidazole (0.56 g, 2.77 mmol) were stirred in refluxing water: acetone: cone. HCl (150: 100: 1, 50 mL) for 24 hours. After this time, the resultant solid was filtered off and dried (1.06 g, 72%).

¹H NMR (de-DMSO) 9.82 (IH, bs), 8.99 (IH, bs), 8.38 (IH, s), 7.79-7.69 (2H, m), 7.52

(IH, bs), 7.42-7.28 (2H, m), 7.0 (IH, d, J=9), 4.28 (2H, s), 3.71 (2H, s); LC/MS RT 2.23 min, M+H 529.5.

The compounds of Examples 38 and 39 were produced using the appropriate aniline and (4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2,2-dioxo-2,3-dihydro-lH-21ambda*6*- benzo[c]thiophen-5-yl)-amine. Subject to any Note, the synthesis was achieved following an analogous procedure to that described in Example 37.

Example 38 N*4*-(6,7-Difluoro-2-trifluoromethyl-lH-benzoimidazol-5-yl)-N*2*-(2,2- dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)-5-trifluoromethyl-pyrimidine- 2,4-diamine

From Intermediate 84. Note 2. 1H NMR (de-DMSO) 9.82 (IH, bs), 9.26 (IH, bs), 8.46 (IH, bs), 7.58-6.75 (5H, m), 4.31 (2H, s), 4.07 (2H, s); LC/MS RT 2.43 min, M+H 565.

Example 39 N*2*-(2,2-Dioxo-2,3-dihydro-lH-21ambda*6*-benzo[c]thiophen-5-yl)- N*4*-(6-fluoro-2-trifluoromethyl-lH-benzoimidazol-5-yl)-5-trifluoromethyl-pyrimidine- 2,4-diamine

From Intermediate 84. Note 2.

¹H NMR (de-DMSO) 9.79 (IH, bs), 8.93 (IH, bs), 8.26 (IH, s), 7.66-7.58 (2H, m), 7.22-

7.02 (3H, m), 6.81 (IH, d, J=8), 4.11 (2H, bs), 3.45 (2H, bs); LC/MS RT 2.21 min, M+H

547.4.

Preparation of Starting Materials and Intermediates

The starting materials for the above examples are either commercially available or are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of the preparation of some of the starting materials and intermediates.

Intermediate 40 (5-Bromo-2-chloro-pyrimidin-4-yl)-(2-trifluoromethyl-lH- benzoimidazol- 5 - yl) - amine

2,4-Dichloro-5-bromopyrimidine (2.95 g, 11.45 mmol), sodium carbonate (6.07 g, 57.3 mmol, 5 eq.) and 2-trifluoromethyl-5-aminobenzimidazole (2.60 g, 12.94 mmol) were stirred in ethanol (140 mL) overnight at room temperature. The solvent was removed in vacuo and the resultant solid sonicated in water (150 mL) until all large particles had dispersed. The resultant solid was filtered off. Further purification was achieved by crystallisation from acetonitrile. The solid was filtered off and dried (3.6 g, 70%). LCMS Rt = 2.13 min; M+H = 392.

Intermediates 41-54

Intermediates 41 to 54 were produced by treating the appropriate 2,4-dichloro-pyrimidine with the appropriate aniline. The synthesis was achieved following an analogous procedure to that described for Intermediate 40. Crystallisation was not performed, but the solid was triturated in water and then filtered off, dried and used directly in the next stage.

Intermediate

Structure Name Comments and Physical Data

No (2-Chloro-5-propyl-pyπmidin- Using Intermediate 82

41 4-yl)-(2-tπfluoromethyl- IH-

benzoimidazol-5-yl)-amine Rt = 2 24 mm, M+H = 356 5

83

= 328 5 benzoimidazol-5-yl)-amine

84

= 396 5 benzoimidazol-5-yl)-amine

(2,5-Dichloro-pynmidin-4-

44 yl)-(2-tπfluoromethyl-lH- Rt 241min, M+H 348 47, 349 46 benzoimidazol-5-yl)-amine

45

(2-Chloro-5-fluoro-pyπmidin- 4-yl)-(2-tπfluoromethyl- IH- Rt 2 34 mm, M+H 332 50

benzoimidazol-5-yl)-amine

= 247

= 246

= 291

M+H = 359

M+H = 307

= 264

= 325

(2-Chloro-pyπmidin-4-yl)-(2-

53 tπfluoromethyl- IH- Rt = 2 00 min, M+H = 314 benzoimidazol-5-yl)-amine

( 1 H-Benzoimidazol-5-yl)-(5-

54 bromo-2-chloro-pyπmidin-4- Rt = 1 52 min, M+H = 3244 yl)-amine

Intermediate 55 (5-Amino-2-chloro-pyrimidin-4-yl)-(lH-indazol-5-yl)-amine (2-Chloro-5-nitro-pyrimidin-4-yl)-(lH-indazol-5-yl)-amine (100 mg, 0.34 mmol) was stirred in degassed ethanol under a hydrogen atmosphere in the presence of 10% palladium on charcoal for 24 hours. The suspension was filtered through diatomaceous earth and the resultant solution was concentrated to provide the crude material as a pink solid (105.96 mg, 98%).

LCMS Rt = 2.21 min; M+H = 319.

Intermediate 56 (2-Chloro-5-fluoro-pyrimidin-4-yl)-isopropyl-(2-trifluoromethyl-lH- benzoimidazol- 5 - yl) - amine (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-trifluoromethyl-lH-benzoimidazol-5-yl)-amine (2.82 g, 8.48 mmol), dimethylaminopyridine (51 mg, 0.05 eq.) and di-'butyl carbonate (1.85 g, 1 eq.) were stirred in dichloromethane (250 mL) for 18 hours. The solvent was then removed and a portion of the crude resultant solid (198.6 mg, 0.46 mmol), cesium carbonate (151 mg, 0.46 mmol) and 2-bromopropane (100 μL, 0.106 mmol) were stirred in dimethylformamide (1 mL) at 90 ⁰C overnight. The solvent was removed in vacuo and the resultant solid sonicated in water (2 mL) and then filtered off and dried (39.6 mg, 23%). LCMS Rt = 2.39 min; M+H = 374.

Intermediates 57 to 79 were produced following an analogous procedure to that described for Intermediate 56. The appropriate 2-chloro-4-anilinopyrimidine was protected using either di-tertbutyl carbonate or methylchloroformate followed by treatment with the appropriate electrophile to provide the respective product.

Intermediate

No Structure Name Data

5-[(5-Bromo-2-chloro-pyπmidin-

57 4-yl)-methyl-amino]-indazole-l- Rt = 2 17 min, M-C5H9O2 = 338 5 carboxylic acid tert-butyl ester

5-[(2-Chloro-pyπmidin-4-yl)- cyanomethyl-amino]-indazole-l- Rt = 2 35 mm, MH+ = 385 5

carboxylic acid tert-butyl ester

Y > ⁰ 5-[(5-Bromo-2-chloro-pyπmidin-

59 L XX/ 4-yl)-ethyl-amino]-indazole- 1- Rt = 2 28 min, M-C5H9O2 = 3524 carboxylic acid tert-butyl ester

60

5- [(2-Chloro-5-fluoro-pyπmidin- no 4-yl)-methyl-amino]-indazole-l- Rt = 2 51 mm, M-C5H9O2 = 278 carboxylic acid tert-butyl ester

5- [(2-Chloro-5-fluoro-pynmidin-

4-yl)-ethyl-amino]-indazole- 1- Rt = 2 63 mm, M-C5H9O2 = 2924 carboxylic acid tert-butyl ester

5- [(2-Chloro-5-fluoro-pyπmidin-

4-yl)-cyanomethyl-amino]-

Rt = 2 98 mm, M-C5H9O2 = 303 5 indazole-1-carboxylic acid tert-

butyl ester

-T

5-[(2-Chloro-pyπmidin-4-yl)-

63 X/ ethyl-amino]-indazole-l- Rt = 2 53 mm, M-C5H9O2 = 274 5 carboxylic acid tert-butyl ester

5-[(2-Chloro-pyπmidin-4-yl)-

64 prop-2-ynyl-amino]-indazole-l- Rt = 2 80 mm, MH+ = 385 carboxylic acid tert-butyl ester

5-[(2-Chloro-pyπmidin-4-yl)-

65 methyl-amino]-indazole-l- Rt = 2 73 mm, MH+ = 361

carboxylic acid tert-butyl ester 66 = 461

67 mm, M+H = 414

= 457

butyl ester = 465

= 419

butyl ester = 438

mm, M+H = 438

(2-Chloro-5-fluoro-pyπmidin-4- yl)-methyl-(2-tπfluoromethyl-lH- Rt = 2 15 mm, M+H = 346 benzoimidazol-5-yl)-amine

(2-Chloro-5-fluoro-pyπmidin-4- yl)-ethyl-(2-tπfluoromethyl-lH- Rt = 2 28 mm, M+H = 360

benzoimidazol-5-yl)-amine

75

= 370

benzoimidazol-5-yl)-amine

76

= 386

benzoimidazol-5-yl)-amine

(2-Chloro-5-fluoro-pyπmidin-4- yl)-methyl-(2-trifluoromethyl-lH- Rt = 2 15 mm, M+H = 346 benzoimidazol-5-yl)-amine

(2-Chloro-5-fluoro-pyπmidin-4- yl)-isobutyl-(2-trifluoromethyl- Rt = 2 53 mm, M+H = 388 lH-benzoimidazol-5-yl)-amine

5-(2-Chloro-5-mtro-pyπmidin-4- ylamino)-indazole- 1 -carboxylic Rt = 248 mm, M-H = 347

acid methyl ester

Intermediate 80 2,4-Dichloro-5-trifluoromethylpyrimidine 5-Trifluoromethyluracil (5 g, 27.8 mmol) and phosphorous oxychloride (21.3 g, 0.136 mmol, 1.5 eq.) were stirred in a 3 neck flask, fitted with reflux condenser, internal thermometer and addition funnel under a nitrogen atmosphere. Concentrated phosphoric acid (200 μL) was added to the slurry followed by dropwise addition of di- ώøpropylethylamine (3.6 g, 27.8 mmol, 1 eq.) at a rate that maintained the internal temperature below 90 ⁰C. Once addition was complete, the solution was heated to 100 ⁰C for 20 hours. After this time HPLC showed no more starting material to be present. The reaction was then allowed to cool before being added slowly to cooled, aqueous 3M hydrochloric acid (3 eq.) at a rate that maintained the temperature below 15 ⁰C. The aqueous product was then twice extracted with diethyl ether (100 mL) and the combined organic extracts were washed with water until the extracts were neutral (5 x 100 mL). After drying with magnesium sulphate the solution was concentrated to produce a light orange oil. Further purification could either be achieved by distillation or solid phase extraction.

Intermediates 81 to 83 were produced following an analogous procedure to that described for Intermediate 80. The materials were used directly in subsequent steps.

Intermediate

Name Physical Data

No

2,4-Dichloro-5-propyl- ¹H NMR (CDCl₃) 8 39 (IH, s), 2 68 (2H, pyπmidine t, J=8), 1 69 (2H, m), 1 00 (3H, t, J=7)

2,4-Dichloro-5-methyl- ¹H NMR (CDCl₃) 8 41 (IH, s), 2 35 (3H,

pyπmidine s) = 231 4

Intermediate 84 (4-Chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2,2-dioxo-2,3-dihydro- lH-21ambda*6*-benzorclthiophen-5-yl)-amine

2,4-Dichloro-5-triflouromethylpyrimidine (2.80 g, 13.04 mmol) and anhydrous ZnCl₂ (1.76 g, 13.04 mmol) were stirred in tert-butanol:l,2-dichloroethane (1:1, 90 mL) for 1 h at room temperature before cooling to 0 ⁰C. 2,2-Dioxo-l,3-dihydrobenzo[c]thiophene-5-yl amine (1.56 g, 8.52 mmol, 80% purity) was then added in a single portion, followed by the dropwise addition Of Et₃N (1.87 mL, 13.04 mmol) in tert-butanol:l,2-dichloroethane (1:1, 6.3 mL). The reagents were allowed to stir and warm to room temperature overnight. The solvent was then removed in vacuo and the tan solid suspended in methanol (200 mL) for 2 h before being filtered off, washed with methanol (10 mL) and diethyl ether (20 mL) and dried to produce a pale tan powder (1.7 g, 69%). Rt = 2.32 min; M-H = 362.

Intermediate 85 6-Fluoro-5-nitro-2-trifluoromethyl-lH-benzoimidazole

4-Fluoro-5-nitrophenylenediamine (151 mg, 0.882 mmol) was stirred in trifluoroacetic acid (2.5 mL), trifluoroacetic anhydride (2.5 mL) and cone, sulphuric acid (5 mL) at 40 ⁰C for 24 hours. Excess reagents were then removed in vacuo to produce a brown oil, which after purification by solid phase extraction provided a yellow solid. Crystallisation from toluene produced yellow crystals (130 mg, 59%). LCMS Rt = 2.05 min; M+H = 250.

Intermediate 86 6J-Difluoro-5-nitro-2-trifluoromethyl-lH-benzoimidazole 2-Trifluoromethyl-4,5-difluoro benzimidazole (423 mg, 1.90 mmol) was stirred at 0 ⁰C in acetonitrile (20 mL) under a nitrogen atmosphere. Nitronium tetrafluoroborate (750 mg, 5.65 mmol) was then added in a single portion and stirring continued whilst allowing the reaction to warm to room temperature over 24 hours. IM Aqueous sodium bicarbonate (20 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate) and concentrated before purifying the oil by solid phase extraction to produce a yellow solid (165 mg, 33%). Rt = 2.13 min; M+H = 268.

Intermediate 87 6-Fluoro-2-trifluoromethyl-lH-benzoimidazol-5-ylamine 2-Trifluoromethyl-4,5-difluoro-6-nitrobenzimidazole (150 mg, 0.56 mmol), 10% Pd/C (100 mg) and ethanol were stirred in degassed ethanol (10 mL) before being exposed to a hydrogen atmosphere for 24 hours. The reaction mixture was then filtered though diatomaceous earth. The resultant pink solution was concentrated in vacuo and the material used crude in the next stage. Rt = 1.60 min; M+H = 220.

Intermediate 88 6J-Difluoro-2-trifluoromethyl-lH-benzoimidazol-5-ylamine 2-Trifluoro-5-nitro-6-flouro benzimidazole (117 mg, 0.47 mmol) was stirred with a suspension of zinc (0.5 g, 7.64 mmol) in acetic acid (10 mL) for 48 hours. The reaction mixture was then partitioned between IM potassium carbonate (100 mL) and ethyl acetate (100 mL), then extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried with magnesium sulphate, concentrated and the resultant solid purified by solid phase extraction to provide a yellow powder (61.8 mg, 60 %). Rt = 1.89 min; M+H = 238.

Pharmacological Activity

A fluorescein group was added to an Aurora A ATP-competitive inhibitor (attached via a hexanoic acid linker) to create a fluorescently-labeled ligand that could be used to monitor binding of Aurora A using a fluorescence readout. Inhibitors that decrease the binding of the ligand to the enzyme were detected as a decrease in fluorescence relative to control samples. Intermediate

A mixture of cyclopropanecarboxylic acid {4-[4-chloro-6-(5-methyl-2H-pyrazol-3- ylamino)-pyrimidin-2-ylsulfanyl] -phenyl} -amide (50 mg) in 4-aminomethylpiperidine (0.5 ml) was heated at 110 ⁰C overnight (18h). The cooled reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (20 ml) and washed with sodium bicarbonate solution (10 ml) and brine solution (10 ml) before drying over anhydrous magnesium sulphate and concentrating in vacuo to yield the crude product. This material was purified via flash column chromatography on silica gel, eluting with DCM: EtOH: ammonia (40:8:1) to yield the purified Intermediate, as a colourless solid (37 mg, 63%). 1H-NMR (de-DMSO): 11.70 (IH, bs), 10.35 (IH, s), 9.15 (IH, s), 7.65 (2H, s), 7.45 (2H, d), 6.10 (IH, bs), 5.45 (IH, s), 4.05 (2H, db), 3.35 (signal obscured), 2.70 (2H, apparent t), 2.40 (IH, d), 1.60 (3H, bm), 1.35 (IH, m), 1.00 (4H, m), 0.80 (4H, 2s);

MS (+ve ESI): 479 (M+H)⁺.

Preparation of N-[5-({l-[2-[4-(cyclopropanecarbonyl-amino)-phenylsulfanyl]-6-(5- methyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-piperidin-4-ylm ethyl }-carbamoyl)- pentyl]-6-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalamic acid A mixture of the above Intermediate (8.2 mg) and 6-(fluoresecein-5-carboxamide) hexanoic acid, succinimidyl ester (5-SFX) (10 mg) in dichloromethane (2 ml) was stirred at ambient temperature overnight (18h). LC/MS revealed the presence of starting material. DMF (1 ml) and triethylamine (5 drops) were added and the reaction stirred for a further 4h. LC/MS revealed complete reaction. The reaction mixture was concentrated in vacuo and purified via preparative HPLC to yield the fluorescently-labelled ligand as an orange solid (12 mg, 76%).

¹H-NMR (de-DMSO): 10.40 (IH, s), 9.15 (IH, s), 8.90 (IH, bs), 8.40 (IH, s), 8.25 (IH, d), 7.80 (IH, apparent t), 7.65 (2H, d), 7.45 (2H, d), 7.40 (IH, d), 6.70 (IH, s), 6.60 (4H, 2d), 6.10 (IH, bs), 5.50 (IH, s), 4.10 (2H, bm), 3.30 (4H, m, partially obscured), 3.05 (2H, m), 2.80 (2H, bt), 2.15 (2H, m), 2.05 (3H, s), 1.90 (IH, m), 1.60 (4H, bm), 1.30 (2H, m), 1.10 (2H, m), 0.80 (4H, d);

MS (+ve ESI): 951 (M+H)⁺. Aurora A fluorescent displacement 96 well microtitre plate based screening assay (on robot)

Compound dilutions and control additions:

Ten compounds were diluted in columns 3 to 12 of a 96 well round bottom plate (top concentration, as required, in row A) in 10% DMSO (in water) such that the compounds were doubly diluted at ten times the required final concentration The same was done with the control compound (5-methyl-2H-pyrazol-3-yl)-(2-o-tolyl-quinazolin-4-yl)- amine in column 2, with a top concentration of 2 μM. To wells Al - Dl 50 μl of 10% DMSO was added, and to wells El - Hl 5 μl of 100 μM cyclopropanecarboxylic acid {4- [4-(4-aminomethyl-piperidin-l-yl)-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2- ylsulfanyl] -phenyl} -amide + 45 μl water. Wells Al - Dl were the positive controls (100% activity) and wells El - Hl were the fully inhibited controls (0% activity) using the unlabelled ligand to compete off the labeled ligand. This format allowed the Aurora A- fluorescent ligand complex to be added to all wells on the plate and thus the assay was performed easily on the robot (Biomek FX robot, Beckman Coulter). The blank ligand mix was made up with 27.7 ml 2x buffer + 22.3 ml water + 55.5 μl of 10 μM ligand. The enzyme-ligand mix was made up with 49.6 ml 2x buffer + 39.5 ml water (enzyme and ligand addedl later). The final assay buffer was 10 mM Hepes (pH 7), 10 mM MgC12, 1 mM DTT, 0.5 mM CHAPS plus 1% DMSO from the compound dilution. The blank-ligand mix was added to the reservoir on the robot and the program started. The first stage of the program added 10 μl of the compound dilutions to triplicate black 96 well plates, and then added 90 μl of the blank-ligand mix to one of each triplicate plates and mixes. This served as a background control which was subtracted from the fluorescence of the sample plates to cancel out any intrinsic fluorescence or quenching the compounds may have had.

When the robot paused and prompted for the enzyme-ligand mix, 99.1 μl of the 10 μM ligand and 36 μl of the 5.5 μM Aurora A ((Upstate #14-511) were added to the 2x buffer/water mix and add to the reservoir. The final stage of the program added 90 μl of the enzyme-ligand mix to the duplicate sample plates. When the robot was finished the plates were incubated at room temperature (shielded from light) for 20 min before being read in the Envision plate reader Perkin Elmer Envision multilabel plate reader) using Ex/Em 480/535 nm.

The aurora A kinase activities of the compounds of the invention are shown in the Table:

Claims

1. A 2,4-diaminopyrimidine derivative of the formula (I), a tautomer thereof, or a pharmaceutically acceptable salt thereof

wherein:

R¹ represents hydrogen, C₁-C₆ alkyl, Ci-C₄ haloalkyl, Cβ-Cio aryl, 5- to 10- membered heteroaryl, hydroxy, -NR⁷R⁷⁷ or -CO₂R⁷ wherein each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl; R² represents hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl or -(C₁-C₄ alkylene)-X, wherein

X represents cyano, nitro, -CO₂R⁷, -CO-NR⁷R⁷⁷, Cβ-Cio aryl, 5- to 10- membered heteroaryl, -CO-(C₆-Cio aryl) or -CO-(5- to 10- membered heteroaryl) wherein each

R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl; R³ represents hydrogen, C₁-C₆ alkyl, C₁-C₄ haloalkyl, halogen, nitro, cyano, hydroxy,

Ci-C₄ alkoxy or -NR⁷R⁷⁷ wherein each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl; R⁴ represents hydrogen or Ci-C₄ alkyl; and - either X is CH and Y is N, or Y is CH and X is N; the aryl and heteroaryl moieties in R¹ and R² being unsubstituted or substituted by

1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C₁-C₆ alkyl, C₁-C₆ alkoxy, and Ci-C₄ haloalkyl substituents.

2. A compound according to claim 1, wherein R¹ is attached on the 5- membered ring.

3. A compound according to claim 1 or 2, wherein when R¹ is attached to a N atom, it is other than hydroxy and -NR Ir R, 11

4. A compound according to any one of the preceding claims, wherein R¹ represents hydrogen, C₁-C₄ haloalkyl, C₁-C₆ alkyl, phenyl, hydroxy or -CO₂-R⁷, wherein R⁷ is Ci-C₄ alkyl.

5. A compound according to any one of the preceding claims, wherein R² represents hydrogen, C₁-C₆ alkyl or -(C₁-C₄ alkylene)-X^/, wherein X⁷ represents -CF₃, cyano, -CO₂R⁷, -CO-NR⁷R⁷⁷, phenyl, 5- to 6- membered heteroaryl, -CO-phenyl or -C0-(5- to 6- membered heteroaryl), wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or C₁- C₄ alkyl.

6. A compound according to any one of the preceding claims, wherein R >3 i •s attached at the 5- position of the pyrimidine ring.

7. A compound according to any one of the preceding claims, wherein R >3 i •s hydrogen, Ci-C₄ alkyl, Ci-C₂ haloalkyl, halogen, nitro, hydroxy or -NH₂.

8. A compound according to any one of the preceding claims, wherein the tautomer of the 2,4-diaminopyrimidine of the formula (I) has the formula (I⁷) or (I⁷⁷)

wherein R¹, R², R³ and R⁴ are as defined in any one of the preceding claims.

9. A compound according to any one of the preceding claims, which is a 2,4-diaminopyrimidine of formula (Ia), a tautomer thereof or a pharmaceutically acceptable salt thereof

wherein:

R¹ is attached at the 1- or 2- position of the benzimidazole/indazole ring, and is hydrogen, -CF₃, phenyl, hydroxy or -CO₂-(Ci-Ci alkyl), the phenyl group being unsubstituted or substituted by a methyl group, provided that when R¹ is attached to a N atom it is other than hydroxy and -CF₃; R² is hydrogen, C₁-C₄ alkyl or -(Ci-C₄ alkylene)-X^/, wherein X¹ represents -CF₃, cyano, -CO₂-(Ci-C₂ alkyl), -CO-NH₂, -CO-phenyl, or pyridyl, the phenyl and pyridyl groups in R² being unsubstituted; R³ is hydrogen, bromine, Ci-C₂ alkyl, -CF₃, nitro or -NH₂; and; - either X is CH and Y is N, or Y is CH and X is N.

10. A compound according claim 9, wherein the tautomer of the 2,4-diaminopyrimidine of formula (Ia) has the formula (Ia⁷) or (Ia^/A)

wherein R¹, R² and R³ are as defined in claim 9.

11. A compound as defined in any one of the preceding claims, for use in the treatment of the human or animal body.

12. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 10, and a pharmaceutically acceptable carrier or diluent.

13. The use of a compound as defined in any one of claims 1 to 10 in the manufacture of a medicament for use in the treatment of a disease where the inhibition of one or more Aurora kinase is beneficial.

14. The use according to Claim 13 wherein the kinase is Aurora-A kinase.

15. The use of a compound as defined in any one of claims 1 to 10 in the manufacture of a medicament for use in the treatment or prevention of proliferative disease.

16. The use according to Claim 15 wherein the proliferative disease is cancer.

17. Use according to claim 16, wherein the cancer is leukaemia, lymphoma, breast cancer, lung cancer, liver cancer, cancer of the colon, rectal cancer, stomach cancer, prostate cancer, cancer of the bladder, pancreatic cancer or ovarian cancer.

18. A method of treating a human suffering from leukaemia, lymphoma, breast cancer, lung cancer, liver cancer, cancer of the colon, rectal cancer, stomach cancer, prostate cancer, cancer of the bladder, pancreatic cancer or ovarian cancer, comprising the steps of administering to a person in need thereof a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof.