BENZAMIDE DERIVATIVES AS THROMBIN INHIBITORS

This invention relates to a new class of chemical compounds and to their use in medicine In particular, the invention concerns novel amide derivatives methods for their preparation, pharmaceutical compositions containing them and their use as thrombin inhibitors Thrombin inhibitors have been described previously in, for example, WO94/20467

Thrombm is a seπne proteinase present in plasma and is formed by conversion from its prothrombin precursor by the action of Factor Xa Thrombin plays a central role in the mechanism of blood coagulation by converting the soluble plasma protein, fibrinogen, into insoluble fibrin The insoluble fibrin matrix is required for the stabilisation of the primary hemostatic plug Many significant disease states are related to abnormal hemostasis With respect to the coronary arterial vasculature, abnormal thrombus formation due to the rupture of an established atherosclerotic plaque is the major cause of acute myocardial infarction and unstable angina Both treatment of an occlusive coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) are often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected extremity and a pre-disposition to pulmonary embolism Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterised by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure

Beyond its direct role in the formation of fibrin rich blood clots, thrombin has been reported to have profound bioregulatory effects on a number of cellular components within the vasculature and blood, (Shuman, M A , Ann NY Acad Sci , 405 349 (1986))

The inhibition of thrombin has been implicated as a potential treatment for a number of disease states Thrombin inhibitors may be useful in the treatment of acute

vascular diseases such as coronary thrombosis, stroke, pulmonary embolism, deep vein thrombosis, restenosis, atrial fibrillation, myocardial infarction, and unstable angina They have been described as anti-coagulant agents both in-vivo and ex- vivo, and in oedema and inflammation, whereby a low dose of thrombm inhibitor can reduce platelet and endothelial ceil thrombm mediated inflammatory responses without concomitant anticoagulant effects Thrombin has been reported to contribute to lung fibroblast proliferation, thus, thrombin inhibitors could be useful for the treatment of some pulmonary fibrotic diseases Thrombin inhibitors have also been reported in the treatment of tumour metastasis whereby the thrombin inhibitor prevents the fibrin deposition and metastasis caused by the inappropriate activation of Factor X by cysteine proteinases produced by certain tumour cells They have been shown to inhibit neurite retraction and thus may have potential in neurogenerative diseases such as Parkinson's and Alzheimer's disease They have also been reported to be used in conjunction with thrombolytic agents by permitting the use of a lower dose of thrombolytic agent Other potential uses have been descπbed in US5371091 for the treatment of Kasabach Merπtt Syndrome and hemolytic uremic syndrome, in EP565897 for the prevention of fibrin deposits in the eye during ophthalmic surgery, and in DE4126277 for the treatment of osteoporosis.

Thus, we have now found a novel class of amide derivatives which act as thrombin inhibitors shown as formula (I)

where R^ and R2 independently represent a group

X

^/ or R1 and R2 together form a C3.7 heterocycloalkyl or heterocycloalkenyl group which may be optionally substituted by C-μ _β alkyl, Cι_4 alkoxy, halogen, carboxylic acid or a C-| _4 carboxylic acid ester group,

R3 represents hydrogen, C-1.3 alkyl, halogen, or C-] _2 alkoxy,

R ⁴ , R*5 and R ⁶ independently represent hydrogen, or halogen,

R7 represents hydrogen or C-μβ alkyl,

R8 represents hydrogen, C3.7 cycloalkyl, C3.7 cycloalkenyl, C3.7 heterocycloalkyl, C3-7 heterocycloalkenyl, aryl, or heteroaryl, which groups are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C-μβ alkyl, C-μβ alkoxy, C-ι_ ₆ acyloxy, NR ⁹ R ^{1 0} , NHCOR ^{1 1} , NHSO ₂ R ¹² , COR ^{1 3} , CO ₂ R ¹⁴ , CONR ¹⁵ R ¹⁶ , and S02NHR ¹⁷ ,

X represents a bond, a C-|_ alkyl chain, or a C3.6 alkenyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C*ι_6 alkyl, C-|_6 alkoxy, C-|_6 acyloxy, NR ⁹ R ¹⁰ , NHCOR ^{1 1} , NHS0 ₂ R ¹² , COR ¹³ , CO ₂ R ¹⁴ , CONR ¹⁵ R ¹⁶ , and S0 ₂ NHR ¹⁷ ;

R9-R17 represent hydrogen, C* _| _e alkyl, or R ⁹ and R ¹⁰ or R ¹⁵ and R ¹⁶ form a C3.7 heterocycloalkyl ring, or R ¹ * ² additionally may represent trifluoromethyl;

and pharmaceutically acceptable deπvatives or solvates thereof.

Referring to the general formula (I), alkyl includes both straight and branched chain saturated hydrocarbon groups

Referring to the general formula (I), alkenyl includes both straight and branched chain hydrocarbon groups with at least one double bond

Referring to the general formula (I), aryl includes optionally substituted monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl

Referring to the general formula (I), heteroaryl includes 5 or 6 membered aromatic heterocyclic rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, and fused bicyclic ring systems containing one or more nitrogen, sulfur, and oxygen atoms Examples of such groups include oxadiazoie, thiazole thiadiazole, triazole, tetrazole, benzimidazole, pyridine, furan and thiophene

Referring to the genera! formula (I) examples of C3.7 cycloalkyl groups include cyclohexyl and cyclopentyl groups

Referring to the general formula (I), a 03.7 cycloalkenyl group includes rings containing at least one double bond incorporated in the ring

Referring to the general formula (I), a 03,7 heterocycloalkyl group includes rings containing containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, for example, a tetrahydropyran-4-yl group

Referring to the general formula (I), a C3.7 heterocycloalkenyl group includes rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms, together with at least on double bond incorporated in the ring

Referring to the general formula (I) where R ¹ represents a group

X

X is suitably a bond or C-| _5 alkyl group, e g methyl, isopropyl or isobutyl, and R ⁸ suitably represents hydrogen, C3_7 cycloalkyl, aryl, or heteroaryl When X represents a bond, R ⁸ is preferably phenyl optionally substuituted by one or more halogen groups, or C3.7 cycloalkyl, e g cyclobutyl, cyclopentyl or cyclohexyl When X represents a C^ alkyl group, R ⁸ is preferably hydrogen, cycloalkyl, e g cyclohexyl, or heteroaryl, e g thienyl or fury!

Referring to the general formula (I) where R ² represents a group

X

^/

X is suitably O^-Q alkenyl, e g allyl, or C-j _5 alkyl, e g methyl, ethyl, propyl or pentyl, which optionally contains an oxygen group within the chain and is optionally substituted by a group selected from hydroxy, C-| _6 alkoxy, NHSO2R ¹² , CO ₂ R ^{1 4} , CONR ^{1 5} R ¹⁶ , or SO ₂ NHR ¹⁷ , and R ⁸ is suitably hydrogen, 03.7 heterocycloalkyl, e g pyrrolidine or morpholine, aryl, e g phenyl which is optionally substituted by C0 ₂ R ¹⁴ , or heteroaryl, e g oxadiazole optionally substituted by hydroxy, triazole, or tetrazole optionally substituted by C-μβ alkyl

R ³ is preferably C**j _3 alkyl, e g methyl, or halogen, e g chlorine or bromine

R ⁴ , R ⁵ and R ⁶ are preferably hydrogen, or halogen, e.g. fluorine.

R7 is preferably hydrogen.

A preferred subclass of the compounds of formula (I) is defined by compounds of formula (IA)

where R ^{1 A} represents a group

8A

^■ R'

X ^A represents a bond or C<|_ alkyl;

R ⁸ A represents hydrogen, C3.7 cycloalkyl, aryl optionally substituted by halogen, or heteroaryl; R ^A represents a group

X ^B represents C-μ alkyl optionally substituted by CO ^R14A R ^8B represents hydrogen, phenyl substituted by CO R ^14A , oxadiazole substituted by a hydroxy group, or an unsubstituted C-linked tetrazole group; R ^A represents C**j_3 alkyl or halogen; and pharmaceutically acceptable derivatives or solvates thereof.

Suitable compounds of general formula (I) for use according to the invention are;

N-Cyclohexyl-3,N-dimethyl-5-[2-(pyridin-4-ylamino)-ethoxy ]-benzamide; 3-Chloro-N-cyclohexyl-N-methyl-5-[2-(pyridin-4-ylamino)-etho xy]-benzamide;

3-Bromo-N-cyclohexyl-N-methyl-5-[2-(pyridin-4-ylamino)-et hoxy]-benzamide;

N-Allyl-3-chloro-N-cyclohexyl-5-[2-(pyridin-4-ylamino)-et hoxy]-benzamide;

N-Allyl-3-bromo-N-cyclohexyl-5-[2-(pyridin-4-ylamino)-eth oxy]-benzamide;

({3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-cycl ohexyl-amino)-acetic acid; ({3-Bromo-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-cyclohex yl-amino)-acetic acid;

N-Allyl-3-chloro-N-cyclopentyl-5-[2-(pyridin-4-ylamino)-e thoxy]-benzamide;

N-Allyl-3-bromo-N-cyclopentyl-5-[2-(pyπdιn-4-ylamιno)-eth oxyj-benzamιde, 3-Chloro-N-propyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-N-(tet rahydro-pyran-4-yl)- benzamide,

3-Bromo-N-propyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-N-(t etrahydro-pyran-4-yl)- benzamide,

3-Chloro-N-propyl-N-pyπdιn-3-yl-5-[2-(pyπdιn-4-ylamι no)-ethoxy]-beπzamide, 3-Bromo-N-propyl-N-pyπdιn-3-yl-5-[2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde, 3-Chloro-N-(3,5-dιfluorophenyl)-N-propyl-5-[2-(pyπdιn-4-y lamιno)-ethoxy]- benzamide, 3-Bromo-N-(3,5-difluorophenyl)-N-propyl-5-[2-(pyridιn-4-yla mιno)-ethoxy]- benzamide;

2-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -(2,4-dιfluoro-benzyl)-amιno]- butyπc acid,

4-[({3-Chloro-5-[2-(pyridιn-4-ylamιno)-ethoxy]-benzoyl} -ιsobutyl-amιno)-methyl]- benzoic acid;

4-[2-({3-Chloro-5-[2-(pyridιn-4-ylamιno)-ethoxy]-benzoy l}-isobutyl-amino)-ethyl]- benzoic acid;

3-Chloro-N-cyclopentyl-5-[2-(pyridin-4-ylamino)-ethoxy]-N -(3- trifluoromethanesulfonylamino-propyl)-benzamide,

3-Chloro-N-isopropyl-N-methyl-5- 2-(pyridin-4-ylamino)-ethoxy]-benzamide; N-[2-(3-Amino-[1 ,2,4]oxadiazol-5-yl)-ethyl]-3-chloro-N-isopropyl-5-[2-(pyrid ιn-4- ylamιno)-ethoxy]-benzamide;

N-(2-Carbamoyl-ethyl)-N-ιsopropyl-3-methyl-5-[2-(pyrιd� �n-4-ylamιno)-ethoxy]- benzamide;

N-(2-Carbamoyl-ethyl)-3-chloro-N-cyclopropylmethyl-5-[2-( pyridin-4-ylamino)- ethoxy]-benzamide,

N-(2-Carbamoyl-ethy!)-3-chloro-5-[2-(pyπdιn-4-ylamino)- ethoxy]-N-(tetrahydro- furan-2-ylmethyl)-benzamide;

N-(2-Carbamoyl-ethyl)-3-chloro-N-(2,2-dιmethyl-propyl)-5 -[2-(pyridιn-4-ylamιno)- ethoxyj-benzamide,

N-(2-Carbamoyl-ethyl)-3-chloro-N-isopropyl-5-[2-(pyπdin- 4-ylamιno)-ethoxy]- benzamide;

N-(2-Carbamoyl-ethyl)-3-chloro-N-ιsobutyl-5-[2-(pyrιdι n-4-ylamιno)-ethoxy]- benzamide;

6-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -(2-fluoro-benzyl)-amino]-

hexanoic acid, 6-({3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}-ιs obutyl-amιno)-hexanoιc acid,

6-[{3-Chloro-5-[2-(ρyπdιn-4-ylamιno)-ethoxy]-benzoyl} -(2-methoxy-ethyl)-amιno]- hexanoic acid,

6-({3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- cyclohexylmethyl-amιno)- hexaπoic acid,

6-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -(3-fluoro-beπzyl)-amιno]- hexanoic acid,

6-({3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -pyπdm-4-ylmethyl-amιno)- hexanoic acid,

N-(5-Carbamoyl-pentyl)-3-chloro-N-furan-2-ylmethyl-5-[2-( pyrιdιn-4-ylamιno)- ethoxy]-benzamιde,

N-(5-Carbamoyl-pentyl)-3-chloro-5-[2-(pyπdιn-4-ylamιno )-ethoxy]-N-(2,2,2-trιfluoro- ethyl)-benzamιde,

N-(5-Carbamoyl-pentyl)-3-chloro-N-(2-fluoro-benzyl)-5-[2- (pyrιdιn-4-ylamιno)- ethoxy]-benzamιde,

N-(5-Carbamoyl-pentyl)-3-chloro-N-(2-methoxy-ethyl)-5-[2- (pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

N-(5-Carbamoyl-pentyl)-3-chloro-N-cyclohexylmethyl-5-[2-( pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

N-(5-Carbamoyl-pentyl)-3-chloro-N-ιsobutyl-5-[2-(pyπdι n-4-ylamιno)-ethoxy]- benzamide,

N-(5-Carbamoyl-pentyl)-3-chloro-5-[2-(pyrιdιn-4-ylamιn o)-ethoxy]-N-thιophen-2- ylmethyl-benzamide,

1-{3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}-p ιperιdιne-2-carboxylιc acιd,

4-({3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- cyclobutyl-amιno)-butyπc acid,

4-({3-Chloro-5-[2-(pyπdιn-4-yiamιno)-ethoxy]-benzoyl}- furan-2-ylmethyl-amιno)- butyπc acid,

4-[{3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- (3-fluoro-benzyl)-amιno]- butyπc acid,

{3-Chloro-5-[2-(pyπdιn-4-ylamιπo)-ethoxy]-phenyl}-(2- methyl-pιpeπdιn-1 -yl)- methanone,

3-Chloro-N-(2-dιethylcarbamoyl-ethyl)-N-ιsopropyl-5-[2- (pyrιdιn-4-ylamιno)- ethoxyj-benzamide,

3-Chloro-N-ιsopropyl-N-(3-methanesulfonylamιno-propyl)-5-[ 2-(pyrιdιn-4-ylamιno)- ethoxy]-benzamιde,

3-Chloro-N-ιsopropyl-N-[3-(propane-1 -sulfonylamιno)-propyl]-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-ιsopropyl-N-(3-oxo-3-pιpeπdιn-1 -yl-propyl)-5-[2-(pyπdιn-4-ylamιno)- ethoxyj-benzamide,

3-Chloro-N-[2-(ethyl-methyl-carbamoyl)-ethyl]-N-ιsopropy l-5-[2-(pyrιdιn-4-ylamιno)- ethoxyj-benzamide,

3-Chloro-N-ιsopropyl-N-(3-oxo-3-pyrrolιdιn-1 -yl-propyl)-5-[2-(pyrιdιn-4-ylamιno)- ethoxy]-benzamιde,

3-Chloro-N-ιsopropyl-N-(3-morpholιn-4-yl-3-oxo-propyl)- 5-[2-(pyπdιn-4-ylamιno)- ethoxyj-benzamide mixture with 3-({3-chloro-5-[2-(pyrιdιn-4-yiamιno)-ethoxy]- benzoyl}-ιsopropyl-amιno)-propιonιc acid (1 2),

N-(2-tert-Butylcarbamoyl-ethyl)-3-chloro-N-ιsopropyl-5-[ 2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

3-Chloro-N-[2-(2,2-dιmethyl-propylcarbamoyl)-ethyl]-N-ι sopropyl-5-[2-(pyπdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-ιsopropyl-N-(3-oxo-3-thιomorpholιn-4-yl-pro pyl)-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-ιsopropyl-N-(3-oxo-3-thιazolιdιn-3-yl-prop yl)-5-[2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

3-Chloro-N-(3-ethanesulfonylamιno-propyl)-N-ιsopropyl-5 -[2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

3-Chloro-N-ιsopropyl-N-[3-(propane-2-sulfonylamιno)-pro pyl]-5-[2-(pyπdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-(4-fluoro-phenyl)-5-[2-(pyπdιn-4-ylamιno)-e thoxy]-N-(3-{1 ,2,4]tπazol-1- yl-propyl)-benzamιde,

3-Chloro-N-cyclopeπtyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy ]-N-(2-[1 ,2,4]tπazol-1 -yl- ethyl)-benzamιde,

3-Chloro-N-cyclopentyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy ]-N-(4-[1 ,2,4]tπazol-1 -yl- butyl)-benzamιde,

3-Chloro-N-(4-fluoro-phenyl)-5-[2-(pyπdιn-4-ylamιno)-e thoxy]-N-(3-tetrazo!-2-yl- propyl)-benzamιde,

3-Chloro-N-(3-fluoro-phenyl)-5-[2-(pyπdιπ-4-ylamιno)- ethoxy]-N-(3-tetrazol-2-yl- propyl)-benzamιde,

3-Chloro-N-(2-fluoro-phenyl)-5-[2-(pyrιdιn-4-ylamιno)- ethoxy]-N-(3-tetrazol-2-yl-

propyl)-benzamιde,

3-Chloro-N-phenyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-N-(2 -tetrazol-2-yl-ethyl)- benzamide

3-Chloro-N-phenyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-N-(2 -[1 2,3]tπazol-2-yl-ethyl)- benzamide,

3-Chloro-N-phenyl-5-[2-(ρyrιdιn-4-ylamιno)-ethoxy]-N- [2-(pyrιdιn-2-yloxy)-ethyl]- benzamide,

3-Chloro-N-ιsopropyl-N-(2-methoxy-ethyl)-5-[2-(pyrιdιn -4-ylamιno)-ethoxy]- benzamide,

6-({3-Chioro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-beπzoyl }-thιophen-2-ylmethyl-amιno)- hexanoic acid,

6-[{3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- (2-methyl-butyl)-amιno]- hexanoic acid

{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-phenyl}-(2, 5-dιmethyl-pyrrolιdιn-1 -yl)- methanone,

4-({3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -naphthalen-1-ylmethyl- amιno)-butyπc acid,

4-[{3-Chloro-5-[2-(pyndιn-4-ylamιno)-ethoxy]-benzoyl}-( 1-methyl-1 H- benzoιmιdazol-2-yl)-amιno]-butyrιc acιd,

3-Chioro-N-ιsopropyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]- N-(3- tπfluoromethanesulfonylamιno-propyl)-benzamιde,

N-(3-Amιno-propyl)-3-chlqro-N-ιsopropyl-5-[2-(pyπdιn- 4-ylamιno)-ethoxy]- benzamide,

({3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}-cy clopentyl-amιno)-acetιc acid,

3-Chloro-N-cyclopentyl-N-propyl-5-[2-(pyndιn-4-ylamιno) -ethoxy]-benzamιde,

3-Chloro-N-cyclopentyl-N-(3-hydroxy-propyl)-5-[2-(pyπdι n-4-ylamιno)-ethoxy]- benzamide,

3-Chloro-N-propyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-N-(t etrahydro-pyran-4-yl)- benzamide,

3-Chloro-N-cyclopentyl-N-(2,3-dιhydroxy-propyl)-5-[2-(py πdιn-4-ylamιno)-ethoxy]- benzamide,

3-Chloro-N-cyclopentyl-N-(3-morpholιn-4-yl-propyl)-5-[2- (pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

4-({3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- cyclopentyl-amιno)-butyrιc acid ethyl ester,

3-Chloro-N-cyclopentyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-N- (3-pyrrolιdιn-1 -yl- propy!)-beπzamιde

N-(3-Carbamoyl-propyl)-3-chloro-N-cyclopentyl-5-[2-(pyπd ιn-4-ylamιno)-ethoxy]- benzamide

N-(2-Carbamoyl-ethyl)-3-chloro-N-cyclopentyl-5-[2-(pyrιd ιn-4-ylamιno)-ethoxy]- benzamide,

N-CarbamoylmethyI-3-chloro-N-cyclopentyl-5-[2-(pyπdιn-4 -ylamιno)-ethoxy]- benzamide,

3-Chloro-N-^thyl-N-phenyl-5-[2^pyπdιn-4-ylamιno)-ethox y]-benzamιde,

N-(2-Carbamoyl-ethyl)-3-chloro-N-cyclopropyl-5-[2-(pyπd� �n-4-ylamιno)-ethoxy}- benzamide,

3-Chloro-N,N-dιpropyl-5-[2-{pyπdιn-4-ylamιno)-ethoxy] -benzamιde,

4-({3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -cyclopentyl-amιno)-butyrιc acid,

N-(2-Carbamoyl-ethyl)-3-chloro- -phenyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]- benza ide,

N-(2-Carbamoyl-ethyl)-3-chloro-N-(2-chloro-phenyl)-5-[2-( pyrιdιn-4-ylamιno)- ethoxyj-benzamide,

N-(2-Carbamoyl-ethyl)-3-chloro-N-(2-fluoro-phenyl)-5-[2-( pyπdιn-4-ylamιno)- ethoxyj-benzamide;

4-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -(2-fluoro-phenyl)-amιno]- butyπc acid methyl ester,

4-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl} -(2-fluoro-phenyl)-amιno]- butyπc acid,

3-Chloro-N-{2-fluoro-phenyl)-N-{4-oxo-4-pyrrolιdιn-1 -yl-butyl)-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde;

N-(3-Carbamoyl-propyl)-3-chloro-N-(2-fluoro-phenyl)-5-[2- (pyπdιn-4-ylamιno)- ethoxyj-benzamide,

4-((2-Carbamoyl-phenyl)- 3-chlcro-5-[2-(pyπdιn-4-yiamιno)-ethoxy]-benzoyl}- amιno)-butyπc acid methyl ester

4-((2-Carbamoyl-phenyl)-{3-chlcro-5-[2-(pyrιdιn-4-ylam� �no)-ethoxy]-benzoyl}- amιno)-butyπc acid

3-Chloro-N-(2-fluoro-phenyl)-5-[2-(pyπdιn-4-ylamιno)-e thoxy]-N-[3-(1 H-tetrazol-5- yl)-propyl]-beπzamιde,

3-Chloro-N-[2-(2,3-dιhydroxy-propoxy)-ethyl]-N-(2-fluoro -phenyl)-5-[2-(pyπdιn-4- ylamιno)-ethoxy]-benzamιde,

(R)-1 -{3-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoyl}- (2-fluoro-phenyl)- amιno]-propyl}-pyrrolιdιne-2 -carboxylic acid,

3-Chloro-N-phenyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-N-( 2-sulfamoyl-ethyl)- benzamide,

3-Chloro-N-[2-(ethyl-methyl-carbamoyl)-ethyl]-N-phenyl-5- [2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

3-Chloro-N-[2-(ethyl-methyl-carbamoyl)-ethyl]-N-phenyl-5- [2-(pyπdιn-4-ylamιno)- ethoxy]-beπzamιde,

N-(2-tert-Butylcarbamoyl-ethyl)-3-chloro-N-phenyl-5-[2-(p yπdιn-4-ylamιno)-ethoxy]- benzamide,

3-Chloro-N-[2-(2,2-dιmethyl-propylcarbamoyl)-ethyl]-N-ph enyl-5-[2-(pyπdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-(3-oxo-3-thιomorpholιn-4-yl-propyl)-N-phenyl -5-[2-(pyrιdιn-4-ylamιno)- ethoxyj-benzamide,

3-Chloro-N-(3-oxo-3-thιazolιdιn-3-yl-propyl)-N-phenyl- 5-[2-(pyrιdιn-4-ylamιno)- ethoxyj-benzamide;

3-Chloro-N-ιsopropyl-N-[2-(1 -methyl-1 H-tetrazol-5-yl)-ethyl]-5-[2-(pyπdtn-- - ylamιno)-ethoxy]-benzamide,

3-Chloro-N-(3,5-difluoro-phenyl)-N-propyl-5-[2-(pyridιn- 4-ylamιno)-ethoxy]- benzamide,

3-Chloro-N-(3-morpholιn-4-yl-proρyl)-5-[2-(pyπdιn-4-y lamιno)-ethoxy]-N-

(tetrahydro-pyran-4-yl)-benzamιde,

3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-N-(3-pyrrol� �dιn-1-yl-propyl)-N-

(tetrahydro-pyran-4-yl)-benzamιde,

N-(2-Carbamoyl-ethyl)-3-chloro-N-(1 -propyl-butyl)-5-[2-(pyridιn-4-ylamιno)-ethoxy]- benzamide,

3-Chloro-N-cyclopentyl-N-(4-oxo-4-pyrrolιdιn-1-yl-butyl )-5-[2-(pyrιdιn-4-ylamιno)- ethoxy]-benzamιde;

3-Chloro-N-ethyl-N-(2-fluoro-phenyl)-5-[2-(pyrιdιn-4-yl amino)-ethoxy]-benzamιde,

3-Chloro-N-propyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-N-[1 ,3,4]thιadιazol-2-yl- benzamide,

3-Chloro-N-propyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-N-th ιazol-2-yl-benzamιde,

3-Chloro-N-[2-(2,3-dιhydroxy-propoxy)-ethyl]-N-phenyl-5- [2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

N-(2-tert-Butylsulfamoyl-ethyl)-3-chloro-N-phenyl-5-[2-(p yrιdιn-4-ylamιno)-ethoxy]-

benzamide

3-Chloro-N-(2-ιsopropylsulfamoyl-ethyl)-N-phenyl-5-[2-(p yrιdιn-4-ylamιno)-ethoxy]- benzamide

3-Chloro-N-ιsopropyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]- N-[2-(pyπdιn-2-yloxy)-ethyl]- benzamide,

3-Chloro-N-[2-(2,3-dιhydroxy-propoxy)-ethyl]-N-(4-fluoro -phenyl)-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-cyclopentyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy ]-N-[2-(1 H-tetrazol-5-yl)- ethyl]-benzamιde,

3-Chloro-N-ιsopropyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy] -N-(2-[1 ,2,4]tπazol-1-yl-ethyl)- benzamide,

3-Chloro-N-[2-(3-methyl-but-2-yl-carbamoyl)-ethyl]-N-ιso propyl-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-[2-(3,3-dιmethyl-but-2-yl-carbamoyl)-ethyl]-N -ιsopropyl-5-[2-(pyπdιn-4- ylamιno)-ethoxy]-benzamιde, 3-Chloro-N-[2-(5-hydroxy-[1 ,2,4]oxadιazol-3-yl)-ethyl]-N-ιsopropyl-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde,

N-tert-Butyl-N-(2-tert-butylcarbamoyl-ethyl)-3-chloro-5-[ 2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

N-(2-tert-Butylcarbamoyl-ethyl)-3-chloro-N-cyclobutyl-5-[ 2-(pyrιdιn-4-ylamιno)- ethoxy]-beπzamιde,

3-Chioro-N-cyclobutyl-N-[2-(2,2-dιmethyl-propylcarbamoyl )-ethyl]-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde,

N-(2-Carbamoyl-ethyI)-3-chloro-N-cyclobutyl-5-[2-(pyπdι n-4-ylamιno)-ethoxy]- benzamide , 3-Chloro-N-ιsopropyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-N-( 2-su!famoyl-ethyl)- benzamide ,

3-Chloro-N-(2,2-dιmethyl-propylsulfamoyl-ethyl)-N-ιsopr opyl-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde ,

6-({3-Chloro-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- ιsopropyl-amιπo)-hexanoιc

N-(2-tert-Butylcarbamoyl-ethyl)-N-ιsopropyl-3-methyl-5-[ 2-(pyrιdιπ-4-ylamιno)- ethoxyj-benzamide,

N-(5-tert-Butylcarbamoyl-pentyl)-N-ιsopropyl-3-methyl-5- [2-(pyπdιn- -ylamιno)- ethoxyj-benzamide ,

3-Chloro-N-[5-(2,2-dιmethyl-propylcarbamoyl)-pentyl]-N-ιso propyl-5-[2-(pyπdιn-4- ylamιno)-ethoxy]-beπzamιde

N-(5-Carbamoyl-pentyl)-N-ιsopropyl-3-methyl-5-[2-(pyπd� �n-4-ylamιno)-ethoxyj- benzamide , 3-Chloro-N-(2-(4-tert-butylphenyl)-ethyl)-N-ιsopropyl-5-[2- (pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

3-Chloro-N-[2-(1 , 1 -dιmethyl-propylcarbamoyl)-ethyl]-N-ιsopropyl-5-[2-(pyπd� �n-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N-ιsopropyl-N-(3-oxo-3-thιazolιdιn-3-yl-prop yl)-5-[2-(pyπdιn-4-ylamιno)- ethoxy]-benzamιde,

N-{2-(2,2-dιmethylpropylcarbamoyl)-ethy!}-N-ιsopropyl-3 -methyl-5-[2-(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde,

3-(lsopropyl-{3-methyl-5-t2-(pyrιdιn-4-ylamιno)-ethoxy ]-benzoyl}-amιno)-propιonιc acid, 3-(lsopropyl-{3-methyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-be nzoyl}-amιno)-propιonιc acid methyl ester,

N-(5-tert-Butylcarbamoyl-pentyl)-3-chloro-N-ιsopropyl-5- [2-(pyπdιn-4-ylamιno)- ethoxyj-benzamide,

6-({3-Methyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- ιsopropyl-amιno)-hexanoιc acid,

N-(2-Cyano-ethyl)-N-ιsopropyl-3-methyl-5-[2-(pyπdιn-4- ylamιno)-ethoxy]-benzamιde,

3-Chloro-N,N-dιιsopropyl-5-[2-(pyrιdιn-4-ylamιno)-et hoxy]-benzamιde,

3-Chloro-N-ιsopropyl-5-[2-(pyrιdιn-4-ylamιno)ethoxy]- N-[3-(2,2-dιmethyl- propιonylamιno)-propyl]-benzamιde, 3-Chloro-N-ιsopropyl-5-[2-(pyrιdιn-4-ylamιno)ethoxy]-N-[ 3-(3,3-dιmethyl- butyrylamιno)-propyl]-benzamιde,

6-({3-Methyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoyl}- ιsopropyl-amιno)-hexanoιc acid, and pharmaceutically acceptable derivatives or solvates thereof

Particularly suitable compounds of the invention include

3-Chloro-N{2-(5-hydroxy-[1 ,2,4]oxadιazol-3-yl)-ethyl}-N-ιsopropyl-5-[2[(pyrιdιn-4- ylamιno)-ethoxy]-benzamιde ,

4-({3-Chloro-5-[2-(pyπdιn- -ylamιno)-ethoxy]-benzoyl}-cyclobutyl-amιno)-butyrιc acid,

6-({3-Chloro-5-[2-(pyridιn-4-ylamino)-ethoxy]-benzoyl}-isob utyl-amino)-hexanoic acid;

4-[({3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-� �sobutyl-amino)-methyl]- benzoic acid ; 4-[2-({3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-is obutyl-amino)-ethyl]- benzoic acid;

4-({3-Chloro-5-[2-(pyridin-4-yiamino)-ethoxy]-benzoyl}-cy clopentyl-amino)-butyric acid ethyl ester;

4-({3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-cy clopentyl-amino)-butyric acid;

3-Chloro-N-cyclopentyl-5-[2-(pyridin-4-ylamino)-ethoxy]-N -[2-(1 H-tetrazol-5-yl)- ethylj-benzamide;

6-({3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-cy clohexylmethyl-amino)- hexanoic acid; 6-({3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]benzoyl}-thioph en-2-ylmethyl-amino)- hexanoic acid;

4-[{3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-(2 -fluoro-phenyl)-amino]- butyric acid methyl ester;

4-[{3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-(2 -fluoro-phenyl)-amino]- butyric acid;

3-Chloro-N-(2-fluoro-phenyl)-5-[2-(pyridin-4-ylamino)-eth oxy]-N-[3-(1 H-tetrazol-5-yl)- propyl]-benzamide; and pharmaceutically acceptable derivatives or soivates thereof.

By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds of formula (I). It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position.

Preferred pharmaceutically acceptable derivatives of the compounds of formula (I) are pharmaceutically acceptable salts thereof

Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric fumaric, maieic, phosphoric, glycollic, lactic, salicylic, succinic, toluene- p-sulphonic di-para-toluoyl tatrate, tartaric, acetic, citric, methanesulphonic, formic, benzoic malonic, naphthaiene-2-sulphonιc and benzenesulphonic acids Other acids such as oxalic, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts

The compounds of formula (I) are thrombin inhibitors and as such are useful in the treatment of clinical conditions susceptible to amelioration by administration of a thrombin inhibitor Such conditions include acute vascular diseases such as coronary thrombosis, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, restenosis, and atrial fibrillation, in oedema and PAF mediated inflammatory diseases such as adult respiratory shock syndrome and reperfusion damage, the treatment of disseminated intravascular coagulopathy as a result of e g septic shock, the treatment of pulmonary fibrosis, the treatment of tumour metastasis, neurogenerative disease such as Parkinson's and Alzheimer's diseases, viral infection, Kasabach Merπtt Syndrome, Haemolytic uremic syndrome, arthritis and osteoporosis They may also be useful as anti-coagulants for extracorporeal blood in for example, dialysis, blood filtration, bypass, and blood product storage, and in the coating of invasive devices such as prostheses, artificial valves and catheters in reducing the risk of thrombus formation

The ability of the compounds of formula (I) to inhibit thrombin may be exhibited by methods as described hereinafter

Accordingly the present invention provides a method of treatment of a mammal including man, suffering from conditions susceptible to amelioration by a thrombin inhibitor which method comprises administering to the subject an effective amount of

a compound of general formula (I) or a pharmaceutics ly acceptable derivative thereof

References in this specification to treatment include proph ylactic treatment as well as the alleviation of symptoms.

In a further aspect, the present invention provides a comoound of formula (I) or a pharmaceutically acceptable derivative thereof for use as a therapeutic agent for use in medicine, particularly human medicine

In a further aspect, the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition susceptible to amelioration by a thrombin inhibitor.

While it is possible that, for use in therapy, a compounα of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients The compounds of the present invention may be used in combination with other antithrombotic drugs such as thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, thrombolytic drugs such as tissue plaminogen activator and streptokinase, non-steroidal anti-inflammatory drugs such as aspirin, and the like.

Thus the compounds for use according to the present invention may be formulated for oral, buccal, parenteral, topical, rectal, or transdermal administration or in a form suitable for administration by inhalation or insufflation (eitner through the mouth or the nose).

For oral administration, the pharmaceutical compositions nay take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically

acceptable excipients such as binding agents (e g pregelatinised maize starch polyvinylpyrrolidone or hydroxypropyl methylcellulose) fillers (e g lactose microcrystalline cellulose or calcium hydrogen phosphate) lubricants (e g magnesium stearate talc or silica), disintegrants (e g potato starch, sodium starch glycollate or croscarmellose sodium) or wetting agents (e g sodium lauryl sulphate) The tablets may be coated by methods well known in the art The capsules may contain a non-aqueous liquid formulation, for example, a solution or suspension 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 (e g sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e g lecithin or acacia), non-aqueous vehicles (e g almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), and preservatives (e g methyl or propyl-p-hydroxybenzoates or sorbic acid) The preparations may also contain buffer salts, flavouring, colouring and 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 according to the present invention may be formulated for parenteral administration by injection e g by bolus injection or continuous infusion Formulations for injection may be presented in unit dosage form e g in ampoules or in multi-dose containers, with an added preservative The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising 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

The compounds according to the present invention may be formulated for topical administration by insufflation and inhalation Examples of types of preparation for topical administration include sprays and aerosols for use in an inhaier or insufflator

Powders for external application may be formed with the aid of any suitable powder base, for example, lactose, talc, or starch Spray compositions may be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as metered dose inhalers, with the use of a suitable propellant

The compounds according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e g containing conventional suppository bases such as cocoa butter or other glycerides

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection Thus, for example, the compounds according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt

For transdermal administration, the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal lontophoretic patch

As stated above, the compounds of the invention may also be used in combination with other therapeutic agents The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent

A proposed dose of the compounds according to the present invention for administration to a human (of approximately 70kg body weight) is 0 01 mg to 10g, suitably 0 1mg to 1g of the active ingredient per unit dose, expressed as the weight of free base The unit dose may be administered, for example, 1 to 4 times per day The dose will depend on the route of administration It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the seventy of the condition to be treated The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian

The compounds of the invention may be prepared by any of the processes known in the art for the preparation of similar compounds. For example, according to a first process (A) wherein R ¹ , R ² , R ³ , R ⁴ , R ^* -*\ R ⁶ and R ⁷ are as previously defined, compounds of formula (I) may be prepared by reaction of a compound of formula (II) with a compound of formula (III),

where R ^7' represents R ⁷ or a suitable protecting group such as tert-butoxycarbonyl. The reaction is carried out in the presence of an activating agent or agents such as 1 -hydroxybenzotriazole, 2-(1 H-benzotriazoI-1-yl)-1 ,1 ,3,3-tetramethyiuronium tetrafluoroborate (TBTU), and a base such as ethyldiisopropylamine in a suitable solvent such as N.N-dimethylformarnide, 2-ethoxy-1-ethoxycarbonyl-1 ,2- dihydroquinolone in a suitable solvent such as acetonitrile, bromo-tris-pyrrolidino- phosphonic hexafluorophosphate in a suitable solvent such as N,N- dimethylformamide, or oxalyl chloride in a suitable solvent such as dichloromethane, followed by deprotection, where appropriate, of any protecting groups present under standard conditions, e.g. acidic conditions for the removal of a tert-butoxycarbonyl group.

Compounds of formula (II) may be prepared by oxidation of the corresponding alcohol of formula (IV)

where R ^7' is as defined above. The conversion is effected by treatment of the alcohol with an oxidising agent such as manganese dioxide or dichlorodicyanobenzoquinone in a suitable solvent such as 1 ,4-dioxan to give the

corresponding aldehyde which is then treated with an oxidising agent such as sodium chlorite in the presence of sulfamic acid in a mixture of water and 1 ,4- dioxan

Where R ³ is C-1.3 alkyl or C-| _ alkoxy and R ⁷ is defined above, compounds of formula (IV) may be prepared by reaction of compounds of formula (V) with compounds of formula (VI),

The reaction is suitably carried out in the presence of an activating agent or agents such as TBTU in a suitable solvent such as N,N-dιmethylformamide, followed by reduction of the carbonyl groups with a reducing agent such as lithium aluminium hydride in tetrahydrofuran

Compounds of formula (V) may be prepared from compounds of formula (VII)

using a suitable ester of bromoacetic acid, for example ethyl, in the presence of a suitable base such as potassium carbonate in a suitable solvent such as N,N- dimethylformamide, followed by deprotection of the ester group by conventional methods, for example using a base such as aqueous sodium hydroxide in a suitable solvent such as methanol

Where R ³ represents halogen and R ⁷ ' is R ⁷ , compounds of formula (IV) may be prepared from compounds of formula (VIII)

where R ³ represents halogen and R ^{1 8} represents a suitable alkyl protecting group, using a suitable reducing agent such as lithium aluminium hydride in a suitable solvent such as tetrahydrofuran

Compounds of formula (VIII) may be prepared from compounds of formula (IX) and

where R "and R ¹ are previously defined The reaction is carried out in the presence of an activating agent or agents such as 1 -hydroxybenzotriazole, TBTU, and a base such as ethyldiisopropylamine in a suitable solvent such as N,N- dimethylformamide

Compounds of formula (IX) may be prepared from compounds of formula (X)

where R ³ and R ⁸ are previously defined, using a suitable ester of bromoacetic acid, for example tert-butyl, in the presence of a suitable base such as potassium carbonate or sodium hydride in a suitable solvent such as N,N-dιmethylformamιde followed by selective deprotection of the alkanoic ester group by conventional methods, for example cleavage under acidic conditions using trifluoroacetic acid

Where R ³ represents halogen, compounds of formula (II) may also be prepared from compounds of formula (XI)

where R ⁷ is a suitable protecting group and R ^{1 8} is as defined above, by reaction with tert-butyl nitrite and the copper (II) salt of the halide in a suitable solvent such as acetonitrile, followed by deprotection of the the ester group under suitable aqueous base conditions Compounds of formula (XI) may be prepared by sequential reaction of ethylene glycol di-p-tosylate with a compound of formula (XH) and a compound of formula

where R ⁷ and R ^{1 8} are as defined above, using a suitable base such as sodium hydride in a suitable solvent such as N,N-dιmethylformamιde

According to a second process (B), compounds of formula (I) may be prepared by reaction of compounds of formula (XIV) and (XV)

(XIV) (XV) where L is a suitable leaving group such as tosylate, in the presence of a suitable base such as sodium hydride in a suitable solvent such as N N-dιmethy!formamιde

A compound of formula (XIV) may be prepared by reaction of a compound of formula (XVI) with a compound of formula (III)

(XVI)

where R ¹ is a suitable protecting group such as methyl, under conditions suitable for amide coupling as hereinbefore described above, followed by deprotection of R ¹⁹ under standard conditions, for example boron tribromide removal of a methyl protecting group

It will be appreciated that a compound of formula (X) may be reacted with a compound of formula (XV) to give a compound which can be converted to a compound of formula (I) by the methods described above and herein below

According to a third process (C), compounds of formula (I) may be prepared by reaction of compounds of formula (II) with compounds of formula (III) which are bound to a solid phase resin via a carboxamide or carboxylate functional group on R ⁸ or X, by amide coupling techniques as described herein above, followed by deprotection of any protecting groups and cleavage from the resin under suitable conditions, such as acid treatment with a mixture of trifluoroacetic acid and dichloromethane Suitable resin mateπals are described hereinafter with reference to the accompanying examples

Compounds of formulae (III), (VI), (VII), (X), (XII) (XIII), (XV), and (XVI) are known compounds or may be prepared by standard methods

It will be appreciated by persons skilled in the art that compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) which are optionally protected by standard protecting groups, as precursors For instance compounds of formula (I) where R ¹ or R ² is R ^θ -X and X is substituted by a CN group, may be converted into compounds of formula (I) where X is substituted by e g

CONH2, NHSO ₂ R ¹² by methods well known in the art Further, compounds of formula (I) which contain an S0 ₂ NHR ¹⁷ substituent may be prepared by coupling compounds of formula (II) with a compound of formula (III) containing a sulfonylfluoπde group under standard coupling conditions followed by reaction with a primary amine R ¹⁷ NH ₂ , optionally in the presence of a suitable solvent such as dichloromethane, followed by deprotection of any protecting groups present

The compounds of the invention possess thrombm inhibitory activity as determined in vitro by their ability to inhibit human α-thrombin in a chromogenic assay, using N- p-tosyl-gly-pro-lys p-nitroani de as the chromogenic substrate All dilutions were made in a buffer consisting of 50 m HEPES, 150 mM NaCl, 5 mM CaCI ₂ 0 1 % PEG and at pH 7 4 Briefly, the substrate (final cone of 100μM) was added to thrombin (final cone of 1 nM) and the reaction monitored for 10 mins at 405nm using a Biotek EL340 plate reader, the assay was performed at room temperature To obtain IC ₅₀ S the data were analyzed using Kineticalc ^® with a 4-parameter curve fitting procedure to obtain the IC50 value To determine the IC50 at zero and 15 mins the compounds were premcubated with thrombin for these times prior to adding the chromogenic substrate

The invention is further illustrated by the following intermediates and examples

Abbreviations hplc high performance liquid chromatography

Rt Retention time DIPEA N-Ethyldiisopropylamine

DMF N,N-Dιmethylformamιde

DMAP 4-Dιmethylamιnopyrιdιne

TBTU 2-( 1 H-Benzotπazole-1 -yl)-1 , 1 ,3,3-tetramethyluronιum tetrafluoroborate

HOBt 1 -Hydroxybenzotriazole PyBrop ^® Bromo-tπs-pyrrolidiπo-phosphonium hexafluorophosphate

HATU ^® O-(7-azabenzotπazol-1 -yl)-1 ,1 ,3,3-tetramethyluronιum hexafluorophosphate

9-BBN 9-borobιcyclo-[3 3 1 ]-nonane

EEDQ= 2-ethoxy-1 -ethoxycarbonyl-1 ,2-dιhydroquιnolιne

Methods

Analytical hplc was carried out on a Hewlett Packard Series II 1090 Liquid Chromatograph using a Rainin Microsorb C18 column (size 4.6 x 150mm, catalog number 80-215-C5) operating at a flow rate of 1.5 ml/min. Eluents were A: 0.1 % trifluoroacetic acid/water, B: 0.05% trifluoroacetic acid/acetonitrile 5 Gradients:

System 1 : 15-95%B in A over 15min System 2: 0-75%B in A over 15min

System 3: Supelcosil LCABZ+Plus column (size 4.3mm x 3.3cm; 3mm particle size) operating at 1 ml/min flow rate. Eluents were A: 0.1 % formic acid in 0.01 M aqueous

10 ammonium acetate, B: 0.05% formic acid in acetonitrile:water (19:1 v/v) with a gradient of 0-100%B over 3.5min and then running isocratically at 100%B for 3.5min

Retention times are given for the wavelength stated.

Preparative hplc was carried out either on on a Dynamax 60A C18 column (size 15 41.4mm x 25cm, catalog number 83-241 -C) operating at a flow rate of 45ml/min

(eluents were the same as for analytical hplc) or a Supelcosil LC-ABZ column (size

21.2mm x 25cm) operating at 15ml/min (eluents were A: 0.1% trifluoroacetic acid

/water, B: 0.01 % trifluoroacetic acid in 95:5 acetonitrile/water) or Supelcosil

LCABZ+Plus column (size 21mm x 10cm; 5mm particle size) operating at 4ml/min 0 flow rate (eluents were A: 0.1 % formic acid in water, B: 0.05% formic acid in acetonitrile with a gradient of 0-95%B over 18.65 min.) This system used a Gilson

233XL autosampler/fraction collector.

Flash chromatography was performed on Silica gel 60 (particle size 40-63μM) Merck catalogue no. 109385

The following amines were synthesized using standard methodology: 5 N-Propyl-4-aminotetrahydropyran; Mass spectrum: Found: M ⁺ 143;

Cyclopentyl-(3-morpholin-4-yl-propyl)-amine; Mass spectrum: Found: MH ⁺ 213;

Cyclopentyl-(3-pyrrolidin-1 -yl-propyl)-amine; Mass spectrum: Found: MH ^* 197;

4-Cyclopentylamino-butyric acid ethyl ester; Mass spectrum: Found: MH" 200;

3-Cyclopentylamino-propionamide; Mass spectrum: Found: MH ⁺ 157; 30 2-Cyclopentylamino-acetamide; Mass spectrum: Found: MH ⁺ 143;

N-Propyl-2,5-difluoroaniline; Mass spectrum: Found: MH ⁺ 172;

3-(2-Fluoro-phenylamino)-propionitrile; Mass spectrum: Found: MH ⁺ 165:

3-(2-Chloro-phenylamino)-propionitrile; Mass spectrum. Found: MH ⁺ 181:

4-(2-Fluoro-phenylamιno)-butyrιc acid methyl ester, Mass spectrum Found MH"

212,

4-(2-Carbamoyl-phenylamιno)-butyπc acid methyl ester Mass spectrum Found

MH ⁺ 237, 5 4-(2-Fluoro-phenylamιno)-butyronιtπle, Hplc system 1 (λ = 254πm) Rt 8 0mm,

[2-(2,2-Dιmethyl-[1 ,3]dιoxolan-4-ylmethoxy)-ethyl]-phenyl-amιne and toluene-4- sulfonic acid 2,2-dιmethyl-[1 ,3]dιoxolan-4-ylmethyl ester, Mass spectrum Found

MH ⁺ 252,

[2-(2,2-Dιmethyl-[1 ,3]dιoxolan-4-ylmethoxy)-ethyl]-(2-fluoro-phenyl)-amιne, Mass 10 spectrum Found MH ⁺ 270,

[2-(2,2-Dιmethyl-[1 ,3]dιoxolan-4-ylmethoxy)-ethyl]-(4-fluoro-phenyl)-amιne Mass spectrum Found MH ⁺ 270,

(R)-1 -[3-(2-Fluoro-phenylamιno)-propyl]-pyrrolιdιne-2-carboxyl ιc acid tert-butyl ester,

Mass spectrum Found MH ⁺ 323, 15 3-Phenylamιno-propιonιc acid methyl ester, Mass spectrum Found MH ⁺ 180,

2-Phenylamιno-ethanesulfonyl fluoride, Mass spectrum Found MH ⁺ 201 ,

N-(3-Pyrrolιdιn-1-yl-propyl)-4-amιnotetrahydropyran; Mass spectrum Found MH ⁺

213,

N-(3-Moφholιn-4-yl-propyl)-4-amιnotetrahydropyran; Mass spectrum Found. MH ⁺ 20 229,

N-(2-Propylbutyl)-3-amιno-propιonamide, Mass spectrum Found MH ⁺ 187,

N-Propyl-2-amιno-thιazole , Mass spectrum Found: MH ⁺ 143,

3-lsopropylamιno propionic acid methyl ester; Mass spectrum Found MH ⁺ 146;

N-Propyl-2-amιno-[1 ,3,4]thιadιazole, Mass spectrum Found MH ^* 144, 25 2-(2-lsopropylamιno-ethyl)-N-[1 , 2, 4]-tπazole; Mass spectrum Found MH ⁺ 154,

3-(2-lsopropylamιno-ethyl)-5-hydroxy-[1 ,2,4]oxadιaxole tπfluoroacetate, Mass spectrum Found. MH ⁺ 172,

4-Fluorophenyl-(3-[1 ,2,4]tπazol-1 -yl-propyl)-amιne, Mass spectrum Found MH ⁺

221 , 30 4-Fluorophenyl-(3-tetrazol-2-yl-propyl)-amιne, Mass spectrum Found MH ⁺ 222,

Cyclopentyl -(2-[1 ,2,4]tπazol-1 -yl-ethyl)-amιne, Mass spectrum Found MH ⁺ 181 ,

Cyclopentyl -(4-[1 , 2, 4]tπazol-1 -yl-butyl)-amιne, Mass spectrum Found MH ⁺ 209,

3-Fluorophenyl-(3-tetrazol-2-yl-propyl)-amιne, Mass spectrum Found MH ⁺ 222,

2-Fluorophenyl-(3-tetrazol-2-yl-propyl)-amιne, Mass spectrum Found MH ^* 222, 35 Phenyl-(3-tetrazol-2-yl-propyl)-amιne, Mass spectrum Found MH ^* 190,

Phenyl-(3-[1 ,2,3]-tπazol-2-yl-propyl)-amιne , Mass spectrum Found MH ⁺ 189,

Phenyl-2-(pyπdιn-2-yloxy)-ethylamιne, Mass spectrum Found MH ⁺ 215, isopropyl-2-methoxy-ethylamιne, Mass spectrum Found MH ⁺ 118, N-(3-Cyclopentylamιno-propyl)-C,C,C-tπfluoro-methanesulfon amιde formate, Mass spectrum Found MH ⁺ 275 5-(2-lsopropylamιno-ethyl)-[1 ,2,4]oxadιazol-3-ylamιne, Mass spectrum Found MH ⁺

171 ,

3-(tert-Butylamιno)-propιonιc acid methyl ester, Mass spectrum Found MH ⁺ 160, 3-Cyclobutylamιno-propιonιc acid methyl ester, Mass spectrum Found MH ⁺ 158, 3-(Cyclobu.ylamιno)propιonιtπle, Mass spectrum Found MH ⁺ 125, 2-lsopropylamιno-ethanesulfonιc acid amide, Mass spectrum Found MH ⁺ 167, 2-lsopropylamιno-ethanesulfonιc acid (2,2-dιmethyl-propyl)-amιde, Mass spectrum Found MH ⁺ 237,

3-(2-lsopropylamιno-ethyl)-5-hydroxy-[1 ,2,4]oxadιaxole tπfluoroacetate, Mass spectrum Found MH ⁺ 172, lsopropyl-2-(4-rerf-butylphenyl)-ethylamιne, Mass spectrum Found MH ⁺ 220, and lsopropyl-2-(pyπdιn-2-yloxy)-ethylam.ne, Mass spectrum Found MH ⁺ 181

Intermediate 1

2-(3-Formyl-5-methyl-phenoxy)-acetιc acid ethyl ester

To a stirred suspension of anhydrous potassium carbonate (1 52g) in dry DMF (20ml) was added 3-hydroxy-5-methylbenzaldehyde ¹ (0 5g) The mixture was stirred under an atmosphere of nitrogen for 1.5h and then ethyl bromoacetate (045ml) was added The mixture was stirred for a further 18h and then evaporated to dryness under reduced pressure The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the combined organic phase was washed with water, saturated lithium chloride solution, and saturated sodium chloride solution The solution was dried over magnesium sulphate and concentrated to give the title compound as an amber-coloured gum (0 79g) Hplc system 1 (λ = 254nm) Rt 8 Omin

Intermediate 2

2-(3-Formyl-5-methyl-phenoxy)-acetιc acιd

A stirred solution of 2-(3-formyl-5-methyl-phenoxy)-acetιc acid ethyl ester (0 79g) in methanol (4ml) at 5 ^° C was treated with a 2M sodium hydroxide solution (3 6ml)

After 15mιn the mixture was allowed to warm to room temperature After a further 2h

the stirred solution was again cooled to 5°C and covered with ethyl acetate and the aqueous layer was adjusted to acidic pH with 2M hydrochloric acid The layers were separated and the aqueous phase was extracted with more ethyl acetate The combined organic phase was washed with water and brine and dried with magnesium sulphate Concentration gave a gummy solid which was triturated with diethyl ether giving, after drying, the title compound (0 47g) as a pale yellow solid Hplc system 1 (λ = 254nm) Rt 5 2mιn

Intermediate 3

2-(3-Formyl-5-methyl-phenoxy)-N-pyπdιn-4-yl-acetamιde

2-(3-Formyl-5-methyl-phenoxy)-acetιc acid (0 47g) and 4-amιnopyπdιne (0 46g) were dissolved in dry DMF (10ml) The resulting solution, stirring under a nitrogen atmosphere, was treated with TBTU (0 82g) The resulting mixture was stirred for 68h and then concentrated at reduced pressure to give a yellow viscous gum This crude material was purified by preparative hplc The purified product was partitioned between ethyl acetate and an aqueous solution saturated with sodium bicarbonate, sodium chloride and ammonium sulphate The organic phase was dried over magnesium sulphate and concentrated under reduced pressure giving the title compound as an off-white solid (040g) Mass spectrum Found MH ⁺ 271

Intermediate 4

(3-Methyl-5-f2-(pyrιαιn-4-ylamιno)-ethoxyl-phenyl, -methanol

A suspension of 2-(3-formyl-5-methyl-phenoxy)-N-pyrιdιn-4-yl-acetamιde (0 30g) in anhydrous tetrahydrofuran (1ml) , stirring under a nitrogen atmosphere, was cooled to about 1 C and treated with a 1 M tetrahydrofuran solution of lithium aluminium hydride (5 47ml) over a peπod of 3mιn After 15mιn the mixture was allowed to warm to room temperature After stirring for a further 22h the mixture was cooled to about 2 C and the excess reagent was quenched with cautious dropwise addition of wet tetrahydrofuran and then water The resulting aqueous mixture was partitioned between ethyl acetate and dilute sodium hydroxide solution saturated with sodium chloride and ammonium sulphate The organic phase was dried with magnesium sulphate and concentrated under reduced pressure and the resulting gum was triturated with diethyl ether giving, after drying, the title compound as an off-white solid (0 13g) Hplc system 2 (λ = 254nm) Rt 7 6mιn

Intermediate 5

3-Methyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxyl-benzaldehvde

A suspension of {3-methyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-phenyi}-methano l

(0 132g) and manganese dioxide (0 370g) in 1 ,4-dιoxan (5ml) was heated to reflux with stirring under an atmosphere of dry nitrogen for 5h After cooling to room temperature the mixture was filtered through Harbor te ^® and the pad washed with

1 ,4-dιoxan and then methanol The combined filtrates were evaporated to dryness under reduced pressure to give an off-white solid Trituration with diethyl ether gave, after drying, the title compound as a white powder (0 074g)

Hplc system 2 (λ = 254nm) Rt 8.9mιn

Intermediate 6

3-Methyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoιc acid trif luoroacetate salt A stirred solution of 3-methyl-5-[2-(pyπdιn-4-ylamino)-ethoxy]-benzaldehyde (0.074g) in a 3.2 v/v mixture of 1 ,4-dioxan and water (7ml) was treated with sulphamic acid (0.163g) and then sodium chlorite (0.208g). After 22h the mixture was cooled to 0 C and treated with an aqueous solution of sodium bisulphite until the mixture was colourless. The pH was adjusted to about 7 by the addition of saturated sodium bicarbonate solution and the mixture concentrated to about 5ml under reduced pressure and subjected to preparative hplc. The required fraction was concentrated and dried by addition of toluene followed by concentration at reduced pressure. This yielded the title compound as a white powder (0 061 g) Hplc system 2 (λ = 254nm) Rt 8.3min

Intermediate 7

3-Bromo-5-hvdroxybenzoιc acid methyl ester

A solution of sodium nitrite (5.9g) in water (17ml) was added to a stirred solution of

3-amιno-5-hydroxybenzoic acid methyl ester (12.2g) in a mixture of methanol (33ml) and concentrated sulphuric acid (66ml) at 0°C over 90min The reaction mixture was stored at 0°C and added over 2 h to a stirred mixture of copper (I) bromide

(32.3g) in 8% w/v aqueous hydrobromic acid (120ml) at 65°C After the addition was complete the reaction mixture was cooled to 0°C and then filtered The residue was washed with water, 1 M hydrochloric acid and further water The solid was extracted with diethyi ether and the residual solids removed by filtration The filtrate was dried

with anhydrous sodium sulphate and then concentrated under reduced pressure. This yielded the title compound as a red solid (10.5g). Hplc system 1 (λ = 254πm) Rt 7.5min

Intermediate 8

2-(5-Bromo-3-methoxycarbonyl-phenoxy)-acetic acid tert-butyl ester

To a stirred solution of 3-bromo-5-hydroxybeπzoic acid methyl ester (10.2g) and tert-butyl bromoacetate (9.7ml) in anhydrous DMF was added sodium hydride (60% dispersion in mineral oil, 2.6g). After 30min water (10ml) aws added. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was removed and the organic phase washed with further water, 1 M sodium hydroxide solution and dried with brine and over sodium sulphate. Concentration under reduced pressure gave the title compound as dark yellow gum (12.8g).

Hplc system 1 (λ = 254nm) Rt 11 4min

Intermediate 9

2-(5-Bromo-3-methoxycarbonyl-phenoxy)-acetic acid

A solution of 2-(5-bromo-3-methoxycarbonyl-phenoxy)-acetic acid tert-butyl ester (12.8g) in a mixture of dichloromethane (100ml) and trifluoroacetic acid (100ml) was stored at room temperature for 2h. The solution was concentrated under reduced pressure. The residual solid was suspended in toluene and the solvent removed under reduced pressure to give the title compound as a brown solid (10.6g). Hplc system 1 (λ = 254nm) Rt 7.3min

Intermediate 10

2-(5-Bromo-3-methoxycarbonyl-phenoxy)-N-pyridin-4-yl-acet amide A solution of 2-(5-bromo-3-rnethoxycarbonyl-phenoxy)-acetic acid (10.6g), TBTU (19.3g) and HOBt (5.1g) in dry DMF (50ml) was treated with DIPEA (9.9ml). The resulting solution was stirred under a nitrogen atmosphere and was then treated with 4-aminopyridine (3.6g) after 30min. The resulting mixture was stirred for 18h and then concentrated at reduced pressure to give a yellow viscous gum which was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with further water, 1 M sodium hydroxide solution, aqueous saturated ammonium chloride, water and dried with brine and over sodium sulphate. The organic phase was concentrated under reduced pressure giving the title compound as a yellow solid (6 60g).

Hplc system 1 (λ = 254nm) Rt 6 7mιn

Intermediate 1 1

(3-Bromo-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-phenyl, -methanol

A stnred solution of 2-(5-bromo-3-methoxycarbonyl-phenoxy)-N-pyπdιn-4-yl- acetamide (6 61 g) in anhydrous tetrahydrofuran (200ml) was treated with a 1 M diethyl ether solution of lithium aluminium hydride (56 1 ml) over a period of 20mιn A brown precipitate appeared and the mixture was stirred at room temperature for 6h The reaction mixture was treated with water (2ml) 1 M sodium hydroxide solution (2ml), water (6ml) and then with 2M hydrochloric acid (150ml) The reaction mixture was extracted with ethyl acetate and then basified with 2M sodium hydroxide solution The reaction mixture was reextracted with ethyl acetate The first organic phase was washed with saturated aqueous sodium bicarbonate and combined with the second organic phase The combined organic phase was washed with water and dried with brine and over sodium sulphate. Concentration of the organic phase gave a gum which was found to be unsatisfactory so the gum was partitioned between ethyl acetate and 2M hydrochloric acid. The aqueous layer was separated, basified to pH 10 and extracted with ethyl acetate. The organic phase was washed with water and dried with brine and over sodium sulphate Concentration under reduced pressure gave the title compound as an off-white solid (1.5g) Hplc system 1 (λ = 254nm) Rt 5 4min

Intermediate 12

3-Bromo-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-benzaldehyde

A suspension of {3-bromo-5-[2-(pyridιn-4-ylamιno)-ethoxy]-phenyi}-methanol (1 4g) and manganese dioxide (3.2g) in 1 ,4-dioxan (50ml) was heated to reflux with stirring under an atmosphere of dry nitrogen for 8h After cooling to room temperature the mixture was stirred at room temperature for 16h, and then filtered through Harborlite ^® and the pad washed with hot methanol The combined filtrates were evaporated to dryness under reduced pressure to give the title compound as an off- white solid (1.2g). Hplc system 1 (λ = 254nm) Rt 9 8mm

Intermediate 13

3-Bromo-5-f2-(pyπdin-4-ylamιno)-ethoxy1-benzoιc acid trifluoroacetate salt

A stirred solution of 3-bromo-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzaldehyde (1 2g) in 1 ,4-dιoxan and water (3 2 v/v, 50ml) was treated with sulphamic acid (2 5g) and then sodium chlorite (3 2g) After 3h the mixture was treated with an aqueous solution of sodium bisulphite until the mixture was colourless The mixture was concentrated under reduced pressure and extracted with several portions of hot ethanol The combined ethanolic solution was concentrated under reduced pressure and purified by preparative hplc The required fraction was concentrated and dried by addition of acetonitrile followed by concentration at reduced pressure This yielded the title compound as a white solid (0 495g) Hplc system 1 (λ = 254nm) Rt 9 Omin

Intermediate 14

3-Amιno-5-f2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno) ethoxVι-benzoιc acid methyl ester

To a stirred solution of pyπdιn-4-yl-carbamιc acid tert-butyl ester ² (3 9g) and ethylene glycol di-p-tosylate (7 4g) in DMF at room temperature under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 0 88g) Stirring was continued for 7h and then 3-amιno-5-hydroxybenzoιc acid, methyl ester ³ (2 5g) and sodium hydride (60% dispersion ιn"mιneral oil, 0 66g) were added The reaction mixture was stirred for 66hr and then water (10ml) added The mixture was concentrated under reduced pressure and the residue partitioned between 2M hydrochloric acid and ethyl acetate The aqueous phase was separated and the organic phase reextracted with 2M Hydrochloric acid The aqueous layers were combined and neutralised with sodium hydroxide pellets and then extracted with ethyl acetate The organic phase was washed with water and then dried with brine and over sodium sulphate Concentration under reduced pressure gave the title compound as a dark brown gum (4 2g) Mass spectrum Found MH ^* 388

Intermediate 1 5

3-[2-(tert-Butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy1-5 -chloro-benzoιc acid methyl ester

To a stirred suspension of anhydrous copper(ll)chloπde (0 67g) in acetonitrile

(20ml) at room temperature was added tert-butyl nitrite (0 7ml) The reaction mixture was heated to reflux and a solution of 3-amιno-5-[2-(tert-butoxycarbonyl- pyπdιn-4-yi-amιno)ethoxy]-benzoιc acid methyl ester (1 94g) in acetonitrile (5ml)

added The reaction was stirred at reflux for 10min, cooled to room temperature and then concentrated under reduced pressure The residue was partitioned between ethyl acetate and 2M hydrochloric acid The organic phase was washed with water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with dιchloromethane:methanol (50 1 v/v) to give the title compound as a red gum (0 58g) Hplc system 1 (λ = 254nm) Rt 12.6min

Intermediate 16

3-f2-(tert-Butoxycarbonyl-pyridιn-4-yl-amino)-ethoxy1-5- chloro-benzoic acid To a stirred solution of 3-f2-(tert-butoxycarbonyl-pyridιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid methyl ester (0.58g) in a mixture of 1 ,4-dioxane (5ml) and water (5ml) was added 2M sodium hydroxide solution (0.72ml). The reaction mixture was stirred at room temperature for 20h, acidified by the addition of 2M hydrochloric acid (0.75ml) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the aqueous layer removed and the organic phase washed with further water and dried with brine and over sodium sulphate. Concentration of the organic phase under reduced pressure gave the title compound as a yellow solid (0.32g). Hplc system 1 (λ = 254nm) Rt 7.7min

Intermediate 17

(2-r3-Chloro-5-(cvclohexyl-methyl-carbamoyl)-phenoxyl-eth yl)-pyridin-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.039g), TBTU (0.064g) and HOBt (0.027g) in DMF (1ml) was added DIPEA (0.036ml) followed by N-methylcyclohexylamine (0.027m!) after 15mιn. The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.036g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 10 7min

Intermediate 18

{2-[3-(Allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxyl-ethyl} -pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 039g), TBTU (0 064g) and HOBt (0 027g) in DMF (1 ml) was added DIPEA (0 036ml) followed by N-allylcyclopentylamine (0 029ml) after 15mιn

The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 030g) obtained by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 11.0mm

Intermediate 19

{2-f3-(Allyl-cvclohexyl-carbamoyl)-5-chloro-phenoxy1-ethy l}-pyπdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.039g), TBTU (0.064g) and HOBt (0 027g) in DMF (1 ml) was added DIPEA (0 036ml) followed by N-allylcyclohexylamine (0 029ml) after 15mιn. The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 032g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 11 5mιn

Intemediate 20

{2-f3-(Propyl -cvclopentyl-carbamoyl)-5-chloro-phenoxy1-ethyl)-pyπdιn-4- yl-carbamιc acid tert-butyl ester

A suspension of 5% Pd on carbon (0.01 g) in a solution of {2-[3-(allyl-cyclopentyl- carbamoyl)-5-chloro-phenoxy]-ethyl}-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 07g) in toluene (10ml) was stirred under an atmosphere of hydrogen for 2h The catalyst was filtered through diatomaceous earth and the filtrate evaporated to give the title compound as a pale yellow gum (0 07g) Mass spectrum Found MH ⁺ 502 ( ³⁵ CI)

Intermediate 21

(2-(3-Chloro-5-fcvclopentyl-(3-hvdroxy-propyl)-carbamoyl1-ph enoxy}-ethyl)-pyrιdιn-4- yl-carbamtc acid tert-butyl ester

To {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl} -pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 11 g) was added 9-BBN (0 5M in THF, 2 2ml) and the resulting solution stirred at room temperature under nitrogen for 20h A mixture of 28% aqueous hydrogen peroxide solution (1 8ml) and 2M aqueous sodium hydroxide (0 9ml) was added and the reaction mixture stirred at reflux for 2h The solvent was removed in vacuo and the residue purified by preparative hplc and the title compound (0 064g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 518 ( ³⁵ CI)

Intermediate 22 (2-[3-Chloro-5-fpropyl-(tetrahvdro-pyran-4-yl)-carbamovπ-ph enoxy}-ethyl)-pyπdιn-4- yl-carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 06g), TBTU (0 096g) and HOBt (0 030g) in DMF (1ml) was added DIPEA (0 052ml) followed by N-propyl-4-amιnotetrahydropyran (0 033g) as a solution in DMF (1ml) after 20mιn The reaction mixture was stirred at room temperature for 20h and then concentrated under reduced pressure The residue was partitioned between ethyl acetate and water The organic phase was washed with further water and saturated aqueous sodium bicarbonate and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a gum (0 07g)

Mass spectrum Found MH ⁺ 518 ( ³⁵ CI)

Intermediate 23 (2-(3-Chloro-5-fcvclopentyl-(2,3-dιhvdroxy-propyl)-carbamov π-phenoxy)-ethvπ- pyndιn-4-yl-carbamιc acid tert-butyl ester

To a solution of {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl} -pyrιdιn- 4-yl-carbamιc acid tert-butyl ester (0 075g) in a mixture of acetone (1 0ml) and water (0 5ml) was added osmium tetroxide (1 52 ml of a 2 5% solution in tert-butanol) After 16h excess sodium sulphite was added to the reaction mixture and the mixture partitioned between chloroform and water The organic layer was concentrated to give the title compound (0 044g) which was used without further purification

Intermediate 24

(2-(3-Chloro-5-fcvclopentyl-(3-morpholin-4-yl-propyl)-car bamovn-phenoxy}-ethvπ- pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0.096g) and HOBt (0.030g) in DMF (1ml) was added DIPEA (0.052ml) followed by cyclopentyl-(3-morpholin-4-yl-propyl)-amine (0.064g) after 5min. The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (O.OGOg) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Hplc system 1 (λ = 254nm) Rt 6.5min

Intermediate 25

(2 3-Chloro-5-[(^dopentyl-(3-pyrrolidin-1-yl-propyl)-carbamovπ -phenoxy>-ethyl)- pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate

To a stirred solution of 3-{2-<tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0.096g) and HOBt (0.030g) in DMF (1ml) was added DIPEA (0.052ml) followed by cyclopentyK3-pyrrolidin-1-yl-propyI)-amine (0.059g) after 15min. The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.080g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH ⁺ 571 (^Cl)

Intermediate 26

4-({3-,2*^tert-Butoxyc^n^nyl-pyridin-4-yl-amino)-ethoχy1 -5-chloro-penzoyl>- cvclopentyl-amino)-butyric acid ethyl ester

To a stirred solution of 3-{2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.300g), TBTU (0.482g) and HOBt (0.150g) in DMF (5ml) was added DIPEA (0.260ml) followed by 4-cyclopentylamino-butyric acid ethyl ester (0.316g) after 10min. The reaction mixture was -stirred at room temperature for 16h and then further 4-cyclopentylarnino-butyric acid ethyl ester (0.316g) was added After 24h, the reaction mixture was concentrated under reduced pressure to give a

viscous gum which was partitioned between ethyl acetate and water The aqueous layer was removed and the organic phase washed with further water, aqueous saturated sodium bicarbonate solution, water and dried with brine and over sodium sulphate The organic phase was concentrated under reduced pressure to give crude product as a black gum (0 420g) which was purified by preparative hplc and the title compound (0 189g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 10.9mιn

Intermediate 27

4-({3-[2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-etho xy]-5-chloro-beπzoyl)- cyclopentyl-amino)-butync acid

2M Aqueous sodium hydroxide (0.33ml) was added to a stirred solution of 4-({3-[2-

(tert-butoxycarbonyl-pyridιn-4-yl-amino)-ethoxy]-5-chlor o-benzoyl}-cyclopentyl- amino)-butyπc acid ethyl ester (0.189g) in 1 ,4-dioxan (2ml). 2M aqueous hydrochloric acid (0.33ml) was added after 1 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase was dried with brine and over sodium sulphate and then concentrated under reduced pressure to give the title compound (0.138g) as a white foam.

Mass spectrum: Found: MH ⁺ 546 ( ³⁵ CI)

lntermedιate.28

(2-(3-f(3-Carbamoyl-propyl)-cvclopentyl-carbamoyll-5-chlo ro-phenoxy}-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy] -5- chloro-benzoyl}-cyclopentyl-amino)-butyric acid (0.049g), TBTU (0.058g) and HOBt (0.024g) in DMF (1 ml) was added DIPEA (0.031ml) followed a 0.5M solution of ammonia in 1 ,4-dιoxane (0.36ml) after 15mιn. The reaction mixture was stirred at room temperature for 43h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 040g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum. Found: MH ⁺ 545 ( ³⁵ CI)

Intermediate 29

(2-{3-Chloro- N-cvclopentyl-N-(4-oxo-4-pyrrolιdιn-1-yl-butyl)-carbamoyl1 -phenoxy}- ethvD-pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5- chloro-beπzoyl}-cyclopentyl-amιno)-butyrιc acid (0 028g), TBTU (0 034g) and HOBt (0 008g) in DMF (0 2ml) was added DIPEA (0 024ml) followed by pyrrolidine (0 008ml) after 15mιn The reaction mixture was stirred at room temperature for 43h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 025g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 599 ( ³⁵ CI)

Intermediate 30

(2-(3-f(2-Carbamoyl-ethyl)-cvclopentyl-carbamoyll-5-chlor o-phenoxy}-ethyl)-pyπdιn- 4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yϊ-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g), TBTU (0096g) and HOBt (0 030g) in DMF (1 ml) was added DIPEA (0 052ml) followed by 3-cyclopentylamιno-propιonamιde (0 047mg) after 10mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0074g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 531 ( ³⁵ CI)

Intermediate 31

(2- 3-Chloro-5-(ethyl-phenyl-carbamoyl)-cvclopentyl-phenoxy1-eth yl>-pyπdιn-4-yl- carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g), TBTU (0 096g) and HOBt (0 030g) in DMF (1 ml) was added DIPEA (0 052ml) followed by 2-cyclopentylamιno-acetamιde (0 043g) after 10mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 064g) was obtained as a colourless gum by

concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced oressure Mass spectrum Found MH ⁺ 531 ( ³⁵ CI)

Intermediate 32

(2-{3-[(2-CarbamovLmethyl)-cyclopentyl-carbamovn-5-chloro -phenoxy)-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0 096g) and HOBt (0030g) in DMF (1 ml) was added DIPEA (0.052ml) followed by 3-cyclopentylamιno-acetamιde (0.043g) after 15mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.057g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum- Found: MH ⁺ 517 ( ³⁵ CI)

Intermediate 33

(2-{3-Chloro-5-r(2-cvano-ethyl)-cvclopropyl-carbamoyn-phe noxyV-ethyl)-pyridin-4-yl- carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0.096g) and HOBt (0.030g) in DMF (1 ml) was added DIPEA (0.052ml) followed by 3-cyclopropylpropionιtrιle (0.050g) after 15mιn The reaction mixture was stirred at room temperature for 18h and tπen concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.075g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Hplc system 1 (λ = 254nm) Rt 8.1 m

Intermediate 34 f2-(3-Chloro-5-dipropylcarbamoyl-phenoxy)-ethvπ-pyrιdιn-4 -yl-carbamιc acid tert- butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyndιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0096g) and HOBt (0030g) in DMF (1ml) was added DIPEA (0 052ml) followed by dipropylamine (0.030mg) aπer 20mιn The

reaction mixture was stirred at room temoerature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0.085g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum: Found. MH ⁺ 476 ( ³⁵ CI)

Intermediate 35

{2-f3-Chloro-5-(ethyl-phenyl-carbamoyl)-phenoxyl-ethyl}-p yhdin-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0.096g) and HOBt (0.030g) in DMF (1 ml) was added DIPEA (0.052ml) followed by N-ethylanilme (0.038ml) after I5mιn. The reaction mixture was stirred at room temperature for 66h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.080g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH ⁺ 496 ( ³⁵ CI)

Intermediate 36

3-Chloro-N-(3.5-difluoro-phenyl)-5-methoxy-N-propyl-benza mide

2M Oxalyl chloride solution in dichloromethane (0.210ml) and DMF (0.010ml) were added to a solution of 3-chloro-5-methoxy-benzoic acid (0.373g) in anhydrous dichloromethane (20ml). The reaction was stirred at room temperature for 2h then N-ρropyl-2,5-difluoroaniline (0.408g), DMAP (0.01 Og) and DIPEA (0.973ml) were added The reaction mixture was stirred at room temperature for 18h, diluted with ethyl acetate and then extracted repeatedly with 2M hydrochloric acid until none of the aniline remained. The organic phase was dried with brine and over sodium sulphate and evaporated under reduceα pressure to give the title compound (0.279g) as a colourless gum Hplc system 1 (λ = 254nm) Rt 11.1 m

Intermediate 37

3-Chloro-N-(3,5-dιfluoro-phenyl)-5-hvdroxy-N-propyl-benz amιde To a stirred solution of 3-chloro-N-(3,5-dιfluoro-phenyl)-5-methoxy-N-propyl- benzamide (0 164g) in anhydrous dichloromethane (5ml) at -78°C was added 1 M boron tribromide solution in dichloromethane (3.5ml) The reaction mixture was stirred at this temperature for 15mιn The reaction was allowed to warm to room temperature, and after 3 5h the reaction was cooled to -78°C and methanol (6ml) added The reaction was allowed to rewarm to room temperature and the solvent removed in vacuo The residue was purified by flash column chromatography eluting with cyclohexane.ethyl acetate (3 1 v/v) to give the title compound as a colourless oil (0 1 1 Og) Hplc system 1 (λ = 254nm) Rt 9 1mιn

Intemediate 38

Toluene-4-sulfonιc acid 2-(tert-butoxycarbonyl-pyridιn-4-yl-amino)-ethyl ester To a solution of pyπdιn-4-yl-carbamic acid tert-butyl ester ² (14 Og) in dry DMF (200ml) was added sodium hydride (60% dispersion in mineral oil, 3.17g) and ethylene glycol tosylate (26.7g). The reaction mixture was stirred for 16h. Water (150ml) was added and the mixture extracted with ethyl acetate, washed with brine (75ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by flash chromatography using eluting with chloroform- methanol (49:1 v/v) to give the title compound as a brown oil (10.7g) Mass spectrum found MH ⁺ 393

Intermediate 39

(2-(3-Chloro-5-r(propyl)-(3,5-difluoro-phenyl)-carbamoyll -phenoxyl-ethyl)-pyπdιn-4- yl-carbamic acid tert-butyl ester

To a solution of 3-chloro-N-(3,5-dιfluoro-phenyl)-5-hydroxy-N-propyl-benzami de (0 050g) in DMF (0.5ml) stirred at room temperature under nitrogen was added sodium hydride (60% dispersion in oil, 0.007 g) and after 10mιn was added toluene- 4-sulfonιc acid 2-(tert-butoxycarbonyl-pyridιn-4-yl-amιno)-ethyl ester ( 0.060g) The reaction was stirred for 66h, quenched with water and then concentrated in vacuo and the residue subjected to preparative hplc The title compound (0 029g) was obtained as an colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile

Hplc system 1 (λ = 254nm) Rt 11.1 min

Intermediate 40

( ^, 2 3-Chloro-5-r(2-cvano-ethvπ-(2-fluoro-phenyl)-carbamoyll-phe noxy}-ethvπ- pyridin-4-yl-carbamic acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0.090ml) and DMF (0.001 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.059g) in anhydrous dichloromethane (1 ml). The reaction was stirred at room temperature for 1.5h then a solution of 3-(2-fluoro-phenylamino)- propionitrile (0.026g) in dichloromethane (1ml), DMAP (0.002g) and DIPEA (0.078ml) were added. The reaction mixture was stirred at room temperature for 66h. The reaction mixture was partitioned between ethyl acetate and 1 M aqueous hydrochloric acid. The aqueous layer was removed and the organic phase washed with further 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate.cyclohexane (4:1 v/v), to give the title compound as a colourless gum (0.028g). Hplc system 1 (λ = 254nm) Rt 9.7min

Intermediate 41

(2 3-Chloro-5-f2-<^ιloro-phenyl)-(2-cvano-ethyπ-(carbamov� �-phenoxyV-ethvπ- pyridin-4-yl-carbamic acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0.090ml) and DMF (0.001ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.059g) in anhydrous dichloromethane (1 ml). The reaction was stirred at room temperature for 1.5h then a solution of 3-(2-chloro-phenylamino)- propionitrile (0.029g) in dichloromethane (1ml), DMAP (0.002g) and DIPEA (0.078ml) were added. The reaction mixture was stirred at room temperature for 66h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with further 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate: cyclohexane (4:1 v/v), to give the title compound as a colourless gum (0.040g).

Hplc system 1 (λ = 254nm) Rt 9 7mιn

Intermediate 42

4-f(3-[2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-etho xy1-5-chloro-benzoylH2-fluoro- phenvD-aminol-butyπc acid methyl ester

2M Oxalyl chloride solution in dichloromethane (0 600ml) and DMF (0 01 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-ammo)-ethoxy]-5- chloro-benzoic acid (0 393g) in anhydrous dichloromethane (5ml) The reaction was stirred at room temperature for 1 h then a solution of 4-(2-fluoro-phenylamιno)- butyπc acid methyl ester (0 422g) in dichloromethane (1.5ml), DMAP (0 006g) and DIPEA (0 522ml) were added The reaction mixture was stirred at room temperature for 2h The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase washed with 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate: cyclohexane (4:1 v/v), to give the title compound as a colourless gum (0.287g) Hplc system 1 (λ = 254nm) Rt 10.5min

Intermediate 43

4-f{3-f2-(tert-Butoxycarbonyl-pyridin-4-yl-amino)-ethoxyl -5-chloro-benzoyl)-(2-fluoro- phenvD-aminol-butyπc acid

2M Aqueous sodium hydroxide (0.75ml) was added to a stirred solution of 4-({3-[2-

(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro -benzoyl}-(2-fluoro-phenyl)- amιno)-butyπc acid ethyl ester (0.270g) in 1 ,4-dιoxan (2ml) 2M aqueous hydrochloric acid (1.0ml) was added after 16h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase was dried with brine and over sodium sulphate and then concentrated under reduced pressure to give the title compound (0 185g) as a white foam

Hplc system 1 (λ = 254nm) Rt 8.7mιn

Intermediate 44

(2-{3-f(3-Carbamoyl-propyl)-(2-fluoro-phenyl)-carbamoyll- 5-chloro-phenoxy)-ethyl)- pyridιn-4-yl-carbamic acid tert-butyl ester

To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5- chloro-benzoyl}-(2-fluoro-phenyl)-amιno)-butyπc acid (0 100g), TBTU (0 1 12g) and HOBt (0 047g) in DMF (2ml) was added DIPEA (0 060ml) followed by a 0 5M solution of ammonia in 1 ,4-dιoxane (0 70ml) after 10mιn The reaction mixture was stirred at room temperature for 70h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 100g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 571 ( ³⁵ CI)

Intermediate 45

(2-(3-Chloro-5-[(2-fluoro-phenyl)-(4-oxo-4-pyrrolιdιn-1 -yl-butyl)-carbamoyl1- phenoxy)-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5- chloro-benzoyl}-(2-fluoro-phenyl)-amιno)-butyπc acid (0 025g), TBTU (0 028g) and HOBt (0 012g) in DMF (1 ml) was added DIPEA (0 015ml) followed by pyrrolidine (0 007ml) after 10mιn The reaction mixture was stirred at room temperature for 16h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 025g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 625 ( ³⁵ CI)

Intermediate 46

4-f(3-f2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-etho xyl-5-chloro-benzoyl}-(2- carbamoyl-phenvD-amino.-butyric acid methyl ester

2M Oxalyl chloride solution in dichloromethane (0 090ml) and DMF (0 01 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g) in anhydrous dichloromethane (1 ml) The reaction was stirred at room temperature for 2h then 4-(2-carbamoyl-phenylamιno)-butyπc acid methyl ester (0 037g), DMAP (0 002g) and DIPEA (0 078ml) were added The reaction mixture was stirred at room temperature for 18h The reaction mixture was partitioned between ethyl acetate and water The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate solution water and dried with brine and over sodium sulphate and concentrated under

reduced pressure The residue was purified by flash column chromatography, eluting with ethyl acetate cyclohexane (9 1 v/v) neat ethyl acetate and dichloromethane methanol (9 1 ) to give the title compound as a colourless gum (0 031 g) Hplc system 1 (λ = 254nm) Rt 7 9mιn

Intermediate 47

(2-(3-Chloro-5-[(3-cvano-propyl)-2-fluoro-phenyl)-carbamo yπ-phenoxy)-ethyl)- pyπdιn-4-yl-carbamιc acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0 300ml) and DMF (0 01 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 195g) in anhydrous dichloromethane (5ml) The reaction was stirred at room temperature for 2h then 4-(2-fluoro-phenylamιno)-buyronιtπle (0 178g) as a solution in dichloromethane (1ml), DMAP (0 012g) and DIPEA (0 105ml) were added The reaction mixture was stirred at room temperature for 40h The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate The aqueous layer was removed and the organic phase washed with 1M aqueous hyαrochloπc acid, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure The residue was purified by flash column chromatography, eluting with ethyl acetate cyclohexane (1 1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (0 132g) Hplc system 1 (λ = 254nm) Rt 9 2mιπ

Intermediate 48 f2-f3-Chloro-5-fr2-f2.2-dιmethyl-π .31dιoxolan-4-ylmethoxy)-ethvn-phenyl- carbamoyl)-phenoxy)-ethyll-pyπdιn-4-yl-carbamιc acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0 115ml) and DMF (0 005ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g) in anhydrous dichloromethane (5ml) The reaction was stirred at room temperature for 1 h then a mixture of [2-(2,2-dιmethyl-[1 ,3]dιoxolan-4- ylmethoxy)-ethyl]-phenyl-amιne and toluene-4-sulfonιc acid 2,2-dιmethyl- [1 ,3]dιoxolan-4-ylmethyl ester compound (0 194g in a ratio of 2 1mol/mol), DMAP (0 005g) and DIPEA (0 080ml) were added The reaction mixture was stirred at room temperature for 20h The reaction mixture was diluted with further dichloromethane and extracted with saturated aqueous sodium bicarbonate The

aqueous layer was removed and the organic phase washed with 1 M aqueous hydrochloric acid saturated aqueous sodium bicarbonate water and dried with brine and over sodium sulphate and concentrated under reduced pressure The residue was purified by flash column chromatography, eluting with ethyl acetate petroleum ether (1 1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (0 037g) Hplc system 1 (λ = 254nm) Rt 1 1 1 mm

Intermediate 49 (2-f3-Chloro-5-fr2-(2.2-dιmethyl-π ,3ldιoxolan-4-ylmethoxy)-ethyll-(2-fluoro-phenyl)- carbamoyll-phenoxy}-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester 2M Oxalyl chloride solution in dichloromethane (0 115ml), and DMF (0 005ml) were added to a suspension of 3-[2-(tert-butoxycarbonyi-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.060g) in anhydrous dichloromethane (5ml) The reaction was stirred at room temperature for 1 5h then [2-(2,2-dιmethyl-[1 ,3]dιoxolan-4- ylmethoxy)-ethyl]-(2-fluoro-phenyl)-amιne (0 121g) as a solution in dichloromethane (0 5ml.), DMAP (0 005g) and DIPEA (0 080ml) were added The reaction mixture was stirred at room temperature for 20h The reaction mixture was diluted with further dichloromethane and extracted with saturated aqueous sodium bicarbonate The aqueous layer was removed and the organic phase washed with water and dried with brine and over sodium sulphate and concentrated under reduced pressure The residue was purified by flash column chromatography, eluting with ethyl acetate petroleum ether (1 1 , 2 1 and 4 1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (0 035g) Hplc system 1 (λ = 254nm) Rt 1 1 0mm

Intermediate 50

(2-(3-Chloro-5-ff2-(2,2-dιmethyl-[1.3ldιoxolan-4-ylmeth oxy)-ethyll-(4-fluoro-ρhenvπ- carbamoyll-phenoxy>-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester 2M Oxalyl chloride solution in dichloromethane (0 115ml) and DMF (0 005ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g) in anhydrous dichloromethane (5ml) The reaction was stirred at room temperature for 1 5h then [2-(2,2-dιmethyl-[1 ,3]dιoxolan-4- ylmethoxy)-€thyl]-(4-fluoro-phenyl)-amιne (0 078g) as a solution in dichloromethane (0 5ml), DMAP (0 002g) and DIPEA (0 080ml) were added The reaction mixture was stirred at room temperature for 16h The reaction mixture was diluted with

further dichloromethane and extracted with saturated aqueous sodium bicarbonate The aqueous layer was removed and the organic phase washed with water and dried with brine and over sodium sulphate and concentrated under reduced pressure The residue was purified by flash column chromatography, eluting with ethyl acetate petroleum ether (1 1 , 2 1 and 4 1 v/v), to give the title compound as a colourless gum (0 037g) Hplc system 1 (λ = 254nm) Rt 11 2mιn

Intermediate 51 (R)-H3-[(3-f2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-et hoxyl-5-chloro-benzoylH2- fluoro-phenyl)-amιnol-propyl}-pyrrolidιne-2-carboxylιc acid tert-butyl ester and (R)-1- f3-(2-fluoro-phenylamιno)-propyll-pyrrolιdιne-2-carboxyl� �c acιd tert butyl ester 2M Oxalyl chloride solution in dichloromethane (0 112ml) and DMF (0.005ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.060g) in anhydrous dichloromethane (2.0ml). The reaction was stirred at room temperature for 1h then a mixture of (R)-1-[3-(2-fluoro- phenylamino)-propyl]-pyrrolιdιne-2-carboxylic acid tert-butyl ester (0.145g), DMAP (0002g) and DIPEA (0.080ml) as a solution in dichloromethane (0.4ml) was added. The reaction mixture was stirred at room temperature for 18h and evaporated in vacuo. The residue was purified by preparative hplc give the title compounds as a colourless gum (0 110g) by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 8.3mιn ((R)-1-[3-(2-fluoro-phenylamιno)-propyl]-pyrrolιdιne-2-ca rboxylιc acid tert butyl ester),

Rt 9.7mιn ((R)-1 -{3-[{3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy ]-5-chloro- benzoyl}-(2-fluoro-phenyl)-amιno]-propyl}-pyrrolιdιne-2-c arboxylιc acid tert-butyl ester)

Intermediate 52

3-(f3-f2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-etho xyl-5-chloro-benzoyl}-phenyl- amιno)-propιonιc acid methyl ester

2M Oxalyl chloride solution in dichloromethane (1 8ml), and DMF (0 05ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (1 18g) in anhydrous dichloromethane (30ml) The reaction was

stirred at room temperature for 1 h then 3-phenylamιno-propιonιc acid methyl ester (0 644g), DMAP (0 036g) and DIPEA (1 04ml) were added The reaction mixture was stirred at room temperature for 20h and partitioned between ethyl acetate and 1 M aqueous hydrochloric acid The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure The residue was purified by flash column chromatography, eluting with ethyl acetate petroleum ether (4 1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (1 22g) Hplc system 1 (λ = 254nm) Rt 9 8mιπ

Intermediate 53

3-({3-[2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-etho xyl-5-chloro-benzoyl)-phenyl- amιno)-propιonιc acid

2M Aqueous sodium hydroxide (2 54ml) was added to a stirred solution of 3-({3-[2-

(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5-chlo ro-benzoyl}-phenyl-amιno)- propionic acid methyl ester (1 22g) in 1 4-dιoxan (15ml) 2M Aqueous hydrochloric acid (2 54ml) was added after 16h The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water The aqueous layer was removed and the organic phase was dried with brine and over sodium sulphate and then concentrated under reduced pressure to give the title compound (1 10g) as a white foam

Mass spectrum Found MH ⁺ 540 ( ³⁵ CI)

Intermediate 54

(2-f3-Chloro-5-[(2-fluorosulfonyl-ethyl)-phenyl-carbamoyl l-phenoxy,-ethyl)-pyrιd)n-4- y -carbamic acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0 9ml) and DMF (0 025ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 610g) in anhydrous dichloromethane (50ml) The reaction was stirred at room temperature for 1h then 2-phenylamιno-ethanesulfonyl fluorιde(0 257g), DMAP (0 018g) and DIPEA (0 261 ml) were added The reaction mixture was stirred at room temperature for 20h and partitioned between ethyl acetate and 1 M aqueous hydrochloric acid The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced

pressure The residue was purified by flash column chromatography eluting with using ethyl acetate petroleum ether (3 1 v/v) to give the title compound as a white foam (0 40g)

Hplc system 1 (λ = 254πm) Rt 10 3mm

Intemediate 55

3-[(3-Chloro-5-methoxy-benzoyl)-ιsopropyl-amιnol-propι onιc acid methyl ester

To a stirred solution of 3-chloro-5-methoxy-benzoιc acid (0932g), TBTU (3 21 g) and in DMF (10ml) was added DIPEA (1 73ml) followed by 3-ιsopropylamιπo propionic acid methyl ester (0 871 g) after 10mιn The reaction mixture was stirred at room temperature for 48h and then concentrated under reduced pressure The residue was partitioned between ethyl acetate and water The organic phase was washed with further water and 2M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (1 6g) Mass spectrum Found MH ⁺ 314

Intemediate 56

3-f(3-Chloro-5-methoxy-benzoyl)-ιsopropyl-amιnol-propι onιc acιd 2M Aqueous sodium hydroxide (4 5ml) was added to a stirred solution of 3-[(3- chloro-5-methoxy-benzoyl)-ιsopropyl-amιno]-proριonιc acid methyl ester (1 50g) in 1 ,4-dιoxan (30ml) 2M aqueous hydrochloric acid (4 5ml) was added after 20h The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water The aqueous layer was removed and the organic phase was dried with brine and over sodium sulphate and then concentrated under reduced pressure to give the title compound (1 41 g) as a brown solid Mass spectrum Found MH ⁺ 300 ( ³⁵ CI)

Intemediate 57

3-Chloro-N-ιsopropyl-5-methoxy-N-(2-methylcarbamoyl-ethy l)-benzamιde To a stirred solution of 3-[(3-chioro-5-methoxy-benzoyl)-ιsopropyl-amιno]-propιon� �c acid (0 600g), TBTU (1 28g) in DMF (10ml) was added DIPEA (0 696ml) followed a 2M solution of methylamme in THF (8 0ml) after 10mιn The reaction mixture was stirred at room temperature for 4h and then concentrated under reduced pressure The residue was partitioned between ethyl acetate and water The organic phase was washed with further water and 1 M aqueous hydrochloric acid, saturated

aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (0 575g)

Mass spectrum Found MH ⁺ 313 ( ³⁵ CI)

Intemediate 58

3-Chloro-N-ιsopropyl-5-methoxy-N-f2-(1-methyl-1 H-tetrazol-5-yl)-ethyll-benzamιde To a stirred solution of 3-chloro-N-isopropyl-5-methoxy-N-(2-methylcarbamoyl- ethyl)-benzamιde (0 312g) in anhydrous dichloromethane (5 0ml) was added sodium azide (0 065g) and the mixture cooled to 0°C Trifluoromethanesulphonic anhydride (0.200ml) was added and the reaction stirred at rooom temperature for 18h The reaction mixture was partitioned between ethyl acetate and water The aqueous layer was removed and the organic layer dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate: petroleum ether (4.1 v/v); to give the title compound as a white solid (0.121g). Hplc system 1 (λ = 254nm) Rt 8.2min

Intemediate 59 3-Chloro-5-hvdroxy-N-isopropyl -N-[2-(1-methyl-1 H-tetrazol-5-yl)-ethvn-benzamide To a stirred solution of 3-chloro-N-ιsopropyl-5-methoxy-N-[2-(1-methyl-1 H-tetrazol- 5-yl)-ethyl]-benzamιde (0.115g) in anhydrous dichloromethane (5 0ml) at -78°C was added 1 M boron tribromide solution in dichloromethane (1.36ml) The reaction mixture was stirred at this temperature for 15mιn The reaction was allowed to warm to room temperature After 24h, the reaction was cooled to -78°C and methanol (1 ml) added. The reaction was allowed to rewarm to room temperature and absorbed on to silica. This was loaded on to an already prepared flash column, eluting with ethyl acetate: petroleum ether (4 1 v/v) and 25 1 dichloromethane. methanol (25.1 v/v) to give the title compound as a white solid (0.072g)

Hplc system 1 (λ = 254nm) Rt 6.6mιn

Intermediate 60 f2-(3-Chloro-5-[ιsopropyl-f2-(1-methyl-1 H-tetrazol-5-yl)-ethyll-carbamoylVphenoxyV ethyl]-pyπdιn-4-yl-carbamιc acid tert-butyl ester

To a solution of 3-chloro-5-hydroxy-N-ιsopropyl -N-[2-(1 -methyl-1 H-tetrazol-5-yl)- ethylj-beπzamide (0 070g) in DMF (2 0ml) stirred at room temperature under nitrogen was added sodium hydride (60% dispersion in oil, 0 010 g) and after 10mιn was added toluene-4-sulfonιc acid 2-(.9rt-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethyl ester ( 0 120g) The reaction was stirre for 88h and the sovent removed in vacuo The residue was partitioned between etnyl acetate and water The organic phase was washed with further water and 1 M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography, eluting with ethyl acetate petroleum ether (4 1 v/v) and 24 1 dichloromethane methanol (24 1 v/v), to give the title compound as a colourless gum (0 028g) Hplc system 1 (λ = 254nm) Rt 8 3mιn

Intermediate 61 (2-(3-Chloro-5-[cvclopentyl-(3-tπfluoromethanesulfonylamιn o-propyl)-carbamoyn- phenoxy>-ethyl)-pyrιdιn-4-yl-carbamιc aαd tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.059g), TBTU (0072g), and HOBt (0.034g) in DMF (1 ml) was added DIPEA (0 078ml) followed by N-(3-cyclopentylamιno-propyl)-C,C,C-tπfluoro- methanesulfonamide formate (0 053g) after 5mιn The reaction mixture was stirred at room temperature for 4 days then more TBTU (0072g), HOBt (0 034g) and DIPEA (0 078ml) were added followed by more of the secondary amme (0 06g) The mixture was heated to 60°C for 3h, the solvent was removed by evaporation at reduced pressure and the residue subjected to preparative hplc This gave the title compound as a colourless gum (0 012g) Hplc system 1 (λ = 254nm) Rt 12 5mιn

Intermediate 62 r2-(3-ff2-(3-Amιno-f1 ,2,41oxadιazol-5-yl)-ethyll-ιsopropyl-carbamoyl}-5-chloro- phenoxy)-ethyll-pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 104g), TBTU (0 128g), and HOBt (0 061 g) in DMF (1 ml) was added DIPEA (0 139ml) and 5-(2-ιsopropyiamιno-ethyl)-[1 ,2,4joxadιazol-3-ylamιne (0 05g) The reaction mixture was stirred at room temperature for 10 days, then silica was added and the solvent removed by evaporation at reduced pressure The resulting silica was loaded onto the top of a column of silica which was then eluted

with a gradient [cyclohexane ethyl acetate (1 1 v/v) to neat ethyl acetate to ethyl acetate methanol (9 1 v/v)] Concentration of the required fraction at reduced pressure furnished the title compound as a yellow glass (0 069g) Hplc system 1 (λ = 254nm) Rt 8 2mιn

Intermediate 63

(2-(3-Chloro-5- (2-cvano-ethyl)-cvclopropylmethyl-carbamoyll-phenoxy}-ethyl) - pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g), TBTU (0 096g) and HOBt (0 030g) in DMF (1 ml) was added DIPEA (0 052ml) followed by 3-(cyclopropylmethyl-amιno)-propιonιtrile ⁴ (0 044g) after 15mιn The reaction was stirred at room temperature for 14h, and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 070g) was obtained as a brown oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 499 ( ³⁵ CI)

Intermediate 64 (2-{3-Chloro-5-f(2-cvano-ethyl)-(2,2-dιmethyl-propyl)-carba movπ-phenoxy)-ethyl)- pyπdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g), TBTU (0 096g) and HOBT (0 030g) in DMF (1ml) was added DIPEA ( 0 052ml) followed by 3-(2,2-dιmethyl-propylamιno)-propιonιtπle ⁵ (0 043g) after 15mιn The reaction was stirred at room temperature for 18h, and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 053g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ^* 515 ( ³⁵ CI)

ntermediate 65

(2-f3-Chloro-5-r(2-cyano-ethyl)-(tetrahvdro-furan-2-ylmet hyl)-carbamoyll-phenoxy}- ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g), TBTU (0 096g) and HOBT (0 030g) in DMF (1 ml) was

added DIPEA (0.052ml) followed by 3-[(tetrahydro-furan-2-ylmethyl)-aminoj- propionitrile (0.047g) after 15min. The reaction was stirred at room temperature for 96h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.078g) was obtained as a brown oil by 5 concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH ⁺ 529 ( ³⁵ CI)

Intermediate 66

10 (2-f3-Chloro-5-f( ^' 2-cvano-ethyl)-isopropyl-carbamoyll-phenoxy -ethyl)-pyridin-^-yl- carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0.096g) and HOBT (0.030g) in DMF (1ml) was added DIPEA ( 0.052ml) followed by 3-isopropylamino-propionitrile ⁶ ( 0.034g) after

15 15min. The reaction was stirred at room temperature for 96h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.072g) was obtained as a brown oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.

20 Mass spectrum: Found: MH ⁺ 487 (∞CI)

Intermediate 67

(2 3*^hlorc>-5-ff2- ^ancr-ethvπ-isobutyl-carbamovπ-phenoxy>-ethyl)-pyridin- 4-yl- carbamic acid tert-butyl ester

25 To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.060g), TBTU (0.096g) and HOBT (0.030g) in DMF (1ml) was added DIPEA (0.052ml) followed by 3-isobutylamino-propionitrile ⁷ (0.038g) after 15min. The reaction was stirred at room temperature for 18h, and then concentrated under reduced pressure. The residue was subjected to preparative

30 hplc and the title compound (0.060g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Mass spectrum: Found: MH ^* 501 ( ³⁵ CI)

35 Intermediate 68

3-((3-f2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy1 -5-chloro-benzoyl}- ιsopropyl-amιno)-propιonιc acid methyl ester trifluoroacetate

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 344g), TBTU (0 549g) and HOBT (0 173g) in DMF (6ml) was added DIPEA (0 296ml) followed by 3-ιsopropylamιno-propιonιc acid methyl ester (0 254g) after 1 5mιn The reaction was stirred at room temperature for 24h, and then concentrated under reduced pressure The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate The aqueous layer was separated and extracted with further ethyl acetate The combined, dried (MgSO ₄ ) organic fractions were concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 332g) as a colourless oil, by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 9 7mιn

Intermediate 69

3-(f3-r2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-etho xyl-5-chloro-benzoyl}- ιsopropyl-amιno)-propιonιc acid hydrochloride

To a solution of 3-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5-chloro- benzoyl}-ιsopropyl-amιno)-propιonιc acid methyl ester trifluoroacetate (0 33g) in dioxan (3ml) was added 2M sodium hydroxide 0 95ml, and the resultant solution was stirred at room temperature for 3h 1 M Hydrochloric acid ica 4ml) was added and the resultant suspension extracted with ethyl acetate The combined, dried (MgSO ₄ ) extracts were concentrated under reduced pressure to give the title compound (0 201 g) as a colourless oil Mass spectrum Found MH ⁺ 506 ( ³⁵ CI)

Intermediate 70 (2-(3-Chloro-5-f(2-dιethylcarbamoyl-ethyl)-ιsopropyl-carba movn-phenoxy}-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester trifluoroacetate

To a stirred solution of 3-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5- chloro-benzoyl}-ιsopropyl-amιno)-propιonιc acid hydrochloride (0 052g) TBTU (0 064g) and HOBT (0 027g) in DMF (1 ml) was added DIPEA ( 0 035ml) followed diethylamine (0 021 ml) after 15mιn The reaction was stirred at room temperature for 3 days, and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 065g) was obtained as a

colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Mass spectrum Found MH ⁺ 561 ( ³⁵ CI)

Intermediate 71

1 -f3-[2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxyl-5 -chloro-benzoyl)- pιperιdιne-2-carboxylιc acid ethyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιπo)-ethoxy]-5- chloro-benzoic acid (0 12g) in dichloromethane (4ml) was added dimethylformamide (0 05ml) followed by 2M oxalyl chloride solution in dichloromethane (0 183ml) The resultant solution was stirred at room temperature for 1 h, and then ethyl pipecolinate (0 096g) followed by DIPEA (0 160ml) were added After 18h, the reaction mixture was concentrated under reduced pressure and the residue was subjected to preparative hplc The title compound (0 165g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 532 ( ³⁵ CI)

Intermediate 72

{2-r3-Chloro-5-(2-methyl-pιperιdιne-1-carbonyl)-phenox yl-ethyl}-pyπdιn-4-yl- carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 060g) in dichloromethane (4ml) was added DMF (0 025ml) followed by 2M oxalyl chloride solution in dichloromethane (0 091 ml) The resultant solution was stirred at room temperature for 1 h, and then 2-methylpιpeπdιne (0 03g) followed by DIPEA (0 080ml) were added After 3h, the solution was concentrated under reduced pressure and the residue was subjected to preparative hplc The title compound (0 080g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 10 4mιn

ntermediate 73 (2-{3-Chloro-5-f(2-cvano-ethyl)-cvclopentyl-carbamoyl1-pheno xy)-ethvn-pyndin-4-yl- carbamtc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 100g), TBTU (0 080g) and HOBt (0 034g) in DMF (3ml) was added DIPEA (0 087ml) followed by 3-(cyclopentylamιno)propιonιtrιle (0 035g) after 15mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was washed with water and extracted with ethyl acetate The organic layer was dried with brine and MgSO ₄ , filtered and concentrated to give the title compound (0 190g) as a brown oil Mass spectrum Found MH ⁺ 513 ( ³⁵ CI)

Intermediate 74

(2-(3-Chloro-5-fιsopropyl-(2-[1 ,2,41tπazol-1 -yl-ethyl)-carbamoyll-phenoxy)-ethyl)- pyπdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.1g) in DMF (1 ml)and dichloromethane (3ml), was added 2M oxalyl chloride in dichloromethane (0.153ml) and after 30min, a catalytic amount of DMAP and DIPEA (0 013ml), followed by 2-(2-ιsopropylamιno-ethyl)-N-[1 ,2,4]- tπazole (0.038g) The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was washed with water and extracted with ethyl acetate. The organic layer was dried with brine and MgSO ₄ , filtered and concentrated to give the title compound (0.097g) as a brown oil Mass spectrum. Found: MH ⁺ 529 ( ³⁵ CI)

Intermediate 75 (2-j3- 3-Amιno-propyl)-ιsopropyl-carbamovn-5-chloro-phenoxy}-ethy l)-pyπdιn-4-yl- carbamic acid tert-butyl ester

A solution of (2-{3-chloro-5-[(-cyano-ethyl)-isopropyl-carbamoyl]-ρhenoxy }-ethyl)- pyrιdιn-4yl-carbamιc acid tert-butyl ester (0.200g) in methanol (2ml) at 0°C was treated with cobalt (II) chloride hexahydrate (0 195g) and sodium borohydride (0 078g) and stirred overnight at room temperature. Silica was added and the mixture was evaporated under reduced pressure, the residue was subjected to flash chromatography eluting with methanol:chloroform ammonιa(0.88) (10:89 1 v/v/v) The required fractions were evaporated under reduced pressure to give the title compound as a pale straw coloured oil (0 128g) Hplc system 1 (λ =254nm) Rt 6 5mιn

Intermediate 76

(2-(3-Chloro-5-[ιsopropyl-(3-trιfluoromethanesulfonylamιn o-propyl)-carbamoyll- phenoxyl-ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester trifluoroacetate To a solution of (2-{3-[(3-amιno-propyl)-ιsopropyl-carbamoyl]-5-chloro-phen oxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 044g) and triethylamine (0 024ml) in dichloromethane (1 ml) at -70°C was added trifluoromethanesulphonic anhydride (0.016ml), and the mixture was stirred overnight at room temperature The mixture was diluted with dιchloromethane(4ml) and washed with saturated sodium bιcarbonate(2ml), dried (sodium sulphate) and evaporated under reduced pressure The residue was subjected to preparative hplc to give the title compound (0.022g) Hplc system 1 (λ= 254nm) Rt 1 1 4min

Intermediate 77

{2-f3-Chloro-5-(2,5-dιmethyl-pyrrolidιne-1-carbonyl)-ph enoxy1-ethyl}-pyπdιn-4-yl- carbamic acid tert-butyl ester 2,5-Dιmethylpyrrolidιne (0.14ml) in DMF (1 ml) was added to a mixture of 3-[2-(tert- butoxycarbonyl-pyridιn-4yl-amino)ethoxy]-5-chlorobenzoic acid (0.30g), HOBT

(0 10g), TBTU (0.37g), and DIPEA (0.30ml) in DMF (1ml) and stirred overnight at room temperature. The mixture was diluted with water, extracted with ether, the ether layer was washed with water, brine, dried over sodium sulphate and , gyaporated under reduced pressure. The residue was subjected to flash chromatography eluting with ethyl acetate:cyclohexane (80:20 v/v) to give the title compound as an oil (0.27g).

Tic Rf(Sι ca gel 60 F ₂₅₄ ) - 0.2 [ethyl acetate: cyclohexane (80:20 v/v)]

Intermediate 78 f2-(3-chloro-5-f[3-(2,2-dimethyl-propionylamino)-propyl1-iso propyl-carbamoyl|- phenoxy)-ethvπ-pyπdιne-4-v!-carbamic acid tert-butyl ester

To a solution of (2-{3-[(3-amino-propyl)-isopropyl-carbamoyl]-5-chloro-phenox y}- ethyl)-pyπdιn-4-yl-carbamic acid tert-butyl ester (0.040g) and DIPEA (0.030ml) in dichloromethane (1 ml) was added a solution of tπmethytacetyl chloride (0.012ml) in dichloromethane (1 ml) and the mixture was stirred for 3h at room temperature The mixture was evaporated under reduced pressure to give the title compound

Hplc system 1 (λ= 254nm) Rt 10 3mιn

Intermediate 79

{2-[3-Chloro-5-(cyclopentyl-(2-f1 ,2,4ltrιazol-1 -yl-ethyl)-carbamoyl)-phenoxy1-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester

A solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5-ch loro-benzoιc acid (0 040g), cyclopentyl-(2-[1 ,2,4]tπazol-1 -yl-ethyl)-amιne (0 05g) and EEDQ (0 040g) in acetonitrile (2ml) was stirred at reflux, under nitrogen, for 2h. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane methanol (95:5 v/v) to give the title compound as a yellow oil (0 022g) Mass spectrum ^' Found: MH ⁺ 555

Intermediate 80

{2-f3-Chloro-5-(cvclopentyl-(4-f1 ,2,4ltrιazol-1 -yl-butyl)-carbamoyl)-phenoxy1-ethyl}- pyridin-4-yl-carbamιc acid tert-butyl ester

A solution of 3-[2-(tert-butoxycarbonyl-pyridιn-4-yl-amιno)-ethoxy]-5-ch loro-benzoιc acid (0.040g), cyclopentyl -(4-[1 ,2,4]triazol-1-yl-butyl)-amine (0.055g) and EEDQ

(0.050g) in acetonitrile (2ml) was stirred at reflux, under nitrogen, for 4h. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (95:5:0.5 then 90:10: 1 v/v/v) to give the title compound as an orange oil (0.022g). Mass spectrum: Found: MH ⁺ 583 (^Cl)

intermediate 81

{2-[3-Chloro-5-(3-fluorophenyl-(3-tetrazol-2-yl-propyl)-c arbamoyl)-phenoxyl-ethyl}- pyridin-4-yl-carbamic acid tert-butyl ester 2M Oxalyl chloride solution in dichloromethane (0 1 1 ml) and dry DMF (0.002ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridιn-4-yl-amino)- ethoxy]-5-chloro-benzoic acid (0.060g) in dry dichloromethane (1 ml) under nitrogen.

After 5mιn, DIPEA (0.090ml) was added followed after a further 40mιn by 3- fluorophenyl-(3-tetrazol-2-yl-propyl)-amιne (0.066g) and DMAP (0.002g). After 3 days the solvent was evaporated and the residue was purified by flash chromatography eluting with dιchloromethane:methanol (98.2 v/v) to give the title compound as a green foam (0.079g)

Mass spectrum- Found ^' MH ⁺ 596 ( ³⁵ CI)

Intermediate 82

(2-f3-Chloro-5-(2-fluorophenyl-(3-tetrazol-2-yl-propyl)-carb amoyl)-phenoxy1-ethyl}- pyrιdιn-4-yl-carbamιc acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0 1 10ml) and dry DMF (0 002ml) were added to a stirred suspension of 3-[2-(tert-butoxycarboπyl-pyπdιπ-4-yl-amιno)- ethoxy]-5-chloro-benzoιc acid (0 060g) in dry dichloromethane (1 ml) under nitrogen After 5mιn DIPEA (0 090ml) was added followed after a further 40mιn by 2- fluorophenyl-(3-tetrazol-2-yl-propyl)-amιne (0 066g) and DMAP (0 002g) After 40h the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane methanol (98 2 v/v) to give the title compound as a viscous yellow oil (0 059g)

Mass spectrum Found MH ⁺ 596 ( ³⁵ CI)

Intermediate 83 {2-[3-Chloro-5-(phenyl-(3-tetrazol-2-yl-propyO-carbamoyl)-ph enoxyl-ethyl)-pyrιdιn-4- yl-carbamic acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0 1 1 ml), and dry DMF (0 005ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)- ethoxy]-5-chloro-benzoιc acid (0 067g) in dry dichloromethane (1 ml) under nitrogen After 10mιn, DIPEA (0 100ml) was added followed after a further 40mιn by phenyl- (3-tetrazol-2-yl-ρropyl)-amιne (0 033g) and DMAP (0 004g) After 7 days the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane methanol (98 2 v/v) to give the title compound as a pale yellow oil (0 024g) Mass spectrum Found MH ⁺ 564 ( ³⁵ CI)

Intermediate 84

(2-[3-Chloro-5-(phenyl-(3-[1 ₁ 2,3]-trιazol-2-yl-propyl)-carbamoyl)-phenoxyl-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester

2M Oxalyl chloride solution in dichloromethane (0 25ml) and dry DMF (0 010ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)- ethoxy]-5-chloro-benzoιc acid (0 161g) in dry dichloromethane (2ml) under nitrogen After 10mιn DIPEA (0 25ml) was added followed after a further 40mιn by phenyl-(3- [1 2,3]-tπazol-2-yl-ρropyl)-amιne (0 077g) and DMAP (0 012g) After 7 days the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane methanol (96 4 v/v) to give the title compound as a yellow oil (0 083g)

Mass spectrum Found MH ⁺ 563 ( ³⁵ CI)

Intermediate 85

(2-f3-Chloro-5-(phenyl-2-(pyrιdιn-2-yloxy)-ethyl-carbam oyl)-phenoxy1-ethyl}-pyrιdιn- 4-yl-carbamιc acid tert-butyl ester

2M Oxalyl chloride in dichloromethane (0 16ml) and dry DMF (0 008ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 1 15g) in dry dichloromethane (1.5ml) under nitrogen After 10mιn, DIPEA (0 18ml) was added followed after a further 40mιn by phenyl-2- (pyπdιn-2-yloxy)-ethylamιne (0.059g) and DMAP (0 008g) After 7 days the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane. methanol (98.2 v/v), to give the title compound as a pale yellow oil (0.065g) Mass spectrum. Found. MH ⁺ 589 ( ³⁵ CI)

Intermediate 86

(2-f3-Chloro-5-(ιsopropyl-2-methoxy-ethyl-carbamoyl)-phe noxy1-ethyl)-pyridin-4-yl- carbamic acid tert-butyl ester

A solution of 3-[2-(tert-butoxycarbonyl-pyridιn-4-yl-amino)-ethoxy]-5-chl oro-benzoιc acid (0.1 OOg) isopropyl-2-methoxy-ethylamine (0.140g) and EEDQ (0.130g) in acetonitrile (2ml) was stirred at 50°C, under nitrogen, for 18h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate The organic layer was washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to an orange oil which was purified by flash chromatography, eluting with dichloromethane:methanol (98:2 then 96 4 v/v) to give the title compound as a pale yellow oil (0.065g). Mass spectrum: Found: MH ⁺ 492 ( ³⁵ CI)

Intermediate 87 f2-f3-Chloro-5-(ιsopropyl-methyl-carbamoyl)-phenoxy1-ethyl) -pyridιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.071 g), TBTU (0.064g), and HOBt (0.03g) in DMF (1 ml) was added N-isopropylmethylamine (0.095ml) after 25mιn The reaction mixture was stirred at room temperature for 2 days then the solvent was removed by evaporation at reduced pressure and the residue partitioned between ethyl acetate and water

The combined organic layers were washed with saturated brine and dried over magnesium sulphate After concentration, the crude product was purified by flash chromatography eluting with ethyl acetate. Evaporation of the required fraction at reduced pressure gave the title compound as a pale yellow gum (0 065g) Hplc system 3 (λ = 220-330nm) Rt 4.2mιπ

ntermediate 88 f2-[3-Chloro-5-(ιsopropyl-2-(pyrιdιn-2-yloxy)-ethyl-carba moyl)-phenoxyl-ethyl)- pyπdιn-4-yl-carbamic acid tert-butyl ester A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amιno)-ethoxy]-5-chl oro-benzoic acid (0.1 Og) ιsopropyl-2-(pyridin-2-yloxy)-ethylamine (0 18g) and EEDQ (0.136g) in acetonitrile (2ml) was stirred at reflux, under nitrogen, for 18h The solvent was evaporated and the residue was purified by flash chromatography on silica eluting with dichloromethane/methanol (98:2 then 96:4) to give the title compound as a pale yellow oil (0.033g).

Mass spectrum: Found: MH ⁺ 555 ( ³⁵ CI)

Intermediate 89 (2-f3-Chloro-5-(diisopropylcarbamoyl)-phenoxyl-ethyl|-pyridi n-4-yl-carbamic acid tert-butyl ester

To a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chlo ro- benzoic acid (0.1 Og) in tetrahydrofuran (5ml) was added DMF (0.005ml) and oxalyl chloride (0.175ml). After 0.5h DIPEA (0.13ml), diisopropylamine (0.20ml) and DMAP (0.002g) were added After 18h the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The combined organic phases were washed with brine and dried over magnesium sulphate. Filtration and evaporation gave the crude product which was purified by flash column chromatography on silica eluting with cyclohexane/ethyl acetate (1 :3). This afforded the title compound as a colourless gum (0.078g). Mass spectrum: Found: MH ⁺ 476.2304 C ₂₅ H ₃ s ³⁵ CIN ₃ O ₄ requires 476.2316

Intermediate 90

3-r2-(Benzyloxycarbonyl-pyridin-4-yl-amino)-ethoxy1-5-chl oro-benzoιc acid methyl ester

A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amιno)-ethoxy]-5-chl oro-benzoιc acid methyl ester (0.950g) in dichloromethane (16ml) and trifluoroacetic acid (4ml)

was stored at room temperature for 1 h. The solution was concentrated in vacuo and residual trifluoroacetic acid removed by co-evaporation with further dichloromethane. The residue was dissolved in dichloromethane (20ml) and the solution stirred with saturated aqueous sodium bicarbonate (25ml). Benzyl chloroformate (0.394ml) was added to the bi-phasic mixture and stirring continued for 20h. The aqueous layer was removed and the organic layer washed with 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate: petroleum ether (3:1 v/v), to give the title compound as a colourless gum (0.32g). Hplc system 1 (λ = 254nm) Rt 10.6min

Intermediate 91

3-f2-fBenzyloxycarbonyl-pyridin-4-yl-amino)-ethoxyl-5-chl oro-benzoic acid To a stirred solution of 3-[2-(benzyloxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro - benzoic acid methyl ester (0.32g) in a mixture of 1,4-dioxane (10ml) and water (5ml) was added 2M sodium hydroxide solution (0.72ml). The reaction mixture was stirred at room temperature for 20h, neutralised by the addition of 2M hydrochloric acid (0.72ml) and then concentrated under reduced pressure. The residue was triturated with water and then dissolved in a mixture of ethyl acetate, chloroform, tetrahydrofuran and methanol until all the gum had dissoved. The solution was dried over sodium sulphate and then concentrated under reduced pressure gave the title compound as a white solid (0.27g). Hplc system 1 (λ = 254nm) Rt 8.1 min

Intermediate 92

3-({3-f2-(Benzyloxycarbonyl-pyridin-4-yl-amino)-ethoxyl-5 -chloro-benzoyl}-tert-butyl- aminoVpropionic acid methyl ester

To a stirred suspension of 3-[2-(benzyloxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0.265g)and DMF (0.010ml) in anhydrous dichloromethane (15ml) was added a 2M solution of oxalyl chloride in dichloromethane (0.434ml). After 1h a mixture of 3-(tert-butylamino)-propionic acid methyl ester (0.987g), DIPEA (0.324ml) and DMAP (0.008g) in dichloromethane (5ml) was added and the reaction stirred at room temperature for 18h. The reaction mixture was diluted with chloroforπτdichloromethane (1 :1 v/v, 50ml) and extracted with 2M aqueous sodium

hydroxide, 2M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and dried with brine and over sodium sulphate The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography, eluting with ethyl acetate petroleum ether (2 1 and 3 1 v/v) to give the title compound as a colourless gum (0 038g) Hplc system 1 (λ = 254nm) Rt 10 5mιn

Intermediate 93

3-({3-f2-(Benzyloxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy |-5-chloro-benzoyl}-tert-butyl- amιno)-propιonιc acid

To a stirred solution of 3-({3-[2-(benzyloxycarbonyl-pyπdιn-yl-amιno)-ethoxy]-5- chloro-benzoyl}-tert-butyl-amino)-propionιc acid methyl ester (0.038g) in a mixture of 1 ,4-dιoxane (1 ml) and water (0.5ml) was added 2M sodium hydroxide solution (0.066ml) The reaction mixture was stirred at room temperature for 1h, neutralised by the addition of 2M hydrochloric acid (0.066ml) and then concentrated under reduced pressure The residue was partitioned between ethyl acetate and brine, the aqueous layer was removed and the organic layer was dried over sodium sulphate and then concentrated under reduced pressure gave the title compound as a white solid (0.034g).

Hplc system 1 (λ = 254nm) Rt 8.5min

Intermediate 94

(2- 3-[tert-Butyl-(2-tert-butylcarbamoyl-ethyl)-carbamoyl1-5-chl oro-phenoxy)-ethyl)- pyrιdιn-4-yl-carbamιc acid benzyl ester

A solution of 3-({3-[2-(benzyloxycarbonyl-pyridin-yl-amιπo)-ethoxy]-5-ch loro- benzoyl}-tert-butyl-amino)-propionιc acid (0.034g), HATU ^® (0046g) and DIPEA (0.020ml) was stirred for 20mιn then tert-butylamine (0.063ml) was added. After 14h the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water The aqueous layer was removed and the organic layer washed with further water, 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate The solvent was removed to give the title compound as a colourless gum (0 024g) Hplc system 1 (λ = 254nm) Rt 8.5mιn

Intermediate 95

3-({3-f2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxyl -5-chloro-benzoyl)- cyclobutyl-amιno)-propιonιc acid methyl ester compound

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 196g) and TBTU (0 321g) in DMF (5ml) was added DIPEA (0 174ml) followed by 3-(cyclobutyl-amιπo)-propιonιc acid methyl ester (0 314g) after 10mιn The reaction mixture was stirred at room temperature for 63h and then concentrated under reduced pressure The residue was partitioned between ethyl acetate and water The aqueous layer was removed and the organic layer washed with further water, saturated aqueous sodium bicarbonate, 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and water The organic layer was dried with brine and over sodium sulphat. The solvent was removed under reduced pressure and the residue purified by flash column chromatography, eluting with ethyl acetate petroleum ether (2 1 v/v), to give the title compound (0 096g) as a colourless gum Mass spectrum Found MH ⁺ 532 ( ³⁵ CI)

Intermediate 96

3-(f3-f2-(tert-Butoxycarbonyl-pyrιdιn-4-yl-amino)-ethox y1-5-chloro-benzoyl}- cvclobutyl-amιno)-propιonic acid

To a stirred solution of 3-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5- chloro-benzoyl}-cyclobutyl-amιno)-propιonιc acid methyl ester (0.096g) in a mixture of 1 ,4-dιoxane (2ml) and water (1 ml) was added 2M sodium hydroxide solution (0 180ml) The reaction mixture was stirred at room temperature for 2h, neutralised by the addition of 2M hydrochloπc acid (0 180ml) and then concentrated under reduced pressure The residue was partitioned between ethyl acetate and water, the aqueous layer removed and the organic layer extracted with 0 2M sodium hydroxide The aqueous layer was acidified with an equivalent volume of 0 2M hydrochloric acid, and extracted with ethyl acetate This solution was dried over sodium sulphate and then concentrated under reduced pressure gave the title compound as a colourless gum (0 050g) Hplc system 1 (λ = 254nm) Rt 8 2mιn

Intermediate 97 (2- 3-r(2-tert-Butvtcarbamoyl-ethyl)-cvclobutyl-carbamovn-5-chlo ro-pnenoxy}-ethyl)- pyπdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of ({3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy)-5 - chloro-beπzoyl}-cyclobutyl-amιno)-propιonιc acid (0 025g) and HATU ^® (0 038g) in DMF (1 ml) was added DIPEA (0 017ml) followed by tert-butylamine (0 053ml) after 10mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 021 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 573 ( ³⁵ CI)

Intermediate 98 f2-(3-Chloro-5-fcyclobutyl-f2-(2 2-dιmethyl-propylcarbamoyl)-ethvπ-carbamoyl}- phenoxy)-ethyll-pyrιdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of ({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoyl}-cyclobutyl-amιno)-propιonιc acid (0 025g) and HATU ^® (0 038g) tn DMF (1ml) was added DIPEA (0017ml) followed by neopentylamine (0 053ml) after 10mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 016g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 587 ( ³⁵ CI)

Intermediate 99

(2-f3-Chloro-5-f(2-cyano-ethyl)-cvclobutyl-carbamoyπ-phe noxy)-ethyl)-pyπdιn-4-yl- carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 030g) and HATU ^® (0 058g) in DMF (0 4ml) was added DIPEA (0 040ml) followed by a solution of 3-(cyclobutylamιno)propιonιtπle (0 038g) in DMF (0 6ml) after 10mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0042g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 499 ( ³⁵ CI)

Intermediate 100

(2-{3-Chloro-5-fιsopropyl-(2-sulfamoyl-ethyl)-carbamovn- phenoxy}-ethyl)-pyrιdιn-4- yl-carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 030g) and HATU ^® (0 058g) in DMF (0 4ml) was added DIPEA

(0 040ml) followed by a solution of 2-ιsopropylamιno-ethanesulfoπιc acid amide

(0 058g) in DMF (0 6ml) after 10mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 012g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Mass spectrum Found MH ⁺ 541 ( ³⁵ CI)

Intermediate 101 r2-(3-Chloro-5-ff2-(2,2-dιmethyl-propylsulfamovπ-ethyn-ιs opropyl-carbamoyl)- phenoxy)-ethvJl-pyπdιn-4-yl-carbamιc acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 030g) and HATU ^® (0 058g) in DMF (0 4ml) was added DIPEA (0 040ml) followed by a solution of 2-ιsopropylamιno-ethanesulfonιc acid (2,2- dιmethyl-propyl)-amιde (0 070g) in DMF (0 6ml) after 10mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 042g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 611 ( ³⁵ CI)

Intermediate 102

3-Chloro-Nf2-f5-hvdroxy-f1.2.4loxadιazol-3-yl)-ethyl)-N- ιsopropyl-5-[2[(pyπdιn-4- ylamιno)-ethoxyl-benzamιde carbamic acid tert-butyl ester

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 100g), TBTU (0 164g) in DMF (3ml) was added DIPEA

(0 174ml) followed by (3-(2-ιsopropylamιno-ethyl)-5-hydroxy-[1 ,2,4]oxadιaxole trifluoroacetate (0 043g) after 15 mm The reaction mixture was stirred at room

temperature for 18h and then concentrated under reduced pressure and the residue subjected to preparative hplc to give the title compound (0 046g) as a colourless oil Mass spectrum Found MH ⁺ 546 ( ³⁵ CI)

Intermediate 103

(2-[3-Chloro-5-(ιsopropyl-(2-(4-tert-butylphenyl)-ethyl- carbamoyl)-phenoxyl-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester

A solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5-ch loro-beπzoic acid (0.1 OOg), ιsopropyl-2-(4-terf-butylpheπyl)-ethylamιne (0 170g) and EEDQ (0 136g) in acetonitrile (2ml) was stirred at reflux, under nitrogen, for 6h The solvent was evaporated and the residue was purified by flash chromatography, eluting with dιchloromethane:methanol (98:2 v/v), to give the title compound as a pale yellow oil

(0.063g)

Mass Spectrum. Found MH ⁺ 594 ( ³⁵ CI)

Example 1

N-Cvclohexyl-3,N-dιmethyl-5-f2-(pyridin-4-ylamino)-ethox yl-benzamide trifluoroacetate salt

A stirred solution of 3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.031 g) in DMF (1ml) was treated with HOBt (0.011g), DIPEA

(0.028ml), N-methylcyclohexylamine (0.010ml), and TBTU (0.026g). The resulting solution was retained in a sealed flask for 64h. The reaction mixture was concentrated under reduced pressure and the resulting gum subjected to preparative hplc. The required fraction was concentrated and then dπed by addition of methanol and concentration under reduced pressure, addition of toluene and again concentration under reduced pressure giving the title compound as a colourless gum (0.034g).

Hplc system 2 (λ = 254nm) Rt 11.6mιn

Mass spectrum: Found: MH ⁺ 368.2336 C ₂₂ H ₃ oN ₃ O ₂ requires 368.2338

Example 2

3-Bromo-N-cvclohexyl-N-methyl-5-f2-(pyridιn-4-ylamino)-e thoxyl-benzamide trifluoroacetate salt

To a stirred solution of 3-bromo-5-[2-(pyridin-4-ylamιno)-ethoxy]-benzoic acid trifluoroacetate salt (0.034g), TBTU (0.048g) and HOBt (0.014g) in DMF (0.3ml) was added DIPEA (0.026ml) followed by N-methylcyclohexylamine (0 020ml) after

15mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 005g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 2 (λ = 254nm) Rt 12 Omin Mass spectrum Found. MH ⁺ 432 ( ⁷⁹ Br)

Example 3 N-Allyl-3-bromo-N-cvclohexyl-5-f2-(pyridιn-4-ylammo)-ethoxy l-benzamιde trifluoroacetate salt

To a stirred solution of 3-bromo-5-[2-(pyridιn-4-ylamιno)-ethoxy]-benzoιc acid trifluoroacetate salt (0.034g), TBTU (0 048g) and HOBt (0.014g) in DMF (0.3ml) was added DIPEA (0.026ml) followed by N-allylcyclohexylamine (0.022ml) after 15mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.01 1 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Hplc system 2 (λ = 254nm) Rt 12.8min

Mass spectrum: Found: MH ⁺ C ₂₃ H ₂₉ ⁷⁹ Br ₁ N ₃ O ₂ requires 458.1443

Example 4 N-Allyl-3-bromo-N-cvclopentyl-5-[2-(pyridιn-4-ylamιno)-eth oxyl-benzamide trifluoroacetate salt

To a stirred solution of 3-bromo-5-[2-(pyπdιn-4-ylamino)-ethoxy]-benzoιc acid trifluoroacetate salt (0.034g), TBTU (0.048g) and HOBt (0 014g) in DMF (0.3ml) was added DIPEA (0.026ml) followed by N-allylcyclopentyamine (0.022ml) after 15mιn The reaction mixture was stirred at room temperature for 18h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.022g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 2 (λ = 254nm) Rt 12 4mιn Mass spectrum- Found: MH ⁺ C ₂₂ H ₂₇ ⁷⁹ Br ₁ N ₃ O ₂ requires 444 1287

6S

Example 5

3-Chloro-N-cyclohexyl-N-methyl-5-(2-(pyrιdιn-4-ylamιno )-ethoxy1-benzamιde trifluoroacetate salt

A solution of {2-[3-chloro-5-(cycloπexyl-metnyl-carbamoyl)-phenoxy]-ethyl }-pyrιdιn-4- yl-carbamic acid tert-butyl ester (0 036g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 024g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 8.1 m Mass spectrum- Found: MH ⁺ requires 388 1792

Example 6 N-Allyl-3-chloro-N-cyclopentyl-5-f2-(pyridin-4-ylamιno)-eth oxy1-benzamιde trifluoroacetate salt

A solution of {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl} -pyridιn-4- yl-carbamic acid tert-butyl ester (0.030g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.026g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Hplc system 1 (λ = 254nm) Rt 8.7mιn Mass spectrum: Found: MH ⁺ 400 ( ^3S CI)

Example 7

N-Allyl-3-chloro-N-cvclohexyl-5-f2-(pyridιn-4-ylamιno)- ethoxy1-benzarnide trifluoroacetate salt A solution of {2-[3-(allyl-cyclohexyl-carbamoyl)-5-chloro-phenoxy]-ethyl}- pyπdιn-4-yl- carbamic acid tert-butyl ester (0 032g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (C 027g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 9 3mιπ

Mass spectrum. Found: MH ⁺ 414 1960 requires 414 1962

Example 8 3-Chloro-N-cvclohexyl-N-propyi-5-f2-(pyrιdιn-4-ylamιno)-e thoxyl-benzamιde trifluoroacetate salt

A solution of {2-[3-(propyl -cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridιn- 4-yl-carbamιc acid tert-butyl ester (0 07g) in a mixture of dichloromethane (2ml) and trifluoroacetic acid (2ml) was stored at room temperature for 1 h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0.036g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. Hplc system 1 (λ = 254nm) Rt 9.2mιn Mass spectrum: Found: MH ⁺ 402.1952 requires 402.1948

Example 9

3-Chloro-N-cvclopentyl-N-(3-hvdroxy-propyl)-5-f2-(pyridin -4-ylamino)-ethoxyl- benzamide trifluoroacetate A solution of (2-{3-chloro-5-[cyclopentyl-(3-hydroxy-propyl)-carbamoyl]-ph enoxy}- ethyl)-pyridιn-4-yl-carbamic acid tert-butyl ester (0.07g) in a mixture of dichloromethane (2ml) and trifluoroacetic acid (2ml) was stored at room temperature for 1 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.011g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.

Hplc system 1 (λ = 254nm) Rt 6.9min

Mass spectrum: Found: MH ⁺ 418 ( ³⁵ CI)

Example 10

3-Chloro-N-propyl-5-[2-(pyridin-4-ylamino)-ethoxy1-N-(tet rahvdro-pyran-4-yl)- benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[propyl-(tetrahydro-pyran-4-yl)-carbamoyl]-ph enoxy}- ethyl)-pyridιn-4-yl-carbamιc acid tert-butyl ester (0.070g) in a mixture of dichloromethane (2ml) and trifluoroacetic acid (2ml) was stored at room temperature for 2h and then concentrated under reduced pressure. The residue was subjected

to preparative hplc and the title compound (0 048g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 6 9mιn Mass spectrum Found MH ⁺ 418 1882 C ₂₂ H ₂ 9 ³⁵ ClιN ₃ O ₃ requires 418 1897

Example 1 1

(f3-Chloro-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl> ;-cvclopentyl-amιno)-acetιc acιd To a solution of {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl} -pyrιαιn- 4-yl-carbamιc acid tert-butyl ester (0 06g) in tert-butanol (3 2ml) was added a solution of potassium permanganate (0 006g), sodium peπodate (0 157g) and sodium bicarbonate (0 051 g) in water (3 2ml) The purple reaction mixture was stirred at room temperature for 1 5h and then added to ethanol (25ml) the precipitate was filtered and the filtrate evaporated in vacuo The residue was dissolved in a mixture of dichloromethane (5ml) and trifluoroacetic acid (5ml) was stored at room temperature for 17h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 021 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure Hplc system 1 (λ = 25^nm) Rt 6 7mιn Mass spectrum Found MH ⁺ 418 1548 C ₂ ιH ₂₅ ³⁵ ClιN ₃ O ₄ requires 418 1534

Example 12

3-Chloro-N-cvclopentyl-N-(2,3-dιhydroxy-propyl)-5-f2-(py rιdιn-4-ylamιno)-ethoxyl- benzamide trifluoroacetate A solution of crude (2-{3-chloro-5-[cyclopentyl-(2,3-dιhydroxy-propyl)-carbamoy l]- phenoxy}-ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 044g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 007g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 6 2mιn

Mass spectrum Found MH ⁺ 434 1862 C ₂ 2H29 ⁵ CI ₁ N ₃ O4 requires 434 1847

Example 13

3-Chloro-N-cyclopentyl-N-(3-morpholιn-4-yl-propyl)-5-f2-(py rιdιn-4-ylamιno)-ethoxyl- benzamide bιs(tπfluoroacetate)

A solution of (2-{3-chloro-5-[cyclopentyl-(3-morpholin-4-yl-propyl)-carbam oylj- phenoxy}-ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester trifluoroacetate (0 060g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 034g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ= 254nm) Rt 6 4mιn

Mass spectrum Found. MH ⁺ 487.2472 C ₂₆ H ₃₆ ³⁵ CI,N ₄ O ₃ requires 487.2476

Example 14 3-Chloro-N-cvclopentyl-5-[2-(pyridιn-4-ylamιno)-ethoxyl-N- (3-pyrrolιdιn-1 -yl-propyl)- benzamide bιs(trifluoroacetate)

A solution of (2-{3-chloro-5-[cyclopentyl-(3-pyrrolidιn-1-yl-propyl)-carb amoyl]- phenoxy}-ethyl)-pyridιn-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.080g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure to give the title compound (0.075g) as a colourless gum

Hplc system 1 (λ= 254nm) Rt 6.6min

Mass spectrum: Found: MH ⁺ 471.2514 C ₂₆ H36 ³⁵ CI,N ₄ O ₂ requires 471.2527

Example 15

3-Chloro-5-f2-(pyridιn-4-ylamino)-ethoxy1-N-(3-pyrrolιd ιn-1 -yl-propyl)-N-(tetrahydro- Pyran-4-yl)-benzamide bis(trifluoroacetate) To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amino)-ethoxy]-5- chloro-benzoic acid (0 059g), TBTU (0.085g) and HOBt (0.020g) in DMF (0.6ml) was added DIPEA (0.052ml) followed by N-(3-pyrrolιdιn-1 -yl-propyl)-4- aminotetrahydropyran (0.048g) after 20mιn. The reaction mixture was stirred at room temperature for 20h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the product (0 005g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure A solution of this product in trifluoroacetic acid (2ml) was stored at room

temperature for 18h and the solvent removed under reduced pressure to give the title compound (0 005g) as a colourless gum Hplc system 1 (λ= 254nm) Rt 5.6mιn Mass spectrum Found MH ⁺ 487 ( ³⁵ CI)

Example 16 3-Chloro-N-(3-morpholιn-4-yl-propyl)-5-[2-(pyrιdιn-4-ylam ιno)-ethoxyl-N-(tetrahydro- pyran-4-yl)-benzamιde bis(trifluoroacetate)

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.059g), TBTU (0.085g) and HOBt (0.020g) in DMF (0.6ml) was added DIPEA (0.052ml) followed by N-(3-morpholιn-4-yl-propyl)-4- aminotetrahydropyran (0.051 g) after 20mιn. The reaction mixture was stirred at room temperature for 20h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the and the product (0.062g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. A solution of this product in TFA (2ml) was stored at room temperature for 18h and the solvent removed under reduced pressure to give the title compound (0.060g) as a colourless gum. Hplc system 1 (λ= 254nm) Rt 4.9min Mass spectrum: Found: MH ⁺ 503 ( ³ CI)

Example 17

4-((3-Chloro-5-r2-(pyridin-4-ylamino)-ethoxyl-benzoyl)-cy clopentyl-amino)-butyric acid ethyi ester trifluoroacetate

A solution of crude 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5- chloro-benzoyl}-cyclopentyl-amino)-butyric acid ethyl ester (0.020g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.005g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ= 254nm) Rt 9 1 min Mass spectrum: Found: MH ⁺ 474.2172 C ₂₅ H3 ₂ ³⁵ CI ₁ N ₃ O4 requires 474.2160

Example 18

4-(|3-Chloro-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl)-cy clopentyl-amιno)-butyrιc

A solution of 4-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5-chloro- beπzoyl} cyclopentyl-amιno)-butyrιc acid (0 015g) in trifluoroacetic acid (3ml) was stored at room temperature for 2h and then the solvent removed under reduced pressure The residue was purified by preparative hplc to give title compound

(0 09g) as a colourless gum

Hplc system 3 (λ= 220nm) Rt 3 7mιn

Mass spectrum Found MH ⁺ 446 ( ³⁵ CI)

Example 19

N-(3-Carbamoyl-propyl)-3-chloro-N-cvclopentyl-5-[2-(pyrι dιn-4-ylamιno)-ethoxy]- benzamide trifluoroacetate

A solution of (2-{3-[(3-carbamoyl-propyl)-cyclopentyl-carbamoyl]-5-chloro- phenoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 040g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure to give the title compound

(0 040g) as a colourless gum

Hplc system 1 (λ= 254nm) Rt 6 7mιn Mass spectrum Found MH ⁺ 445 1989 C ₂₃ H ₃ o ³⁵ CliN ₄ O ₃ requires 445 2006

Example 20

3-Chloro-N-cvclopentyl-N-(4-oxo-4-pyrrolιdιn-1 -yl-butyl)-5-r2-(pyπdιn-4-ylamιno)- ethoxyl-benzamide bιs(tπfluoroacetate) A solution of (2-{3-chloro-N-cyclopentyl-N-(4-oxo-4-pyrrolιdιn-1 -yl-butyl)-carbamoyl]- phenoxy}-ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 025g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1ml) was stored at room temperature for 2h and then concentrated under reduced pressure to give the title compound

(0 025g) as a colourless gum Hplc system 1 (λ = 254nm) Rt 8 5mιn

Mass spectrum Found MH ⁺ 499 (∞CI)

Example 21

N-(2-Carbamoyl-ethyl)-3-chloro-N-cvclopentyl-5-f2-(pyrιd ιn-4-ylamιno)-ethoxy1- benzamide trifluoroacetate

A solution of (2-{3-[(2-carbamoyl-ethyl)-cyclopentyl-carbamoyl]-5-chloro-p henoxy}- ethyi)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 074g) in a mixture of dichloromethane (1ml) and trifluoroacetic acid (1 l) was stored at room temperature for 2h and then concentrated under reduced pressure to give the title compound (0.060g) as a colourless gum

Hplc system 1 (λ = 254nm) = 254nm) Rt 6.2mιn

Mass spectrum Found: MH ⁺ 431.1857 C ₂₂ H ₂₈ ³⁵ ClιN ₄ O ₃ requires 431 1830

Example 22 N-Carbamoylmethyl-3-chloro-N-cyclopentyl-5-f2-(pyndιn-4-yla mιno)-ethoxyl- benzamide trifluoroacetate

A solution of (2-{3-[(2-carbamoyl-methyl)-cyclopentyl-carbamoyl]-5-chloro- phenoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0.064g) in a mixture of dichloromethane (1ml) and trifluoroacetic acid (1ml) was stored at room temperature for 2h and then concentrated under reduced pressure to give the title compound

(0.057g) as a colourless gum

Hplc system 1 (λ = 254nm) Rt 6.0min

Mass spectrum. Found: MH ⁺ 417.1703 C ₂ ιH26 ³⁵ CI ₁ N ₄ O requires 417.1693

Example 23

N-(2-Carbamoyl-ethyl)-3-chloro-N-cvclopropyl-5-r2-(pyrid� �n-4-ylamιno)-ethoxyl- benzamide hydrochloride

A solution of (2-{3-chioro-5-[(2-cyano-ethyl)-cyclopropyl-carbamoyl]-pheno xy}-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0.075g) in a mixture of dichloromethane (5ml) and trifluoroacetic acid (5ml) was stored at room temperature for 18h and then concentrated under reduced pressure. The residue was triturated with ethereal hydrogen chloride to give the title compound (0.065g) as a colourless gum.

Hplc system 1 (λ = 254nm) Rt 5 1mιn

Mass spectrum. Found MH ^* 417.1532 C ₂ oH ₂₄ ³⁵ CI ₁ N ₄ O ₃ requires 417.1537

Example 24

N-(2-Carbamoyl-ethyl)-3-chloro-N-(1-propyl-butyl)-5-f2-(p yrιdιn-4-ylamιno)-ethoxyl- benzamide trifluoroacetate

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 118g), TBTU (0 170g) and HOBt (0 040g) in DMF (0 6ml) was added DIPEA (0 104ml) followed by N-(2-propylbutyl)-3-amιno-propιonamιde

(0 086g) after 15mιn The reaction mixture was stirred at room temperature for 20h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the product (0 005g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure A solution of this product in tπflouroacetic acid (2ml) was stored at room temperature for 18h and the solvent removed under reduced pressure to give the title compound (0 090g) as a colourless gum Hplc system 1 (λ = 254nm) Rt 7 6mιn Mass spectrum Found MH ⁺ 461 ( ³⁵ CI)

Example 25

3-Chloro-N,N-dιpropyl-5-f2-(pyπdιn-4-ylamιno)-ethoxy1 -benzamιde hydrochloride

A solution of [2-(3-chloro-5-dιpropylcarbamoyl-phenoxy)-ethyl]-pyπdιn-4 -yl-carbamιc acid tert-butyl ester (0 085g) in a mixture of dichloromethane (2ml) and trifluoroacetic acid (2ml) was stored at room temperature for 18h and then concentrated under reduced pressure The residue was triturated with ethereal hydrogen chloride to give the title compound (0 063g) as a colourless gum Hplc system 1 (λ = 254nm) Rt 7 9mιn Mass spectrum Found MH ⁺ 376 1782 C ₂ oH ₂₇ ³⁵ ClιN ₃ O ₂ requires 376 1792

Example 26

3-Chloro-N-propyl-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-N-f 1 ,3,41thιadιazol-2-yl- benzamide trifluoroacetate To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0 050g), TBTU (0 074g) and HOBt (0 018g) in DMF (0 9ml) was added DIPEA (0 045ml) followed by N-propyl-2-amιno-[1 ,3,4]thιadιazole (0 037g) after 15mιn The reaction mixture was stirred at room temperature for 20h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the product (0 007g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure A solution of this product in trifluoroacetic acid (2ml) was stored at room temperature for 18h and the solvent removed under reduced pressure to give the title compound (0 005g) as a colourless gum

Hplc system 1 (λ = 254nm) Rt 7 2mιn

Mass spectrum Found MH ⁺ 418 ( ³⁵ CI)

Example 27

3-Chloro-N-propyl-5-f2-(pyπdιn-4-ylamιno)-ethoxy1-N-th ιazol-2-yl-benzamιde trifluoroacetate

To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.050g), TBTU (0 074g) and HOBt (0 018g) in DMF (0 9ml) was added DIPEA (0.045ml) followed by N-propyl-2-amιno-thiazole (0.037g) after 15mιn The reaction mixture was stirred at room temperature for 20h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the product (0.022g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure. A solution of this product in trifluoroacetic acid (2ml) was stored at room temperature for 18h and the solvent removed under reduced pressure to give the title compound (0.019g) as a colourless gum.

Hplc system 1 (λ = 254nm) Rt 8.5min Mass spectrum: Found: MH ⁺ 417 ( ³⁵ CI)

Example 28

3-Chloro-N-ethyl-N-phenyl-5-f2-(pyridin-4-ylamιno)-ethox y1-benzamide hydrochloride

A solution {2-[3-chloro-5-(ethyl-phenyl-carbamoyl)-phenoxy]-ethyl}-pyri din-4-yl- carbamic acid tert-butyl ester (0.080g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 90min and then concentrated under reduced pressure. The residue was triturated with ethereal hydrogen chloride to give the title compound (0.068g) as a colourless solid.

Hplc system 1 (λ = 254nm) Rt 7.7min

Mass spectrum. Found: MH ⁺ 396 1483 C-^H^C^NsOz requires 396 1479

Example 29

3-Chloro-N-(3.5-dιfluoro-phenyl)-N-propyl-5-r2-(pyridιn -4-ylamιno)-ethoxy1- benzamide trifluoroacetate

A solution (2-{3-chloro-5-[(propyl)-(3,5-dιfluoro-phenyl)-carbamoyl]-p henoxy}-ethyl)- pyπdιn-4-yl-carbamιc acid tert-butyl ester (0.029g) in trifluoroacetic acid (2ml) was stored at room temperature for 18h and then concentrated under reduced pressure

The residue was subjected to preparative hplc and the title compound (0 020g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 9 Omin Mass spectrum Found. MH ⁺ 446 ( ³⁵ CI)

Example 30 3-Chloro-N-ethyl-N-(2-fluoro-phenyl)-5-f2-(pyrιdιn-4-ylam� �no)-ethoxy1-benzamιde trifluoroacetate

2M Oxalyl chloride solution in dichloromethane (0 080ml) and DMF (0 001 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.050g) in anhydrous dichloromethane (1 ml) The reaction was stirred at room temperature for 2h then a solution of N-ethyl-2-fluoroanιlιne (0.029g), DMAP (0.001 g) and DIPEA (0.070ml) were added The reaction mixture was stirred at room temperature for 16h and then triflouroacetic acid (1 ml) was added. The solvent was removed in vacuo, the residue was subjected to preparative hplc and the required fraction dried by repetitive addition of acetonitrile and concentration under reduced pressure to give the title compound (0.020g) as a colourless gum. Hplc system 1 (λ = 254nm) Rt 7.9min Mass spectrum: Found: MH ⁺ 414 ( ³⁵ CI)

Example 31 N-(2-Carbamoyl-ethyl)-3-chloro-N-phenyl-5-f2-(pyridιn-4-yla mιno)-ethoxyl- benzamide trifluoroacetate

2M Oxalyl chloride solution in dichloromethane (0 090ml) and DMF (0.001 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amιno)-ethoxy]-5- chloro-benzoic acid (0.059g) in anhydrous dichloromethane (1 ml) The reaction was stirred at room temperature for 2h then 3-phenylamιno-propιonιtπle ⁸ (0.027g), DMAP (0.002g) and DIPEA (0.078ml) were added The reaction mixture was stirred at room temperature for 2h then trifluoroacetic acid (2ml) was added and the reaction mixture stirred overnight open to the air The reaction mixture was concentrated in vacuo and the residue was subjected to preparative hplc The title compound (0 060g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 5 9mιn

Mass spectrum Found MH ⁺ 439 1528 C ₂ 3H ₂ 4 ³⁵ CI ₁ N ₄ θ3 requires 439 1537

Example 32 N-(2-Carbamoyl-ethyl)-3-chloro-N-(2-fluoro-phenyl)-5-f2-(pyr ιdιn-4-ylamιno)-ethoxy]- benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-(2-fluoro-phenyl)-carbamoyl] -phenoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 055g) and water (0 020ml) in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 mι) was stirred at room temperature for 2h and then the solvent removed under reduced pressure The residue was purified by preparative hplc to give the title compound (0 035g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 5 7mιn

Mass spectrum Found MH ⁺ 457 1435 C ₂₃ H ₂₃ ³⁵ CI ₁ F ₁ N ₄ O ₃ requires 457 1443

Example 33 N-(2-Carbamoyl-ethyl)-3-chloro-N-(2-chloro-phenyl)-5-f2-(pyr ιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-chloro-phenyl)-(2-cyano-ethyl)-carbamoyl] -phenoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 055g) and water (0 020ml) in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stirred at room temperature for 2h and then the solvent removed under reduced pressure The residue was purified by preparative hplc to give title compound (0 035g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 6 0mm Mass spectrum Found MH ⁺ 473 1130 C ₂₃ H ₂ 3 ³⁵ CI ₂ N ₄ O ₃ requires 473 1 147

Example 34

4-[f3-Chioro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy1-benzoylH 2-fluoro-phenyl)-amιno1- butyπc acid methyl ester trifluoroacetate A solution of 4-[{3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5-chloro- benzoyl}-(2-fluoro-phenyl)-amιno]-butyrιc acid methyl ester (0 020g) in a mixture of

dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 16h and then concentrated under reduced pressure to give the title compound (0 022g) as a colourless gum Hplc system 1 (λ = 254nm) Rt 8 1 mιn Mass spectrum Found MH ⁺ 486 1576 C^H-Λl- F.N^ requires 486 1596

Example 35

4-f{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy1-benzoylH 2-fluoro-phenyl)-amιno1- butyπc acid A solution of 4-[{3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy] -5-chloro- benzoyl}-(2-fluoro-phenyl)-amιno]-butyπc acid (0 020g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure to give the title compound

(0 023g) as a colourless gum Hplc system 3 (λ = 220-330nm) Rt 3 1 mιn

Mass spectrum Found MH ^* 472 1453 C ₂₄ H ₂ 4 ³⁵ CI ₁ F ₁ N ₃ O4 requires 472 1439

Example 36

N-(3-Carbamoyl-propyπ-3-chloro-N-(2-fluoro-phenyl)-5-f2- (pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

A solution of (2-{3-[(3-Carbamoyl-propyl)-(2-fluoro-phenyl)-carbamoylJ-5-c hloro- phenoxy -ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 030g) in trifluoroacetic acid (2ml) was stored at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 009g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 6 Omin

Mass spectrum Found MH ⁺ 471 1594 C ₂₄ H ₂₅ ³⁵ CI ₁ F ₁ N ₄ O ₃ requires 471 1599

Example 37

3-Chloro-N-(2-fluoro-phenyl)-N-(4-oxo-4-pyrrolιdιn-1 -yl-butyl)-5-f2-(pyrιdιn-4- ylamιno)-ethoxy1-benzamιde trifluoroacetate

A solution of (2-{3-chloro-5-[(2-fluoro-phenyl)-(4-oxo-4-pyrrolιdιn-1 -yl-butyl)- carbamoyl]-phenoxy}-ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 025g) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room

temperature for 1 h and then the solvent removed under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 024g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 7 7mιn

Mass spectrum Found MH ⁺ 525 2063 C ₂₈ H ₃₁ ³⁵ ClιF ₁ N ₄ θ ₃ requires 525 2068

Example 38 4-((2-Carbamoyl-phenyl)-(3-chloro-5-[2-(pyrιdιn-4-ylamιno )-ethoxy1-benzoyl}-amιno)- butyπc acid methyl ester trifluoroacetate

A solution of 4-[{3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy] -5-chloro- benzoyl}-(2-carbamoyl-phenyl)-amιno]-butyπc acid methyl ester (0 031 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure to give the title compound (0 032g) as a colourless gum

Hplc system 1 (λ = 254nm) Rt 6 2mιn

Mass spectrum Found MH ⁺ 51 1

Example 39

4-((2-Carbamoyl-phenyl)-{3-chloro-5-f2-(pyrιdιn-4-ylam� �no)-ethoxy1-benzoyl)-amιno)- butyπc acid

2M Aqueous sodium hydroxide (0 200ml) was added to a stirred solution of 4-((2- carbamoyl-phenyl)-{3-chloro-5-[2-(pyπdιn-4-ylamιno)-ethox y]-benzoyl}-amιno)- butyric acid methyl ester trifluoroacetate (0 030g) in 1 ,4-dιoxan (1 ml) 2M Aqueous hydrochloric acid (0 2ml) was added after 16h The reaction mixture was evaporated in vacuo and the residue was subjected to preparative hplc to give the title compound (0 024g as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 2 (λ = 254) Rt 8 0mm Mass spectrum Found (M-H ₂ O)H ⁺ 479 1492 C ₂₅ H ₂₄ ³⁵ ClιN ₄ O ₄ requires 479 1486

Example 40 3-Chloro-N-ι2-fluoro-phenyl)-5-r2-(pyrιdιn-4-ylamιno)-et hoxy1-N-f3-(1 H-tetrazol-5-yf)- propyll-benzamide

A mixture of (2-{3-chloro-5-[(3-cyano-propyl)-2-fluoro-phenyl)-carbamoyl] -phenoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 132g) and tπbutyltin azide (1 2ml) was heated at 160°C for 5h The reaction mixture was cooled to room temperature and 1 M ethereal hydrogen chloride was added The reaction mixure was partioned between acetonitrile and petroleum ether The acetonitrile layer was removed and extracted further with petroleum ether The acetonitrile layer was then sub _j ected to prepartive hplc to give the title compound as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 6 6mιn

Mass spectrum Found MH ⁺ 496 1684 C ₂₄ H ₂ 4 ³⁵ ClιF ₁ N ₇ O ₂ requires 496 1664

Example 41 3-Chloro-N-f2-(2.3-dιhvdroxy-propoxy)-ethyll-N-phenyl-5-f2- (pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

A solution of [2-(3-chloro-5-{[2-(2,2-dιmethyl-[1 ,3}dιoxolan-4-ylmethoxy)-ethyl]- phenyl-carbamoyl}-phenoxy)-ethyl]-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 037g) in mixture of trifluoroacetic acid (1ml) and dichloromethane (1 ml) was stored at room temperature for 3h and then the solvent removed under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 010g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 5 9mιn Mass spectrum Found MH ⁺ 486 ( ³⁵ CI)

Example 42

3-Chloro-N-f2-(2.3-dιhvdroxy-ρropoxy)-ethvn-N-(2-fluoro -phenyl)-5-[2-(pyπdιn-4- ylamιno)-ethoxy1-benzamιde trifluoroacetate A solution of (2-{3-chloro-5-[[2-(2,2-dιmethyl-[1 ,3]dιoxolan-4-ylmethoxy)-ethyl]-(2- fluoro-phenyl)-carbamoyl]-phenoxy}-ethyl)-pyπdιn-4-yl-carb amιc acid tert-butyl ester (0 035g) and water (0 010ml) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 3h and then the solvent removed under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 022g) as a colourless gum by concentration of the

required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.

Hplc system 1 (λ = 254nm) Rt 5.8mιn

Mass spectrum Found. MH ⁺ 504.1709 C ₂₅ H ₂ 8 ³⁵ CI ₁ F ₁ N ₃ O5 requires 504 1701

Example 43

3-Chloro-N-f2-(2,3-dιhydroxy-propoxy)-ethyll-N-(4-fluoro -phenyl)-5-[2-(pyridιn-4- ylamιno)-ethoxy1-benzamιde hydrochloride

A solution of (2-{3-chloro-5-[[2-(2,2-dιmethyl-[1 ,3]dιoxolan-4-ylmethoxy)-ethyl]-(4- fluoro-phenyl)-carbamoyl]-phenoxy}-ethyl)-pyridιn-4-yl-carb amic acid tert-butyl ester

(0.042g) in mixture of trifluoroacetic acid (1ml) and dichloromethane (1 ml) was stored at room temperature for 3h and then the solvent removed under reduced pressure The residue was dissolved in a mixture of acetonitrile (2ml) amd 2M aqueous hydrochloric acid (0.5ml) and subjected to preparative hplc to give title compound (0.022g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.

Hplc system 1 (λ = 254nm) Rt 5.8min

Mass spectrum: Found: MH ⁺ 504.1709 C ₂₅ H ₂₈ ³⁵ CI ₁ FιN ₃ O ₅ requires 504.1701

Example 44

(R)-1 -(3-f{3-Chloro-5-f2-(pyridin-4-ylamino)-ethoxy1-benzoylH2-fl uoro-phenyl)- aminol-propyll-pyrrolidιne-2-carboxylic acid trifluoroacetate

A solution of (R)-1 -{3-[{3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy ]-5- chloro-beπzoyl}-(2-fluoro-phenyl)-amino]-propyl}-pyrrolidin e-2 -carboxylic acid tert- butyl ester and (R)-1-[3-(2-fluoro-phenylamιno)-propyl]-pyrroiidιne-2-carb oxylic acid tert butyl ester (0.110g) in trifluoroacetic acid (5ml) for 18h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.027g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.

Hplc system 1 (λ = 254nm) Rt 5.5mιn

Mass spectrum: Found: MH ⁺ 541.2000 C ₂ 8H ₃ o ³⁵ CI ₁ F ₁ N ₄ O ₄ requires 541.2018

Example 45

3-Chloro-N-(3-oxo-3-pιperιdιn-1 -yl-propyl)-N-phenyl-5-[2-(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

The following procedure was performed using a TECAN despensmg robot To a 0 1 M solution of 3-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5-chloro- benzoyl}-phenyl-amιno)-propιonιc acid in DMF (0 250ml) was dispensed a 0 4M solution of PyBroP ^G in DMF (0 125ml) and a 0 2M solution of piperidine (0 375ml) Finally a 1 M solution of DIPEA in DMF (0 100ml) was added to the reaction mixture The reaction mixture was stored at room temperature for 24h, and then concentrated. The residue was stored in a mixture of dichloromethane (0 5ml) and trifluoroacetic acid (1 ml) for 6h and concentrated The residue was then subjected to preparative hplc and the title compound (0 008g) obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 3 (λ = 220-330nm) Rt 3.8mιn Mass spectrum Found MH ⁺ 506 ( ³⁵ CI)

Using commercially available amines, the following compounds were prepared by the same method:

Example 46

3-Chloro-N-r2-(ethyl-methyl-carbamoyl)-ethvn-N-phenyl-5-[ 2-(pyridιn-4-ylamino)- ethoxyl-benzamide trifluoroacetate

Hplc system 3 (λ = 220-330nm) Rt 3.6min

Mass spectrum. Found: MH ⁺ 481 ( ³⁵ CI)

Example 47

N-(2-tert-Butylcarbamoyl-ethyl)-3-chloro-N-phenyl-5-r2-(p yridιn-4-ylamino)-ethoxyl- benzamide trifluoroacetate

Hplc system 3 (λ = 220-330nm) Rt 3 7mιn Mass spectrum: Found: MH ⁺ 495 ( ³⁵ CI)

Example 48

3-Chloro-N-f2-(2,2-dιmethyl-propylcarbamoyl)-ethyn-N-phe nyl-5-[2-(pyrιdιn-4- ylamιno)-ethoxy1-benzamιde trifluoroacetate Hplc system 3 (λ = 220-330nm) Rt 3 8mιn Mass spectrum Found MH ⁺ 509 ( ³⁵ CI)

Example 49

3-Chloro-N-(3-oxo-3-thιomorpholιn-4-vl-propyl)-N-phenyl -5-[2-(pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate Hplc system 3 (λ = 220-330nm) Rt 3 7mιn Mass spectrum Found MH ⁺ 525 ( ³⁵ CI)

Example 50

3-Chloro-N-(3-oxo-3-thιazolιdιn-3-yl-propyl)-N-phenvι -5-r2-(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

Hplc system 3 (λ = 220-330nm) Rt 3 6mιn Mass spectrum Found MH ⁺ 51 1 ( ³⁵ CI)

Example 51 3-Chloro-N-phenyl-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-N-(2-s ulfamoyl-ethyl)-benzamιde trifluoroacetate

A solution of (2-{3-chloro-5-[(2-fluorosulfonyl-ethyl)-phenyl-carbamoyl]-p henoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 017g) in a mixture of acetone (10ml) and ammoπιa(0 88) was stirred at 80°C for 3h The solvent was removed under reduced pressure and the residue subjected to preparative hplc A solution of this product in a mixture of trifluoroacetic acid (3ml) and dichloromethane (1 5ml) was stored for 1 h then evaporated to give the title compound as a colourless gum (0 009g) Hplc system 1 (λ = 254nm) Rt 6 4mιn Mass spectrum Found MH ⁺ 475 1214 C ₂₂ H ₂ 4 ³⁵ CliN ₄ O ₄ Si requires 475 1207

Example 52

N-(2-tert-Butylsulfamoyl-ethyl)-3-chloro-N-phenyl-5-[2-(p yrιdιn-4-ylamιno)-ethoxy1- benzamide trifluoroacetate A solution of (2-{3-chloro-5-[(2-fluorosulfonyl-ethyl)-phenyl-carbamoyl]-p henoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 020g) in tert-butylamine (0 75ml) was stored at room temperature for 24h The amine was evaporated and the residue dissolved in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (0 5ml) and was stored for 64h The solvent was removed and the residue subjected to preparative hplc The title compound (0 015g) was obtained as a yellow

gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 7 8mιn

Mass spectrum Found MH ⁺ 531 ( ³ CI)

Example 53

3-Chloro-N-(2-ιsopropylsulfamoyl-ethyl)-N-phenyl-5- 2-(pyrιdιn-4-ylamιno)-ethoxy1- benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-fluorosulfonyl-ethyl)-phenyl-carbamoyl]-p henoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 020g) in isopropylamme (0 75ml) was stored at room temperature for 24h The amme was evaporated in vacuo and the residue dissolved in a mixture of trifluoroacetic acid (1ml) and dichloromethane

(0 5ml) was stored for 64h The solvent was removed and the residue subjected to preparative hplc. The title compound (0 015g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 7.8min

Mass spectrum: Found: MH ⁺ 517 ( ³⁵ CI)

Example 54

3-Chloro-N-ιsopropyl-N-[2-(1 -methyl-1 H-tetrazol-5-yl)-ethyll-5-f2-(pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

A solution of [2-(3-chloro-5-{ιsopropyl-[2-(1 -methyl-1 H-tetrazol-5-yl)-ethyl]- carbamoyl}-phenoxy)-ethyl]-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 028g) in a mixture of dichloromethane (0.5ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 023g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 6 1 mιn

Mass spectrum Found MH ⁺ 444 1913 C ₂₁ H ₂₇ ³⁵ CI ₁ N ₇ 0 ₂ requires 444 1915

Example 55 N-(2-Carbamoyl-ethvπ-3-chloro-N-cvclopropylmethyl-5-f2-(py� �dιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-cyclopropylmethyl-carbamoyl] - phenoxy}-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 07g) in a mixture of dichloromethane (5ml) and trifluoroacetic acid (2ml) was stored at room temperature for 18h and then concentrated under reduced pressure to give the title compound as a light brown oil (0 071 g)

Hplc system 1 (λ = 254nm) Rt 5 8mιn

Mass spectrum Found MH ⁺ 417 1709 C ₂ ιH ₂₆ ³⁵ CIN4θ ₃ requires 417 1693

Example 56 N-f2-Carbamoyl-ethyl)-3-chloro-N-(2,2-dιmethyl-propyl)-5-f2 -(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-(2,2-dιmethyl-propyl)-carba moyl]- phenoxy}-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 052g) in a mixture of dichloromethane (5ml) and trifluoroacetic acid (2ml) was stored at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 02g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 6 4mιn Mass spectrum- Found MH ⁺ 433.1995 C ₂₂ H ₃₀ ³⁵ CIN ₄ O ₃ requires 433.2006

Example 57

N-(2-Carbamoyl-ethyl)-3-chloro-5-f2-(pyrιdιn-4-ylamιno )-ethoxy1-N-(tetrahydro-furan-

2-ylmethyl)-benzamιde trifluoroacetate A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl )- carbamoyl]-phenoxy}-ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 052g) in a mixture of dichloromethane (5ml) and trifluoroacetic acid (2ml) was stored at room temperature for 18h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 037g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 5 3mιn

Mass spectrum Found MH ⁺ 447 1807 C22H ₂ 8 ³⁵ CI ₄ O4 requires 447 1799

Example 58

N-(2-Carbamoyl-ethyl)-3-chloro-N-ιsopropyl-5-[2-(pyπdιn-4 -ylamιno)-ethoxyl- benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-ιsopropyl-carbamoyl]-phenox y}-ethyl)- pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 071 g) in a mixture of dichloromethane (4ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 12h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.045g) was obtained as a yellow oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 5 1 m Mass spectrum: Found: MH ⁺ 405 ( ³⁵ CI)

Example 59

N-(2-Carbamoyl-ethyl)-3-chloro-N-ιsobutyl-5-r2-(pyridιn -4-ylamιno)-ethoxy1- benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-isobutyl-carbamoyl]-phenoxy} -ethyl)- pyridin-4-yl-carbamic acid tert-butyl ester (0.059g) in a mixture of dichloromethane

(5ml) and trifluoroacetic acid (2ml) was stored at room temperature for 18h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.047g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.

Hplc system 1 (λ = 254nm) Rt 5.7mιn

Mass spectrum: Found: MH ⁺ 419 ( ³⁵ CI)

Example 60

3-Chloro-N-(2-diethylcarbamoyl-ethyl)-N-isopropyl-5-r2-(p yridin-4-ylamino)-ethoxy1- benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-diethylcarbamoyl-ethyl)-isopropyi-carbamo yi]- phenoxy}-ethyl)-pyridin-4-yl-carbamιc acid tert-butyl ester trifluoroacetate (0.06g) in a mixture of dichloromethane (2ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 3h and then concentrated under reduced pressure to give the title compound as a colourless oil (0.043g).

Hplc system 1 (λ = 254nm) Rt 7.6mιn Mass spectrum: Found: MH ⁺ 461 ( ³⁵ CI)

Example 61

3-Chloro-N-ιsopropyl-N-(3-oxo-3-pιperιdιn-1 -yl-propyl)-5-f2-(pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

To a stirred solution of 3-({3-[2-(tert-butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]- 5- chloro-benzoyl}-ιsopropyl-amιno)-propιonιc acid hydrochloride (0 02g) and PyBroP (0 035g) in DMF (0 45m!) was added DIPEA (0 026ml) followed by piperidine (0 014ml) after 5mιn The reaction was stirred at room temperature for 24h, and then concentrated under reduced pressure The remaining solid residue was stored in a mixture of dichloromethane (2ml) and trifluoroacetic acid (1 ml) for 6h, and then concentrated under reduced pressure The residue was then subjected to preparative hplc and the title compound (0 011g) obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 3 (λ = 220-330nm) Rt 3 65mιn Mass spectrum Found MH ⁺ 473 (∞CI)

Using commercially available amines, the following compounds were prepared in a similar manner

Example 62

3-Chloro-N-f2-(3-methyl-but-2-yl-carbamoyl)-ethvπ-N-ιso propyl-5-f2-(pyrιdιn-4- ylaminol-ethoxyl-benzamide trifluoroacetate

Hplc system 1 (λ =254nm) Rt 8 0 mm

Mass spectrum Found MH ⁺ 475 (^Cl)

Example 63

3-Chloro-N-r2-(3.3-dιmethyl-but-2-yl-carbamoyl)-ethvn-N- ιsopropyl-5-r2-(pyπdιn-4- ylamιno)-ethoxyl-benzamιde trifluoroacetate

Hplc system 1 (λ = 254nm) Rt 8 5 mm Mass spectrum Found MH ⁺ 489 (^Cl)

Example 64

3-Chloro-N-[2-(ethyl-methyl-carbamoyl)-ethvn-N-ιsopropyl -5-f2-(pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate Hplc system 3 (λ = 220-330πm) Rt 3 5mιn, Mass spectrum Found MH ⁺ 447 ( ³⁵ CI)

Example 65

3-Chloro-N-ιsopropyl-N-(3-oxo-3-pyrrolidιn-1 -yl-propyl)-5- 2-(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate Hpic system 3 (λ = 220-330nm) Rt 3.5mιn, Mass spectrum- Found MH ⁺ 459

( ³⁵ CI)

Example 66

3-Chloro-N-ιsopropyl-N-(3-morpholin-4-yl-3-oxo-propyl)-5 -[2-(pyπdιn-4-ylamιno)- ethoxyl-benzamide mixture with 3-((3-chloro-5-[2-(pyπdιn-4-ylamino)-ethoxyl- benzoyl)-ιsopropyl-amino)-propιonιc acid (1.2) trifluoroacetate

Hplc system 3 (λ = 220-330nm) Rt 3.4mιn, Mass spectrum Found MH ⁺ 475

( ³⁵ CI)

Example 67

N-(2-tert-Butylcarbamoyl-ethvh-3-chloro-N-ιsopropyl-5-f2 -(pyridin-4-ylamino)- ethoxyl-benzamide trifluoroacetate

Hplc system 3 (λ = 220-330nm) Rt 3.7min; Mass spectrum: Found MH ⁺ 461

( ³⁵ CI)

Example 68

3-Chloro-N-r2-(2,2-dιmethyl-propylcarbamoyl)-ethyll-N-ι sopropyl-5-[2-(pyridin-4- ylamino)-ethoxy1-benzamide trifluoroacetate

Hplc system 3 (λ = 220-330nm) Rt 3.7min, Mass spectrum: Found MH ⁺ 475 ( ³⁵ CI)

Example 69

3-Chloro-N-ιsopropyl-N-(3-oxo-3-thiomorpholιn-4-yl-prop yl)-5-f2-(pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate Hplc system 3 (λ = 220-330nm) Rt 3.6mιn; Mass spectrum Found. MH ⁺ 491

( ³⁵ CI)

Example 70

3-Chloro-N-ιsopropyl-N-(3-oxo-3-thιazolidιn-3-yl-propy l)-5-f2-(pyπdιn-4-ylamino)- ethoxyl-benzamide trifluoroacetate

Hplc system 3 (λ = 220-330nm) Rt 3 6mιn Mass spectrum Found MH ^* 477

( ³⁵ CI)

Example 71 3-Chloro-N-[2-(1 , 1 -dιmethyl-propylcarbamoyl)-ethyll-N-ιsopropyl-5-[2-(pyrιd ιn-4- ylamιno)-ethoxyl-benzamιde trifluoroacetate Hplc system 1 (λ = 254nm) Rt 8 4mιn Mass spectrum Found MH ⁺ 475

Example 72

3-Chloro-N-isopropyl-N-(3-methanesulfonylamino-propyl)-5- [2-(pyridin-4-ylamino)- ethoxyl-benzamide trifluoroacetate

To a solution of N-(3-amιno-propyl)-3-chloro-N-ιsopropyl-5-[2-(pyπdιn-4-y lamιno)- ethoxyj-benzamide trifluoroacetate (0 02g) in dry acetonitrile (1ml) was added a mixture of methanesulfonyl chloride (0005g) and triethylamine (0 017ml) in acetonitrile (1ml) The resultant mixture was stirred at room temperature for 15h, and then concentrated under reduced pressure The residue was stored in a mixture of dichloromethane (1ml) and trifluoroacetic acid (2ml) for 4h, and then concentrated under reduced pressure The residue was then subjected to preparative hplc and the title compound obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 6 5mιn

Mass spectrum Found MH ⁺ 469 ( ³⁵ CI)

Using commercially available sulfonyl chlorides, the following compounds were prepared in a similar manner -

Example 73 3-Chloro-N-ιsopropyl-N-f3-(propane-1-sulfonylamιno)-propyl l-5-f2-(pyrιdιn-4- ylamιno)-ethoxy1-benzamιde trifluoroacetate Hplc system 1 (λ = 254nm) Rt 8 Omin, Mass spectrum Found MH ⁺ 497 ( ³⁵ CI)

Example 74 3-Chloro-N-(3-ethanesulfonylamιno-propyl)-N-ιsopropyl-5-f2 -(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

Hplc system 1 (λ = 254nm) Rt 6 7mιn, Mass spectrum Found MH ⁺ 483 ( ³⁵ CI)

Example 75

3-Chloro-N-ιsopropyl-N-[3-(propane-2-sulfonylamιno)-pro pyπ-5-[2-(pyrιdιn-4- ylamιno)-ethoxy1-benzamιde trifluoroacetate

Hplc system 1 (λ = 254nm) Rt 8 9mιn, Mass spectrum Found MH ⁺ 497 ( ³⁵ CI)

Example 76

1 -f3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl)-pιp erιdιne-2 -carboxylic acid trifluoroacetate

1 -{3-[2-(tert-Butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5- chloro-beπzoyl}- pιpeπdιne-2 -carboxylic acid ethyl ester (0 16g) in 1 ,4-dιoxan (2ml) was treated with 2M sodium hydroxide solution (0 6ml) and stored at room temperature for 18h The solution was concentrated under reduced pressure and the residue stored in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) After 3h, the solution was concentrated under reduced pressure and the residue was subjected to preparative hplc The title compound (0 10Og) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 7 6mιn Mass spectrum Found MH ⁺ 404 ( ³⁵ CI)

Example 77 {3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy1-phenylH2-methy l-pιpeπdιn-1 -yl)- methanone trifluoroacetate

A solution of {2-[3-chloro-5-(2-methyl-pιpeπdιne-1 -carbonyl)-phenoxy]-ethyl}-pyπdιn- 4-yl-carbamιc acid tert-butyl ester (0 065g) in a mixture of dichloromethane (5ml) and trifluoroacetic acid (2ml) was stored at room temperature for 5h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 061 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 8 1 mιn Mass spectrum Found MH ⁺ 374 ( ³⁵ CI)

Example 78

3-Chloro-N-cyclopentyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxyl-N -(3- tnfluoromethanesulfonylamino-propyD-benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[cyclopentyl-(3-trιfluoromethanesulfony!amι no-propyl)- carbamoyl]-phenoxy}-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 01 18g) in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 19h and then concentrated under reduced pressure The title compound was obtained as a pale brown gum (0 01 Og)

Hplc system 1 (λ = 254nm) Rt 10 2mιn

Mass spectrum Found MH ⁺ 549 1567 C ₂₃ H ₂₉ ^3D CIF ₃ N ₄ θ S requires 549 1550

Example 79

3-Chloro-N-ιsopropyl-N-methyl-5-f2-(pyπdιn-4-ylamιno) -ethoxyl-benzamιde trifluoroacetate

A solution of {2-[3-chloro-5-(ιsopropyl-methyl-carbamoyl)-phenoxy]-ethyl} -pyπdιn-4- yl-carbamic acid tert-butyl ester (0 060g) in dichloromethane (4ml) and trifluoroacetic acid (4ml) was stored at room temperature for 2h and then concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound as a yellow gum (0 061 g)

Hplc system 1 (λ = 254nm) Rt 6 8mιn Mass spectrum Found MH ⁺ 348 1470 requires 348 1479

Example 80

N-f2-(3-Amιno-f1 ,2,41oxadιazol-5-yl)-ethyll-3-chloro-N-ιsopropyl-5-[2-(pyr ιdιn-4- ylamιno)-ethoxy1-benzamιde trifluoroacetate A solution of [2-(3-{[2-(3-amιno-[1 ,2,4]oxadιazol-5-yl)-ethyl]-ιsopropyl-carbamoyl}-5- chloro-phenoxy)-ethyl]-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 064g) in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 5h and then concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound as a pale yellow foam (0 043g) Hplc system 1 (λ = 254nm) Rt 6 2mιn

Mass spectrum Found MH ⁺ 445 1743 C ₂ iH ₂₆ ³⁵ CIN ₆ O ₃ requires 445 1755

Example 81

N-(2-Cyano-ethyl)-N-ιsopropyl-3-methyl-5-f2-(pyrιdιn-4 -ylamιno)-ethoxyl-benzamιde trifluoroacetate

A solution of 3-methyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy]-benzoιc acid trifluoroacetate salt (0 026g) in anhydrous DMF (2ml) was treated at room temperature with 3- isopropylamino-propionitπle ⁹ (0 017g), PyBrop ^® (0 062g) and DIPEA (0 025ml) More PyBrop ^® was added after 2 days (0 072g) and 7 days (0 065g) More 3- isopropylamino-propionitrile was added after 2 days (0.03ml), 4 days (0 1 ml) and 7 days (0 1 ml) After 24h more, the mixture was evaporated to dryness under reduced pressure and the residue subjected to preparative hplc giving the title compound as a clear colourless gum (0.016g). Hplc system 2 (λ = 254nm) Rt 9.6mιn Mass spectrum Found MH ⁺ 367.2140 C21H2--N ₄ O ₂ requires 367.2134

Example 82

N-(2-Carbamoyl-ethyl)-N-ιsopropyl-3-methyl-5-[2-(pyrιdi n-4-ylamιno)-ethoxyl- benzamide trifluoroacetate A solution of N-(2-cyano-ethyl)-N-ιsopropyl-3-methyl-5-[2-(pyrιdιn-4-yl amιno)- ethoxyj-benzamide trifluoroacetate (0.01 1 g) in dichloromethane (1.5ml) and trifluoroacetic acid (0.5ml) was stored at room temperature overnight and then concentrated under reduced pressure. The title compound was obtained as a pale yellow foam (0.012g). Hplc system 2 (λ = 254nm) Rt 8.2min

Mass spectrum: Found: MH ^* 385

Example 83 3-Chloro-N-isopropyl-5-f2-(pyridιn-4-ylamιno)1-N-(2-[1.2,4 1triazol-1 -yl-ethyl)- benzamide

Tributyltin azide (1.0g) was added to (2-{3-chloro-5-[(2-cyaπo-ethyl)-cyclopentyl- carbamoyl]-phenoxy}-ethyl)-pyridιn-4-yl-carbamιc acid tert-butyl ester (0 1 1 g). The neat mixture was heated at 160°C for 4h. cooled to room temperature and quenched with 2M sodium hydroxide solution and extracted with ether. The aqueous layer was acidified with 5M hydrochloric acid and subjected to preparative hplc to give the title compound (0.022g) as a colourless oil Hplc system 1 (λ = 254nm) Rt 6.5mιn Mass spectrum- Found: MH ⁺ 456 ( ³⁵ CI)

Example 84

3-Chloro-N-ιsopropyl-5-f2-(pyndιn-4-ylamιno)-ethoxy]-N-(2 -f1 ,2,4ltπazol-1 -yl-ethyl)- benzamide trifluoroacetate

To a solution of (2-{3-chloro-5-[ιsopropyl-(2-[1 ,2,4]trιazol-1 -yl-ethyl)-carbamoyl]- phenoxy}-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 097g) in dichloromethane (5ml) was added trifluoroacetic acid (2ml) and the mixture was stirred at room temperature for 3h The solvent was evaporated under reduced pressure and the residue subjected to preparative hplc to give the title compound (0 093g) as a clear oil Hplc system 1 (λ = 254nm) Rt 6 0mm Mass spectrum Found MH ⁺ 544 ( ³⁵ CI)

Example 85

N-(3-Amιno-propyl)-3-chloro-N-ιsopropyl-5-[2-(pyrιdm-4 -ylamιno)-ethoxy1-benzamιde bιs(tnfluoroacetate) A solution of (2-{3-[(3-amιno-propyl)-ιsopropyl-carbamoyl]-5-chloro-phen oxy}-ethyl)- pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 025g) in dichloromethane (1ml) was treated with dichloromethane trifluoroacetic acid (1 1 v/v) (1 ml), stirred for 3h at room temperature and concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 018g) as a light brown oil Hplc system 1 (λ= 254nm) Rt 4 9mιn Mass spectrum Found MH ⁺ 377 ( ³⁵ CI)

Example 86 3-Chloro-N-ιsopropyl-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-N- (3- tπfluoromethanesulfonylamino-propyD-benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[ιsopropyl-(3-tπfluoromethanesulfonylamιno -propyl)- carbamoyl]-phenoxy}-ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester trifluoroacetate (0 038g) in dichloromethane (1 ml) was treated with dichloromethane trifluoroacetic acid (1 1 v/v) (1 ml) stirred for 3h at room temperature and concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 024g) as an oil Hplc system 1 (λ= 254nm) Rt 8 9mιn Mass spectrum Found MH ⁺ 523 ( ³⁵ CI)

Example 87

(3-Chloro-5-f2-(pyπdιn-4-ylamιno)-ethoxyl-phenyl}-(2,5-d� �methyl-pyrrolιdιn-1 -yl)- methanone trifluoroacetate

A solution of {2-[3-chloro-5-(2,5-dιmethyl-pyrrolιdιne-1 -carbonyl)-phenoxy]-ethyl}- pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 260g) in dichloromethane (1 ml) was treated with dichloromethane trifluoroacetic acid (1 1 v/v) (1 ml), stirred for 3h at room temperature and concentrated under reduced pressure The residue was taken up into ethyl acetate and filtered through silica (50g) to give the title compound (0 102g) as an oil Hplc system 1 (λ= 254nm) Rt 7 5mιn Mass spectrum Found MH ⁺ 374 ( ³⁵ CI)

Example 88

3-Chloro-N-[3-(2,2-dιmethyl- propιonylamιno)-propyπ-N- ιsopropyl-5-f2-(pyrιdιn-4- ylamιno)-ethoxyl- benzamide trifluoroacetate A solution of [2-(3-chloro-5-{[3-(2,2-dιmethyl-propιonylamιno)-propyl]- ιsopropyl- carbamoyl}-phenoxy)-ethyl]-pyrιdιne-4-yl-carbamιc acid tert-butyl ester in dichloromethane (1 ml) was treated with dichloromethane trifluoroacetic acid (1 1 v/v) (1 ml), stirred for 3h at room temperature and concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 039g)

Hplc system 3 (λ=220-330nm) Rt 3 7mιn Mass spectrum Found MH ⁺ 475 ( ³⁵ CI)

Example 89 3-Chloro-N-f3-(2,2-dιmethyl-propιonylamιno)-propyll-N-ιs opropyl-5-f2-(pyπdιn-4- ylamιno)-ethoxy ^" l-benzamιde trifluoroacetate

To a solution of (2-{3-[(3-amιno-propyl)-ιsopropyl-carbamoyl]-5-chloro-phen oxy}- ethyl)-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 040g), DIPEA (0 03ml) in dichloromethane (1 ml) was added a solution of tert-butyl acetyl chloride (0 014ml) in dichloromethane (1 ml) and the mixture was stirred for 3h at room temperature The mixture was evaporated under reduced pressure, was dissolved in dichloromethane (1 ml), was treated with 1 ml of dichloromethane trifluoroacetic acid (1 1 ), stirred for 3h at room temperature and concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 037g) as an oil Hplc system 3 (λ=220-330nm) Rt 2 7mιn Mass spectrum Found MH ⁺ 489 ( ³⁵ CI)

Example 90

3-Chloro-N-(4-fluoro-ρhenyl)-5-r2-(pyrιdιn-4-ylamιno) -ethoxy1-N-(3-f1 ,2,41trιazol-1 -yl- propyQ-benzamide bιs(trιfluoroacetate) A suspension of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιπo)-ethoxy]-5- chloro- benzoic acid (0 050g), 4-fluorophenyl-(3-[1 ,2,4]tπazol-1 -yl-propyl)-amιπe (0 056g) and EEDQ (0 050g) in acetonitrile (1 ml) was stirred at 50°C under nitrogen for 5h The solvent was removed and the residue was purified by flash chromatography on silica eluting with dichloromethane methanol ammonia (99 1 0 1 v/v/v) The resultant oil was treated with trifluoroacetic acid then concentrated under vacuum to give the title compound as a colourless gum (0 008g) Hplc system 3 (λ=220-330nm) Rt 3 7mιn Mass spectrum Found MH ⁺ 495 ( ³⁵ CI)

Example 91

3-Chloro-N-cyclopentyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxy 1-N-(2-ri ,2,4ltrιazol-1 -yl- ethvQ-beπzamide

A solution of 2-[3-chloro-5-(cyclopentyl-(2-[1 ,2,4]trιazol-1 -yl-ethyl)-carbamoyl)- phenoxy]-ethyl}-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 022g) and trifluoroacetic acid (0 5ml) in dicloromethane (0 5ml) was stirred at room temperature for 1 h then concentrated under vacuum The residue was purified by flash chromatography eluting with dichloromethane methanol (90 10 then 80 20 v/v) to give the title compound as an off-white powder (0 013g)

Mass spectrum Found MH ⁺ 455 ( ³⁵ CI) Hplc system 1 (λ = 254nm) Rt 7 Omin

Example 92

3-Chloro-N-cvclopentyl-5-f2-(pyrιdιn-4-ylamιno)-ethoxy 1-N-(4-[1.2,41trιazol-1 -yl- butvD-benzamide A solution of {2-[3-chloro-5-(cyclopentyl-(4-[1 ,2,4]tπazol-1-yl-butyl)-carbamoyl)- phenoxy]-ethyl}-pyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 069g) and trifluoroacetic acid (0 5ml) in dichloromethane (0 5ml) was stirred at room temperature for 1 h then concentrated under vacuum The residue was purified by flash chromatography eluting with dichloromethane methanol ammonia (92 8 1 v/v/v), to give the title compound as a white foam (0 026g) Mass spectrum Found MH ⁺ 483 ( ³⁵ CI)

Hplc system 1 (λ = 254nm) Rt 6 9mιn

Example 93

3-Chloro-N-(4-fluoro-phenyl)-5-r2-(pyrιdιn-4-ylamιno)- ethoxyl-N-(3-tetrazol-2-yl- propyO-benzamide trifluoroacetate

A suspension of 3-[2-(tert-butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5-c hloro- benzoic acid (0.05g) 4-fluoroρhenyl-(3-tetrazol-2-yl-proρyl)-amιne (0 056g) and

EEDQ (005g) in acetonitrile (1ml) was stirred under nitrogen at room temperature for 18h then at 50°C for 2h The solvent was removed and the residue was purified by flash chromatography, eluting with dichloromethane-methanol ammonia (99 1.0 1 v/v/v) The resultant oil was treated with trifluoroacetic acid then concentrated under vacuum to give the title compound as a colourless gum (0 004g)

Mass spectrum Found MH ^* 496 (^Cl)

Hplc system 3 (λ =220-330nm) Rt 36mιn

Example 94

3-Chloro-N-(3-fluoro-phenyl)-5-f2-(pyπdιn-4-ylamιno)-e thoxyl-N-(3-tetrazol-2-yl- propyD-benzamide

A solution of {2-[3-chloro-5-(3-fiuorophenyl-(3-tetrazol-2-yl-propyl)-carb amoyl)- phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.07g) in trifluoroacetic acid (0.75ml) and dichloromethane (0.75ml) was stirred at room temperature for 1h then concentrated under vacuum. The residue was purified by flash chromatography, eluting with dichloromethane/methanol/ammonia (90 10 1 ) to give the title compound as a white foam (0.042g) Mass spectrum: Found- MH ⁺ 496 (^Cl)

Hplc system 3 (λ = 220-330nm) Rt 3 5mιn

Example 95 3-Chloro-N-(2-fluoro-phenyl)-5-f2-(pyrιdιn-4-ylamιno)-eth oxyl-N-(3-tetrazol-2-yl- propyl )-benzamtde

A solution of (2-[3-chloro-5-(2-fluorophenyl-(3-tetrazol-2-yl-propyl)-carb amoyl)- phenoxy]-ethyl}-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0048g) in trifluoroacetic acid (0 5ml) and dichloromethane (0 5ml) was stirred at room temperature for 1h then concentrated under vacuum The residue was purified by flash chromatography, eluting with dichloromethane methanol ammonia (95 5 0 5 then 90 10 1 v/v/v), to give the title compound as an off-white foam (0 035g)

Mass spectrum Found MH ⁺ 496 ( ³⁵ CI) Hplc system 3 (λ = 220-330nm) Rt 3 5mιn

Example 96 3-Chloro-N-phenyl-5-[2-(pyπdιn-4-ylamιno)-ethoxyl-N-(2-te trazol-2-yl-ethyl)- benzamide trifluoroacetate

A solution of {2-[3-chloro-5-(phenyl-(3-tetrazol-2-yl-propyl)-carbamoyl)-p henoxy]- ethyl}-ρyrιdιn-4-yl-carbamιc acid tert-butyl ester (0 024g) in trifluoroacetic acid (0 25ml) and dichloromethane (0 25ml) was stirred at room temperature for 2h then concentrated under vacuum, co-evaporating with dichloromethane to give the title compound as an off-white foam (0 026g) Mass spectrum Found MH ⁺ 464 ( ³⁵ CI) Hplc system 3 (λ = 220-330nm) Rt 3 5mιn

Example 97

3-Chloro-N-phenyl-5-[2-(pyrιdιn-4-ylamιno)-ethoxyl-N-( 2-f1.2.31trιazol-2-yl-ethvn- benzamide trifluoroacetate

A solution of {2-[3-chloro-5-(phenyl-(3-[1 ,2,3]-trιazol-2-yl-propyl)-carbamoyl)- phenoxy]-ethyi}-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 083g) and trifluoroacetic acid (1 ml) in dichloromethane (1 ml) was stirred at room temperature for 2h then concentrated under vacuum, co-evaporating with dichloromethane to give the title compound as a yellow-brown oil (0 103g)

Mass spectrum Found MH ⁺ 463 ( ³⁵ CI)

Hplc system 3 (λ = 220-330nm) Rt 3 6mιn

Example 98

3-Chloro-N-phenyl-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-N-f 2-(pyrιdιn-2-yloxy)-ethyll- benzamide bιs(tπfluoroacetate)

A solution of {2-[3-chloro-5-(phenyl-2-(pyπdιn-2-yloxy)-ethyl-carbamoyl) -phenoxy]- ethyl}-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 065g) and trifluoroacetic acid

(0 75ml) in dichloromethane (0 75ml) was stirred at room temperature for 2h then concentrated under vacuum, co-evaporating with dichloromethane to give the title compound as a yellow oil (0 086g)

Mass spectrum Found MH ⁺ 489 ( ³⁵ CI) Hplc system 3 (λ = 220-330nm) Rt 3 8mιn

Example 99

3-Chloro-N-ιsopropyl-N-(2-methoxy-ethyl)-5-[2-(pyrιdιn -4-ylamιno)-ethoxyl- benzamide

A solution of {2-[3-chloro-5-(ιsopropyl 2-methoxy-ethyl-carbamoyl)-phenoxy]-ethyl}- pyπdιn-4-yl-carbamιc acid tert-butyl ester (Intermediate SS8) (0 056g) and trifluoroacetic acid (0 6ml) in dichloromethane (0 6ml) was stirred at room temperature for 1 h then concentrated under vacuum The residue was purified by flash chromatography eluting with dichloromethane methanol ammonia (94 6 1 then 92 8 1 v/v/v), to give the title compound as a colourless gum (0 036g) Mass spectrum Found MH ⁺ 392 ( ³⁵ CI) Hplc System 3 (λ = 220-330nm) Rt 3 5mιn

Examplel OO 3-(lsopropyl-(3-methyl-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-b enzoyl}-amιno)-propιonιc acid methyl ester trifluoroacetate

To a stirred solution of 3-methyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-benzoιc acid trifluoroacetate (0 025g) and TBTU (0 021 g) in DMF (1 ml) was added DIPEA (0 022ml) followed by 3-ιsopropylamιno-propιonιc acid methyl ester ( 0 01 g) after 3 mm The reaction was stirred at room temperature for 18h, and then concentrated under reduced pressure The residue was subjected to preparative hplc to give the title compound (0 031 g) as a colourless oil, by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 6 8mιn ¹ H-NMR (CD ₃ OD, 250 MHz) δ 8 15 (d,1 H) 7 98 (d, 1 H), 7 05 (m,1 H), 6 9 (m,2H), 6 75 (m,2H), 4 21 (t,2H), 3 95 (m, 1 H), 3 55-3 80 (m,7H), 2 65 (t,2H), 2 35 (s,3H) 1 15 (d,6H)

Example 101 3-(lsopropyl-|3-methyl-5-f2-(pyπdιn-4-ylamιno)-ethoxyl-be nzoyl|-amιno)-propιonιc acid trifluoroacetate

To a solution of 3-(ιsopropyl-{3-methyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]-b enzoyl}- amιno)-propιonιc acid methyl ester trifluoroacetate (0 031 g) in dioxan (1 ml) was added 2M aqueous sodium hydroxide (0 078ml), and the resultant solution was stirred at room temperature for 3h 1M Aqueous hydrochloric acid ica 0 5ml) was added and the resultant solution was concentrated under reduced pressure Th

residue was subjected to preparative hplc and the title compound (0 027g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Mass spectrum Found MH ⁺ 386 hplc system 1 (λ=254nm) Rt 5 5mιn

Example 102 6-((3-Methyl-5-f2-(pyrιdιn-4-ylamιno)-ethoxy1-benzoyl)-ι sopropyl-amιno)-hexanoιc acid trifluoroacetate

P-Benzyloxybenzylalcohol (Wang) resin ¹⁰ (0.54mmol/g, 0.250g) was wetted with DMF ica 2ml) and then treated with a mixture of 6-bromohexanoιc acid (0.173g), diisopropylcarbodiimide (0.139ml) and 4-dimethylamιnopyπdιne (2mg) in dry DMF (1 ml) The mixture was agitated for 5 days and then filtered dry under suction The resin was repeatedly washed with DMF (x3), and dichloromethane (x3) before drying under suction. The resin was then agitated with isopropylamme (1.5ml) in dry DMF (1.5ml) for 2 days. After filtration, the resin was repeatedly washed with DMF (x3) and dichloromethane (x3). The resin was then agitated with 3-methyl-5-[2-(pyridιn- 4ylamino)-ethoxy]-benzoic acid (0.16g), diisopropylcarbodiimide (0.127ml) and 4- dimethylaminopyπdine (0.012g) for 3 days. After the excess reagents were removed by filtration, the resm was washed with DMF (x3) and dichloromethane (x3) before treatment with dichloromethane (1ml) and trifluoroacetic acid (1 ml) After 1 .5h, the resm was filtered and washed thoroughly with dichloromethane The combined filtrate and washings were evaporated to dryness under reduced pressure and subjected to preparative hplc Evaporation of the required fraction gave the title compound as a gum (0.048g) Hplc system 1 (λ = 254nm) Rt 6.7min

¹⁰ p-Benzyloxybenzyl alcohol resm - polymer matrix is copoly(styrene-1 % divinylbenzene), 100-200 mesh, Novabiochem cat. no. 01 -64-0014 Mass Spectrum: Found. MH ⁺ 428

Example 103

N-tert-Butyl-N-(2-tert-butylcarbamoyl-ethyl)-3-chloro-5-f 2-(pyridin-4-ylamino)- ethoxyl-benzamide trifluoroacetate A suspension of 5% Pd on carbon (0.020g) in a solution of (2-{3-[tert-butyl-(2-tert- butylcarbamoyl-ethyl)-carbamoyl]-5-chloro-phenoxy}-ethyl)-py rιdιn-4-yl-carbamic

acid benzyl ester (0 024g) in 1 ,4-dιoxan (5ml) was stirred under an atmosphere of hydrogen for 20h The catalyst was removed by filtration and the filtrate evaporated in vacuo The residue was subjected to preparative hplc to give the title compound (0 003g) as a colourless gum Hplc system 1 (λ = 254nm) Rt 8 2mιn

Mass spectrum Found MH ⁺ 475 2478 C ₂ sH ₃ 6 ³⁵ ClιN ₄ θ ₃ requires 475 2476

Example 104 N-(2-tert-Butylcarbamoyl-ethyl)-3-chloro-N-cvclobutyl-5-[2-( pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

A solution of (2-{3-[(2-tert-butylcarbamoyl-ethyl)-cyclobutyi-carbamoyl]-5 -chloro- phenoxy}-ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 021g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64h and then concentrated under reduced pressure to give the title compound (0 020g) as a colourless gum

Hplc system 1 (λ = 254nm) Rt 7 6mm

Mass spectrum Found MH ⁺ 473 2332 C ₂₅ H ₃₄ ³⁵ CI ₁ N ₄ O3 requires 473 2319

Example 105 3-Chloro-N-cvclobutyl-N-f2-(2.2-dιmethyl-propylcarbamoyl -ethyll-5-r2-(pyπdιn-4- ylaminoVethoxyl-benzamide trifluoroacetate

A solution of [2-(3-chloro-5-{cyclobutyl-[2-(2,2-dιmethyl-propylcarbamoyl )-ethyl]- carbamoyl}-phenoxy)-ethyl]-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 016g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64h and then concentrated under reduced pressure to give the title compound (0 012g) as a colourless gum

Hplc system 1 (λ = 254nm) Rt 8 1 mιn

Mass spectrum Found MH ⁺ 487 2462 C ₂₆ H ₃ 6 ³⁵ ClιN4θ3 requires 487 2476

Example 106

N-(2-Carbamoyl-ethyl)-3-chloro-N-cvclobutyl-5-[2-(pyrιd� �n-4-ylamιno)-ethoxyl- benzamide trifluoroacetate

A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-cyclobutyl-carbamoyl]-phenox y}-ethyl)- pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 042g) and water (0 050ml) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 mi) was stored at room temperature for 24h and then the solvent removed under reduced pressure The residue was

subjected to preparative hplc to give the title compound (0 027g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 1 (λ = 254nm) Rt 5 6mιn Mass spectrum Found. MH ⁺ 417

Example 107

3-Chloro-N-ιsopropyl-5-f2-(pyridιn-4-ylamιno)-ethoxyl- N-(2-sulfamoyi-ethyl)- benzamide trifluoroacetate A solution of (2-{3-chloro-5-[ιsopropyl-(2-sulfamoyl-ethyl)-carbamoyl]-ph enoxy}- ethyl)-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 012g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64h and then concentrated under reduced pressure to give the title compound

(0 01 1 g) as a colourless gum. Hplc system 1 (λ = 254nm) Rt 5 6min

Mass spectrum: Found: MH ⁺ 441

Example 108 3-Chloro-N-(2.2-dιmethyl-propylsulfamoyl-ethyl)-N-isopropyl -5-f2-(pyrιdin- - ylamιno)-ethoxyl-benzamide trifluoroacetate

A solution of [2-(3-chloro-5-{[2-(2,2-dιmethyl-propylsulfamoyl)-ethyl]-is opropyl- carbamoyl}-phenoxy)-ethyl]-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0.042g) in a mixture of dichloromethane (1ml) and trifluoroacetic acid (1ml) was stored at room temperature for 64h and then concentrated under reduced pressure to give the title compound (0.024g) as a straw coloured gum. Hplc system 1 (λ = 254πm) Rt 8 7mιn Mass spectrum: Found: MH ⁺ 51 1.2143 C ₂₂ H ₃₅ ³⁵ CI ₁ N ₄ O ₄ S ₁ requires 51 1.2146

Example 109 3-Chloro-N- 2-(5-hvdroxy-f1.2,41oxadiazol-3-yl)-ethyl>-N-isopropyl-5- f2f(pyπdιn-4- ylamιno)-ethoxyl-benzamιde trifluoroacetate

A solution of (3-chloro-N-{2-(5-hydroxy-[1 ,2,4]oxadιazol-3-yl)-ethyl}-N-ιsopropyl-5- [2[(pyrιdιn-4-ylamιno)-ethoxy]-benzamιde carbamic acid tert-butyl ester (0.046g) in a mixture of DCM (3ml) and trifluoroacetic acid (1 ml) was stirred at room temperature for 3h The solvent was evaporated under pressure and the residue subjected to preparative hplc to give the title compound (0.027g) as a clear oil.

Mass spectrum Found MH ⁺ 446 ( ³⁵ CI) Hplc system 1 (λ = 254πm) Rt 6 16mιπ

Example 1 10 N-(2-tert-Butylcarbamoyl-ethyl)-N-ιsopropyl-3-methyl-5-[2-( pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

To a stirred solution of 3-(ιsopropyl-{3-methyl-5-[2-(pyπdιn-4-ylamιno)-ethoxy]- benzoyl}-amιno)-propιonιc acid trifluoroacetate (0 018g) and PyBroP ^® (0 017g) in DMF ( 1 ml) was added DIPEA (0 012ml) followed by tert-butylamine (0 005ml), after 1 mιn The reaction mixture was stirred at room temperature for 18h, and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 009g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure Hplc system 3 (λ = 220-330nm) Rt 3 8mιn Mass spectrum Found MH ⁺ 441

Similarly prepared was

Example 1 11

N-f2-(2.2-dιmethylpropylcarbamoyl)-ethyl)-N-ιsopropyl-3 -methyl-5-[2-(pyrιdιn-4- ylamιno)-ethoxyl-benzamιde

Hplc system 3 (λ = 220-330nm) Rt 4 1 mιn

Mass spectrum Found MH ⁺ 455

Example 112

N-(5-tert-Butylcarbamoyl-pentyl)-3-chloro-N-ιsopropyl-5- [2-(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

To a stirred solution of 6-({3-chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxyj-beπzoyl}- ιsopropyi-amιno)-hexanoιc acid trifluoroacetate (0 02g) and PyBroP® (0 021 g) in

DMF (1 ml) was added DIPEA (0 016ml) followed by tert-butylamine (0 005ml), after

1 mιn The reaction mixture was stirred at room temperature for 18h, and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0 0094g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254πm) Rt 8 3mιn Mass spectrum Found MH" 503

Similarly prepared was

Example 13

3-Chloro-N-f5-(2,2-dιmethyl-propylcarbamoyl)-pentyll-N-� �sopropyl-5- 2-(pyrιdιn-4- ylamino)-ethoxyl-benzamιde trifluoroacetate Hplc system 1 (λ = 254nm) Rt 8 7mιn Mass spectrum Found MH ⁺ 517

Example 114

N-f5-tert-Butylcarbamoyl)-pentyll-N-ιsopropyl-3-methyl-5 -[2-(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate) To a stirred solution of 6-[{3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-

(isopropyl) -amιno]-hexanoic acid trifluoroacetate (0.026g) and PyBroP ^® (0.022g) in

DMF (1ml) was added DIPEA (0.018ml) followed by tert-butylamine (0.005ml), after

1min. The reaction mixture was stirred at room temperature for 18h, and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.002g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure

Hplc system 1 (λ = 254nm) Rt 8.2mιn

Mass spectrum: Found ^" MH ⁺ 483

Example 115

N-(5-Carbamoyl-pentyl)-N-isopropyl-3-methyl-5-f2-(pyridin -4-ylamino)-ethoxy1- benzamide trifluoroacetate

To a solution of 6-[{3-methyl-5-[2-(pyridin-4-ylamιno)-ethoxy}-benzoyl}-(iso propyl) - ammoj-hexanoic acid trifluoroacetate (0.022g) in DMF (1 ml) was added HATU ^®

(0.039g), DIPEA (0.018ml) and 0.5M ammonia in 1 ,4-dιoxane solution (0.2ml). The mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure, the residue obtained was subjected to preparative hplc to give the title compound as a colourless oil(O.OOδg) Hplc system 1 (λ= 254nm) Rt 5.9 mm

Mass spectrum. Found' MH ⁺ 427

Example 16

3-Chloro-N-(2-(4-tert-butylphenyl)-ethyl)-N-isopropyl-5-[ 2-(pyridin-4-ylamino)- ethoxyl-benzamide A solution of {2-[3-chloro-5-(ιsopropyl-(2-(4-tert-butylpheπyl)-e.hyl-ca rbamoyl)- phenoxy]-ethyl}-pyridin-4-yl-carbamιc acid tert-butyl ester (0.062g) in trifluoroacetic acid (0.75ml) and dichloromethane (0.75ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatograpy, eluting with dichloromethane:methanol:ammonia(0.88) (94:6: 1 v/v/v) to give the title compound as a pale yellow gum (0.033g). Mass Spectrum: Found: MH ⁺ 494 ( ³⁵ CI) Hplc System 3 (λ = 220-330nm) Rt 4.4min

Example 1 17 2-[(3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxyl-benzoyl>-(2 ,4-difluoro-benzyl)-amino1- butyric acid trifluoroacetate p-Benzyloxybenzylaicohol resin ¹⁰ (0.54mmol/g; 0.253g) was wetted with DMF and then treated with a mixture of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-butyric acid (0.221 g) and diisopropylcarbodiimide (0.107ml) in dry DMF (1ml). The mixture was agitated for 26h and then filtered dry under suction. The resin was repeatedly washed with DMF (x3), dichloromethane (x3), and diethyl ether (x3) before drying under suction. The resin was then agitated with a 20% v/v solution of piperidine in DMF (2ml) for 1.3h. After filtration the resin was repeatedly washed with DMF (x3) and dichloromethane (x3). Trimethylorthoformate (0.3ml), 2,4-difluorobenzaldehyde (0.3ml), and dichloromethane (0.9ml) were added and the mixture agitated for 4 days. The resin was filtered dry and washed with dichloromethane (x3) then a solution of tetramethylammonium triacetoxyborohydride (0.14g) and glacial acetic acid (0.03ml) in dichloromethane (1 ml) was added. The resin was agitated for 2 days, filtered dry, washed with dichloromethane (x3) and DMF (x3) and a solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chlo ro-benzoic acid (0.106g), diisopropylcarbodiimide (0.046ml), and 4-(N,N-dimethylamino)pyridine (trace) in DMF (0.75ml) was added. After agitating for 19h excess reagents were removed by filtration and the resin was washed with DMF (x3) and dichloromethane (x3) before treatment with dichloromethane (0.5ml) and 95:5 v/v trifluoroacetic acid and water (2ml). After 2h the resin was filtered and washed thoroughly with dichloromethane. The combined filtrate and washings were evaporated to dryness under reduced

pressure and subjected to preparative hplc Evaporation of the required fraction gave the title compound as a pale cream foam (0 021 g) Hplc system 1 (λ= 254nm) Rt 8 4mιn

Mass spectrum Found MH ⁺ 504 1485 C ₂ 5H ₂ 4 ³⁵ CIF ₂ N ₃ O4 requires 504 1502

Example 1 18

4-f((3-Chloro-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl )-ιsobutyl-amιno)-methyll- benzoic acid trifluoroacetate p-Benzyloxybenzylalcohol resin ¹⁰ (0 54 mmol/g, 0 25g) was wetted with DMF and then treated with a solution of 4-(chloromethyl)benzoιc acid (0 23g) and diisopropylcarbodiimide (0 106ml) in DMF (1 ml) The mixture was agitated overnight and the resin filtered and washed with DMF (x2) before repeating the entire coupling procedure The resm was washed with DMF (x6) and then treated with isobutylamine (0 2ml) in DMF (0 5ml) together with a trace of sodium iodide After agitating for 3 days the resm was filtered and washed with DMF (x3) and the amme reaction repeated this time overnight The resm was then filtered dry, washed with DMF (x6), dichloromethane (x6) and diethyl ether (x2) and dned by suction After wetting the resin with DMF it was treated with 3-[2-(tert- butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5-chloro-benzo� �c acid (0 053g), diisopropylcarbodiimide (0 021 ml), and 4-(N,N-dιmethylamιno)pyrιdιne (trace) in DMF (0.5ml) After agitating for 24h the resin was filtered and washed with DMF (x6) and the coupling procedure repeated The resin was then filtered and washed with DMF (x6), dichloromethane (x6) and diethyl ether (x2) before drying by suction The res was treated with a 1 1 v/v mixture of trifluoroacetic acid and dichloromethane (2ml) with agitation for 80mιn The resm was filtered and washed with more of the trifluoroacetic acid mixture and then dichloromethane The combined filtrate and washings were evaporated to dryness under reduced pressue and subjected to preparative hplc The title compound was obtained as a colourless gum (0 019g) Hplc system 3 (λ = 220-330nm) Rt 4 2 mm

Mass spectrum Found MH ⁺ 482 1864 C ₂₆ H ₂₉ ³⁵ CIN ₃ O4 requires 482 1847

Example 1 19

4-f2-(f3-Chloro-5- 2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl)-ιsobutyl-amιno)- ethyll- benzoic acid trifluoroacetate

p-Benzyloxybenzylalcohol resm ¹⁰ (0 54 mmol/g, 0 25g) was wetted with DMF and then treated with a solution of 4-(2-chloroethyl)benzoιc acid (0 25g), diisopropylcarbodiimide (0 106ml) and 4-(N, N-dιmethylamιno)pyπdιne (trace) in DMF (1 ml) The mixture was agitated overnight and the resin filtered and washed with DMF (x2) before repeating the entire coupling procedure The resin was filtered and washed with DMF (x6) and then treated with isobutylamme ( 1 ml), DMF (0 7ml) and sodium iodide (0 1 g) and the resin shaken and subjected to sonication alternately for 35mιn The resm was then agitated for 3 days and then filtered and washed with DMF (x6), dichloromethane (x6) and diethyl ether (x2) before drying by suction After wetting the resm with DMF it was treated with 3-[2-(tert- butoxycarbonyl-pyrιdιn-4-yl-amιno)-ethoxy]-5-chloro-benzo ιc acid (0 053g), diisopropylcarbodiimide (0 021 ml), and 4-(N,N-dιmethylamιno)pyrιdιne (trace) in DMF (0 5ml) After agitating for 24h the resin was filtered and washed with DMF (x6) and the coupling procedure repeated The resm was then filtered and washed with DMF (x6), dichloromethane (x6) and diethyl ether (x2) before drying by suction The resm was then treated with a 1 1 v/v mixture of trifluoroacetic acid and dichloromethane (2ml) with agitation for 1 25h The resin was filtered and washed with more of the trifluoroacetic acid mixture and then dichloromethane The combined filtrate and washings were evaporated to dryness under reduced pressure and subjected to preparative hplc and the title compound was obtained as a clear brown-tinged oil (0 012g) Hplc system 1 (λ = 254nm) Rt 8 5mιn Mass spectrum Found MH ⁺ 496 1990 C ₂₇ H ₃ ι ³⁵ CIN ₃ O ₄ requires 496 2003

Example 120

6-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl) -(2-fluoro-benzyl)-amιnol- hexanoic acid trifluoroacetate p-Benzyloxybenzylalcohol resin ¹⁰ (0 54mmol/g, 0 250g) was wetted with DMF ica 2ml) and then treated with a mixture of 6-bromohexanoιc acid (0 173g), diisopropylcarbodiimide (0 139ml) and 4-(N,N-dιmethylamιnopyπdιne (0 02g) in dry DMF (1 ml) The mixture was agitated for 5 days and then filtered dry under suction The resin was repeatedly washed with DMF (x3), and dichloromethane (x3) before drying under suction The resin was then agitated with 2-fluorobenzylamιne (1 5ml) in dry DMF (1 5ml) for 2 days After filtration, the resin was repeatedly washed with DMF (x3) and dichloromethane (x3) The resm was then agitated with 3-[2-(tert- butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5-chloro-benzo� �c acid (0 16g)

diisopropylcarbodiimide (0.127ml) and 4-dtmethylamιnopyrιdιne (0 012g) for 3 days After the excess reagents were removed by filtration, the resm was washed with DMF (x3) and dichloromethane (x3) before treatment with dichloromethane (1 ml) and trifluoroacetic acid (1 ml) After 1 5h, the resm was filtered and washed thoroughly with dichloromethane The combined filtrate and washings were evaporated to dryness under reduced pressure and subjected to preparative hplc Evaporation of the required fraction gave the title compound as a gum (0.0082g) Hplc system 1 (λ = 254nm) Rt 8.0mιn Mass spectrum Found: MH ⁺ 514 ( ³⁵ CI)

Similarly prepared, using commercially available amines, were -

Example 121

6-r{3-Chloro-5-r2-(pyridιn-4-ylamιno)-ethoxyl-benzoylH3 -fluoro-benzyl)-amιnol- hexanoic acid trifluoroacetate

Hplc system 1 (λ = 254nm) Rt 8.0min; Mass spectrum" Found: MH ⁺ 514 ( ³⁵ CI)

Example 122

6-f{3-Chloro-5-f2-(pyridin-4-ylamino)-ethoxyl-benzoylH2-m ethoxy-ethyl)-amιnol- hexanoic acid trifluoroacetate

Hplc system 1 (λ= 254nm) Rt 5.9mιn Mass spectrum: Found: MH ⁺ 464 ( ³⁵ CI)

Example 123

6-({3-Chloro-5-[ ^' 2-(pyridin-4-ylamino)-ethoxy]-benzoyl)-pyrιdιn-4-ylm ethyl-amino)- hexanoic acid trifluoroacetate

Hplc system 1 (λ= 254nm) Rt 4 4min Mass spectrum: Found: MH ⁺ 496 ( ³⁵ CI)

Example 124

6-({3-Chloro-5-[2-(pyridin-4-ylamino)-ethoxy1-benzoyl)-cv clohexylmethyl-amino)- hexanoic acid trifluoroacetate

Hplc system 1 (λ= 254nm) Rt 8.9mιn Mass spectrum: Found: MH ⁺ 502 ( ³⁵ CI)

Example 125

6-({3-Chloro-5-r2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl& gt;-ιsobutyl-amino)-hexanoιc acid trifluoroacetate

Hplc system 1 (λ= 254nm) Rt 7.5mιn Mass spectrum: Found: MH ⁺ 462 ( ³⁵ CI)

Example 126

6-({3-Chloro-5- 2-(pyrιdιn-4-ylamιno)-ethoxylbenzoyl}-thιophen-2-ylmethy l-amιno)- hexanoic acid trifluoroacetate Hplc system 3 (λ= 220-330nm) Rt 3 75mιn Mass spectrum Found MH ⁺ 501 ( ³⁵ CI)

Example 127

6-((3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxylbenzoylH2 -methyl-butyl)-amιnol- hexanoic acid trifluoroacetate

Hplc system 3 (λ= 220-330 nm) Rt 3 8mιn Mass spectrum Found MH ⁺ 476

( ³⁵ CI)

Example 128 4-((3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxy1-benzoyl)-cv clobutyl-amιno)-butvπc acιd trifluoroacetate p-Benzyloxybenzylalcohol resm ¹⁰ (0 54mmol/g, 0 250g) was wetted with DMF {ca 2ml) and then treated with a mixture of 4-bromobutanoιc acid (0 112g), diisopropylcarbodiimide (0 139ml) and 4-(N,N-dιmethylamιnopyπdιne) (0 02g) in dry DMF (1ml) The mixture was agitated for 2 days and then filtered dry under suction The resin was repeatedly washed with DMF (x3), and dichloromethane (x3) before drying under suction The resm was then agitated with cyclobutylamine (1 5ml) in dry DMF (1 5ml) for 1 day After filtration, the res was repeatedly washed with DMF (x3) and dichloromethane (x3) The resin was then agitated with 3-[2-(tert- butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5-chloro-benzo� �c acid (0 16g), diisopropylcarbodiimide (0 127ml) and 4-(N,N-dιmethylamιnopyπdιne) (0 012g) for 3 days After the excess reagents were removed by filtration, the resm was washed with DMF (x3) and dichloromethane (x3) before treatment with dichloromethane (1 ml) and trifluoroacetic acid (1 ml) After 1 5h, the resin was filtered and washed thoroughly with dichloromethane The combined filtrate and washings were evaporated to dryness under reduced pressure and subjected to preparative hplc Evaporation of the required fraction gave the title compound as a gum (0 0152g) Hplc system 1 (λ= 254nm) Rt 6 6mιn Mass spectrum Found MH ⁺ 432 ( ³⁵ CI)

Similarly prepared, using commercially available amines, were

Example 129

4-[(3-Chloro-5- 2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl}-(3-fluoro-benzyl)- amιnol- butyπc acid trifluoroacetate Hplc system 1 (λ= 254nm) Rt 7 6mιn, Mass spectrum Found MH ⁺ 486 ( ³⁵ CI)

Example 130

4-((3-Chloro-5-f2-(pyridin-4-ylamino)-ethoxy1-benzoyl}-fu ran-2-ylmethyl-amino)- butvπc acid trifluoroacetate Hplc system 1 (λ= 254nm) Rt 6 7mm, Mass spectrum Found MH ⁺ 458 ( ³⁵ CI)

Example 131

4-[{3-Chloro-5-[2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoylH 1-methyl-1 H-benzoιmιdazol- 2-yl)-amιnol-butyπc acid trifluoroacetate Hplc system 3 (λ = 220-330 nm) Rt 3 8mιn, Mass spectrum Found MH ⁺ 508 ( ³⁵ CI)

Example 132

4-f{3-Chloro-5-f2-(pyrιdιn-4-ylamιno)-ethoxyl-benzoyl) -naphthalen-1-ylmethyl- amιno)-butyrιc acid trifluoroacetate

Hplc system 3 (λ= 220-330 nm) Rt 4.2mιn Mass spectrum Found MH ⁺ 518

( ³⁵ CI)

Example 133 N-(5-Carbamoyl-pentyl)-3-chloro-N-(2-fluoro-benzyl)-5-r2-(py rιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate

Rink amide resin ¹¹ (0 45mmol/g, 0.250g) was treated with piperidine (20% in DMF) and agitated for 30mιn and then filtered dry under suction The resm was repeatedly washed with DMF (x3) and dichloromethane (x3) before drying under suction The resin was then treated with a mixture of 6-bromohexanoιc acid (0 11g), diisopropylcarbodiimide (0 11 ml) and 4-(N,N-dιmethylamιnopyrιdιne) (0 02g) in dry DMF (2ml) The mixture was agitated for 24h and then filtered dry under suction The resm was repeatedly washed with DMF (x3), and dichloromethane (x3) before drying under suction The resin was then agitated with 2-fluorobenzylamιne (1 5ml) in dry DMF (1.5ml) for 3 days After filtration, the resin was repeatedly washed with DMF (x3) and dichloromethane (x3) The resm was then agitated with 3-[2-(tert-

butoxycarbonyl-pyπdιn-4-yl-amιno)-ethoxy]-5-chloro-benzo� �c acid (0 16g), diisopropylcarbodiimide (0 127ml) and 4-(N,N-dιmethylamιnopyπdιne) (0 012g) for 3 days After the excess reagents were removed by filtration, the resm was washed with DMF (x3) and dichloromethane (x3) before treatment with dichloromethane (2ml) and trifluoroacetic acid (0 2ml) After 1 5h, the resin was filtered and washed thoroughly with dichloromethane The combined filtrate and washings were evaporated to dryness under reduced pressure The residue was dissolved in a mixture of dichloromethane (2ml) and trifluoroacetic acid (1 ml) and stirred at room temperature for 2h, after which the solution was evaporated to dryness under reduced pressure and subjected to preparative hplc Evaporation of the required fraction gave the title compound as a gum (0 024g) Hplc system 1 (λ= 254nm) Rt 7 35mιn Mass spectrum Found MH ⁺ 513 ( ³⁵ CI)

Similarly prepared, using commercially available amines, were

Example 134

N-(5-Carbamoyl-pentyl)-3-chloro-5-f2-(pyrιdιn-4-ylamιn o)-ethoxyl-N-(2,2,2-tπfluoro- ethvP-benzamide trifluoroacetate Hplc system 1 (λ= 254nm) Rt 6 9mιn, Mass spectrum Found MH ^* 487 (^Cl)

Example 135

N-(5-Carbamoyl-pentyl)-3-chloro-N-(2-methoxy-ethvι)-5-r2 -(pyπdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate Hplc system 1 (λ= 254nm) Rt 5 4mιn, Mass spectrum Found MH' 463 (^Cl)

Example 136

N-(5-Carbamoyl-pentyl)-3-chloro-N-cvclohexylmethyl-5-[2-( pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate Hplc system 3 (λ= 220-330nm) Rt 4 1 mιn, Mass spectrum Found MH ⁺ 501

( ³⁵ CI)

Example 137

N-(5-Carbamoyl-pentyl)-3-chloro-N-ιsobutyl-5-f2-(ρyrιd ιn-4-ylamιno)-ethoxyl- benzamide trifluoroacetate

Hplc system 3 (λ=220-330πm) Rt 3 8mιn, Mass spectrum Found MH ⁺ 461

( ³⁵ CI)

Example 138 N-(5-Carbamoyl-pentyl)-3-chloro-N-furan-2-vimethv -5-[2-(pyrιdιn-4-ylamιno)- ethoxyl-benzamide trifluoroacetate Hplc system 1 (λ= 254nm) Rt 6 4mιn Mass specrum Found MH ⁺ 485 ( ³⁵ CI)

Example 1 39 N-(5-Carbamoyl-pentyl)-3-chloro-5-f2-(pyπdιn-4-yl3mιno)-e thoxyl-N-thιophen-2- ylmethyl-benzamide trifluoroacetate

Hplc system 3 (λ=220-330nm) Rt 3 9mιn, Mass spectrum Found MH ⁺ 501

( ³⁵ CI)

Example 140

6-« ^" 3-Chloro-5-r2-(pyrιdιn-4-ylamιno)-ethoxy1-benzoyl}- ιsopropyl-amιno)-hexanoιc acid trifluoroacetate

Hplc system 1 (λ= 254nm) Rt 7 Omin, Mass spectrum Found MH ⁺ 448 ( ³⁵ CI)

Example 141

3-Chloro-N-ιsopropyl-5-[2-(pyπdιn-4-ylamιno)-ethoxyl- N-[2-(pyrιdιn-2-yloxy)-ethyll- benzamide)

A solution of {2-[3-chloro-5-(isopropyl-2-(pyridin-2-yloxy)-ethyi-carbamoy l)-phenoxyJ- ethyl}-pyπdιn-4-yl-carbamιc acid tert-butyl ester (0 033g) and TFA (0 4ml) in dichloromethane (0 4ml) was stirred at room temp for 3h then concentrated under vacuum The residue was purified by flash chromatography on silica eluting with dichloromethane/methanol/ammonia (94 6 1 ) to give the title compound as a colourless gum (0 005g)

Mass spectrum Found MH ⁺ 455 ( ³⁵ CI) Hplc system 3 (λ = 220-330nm) Rt 3 8mιn

Example 142

3-Chloro-N N-dιιsopropyl-5-f2-(pyπdιn-4-ylamιno)-e,noxyl-benzamιd e trifluoroacetate {2-[3-Chloro-5-(diisopropylcarbamoyl)-phenoxy]-ethyl}-pyridm -4-yl-carbamic acid tert-butyl ester (0 073g) was treated with dichloromethane (2ml) containing

trifluoroacetic acid (1 ml) After 2h the excess solvents and reagents were evaporated at reduced pressure to give the title compound as a colourless gum (0 08g)

Mass spectrum Found MH ⁺ 375 1 799 C ₂ oH ₂ 7 ³⁵ CIN ₃ θ ₂ requires 376 1791 Hplc system 1 (λ = 254nm) Rt 8 2mιn

References Brown, P M , Thomson, R H J Chem Soc , Perkin Trans I, 1976, 997

² Kelly, T A , McNeil, D W Tetrahedron Lett , 1994, 900

³ Becker A M , Rickards R W, Brown R F C Tetrahedron, 1983, 4189

⁴ US patent 4016267

⁵ S Dragon et al , Makromol Chem , 1986, 187(1 ), 9-22

⁶ Japanese patent 60156659

⁷ J Chem Soc , Perkin Trans 2 1987, (12), 1789

⁸ US patent 5334745

⁹ Japanese patent 60156659

10 p-Benzyioxybenzyl alcohol resin - polymer matrix is copoly(styreπe-1 % divinylbenzene), 100-200 mesh Novabiochem cat no 01 -64-0014 ¹¹ Rink amide resm - polymer matrix is copoly(styrene-1 % divinylbenzene), 100-200 mesh, Novabiochem cat no 01-64-0013

Compounds of formula (I) have been included in pharmacy formulations, and details of such formulations are given below

TABLETS FOR ORAL ADMINISTRATION A Direct Compression

% w/w

Active ingredient 32 7

Anhydrous lac ^* ose 36 8

Microcrystalline cellulose 25 0

Pregelatmisec maize starch 5 0

Magnesium stearate 0 5

The active ingredient was sieved and blended with the excipients The resultant mix was compressed into tablets using a tablet machine fitted with suitable diameter punches

A rotary machine may also be used for tabletting

Tablets of various strengths may be prepared by for example altering the ratio of active ingredient to lactose or the compression weight and using punches to suit

B Wet Granulation Formulation ( )

% w/w

Active ingredient 3 5

Lactose 73 25

Starch 15 0

Pregelatinised maize starch 7 5

Magnesium stearate 0 75

The active ingredient was sieved through a suitable sieve and blended with lactose, starch and pregelatinised maize starch Suitable volumes of purified water were added and the powders were granulated After drying, the granules were screened and blended with the magnesium stearate The granules were then compressed into tablets using suitable diameter punches The water used for granlation does not appear in the final product

A rotary machine may also be used for tabletting

Tablets of various strengths may be prepared by for example altering the ratio of active ingredient to lactose or the compression weight and using punches to suit

Formulation (n)

% w/w

Active ingredient/lactose granule ^* 93 0 Microcrystalline cellulose 5 5 Crosscarmellose sodium 1 0 Magnesium stearate 0 5

^* Active ingredient/lactose granule % w/w

Active ingredient 50 0 Lactose 50 0 Purified water qs +

+ The water does not appear in the final product Typical range 100-140g per kg of blend

The active ingredient and lactose were mixed together and granulated by the addition of purified water The granules obtained after mixing were dried and passed through a screen, and the resulting granules were then mixed with the othe ^r tablet core excipients The mix is compressed into tablets

A rotary machine may also be used for tabletting

Tablets of various strengths may be prepared by for example altering the ratio of active ingredient to lactose or the compression weight and using punches to suit

The tablets may be film coated with suitable film-forming materials such as hydroxypropyl methylcellulose, preferably incorporating pigments in the formulation using standard techniques Alternatively the tablets may be sugar coated, or enteric coated

Coating Suspension % w/w

Hydroxypropyl methylcellulose 10 0

Opaspray 5 0

Purified water to 100 0++

or

Coating Suspension % w/w

Opadry 10 0 Purified Water to 100 00 ++

++ The water does not appear in the final product

COMPRESSION COATED TABLET

The active ingredient may also be formulated as a tablet core using conventional excipients such as fillers, binders, disintegrants and lubricants, and this core then compressed within an outer tablet (compression coated) using conventional excipients such as a pH-mdependent hydrophilic polymer, fillers, binders, disintegrants and lubricants This outer coat may also contain active ingredient The compression of both the core and the outer compression coat can be achieved using conventional tabletting machinery

Such a dosage form can be designed so as to control the release of active ingredient as required

EFFERVESCENT TABLET

% w/w

Active ingredient 8 75

Sodium bicarbonate 41 03

Monosodium citrate anhydrous 41.22

Aspartame 2 5

Polyvinylpyrrolidone 2 0

Sodium benzoate 3 0

Orange flavour 1 0

Lemon flavour 0 5

Absolute alcohol for granulation qs

The active ingredient, anhydrous monosodium citrate, sodium bicarbonate and aspartame were mixed together and granulated by the addition of a solution of the polyvinylpyrrolidone in the alcohol The granules obtained after mixing were dried

and passed through a screen, and the resulting granules were then mixed with the sodium benzoate and flavourings The granulated material was compressed into tablets using suitable diameter punches

A rotary machine may also be used for tabletting

LIQUID-FILLED CAPSULE FORMULATIONS FOR ORAL ADMINISTRATION

Liquid formulations were prepared by slow addition of active ingredient into the other ingredients with constant mixing

Example A B

% w/w % w/w

Active ingredient 18 2 18 2

Oleic acid 60 985 68 485

Polyethylene glycol 600 7 3 7 3

Propylene glycol 6 0 6 0

Polysorbate 80 7 5 -

Ascorbyl palmitate 0 015 0 015

The liquid formulations were filled into gelatin capsules, the size of the capsule being used and the filler determining the possible fill weight/volume and hence the dose of active ingredient per capsule

POWDER-FILLED CAPSULES

% w/w

Active ingredient 24 5 Lactose 75 0 Magnesium stearate 0 5

The active ingredient was sieved and blended with the excipients The mix was filled into hard gelatin capsules using suitable machinery The dose is determined by the fill weight and the capsule size

SYRUP

The hydroxypropyl methylcellulose was dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation The resultant solution was adjusted to volume and mixed The syrup was clarified by filtration

SUSPENSION

The aluminium monostearate was dispersed in about 90% of the fractionated coconut on The resulting suspension was heated to 115°C while stirring and then cooled The sweetening agent, flavour and colour were added and the active ingredient was suitably dispersed The suspension was made up to volume with the remaining fractionated coconut oil and mixed

SUB-LINGUAL TABLET

% w/w

Active ingredient/lactose granule ^* 49 0 Compressible sugar 50.5 Magnesium stearate 0.5

The active ingredient was sieved through a suitable sieve, blended with the excipients and compressed using suitable punches Tablets of various strengths may be prepared by altering either the ratio of active ingredient to excipients or the compression weight and using punches to suit

A rotary machine may also be used for tabletting

SUPPOSITORY FOR RECTAL ADMINISTRATION

Active ingredient 49.0mg ^• Witepsol W32 1 0g

^* A proprietary grade of Adeps Solidus Ph Eur

A suspension of the active ingredient in molten Witepsol was prepared and filled using suitable machinery, into 1 g size suppository moulds

FOR INJECTION

% w/v

Active ingredient 1.0

Water for injections B P. to 100

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate soution of the active ingredient using dilute acid or alkali or by the addittion of suitable buffer salts Antioxidants and metal chelating salts may also be included The solution is clarified, made up to final volume with water and the pH re-measured and adjusted if necessary

The solution may be packaged for injection, for example by filling and sealing in ampoules vials or syringes The ampoules, vials or syringes mat be aseptically filled (e g the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions) and/or terminally sterilised (e g by heating in an autoclave using one of the acceptable cycles) The solution may be packed under an inert atmosphere of nitrogen

Preferably the solution is filled into ampoules, sealed by fusion of the glass and terminally sterilised

FOR INHALATION Inhalation Cartridges

mg/cartridge

Active ingredient (micronised) 0.56 Lactose 25.00

The active ingredient was micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend was filled into No 3 hard gelatin capsules on a suitable encapsulating machine. The contents of the cartridges were administered using a powder inhaler such as the Glaxo Rotahaler.

Metered Dose Pressurised Aerosol

Suspension Aerosol mg/metered Per can dose

Active ingredient (micronised) 0.280 73.92mg

Oleic acid 0.020 5 28mg

Isopentane 23.64 5.67g

Tetrafluroethane 61.25 14.70g

The active ingredient was micronised in a fluid energy mill to a fine particle size range. The oleic acid was mixed with the above at a temperature of 10-15°C and the micronised drug was mixed into the solution with a high shear mixer The

suspension was metered into aluminium aerosol cans and suitable metering valves delivering 85mg of suspension, were crimped onto the cans and the dichlorodifluoromethane was pressure filled into the cans through the valves

NASAL SPRAY

% w/v

Active ingredient 7 0

Sodium chloride 0 9

Purified water to 100

Shot weight 100mg (equivalent to 7mg active ingredient)

The active ingredient and sodium chloride were dissolved in a portion of the water, the solution made to volume with the water and the solution thoroughly mixed

The pH may be adjusted to facilitate solution of the active ingredient, using acid or alkali and/or subsequently adjusted if necessary taking into account the pH for optimum stability Alternatively, suitable buffer salts may be used The solution may be preserved with, for example, benzalkanium chloride and phenylethyl alcohol, for a muiti-dose nasal spray

Biological Results

The compounds of the present invention are thrombin inhibitors The results below illustrate the thrombm activity of a range of of compounds of formula (I) using the previously described biological method

Example no ICsn nm

1 8

6 5

9 7

13 15

17 14

20 9

29 62

37 17

40 9

41 28

47 61

49 38

55 50

58 107

69 63

87 22

89 15

91 34

96 40

132 10

134 140

138 28

142 41

152 91