Autotaxin inhibitory compounds

Abstract

The present invention relates to compounds of formula I ##STR00001##
wherein A.sub.1, A.sub.2, A.sub.3, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, L, Ar and Q are each as defined herein. The compounds of the present invention are inhibitors of autotaxin (ATX) enzyme activity. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions (e.g. fibrosis) in which ATX activity is implicated.

Claims

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structural formula Ic shown below: ##STR00783## wherein: R.sub.1 and R.sub.2 are independently selected from H, (1-2C)alkyl, halo, cyano, nitro, hydroxyl, amino, mercapto, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)fluoroalkoxy, A.sub.1 is C—R.sub.d, wherein R.sub.d is selected from H, halo, (1-2C)alkyl, cyano, nitro, hydroxyl, amino, (1-2C)haloalkyl, (1-2C)alkoxy, or (1-2C)haloalkoxy; A.sub.2 is N; A.sub.3 is N; L is a methylene optionally substituted by (1-2C)alkyl or oxo; Ar is either a 5 or 6 membered heteroaryl optionally substituted by H, halo, (1-4C)alkyl, (1-4C)haloalkyl, OCF.sub.3, (1-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or a group of the formula: ##STR00784## wherein: R.sub.a and R.sub.a′ are independently selected from H, fluoro, (1-2C)alkyl (1-2C)alkoxy or (1-2C)fluoroalkoxy; R.sub.b and R.sub.b′ are independently selected from H, fluoro, chloro, (1-2C)alkyl, (1-2Cfluoroalkoxy or (1-2C)alkoxy; R.sub.c is selected from is H, (1-4C)alkyl, halo, hydroxyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, NR.sub.iR.sub.j, OR.sub.i, C(O)R.sub.i, C(O)OR.sub.i, OC(O)R.sub.i, C(O)N(R.sub.j)R.sub.i, N(R.sub.j)C(O)R.sub.i, S(O).sub.yR.sub.i (where y is 0, 1 or 2), SO.sub.2N(R.sub.j)R.sub.i, N(R.sub.j)SO.sub.2R.sub.i or (CH.sub.2).sub.zNR.sub.jR.sub.i (where z is 1, 2 or 3), wherein R.sub.i and R.sub.j are each independently selected from H or (1-2C)alkyl; or R.sub.c is a group of the formula:
-L.sub.1-B wherein: L.sub.1 is (1-2C)alkylene or —O-(1-2C)alkylene, each of which is optionally substituted by (1-2C)alkyl or oxo; B is phenyl or 5 or 6 membered heteroaryl optionally substituted with halo or (1-2C)alkyl; Q is either a group of the formula:
—CHR.sub.x—R.sub.k— wherein: R.sub.k is CH.sub.2, NR.sub.l or O, wherein R.sub.l is selected from H or (1-2C)alkyl; and R.sub.x is H or (1-2C)alkyl; or Q is a group of the formula:
—R.sub.m—CHR.sub.y— wherein: R.sub.m is O, S, SO, SO.sub.2 or SO(NH); and R.sub.y is H or (1-2C)alkyl; R.sub.3 is H; R.sub.4 is H, (1-4C)alkyl, carboxyl, carbamoyl, sulphamoyl, amido, ureido, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-4C)alkyl, wherein said (1-4C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-4C)alkyl is optionally substituted with one or more substituents selected from halo, amino, mercapto, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, NR.sub.pR.sub.q, OR.sub.p, C(O)R.sub.p, C(O)OR.sub.p, OC(O)R.sub.p, C(O)N(R.sub.q)R.sub.p, N(R.sub.q)C(O)R.sub.p, S(O).sub.yR.sub.p (where y is 0, 1 or 2), SO.sub.2N(R.sub.q)R.sub.p, N(R.sub.q)SO.sub.2R.sub.p or (CH.sub.2).sub.zNR.sub.qR.sub.p (where z is 1, 2 or 3), wherein R.sub.p and R.sub.q are each independently selected from H or (1-4C)alkyl; R.sub.5 is a group of formula Z, wherein: Z is phenyl, heteroaryl, heterocyclyl or (3-6C)carbocyclyl, optionally substituted with one or more substituents selected from halo, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (2-4C)alkenyl, (2-4C)alkynyl, amino, mercapto, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, (1-4C)alkyl, NR.sub.sR.sub.t, OR.sub.s, C(O)R.sub.s, C(O)OR.sub.s, OC(O)R.sub.s, C(O)N(R.sub.t)R.sub.s, N(R.sub.t)C(O)R.sub.s, S(O).sub.yR.sub.s (where y is 0, 1 or 2), SO.sub.2N(R.sub.t)R.sub.s, N(R.sub.t)SO.sub.2R.sub.s or (CH.sub.2).sub.zNR.sub.sR.sub.t (where z is 1, 2 or 3), wherein R.sub.s and R.sub.t are each independently selected from H or (1-4C)alkyl; or Z is optionally substituted by a group of formula:
—V-L.sub.6-Y wherein V is absent or selected from O, S, SO, SO.sub.2, N(R.sub.u), C(O), C(O)O or OC(O), wherein R.sub.u is hydrogen or (1-2C)alkyl; L.sub.6 is absent or a (1-4C)alkylene optionally substituted by (1-2C)alkyl or oxo; Y is selected from amino, (1-6C)alkyl, phenyl, 5 or 6 membered heteroaryl, (3-7C)heterocyclyl or amino, optionally substituted with one or more substituents selected from halo, (1-2C)alkyl, cyano, nitro, hydroxyl, (1-2C)hydroxyalkyl, amino, (1-2C)haloalkyl, NR.sub.aaR.sub.bb, OCF.sub.3 or (1-2C)alkoxy, wherein R.sub.aa and R.sub.bb are each independently selected from H or (1-2C)alkyl; or R.sub.4 and R.sub.5 are linked such that, together with the carbon atom to which they are attached, they form a 5 or 6 membered cycloalkyl ring which is fused with a phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclyl or (3-6C)carbocyclyl ring; each of which is optionally substituted with one or more substituents selected from halo, amino, mercapto, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (2-4C)alkenyl, (2-4C)alkynyl, NR.sub.vR.sub.w, C(O)R.sub.v, C(O)OR.sub.v, OC(O)R.sub.v, C(O)N(R.sub.w)R.sub.v, N(R.sub.w)C(O)R.sub.v, S(O).sub.yR.sub.v (where y is 0, 1 or 2), SO.sub.2N(R.sub.w)R.sub.v, N(R.sub.w)SO.sub.2R.sub.v or (CH.sub.2).sub.zNR.sub.vR.sub.w (where z is 1, 2 or 3), wherein R.sub.v and R.sub.w are each independently selected from H or (1-4C)alkyl; with the proviso that: (i) when R.sub.1 and R.sub.2 are H, A.sub.1 is CH, Q is ethylene, R.sub.3 is H, R.sub.4 is H, L is methylene, R.sub.5 is: phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,5-dimethoxyphenyl, 4-methylsulfanyl-phenyl, 4-fluorophenyl, 2-furanyl, 5-(4-morpholinylmethyl)-2-furanyl, 2-pyridyl, 3-pyridyl, 1,3-benzodioxyl-5-yl, or 1-[(3-chlorophenyl)methyl]-4-piperidinyl; then Ar is not phenyl, furanyl, thiophenyl or paramethoxyphenyl; and (ii) when R.sub.4 is H, R.sub.5 is furanyl and Ar is phenyl, R.sub.m is not S.

2. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein A.sub.1 is CH.

3. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein L is methylene.

4. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sub.a and R.sub.a′ are H.

5. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is either a 5 membered heteroaryl optionally substituted by H, fluoro, methyl, CF.sub.3, OCF.sub.3, OMe or a group of the formula: ##STR00785## wherein R.sub.a, R.sub.a′, R.sub.b, R.sub.b′ and R.sub.c are as defined in claim 1.

6. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sub.b and R.sub.b′ are independently selected from H, fluoro, methyl, OCF.sub.3 or methoxy.

7. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sub.c is selected from is H, halo, hydroxyl, (1-2C)fluoroalkyl, (1-2C)alkoxy, (1-2C)fluoroalkoxy, or R.sub.c is a group of the formula:
-L.sub.1-B wherein: L.sub.1 is (1-2C)alkylene or —O-(1-2C)alkylene optionally substituted by methyl or oxo; and B is phenyl optionally substituted with fluoro or methyl.

8. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Q is either a group of the formula:
—CH.sub.2—R.sub.k— wherein: R.sub.k is CH.sub.2, NR.sub.l or O, wherein R.sub.l is selected from H or methyl; or Q is a group of the formula:
—R.sub.m—CHR.sub.y— wherein: R.sub.m is O, S, SO or SO.sub.2; and R.sub.y is H or methyl.

9. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sub.1 and R.sub.2 are H, methyl or fluoro.

10. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sub.4 is (1-4C)alkyl, carboxyl, wherein said (1-4C)alkyl, is optionally substituted with one or more substituents selected from amino, mercapto or hydroxyl.

11. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sub.5 is selected from a group of formula, Z, wherein: Z is phenyl, heteroaryl, heterocyclyl or (3-6C)carbocyclyl, optionally substituted with one or more substituents selected from halo, CF.sub.3, (1-2C)alkoxy, OCF.sub.3 amino, mercapto, hydroxyl, (1-2C)alkyl, NR.sub.sR.sub.t, C(O)R.sub.s, C(O)OR.sub.s, S(O).sub.yR.sub.s (where y is 0, 1 or 2), wherein R.sub.s and R.sub.t are each independently selected from H or (1-4C)alkyl; or Z is optionally substituted by a group of formula:
—V-L.sub.6-Y wherein V is absent or selected from O or N(R.sub.o) wherein R.sub.o is hydrogen or methyl; L.sub.6 is absent or a (1-4C)alkylene optionally substituted by methyl or oxo; Y is selected from (3-7C)heterocyclyl or amino, optionally substituted with one or more substituents selected from halo, (1-2C)alkyl, hydroxyl, (1-2C)hydroxyalkyl, NR.sub.aaR.sub.bb, CF.sub.3, OCF.sub.3 or OMe, wherein R.sub.aa and R.sub.bb are each independently selected from H or methyl; or R.sub.4 and R.sub.5 are linked such that, together with the carbon atom to which they are attached, they form a 5 or 6 membered cycloalkyl ring which is fused with a phenyl; each of which is optionally substituted with one or more substituents selected from hydroxyl, methyl, CF.sub.3, or OCF.sub.3.

12. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from any one of the following: 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N—((S)-1-phenyl-ethyl)-propionamide; 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-thiophen-2-ylmethyl-propionamide; 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N—((R)-1-phenyl-ethyl)-propionamide; 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-(2-methyl-benzyl)-propionamide; N-(3-Trifluoromethoxy-benzyl)-3-[3-(3-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—((R)-2-Hydroxy-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-((1R,2S)-2-Hydroxy-indan-1-yl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-((1R,2R)-2-Hydroxy-indan-1-yl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[4-(3-Dimethylamino-propoxy)-benzyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(4-difluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethyl-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Methoxy-benzyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[1-(4-Fluoro-phenyl)-2-hydroxy-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Bromo-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide; N—[(S)-1-(4-Bromo-phenyl)-ethyl]-3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Chloro-benzyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[4-(2-Dimethylamino-ethoxy)-benzyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[2-Hydroxy-1-(4-trifluoromethoxy-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Bromo-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-chloro-phenyl)-ethyl]-propionamide; N-(4-Trifluoromethoxy-benzyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[2-Hydroxy-1-(4-trifluoromethyl-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(3-fluoro-4-methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—(S)-Indan-1-yl-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[4-(3-Dimethylamino-propoxy)-benzyl]-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(3-Fluoro-4-methoxy-benzyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((R)-2-hydroxy-1-phenyl-ethyl)-propionamide; N—((S)-1-Pyridin-2-yl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Fluoro-benzyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Dimethylamino-benzyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[2-Hydroxy-1-(4-trifluoromethoxy-phenyl)-ethyl]-3-[3-(4-trifluoromethyl-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-[2-hydroxy-1-(4-trifluoromethoxy-phenyl)-ethyl]-propionamide; N-(1-Pyridin-4-yl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-[1-(4-Chloro-phenyl)-2-hydroxy-ethyl]-3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—(S)-1,2,3,4-Tetrahydro-naphthalen-1-yl-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-[2-hydroxy-1-(4-trifluoromethoxy-phenyl)-ethyl]-propionamide; N-Cyclohexylmethyl-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 4-(1-{3-[3-(4-Trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-ethyl)-piperidine-1-carboxylic acid tert-butyl ester; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-(3-thiophen-2-ylmethyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-morpholin-4-yl-phenyl)-ethyl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-((1R,2S)-2-hydroxy-indan-1-yl)-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-[1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-[1-(4-fluoro-phenyl)-3-hydroxy-propyl]-propionamide; N—[(R)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-[1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-propionamide; 4-({3-[3-(4-Trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester; N-(3-Fluoro-4-methoxy-benzyl)-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Methoxy-benzyl)-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; (S)-3-({3-[3-(4-Trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—(S)-indan-1-yl-propionamide; N-[1-(Tetrahydro-pyran-4-yl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(4-trifluoromethoxy-benzyl)-propionamide; N-(4-Dimethylamino-benzyl)-3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-((1R,2R)-2-hydroxy-indan-1-yl)-propionamide; N—((S)-1-Cyclopropyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[6-Bromo-3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-chloro-propionimide)]; N-(Tetrahydro-pyran-4-ylmethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(4-dimethylamino-benzyl)-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-2-hydroxy-1-phenyl-ethyl)-propionamide; (R)-3-({3-[3-(4-Trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-pyridin-2-yl-ethyl)-propionamide; 3-[6-Bromo-3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-chloro-propionimide)]; N-Cyclohexylmethyl-3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-pyridin-2-yl-ethyl)-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(2-methoxy-4-trifluoromethoxy-benzyl)-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-pyridin-2-ylmethyl-propionamide; 3-[3-(4-Benzyloxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-chloro-phenyl)-ethyl]-propionamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(4-fluoro-benzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Benzyloxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-pyridin-4-ylmethyl-propionamide; N—[(S)-1-(4-Bromo-phenyl)-ethyl]-3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(4-methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-p-tolyl-ethyl)-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-phenyl-ethyl)-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-phenyl-ethyl)-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-phenyl-propyl)-propionamide; 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-p-tolyl-ethyl)-propionamide; 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-phenyl-ethyl)-propionamide; 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-phenyl-propyl)-propionamide; N-(4-Fluoro-benzyl)-3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide; N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-3-[3-(4-methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(4-methoxy-benzyl)-propionamide; N-(4-Methoxy-benzyl)-3-[3-(3-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((S)-1-methyl-1-phenyl-butyl)-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(4-methoxy-benzyl)-propionamide; 3-[6-Fluoro-3-(2-methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(4-methoxy-benzyl)-propionamide; N-(4-Methoxy-benzyl)-3-[3-(4-methyl-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(2-methyl-benzyl)-propionamide; N-(3,4-Difluoro-benzyl)-3-[3-(4-methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Fluoro-benzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-2-yl]-N-(4-methoxy-benzyl)-propionamide; 3-[3-(3-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(4-methoxy-benzyl)-propionamide; 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-cyclohexylmethyl-propionamide; 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—((R)-1-phenyl-ethyl)-propionamide; N-(2-Fluoro-benzyl)-3-[3-(4-methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N-(3-methyl-benzyl)-propionamide; N-(3-Fluoro-benzyl)-3-[3-(4-methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Methoxy-benzyl)-3-[3-(3-methyl-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Trifluoromethoxy-benzyl)-3-[3-(2-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(4-Fluoro-benzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide; N—((R)-2-Hydroxy-1-phenyl-ethyl)-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetamide; 2-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-N—((R)-2-hydroxy-1-phenyl-ethyl)-acetamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetamide; N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetamide; 2-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-acetamide; 2-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-N—[(S)-1-(4-morpholin-4-yl-phenyl)-ethyl]-acetamide; N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-sulfinyl]-acetamide (diastereomer 1); N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-sulfinyl]-acetamide (diastereomer 2); N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-sulfonyl]-acetamide; N—((R)-2-Hydroxy-1-phenyl-ethyl)-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetamide; 2-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-acetamide; N—((R)-2-Hydroxy-1-phenyl-ethyl)-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-propionamide; N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-3-[3-(4-hydroxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Fluoro-phenyl)-ethyl]-3-[3-(4-isobutoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 1-[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-urea; 1-[(S)-1-(4-Bromo-phenyl)-ethyl]-3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-urea; 1-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-[(S)-1-(4-methoxy-phenyl)-ethyl]-urea; 1-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-[(S)-1-(4-fluoro-phenyl)-ethyl]-urea; 1-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-((S)-1-phenyl-ethyl)-urea; 1-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-((R)-2-hydroxy-1-phenyl-ethyl)-urea; 1-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-[(S)-1-(4-morpholin-4-yl-phenyl)-ethyl]-urea; [3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-carbamic acid (S)-1-(4-fluoro-phenyl)-ethyl ester; 1-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-[(S)-1-(3-methoxy-phenyl)-ethyl]-urea; [(S)-1-(4-Fluoro-phenyl)-ethyl]-carbamic acid 3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl ester; N—{(S)-1-[4-(4-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((R)-3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((S)-3-Dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-[1,4]Diazepan-1-yl-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((cis)-3,5-Dimethyl-piperazin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((S)-3-Ethyl-piperazin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-(1-Methyl-piperidin-4-ylamino)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((R)-3-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((S)-Pyrrolidin-3-ylamino)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((S)-3-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-(3-dimethylamino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-propionamide; N—[(S)-1-(4-Azepan-1-yl-phenyl)-ethyl]-3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-(3-trifluoromethyl-piperazin-1-yl)-phenyl]-ethyl}-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-pyrrolidin-1-yl-phenyl)-ethyl]-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-ethyl}-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-pyrrolidin-1-yl-phenyl)-ethyl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-((S)-3-methyl-piperazin-1-yl)-phenyl]-ethyl}-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-morpholin-4-yl-phenyl)-ethyl]-propionamide; 3-[3-(4-Fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-piperidin-1-yl-phenyl)-ethyl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-piperidin-1-yl-phenyl)-ethyl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-((R)-3-methyl-piperazin-1-yl)-phenyl]-ethyl}-propionamide; 3-[6-Methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-((S)-pyrrolidin-3-ylamino)-phenyl]-ethyl}-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—{(S)-1-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-phenyl]-ethyl}-propionamide; N—[(S)-1-(4-[1,4]Diazepan-1-yl-phenyl)-ethyl]-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—{(S)-1-[4-((S)-3-Methyl-piperazin-1-yl)-phenyl]-ethyl}-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-piperazin-1-yl-phenyl)-ethyl]-propionamide; (R)-Cyclohexyl-{3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-acetic acid; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-propionamide; N—[(S)-1-(4-Diethylaminomethyl-phenyl)-ethyl]-3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; 3-[3-(3,4-Difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-dimethylaminomethyl-phenyl)-ethyl]-propionamide; N—((R)-2-Mercapto-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—((R)-2-Amino-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Methoxy-phenyl)-ethyl]-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N—[(S)-1-(4-Chloro-phenyl)-ethyl]-3-[3-(4-fluoro-benzyl)-6-methyl-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(1-Methanesulfonyl-piperidin-4-ylmethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(1-Cyclopropanecarbonyl-piperidin-4-ylmethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(1-Acetyl-piperidin-4-ylmethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide; N-(4-Fluoro-benzyl)-3-(3-thiophen-2-ylmethyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide; and N-Benzyl-3-(3-thiophen-2-ylmethyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide.

13. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier, and wherein the compounds of claim 1 are not limited by proviso (i) recited in claim 1.

14. A method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compounds of claim 1 are not limited by proviso (i) recited in claim 1; wherein treating means inhibiting, relieving or attenuating the disorder, or at least one clinical or subclinical symptom thereof.

15. A method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compounds of claim 1 are not limited by proviso (i) recited in claim 1; wherein treating means inhibiting, relieving or attenuating the cancer, or at least one clinical or subclinical symptom thereof.

16. A method of treating fibrosis in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compounds of claim 1 are not limited by proviso (i) recited in claim 1; wherein treating means inhibiting, relieving or attenuating the fibrosis, or at least one clinical or subclinical symptom thereof.

17. A combination of a compound, or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1, wherein the compounds of claim 1 are not limited by proviso (i) recited in claim 1, with one or more additional therapeutic agents for the use in the treatment of cancer, inflammation, pain, diabetes mellitus, hypertension, atherosclerosis, thrombosis, urethral obstructive disease, fibrosis, hepatitis B and C and/or pruritus.

18. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is phenyl optionally substituted with one or more substituents selected from halo, CF.sub.3, (1-2C)alkoxy, OCF.sub.3 amino, mercapto, hydroxyl, (1-2C)alkyl, NR.sub.sR.sub.t, C(O)R.sub.s, C(O)OR.sub.s, S(O).sub.yR.sub.s (where y is 0, 1 or 2), wherein R.sub.s and R.sub.t are each independently selected from H or (1-4C)alkyl.

19. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is a group of the formula: ##STR00786## wherein R.sub.a and R.sub.a′ are H; R.sub.b and R.sub.b′ are H; and R.sub.c is (1-2C)fluoroalkoxy.

20. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R.sub.4 is (1-4C)alkyl.

Description

EXAMPLES

Description of Drawings

(1) Embodiments of the invention will be described, by way of example only, with reference to the accompanying drawings, in which:

(2) FIG. 1 shows the total volume of lung metastases achieved through administration of Example 40 compared to the administration of the vehicle, using the 4T1 orthotopic metastatic breast cancer model, described hereinbelow.

(3) FIG. 2 shows the number of lung metastases achieved through administration of Example 40 compared to the administration of the vehicle, using the 4T1 orthotopic metastatic breast cancer model, described hereinbelow.

(4) FIG. 3 shows the effect on bone metastatic colony formation in the presence of Example 40 compared to the vehicle, using the 4T1 orthotopic metastatic breast cancer model, described hereinbelow.

(5) FIG. 4 shows a schematic of the experimental procedure steps for the 4T1 orthotopic metastatic breast cancer model, described herein below.

GENERAL EXPERIMENTAL

(6) Analytical Methods

(7) NMR

(8) Method 1: Proton NMR spectra are recorded using an Oxford Instruments AS400 9.4 Tesla 400 MHz magnet with either a 5 mm BBO or PH SEF 400SB F-H-D-05 probe and an AVANCE/DPX400 console machine at 400 MHz.

(9) Method 2: Proton NMR spectra are recorded using a 300 MHz Bruker spectrometer.

(10) For both methods, NMR solutions were typically prepared in either deuterated CDCl.sub.3 or deuterated DMSO. Shifts are reported in ppm values relative to an internal standard of tetramethylsilane (TMS) or residual protic solvent. The following abbreviations are used to describe the splitting patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet-doublet), dt (doublet-triplet), br (broad signal). Deuterated solvents were obtained from the Sigma-Aldrich Chemical Company, Goss or Fluorochem.

(11) LCMS

(12) Method 1 employed Waters 2545 pumps, a Waters SFO mixer and a Waters 2998 UV detector (single wavelength 254 nM). The mass spectrometer was an Acquity SQ which detected masses between 100 and 700 g/mol. A Waters SunFire, 5 micron pore size, C18 of dimensions 50×4.60 mm was used. The injection volume was 10 μl. The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent flow rate was 1.5 ml/min, using 95% water:5% acetonitrile, changed linearly to 5% water:95% acetonitrile over 5.0 minutes and then maintained at this mixture for 0.50 minutes before the eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 6 seconds. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total.

(13) Method 2 employed Waters 2545 pumps, a Waters SFO mixer and a Waters 2998 UV detector (single wavelength 254 nM). The mass spectrometer was an Acquity SQ which detected masses between 100 and 700 g/mol. The detection was done at 254 nm and an array between 210-600 nm. A Waters SunFire, 5 micron pore size, C18 of dimensions 50×4.60 mm was used. The injection volume was 10 μl. The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent flow rate was 1.5 ml/min, using 95% water:5% acetonitrile, changed linearly to 5% water:95% acetonitrile over 10 min and then maintained at this mixture for 0.50 min before the eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 6 seconds. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 12 minutes in total.

(14) Method 3 employed Waters 2545 pumps, a Waters SFO mixer and a Waters 2998 UV detector (single wavelength 254 nM). The mass spectrometer was a Waters 3100 which detected masses between 100 and 700 g/mol. The detection was done at 254 nm and an array between 210-600 nm. A SunFire, 5 micron pore size, C18 column of dimensions 50×4.60 mm was used. The injection volume was 10 μl. The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent flow rate was 1.5 ml/min, using 95% water:5% acetonitrile, changed linearly to 5% water:95% acetonitrile over 5.0 min and then maintained at this mixture for 0.50 min before the eluent level was returned to the starting conditions of 95% water:5% acetonitrile over 6 seconds. These conditions were held for 1.4 minutes to allow equilibration of the column before the next sample was injected. The run lasted 7 minutes in total.

(15) Method 4 employed a Waters Acquity UPLC system fitted with a UV diode array detection and a Waters SQD detector. The detection was done at an array between 210-400 nm. A BEH C18 1.7 μM column of dimensions 2.1×50 mm was used. The mobile phase consisted of a mixture of water and 10 mM NH.sub.4HCO.sub.3 with 0.1% ammonia solution (solvent A) and acetonitrile with 0.1% ammonia solution (solvent B). The eluent flow rate was 0.6 ml/min, using 95% solvent A:5% solvent B, changed linearly to 5% solvent A:95% solvent B over 1.2 min and then maintained at this mixture for 0.5 min.

(16) Method 5 employed Waters 2545 pumps, a Waters SFO mixer with valves directing to the different columns and a Waters 2998 UV detector. The detection was done at 254 nm and an array between 210-600 nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700 g/mol. A SunFire, 5 micron pore size, C18 column of dimensions 50×19 mm was used. The injection volume was chosen by the user and could be up to 500 μl of solution (maximum 50 mg/ml). The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The flow rate was 25 mL/min with elution starting at 95% water:5% acetonitrile and held at this for 0.3 min, changed linearly to 5% water:95% acetonitrile over 5 min. This is then held until 5.8 min. There are 2 purification columns so the second one was equilibrated at 5% water:95% acetonitrile during the previous run so the next injection could be performed straight away.

(17) Method 6 employed Waters 2545 pumps, a Waters SFO mixer with valves directing to the different columns and a Waters 2998 UV detector. The detection was done at 254 nm and an array between 210-600 nm. The mass spectrometer used was a Waters 3100 which detected masses between 100 and 700 g/mol. A SunFire, 5 micron pore size, C18 column of dimensions 50×19 mm was used. The injection volume was chosen by the user and can be up to 500 μl of solution (maximum 50 mg/mL). The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent flow rate was 25 ml/min with elution starting at 95% water:5% acetonitrile and held at this for 1.5 min, changed linearly to 5% water:95% acetonitrile over 10 min and then held until 12 min. There are 2 purification columns so the second one was equilibrated at 5% water:95% acetonitrile during the previous run so the next injection could be performed straight away.

(18) Method 7 employed Waters 2545 pumps, a Waters SFO mixer with valves directing to the different columns, and a Waters 2998 UV detector. The detection was done at 254 nm and an array between 210-600 nm. The mass spectrometer was a Waters 3100 which detected masses between 100 and 700 g/mol. A SunFire, 5 micron pore size, C18 column of dimensions 30×100 mm was used. The injection volume was chosen by the user and can be up to 2.5 ml of the solution (max 50 mg/ml). The mobile phase consisted of a mixture of water and acetonitrile containing 0.1% formic acid. The eluent flow rate was 30 ml/min, with elution starting at 95% water:5% acetonitrile and held at this for 2 min, changed linearly to 5% water:95% acetonitrile over 13 min and then held for 5 min. This returns to 95% water:5% acetonitrile over 12 seconds then held until 24 min.

(19) Method 8 employed a Waters FractionLynx MS autopurification system with UV diode array detection at an array between 210-400 nm and mass-directed collection using both positive and negative mass ion detection. A Waters XBridge 5 micron C18, 100 mm×19 mm column was used. Purifications were performed using buffered acidic or basic solvent systems as appropriate. The mobile phase consisted of a mixture of water and 10 mM NH.sub.4HCO.sub.3 with 0.1% ammonia solution (solvent A) and acetonitrile with 5% water and 0.1% formic acid (solvent B). The eluent flow rate was 20 ml/min, with elution starting at 90% solvent A:10% solvent B, changed linearly to 2% solvent A:98% solvent B over 8.5 min and then maintained at this mixture for 3.5 min.

List of Abbreviations

(20) SM starting material

(21) UV ultraviolet

(22) Pd/C palladium on carbon

(23) H.sub.2SO.sub.4 sulphuric acid

(24) EtOH ethanol

(25) KtOBu potassium tert-butoxide

(26) Cs.sub.2CO.sub.3 caesium carbonate

(27) EtOAc ethyl acetate

(28) N.sub.2 nitrogen

(29) NaHCO.sub.3 sodium hydrogen carbonate

(30) Et.sub.2O diethyl ether

(31) MgSO.sub.4 magnesium sulphate

(32) DCM dichloromethane

(33) HOAc acetic acid

(34) HBTU O-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate

(35) Et.sub.3N triethylamine

(36) MTBE methyl tert-butyl ether

(37) DMF dimethylformamide

(38) CDI 1,1′-carbonyldiimidazole

(39) Fe iron

(40) EDTA ethylenediaminetetraacetic acid

(41) NaOH sodium hydroxide

(42) IPA isopropanol

(43) H.sub.2 hydrogen

(44) r.t. room temperature

(45) SCX propylsulfonic acid bonded sorbent

(46) μl microlitres

(47) ml millilitres

(48) HPLC high performance liquid chromatography

(49) NMP N-methyl pyrrolidine

(50) LiOH lithium hydroxide

(51) LiOHxH.sub.2O lithium hydroxide monohydrate

(52) DMSO dimethyl sulfoxide

(53) CuI copper (I) iodide

(54) TBAI tetrabutylammonium iodide

(55) CS.sub.2 carbon disulfide

(56) K.sub.2CO.sub.3 potassium carbonate

(57) TFA trifluoroacetic acid

(58) KMnO.sub.4 potassium permanganate

(59) NaH sodium hydride

(60) THF tetrahydrofuran

(61) POCl.sub.3 phosphorus oxychloride

(62) PCl.sub.5 phosphorus pentachloride

(63) 1H-NMR proton nuclear magnetic resonance

(64) ppm parts per million

(65) MHz megahertz

(66) RT retention time

(67) conc. concentrated

(68) MW microwave

(69) CHCl.sub.3 chloroform

(70) Pd(PPh.sub.3).sub.2Cl.sub.2 bis(triphenylphosphine)palladium (II) dichloride

(71) Na.sub.2CO.sub.3 sodium carbonate

(72) Mel methyl iodide

(73) DABAL-Me.sub.3 bis(trimethylaluminium)-1,4-diazabicyclo[2.2.2]octane adduct

(74) NH.sub.4HCO.sub.3 ammonium hydrogen carbonate

(75) PPh.sub.3 triphenylphosphine

(76) DIAD diisopropyl azodicarboxylate

(77) AcN acetonitrile

(78) Pd(OH).sub.2/C Pearlman's catalyst

(79) NH.sub.4Cl ammonium chloride

(80) ° C. degrees Celsius

(81) HCl hydrochloric acid

(82) Na.sup.tOBu sodium tert-butoxide

(83) X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

(84) Pd.sub.2dba.sub.3 palladium (0) bis (dibenzylideneacetone)

(85) min minutes

(86) nm nanometers

(87) μm micrometers

(88) mm millimeters

(89) mmol millimol

(90) LiAlH.sub.4 lithium aluminium hydride

(91) K.sub.3PO.sub.4 potassium phosphate

(92) t-BuOH tert-buthanol

(93) Pd(OAc).sub.2 palladium acetate

(94) PPh.sub.3 triphenylphosphine

(95) X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

(96) M molar

(97) g gram

(98) mg milligram

(99) FBS foetal bovine serum

(100) PBS phosphate buffered saline

(101) RPMI Roswell Park Memorial Institute

General Synthesis of 3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-5 (Scheme 001)

(102) ##STR00024##

(103) Commercially available 2-chloro-3-nitro-pyridine of general formula F-1 was reacted with Cs.sub.2CO.sub.3 and the required Amine 1 in methanol at reflux to yield the aralkyl-(3-nitro-pyridin-2-yl)-amine derivatives of general formula F-2, which was hydrogenated over Pd/C in EtOH to afford N′2′-aralkyl-pyridine-2,3-diamine of general formula F-3. This diamine could alternatively be obtained through a reduction with iron in HCl. Intermediate F-3 was reacted with succinic anhydride in dioxane at reflux, and then treated with H.sub.2SO.sub.4 and EtOH under reflux. The obtained ester, of general formula F-4, was treated with KtOBu and the required Amine 2 in the MW at 150° C. to afford the final compounds of general formula F-5.

(104) F-1 could be any of the following intermediates:

(105) ##STR00025##

(106) The above synthesis (Scheme 001) is illustrated by the preparation of 3-(3-benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N—((S)-1-phenyl-ethyl)-propionamide (Ex. 1) described below.

Synthesis of benzyl-(3-nitro-pyridin-2-yl)-amine

(107) ##STR00026##

(108) In a round bottom flask fitted with magnetic stirrer and reflux condenser, a solution of 2-chloro-3-nitropyridine (580 mg, 3.70 mmol) in dioxane (10 ml) was treated with Cs.sub.2CO.sub.3 (2.41 g, 7.40 mmol) and 4-fluorobenzylamine (850 μl, 7.40 mmol) and heated to 80° C. for 2 hours. The mixture was allowed to cool down to r.t., filtered and washed with EtOAc. The filtrate was purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 10% EtOAc. Product fractions were combined and evaporated to provide the title compound (913 mg, 100%).

(109) LCMS Method: 3, RT: 4.45 min, MI: 248 [M+1]

(110) .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.50 (br 1H), 8.45 (dd 1H), 8.43 (s 1H), 7.37-7.32 (m 2H), 7.03 (tt 2H), 6.71-6.68 (m 1H), 4.83 (d 2H).

Synthesis of N′2′-benzyl-pyridine-2,3-diamine

(111) ##STR00027##

(112) To a round bottom flask fitted with magnetic stirrer and containing benzyl-(3-nitro-pyridin-2-yl)-amine (912 mg, 3.69 mmol) and 10% Pd/C (90 mg) was added MeOH (10 ml), whilst stirring under N.sub.2. Mixture was purged with more N.sub.2 and a double balloon filled with H.sub.2 was fitted onto the flask. Suspension was allowed to stir at r.t. for 90 min under an atmosphere of H.sub.2 and subsequently filtered through Celite®. The filtrate was evaporated under reduced pressure to provide the title compound (800 mg, 100%).

(113) LCMS Method: 3, RT: 1.71 min, MI: 218 [M+1]

(114) .sup.1H-NMR, Method 1: (DMSO) 7.42-7.38 (m 2H), 7.31 (dd 1H), 7.15 (t 2H), 6.93 (br 1H), 6.83 (d 1H), 6.50 (dd 1H), 5.22 (br 2H), 4.59 (d 2H).

Synthesis of N′2′-(4-fluoro-benzyl)-pyridine-2,3-diamine (Example of Alternative Reduction Method)

(115) ##STR00028##

(116) In a round bottom flask fitted with magnetic stirrer and reflux condenser, HCl conc. (45 ml) was added to a stirred solution of (4-fluoro-benzyl)-(3-nitro-pyridin-2-yl)-amine (3.15 g, 12.73 mmol) and Fe powder (2.85 g, 50.95 mmol) in EtOH (135 ml). The reaction was stirred at 40° C. for 1 h, and then allowed to cool down overnight. Reaction crude was basified to pH 8 with NaHCO.sub.3 aqueous solution and then extracted into DCM (2×450 ml). The organic phases were combined, filtered through a silicone treated filter paper and concentrated under reduced pressure to afford the title compound (2.67 g, 96%).

Synthesis of 3-(3-benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionic Acid Ethyl Ester

(117) ##STR00029##

(118) In a round bottom flask fitted with magnetic stirrer and reflux condenser, to a stirred solution of N′2′-benzyl-pyridine-2,3-diamine (9.7 g, 48.6 mmol) in dioxane was added succinic anhydride (5.84 g, 58.3 mmol) and the reaction mixture was heated to 80° C. for 16 hours with stirring under N.sub.2. The dioxane was removed under reduced pressure and the resulting crude treated with EtOH (100 ml). To this mixture was added conc. H.sub.2SO.sub.4 (3 ml) cautiously with stirring. After addition, the mixture was heated at reflux under N.sub.2 for 20 hours. The mixture was cooled to r.t. and poured into saturated NaHCO.sub.3 aqueous solution and extracted (×3) with Et.sub.2O. Organic phases were washed with brine and dried over anhydrous MgSO.sub.4. The solvent was removed under reduced pressure and the crude material (16.35 g) was purified by column chromatography with a gradient of DCM and Et.sub.2O to give the title compound (1.98 g, 13%).

(119) LCMS Method: 4, RT: 1.09 min, MI: 310 [M+1]

(120) .sup.1H-NMR, Method 2: (DMSO) 8.30 (d 1H), 8.01 (d 1H), 7.36-7.18 (m 6H), 5.54 (s 2H), 4.03 (q 2H), 3.09 (t 2H), 2.87 (t 2H), 1.14 (t 3H)

Synthesis of 3-(3-benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N—((S)-1-phenyl-ethyl)-propionamide (Ex. 1)

(121) ##STR00030##

(122) To a 10 ml MW vial fitted with a magnetic stirrer was added 3-(3-benzyl-3H-imidazo [4,5-b]pyridin-2-yl)-propionic acid ethyl ester (154 mg, 0.5 mmol), (3)-1-phenylethylamine (121 mg, 1 mmol) and K.sup.tOBu (56 mg, 0.5 mmol). The reaction mixture was heated at 150° C. for 45 min in the MW. Reaction crude was treated with HOAc (8 drops) and MeOH (1 ml) and purified by reverse phase mass-directed preparative HPLC using Method 8 to afford the title compound (3 mg, 2%).

(123) The following compounds of general formula F-5 were prepared according to the general synthesis shown in Scheme 001:

(124) TABLE-US-00001 Example SM Amine 1 Amine 2 Characterisation 1 F-1a LCMS Method: 4, RT: 1.10 min, MI: 385 [M + 1] .sup.1H NMR, Method 2: (DMSO) 8.49-8.40 (m 1H), 8.32-8.29 (m 1H), 8.02-7.99 (m 1H), 7.34-7.15 (m 9H), 5.50 (s 2H), 4.91-4.86 (m 1H), 3.09- 2.98 (m 2H), 2.79-2.67 (m 2H), 1.32 (d 3H) 3 F-1a LCMS Method: 4, RT: 1.04 min, MI: 377 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.63-8.59 (m 1H), 8.32-8.29 (m 1H), 7.99 (d 1H), 7.43- 7.17 (m 7H), 6.95-6.90 (m 2H), 5.54 (s 2H), 4.41 (d 2H), 3.07 (t 2H), 2.72 (t 2H) 4 F-1a LCMS Method: 4, RT: 1.10 min, MI: 386 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.49-8.40 (m 1H), 8.32-8.29 (m 1H), 8.02-7.99 (m 1H), 7.34-7.15 (m 9H), 5.50 (s 2H), 4.91-4.86 (m 1H), 3.09- 2.98 (m 2H), 2.79-2.67 (m 2H), 1.32 (d 3H) 5 F-1a LCMS Method: 4, RT: 1.10 min, MI: 386 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.38-8.29 (m 2H), 8.02-7.98 (m 1H), 7.36-7.01 (m 10H), 5.53 (s 2H), 4.22 (d 2H), 3.09 (t 2H), 2.76 (t 2H), 2.21 (s 3H) 6 F-1a 0 LCMS Method: 4, RT: 1.26 min, MI: 540 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.60 (t 1H), 8.31 (dd 1H), 8.00 (dd 1H), 7.33 (m 9H), 5.60 (s 2H), 4.32 (d 2H), 3.12 (t 2H), 2.80 (t 2H)

General Synthesis of 3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-5 (Scheme 002-A)

(125) ##STR00041##

(126) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-3 was reacted with succinic anhydride in dioxane at reflux, and then treated with HOAc. The obtained carboxylic acid, of general formula F-6, was treated with HBTU, Et.sub.3N and the required amine 2 at r.t. to afford the final compounds of general formula F-5.

(127) F-1 could be any of the following intermediates:

(128) ##STR00042##

(129) The above synthesis (Scheme 002-A) is illustrated by the preparation of N—[(S)-1-(4-chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 40) described below.

Synthesis of 3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionic Acid

(130) ##STR00043##

(131) In a round bottom flask fitted with a magnetic stirrer and reflux condenser, a solution of N′2′-(4-trifluoromethoxy-benzyl)-pyridine-2,3-diamine (2.5 g, 8.83 mmol) in dioxane (50 ml) was treated with succinic anhydride (880 mg, 8.83 mmol) and heated at 80° C. for 5 hours under N.sub.2. The reaction mixture was then treated with HOAc (25 ml) and heated to reflux overnight. Reaction crude was allowed to cool down, then solvent was evaporated under reduced pressure and azeotroped from toluene and CHCl.sub.3 to give a dark solid. This solid was stirred in Et.sub.2O (100 ml) for 2 hours and filtered. The solid was washed with Et.sub.2O (50 ml) and dried to afford the title compound (1.89 g, 59%).

(132) LCMS Method: 1, RT: 3.79 min, MI: 366 [M+1]

Synthesis of N—[(S)-1-(4-chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 40)

(133) ##STR00044##

(134) In a round bottom flask fitted with a magnetic stirrer, 3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionic acid (73 mg, 0.2 mmol), Et.sub.3N (70 μl, 0.5 mmol) and (S)-1-(4-chlorophenyl)ethylamine (31 mg, 0.20 mmol) were dissolved in DCM (2 ml). Finally, HBTU (83 mg, 0.22 mmol) was added in. Reaction mixture was allowed to stir at r.t. for 1 hour, then diluted with EtOAc, washed with water and brine, dried and evaporated under reduced pressure. The crude product was purified by reverse phase mass-directed preparative HPLC using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the title compound (79 mg, 79%).

(135) The following compounds of general formula F-5 were prepared according to the general synthesis shown in Scheme 002-A:

(136) TABLE-US-00002 Ex- am- ple SM Amine 1 Amine 2 Characterisation 7 F- 1a LCMS Method: 1, RT: 4.02 min, MI: 485 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.38 (d 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.31-7.17 (m 10H), 5.54 (s 2H), 4.87- 4.81 (m 2H), 3.59-3.50 (m 2H), 3.13-3.00 (m 2H), 2.86-2.73 (m 2H) 8 F- 1a LCMS Method: 1, RT: 4.30 min, MI: 497 .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.36 (dd 1H), 8.00 (dd 1H), 7.31-7.16 (m 9H), 6.47 (d 1H), 5.57 (d 1H), 5.44 (d 1H), 5.39-5.36 (m 1H), [M + 1] 4.73 (td 1H), 3.48-3.40 (m 1H), 3.15 (dd 1H), 3.05- 2.97 (m 2H), 2.82-2.79 (m 2H) 9 F- 1a 0 LCMS Method: 1, RT: 4.17 min, MI: 497 .sup.1H-NMR, Method 1: (DMSO) 8.34-8.31 (m 2H), 8.01 (dd 1H), 7.38-7.33 (m 4H), 7.30 (dd 1H), 7.18-7.15 (m 2H), 7.11-7.03 (m 2H), [M + 1] 5.61 (s 2H), 5.28 (d 1H), 5.02 (t 1H), 4.22-4.16 (m 1H), 3.22-3.06 (m 3H), 2.87-2.65 (m 3H) 10 F- 1a LCMS Method: 1, RT: 2.79 min, MI: 556 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.44 (t 1H), 8.31 (dd 1H), 8.02 (dd 1H), 7.33 (br 4H), 7.28 (dd 1H), 7.12 (dt 2H), 6.79 (dt 2H), 5.57 (s 2H), 4.20 (d 2H), 3.94 (t 2 H), 3.10 (t 2H), 2.77 (t 2H), 2.44 (t 2H), 2.21 (s 6H), 1.88-1.82 (m 2H) 11 F- 1a LCMS Method: 1, RT: 4.50 min, MI: 418 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.46 (d 1H), 8.30 (dd 1H), 8.01 (dd 1H), 7.30-7.24 (m 7H), 7.18 (t 1H), 7.12-7.10 (m 2H), 5.49 (s 2H), 4.92- 4.83 (m 1H), 3.12-2.98 (m 2H), 2.82-2.67 (m 2H), 1.31 (d 3H) 12 F- 1a LCMS Method: 1, RT: 4.81 min, MI: 487 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.46 (d 1H), 8.31 (dd 1H), 8.04 (dd 1H), 7.68 (d 2H), 7.36 (d 2H), 7.31-7.24 (m 5H), 5.61 (s 2H), 4.90-4.82 (m 1H), 3.11-2.97 (m 2H), 2.83-2.67 (m 2H), 1.31 (d 3H) 13 F- 1a LCMS Method: 1, RT: 4.64 min, MI: 487 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.44 (d 1H), 8.31 (dd 1H), 8.03 (dd 1H), 7.31 (br 4H), 7.31-7.27 (m 3H), 7.04 (tt 2H), 5.54 (s 2H), 4.89 (m 1H), 3.13-3.00 (m 2H), 2.82-2.68 (m 2H), 1.32 (d 3H) 14 F- 1a 0 LCMS Method: 1, RT: 4.42 min, .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.38 (dd 1H), 7.93 (dd 1H), 7.25-7.23 (m 3H), 7.15- 7.13 (m 2H), 7.06 (dt 2H), MI: 485 6.73 (dt 2H), 6.46 (t 1H), [M + 1] 5.54 (s 2H), 4.31 (d 2H), 3.76 (s 3H), 3.15 (t 2H), 2.86 (t 2H) 15 F- 1a LCMS Method: 1, RT: 4.10 min, MI: 503 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.38 (d 1H), 8.30 (dd 1H), 8.01 (dd 1H), 7.32-7.26 (m 7H), 7.05 (tt 2H), 5.53 (s 2H), 4.86 (t 1H), 4.82 (q 1H), 3.52 (t 2H), 3.12-2.99 (m 2H), 2.84-2.71 (m 2H) 16 F- 1a LCMS Method: 1, RT: 4.51 min, MI: 481/483 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.43 (d 1H), 8.32 (dd 1H), 8.03 (dd 1H), 7.51 (dt 2H), 7.31-7.28 (m 3H), 7.14 (dt 2H), 7.04 (tt 2H), 5.49 (s 2H), 4.92-4.85 (m 1H), 3.11-2.98 (m 2H), 2.80-2.67 (m 2H), 1.32 (d 3H) 17 F- 1a LCMS Method: 1, RT: 4.58 min, MI: 499/501 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.45 (d 1H), 8.30 (dd 1H), 8.02 (dd 1H), 7.40-7.27 (m 5H), 7.24-7.20 (m 2H), 7.01-6.98 (m 1H), 5.48 (s 2H), 4.87-4.81 (m 1H), 3.12-2.98 (m 2H), 2.82- 2.67 (m 2H), 1.30 (d 3H) 18 F- 1a LCMS Method: 1, RT: 4.77 min, MI: .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.40 (dd 1H), 7.91 (dd 1H), 7.28-7.23 (m 3H), 7.15- 7.12 (m 4H), 7.06-7.04 (m 489/491 2H), 6.78 (t 1H), 5.53 (s [M + 1] 2H), 4.34 (d 2H), 3.15 (t 2H), 2.87 (t 2H) 19 F- 1a 0 LCMS Method: 1, RT: 2.71 min, .sup.1H-NMR, Method 1: (DMSO) 8.43 (t 1H), 8.31 (dd 1H), 8.02 (dd 1H), 7.33 (br 4H), 7.28 (dd 1H), 7.12 (d 2H), MI: 542 6.80 (d 2H), 5.57 (s 2H), [M + 1] 4.19 (d 2H), 4.00 (t 2H), 3.10 (t 2H), 2.76 (t 2H), 2.62 (t 2H), 2.22 (s 6H) 20 F- 1a LCMS Method: 1, RT: 4.56 min, MI: 569 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.47 (d 1H), 8.31 (dd 1H), 8.02 (dd 1H), 7.41 (d 2H), 7.30 (s 4H), 7.28 (dd 1H), 7.21 (d 2H), 5.54 (s 2H), 4.94 (br 1H), 4.87 (q 1H), 3.58 (d 2H), 3.15-3.01 (m 2H), 2.89-2.74 (m 2H) 21 F- 1a LCMS Method: 1, RT: 4.76 min, MI: 497/499 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.47 (d 1H), 8.34 (dd 1H), 8.05 (dd 1H), 7.51 (dt 2H), 7.32 (dd 1H), 7.28 (s 4H), 7.15 (dt 2H), 5.50 (s 2H), 4.90-4.83 (m 1H), 3.13- 3.00 (m 2H), 2.81-2.68 (m 2H), 1.31 (d 3H) 22 F- 1a LCMS Method: 1, RT: 4.95 min, .sup.1H-NMR, Method 1: (DMSO) 8.56 (t 1H), 8.31 (dd 1H), 8.03 (dd 1H), 7.37-7.31 (m 6H), 7.29 (dd 1H), 7.23- MI: 539 7.21 (m 2H), 5.57 (s 2H), [M + 1] 4.29 (d 2H), 3.11 (t 2H), 2.78 (t 2H) 23 F- 1a LCMS Method: 1, RT: 4.49 min, MI: 553 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.62 (dd 1H), 7.40-7.30 (m 5H), 7.21- 7.10 (m 5H), 5.49 (d 1H), 5.41 (d 1H), 5.12-5.07 (m 1H), 3.94 (ddd 2H), 3.14 (t 2H), 3.00-2.93 (m 1H), 2.84-2.77 (m 1H) 24 F- 1a 0 LCMS Method: 1, RT: 4.34 min, MI: 467 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.46 (d 1H), 8.32 (dd 1H), 8.01 (dd 1H), 7.31-7.26 (m 5H), 7.13-7.07 (m 2H), 6.96 (d 1H), 5.42 (s 2H), 4.91-4.83 (m 1H), 3.78 (s 3H), 3.13-2.99 (m 2H), 2.82-2.67 (m 2H), 1.32 (d 3H) 25 F- 1a LCMS Method: 1, RT: 4.76 min, MI: 481 .sup.1H-NMR, Method 1: (DMSO) 8.35-8.31 (m 2H), 8.01 (dd 1H), 7.38-7.33 (m 4H), 7.29 (dd 1H), 7.24-7.16 (m 2H), 7.14-7.08 (m 2H), [M + 1] 5.61 (s 2H), 5.28 (q 1H), 3.21-3.07 (m 2H), 2.94- 2.87 (m 1H), 2.83-2.68 (m 3H), 2.39-2.31 (m 1H), 1.81-1.72 (m 1H) 26 F- 1c LCMS Method: 1, RT: 2.83 min, MI: 570 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.42 (t 1H), 8.15 (d 1H), 7.81 (d 1H), 7.31 (s 4H), 7.12 (d 2H), 6.80 (d 2H), 5.53 (s 2H), 4.19 (d 2H), 3.97 (t 2H), 3.07 (t 2H), 2.87 (t 2H), 2.74 (t 2H), 2.55 (s 6H), 2.42 (s 3H), 2.01-1.94 (m 2H) 27 F- 1a LCMS Method: 1, RT: 4.46 min, .sup.1H-NMR, Method 1: (DMSO) 8.47 (t 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.36 (s 4H), 7.28 (dd 1H), 7.10 (dd 1H), MI: 503 7.03-6.96 (m 2H), 5.57 (s [M + 1] 2H), 4.21 (d 2H), 3.79 (s 3H), 3.11 (t 2H), 2.77 (t 2H) 28 F- 1a LCMS Method: 1, RT: 3.44 min, MI: 419 [M + 1] .sup.1H-NMR, Method 1: (MeOD) 8.36 (dd 1H), 8.03 (dd 1H), 7.34 (dd 1H), 7.24-7.18 (m 7H), 7.01 (tt 2H), 5.51 (s 2H), 4.96-4.92 (m 1H), 3.74- 3.64 (m 2H), 3.17-3.13 (m 2H), 2.84 (t 2H) 29 F- 1a 0 LCMS Method: 1, RT: 3.13 min, MI: 470 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.49-8.46 (m 2H), 8.31 (dd 1H), 8.03 (dd 1H), 7.62 (td 1H), 7.34 (br 1H), 7.32 (s 4H), 7.29 (dd 1H), 7.20 (ddd 1H), 5.55 (s 2H), 4.96-4.88 (m 1H), 3.15-3.00 (m 2H), 2.87-2.72 (m 2H), 1.36 (d 3H) 30 F- 1a LCMS Method: 1, RT: 4.53 min, .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.40 (dd 1H), 7.93 (dd 1H), 7.28-7.23 (m 3H), 7.15- 7.09 (m 4H), 6.87 (tt 2H), MI: 473 6.66 (t 1H), 5.54 (s 2H), [M + 1] 4.35 (d 2H), 3.16 (t 2H), 2.88 (t 2H) 31 F- 1a LCMS Method: 1, RT: 3.17 min, MI: 498 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.33-8.29 (m 2H), 8.01 (dd 1H), 7.32 (s 4H), 7.27 (dd 1H), 7.00 (d 2H), 6.58 (d 2H), 5.57 (s 2H), 4.12 (d 2H), 3.08 (t 2H), 2.83 (s 6H), 2.73 (t 2H) 32 F- 1a LCMS Method: 1, RT: 4.52 min, MI: 553 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.68 (dd 1H), 7.53 (d 2H), 7.27-7.23 (m 5H), 7.21 (dd 1H), 6.99 (d 2H), 5.55 (d 1H), 5.48 (d 1H), 5.08-5.04 (m 1H), 3.93 (ddd 2H), 3.12 (t 2H), 2.98-2.76 (m 2H) 33 F- 1a LCMS Method: 1, RT: 4.10 min, MI: 503 [M + 1] .sup.1H-NMR, Method 1: (1H 400 CDCl3) 8.38 (dd 1H), 7.83 (dd 1H), 7.29 (dt 2H), 7.23 (dd 1H), 7.18-7.14 (m 2H), 7.09-7.05 (m 3H), 6.97 (tt 2H), 5.45 (s 2H), 5.08-5.04 (m 1H), 3.90 (ddd 2H), 3.23-3.07 (m 2H), 2.92-2.76 (m 2H) 34 F- 1a 00 LCMS Method: 1, RT: 2.70 min, MI: 470 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.55 (d 1H), 8.39 (dd 2H), 8.31 (dd 1H), 8.05 (dd 1H), 7.31 (s 4H), 7.30-7.26 (m 3H), 5.54 (s 2H), 4.89-4.82 (m 1H), 3.15-3.00 (m 2H), 2.89-2.70 (m 2H), 1.33 (d 3H) 35 F- 1a 01 02 LCMS Method: 1, RT: 3.96 min, MI: 471 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.40 (d 1H), 8.30 (dd 1H), 8.01 (dd 1H), 7.39-7.26 (m 7H), 7.01-6.98 (m 1H), 5.48 (s 2H), 4.88 (t 1H), 4.80 (q 1H), 3.53 (t 2H), 3.12-2.99 (m 2H), 2.85- 2.71 (m 2H) 36 F- 1a 03 04 LCMS Method: 1, RT: 4.10 min, MI: 485 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31 (dd 1H), 8.07 (t 1H), 8.01 (dd 1H), 7.36-7.19 (m 10H), 5.57 (s 2H), 5.45 (br 1H), 4.59 (t 1H), 3.29-3.23 (m 2H), 3.06-3.00 (m 2H), 2.71-2.68 (m 2H) 37 F- 1a 05 06 LCMS Method: 1, RT: 4.10 min, MI: 485 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.97 (d 1H), 7.35-7.33 (m 2H), 7.31- 7.28 (m 2H), 7.25-7.21 (m 4H), 7.17-7.15 (m 2H), 6.52 (br 1H), 5.55 (d 1H), 5.48 (d 1H), 4.87 (dd 1H), 3.77-3.71 (m 1H), 3.31- 3.17 (m 2H), 3.12-3.05 (m 1H), 2.86-2.74 (m 2H) 38 F- 1a 07 08 LCMS Method: 1, RT: 4.93 min, MI: 495 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (d 1H), 8.32 (dd 1H), 8.00 (dd 1H), 7.37-7.32 (m 4H), 7.29 (dd 1H), 7.14- 6.99 (m 4H), 5.60 (s 2H), 4.96 (m 1H), 3.21-3.05 (m 2H), 2.83-2.66 (m 4H), 1.86-1.84 (m 2H), 1.73- 1.59 (m 2H) 39 F- 1a 09 0 LCMS Method: 1, RT: 4.25 min, MI: 521 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.38 (dd 1H), 7.82 (dd 1H), 7.28 (dt 2H), 7.24 (dd 1H), 7.11-6.98 (m 5H), 6.93- 6.89 (m 1H), 5.44 (d 1H), 5.40 (d 1H), 5.08-5.04 (m 1H), 3.91 (ddd 2H), 3.22- 3.07 (m 2H), 2.96-2.79 (m 2H) 40 F- 1a LCMS Method: 2, RT: 7.8 min, MI: 503/505 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.47 (d 1H), 8.31 (dd 1H), 8.03 (dd 1H), 7.31-7.25 (m 9H), 5.53 (s 2H), 4.90-4.83 (m 1H), 3.13-2.99 (m 2H), 2.83-2.69 (m 2H), 1.31 (d 3H) 41 F- 1a LCMS Method: 1, RT: 4.27 min, MI: 498 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.35 (dd 1H), 7.91 (dd 1H), 7.34-7.32 (m 2H), 7.28- 7.15 (m 8H), 6.34 (d 1H), 5.58 (d 1H), 5.45 (d 1H), 4.91 (d 1H), 4.34-4.26 (m 1H), 3.31-3.23 (m 1H), 3.07-3.00 (m 1H), 2.86- 2.71 (m 2H), 0.96 (d 3H) 42 F- 1a LCMS Method: 1, RT: 4.86 min, .sup.1H-NMR, Method 1: (DMSO) 8.30 (dd 1H), 7.98 (dd 1H), 7.90 (t 1H), 7.33 (br 4H), 7.27 (dd 1H), 5.57 (s 2H), MI: 461 3.05 (t 2H), 2.87 (t 2H), [M + 1] 2.68 (t 2H), 1.60-1.57 (m 5H), 1.35-1.26 (m 1H), 1.15-1.03 (m 3H), 0.82-0.73 (m 2H) 43 F- 1a LCMS Method: 1, RT: 4.83 min, MI: 576 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.95 (dd 1H), 7.25-7.23 (m 3H), 7.16- 7.14 (m 2H), 6.04 (d 1H), 5.57 (d 1H), 5.50 (d 1H), 4.05 (br 2H), 3.87-3.78 (m 1H), 3.20-3.04 (m 2H), 2.83-2.79 (m 2H), 2.54- 2.48 (m 2H), 1.53-1.50 (m 2H), 1.44 (s 9H), 1.43-1.33 (m 1H), 1.17-1.05 (m 2H), 1.02 (d 3H) 44 F- 1a 0 LCMS Method: 1, RT: 4.24 min, MI: 425 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.48 (d 1H), 8.34 (dd 1H), 8.00 (dd 1H), 7.43 (dd 1H), 7.32-7.27 (m 5H), 7.11 (dd 1H), 6.97 (dd 1H), 5.66 (s 2H), 4.92-4.85 (m 1H), 3.22-3.08 (m 2H), 2.83- 2.69 (m 2H), 1.32 (d 3H) 45 F- 1a LCMS Method: 1, RT: 3.80 min, MI: 506 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.29 (m 2H), 8.01 (dd 1H), 7.40-7.30 (m 2H), 7.28 (dd 1H), 7.10 (d 2H), 7.01-6.97 (m 1H), 6.79 (d 2H), 5.49 (s 2H), 4.85-4.78 (m 1H), 3.72 (t 4H), 3.08- 3.01 (m 6H), 2.79-2.66 (m 2H), 1.29 (d 3H) 46 F- 1a LCMS Method: 1, RT: 3.88 min, MI: 449 .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.35 (dd 1H), 8.01 (dd 1H), 7.31-7.20 (m 5H), 7.15- 7.04 (m 2H), 6.97-6.94 (m 1H), 6.44 (d 1H), 5.52 (d [M + 1] 1H), 5.39 (d 1H), 5.39-5.36 (m 1H), 4.73 (dt 1H), 3.46- 3.39 (m 1H), 3.18-3.13 (m 1H), 3.05-2.96 (m 2H), 2.87-2.76 (m 2H) 47 F- 1a LCMS Method: 1, RT: 3.57 min, MI: 437 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.38 (d 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.33-7.23 (m 5H), 7.14 (tt 2H), 7.06 (tt 2H), 5.49 (s 2H), 4.87 (t 1H), 4.82 (q 1H), 3.53 (t 2H), 3.12-2.99 (m 2H), 2.83-2.70 (m 2H) 48 F- 1a LCMS Method: 1, RT: 3.77 min, MI: 469 [M + 1] — 49 F- 1a 0 LCMS Method: 1, RT: 4.93 min, MI: 503 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.48 (d 1H), 8.32 (dd 1H), 8.04 (dd 1H), 7.31-7.25 (m 9H), 5.54 (s 2H), 4.90-4.83 (m 1H), 3.12-3.02 (m 2H), 2.83-2.71 (m 2H), 1.31 (d 3H) 50 F- 1a LCMS Method: 1, RT: 3.74 min, MI: 455 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.38 (d 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.40-7.27 (m 5H), 7.05 (tt 2H), 7.02-6.98 (m 1H), 5.49 (s 2H), 4.86 (t 1H), 4.82 (q 1H), 3.53 (t 2H), 3.11-3.02 (m 2H), 2.85-2.72 (m 2H) 51 F- 1a LCMS Method: 1, RT: 4.72 min, MI: 562 [M + 1] — 52 F- 1c LCMS Method: 1, RT: 4.53 min, .sup.1H-NMR, Method 1: (DMSO) 8.46 (t 1H), 8.15 (d 1H), 7.81 (d 1H), 7.32 (s 4H), 7.09 (dd 1H), 7.03-6.95 (m 2H), MI: 517 5.53 (s 2H), 4.20 (d 2H), [M + 1] 3.80 (s 3H), 3.08 (t 2H), 2.75 (t 2H), 2.42 (s 3H) 53 F- 1c LCMS Method: 1, RT: 4.45 min, .sup.1H-NMR, Method 1: (DMSO) 8.41 (t 1H), 8.15 (d 1H), 7.82 (d 1H), 7.31 (s 4H), 7.11 (d 2H), 6.79 (d 2H), 5.53 (s MI: 499 2H), 4.18 (d 2H), 3.70 (s [M + 1] 3H), 3.06 (t 2H), 2.73 (t 2H), 2.42 (s 3H) 54 F- 1a 0 LCMS Method: 1, RT: 4.80 min, MI: 562 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.38 (dd 1H), 7.99 (d 1H), 7.26-7.23 (m 3H), 7.15- 7.13 (m 2H), 6.57 (br 1H), 5.55 (s 2H), 3.70 (d 1H), 3.60 (br 1H), 3.20 (br 1H), 3.15 (t 2H), 2.99 (br 1H), 2.85 (t 2H), 2.72 (br 1H), 2.48 (br 2H), 1.69-1.53 (m 2H), 1.43 (s 9H), 1.38-1.27 (m 1H), 1.15 (br 1H) 55 F- 1a LCMS Method: 1, RT: 4.35 min, MI: 433 .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.38 (dd 1H), 7.92 (dd 1H), 7.25 (dd 1H), 7.22-7.17 (m 2H), 7.14-7.03 (m 4H), 6.99-6.96 (m 1H), 6.34 (d [M + 1] 1H), 5.54 (d 1H), 5.49 (d 1H), 5.41 (q 1H), 3.23-3.09 (m 2H), 2.95-2.78 (m 4H), 2.55-2.48 (m 1H), 1.77- 1.68 (m 1H) 56 F- 1a LCMS Method: 1, RT: 3.97 min, MI: 477 .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.95 (dd 1H), 7.26-7.22 (m 3H), 7.16- 7.14 (m 2H), 6.01 (d 1H), 5.57 (d 1H), 5.50 (d 1H), [M + 1] 3.90-3.79 (m 3H), 3.26- 3.05 (m 4H), 2.87-2.75 (m 2H), 1.50-1.38 (m 3H), 1.33-1.16 (m 2H), 1.03 (d 3H) 57 F- 1a LCMS Method: 1, RT: 4.65 min, .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.39 (dd 1H), 7.92 (dd 1H), 7.28-7.24 (m 1H), 7.17- 7.01 (m 6H), 6.97-6.94 (m MI: 491 1H), 6.60 (t 1H), 5.48 (s [M + 1] 2H), 4.40 (d 2H), 3.15 (t 2H), 2.89 (t 2H) 58 F- 1a LCMS Method: 1, RT: 2.67 min, MI: 432 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.33-8.31 (m 2H), 8.00 (dd 1H), 7.29-7.25 (m 3H), 7.15 (tt 2H), 7.01 (d 2H), 6.60 (d 2H), 5.52 (s 2H), 4.13 (d 2H), 3.08 (t 2H), 2.84 (s 6H), 2.72 (t 2H) 59 F- 1a 0 LCMS Method: 1, RT: 3.76 min, MI: 449 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.39 (dd 1H), 7.95 (dd 1H), 7.34 (d 1H), 7.28-7.19 (m 3H), 7.15-7.03 (m 3H), 6.98-6.95 (m 1H), 5.49 (s 2H), 5.06 (t 1H), 4.36 (q 1H), 3.27 (dd 1H), 3.18 (t 2H), 3.05-2.88 (m 3H) 60 F- 1a LCMS Method: 1, RT: 4.35 min, .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.98 (dd 1H), 7.25-7.22 (m 3H), 7.15- 7.13 (m 2H), 5.98 (d 1H), MI: 433 5.54 (s 2H), 3.39-3.29 (m [M + 1] 1H), 3.13 (td 2H), 2.86- 2.74 (m 2H), 1.11 (d 3H), 0.77-0.68 (m 1H), 0.45- 0.39 (m 1H), 0.33-0.26 (m 1H), 0.21-0.10 (m 2H) 61 F- 1d LCMS Method: 1, RT: 5.64 min, MI: 580/582 [M + 1] — 62 F- 1a LCMS Method: 1, RT: 3.81 min, .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.40 (dd 1H), 7.97 (dd 1H), 7.28-7.25 (m 3H), 7.17- 7.15 (m 2H), 6.30 (br 1H), MI: 463 5.56 (s 2H), 3.87 (dd 2H), [M + 1] 3.25 (td 2H), 3.17-3.09 (m 4H), 2.85 (t 2H), 1.70-1.58 (m 1H), 1.49-1.45 (m 2H), 1.30-1.16 (m 2H) 63 F- 1a LCMS Method: 1, RT: 2.76 min, MI: 450 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.33-8.29 (m 2H), 8.01 (dd 1H), 7.41-7.32 (m 2H), 7.28 (dd 1H), 7.03-6.99 (m 3H), 6.59 (d 2H), 5.52 (s 2H), 4.13 (d 2H), 3.08 (t 2H), 2.83 (s 6H), 2.73 (t 2H) 64 F- 1a 0 LCMS Method: 1, RT: 3.44 min, MI: 419 [M + 1] .sup.1H-NMR, Method 1: (MeOD) 8.36 (dd 1H), 8.03 (dd 1H), 7.34 (dd 1H), 7.22-7.18 (m 7H), 7.01 (tt 2H), 5.51 (s 2H), 4.96-4.93 (m 1H), 3.74-3.64 (m 2H), 3.17- 3.13 (m 2H), 2.84 (t 2H) 65 F- 1a LCMS Method: 1, RT: 3.72 min, MI: 437 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.36 (dd 1H), 7.93 (dd 1H), 7.35-7.33 (m 2H), 7.30- 7.28 (m 2H), 7.25-7.19 (m 2H), 7.14-7.07 (m 1H), 7.06-7.01 (m 1H), 6.96- 6.93 (m 1H), 6.56 (t 1H), 5.49 (d 1H), 5.42 (d 1H), 4.86 (dd 1H), 3.76-3.70 (m 1H), 3.30-3.14 (m 2H), 3.10-3.03 (m 1H), 2.86- 2.74 (m 2H) 66 F- 1a LCMS Method: 1, RT: 4.81 min, MI: 562 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.36 (dd 1H), 7.98 (d 1H), 7.25-7.21 (m 3H), 7.15- 7.13 (m 2H), 6.57 (br 1H), 5.54 (s 2H), 3.70 (dd 1H), 3.61 (br 1H), 3.22 (br 1H), 3.13 (t 2H), 2.96 (br 1H), 2.84 (t 2H), 2.71 (br 1H), 2.25 (br 1H), 1.68-1.53 (m 3H), 1.43 (s 9H), 1.38-1.27 (m 1H), 1.15 (br 1H) 67 F- 1a LCMS Method: 1, RT: 3.70 min, MI: 437 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.97 (dd 1H), 7.35-7.27 (m 4H), 7.25- 7.22 (m 2H), 7.14-7.02 (m 2H), 6.97-6.94 (m 1H), 6.49 (t 1H), 5.50 (d 1H), 5.43 (d 1H), 4.87 (dd 1H), 3.77-3.71 (m 1H), 3.31- 3.16 (m 2H), 3.12-3.04 (m 1H), 2.87-2.75 (m 2H) 68 F- 1a LCMS Method: 1, RT: 2.57 min, MI: 404 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.49-8.47 (m 2H), 8.31 (dd 1H), 8.02 (dd 1H), 7.62 (td 1H), 7.33 (d 1H), 7.29-7.24 (m 3H), 7.21 (ddd 1H), 7.14 (tt 2H), 5.49 (s 2H), 4.95- 4.88 (m 1H), 3.14-3.00 (m 2H), 2.85-2.71 (m 2H), 1.36 (d 3H) 69 F- 1a 0 LCMS Method: 1, RT: 4.31 min, .sup.1H-NMR, Method 1: (DMSO) 12.24 (s 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.46 (d 1H), 7.38-7.33 (m 4H), 7.27 (dd MI: 448 1H), 7.18 (d 1H), 5.60 [M + 1] (s 2H), 3.20 (t 2H), 3.08 (t 2H) 70 F- 1d LCMS Method: 1, RT: 5.23 min, MI: 515/517 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.45 (d 1H), 8.41 (d 1H), 8.29 (d 1H), 7.30-7.23 (m 6H), 7.14 (tt 2H), 5.47 (s 2H), 4.90-4.82 (m 1H), 3.12-2.99 (m 2H), 2.80- 2.67 (m 2H), 1.31 (d 3H) 71 F- 1a LCMS Method: 1, RT: 4.46 min, .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.40 (dd 1H), 7.99 (dd 1H), 7.28 (dd 1H), 7.14-7.03 (m 2H), 7.00-6.97 (m 1H), MI: 413 6.13 (br 1H), 5.52 (s 2H), [M + 1] 3.16 (t 2H), 3.05 (t 2H), 2.85 (t 2H), 1.63-1.56 (m 5H), 1.40-1.31 (m 1H), 1.16- 1.03 (m 3H), 0.86-0.77 (m 2H) 72 F- 1a LCMS Method: 1, RT: 2.80 min, MI: 422 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.45 (dd 1H), 8.35 (dd 1H), 7.98 (dd 1H), 7.59 (td 1H), 7.24 (dd 1H), 7.17-6.99 (m 5H), 6.95-6.92 (m 1H), 5.48 (s 2H), 5.11-5.04 (m 1H), 3.13 (t 2H), 2.91 (t 2H), 1.41 (d 3H) 73 F- 1a LCMS Method: 1, RT: 3.98 min, .sup.1H-NMR, Method 1: (DMSO) 12.71 (s 1H), 9.14 (s 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.38-7.33 (m 4H), 7.27 (dd MI: 449 1H), 5.60 (s 2H), 3.22 [M + 1] (t 2H), 3.13 (t 2H) 74 F- 1a 0 LCMS Method: 1, RT: 4.74 min, MI: 521 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.41 (t 1H), 8.33 (dd 1H), 8.04 (dd 1H), 7.41-7.33 (m 2H), 7.31 (dd 1H), 7.20 (d 1H), 7.06-7.02 (m 1H), 6.94 (d 1H), 6.73 (dq 1H), 5.52 (s 2H), 4.19 (d 2H), 3.81 (s 3H), 3.12 (t 2H), 2.80 (t 2H) 75 F- 1a LCMS Method: 1, RT: 2.61 min, MI: 408 .sup.1H-NMR, Method 1: (DMSO) 8.61 (t 1H), 8.46 (dd 1 H), 8.32 (dd 1H), 8.04 (dd 1H), 7.64 (td 1H), 7.42-7.33 (m 2H), 7.31-7.27 (m 2H), [M + 1] 7.24-7.21 (m 1H), 7.05- 7.02 (m 1H), 5.52 (s 2H), 4.35 (d 2H), 3.12 (t 2H), 2.82 (t 2H) 76 F- 1a LCMS Method: 1, RT: 5.02 min, MI: 525 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.47 (d 1H), 8.36 (dd 1H), 8.04 (dd 1H), 7.43-7.29 (m 10H), 7.17 (d 2H), 6.95 (d 2H), 5.45 (s 2H), 5.05 (s 2H), 4.91-4.83 (m 1H), 3.14-3.04 (m 2H), 2.81- 2.68 (m 2H), 1.32 (d 3H) 77 F- 1a LCMS Method: 1, RT: 4.49 min, MI: 462 .sup.1H-NMR, Method 1: (DMSO) 12.15 (br 1H), 8.31 (d 1H), 8.01 (d 1H), 7.35 (br 4H), 7.28-7.24 (m 1H), 6.71 (s 1H), 5.59 (s 2H), [M + 1] 3.19 (t 2H), 3.05 (t 2H), 2.25 (s 3H) 78 F- 1a LCMS Method: 1, RT: 3.81 min, .sup.1H-NMR, Method 1: (DMSO) 11.31 (br 1H), 8.30 (dd 1H), 8.01 (dd 1H), 7.83 (d 1H), 7.34 (s 4H), 7.26 (dd 1H), MI: 432 7.07 (d 1H), 5.59 (s 2H), [M + 1] 3.17-3.12 (m 2H), 3.06- 2.97 (m 2H) 79 F- 1e 0 LCMS Method: 1, RT: 4.34 min, MI: 451 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.44 (d 1H), 7.89 (d 1H), 7.31-7.19 (m 6H), 7.16- 7.12 (m 3H), 5.44 (s 2H), 4.90-4.82 (m 1H), 3.05- 2.92 (m 2H), 2.77-2.63 (m 2H), 2.57 (s 3H), 1.31 (d 3H) 80 F- 1a LCMS Method: 1, RT: 4.77 min, MI: 509 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.44 (d 1H), 8.34 (dd 1H), 8.02 (dd 1H), 7.43-7.35 (m 4H), 7.33-7.27 (m 4H), 7.16 (dt 2H), 7.05 (tt 2H), 6.95 (dt 2H), 5.43 (s 2H), 5.05 (s 2H), 4.93-4.86 (m 1H), 3.14-3.00 (m 2H), 2.80-2.67 (m 2H), 1.32 (d 3H) 81 F- 1a LCMS Method: 1, RT: 4.50 min, .sup.1H-NMR, Method 1: (DMSO) 12.04 (br 1H), 8.31 (d 1H), 8.01 (d 1H), 7.35 (br 4H), 7.27 (dd 1H), 7.11 (d 1H), MI: 462 5.60 (s 2H), 3.19 (t 2H), [M + 1] 3.04 (t 2H), 2.31 (br 3H) 82 F- 1a LCMS Method: 1, RT: 2.58 min, MI: 408 .sup.1H-NMR, Method 1: (DMSO) 8.61 (t 1H), 8.46 (dq 1H), 8.32 (dd 1H), 8.04 (dd 1H), 7.64 (td 1H), 7.42-7.33 (m 2H), 7.31-7.27 (m 2H), [M + 1] 7.24-7.21 (m 1H), 7.05- 7.02 (m 1H), 5.52 (s 2H), 4.35 (d 2H), 3.12 (t 2H), 2.82 (t 2H)

General Synthesis of 3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-5 (Scheme 002-B)

(137) ##STR00197##

(138) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-6, was treated with CDI and the required amine 2 in DMF at r.t. to afford the final compounds of general formula F-5.

(139) F-1 could be any of the following intermediates:

(140) ##STR00198##

(141) The above synthesis (Scheme 002-A) is illustrated by the preparation of N—[(S)-1-(4-bromo-phenyl)-ethyl]-3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 83) described below.

Synthesis of N—[(S)-1-(4-bromo-phenyl)-ethyl]-3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 83)

(142) ##STR00199##

(143) In a round bottom flask fitted with a magnetic stirrer, 3-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionic acid (500 mg, 1.67 mmol) and CDI (410 mg, 2.51 mmol) were dissolved in anhydrous DMF (7 ml) and stirred at r.t. for 30 min. (S)-(−)-1-(4-bromophenyl)ethylamine (670 mg, 3.34 mmol) was then added and the reaction stirred over the weekend at r.t. Reaction mixture was quenched with water (30 ml) and extracted with EtOAc (40 ml×2). Organic phases were combined, washed with brine (30 ml), dried and concentrated under reduced pressure to afford a brown oily crude material which was purified on silica gel by column chromatography with a gradient of MeOH and DCM, product eluted with 3% MeOH. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (688 mg, 86%).

(144) The following compounds of general formula F-5 were prepared according to the general synthesis shown in Scheme 002-B:

(145) TABLE-US-00003 Example SM Amine 1 Amine 2 Characterisation 83 F-1a 00 01 LCMS Method: 1, RT: 4.47 min, MI: 481/483 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.45 (d 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.40 (dt 2H), 7.29-7.21 (m 5H), 7.13 (tt 2H), 5.48 (s 2H), 4.88-4.80 (m 1H), 3.11- 2.97 (m 2H), 2.80-2.66 (m 2H), 1.30 (d 3H) 84 F-1a 02 03 LCMS Method: 1, RT: 4.19 min, MI: 449 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.46 (d 1H), 8.32 (d 1H), 8.00 (d 1H), 7.31- 7.26 (m 5H), 7.15 (d 2H), 6.86 (d 2H), 5.42 (s 2H), 4.91-4.84 (m 1H), 3.70 (s 3H), 3.11-2.98 (m 2H), 2.80-2.66 (m 2H), 1.32 (d 3H) 85 F-1a 04 05 LCMS Method: 4, RT: 1.19 min, MI: 436 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.29 (dd 1H), 7.99 (dd 1H), 7.38-7.26 (m 3H), 7.12 (d 2H), 7.04-6.97 (m 3H), 5.49 (s 2H), 4.89-4.80 (m 1H), 3.08-3.03 (m 2H), 2.76-2.70 (m 2H), 2.23 (s 3H), 1.28 (d 3H) 86 F-1a 06 07 LCMS Method: 4, RT: 1.14 min, MI: 422 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.44-8.39 (m 2H), 8.29 (dd 1H), 7.99 (dd 1H), 7.19-7.16 (m 8H), 7.02- 6.98 (m 1H), 5.49 (s 2H), 4.93-4.84 (m 1H), 3.09- 3.04 (m 2H), 2.78-2.72 (m 2H), 1.31 (d 3H) 87 F-1a 08 09 LCMS Method: 1, RT: 4.04 min, MI: 403 [M + 1] .sup.1H-NMR, Method 1: (MeOD) 8.41 (d 1H), 8.30 (dd 1H), 8.00 (dd 1H), 7.30-7.21 (m 5H), 7.12 (tt 2H), 7.03 (tt 2H), 5.47 (s 2H), 4.90- 4.83 (m 1H), 3.10-2.96 (m 2H), 2.78-2.64 (m 2H), 1.30 (d 3H) 88 F-1a 0 LCMS Method: 1, RT: 4.09 min, MI: 421 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.42 (d 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.31- 7.23 (m 5H), 7.13 (tt 2H), 7.04 (tt 2H), 5.48 (s 2H), 4.91-4.84 (m 1H), 3.11- 2.98 (m 2H), 2.79-2.66 (m 2H), 1.31 (d 3H) 89 F-1a LCMS Method: 4, RT: 1.20 min, MI: 436 [M + 1] .sup.1H-NMR: Method 1: (DMSO) 8.34 (br d 1H), 8.29 (dd 1H), 7.97 (dd 1H), 7.38-7.18 (m 8H), 7.02- 6.99 (m 1H), 5.48 (s 2H), 4.70-4.62 (m 1H), 3.08- 3.03 (m 2H), 2.78-2.73 (m 2H), 1.67-1.61 (m 2H), 0.78 (t 3H) 90 F-1a LCMS Method: 4, RT: 1.17 min, MI: 430 [M + 1] .sup.1H-NMR; Method 1: (DMSO) 8.37-8.30 (m 2H), 8.01-7.97 (m 1H), 7.29- 7.24 (m 1H), 7.17-7.13 (m 4H), 7.06-7.02 (m 2H), 6.89-6.84 (m 2H), 5.42 (s 2H), 4.90-4.83 (m 1H), 3.70 (s 3H), 3.11-3.01 (m 2H), 2.78-2.66 (m 2H), 2.25 (s 3H), 1.30 (d 3H) 91 F-1b LCMS Method: 4, RT: 1.11 min, MI: 449 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.41 (t 1H), 7.41 (d 1H), 7.15 (m 5H), 6.88 (d 2H), 6.79 (d 2H), 4.20 (d 2H), 3.70 (s 3H), 3.32 (s 3H), 3.09 (t 2H), 2.74 (t 2H) 92 F-1a LCMS Method: 1, RT: 3.90 min, MI: 415 [M + 1] .sup.1H-NMR, Method 1: (MeOD) 8.36 (dd 1H), 8.01 (dd 1H), 7.34 (dd 1H), 7.20-7.16 (m 5H), 7.11 (dt 2H), 6.83 (dt 2H), 5.46 (s 2H), 4.94 (q 1H), 3.73 (s 3H), 3.19- 3.05 (m 2H), 2.75 (t 2H), 1.39 (d 3H) 93 F-1a 0 LCMS Method: 4, RT: 1.16 min, MI: 430 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.38-8.30 (m 2H), 8.00-7.95 (m 1H), 7.30- 7.11 (m 8H), 6.89-6.83 (m 2H), 5.42 (s 2H), 4.72-4.63 (m 1H), 3.70 (s 3H), 3.04 (t 2H), 2.74 (t 2H), 1.70-1.59 (m 2H), 0.81 (t 3H) 94 F-1a LCMS Method: 1, RT: 3.98 min, MI: 407 [M + 1] .sup.1H-NMR, Method 1: (MeOD) 8.36 (dd 1H), 8.00 (dd 1H), 7.34 (dd 1H), 7.26-7.22 (m 2H), 7.19-7.16 (m 2H), 7.03 (tt 2H), 6.91 (tt 2H), 5.56 (s 2H), 4.30 (br 2H), 3.16 (t 2H), 2.79 (t 2H) 95 F-1a LCMS Method: 4, RT: 1.14 min, MI: 440 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.42 (d 1H), 8.30 (d 1H), 8.00 (d 1H), 7.35- 7.27 (m, rotameric forms 4H), 7.16-7.00 (m, rotameric forms 3H), 6.26 (d 1H), 5.49 (s 2H), 4.71-4.67 (m, rotameric forms 1H), 3.10-2.95 (m 2H), 2.78- 2.70 (m 2H), 1.32-1.26 (m 3H) 96 F-1a LCMS Method: 4, RT: 1.12 min, MI: 434 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.42 (br d 1H), 8.33-8.30 (m 1H), 8.02- 7.98 (m 1H), 7.33-7.01 (m 7H), 6.89-6.84 (m 2H), 5.42 (s 2H), 4.92-4.85 (m 1H), 3.70 (s 3H), 3.12-3.00 (m 2H), 2.82-2.65 (m 2H), 1.31 (d 3H) 97 F-1a LCMS Method: 4, RT: 1.06 min, MI: 420 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.38 (t 1H), 8.30 (dd 1H), 7.99 (dd 1H), 7.10 (m 7H), 6.78 (d 2H), 5.52 (s 2H), 4.18 (d 2H), 3.71 (s 3H), 3.07 (t 2H), 2.72 (t 2H) 98 F-1a 0 LCMS Method: 4, RT: 1.17 min, MI: 484 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.38 (m 3H), 8.02 (d 1H), 7.32 (m 7H), 6.79 (m 2H), 5.60 (m 2H), 4.20 (m 2H), 3.71 (s 3H), 3.10 (m 2H), 2.75 (m, 2H) 99 F-1a LCMS Method: 4, RT: 1.23 min, MI: 444 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.38-8.30 (m 2H), 7.95- 7.99 (m 1H), 7.30-7.11 (m 8H), 6.89-6.83 (m 2H), 5.42 (s 2H), 4.81-4.72 (m 1H), 3.70 (s 3H), 3.08-3.01 (m 2H), 2.79-2.67 (m 2H), 1.65-1.51 (m 2H), 1.34- 1.10 (m 2H), 0.81 (t 3H) 100 F-1a LCMS Method: 4, RT: 1.09 min, MI: 437 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.38 (t 1H), 8.30 (dd 1H), 7.99 (dd 1H), 7.26 (m 3H), 7.11 (d 2H), 7.01 (m 1H), 6.78 (d 2H), 5.52 (s 2H), 4.18 (d 2H), 3.71 (s 3H), 3.08 (t 2H), 2.73 (t 2H) 101 F-1f LCMS Method: 4, RT: 1.15 min, MI: 449 [M + 1] .sup.1H-NMR; Method 1: (DMSO) 8.40 (t 1H), 8.34 (t 1H), 7.95 (dd 1H), 7.17 (d 2H), 7.14 (d 2H), 6.87 (d 2H), 6.81 (d 2H), 5.44 (s 2H), 4.18 (d 2H), 3.71 (s 3H), 3.70 (s 3H), 3.09 (t 2H), 2.72 (t 2H) 102 F-1a LCMS Method: 4, RT: 1.13 min, MI: 415 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.29 (m 1H), 7.97 (m 1H), 7.19 (m 6H), 6.86 (d 2H), 4.51 and 5.47 (2 x s, rotamers 2H), 3.70 (s 3H), 3.08 (m 2H), 2.95 (m 5H) 103 F-1a 0 LCMS Method: 4, RT: 1.11 min, MI: 415 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.37 (t 1H), 8.30 (dd 1H), 7.98 (dd 1H), 7.25 (dd 2H), 7.07 (m 6H), 6.78 (d 2H), 5.48 (s 2H), 4.18 (d 2H), 3.71 (s 3H), 2.75 (t 2H), 2.70 (t 2H), 2.25 (s 3H) 104 F-1a LCMS Method: 4, RT: 1.20 min, MI: 429 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.32-8.30 (m 1H), 8.01-7.96 (m 1H), 7.42- 7.17 (m 8H), 6.88 (d 2H), 5.49 (s 2H), 5.28, 5.78 (q 1H), 3.70 (s 3H), 3.25-2.70 (m 4H), 2.68 (s 3H), 1.54 (3H d) 105 F-1a LCMS Method: 4, RT: 1.08 min, MI: 454 [M + 1] — 106 F-1a LCMS Method: 4, RT: 1.10 min, MI: 415 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.35 (t 1H), 8.30 (d 1H), 7.98 (d 1H), 7.25 (d 1H), 7.02 (m 6H), 6.86 (d 2H), 5.45 (s 2H), 4.22 (d 2H), 3.70 (s 3H), 3.07 (t 2H), 2.73 (t 2H), 2.21 (s 3H) 107 F-1a LCMS Method: 4, RT: 1.09 min, MI: 437 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.54 (t 1H), 8.31 (dd 1H), 7.97 (dd 1H), 7.10 (m 6H), 6.86 (d 2H), 5.45 (s 2H), 4.25 (d 2H), 3.70 (s 3H), 3.09 (t 2H), 2.74 (t 2H) 108 F-1a 0 LCMS Method: 4, RT: 1.15 min, MI: 430 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.33-8.30 (m 1H), 8.04-7.96 (m 2H), 7.28- 7.23 (m 1H), 7.18-7.14 (m 2H), 7.07-7.01 (m 4H), 6.91-6.85 (m 2H), 5.45 (s 2H), 3.71 (s 3H), 3.33-3.18 (m 2H), 3.07-2.99 (m 2H), 2.74-2.60 (m 4H), 2.24 (s 3H) 109 F-1c LCMS Method: 1, RT: 3.89 min, MI: 433 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.40 (t 1H), 8.16 (d 1H), 7.81 (d 1H), 7.27-7.23 (m 2H), 7.17-7.11 (m 4H), 6.80 (dt 2H), 5.48 (s 2H), 4.19 (d 2H), 3.71 (s 3H), 3.06 (t 2H), 2.72 (t 2H), 2.42 (s 3H) 110 F-1a LCMS Method: 4, RT: 1.06 min, MI: 419 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.38 (t 1H), 8.30 (dd 1H), 8.00 (dd 1H), 7.33 (m 1H), 7.26 (dd 2H), 6.99 (m 5H), 6.78 (d 2H), 5.56 (s 2H), 4.18 (d 2H), 3.71 (s 3H), 3.07 (t 2H), 2.73 (t 2H) 111 F-1a LCMS Method: 1, RT: 4.18 min, MI: 377 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30 (d 1H), 7.97 (d 1H), 7.89 (t 1H), 7.34- 7.24 (m 4H), 7.20-7.18 (m 2H), 5.54 (s 2H), 3.04 (t 2H), 2.87 (t 2H), 2.66 (t 2H), 1.60-1.58 (m 5H), 1.36- 1.26 (m 1H), 1.15-1.04 (m 3H), 0.82-0.74 (m 2H) 112 F-1a LCMS Method: 4, RT: 1.09 min, MI: 415 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 1.31 (d 3H), 2.72 (m 2H), 3.03 (m 2H), 3.70 (s 3H), 4.84 (m 1H), 5.42 (s 2H), 6.85 (d 2H), 7.14 (m 8H), 7.98 (dd 1H), 8.30 (dd 1H), 8.38 (d 1H) 113 F-1a 0 LCMS Method: 4, RT: 0.98 min, MI: 353 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.29 (dd 1H), 7.96 (dd 1H), 7.78 (d 1H), 7.23 (dd 2H), 7.15 (d 2H), 6.87 (d 2H), 5.45 (s 2H), 3.76 (m 1H), 3.71 (s 3H), 3.01 (t 2H), 2.60 (t 2H), 1.01 (d 6H) 114 F-1a LCMS Method: 4, RT: 1.07 min, MI: 419 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.50 (t 1H), 8.31 (dd 1H), 7.98 (dd 1H), 7.04 (m 7H), 6.86 (d 2H), 5.44 (s 2H), 4.29 (d 2H), 3.70 (s 3H), 3.07 (t 2H), 2.74 (t 2H) 115 F-1a LCMS Method: 4, RT: 1.11 min, MI: 415 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.45 (t 1H), 8.30 (dd 1H), 7.97 (m 1H), 7.24 (dd 1H), 7.00 (m 6H), 6.86 (d 2H), 5.45 (s 2H), 4.22 (d 2H), 3.70 (s 3H), 3.07 (t 2H), 2.73 (t 2H), 2.22 (s 3H) 116 F-1a LCMS Method: 4, RT: 1.08 min, MI: 446 [M + 1] .sup.1H-NMR; Method 2: (DMSO) 8.30 (dd 1H), 7.96 (m 2H), 7.23 (dd 1H), 7.15 (d 2H), 7.07 (d 2H), 6.87 (d 2H), 6.78 (d 2H), 5.45 (s 2H), 3.71 (s 3H), 3.70 (s 3H), 3.18 (m 2H), 3.02 (t 2H), 2.59 (m 4H) 117 F-1a LCMS Method: 4, RT: 1.07 min MI: 420 .sup.1H-NMR, Method 2: (DMSO) 8.52 (t 1H), 8.31 (dd 1H), 7.97 (dd 1H), 7.24 (m 2H), 7.17 (d 2H), 6.99 (m 3H), 6.86 (d 2H), 5.45 (s 2H), 4.41 (d 2H), 3.70 (s 3H), 3.09 (t 2H), 2.75 (t 2H) 118 F-1a 0 LCMS Method: 4, RT: 1.13 min MI: 416 .sup.1H-NMR, Method 2: (DMSO) 8.38 (t 1H), 8.30 (dd 1H), 7.99 (dd 1H), 7.25 (dd 2H), 6.94 (m 6H), 6.78 (d 2H), 5.49 (s 2H), 4.18 (d 2H), 3.71 (s 3H), 3.05 (t 2H), 2.71 (t 2H), 2.24 (s 3H) 119 F-1a LCMS Method: 4, RT: 1.17 min MI: 434 .sup.1H-NMR: Method 2: (DMSO) 8.32-8.30 (m 1H), 8.03-8.00 (m 1H), 7.39- 7.08 (m 7H), 6.89-6.86 (m 2H), 5.48, (s 2H), 4.60 and 4.48 (s 2H, rotamers), 3.70 (s 3H), 3.14-3.09 (m 2H), 2.94 (s 3H), 2.98-2.91 (m 2H) 120 F-1a LCMS Method: 4, RT: 1.33 min MI: 539 .sup.1H-NMR, Method 2: (DMSO) 8.53 (t 1H), 8.28 (dd 1H), 8.03 (dd 1H), 7.44 (d 2H), 7.30 (m 6H), 6.83 (d 1H), 5.59 (s 2H), 4.27 (d 2H), 3.03 (t 2H), 2.77 (t 2H)

General Synthesis of 3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-5 (Scheme 002-C)

(146) ##STR00276##

(147) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-6, was treated with oxalyl chloride and the required Amine 2 in DCM at r.t. to afford the final compounds of general formula F-5.

(148) F-1 could be any of the following intermediates:

(149) ##STR00277##

(150) The above synthesis (Scheme 002-C) is illustrated by the preparation of 3-[3-(4-fluoro-benzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide (Ex. 121) described below.

Synthesis of 3-[3-(4-fluoro-benzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide (Ex. 121)

(151) ##STR00278##

(152) In a round bottom flask fitted with magnetic stirrer, 3-[3-(4-fluoro-benzyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl]-propionic acid (360 mg, 1.150 mmol) were suspended in DCM (15 ml). This suspension was cooled in an ice bath and then treated with 2 drops of DMF followed by dropwise addition of oxalyl chloride (0.5 ml, 5.75 mmol). The resultant solution was warmed to r.t. whilst stirring for 1 hour. The solution was evaporated and azeotroped from DCM and the crude acid chloride was redissolved in DCM (5 ml). In a separate round bottom flask fitted with magnetic stirrer, a solution of (S)-1-(4-fluoro-phenyl)-ethylamine (310 μl, 2.30 mmol) in pyridine (4 ml) was treated with the aforementioned acid chloride solution and stirred at r.t. for 5 hours. Reaction mixture was diluted with DCM, washed with water and brine, dried and evaporated under reduced pressure. The crude product was dissolved in MeOH and half of the solution was purified by reverse phase mass-directed preparative HPLC using either LCMS method 5 or 6. Product fractions were combined and evaporated in the Genevac™ to afford the title compound (66 mg, 24%).

(153) LCMS Method: 5 LCMS1, RT: 3.94 min, MI: 435 [M+1]

(154) .sup.1H NMR, Method 1: (DMSO) 8.43 (d 1H), 7.89 (d 1H), 7.31-7.28 (m 2H), 7.23-7.19 (m 2H), 7.17-7.12 (m 3H), 7.04 (tt 2H), 5.44 (s 2H), 4.91-4.84 (m 1H), 3.04-2.91 (m 2H), 2.77-2.63 (m 2H), 2.56 (s 3H), 1.31 (d 3H).

General Synthesis of 3-(3-aralkyl-3H-imidazo[4,5-c]pyridin-2-yl)-propionamide of General Formula F-12 (Scheme 003)

(155) ##STR00279##

(156) Commercially available 3-bromo-4-nitro-pyridine 1-oxide of formula F-7 was reacted with the required amine 1 in propanol at 90° C. to yield the aralkyl-(4-nitro-1-oxy-pyridin-3-yl)-amine derivative of general formula F-8, which was hydrogenated over Pd/C in EtOH to afford N′3′-aralkyl-1-oxy-pyridine-3,4-diamine of general formula F-9. This was treated with Fe powder in HOAc at reflux to yield N′3′-aralkyl-pyridine-3,4-diamine of general formula F-10. This intermediate was reacted with succinic anhydride in dioxane at reflux, and then treated with HOAc. The obtained carboxylic acid, of general formula F-11, was treated with HBTU and the required amine 2 in DCM to afford the final compounds of general formula F-12. The final compounds could alternatively have been obtained from treatment of the same carboxylic acid with CDI and the required amine 2 as described in Scheme 002-B.

(157) The above synthesis (Scheme 003) is illustrated by the preparation of N—[(S)-1-(4-chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-c]pyridin-2-yl]-propionamide (Ex. 122) described below.

Synthesis of (4-nitro-1-oxy-pyridin-3-yl)-(4-trifluoromethoxy-benzyl)-amine

(158) ##STR00280##

(159) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 3-bromo-4-nitro-pyridine 1-oxide (5.3 g, 24.25 mmol) and 4-(trifluoromethoxy)benzylamine (9.28 g, 48.55 mmol) were dissolved in propanol (50 ml) and heated to 90° C. for 5 hours. Reaction mixture was allowed to cool overnight whilst stirring, with a solid crashing out of the reaction crude. This solid was filtered off, washed with IPA (2×10 ml) and dried in vacuo to afford the title compound (4.64 g, 58%).

(160) LCMS Method: 2, RT: 6.50 min, MI: 330 [M+1]

(161) .sup.1H NMR, Method 1: (DMSO) 8.82 (t 1H), 8.05 (d 1H), 7.94 (d 1H), 7.52 (d 2H), 7.49 (dd 1H), 7.36 (d 2H), 4.68 (d 2H).

Synthesis of 1-oxy-N′3′-(4-trifluoromethoxy-benzyl)-pyridine-3,4-diamine

(162) ##STR00281##

(163) In a round bottom flask fitted with magnetic stirrer, (4-nitro-1-oxy-pyridin-3-yl)-(4-trifluoromethoxy-benzyl)-amine (3.36 g, 10.2 mmol) were added in and flask was purged with N.sub.2. Pd/C (400 mg) was added and solids were suspended in MeOH (200 ml). Mixture was purged with more N.sub.2 and a double balloon filled with H.sub.2 was fitted onto the flask. Suspension was allowed to stir at r.t. overnight under an atmosphere of H.sub.2 and subsequently filtered through Celite® to remove the catalyst. Filtrate was concentrated at reduced pressure to afford the title compound (3 g, 98%).

(164) LCMS Method: 1, RT: 2.70 min, MI: 300 [M+1]

Synthesis of N′3′-(4-trifluoromethoxy-benzyl)-pyridine-3,4-diamine

(165) ##STR00282##

(166) In a round bottom flask fitted with a magnetic stirrer and a reflux condenser, 1-oxy-N′3′-(4-trifluoromethoxy-benzyl)-pyridine-3,4-diamine (3.01 g, 10.05 mmol) and Fe powder (800 mg, 15 mmol) were dissolved in HOAc (40 ml) and heated at 90° C. overnight. Reaction crude was quenched with NaOH 2N aqueous solution until pH 7, and then extracted with EtOAc. Organic phases were combined, washed with 10% EDTA solution, filtered through a silicone treated filter paper and concentrated under reduced pressure. Crude material was purified by column chromatography with a gradient of cyclohexane and EtOAc, followed by a gradient of EtOAc and MeOH, product eluted with 20% MeOH in EtOAc. Product fractions were combined and concentrated under reduced pressure to afford the title compound (2.86 g, 100%).

(167) LCMS Method: 1, RT: 2.51 min, MI: 284 [M+1]

Synthesis of 3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-c]pyridin-2-yl]-propionic Acid

(168) ##STR00283##

(169) In a round bottom flask, fitted with a magnetic stirrer and reflux condenser, N′3′-(4-trifluoromethoxy-benzyl)-pyridine-3,4-diamine (2.86 g, 10.1 mmol) and succinic anhydride (1 g, 10.1 mmol) were dissolved in dioxane (70 ml) and HOAc (35 ml). This mixture was heated at 80° C. over the weekend. The reaction mixture was treated then with further HOAc (25 ml) and heated to reflux for a further 24 hours. Reaction crude was allowed to cool down and then concentrated under reduced pressure. Crude material was dissolved in MeOH (30 ml) and filtered through SCX (25 g) previously soaked in MeOH. Title compound was released off the SCX resin with ammonia in MeOH 0.4 M. Eluent was concentrated under reduced pressure and recrystallized in DCM to afford the title compound (1.16 g, 31%).

(170) LCMS Method: 1, RT: 2.34 min, MI: 366 [M+1]

Synthesis of N—[(S)-1-(4-chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-c]pyridin-2-yl]-propionamide (Ex. 122)

(171) ##STR00284##

(172) In a round bottom flask fitted with a magnetic stirrer, 3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-c]pyridin-2-yl]-propionic acid (100 mg, 0.27 mmol), Hunig's base (100 μl, 0.54 mmol) and (S)-1-(4-chloro-phenyl)-ethylamine (50 μl, 0.324 mmol) were dissolved in DCM (20 ml). Mixture was cooled with an ice bath, and then HBTU (204 mg, 0.54 mmol) was added. Reaction mixture was allowed to stir at r.t. for 1 hour until complete conversion. Crude mixture was concentrated under reduced pressure and purified by column chromatography with a gradient of EtOAc and cyclohexane, required product eluted with neat EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford a solid which was further purified by reverse phase mass-directed preparative HPLC, using either LCMS Method 5 or 6. Required fractions were concentrated in the Genevac™ to afford the title compound (28 mg, 30%).

(173) The following compounds of general formula F-12 were prepared according to the general synthesis shown in Scheme 003:

(174) TABLE-US-00004 Ex- am- ple SM Amine 1 Amine 2 Characterisation 122 F-7 LCMS Method: 1, RT: 3.05 min, MI: 503/505 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.63 (s 1H), 8.47 (d 1H), 7.61 (dd 1H), 7.16-7.06 (m 8H), 6.47 (d 1H), 5.41 (d 1H), 5.36 (d 1H), 5.00- 4.93 (m 1H), 3.21-3.08 (m 2H), 2.95-2.83 (m 2H), 1.39 (d 3H) 123 F-7 LCMS Method: 1, RT: 2.61 min, MI: 485 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.55 (d 1H), 8.34 (d 1H), 7.20-7.00 (10H), 5.34 (s 2H), 5.07-5.03 (m 1H), 3.98-3.87 (m 2H), 3.65 (br 2H), 3.25-3.03 (m 3H), 2.88-2.82 (m 1H) 124 F-7 0 LCMS Method: 1, RT: 2.94 min, MI: 487 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.63 (d 1H), 8.45 (d 1H), 7.60 (dd 1H), 7.16-7.07 (m 6H), 6.82 (tt 2H), 6.56 (d 1H), 5.42 (d 1H), 5.37 (d 1H), 5.02-4.95 (m 1H), 3.21-3.08 (m 2H), 2.94- 2.83 (m 2H), 1.38 (d 3H) 125 F-7 LCMS Method: 1, RT: 2.05 min, MI: 284 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.62 (s 1H), 8.45 (d 1H), 7.63 (d 1H), 7.16-7.00 (m 6H), 6.67 (d 2H), 6.25 (d 1H), 5.43 (d 1H), 5.37 (d 1H), 4.98-4.91 (m 1H), 3.19-3.14 (m 6H), 2.93- 2.81 (m 2H), 2.72 (t 4H), 2.43 (s 3H), 1.37 (d 3H) 126 F-7 LCMS Method: 1, RT: 2.95 min, MI: 569 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.60 (s 1H), 8.40 (d 1H), 7.39 (dd 1H), 7.26-7.21 (m 2H), 7.15-7.13 (m 2H), 7.07-7.05 (m 2H), 6.99- 6.97 (m 2H), 5.37 (s 2H), 5.07-5.03 (m 1H), 3.91 (ddd 2H), 3.18 (t 2H), 3.03- 2.96 (m 1H), 2.91-2.84 (m 1H) 127 F-7 LCMS Method: 4, RT: 1.05 min, MI: 418 [M + 1] .sup.1H-NMR, Method 2: (DMSO) 8.86 (br s 1H), 8.45- 8.34 (m 2H), 7.64-7.60 (m 1H), 7.34-7.16 (m 9H), 5.61 (s 2H), 4.77-4.68 (m 1H), 3.16 (t 2H), 2.85 (t 2H), 1.79-1.63 (m 2H), 0.86 (t 3H) 128 F-7 LCMS Method: 1, RT: 2.06 min, MI: 278 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.82 (s 1H), 8.43 (t 1H), 8.32 (d 1H), 7.60 (d 1H), 7.36-7.31 (m 4H), 7.10 (dt 2H), 6.77 (dt 2H), 5.66 (s 2H), 4.19 (d 2H), 3.94 (t 2H), 3.14 (t 2H), 2.79 (t 2H), 2.40 (t 2H), 2.19 (s 6H), 1.87-1.80 (m 2H) 129 F-7 00 LCMS Method: 1, RT: 2.96 min, MI: 489/491 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.64 (d 1H), 8.45 (d 1H), 7.58 (dd 1H), 7.20-7.04 (m 8H), 6.66 (t 1H), 5.44 (s 2H), 4.35 (d 2H), 3.17 (t 2H), 2.93 (t 2H) 130 F-7 01 02 LCMS Method: 4, RT: 0.99 min, MI: 404 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.81 (s 1H), 8.43 (br d 1H), 8.30 (d 1H), 7.60- 7.57 (m 1H), 7.29-7.12 (m 9H), 5.56 (s 2H), 4.92- 4.85 (m 1H), 3.15-3.07 (m 2H), 2.83-2.70 (m 2H), 1.33 (d 3H) 131 F-7 03 04 LCMS Method: 4, RT: 1.07 min, MI: 418 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.81 (s 1H), 8.37 (br d 1H), 8.30 (d 1H), 7.59- 7.56 (m 1H), 7.28-7.00 (m 8H), 5.56 (s 2H), 4.89- 4.82 (m 1H), 3.14-3.07 (m 2H), 2.80-2.72 (m 2H), 2.24 (s 3H), 1.30 (d 3H) 132 F-7 05 06 LCMS Method: 4, RT: 1.03 min, MI: 422 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.81 (s 1H), 8.45 (brd 1H), 8.31 (d 1H), 7.60- 7.56 (m 1H), 7.32-6.98 (m 8H), 5.56 (s 2H), 4.94- 4.84 (m 1H), 3.20-3.02 (m 2H), 2.87-2.69 (m 2H), 1.32 (d 3H) 133 F-7 07 08 LCMS Method: 1, RT: 2.85 min, MI: 473 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.63 (s 1H), 8.43 (d 1H), 7.57 (d 1H), 7.18-7.06 (m 6H), 6.84 (t 2H), 6.76 (br 1H), 5.45 (s 2H), 4.34 (d 2H), 3.16 (t 2H), 2.92 (t 2H) 134 F-7 09 0 LCMS Method: 4, RT: 1.03 min, MI: 422 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.81 (s 1H), 8.45 (br d 1H), 8.31 (d 1H), 7.60- 7.56 (m 1H), 7.32-6.98 (m 8H), 5.56 (s 2H), 4.94- 4.84 (m 1H), 3.20-3.02 (m 2H), 2.87-2.69 (m 2H), 1.32 (d 3H) 135 F-7 LCMS Method: 1, RT: 3.00 min, MI: 562 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.67 (s 1H), 8.45 (d 1H), 7.60 (dd 1H), 7.20-7.13 (m 4H), 6.20 (t 1H), 5.48 (s 2H), 4.02 (br 2H), 3.17 (t 2H), 3.11 (br 2H), 2.89 (t 2H), 2.57 (t 2H), 2.39 (br 1H), 1.55 (br 2H), 1.44 (s 9H), 1.09-1.01 (m 2H) 136 F-7 LCMS Method: 1, RT: 1.04 min, MI: 418 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.82 (s 1H), 8.34- 8.30 (m 1H), 8.20 (br s 1H), 7.64-7.61 (m 1H), 7.26- 7.04 (m 9H), 5.54 (s 2H), 3.06 (br t 2H), 2.80 (br t 2H), 1.51 (s 6H)

General Synthesis of 3-(1-aralkyl-1H-pyrrolo[2,3-b]pyridin-2-yl-propionamide of General Formula F-17 (Scheme 004)

(175) ##STR00315##

(176) Commercially available 4-pentynoic acid of formula F-13 was reacted with the required amine and HBTU in DMF at r.t. to afford the pent-4-ynoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide of formula F-14. This intermediate was submitted to a Sonogashira coupling with N-(3-bromo-pyridin-2-yl)-butyramide of general formula F-19 to yield the 5-(2-butyrylamino-pyridin-3-yl)-pent-4-ynoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide of general formula F-15. This was treated with K.sup.tOBu in NMP at 50° C. to yield the N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-propionamide of general formula F-16 which was subsequently reacted with the required halide and LiOH in DMSO to afford the final compounds of general formula F-17.

(177) F-18 could be any of the following intermediates:

(178) ##STR00316##

(179) The above synthesis (Scheme 004) is illustrated by the preparation of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-[1-(4-trifluoromethoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionamide (Ex. 137) described below.

Synthesis of N-(3-bromo-pyridin-2-yl)-butyramide

(180) ##STR00317##

(181) In a round bottom flask fitted with magnetic stirrer, 2-amino-3-bromopyridine (5.72 g, 33.09 mmol) was dissolved in pyridine (30 ml). This solution was cooled with an ice bath and butyryl chloride (3.5 ml, 33.5 mmol) was added dropwise. Reaction mixture was allowed to stir at 10° C. for 2 hours and then at r.t. overnight. Reaction crude was diluted with EtOAc and washed (×3) with water. Organic phase was, filtered through a silicone treated filter paper and concentrated under reduced pressure. The crude product was purified by column chromatography with a gradient of MeOH and DCM, required product eluted with 3% of MeOH. Product fractions were combined and concentrated under reduced pressure to afford the title compound (5.72 g, 71%) as an oil which crystallized upon standing.

(182) LCMS Method: 1, RT: 2.84 min, MI: 243 [M+1]

(183) .sup.1H NMR, Method 1: (CDCl.sub.3) 8.36 (dd 1H), 7.86 (dd 2H), 6.95 (dd 1H), 2.64 (t 2H), 1.82-1.72 (m 2H), 1.02 (t 3H).

Synthesis of pent-4-ynoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide

(184) ##STR00318##

(185) In a round bottom flask fitted with magnetic stirrer, 4-pentynoic acid (1.5 g, 15.3 mmol) and (S)-1-(4-fluoro-phenyl)-ethylamine (1.8 ml, 16.83 mmol) were dissolved in DCM (50 ml) and then treated with Hunig's base (5.4 ml, 30.6 mmol) and HBTU (11.6 g, 30.6 mmol). This mixture was allowed to stir overnight at r.t. Reaction crude was concentrated under reduced pressure and purified by column chromatography with a gradient of EtOAc and cyclohexane, required product eluted with 40% EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (3.21 g, 96%).

(186) LCMS Method: 1, RT: 3.78 min, MI: 220 [M+1]

Synthesis of 5-(2-butyrylamino-pyridin-3-yl)-pent-4-ynoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide

(187) ##STR00319##

(188) In a round bottom flask fitted with magnetic stirrer, pent-4-ynoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide (2.65 g, 12.1 mmol), N-(3-bromo-pyridin-2-yl)-butyramide (2.67 g, 11 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (231 mg, 0.33 mmol), CuI (100 mg, 0.55 mmol) and TBAI (4 g, 11 mmol) were dissolved in anhydrous DMF (25 ml) and treated with Et.sub.3N (4.6 ml, 33 mmol). This mixture was allowed to stir under N.sub.2 at r.t. for 4 days. Reaction crude was quenched with water and extracted with EtOAc. Organic phases were combined, filtered through a silicone treated filter paper and concentrated under reduced pressure. Crude material was purified by column chromatography with a gradient of EtOAc and cyclohexane, required product eluted with 75% EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (2.8 g, 67%)

(189) LCMS Method: 1, RT: 3.45 min, Ml: 382 [M+1]

(190) .sup.1H NMR, Method 1: (CDCl.sub.3) 8.31 (dd 1H), 7.74 (dd 1H), 7.21-7.15 (m 3H), 6.92 (tt 2H), 6.35 (s 1H), 5.92 (d 1H), 3.59 (t 2H), 3.37 (td 2H), 2.60 (t 2H), 1.87-1.78 (m 2H), 1.57-1.54 (m 1H), 1.43 (d 3H), 1.07 (t 3H).

Synthesis of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-propionamide

(191) ##STR00320##

(192) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 5-(2-butyrylamino-pyridin-3-yl)-pent-4-ynoic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide (2.82 g, 7.4 mmol) and K.sup.tOBu (913 mg, 8.14 mmol) were dissolved in NMP (25 ml). Mixture was heated at 50° C. for 24 hours. Reaction crude was quenched with water and extracted with EtOAc. Organic phases were combined, filtered through a silicone treated filter paper and concentrated under reduced pressure. Residue obtained was purified by column chromatography with a gradient of EtOAc and cyclohexane, required product eluted with neat EtOAc. Required fractions were combined and concentrated under reduced pressure to afford the title compound (2.3 g, 100%)

(193) LCMS Method: 1, RT: 2.68 min, MI: 312 [M+1]

Synthesis of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-[1-(4-trifluoromethoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionamide (Ex. 137)

(194) ##STR00321##

(195) In a round bottom flask fitted with magnetic stirrer, N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-propionamide (500 mg, 1.60 mmol), 4-(trifluoromethoxy)benzyl bromide (490 mg, 1.92 mmol) and LiOHxH.sub.2O (90 mg, 2.15 mmol) were dissolved in DMSO (8 ml). This mixture was allowed to stir at r.t. for 3 hours. Reaction crude was quenched with water and extracted with EtOAc. Organic phases were combined, filtered through a silicone treated filter paper and concentrated under reduced pressure. Residue obtained was purified by column chromatography with a gradient of EtOAc and cyclohexane, required product eluted with neat EtOAc. Product fractions were combined and concentrated under reduced pressure to afford a solid which was further purified by reverse phase mass-directed preparative HPLC, using either LCMS Method 5 or 6. Required fractions were concentrated in the Genevac™ to afford the title compound (208 mg, 27%)

(196) The following compounds of general formula F-17 were prepared according to the general synthesis shown in Scheme 004:

(197) TABLE-US-00005 Example SM Halide Amine Characterisation 137 F-18a LCMS Method: 1, RT: 5.26 min, MI: 486 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.28 (dd 1H), 7.83 (dd 1H), 7.15-7.02 (m 7H), 6.92 (tt 2H), 6.22 (s 1H), 5.58-5.47 (m 3H), 5.09-5.02 (m 1H), 3.03-2.99 (m 2H), 2.55-2.39 (m 2H), 1.40 (d 3H) 138 F-18a LCMS Method: 1, RT: 5.06 min, MI: 436 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.41 (d 1H), 8.18 (dd 1H), 7.89 (dd 1H), 7.35-7.31 (m 2H), 7.30-7.25 (m 2H), 7.10-7.02 (m 5H), 6.28 (s 1H), 5.50 (s 2H), 4.94-4.87 (m 1H), 2.89 (t 2H), 2.55 (t 2H), 1.32 (d 3H) 139 F-18b LCMS Method: 1, RT: 5.48 min, MI: 504 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.42 (d 1H), 8.16 (dd 1H), 7.82 (dd 1H), 7.29-7.26 (m 4H), 7.13 (dt 2H), 7.07 (tt 2H), 6.30 (s 1H), 5.53 (s 2H), 4.94-4.87 (m 1H), 2.91 (t 2H), 2.56 (t 2H), 1.32 (d 3H) 140 F-18a LCMS Method: 1, RT: 4.81 min, MI: 420 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.28 (dd 1H), 7.82 (dd 1H), 7.16-7.11 (m 2H), 7.08 (dd 1H), 7.03-6.99 (m 2H), 6.95-6.87 (m 4H), 6.21 (s 1H), 5.50 (q 3H), 5.09-5.02 (m 1H), 3.03-2.99 (m 2H), 2.51-2.37 (m 2H), 1.40 (d 3H) 141 F-18b 0 LCMS Method: 1, RT: 5.35 min, MI: 454 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.41 (d 1H), 8.17 (dd 1H), 7.82 (dd 1H), 7.34 (dt 2H), 7.29-7.26 (m 2H), 7.10-7.02 (m 4H), 6.29 (s 1H), 5.49 (s 2H), 4.94-4.87 (m 1H), 2.89 (t 2H), 2.54 (t 2H), 1.32 (d 3H)

General Synthesis of: 2-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl-acetamide of General Formula F-23, 2-(3-aralkyl-3H-imidazo[4,5-b]pyridine-2-sulfinyl)-acetamide of General Formula F-24 2-(3-aralkyl-3H-imidazo[4,5-b]pyridine-2-sulfonyl)-acetamide of General Formula F-25 (Scheme 005)

(198) ##STR00332##

(199) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-3 was treated with CS.sub.2 to give the thiol intermediates of general formula F-20. Treatment of this intermediate with tert-butyl bromoacetate and K.sub.2CO.sub.3 afforded the ester of general formula F-21, which was hydrolyzed with TFA to the corresponding carboxylic acid of general formula F-22. The obtained acid was treated with HBTU and the required Amine 2 at r.t. to afford the final compounds of general formula F-23. Treatment of the final compound of general formula F-23 with a peroxide afforded the final compounds of general formula F-24. Treatment of the final compound of general formula F-23 with KMnO.sub.4 afforded the final compounds of general formula F-25.

(200) F-1 was the following intermediate:

(201) ##STR00333##

(202) The above synthesis (Scheme 005) is illustrated by the preparation of Examples 145, 148, 149 and 150 described below.

Synthesis of 3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-thiol

(203) ##STR00334##

(204) In a round bottom flask fitted with magnetic stirrer and reflux condenser, N′2′-(4-trifluoromethoxy-benzyl)-pyridine-2,3-diamine (200 mg, 0.92 mmol) was dissolved in EtOH and CS.sub.2 (160 μl, 2.76 mmol) was added in. The reaction mixture was heated to reflux overnight. Reaction mixture was allowed to cool down to r.t. and after a few hours a solid precipitated out of solution. This solid was filtered to afford the title compound (150 mg, 63%).

(205) LCMS Method: 1, RT: 4.06 min, MI: 260 [M+1]

(206) .sup.1H NMR, Method 1: (DMSO) 13.13 (bs 1H), 8.20 (dd 1H), 7.58 (dd 1H), 7.48-7.44 (m 2H), 7.23 (dd 1H), 7.15 (tt 2H), 5.45 (s 2H).

Synthesis of [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetic Acid Tert-Butyl Ester

(207) ##STR00335##

(208) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-thiol (150 mg, 0.58 mmol), tert-butyl bromoacetate (85 μl, 0.58 mmol) and K.sub.2CO.sub.3 (120 mg, 0.87 mmol) were dissolved in acetone (4 ml) and refluxed for 5 hours. Reaction crude was allowed to cool down overnight. Solvent was evaporated under reduced pressure, crude material taken up in water and extracted with EtOAc. Organic phases were combined and washed with diluted NaOH aqueous solution. Organic phases were dried and concentrated under reduced pressure to afford the title compound (210 mg, 100%).

(209) LCMS Method: 1, RT: 5.25 min, MI: 374 [M+1]

(210) .sup.1H NMR, Method 1: (CDCl.sub.3) 8.29 (dd 1H), 7.88 (dd 1H), 7.37-7.34 (m 2H), 7.18 (dd 1H), 6.99 (tt 2H), 5.40 (s 2H), 4.13 (s 2H), 1.45 (s 9H).

Synthesis of [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetic Acid

(211) ##STR00336##

(212) In a round bottom flask fitted with a magnetic stirrer, [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetic acid tert-butyl ester (216 mg, 0.58 mmol) was dissolved in DCM (4 ml) and TFA (2 ml) was added in. Reaction mixture was stirred at r.t. overnight. The solvent had evaporated off overnight so DCM (3 ml) was added. This solution was then poured onto Et.sub.2O (10 ml). The solution was concentrated under reduced pressure to afford the title compound (200 mg, 111%). The title compound was found to contain additional impurities but was used in subsequent reactions without further purification.

(213) LCMS Method: 1, RT: 4.01 min, MI: 318 [M+1]

(214) .sup.1H NMR, Method 1: (DMSO) 8.28 (dd 1H), 7.97 (dd 1H), 7.37-7.34 (m 2H), 7.27 (dd 1H), 7.18 (tt 2H), 5.41 (s 2H), 4.22 (s 2H).

Synthesis of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetamide (Ex. 145)

(215) ##STR00337##

(216) In a round bottom flask fitted with magnetic stirrer, [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetic acid (60 mg, 0.189 mmol) and (S)-1-(4-fluorophenyl)ethylamine (26 μl, 0.19 mmol) were dissolved in anhydrous DMF (3 ml) and then treated with HBTU (79 mg, 0.21 mmol) and Et.sub.3N (80 μl, 0.57 mmol). This mixture was stirred at r.t. for 18 h. Reaction crude was diluted with EtOAc (15 ml) and washed with water (15 ml) and brine (10 ml). The organic phase was dried and concentrated under reduced pressure to give 146 mg of an orange oil, which was purified by reverse phase mass-directed preparative HPLC, using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the title compound (15 mg, 19%).

Synthesis of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-sulfinyl]-acetamide (Ex. 148 and 149)

(217) ##STR00338##

(218) In a round bottom flask fitted with magnetic stirrer, N—[(S)-1-(4-fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetamide (230 mg, 0.46 mmol) was dissolved in anhydrous DCM (100 ml). This solution was cooled to 0° C. and flushed with N.sub.2. A solution of 3-chloroperoxybenzoic acid, 77% in DCM (8 ml) was added dropwise at 0° C. and under N.sub.2. This mixture was stirred at r.t. for 6 hours. Solvent was evaporated under reduced pressure and residue extracted with brine (50 ml) and EtOAc (50 ml). Organic phases were dried and concentrated under reduced pressure to afford 242 mg of a crude material which was purified by reverse phase mass-directed preparative HPLC, using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the title compound as two separate diastereoisomers of which the stereochemistry at the sulfoxide was unknown. For diastereoisomer A (r.t. 4.73 min), 32 mg were afforded (14% yield). For diastereoisomer B (r.t. 4.83 min), 10.5 mg were afforded (5% yield).

(219) LCMS Method (diastereoisomer A): 1, RT: 4.73 min, MI: 521 [M+1]

(220) LCMS Method (diastereoisomer B): 1, RT: 4.83 min, MI: 521 [M+1]

Synthesis of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-sulfonyl]-acetamide (Ex. 150)

(221) ##STR00339##

(222) In a round bottom flask fitted with magnetic stirrer, N—[(S)-1-(4-fluoro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-acetamide (132 mg, 0.26 mmol) was dissolved in acetic acid (10 ml) and KMnO.sub.4 0.1 M aqueous solution (3.54 ml, 0.35 mmol) was added dropwise over 15 min and then stirred for 2.5 hours at r.t. Sodium sulfite was added to decolourise. The reaction mixture was then concentrated under reduced pressure. The solid was dissolved in DCM and the insoluble material filtered off. The filtrate was concentrated under reduced pressure and purified by reverse phase mass-directed preparative HPLC, using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the title compound (31 mg, 22%).

(223) Amine 2 used in the HBTU coupling step for the synthesis of Ex. 147 was made according to the following synthetic scheme:

(224) ##STR00340##

Step 1: Synthesis of [(S)-1-(4-bromo-phenyl)-ethyl]-carbamic Acid Tert-Butyl Ester

(225) ##STR00341##

(226) In a round bottom flask fitted with magnetic stirrer, a solution of (S)-1-(4-bromo-phenyl)-ethylamine (600 mg, 3 mmol) in DCM (15 ml) was cooled in an ice bath and treated with NEt.sub.3 (460 μl, 3.3 mmol) and di-tert-butyldicarbonate (680 mg, 3.15 mmol). The reaction mixture was warmed to r.t. and stirred for 2 hours. Reaction crude was diluted with DCM and washed with ice-cold 1M HCl aqueous solution, saturated NaHCO.sub.3 aqueous solution and brine, dried and evaporated in vacuo to afford the title compound (923 mg, 100%).

(227) LCMS Method: 1, RT: 5.21 min, MI: 244/246 [M+1]

Step 2: Synthesis of [(S)-1-(4-morpholin-4-yl-phenyl)-ethyl]-carbamic Acid Tert-Butyl Ester

(228) ##STR00342##

(229) In a MW vial fitted with magnetic stirrer, a mixture of [(S)-1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (900 mg, 3 mmol), morpholine (800 μl, 9.2 mmol), Pd.sub.2dba.sub.3 (35 mg, 0.06 mmol), X-Phos (86 mg, 0.18 mmol) and Na.sup.tOBu (433 mg, 4.5 mmol) in dioxane (12 ml) was heated to 90° C. in the MW for 2 hours. Reaction crude was diluted with EtOAc, washed with water and brine, dried and concentrated under reduced pressure. The crude product was purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 30% EtOAc. Product fractions were combined and concentrated under reduced pressure to afford the title compound (730 mg, 79%).

(230) LCMS Method: 1, RT: 4.27 min, MI: 307 [M+1]

Step 3: Synthesis of (S)-1-(4-morpholin-4-yl-phenyl)-ethylamine

(231) ##STR00343##

(232) In a round bottom flask fitted with magnetic stirrer, acetyl chloride (1.5 ml, 21.1 mmol) was added to MeOH (10 ml), whilst stirring in an ice bath. The resultant 2M HCl solution was added to a flask containing [(S)-1-(4-morpholin-4-yl-phenyl)-ethyl]-carbamic acid tert-butyl ester and the mixture was stirred for 2 hours at r.t. Reaction crude was concentrated under reduced pressure and the resultant solid triturated in Et.sub.2O. The suspension was filtered and the solid product dried to afford the title compound (550 mg, 83%).

(233) LCMS Method: 1, RT: 1.65 min, MI: 207 [M+1]

(234) .sup.1H NMR, Method 1: (CD.sub.3OD) 7.77-7.73 (m 2H), 7.69-7.66 (m 2H), 4.56 (q 1H), 4.10 (t 4H), 3.65 (t 4H), 1.65 (d 3H).

(235) The following compounds were prepared according to the general synthesis shown in Scheme 005:

(236) TABLE-US-00006 General Example formula Amine 1 Amine 2 Characterisation 142 F-23 LCMS Method: 1, RT: 4.55 min, MI: 503 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.75 (d 1H), 8.27 (d 1H), 7.96 (d 1H), 7.40-7.19 (m 10H), 5.45 (s 2H), 4.90 (t 1H), 4.83 (q 1H), 4.26 (d 1H), 4.20 (d 1H), 3.61-3.51 (m 2H) 143 F-23 LCMS Method: 1, RT: 4.04 min, MI: 437 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.74 (d 1H), 8.34 (dd 1H), 7.80 (dd 1H), 7.36-7.32 (m 2H), 7.24-7.18 (m 6H), 6.99 (tt 2H), 5.41 (d 1H), 5.36 (d 1H), 5.07-5.03 (m 1H), 3.98 (d 1H), 3.88 (d 1H), 3.87-3.79 (m 2H), 2.83 (br 1H) 144 F-23 LCMS Method: 1, RT: 5.50 min, MI: 521 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.44 (d 1H), 8.37 (dd 1H), 7.81 (dd 1H), 7.39 (dt 2H), 7.27 (dd 1H), 7.17-7.08 (m 6H), 5.43 (d 1H), 5.44 (d 1H), 5.00-4.93 (m 1H), 3.95 (d 1H), 3.88 (d 1H), 1.38 (d 3H) 145 F-23 0 LCMS Method: 1, RT: 5.26 min, MI: 505 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.42 (d 1H), 8.35 (dd 1H), 7.79 (dd 1H), 7.38 (dt 2H), 7.25 (dd 1H), 7.16-7.10 (m 4H), 6.84 (tt 2H), 5.39 (s 2H), 5.01-4.94 (m 1H), 3.93 (d 1H), 3.86 (d 1H), 1.38 (d 3H) 146 F-23 LCMS Method: 1, RT: 4.79 min, MI: 439 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.45 (d 1H), 8.35 (dd 1H), 7.79 (dd 1H), 7.36-7.32 (m 2H), 7.24 (dd 1H), 7.13-7.08 (m 2H), 6.99 (tt 2H), 6.83 (tt 2H), 5.37 (s 2H), 5.01-4.93 (m 1H), 3.92 (d 1H), 3.85 (d 1H), 1.38 (d 3H) 147 F-23 LCMS Method: 1, RT: 4.38 min, MI: 506 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.33 (dd 1H), 8.28 (d 1H), 7.79 (dd 1H), 7.34-7.31 (m 2H), 7.22 (dd 1H), 7.04 (d 2H), 6.99 (tt 2H), 6.68 (d 2H), 5.36 (s 2H), 4.98-4.91 (m 1H), 3.95 (d 1H), 3.85 (d 1H), 3.84 (t 4H), 3.06 (t 4H), 1.36 (d 3H) 148 F-24 LCMS Method: 1, RT: 4.83 min, MI: 521 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.58 (dd 1H), 8.10 (dd 1H), 7.50 (dt 2H), 7.39 (dd 1H), 7.22-7.15 (m 4H), 7.00-6.94 (m 3H), 5.87 (d 1H), 5.79 (d 1H), 5.04-4.97 (m 1H), 4.30 (d 1H), 4.17 (d 1H), 1.30 (d 3H) 149 F-24 LCMS Method: 1, RT: 4.73 min, MI: 521 [M + 1] — 150 F-25 0 LCMS Method: 1, RT: 5.15 min, MI: 537 [M + 1] .sup.1H NMR, Method 1: (CDCl.sub.3) 8.65 (dd 1H), 8.06 (dd 1H), 7.56 (dt 2H), 7.43 (dd 1H), 7.16-7.12 (m 4H), 6.86 (tt 2H), 5.83 (s 2H), 5.05-4.98 (m 1H), 4.48 (d 1H), 4.44 (d 1H), 1.43 (d 3H)

General Synthesis of 2-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yloxy)-acetamide of General Formula F-30 (Scheme 006-A)

(237) ##STR00362##

(238) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-20 was prepared as in Scheme 005. Intermediate F-20 was treated with Mel to afford the methylated analogue of general formula F-26. Oxidation with KMnO.sub.4 of the methylated analogue yielded the sulfone of general formula F-27. Reaction of this intermediate with hydroxy-acetic acid benzyl ester and NaH afforded the ester of general formula F-28. Hydrogenation of this ester afforded the carboxylic acid of general formula F-29. The obtained acid was treated with HBTU and the required amine 2 at r.t. to afford the final compounds of general formula F-30.

(239) F-1 was specifically the following intermediate:

(240) ##STR00363##

(241) The above synthesis (Scheme 006-A) is illustrated by the preparation of N—[(S)-1-(4-chloro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetamide (Ex. 152) described below.

Synthesis of 2-methylsulfanyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine

(242) ##STR00364##

(243) In a round bottom flask fitted with magnetic stirrer, 3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-thiol (680 mg, 2.09 mmol) were dissolved in acetone (30 ml). This solution was cooled down to 0° C. with an ice bath and then K.sub.2CO.sub.3 (144 mg, 1.05 mmol) and Mel (65 μl, 1.05 mmol) were added in. Ice bath was removed and reaction mixture was allowed to stir at r.t. for 1.5 hours. After that time, K.sub.2CO.sub.3 (144 mg, 1.05 mmol) and Mel (65 μl, 1.05 mmol) were added in again and mixture was allowed to stir overnight at r.t. Reaction mixture was concentrated under reduced pressure and then dissolved in EtOAc (150 ml) and washed with water (100 ml) and brine (100 ml). Organic phase was dried and concentrated under reduced pressure to give 600 mg of crude material. This material was purified by column chromatography with a gradient of EtOAc and cyclohexane, required product eluted with 45% EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (603 mg, 85%).

(244) LCMS Method: 1, RT: 4.89 min, MI: 340 [M+1]

(245) .sup.1H NMR, Method 1: (CDCl.sub.3) 8.28 (dd 1H), 7.93 (dd 1H), 7.38 (d 2H), 7.20 (dd 1H), 7.15 (d 2H), 5.40 (s 2H), 2.79 (s 3H).

Synthesis of 2-methanesulfonyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine

(246) ##STR00365##

(247) In a round bottom flask fitted with magnetic stirrer, 2-methylsulfanyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine (571 mg, 1.68 mmol) was dissolved in HOAc (50 ml) and KMnO.sub.4 0.1 M aqueous solution (24 ml, 2.39 mmol) was added dropwise at r.t. over 15 min and then stirred for 3 hours at r.t. Sodium sulphite was added to decolourise. Reaction crude was diluted with water (250 ml), adjusted to pH 8 with Na.sub.2CO.sub.3 (extra 50 ml of water added to ensure solution remained homogeneous) and extracted with DCM (4×150 ml). Organic phases were combined and washed with brine (150 ml), dried and concentrated under reduced pressure. Crude material was purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 40% EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (220 mg, 35%).

(248) LCMS Method: 1, RT: 4.78 min, MI: 372 [M+1]

(249) .sup.1H NMR, Method 1: (DMSO) 8.64 (dd 1H), 8.39 (dd 1H), 7.55 (dd 1H), 7.42 (d 2H), 7.34 (d 2H), 5.87 (s 2H), 3.62 (s 3H).

Synthesis of [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetic Acid Benzyl Ester

(250) ##STR00366##

(251) A previously dried round bottom flask fitted with a magnetic stirrer was charged with NaH (19 mg, 0.81 mmol) and then benzyl glycolate (230 μl, 1.62 mmol) in anhydrous THE (3 ml) were added in dropwise. Immediately after the addition was complete, a solution of 2-methanesulfonyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine (90 mg, 0.24 mmol) in anhydrous THF (3 ml) was added. Reaction was left stirring under N.sub.2 at r.t. over the weekend. The reaction was quenched with water and a white solid crashed out of solution. This solid was filtered off and dried to afford the title compound (76 mg, 69%).

(252) LCMS Method: 1, RT: 5.51 min, MI: 458 [M+1]

(253) .sup.1H NMR, Method 1: (DMSO) 8.17 (dd 1H), 7.84 (dd 1H), 7.43 (d 2H), 7.40-7.36 (m 1H), 7.32 (s 4H), 7.27 (d 2H), 7.22 (dd 1H), 5.34 (s 2H), 5.29 (s 2H), 5.22 (s 2H).

Synthesis of [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetic Acid

(254) ##STR00367##

(255) To a round bottom flask fitted with magnetic stirrer and containing [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetic acid benzyl ester (64 mg, 0.14 mmol) and 10% Pd/C (7 mg) was added EtOAc (5 ml), whilst stirring under N.sub.2. Mixture was purged with more N.sub.2 and a double balloon filled with H.sub.2 was fitted onto the flask. Suspension was allowed to stir at r.t. for 2 hours under an atmosphere of H.sub.2 and subsequently filtered through Celite® with EtOAc. Filtrate was evaporated under reduced pressure to afford the title compound (50 mg, 100%).

(256) .sup.1H NMR, Method 1: (CDCl.sub.3) 8.22 (dd 1H), 7.80 (dd 1H), 7.44 (d 2H), 7.17-7.13 (m 3H), 5.34 (s 2H), 5.15 (s 2H).

Synthesis of N—[(S)-1-(4-chloro-phenyl)-ethyl]-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetamide (Ex. 152)

(257) ##STR00368##

(258) In a round bottom flask fitted with a magnetic stirrer, [3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetic acid (24 mg, 0.07 mmol), Et.sub.3N (30 μl, 0.2 mmol) and (S)-1-(4-chloro-phenyl)-ethylamine (10 μl, 0.07 mmol) were dissolved in anhydrous DMF (2 ml). Mixture was cooled with an ice bath, and then HBTU (27 mg, 0.07 mmol) was added. This mixture was allowed to stir at r.t. overnight. Reaction mixture was diluted with EtOAc (15 ml) and washed with water (15 ml) and brine (10 ml). Organic phase was dried and concentrated under reduced pressure to give a crude material which was purified by reverse phase mass-directed preparative HPLC, using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the title compound (10 mg, 33%).

(259) The following compounds of general formula F-30 were prepared according to the general synthesis shown in Scheme 006-A:

(260) TABLE-US-00007 Example Amine 1 Amine 2 Characterisation 151 0 LCMS Method: 1, RT: 4.40 min, MI: 487 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.58 (d 1H), 8.14 (dd 1H), 7.80 (dd 1H), 7.49 (dt 2H), 7.35-7.28 (m 6H), 7.23 (dt 1H), 7.19 (dd 1H), 5.34 (s 2H), 5.11 (d 1H), 5.07 (d 1H), 4.96-4.87 (m 2H), 4.04 (m 2H), 3.65-3.55 (m 2H) 152 LCMS Method: 1, RT: 5.27 min, MI: 505 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.26 (dd 1H), 7.80 (dd 1H), 7.31 (d 2H), 7.25-7.18 (m 3H), 7.12-7.09 (m 4H), 6.21 (d 1H), 5.33 (s 2H), 5.14-5.06 (m 1H), 5.03 (d 2H), 1.36 (d 3H) 153 LCMS Method: 1, RT: 4.57 min, MI: 423 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.26 (dd 1H), 7.80 (dd 1H), 7.26-7.18 (m 3H), 7.14-7.10 (m 2H), 6.97-6.89 (m 4H), 6.10 (d 1H), 5.30 (s 2H), 5.16-5.08 (m 1H), 5.03 (d 2H), 1.36 (d 3H)

(261) The aforementioned compounds in Scheme 006-A could have alternatively been obtained through the following synthetic route (Scheme 006-B):

(262) ##STR00375##

(263) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-20 was prepared as in Scheme 005. Intermediate F-26 and F-27 were prepared as in scheme 006-A. Intermediate F-31 was prepared following the same procedure as for intermediate F-28 in scheme 006-A, using hydroxy-acetic acid methyl ester as the ester. Intermediate F-31 was treated with DABAL-Me.sub.3 and the required amine 2 at reflux to afford the final compounds of general formula F-30.

(264) F-1 was the following intermediate:

(265) ##STR00376##

(266) The above synthesis (Scheme 006-B) is illustrated by the preparation of 2-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-acetamide (Ex. 153) described below.

Synthesis of 2-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-acetamide (Ex. 153)

(267) ##STR00377##

(268) In a round bottom flask fitted with magnetic stirrer and reflux condenser, to a stirred suspension of DABAL-Me.sub.3 (26 mg, 0.1 mmol) in anhydrous THF (1 ml) under an atmosphere of N.sub.2, (S)-1-(4-fluoro-phenyl)-ethylamine (13 μl, 0.1 mmol) was added in. The solution was stirred and warmed to 40° C. for 1 hour. A solution of [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetic acid methyl ester (22 mg, 0.07 mmol) in anhydrous THF (0.75 ml) was added and mixture was refluxed overnight. The reaction was cooled to r.t. and cautiously quenched with 2M HCl aqueous solution (1.5 ml) and stirred at r.t. for 30 minutes. The solution was transferred to a larger flask and the water evaporated. Crude material was purified by column chromatography. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (1 mg, 3%).

(269) The aforementioned compounds in Scheme 006-A could have alternatively been obtained through the following synthetic route (Scheme 006-C):

(270) ##STR00378##

(271) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-3 was treated with CDI to give the oxo intermediates of general formula F-32. This intermediate was treated with POCl.sub.3 and PCl.sub.5 to afford the chlorinated analogues of general formula F-33. Reaction of this intermediate with hydroxy-acetic acid methyl ester and NaH afforded the ester of general formula F-28. Final compounds of general formula F-30 were prepared from intermediate F-28 as in Scheme 006-B.

(272) F-1 was the following intermediate:

(273) ##STR00379##

(274) The above synthesis (Scheme 006-C) is illustrated by the preparation of [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetic acid methyl ester described below.

Synthesis of 3-(4-fluoro-benzyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

(275) ##STR00380##

(276) In a round bottom flask fitted with magnetic stirrer, N′2′-(4-fluoro-benzyl)-pyridine-2,3-diamine (600 mg, 2.76 mmol) and CDI (896 mg, 5.52 mmol) were dissolved in anhydrous THE (70 ml). This mixture was allowed to stir at r.t. for 24 hours. Reaction crude was concentrated under reduced pressure and the residue diluted in EtOAc (50 ml), and then washed with water (50 ml) and brine (50 ml). Organic phase was filtered through a silicone treated filter paper and concentrated under reduced pressure to give 800 mg of crude product. This was purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 30 to 70% EtOAc. Required product fractions were concentrated under reduced pressure to afford the title compound (458 mg, 68%).

(277) LCMS Method: 1, RT: 3.48 min, MI: 244 [M+1]

(278) .sup.1H-NMR, Method 1: (CDCl.sub.3) 9.91 (br 1H), 8.08 (dd 1H), 7.50-7.47 (m 2H), 7.31 (dd 1H), 7.02-6.97 (m 3H), 5.15 (s 2H).

Synthesis of 2-chloro-3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridine

(279) ##STR00381##

(280) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 3-(4-fluoro-benzyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (458 mg, 1.88 mmol) was dissolved in POCl.sub.3 (6 ml) and heated to reflux at 110° C. PCl.sub.5 (392 mg, 1.88 mmol) was added to the refluxing suspension and mixture was refluxed for 20 hours. Reaction crude was cooled down to r.t. and quenched by gradually adding the crude solution to a stirring flask of water. It was then basified with 6M NaOH aqueous solution. This was extracted with EtOAc (250 ml), organic phases were filtered through a silicone treated filter paper and concentrated under reduced pressure to give 400 mg of crude product. This material was purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 20% EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (184 mg, 38%).

(281) LCMS Method: 4LCMS1, RT: 4.37 min, MI: 262 [M+1]

(282) .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.41 (dd 1H), 7.98 (dd 1H), 7.38-7.35 (m 2H), 7.28 (dd 1H), 7.00 (tt 2H), 5.48 (s 2H).

Synthesis of [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yloxy]-acetic Acid Methyl Ester

(283) ##STR00382##

(284) In a round bottom flask, fitted with magnetic stirrer and reflux condenser, methyl glycolate (90 μl, 1 mmol) was dissolved in DMF (4 ml) and allowed to stir at r.t. under N.sub.2. NaH 60% in oil (50 mg, 1.25 mmol) was then added and the mixture was stirred at 40° C. for 1 h under N.sub.2. 2-Chloro-3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridine (131 mg, 0.5 mmol) was added and mixture stirred at 80° C. overnight. Reaction crude was concentrated under reduced pressure and then partitioned between water and DCM. Organic phases were filtered through a silicone treated filter paper and concentrated under reduced pressure. Crude material was purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 70% EtOAc. Required product fractions were combined and concentrated under reduced pressure to afford the title compound (42 mg, 26%).

(285) LCMS Method: 1, RT: 4.19 min, MI: 316 [M+1]

(286) .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.20 (dd 1H), 7.74 (dd 1H), 7.44-7.40 (m 2H), 7.12 (dd 1H), 6.98 (tt 2H), 5.30 (s 2H), 5.12 (s 2H), 3.79 (s 3H).

General Synthesis of 2-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl)-propionamide of General Formula F-35 (Scheme 007)

(287) ##STR00383##

(288) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-20 was prepared as in Scheme 005. Treatment of intermediate F-20 with tert-butyl 2-bromopropionate afforded the ester of general formula F-34. Hydrolysis of this ester with TFA yielded the carboxylic acid of general formula F-35. Reaction of this acid with the required amine 2 and HBTU afforded the final compounds of general formula F-36.

(289) F-1 was the following intermediate:

(290) ##STR00384##

(291) The above synthesis (Scheme 007) is illustrated by the preparation of N—((R)-2-hydroxy-1-phenyl-ethyl)-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-propionamide (Ex. 154) described below.

Synthesis of 2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-propionic Acid Tert-Butyl Ester

(292) ##STR00385##

(293) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridine-2-thiol (150 mg, 0.46 mmol) and tert-butyl 2-bromopropionate (77 μl, 0.46 mmol) were refluxed for 2 h in acetone (5 ml) in the presence of K.sub.2CO.sub.3 (96 mg, 0.69 mmol). Heat was switched off and reaction mixture left stirring overnight. Solvent was concentrated under reduced pressure and residue taken up in water (20 ml) and extracted with EtOAc (20 ml). The organic layer was washed with 2M NaOH aqueous solution (20 ml) and subsequently dried and evaporated under reduced pressure to afford 224 mg of crude product. This was purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 30% EtOAc. Product fractions were concentrated under reduced pressure to afford the title compound (192 mg, 91%).

(294) LCMS Method: 1, RT: 6.00 min, MI: 454 [M+1]

(295) .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.30 (dd 1H), 7.90 (dd 1H), 7.39 (dt 2H), 7.20 (dd 1H), 7.15 (d 2H), 5.46 (d 1H), 5.39 (d 1H), 4.70 (q 1H), 1.67 (d 3H), 1.41 (s 9H).

Synthesis of 2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-propionic Acid

(296) ##STR00386##

(297) In a round bottom flask fitted with magnetic stirrer, 2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-propionic acid tert-butyl ester (97 mg, 0.21 mmol) was dissolved in DCM (2 ml) and TFA (1 ml) was added in. Mixture was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure to afford the title compound (80 mg, 100%).

(298) LCMS Method: 1, RT: 4.93 min, MI: 398 [M+1]

(299) .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.50 (dd 1H), 8.07 (dd 1H), 7.42 (dd 1H), 7.39 (dt 2H), 7.20 (d 2H), 5.58 (d 1H), 5.45 (d 1H), 4.47 (q 1H), 1.70 (d 3H).

Synthesis of N—((R)-2-hydroxy-1-phenyl-ethyl)-2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-propionamide (Ex. 154)

(300) ##STR00387##

(301) In a round bottom flask fitted with magnetic stirrer, a solution of 2-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylsulfanyl]-propionic acid (97 mg, 0.24 mmol) and (R)-2-amino-2-phenyl-ethanol (37 μl, 0.27 mmol) in anhydrous DMF (3 ml) were treated with HBTU (102 mg, 0.27 mmol) and NEt.sub.3 (34 μl, 0.47 mmol) and stirred at r.t. overnight. The reaction mixture was diluted with EtOAc (15 ml) and washed with NaHCO.sub.3 aqueous solution (15 ml) and brine (10 ml). The organic layer was then filtered through a silicone treated filter paper and concentrated under reduced pressure. Crude material was purified by reverse phase mass-directed preparative HPLC, using LCMS Method 5 or 6. Product fractions were concentrated in the Genevac™ to afford the title compound (58 mg, 45%).

(302) LCMS Method: 1, RT: 4.74 and 4.87 min, MI: 517 [M+1], 2 diastereoisomers.

General Synthesis of 3-[3-(4-hydroxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-41 and 3-(3-(4-alkoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide of General Formula F-42 (Scheme 008)

(303) ##STR00388##

(304) Intermediate F-37 was prepared following the same procedure as for intermediate F-2 in Scheme 001, using 4-benzyloxy-benzylamine as the amine. Intermediate F-38 was prepared following the same procedure as for intermediate F-3 in Scheme 001. Intermediates F-39 and F-40 were prepared following the same procedure as for intermediates F-6 and F-5 in Scheme 002-A. Hydrogenation of intermediate F-40 over Pd(OH).sub.2/C afforded the 3-[3-(4-hydroxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide of general formula F-41. Treatment of this intermediate with K.sub.2CO.sub.3 and the required halide afforded the final compounds of general formula F-42.

(305) F-1 was the following intermediate:

(306) ##STR00389##

(307) The above synthesis (Scheme 008) is illustrated by the preparation of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-[3-(4-isobutoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 156) described below.

Synthesis of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-[3-(4-hydroxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 155)

(308) ##STR00390##

(309) In a round bottom flask fitted with magnetic stirrer, 3-[3-(4-benzyloxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-fluoro-phenyl)-ethyl]-propionamide (410 mg, 0.81 mmol) and 20% Pd(OH).sub.2/C (50 mg) were purged with N.sub.2 and then treated with MeOH (20 ml). The suspension was stirred under a H.sub.2 atmosphere for 24 hours at r.t. Suspension was filtered through Celite® with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (340 mg, 100% yield). From this material, 90 mg were further purified by reverse phase mass-directed preparative HPLC, using LCMS Method 5 or 6. Product fractions were concentrated in the Genevac™ to the title compound (38 mg).

Synthesis of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-[3-(4-isobutoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 156)

(310) ##STR00391##

(311) In a round bottom flask fitted with magnetic stirrer and reflux condenser, a mixture of N—[(S)-1-(4-fluoro-phenyl)-ethyl]-3-[3-(4-hydroxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (65 mg, 0.15 mmol) and K.sub.2CO.sub.3 (26 mg, 0.19 mmol) in acetonitrile (1.5 ml) was treated with isobutyl bromide (18 μl, 0.17 mmol) and heated to 90° C. in a sealed tube overnight. The reaction mixture was treated with additional isobutyl bromide and K.sub.2CO.sub.3 and heated for a further 24 hours. The reaction mixture was diluted with EtOAc, washed with saturated NH.sub.4Cl aqueous solution and brine, dried and concentrated under reduced pressure. Crude product was purified by reverse phase mass-directed preparative HPLC, using either LCMS Method 5 or 6. Product fractions were concentrated in the Genevac™ to afford the title compound (16 mg, 23%).

(312) The following compounds were prepared according to the general synthesis shown in Scheme 008:

(313) TABLE-US-00008 General Example formula Halide Amine Characterisation 155 F-41 None LCMS Method: 1, RT: 3.40 min, MI: 419 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 9.43 (bs 1H), 8.43 (d 1H), 8.35 (dd 1H), 8.02 (dd 1H), 7.32-7.28 (m 3H), 7.08-7.03 (m 4H), 6.68 (dt 2H), 5.38 (s 2H), 4.92-4.85 (m 1H), 3.14-3.01 (m 2H), 2.79-2.66 (m 2H), 1.31 (d 3H) 156 F-42 LCMS Method: 1, RT: 4.89 min, MI: 475 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.43 (d 1H), 8.32 (dd 1H), 8.00 (dd 1H), 7.32-7.25 (m 3H), 7.14 (d 2H), 7.05 (tt 2H), 6.86 (dt 2H), 5.41 (s 2H), 4.93-4.86 (m 1H), 3.68 (d 2H), 3.11-2.98 (m 2H), 2.79-2.66 (m 2H), 2.01-1.91 (m 1H), 1.32 (d 3H), 0.94 (d 6H)

General synthesis of (3-aralkyl-3H-imidazo[4,5-b]pyridin-2-ylmethyl)-urea of General Formula F-46 and (3-aralkyl-3H-imidazo[4,5-b]pyridin-2-ylmethyl)-carbamate of General Formula F-47 (Scheme 009)

(314) ##STR00395##

(315) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-3 was reacted with glycolic acid to give the alcohol of general formula F-43, which was submitted to a Mitsunobu reaction with phthalimide to yield the imide of general formula F-44. Cleavage of the imide with hydrazine hydrate in ethanol afforded the primary amine of general formula F-45. Reaction of this intermediate with either the required isocyanate or with a mixture of triphosgene and the required amine afforded the ureas of general formula F-46. Finally, reaction of the same amine (F-45) with the required alcohol and CDI afforded the carbamates of general formula F-47.

(316) F-1 was the following intermediate:

(317) ##STR00396##

(318) The above synthesis (Scheme 009) is illustrated by the preparation of Example 161 and Example 162 described below.

Synthesis of [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-methanol

(319) ##STR00397##

(320) In a round bottom flask fitted with magnetic stirrer and reflux condenser, a mixture of N′2′-(4-fluoro-benzyl)-pyridine-2,3-diamine (2.56 g, 11.82 mmol) and glycolic acid (2.25 g, 29.55 mmol) was heated at 150° C. for 24 hours. Reaction crude was cooled and then treated with 2M HCl aqueous solution (20 ml). This mixture was sonicated to break up the thick oil and then stirred for a further 3 h. Aqueous ammonia (15 ml) was added followed by MeOH to give a black solution which was concentrated under reduced pressure. The crude product was purified by column chromatography with a gradient of MeOH and DCM, product eluted with 1 to 4% MeOH. Product fractions were combined and concentrated under reduced pressure to provide the title compound (2.38 g, 78%).

(321) LCMS Method: 1, RT: 2.90 min, MI: 258 [M+1]

(322) .sup.1H-NMR, Method 1: (DMSO) 8.35 (dd 1H), 8.06 (dd 1H), 7.36-7.32 (m 2H), 7.29 (dd 1H), 7.14 (tt 2H), 5.80 (t 1H), 5.57 (s 2H), 4.72 (d 2H).

Synthesis of 2-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-isoindole-1,3-dione

(323) ##STR00398##

(324) In a round bottom flask fitted with magnetic stirrer, [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-methanol (2.38 g, 9.25 mmol), phthalimide (1.76 g, 12 mmol) and PPh.sub.3 (3.2 g, 12.2 mmol) were dissolved in THE (100 ml) and the mixture was cooled to 0° C. with stirring under N.sub.2. DIAD (2.4 ml, 12.2 mmol) was added dropwise and the reaction mixture was slowly allowed to reach r.t. and then stirred overnight. The suspension was filtered and the white solid obtained washed with Et.sub.2O. The filtrate was evaporated, re-dissolved in EtOAc and washed with water and brine. The organic extract was dried and concentrated under reduced pressure and the crude product purified by column chromatography with a gradient of EtOAc and cyclohexane, product eluted with 30 to 100% EtOAc. Product fractions were combined and evaporated under reduced pressure to afford the title compound (2.15 g, 60%).

(325) LCMS Method: 1, RT: 4.22 min, MI: 231 [M+1]

Synthesis of [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-methylamine

(326) ##STR00399##

(327) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 2-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-isoindole-1,3-dione (2.15 g, 5.56 mmol) in EtOH (80 ml) was treated with hydrazine hydrate (1.35 ml, 27.8 mmol) and heated to reflux overnight. The thick suspension was cooled in an ice bath and filtered. The obtained white solid was washed with cold EtOH. The filtrate was concentrated under reduced pressure and purified by column chromatography with a gradient of MeOH and DCM, product eluted with 5-10% MeOH. Product fractions were combined and concentrated under reduced pressure to afford the title compound (1.37 g, 97%).

(328) LCMS Method: 1, RT: 2.05 min, MI: 257 [M+1]

(329) .sup.1H-NMR, Method 1: (DMSO) 8.32 (dd 1H), 8.03 (dd 1H), 7.32-7.26 (m 3H), 7.15 (tt 2H), 5.56 (s 2H), 3.94 (s 2H).

Synthesis of 1-[3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-((S)-1-phenyl-ethyl)-urea (Ex. 161)

(330) ##STR00400##

(331) In a round bottom flask fitted with magnetic stirrer, a solution of [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-methylamine (50 mg, 0.19 mmol) in DCM (4 ml) was treated with NEt.sub.3 (200 μl, 1.47 mmol) and ((S)-1-isocyanato-ethyl)-benzene (31 μl, 0.22 mmol) and mixture was stirred at r.t. overnight. Reaction mixture was diluted with DCM, washed with brine, dried and concentrated under reduced pressure. The crude product was purified by reverse phase mass-directed preparative HPLC, using LCMS Method 5 or 6. Product fractions were combined and concentrated in the Genevac™ to afford the title compound (55 mg, 69%).

Synthesis of 1-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl]-3-((R)-2-hydroxy-1-phenyl-ethyl)-urea (Ex. 162)

(332) ##STR00401##

(333) In a round bottom flask fitted with magnetic stirrer, to a solution of triphosgene (56 mg, 0.189 mmol) in dry DCM (1 ml) at 0° C. was added [3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-methylamine (140 mg, 0.51 mmol) in dry DCM (1 ml) dropwise (gave a bright pink solution). NEt.sub.3 (141 μl, 1.02 mmol) in DCM (1 ml) was added immediately (reaction mixture turned yellow) and the resulting solution was stirred at 0° C. for 30 min. (R)-2-amino-2-phenyl-ethanol (105 mg, 0.77 mmol) was added and the reaction mixture stirred overnight. Reaction crude was concentrated under reduced pressure and triturated in EtOAc (15 ml). A white precipitate was filtered off and the filtrate concentrated under reduced pressure. Filtrate was purified by reverse phase mass-directed preparative HPLC, using LCMS Method 5 or 6. Product fractions were concentrated in the Genevac™ to give the title compound (10 mg, 5%).

(334) The following compounds were prepared according to the general synthesis shown in Scheme 009:

(335) TABLE-US-00009 General Example formula Amine 1 Amine 2 Characterisation 157 F-46 02 03 LCMS Method: 1, RT: 4.26 min, MI: 438 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (dd 1H), 8.05 (dd 1H), 7.37-7.33 (m 2H), 7.31-7.25 (m 5H), 7.12 (tt 2H), 6.73 (d 1H), 6.51 (t 1H), 5.50 (s 2H), 4.75-4.68 (m 1H), 4.53-4.42 (m 2H), 1.29 (d 3H) 158 F-46 04 05 LCMS Method: 1, RT: 4.47 min, MI: 500 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (dd 1H), 8.06 (dd 1H), 7.48 (dt 2H), 7.39-7.28 (m 3H), 7.23 (dt 2H), 7.04-7.01 (m 1H), 6.71 (d 1H), 6.52 (t 1H), 5.50 (s 2H), 4.72-4.65 (m 1H), 4.56-4.44 (m 2H), 1.28 (d 3H) 159 F-46 06 07 LCMS Method: 1, RT: 3.86 min, MI: 434 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (dd 1H), 8.05 (dd 1H), 7.31-7.26 (m 3H), 7.20 (dt 2H), 7.13 (tt 2H), 6.86 (dt 2H), 6.59 (d 1H), 6.48 (t 1H), 5.51 (s 2H), 4.72-4.65 (m 1H), 4.54-4.44 (m 2H), 3.72 (s 3H), 1.28 (d 3H) 160 F-46 08 09 LCMS Method: 1, RT: 3.99 min, MI: 422 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (dd 1H), 8.05 (dd 1H), 7.33-7.26 (m 5H), 7.15-7.10 (m 4H), 6.69 (d 1H), 6.50 (t 1H), 5.51 (s 2H), 4.77-4.70 (m 1H), 4.54-4.43 (m 2H), 1.30 (d 3H) 161 F-46 0 LCMS Method: 1, RT: 3.90 min, MI: 404 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (dd 1H), 8.05 (dd 1H), 7.32-7.26 (m 7H), 7.23-7.19 (m 1H), 7.13 (tt 2H), 6.68 (d 1H), 6.51 (t 1H), 5.51 (s 2H), 4.77-4.70 (m 1H), 4.55-4.44 (m 2H), 1.31 (d 3H) 162 F-46 LCMS Method: 1, RT: 3.50 min, MI: 437 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.33 (dd 1H), 8.05 (dd 1H), 7.37-7.19 (m 8H), 7.05-7.02 (m 1H), 6.76-6.71 (m 2H), 5.51 (s 2H), 4.87 (t 1H), 4.69-4.64 (m 1H), 4.56-4.46 (m 2H), 3.58-3.49 (m 2H) 163 F-46 LCMS Method: 1, RT: 3.63 min, MI: 506 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.33 (dd 1H), 8.05 (dd 1H), 7.38-7.28 (m 3H), 7.13 (d 2H), 7.04-7.01 (m 1H), 6.87 (d 2H), 6.52 (d 1H), 6.47 (t 1H), 5.51 (s 2H), 4.68-4.61 (m 1H), 4.56-4.45 (m 2H), 3.73 (t 4H), 3.05 (t 4H), 1.26 (d 3H) 164 F-47 LCMS Method: 1, RT: 4.35 min, MI: 423 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.35 (dd 1H), 8.06 (dd 1H), 7.92 (t 1H), 7.41-7.37 (m 2H), 7.31 (dd 1H), 7.27-7.11 (m 6H), 5.66 (q 1H), 5.51 (s 2H), 4.54-4.43 (m 2H), 1.42 (d 3H) 165 F-46 LCMS Method: 1, RT: 3.91 min, MI: 434 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (dd 1H), 8.04 (dd 1H), 7.31-7.26 (m 3H), 7.22 (t 1H), 7.13 (tt 2H), 6.86-6.85 (m 2H), 6.79-6.76 (m 1H), 6.68 (d 1H), 6.50 (t 1H), 5.51 (s 2H), 4.74-4.67 (m 1H), 4.54-4.44 (m 2H), 3.73 (s 3H), 1.29 (d 3H)

General Synthesis of Alkyl-Carbamic Acid 3-aralkyl-3H-imidazo[4,5-b]pyridin-2-ylmethyl Ester of General Formula F-48 (Scheme 010)

(336) ##STR00420##

(337) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-43 was prepared as in Scheme 009. Alcohol of general formula F-43 was reacted with the required isocyanate to afford the final compounds of general formula F-48.

(338) F-1 was the following intermediate:

(339) ##STR00421##

(340) The above synthesis (Scheme 010) is illustrated by the preparation of [(S)-1-(4-fluoro-phenyl)-ethyl]-carbamic acid 3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl ester (Ex. 166) described below.

Synthesis of [(S)-1-(4-fluoro-phenyl)-ethyl]-carbamic acid 3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-ylmethyl Ester (Ex. 166)

(341) ##STR00422##

(342) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 1-fluoro-4-((S)-1-isocyanato-ethyl)-benzene (225 mg, 1.36 mmol) was added to a solution of [3-(4-fluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-methanol (70 mg, 0.27 mmol) in THE (1 ml) with ice-cooling. After 1.5 hours of stirring at 0° C., the ice-bath was removed and reaction crude heated to 40° C. overnight. Reaction crude was diluted with EtOAc (15 ml), washed with water (10 ml), filtered through a silicone treated filter paper and concentrated under reduced pressure to yield 174 mg of crude product. This material was purified by reverse phase mass-directed preparative HPLC using either LCMS Method 5 or 6 and concentrated in the Genevac™ to afford the title compound (4 mg, 4%).

(343) LCMS Method: 1, RT: 4.55 min, MI: 423 [M+1]

(344) .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.44 (dd 1H), 8.08 (dd 1H), 7.29 (dd 1H), 7.24-7.21 (m 2H), 7.17-7.11 (m 2H), 7.03-6.92 (m 4H), 5.54 (s 2H), 5.32 (d 1H), 5.22 (d 1H), 4.91 (bs 1H), 4.80-4.73 (m 1H), 1.43 (d 3H).

General Synthesis of N-(4-amino-benzyl)-3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide F-50 (Scheme 011)

(345) ##STR00423## ##STR00424##

(346) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-49 was prepared following the same procedure as for intermediate F-5 in Scheme 002-A, using (S)-1-(4-bromo-phenyl)-ethylamine as the required amine. Compounds of general formula F-49 were submitted to a Buchwald coupling with the required amine 2 to afford the final compounds of general formula F-50.

(347) F-1 could be any of the following intermediates:

(348) ##STR00425##

(349) The above synthesis (Scheme 011) is illustrated by the preparation of N—{(S)-1-[4-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 167) described below.

Synthesis of N—{(S)-1-[4-(4-methyl-piperazin-1-yl)-phenyl]-ethyl}-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 167)

(350) ##STR00426##

(351) In a MW vial, N—[(S)-1-(4-bromo-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (218 mg, 0.39 mmol), 1-methylpiperazine (0.16 mL, 1.593 mmol), Pd.sub.2(dba).sub.3 (20 mg, 0.02 mmol), X-Phos (19 mg, 0.04 mmol) and Na.sup.tOBu (61 mg, 0.64 mmol) were dissolved in 4 mL of dioxane and heated in the MW to 140° C. for 1 hour. Solvent was concentrated under reduced pressure and the crude product was purified by reverse phase mass-directed preparative HPLC using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ and material obtained was passed through an SCX cartridge. Required product was eluted with ammonia in MeOH solution. Eluent was concentrated under reduced pressure to afford the title compound (74 mg, 32%).

(352) The following compounds of general formula F-50 were prepared according to the general synthesis shown in Scheme 011:

(353) TABLE-US-00010 Example SM Amine 1 Amine 2 Characterisation 167 F-1a LCMS Method: 1, RT: 2.69 min, MI: 567 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.28 (m 2H), 8.01 (dd 1H), 7.30 (s 4H), 7.27 (dd 1H), 7.08 (d 2H), 6.77 (d 2H), 5.53 (s 2H), 4.84-4.77 (m 1H), 3.11-2.98 (m 6H), 2.79-2.66 (m 2H), 2.45 (t 4H), 2.22 (s 3H), 1.28 (d 3H) 168 F-1a 0 LCMS Method: 1, RT: 2.78 min, MI: 581 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30 (dd 1H), 8.25 (d 1H), 8.02 (dd 1H), 7.30 (s 4H), 7.28 (dd 1H), 7.03 (d 2H), 6.37 (d 2H), 5.54 (s 2H), 4.82-4.75 (m 1H), 3.28 (td 2H), 3.20-3.14 (m 1H), 3.05 (td 2H), 2.98 (t 1H), 2.83-2.76 (m 1H), 2.76-2.65 (m 2H), 2.22 (s 6H), 2.18-2.10 (m 1H), 1.83-1.74 (m 1H), 1.27 (d 3H) 169 F-1a LCMS Method: 1, RT: 2.78 min, MI: 581 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30 (dd 1H), 8.25 (d 1H), 8.02 (dd 1H), 7.30 (bs 4H), 7.28 (dd 1H), 7.03 (d 2H), 6.37 (d 2H), 5.54 (s 2H), 4.82-4.75 (m 1H), 3.36 (td 1H), 3.28 (td 1H), 3.20-3.13 (m 1H), 3.05 (td 2H), 2.97 (t 1H), 2.82-2.75 (m 1H), 2.75-2.66 (m 2H), 2.21 (s 6H), 2.17-2.10 (m 1H), 1.83-1.73 (m 1H), 1.28 (d 3H) 170 F-1a LCMS Method: 1, RT: 2.77 min, MI: 567 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30 (dd 1H), 8.24 (d 1H), 8.01 (dd 1H), 7.31 (s 4H), 7.28 (dd 1H), 7.00 (d 2H), 6.52 (d 2H), 5.54 (s 2H), 4.78 (m 1H), 3.47 (t 2H), 3.41 (t 2H), 3.08-3.03 (m 2H), 2.82 (t 2H), 2.77-2.66 (m 2H), 2.60 (t 2H), 1.75 (q 2H), 1.28 (d 3H) 171 F-1a LCMS Method: 1, RT: 2.78 min, MI: 581 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.29 (m 2H), 8.02 (dd 1H), 7.30 (s 4H), 7.28 (dd 1H), 7.05 (d 2H), 6.74 (d 2H), 5.54 (s 2H), 4.80 (m 1H), 3.43 (d 2H), 3.07-3.03 (m 2H), 2.87-2.78 (m 2H), 2.77-2.65 (m 2H), 2.06 (td 2H), 1.28 (d 3H), 1.02 (d 6H) 172 F-1a LCMS Method: 1, RT: 2.79 min, MI: 581 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.29 (m 2H), 8.02 (dd 1H), 7.30 (s 4H), 7.28 (dd 1H), 7.07 (d 2H), 6.76 (d 2H), 5.54 (s 2H), 4.80 (m 1H), 3.43 (t 2H), 3.05 (td 2H), 2.97 (dt 1H), 2.79-2.66 (m 4H), 2.59-2.54 (m 1H), 2.53-2.46 (m 1H), 2.16 (t 1H), 1.41-1.33 (m 2H), 1.28 (d 3H), 0.93 (t 3H) 173 F-1a 0 LCMS Method: 1, RT: 2.66 min, MI: 581 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31 (dd 1H), 8.21 (d 1H), 8.01 (dd 1H), 7.31 (s 4H), 7.27 (dd 1H), 6.95 (d 2H), 6.44 (d 2H), 5.54 (s 2H), 5.27 (bs 1H), 4.78-4.75 (m 1H), 3.14-3.09 (m 1H), 3.05 (td 2H), 2.77-2.64 (m 4H), 2.20 (s 3H), 2.05 (t 2H), 1.86-1.83 (m 2H), 1.41-1.30 (m 2H), 1.26 (d 3H) 174 F-1a LCMS Method: 1, RT: 2.71 min, MI: 567 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.29 (m 2H), 8.01 (dd 1H), 7.30 (s 4H), 7.28 (dd 1H), 7.09 (d 2H), 6.76 (d 2H), 5.53 (s 2H), 4.83-4.77 (m 1H), 4.19 (bs 1H), 3.79 (d 1H), 3.49 (d 1H), 3.39 (d 1H), 3.12 (td 1H), 3.04 (td 2H), 2.79-2.67 (m 4H), 2.52 (td 1H), 1.28 (d 3H), 1.18 (d 3H) 175 F-1a LCMS Method: 1, RT: 2.70 min, MI: 553 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31 (dd 1H), 8.23 (d 1H), 8.01 (dd 1H), 7.32 (s 4H), 7.28 (dd 1H), 6.98 (d 2H), 6.45 (d 2H), 5.60 (t 1H), 5.55 (s 2H), 4.81-4.74 (m 1H), 4.49 (bs 1H), 3.86-3.30 (m 2H), 3.12-2.99 (m 3H), 2.93-2.61 (m 4H), 2.06-1.91 (m 1H), 1.54 (bs 1H), 1.27 (d 3H) 176 F-1a LCMS Method: 1, RT: 2.70 min, MI: 567 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.32-8.29 (m 2H), 8.02 (dd 1H), 7.07 (d 2H), 6.76 (d 2H), 5.54 (s 2H), 4.84-4.77 (m 1H), 3.53 (bs 2H), 3.43 (d 2H), 3.05 (td 2H), 2.97 (dt 1H), 2.82-2.66 (m 4H), 2.16 (t 1H), 1.27 (d 3H), 1.03 (d 3H) 177 F-1a LCMS Method: 1, RT: 2.53 min, MI: 533 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30 (dd 1H), 8.24 (d 1H), 8.01 (dd 1H), 7.40-7.30 (m 2H), 7.28 (dd 1H), 7.03 (d 2H), 7.00-6.97 (m 1H), 6.38 (d 2H), 5.49 (s 2H), 4.82-4.75 (m 1H), 3.39-3.33 (m 1H), 3.32-3.26 (m 1H), 3.21-3.13 (m 1H), 3.05 (td 2H), 2.99 (td 1H), 2.87-2.79 (m 1H), 2.77-2.65 (m 2H), 2.24 (s 6H), 2.18-2.11 (m 1H), 1.85-1.75 (m 1H), 1.28 (d 3H) 178 F-1a 0 LCMS Method: 1, RT: 4.45 min, MI: 500 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31 (dd 1H), 8.23 (d 1H), 8.00 (dd 1H), 7.28-7.23 (m 3H), 7.14 (tt 2H), 7.00 (d 2H), 6.50 (d 2H), 5.49 (s 2H), 4.82-4.75 (m 1H), 3.39 (t 4H), 3.11-2.98 (m 2H), 2.77-2.63 (m 2H), 1.69 (bs 4H), 1.43 (t 4H), 1.28 (d 3H) 179 F-1a LCMS Method: 1, RT: 3.12 min, MI: 573 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.33-8.29 (m 2H), 8.02 (dd 1H), 7.39-7.29 (m 2H), 7.27 (dd 1H), 7.09 (d 2H), 7.00-6.97 (m 1H), 6.79 (d 2H), 5.48 (s 2H), 4.85-4.78 (m 1H), 3.53-3.45 (m 2H), 3.40-3.37 (m 1H), 3.10-2.98 (m 3H), 2.82-2.58 (m 5H), 1.29 (d 3H) 180 F-1a LCMS Method: 1, RT: 4.04 min, MI: 472 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31 (dd 1H), 8.23 (d 1H), 8.00 (dd 1H), 7.28-7.22 (m 3H), 7.13 (tt 2H), 7.03 (d 2H), 6.38 (d 2H), 5.49 (s 2H), 4.82-4.75 (m 1H), 3.16-3.14 (m 4H), 3.03 (td 2H), 2.71-2.67 (m 2H), 1.94-1.91 (m 4H), 1.27 (d 3H) 181 F-1a LCMS Method: 1, RT: 2.35 min, MI: 516 [M + 1] — 182 F-1a LCMS Method: 1, RT: 2.41 min, MI: 519 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.28 (m 2H), 8.01 (dd 1H), 7.40-7.30 (m 2H), 7.28 (dd 1H), 7.08 (d 2H), 7.01-6.98 (m 1H), 6.78 (d 2H), 5.49 (s 2H), 4.84-4.77 (m 1H), 3.09-3.00 (m 6H), 2.78-2.66 (m 2H), 2.45 (t 4H), 2.23 (s 3H), 1.28 (d 3H) 183 F-1a 0 LCMS Method: 1, RT: 4.35 min, MI: 490 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31 (dd 1H), 8.23 (d 1H), 8.01 (dd 1H), 7.40-7.30 (m 2H), 7.28 (dd 1H), 7.03 (d 2H), 7.00-6.98 (m 1H), 6.38 (d 2H), 5.50 (s 2H), 4.83-4.75 (m 1H), 3.16 (t 4H), 3.05 (td 2H), 2.76-2.66 (m 2H), 1.95-1.92 (m 4H), 1.28 (d 3H) 184 F-1a LCMS Method: 1, RT: 2.47 min, MI: 519 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.29 (m 2H), 8.01 (dd 1H), 7.39-7.30 (m 2H), 7.28 (dd 1H), 7.07 (d 2H), 7.00-6.97 (m 1H), 6.75 (d 2H), 5.49 (s 2H), 4.84-4.77 (m 1H), 3.44-3.39 (m 2H), 3.08-3.03 (m 2H), 2.96 (dt 1H), 2.81-2.66 (m 4H), 2.49 (td 2H), 2.13 (t 1H), 1.28 (d 3H), 1.03 (d 3H) 185 F-1a LCMS Method: 1, RT: 3.60 min, MI: 488 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.32-8.29 (m 2H), 8.01 (dd 1H), 7.29-7.23 (m 3H), 7.16-7.10 (m 4H), 6.80 (dt 2H), 5.49 (s 2H), 4.86-4.79 (m 1H), 3.73 (t 4H), 3.11-3.00 (m 6H), 2.77-2.65 (m 2H), 1.29 (d 3H) 186 F-1a LCMS Method: 1, RT: 2.64 min, MI: 486 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.32-8.27 (m 2H), 8.01 (dd 1H), 7.29-7.23 (m 3H), 7.14 (tt 2H), 7.07 (dt 2H), 6.77 (dt 2H), 5.49 (s 2H), 4.85-4.77 (m 1H), 3.06-3.02 (m 6H), 2.77-2.65 (m 2H), 1.62-1.57 (m 4H), 1.53-1.49 (m 2H), 1.29 (d 3H) 187 F-1a LCMS Method: 1, RT: 2.69 min, MI: 504 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30-8.26 (m 2H), 8.01 (dd 1H), 7.39-7.30 (m 2H), 7.28 (dd 1H), 7.06 (d 2H), 7.00-6.97 (m 1H), 6.76 (d 2H), 5.48 (s 2H), 4.83-4.76 (m 1H), 3.07-3.03 (m 6H), 2.78-2.65 (m 2H), 1.62-1.56 (m 4H), 1.53-1.48 (m 2H), 1.28 (d 3H) 188 F-1a 0 LCMS Method: 1, RT: 2.47 min, MI: 519 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31-8.29 (m 2H), 8.01 (dd 1H), 7.39-7.30 (m 2H), 7.28 (dd 1H), 7.07 (d 2H), 7.01-6.97 (m 1H), 6.76 (d 2H), 5.49 (s 2H), 4.84-4.77 (m 1H), 3.44-3.42 (m 4H), 3.06 (td 2H), 2.97 (d 1H), 2.83-2.66 (m 4H), 2.16 (t 1H), 1.28 (d 3H), 1.04 (d 3H) 189 F-1c LCMS Method: 1, RT: 2.77 min, MI: 567 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.24 (d 1H), 8.15 (d 1H), 7.81 (d 1H), 7.32-7.27 (m 4H), 6.97 (d 2H), 6.44 (d 2H), 5.60 (t 1H), 5.51 (s 2H), 4.80-4.73 (m 1H), 3.75 (bs 1H), 3.57-3.25 (m 1H), 3.07-2.97 (m 3H), 2.92-2.86 (m 1H), 2.81-2.75 (m 1H), 2.71 (q 2H), 2.61 (dd 1H), 2.41 (s 3H), 2.00-1.91 (m 1H), 1.56-1.47 (m 1H), 1.27 (d 3H) 190 F-1a LCMS Method: 1, RT: 3.60 min, MI: 506 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30 (dd 1H), 8.23 (d 1H), 8.00 (dd 1H), 7.40-7.30 (m 2H), 7.28 (dd 1H), 7.02 (d 2H), 7.00-6.97 (m 1H), 6.35 (d 2H), 5.49 (s 2H), 4.91 (bs 1H), 4.82-4.75 (m 1H), 4.37 (bs 1H), 3.36-3.24 (m 2H), 3.19 (td 1H), 3.07-2.98 (m 3H), 2.76-2.64 (m 2H), 2.06-1.97 (m 1H), 1.89-1.82 (m 1H), 1.27 (d 3H) 191 F-1c LCMS Method: 1, RT: 2.81 min, MI: 581 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.27 (d 1H), 8.15 (d 1H), 7.83 (d 1H), 7.29 (s 4H), 7.00 (d 2H), 6.50 (d 2H), 5.51 (s 2H), 4.83-4.75 (m 1H), 3.47 (t 2H), 3.41-3.38 (m 3H), 3.09-2.97 (m 2H), 2.81 (t 2H), 2.78-2.64 (m 2H), 2.58 (t 2H), 2.41 (s 3H), 1.77-1.71 (m 2H), 1.28 (d 3H) 192 F-1c LCMS Method: 1, RT: 2.80 min, MI: 581 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.31 (d 1H), 8.15 (d 1H), 7.83 (d 1H), 7.31-7.26 (m 4H), 7.06 (d 2H), 6.73 (d 2H), 5.50 (s 2H), 4.84-4.77 (m 1H), 3.41 (d 2H), 3.09-2.92 (m 3H), 2.79-2.64 (m 4H), 2.45 (td 1H), 2.42 (s 3H), 2.11 (t 1H), 1.28 (d 3H), 1.02 (d 3H) 193 F-1a 0 LCMS Method: 1, RT: 2.43 min, MI: 505 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.30-8.28 (m 2H), 8.00 (dd 1H), 7.39-7.29 (m 2H), 7.27 (dd 1H), 7.08 (d 2H), 7.00-6.97 (m 1H), 6.77 (d 2H), 5.48 (s 2H), 4.84-4.76 (m 1H), 3.07-3.00 (m 6H), 2.87 (t 4H), 2.78-2.65 (m 2H), 1.28 (d 3H)

General Synthesis of [3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl-propionylamino)-acetic Acid of General Formula F-52 (Scheme 012)

(354) ##STR00481##

(355) R.sub.8 is (1-6C)alkyl.

(356) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-51 was prepared following the same procedure as for intermediate F-5 in Scheme 002-A, using an α-aminoacid as the required amine 2. Intermediate of general formula F-51 was hydrolysed in basic conditions (LiOH or NaOH in THE/water) or acid conditions (TFA in DCM) to afford the final compounds of general formula F-52.

(357) F-1 could be any of the following intermediates:

(358) ##STR00482##

(359) The above synthesis (Scheme 012) is illustrated by the preparation of (R)-cyclohexyl-{3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-acetic acid (Ex. 194) described below.

Synthesis of (R)-cyclohexyl-{3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-acetic Acid (Ex. 194)

(360) ##STR00483##

(361) In a round bottom flask fitted with magnetic stirrer, (R)-cyclohexyl-{3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-acetic acid methyl ester (130 mg, 0.25 mmol) was dissolved in THE (5 mL) and water (2.5 mL) and then treated with LiOH monohydrate (31 mg, 0.75 mmol). This mixture was allowed to stir at r.t. for 2 hours. Reaction crude was neutralized to pH 7 with HCl 2 N aqueous solution and concentrated under reduced pressure. Crude product was purified by column chromatography with a gradient of EtOAc/MeOH, required product eluted with 15% MeOH. Product fractions were combined and concentrated under reduced pressure, then further purified by reverse phase mass-directed preparative HPLC using LCMS Method 5. Product fractions were combined and concentrated in the Genevac™ to afford the title compound (31.5 mg, 23%).

(362) The following compounds of general formula F-52 were prepared according to the general synthesis shown in Scheme 012:

(363) TABLE-US-00011 Example SM Amine 1 Amine 2 Characterisation 194 F-1a LCMS Method: 1, RT: 4.42 min, MI: 505 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.53 (bs 1H), 8.30 (dd 1H), 8.13 (d 1H), 7.98 (dd 1H), 7.32 (s 4H), 7.27 (dd 1H), 5.57 (s 2H), 4.14 (dd 1H), 3.11-2.98 (m 2H), 2.87-2.80 (m 1H), 2.76-2.67 (m 1H), 1.68-1.49 (m 6H), 1.17-0.92 (m 5H) 195 F-1a LCMS Method: 1, RT: 4.27 min, MI: 513 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.71 (bs 1H), 8.37-8.35 (m 2H), 8.05 (d 1H), 7.35-7.30 (m 5H), 7.19 (bs 2H), 7.18 (bs 2H), 7.17-7.11 (m 1H), 5.57 (s 2H), 4.44-4.39 (m 1H), 3.05-3.01 (m 3H), 2.84 (dd 1H), 2.73-2.69 (m 2H) 196 F-1a LCMS Method: 1, RT: 4.25 min, MI: 497 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.69 (bs 1H), 8.33 (d 1H), 8.29 (dd 1H), 8.00 (dd 1H), 7.69 (d 2H), 7.35 (d 2H), 7.28 (dd 1H), 7.18-7.11 (m 5H), 5.61 (s 2H), 4.44-4.38 (m 1H), 3.03 (dd 1H), 2.95 (t 2H), 2.83 (dd 1H), 2.69 (t 2H) 197 F-1a 0 LCMS Method: 1, RT: 3.89 min, MI: 495 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.71 (bs 1H), 8.34 (d 1H), 8.31 (dd 1H), 7.99 (dd 1H), 7.20 (t 1H), 7.29-7.12 (m 10H), 5.49 (s 2H), 4.45-4.40 (m 1H), 3.04 (dd 1H), 2.98 (t 2H), 2.85 (dd 1H), 2.69 (t 2H) 198 F-1a LCMS Method: 1, RT: 3.88 min, MI: 465 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.70 (bs 1H), 8.33 (d 1H), 8.31 (dd 1H), 7.99 (dd 1H), 7.41-7.28 (m 2H), 7.27 (dd 1H), 7.20-7.12 (m 5H), 6.99-6.96 (m 1H), 5.48 (s 2H), 4.44-4.39 (m 1H), 3.06-2.96 (m 3H), 2.84 (dd 1H), 2.69 (t 2H) 199 F-1a LCMS Method: 1, RT: 4.28 min, MI: 513 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.71 (bs 1H), 8.33 (d 1H), 8.30 (dd 1H), 7.99 (dd 1H), 7.34-7.26 (m 5H), 7.19-7.12 (m 5H), 5.54 (s 2H), 4.45-4.39 (m 1H), 3.04 (dd 1H), 2.97 (t 2H), 2.85 (dd 1H), 2.70 (t 2H) 200 F-1a LCMS Method: 1, RT: 3.74 min, MI: 529 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.61 (bs 1H), 9.20 (bs 1H), 8.30 (dd 1H), 8.26 (d 1H), 8.00 (dd 1H), 7.34-7.30 (m 4H), 7.27 (dd 1H), 6.99 (d 2H), 6.62 (d 2H), 5.54 (s 2H), 4.36-4.30 (m 1H), 2.99 (t 2H), 2.91 (dd 1H), 2.73 (dd 1H), 2.70 (t 2H) 201 F-1a LCMS Method: 1, RT: 3.87 min, MI: 461 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.70 (s 1H), 8.32 (d 1H), 8.25 (dd 1H), 7.94 (dd 1H), 7.38-7.35 (m 2H), 7.23-7.12 (m 8H), 5.99 (q 1H), 4.46 (m 1H), 3.04 (dd 1H), 2.98 (t 2H), 2.85 (dd 1H), 2.73-2.64 (m 2H), 2.03 (d 3H) 202 F-1a 00 01 LCMS Method: 1, RT: 3.55 min, MI: 435 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 12.70 (bs 1H), 8.35-8.32 (m 2H), 7.97 (dd 1H), 7.43 (dd 1H), 7.27 (dd 1H), 7.22-7.14 (m 5H), 7.09 (dd 1H), 6.97 (dd 1H), 5.66 (s 2H), 4.46-4.40 (m 1H), 3.08-3.02 (m 3H), 2.85 (dd 1H), 2.69 (t 2H)

General Synthesis of 3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-(2-hydroxy-ethyl)-propionamide of General Formula F-53 (Scheme 013)

(364) ##STR00502##

(365) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-51 was prepared following the same procedure as for intermediate F-5 in Scheme 002-A, using an α-aminoacid as the required amine 2. Compounds of general formula F-51 were reduced with LiAlH.sub.4 to afford the final compounds of general formula F-53.

(366) F-1 could be any of the following intermediates:

(367) ##STR00503##

(368) R.sub.8 could be either methyl or tert-butyl.

(369) The above synthesis (Scheme 013) is illustrated by the preparation of N—((R)-1-Hydroxymethyl-2-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 203) described below.

Synthesis of N—((R)-1-Hydroxymethyl-2-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 203)

(370) ##STR00504##

(371) In a round bottom flask fitted with a magnetic stirrer and N.sub.2 connection, LiAlH.sub.4 (39 mg, 1.2 mmol) was dissolved in anhydrous THE (5 ml) under N.sub.2 and cooled to 0° C. with an ice bath. Then, (R)-3-phenyl-2-{3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-propionic acid methyl ester (180 mg, 0.34 mmol) dissolved in anhydrous THE (5 ml) was added in. Reaction mixture was allowed to stir whilst warming to r.t. overnight. Reaction crude was extracted with EtOAc and water, organic phase washed with brine, dried over MgSO.sub.4 and filtered. Filtrate was concentrated under reduced pressure and purified by reverse phase mass-directed preparative HPLC using either LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the title compound (20 mg, 12%).

(372) The following compounds of general formula F-53 were prepared according to the general synthesis shown in Scheme 013:

(373) TABLE-US-00012 Example SM Amine 1 Amine 2 Characterisation 203 F-1a 05 06 LCMS Method: 1, RT: 4.10 min, MI: 499 [M + 1] — 204 F-1a 07 08 LCMS Method: 1, RT: 4.12 min, MI: 499 [M + 1] — 205 F-1a 09 0 LCMS Method: 1, RT: 3.60 min, MI: 514 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 9.13 (bs 1H), 8.30 (dd 1H), 7.99 (dd 1H), 7.79 (d 1H), 7.32 (s 4H), 7.27 (dd 1H), 6.96 (d 2H), 6.61 (d 2H), 5.55 (s 2H), 4.71 (bs 1H), 3.84-3.77 (m 1H), 3.31-3.24 (m 2H), 3.00 (t 2H), 2.71-2.62 (m 3H), 2.54-2.46 (m 1H)

General Synthesis of N-(4-Aminomethyl-benzyl)-3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-54 (Scheme 014)

(374) ##STR00511##

(375) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-49 was prepared following the same procedure as for intermediate F-5 in Scheme 002-A, using (S)-1-(4-bromo-phenyl)-ethylamine as the required amine. Compounds of general formula F-49 were submitted to a Molander coupling to afford the final compounds of general formula F-54.

(376) F-1 could be any of the following intermediates:

(377) ##STR00512##

(378) The above synthesis (Scheme 014) is illustrated by the preparation of 3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-propionamide (Ex. 206) described below.

Synthesis of 3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-propionamide (Ex. 206)

(379) ##STR00513##

(380) In a round bottom flask fitted with a magnetic stirrer and reflux condenser, N—[(S)-1-(4-bromomethyl-phenyl)-ethyl]-3-[3-(3,4-difluoro-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (100 mg, 0.20 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (50 mg, 0.24 mmol) and K.sub.3PO.sub.4 (300 mg, 1.4 mmol) were dissolved in a 1:1 mixture of tert-BuOH and water (2 ml). Then, Pd(OAc).sub.2 (1 mg, 0.002 mmol) and X-Phos (2 mg, 0.004 mmol) were added in. This mixture was heated to 110° C. for 20 hours. Reaction mixture was filtered through Celite® and the solvent concentrated under reduced pressure. Crude material was purified by reverse phase mass-directed preparative HPLC using LCMS Method 5 or 6. Required product fractions were concentrated in the Genevac™ to afford the title compound (21 mg, 21%).

(381) The following compounds of general formula F-54 were prepared according to the general synthesis shown in Scheme 014:

(382) TABLE-US-00013 Example SM Amine Trifluoroborate Characterisation 206 F-1a LCMS Method: 1, RT: 2.36 min, MI: 520 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.40 (d 1H), 8.31 (dd 1H), 8.01 (dd 1H), 7.39-7.27 (m 3H), 7.20 (d 2H), 7.15 (d 2H), 7.01-6.98 (m 1H), 5.48 (s 2H), 4.92-4.84 (m 1H), 3.55 (t 4H), 3.39 (s 2H), 3.11-3.01 (m 2H), 2.81-2.69 (m 2H), 2.30 (bs 4H), 1.31 (d 3H) 207 F-1a LCMS Method: 1, RT: 2.50 min, MI: 506 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.39 (d 1H), 8.30 (dd 1H), 8.01 (dd 1H), 7.39-7.25 (m 3H), 7.20-7.14 (m 4H), 7.01-6.98 (m 1H), 5.49 (s 2H), 4.92-4.84 (m 1H), 3.45 (s 2H), 3.12-3.02 (m 2H), 2.82-2.68 (m 2H), 2.42 (q 4H), 1.32 (d 3H), 0.95 (t 6H) 208 F-1a LCMS Method: 1, RT: 2.40 min, MI: 478 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.40 (d 1H), 8.30 (dd 1H), 8.01 (dd 1H), 7.39-7.30 (m 2H), 7.28 (dd 1H), 7.21 (d 2H), 7.14 (d 2H), 7.01 (m 1H), 5.49 (s 2H), 4.93-4.85 (m 1H), 3.32 (s 2H), 3.11-3.02 (m 2H), 2.82-2.69 (m 2H), 2.11 (s 6H), 1.32 (d 3H)

General Synthesis of 3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-(2-mercapto-ethyl)-propionamide of General Formula F-56 (Scheme 015)

(383) ##STR00520##

(384) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-53 was prepared following the same procedure as for intermediate F-5 in Scheme 002-A, using an α-aminoalcohol as the required amine 2. Compounds of general formula F-53 were submitted to a Mitsunobu reaction with thioacetic acid. The obtained thioester, of general formula F-55, was hydrolyzed in basic media to afford the final compounds of general formula F-56.

(385) F-1 was the following intermediate:

(386) ##STR00521##

(387) The above synthesis (Scheme 015) is illustrated by the preparation of N—((R)-2-mercapto-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 209) described below.

Synthesis of thioacetic acid S—((R)-2-phenyl-2-{3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-ethyl) Ester

(388) ##STR00522##

(389) In a round bottom flask fitted with magnetic stirrer, PPh.sub.3 (484 mg, 1.85 mmol) was dissolved in THE (7 ml) and solution cooled to 0° C. with an ice bath. Once cooled, DIAD (362 mg, 1.85 mmol) was added in and the mixture was stirred for 30 min. A solution of N—((R)-2-hydroxy-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (416 mg, 0.86 mmol) in THE (14 ml) was added in dropwise. Then, thioacetic acid (0.13 ml, 1.85 mmol) was added in. Reaction mixture was stirred at r.t. for 3 hours and then solvent was concentrated under reduced pressure. Crude material was dissolved in EtOAc and washed with water and brine. Organic phase was dried and concentrated under reduced pressure. Residue was purified by column chromatography with a gradient of 50-80% EtOAc/cyclohexane. Product fractions were concentrated under reduced pressure to afford the title compound (138 mg, 30%).

(390) LCMS Method: 1, RT: 4.82 min, MI: 543 [M+1]

Synthesis of N—((R)-2-mercapto-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 209)

(391) ##STR00523##

(392) In a round bottom flask fitted with magnetic stirrer, thioacetic acid S—((R)-2-phenyl-2-{3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-ethyl) ester was dissolved in MeOH and the solution was degassed with N.sub.2 for 1 hour. Solution was cooled to 0° C. with an ice bath and 1M NaOH aqueous solution was then added at 0° C. under N.sub.2. The reaction mixture was stirred for 2 h at 0° C. Reaction mixture was poured into 1M HCl aqueous solution (3 ml) and brine (10 ml). Aqueous phase was extracted with EtOAc and organic phase filtered through a silicone treated filter paper and concentrated under reduced pressure. Crude material was purified by reverse phase mass-directed preparative HPLC using LCMS Method 5 or 6. Product fractions were concentrated in the Genevac™ to afford the title compound (26 mg, 22%).

(393) LCMS Method: 1, RT: 4.73 min, MI: 501 [M+1]

(394) .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.38 (dd 1H), 7.99 (dd 1H), 7.27 (dd 1H), 7.23-7.11 (m 10H), 5.49 (s 2H), 5.17 (dt 1H), 3.16-3.12 (m 2H), 2.97-2.90 (m 3H), 2.88-2.81 (m 1H), 1.18 (dd 1H).

General Synthesis of N-(2-amino-ethyl)-3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-58 (Scheme 016)

(395) ##STR00524##

(396) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-53 was prepared following the same procedure as for intermediate F-5 in Scheme 002-A, using an α-aminoalcohol as the required amine 2. Compounds of general formula F-53 were submitted to a Mitsunobu with phthalimide. The obtained intermediate, of general formula F-57, was treated with hydrazine in ethanol to afford the final compounds of general formula F-58.

(397) F-1 was the following intermediate:

(398) ##STR00525##

(399) The above synthesis (Scheme 016) is illustrated by the preparation of N—((R)-2-amino-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 210) described below.

Synthesis of N—[(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-phenyl-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide

(400) ##STR00526##

(401) In a round bottom flask fitted with magnetic stirrer, PPh.sub.3 (343 mg, 1.31 mmol), phthalimide (192 mg, 1.31 mmol) and N—((R)-2-hydroxy-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (300 mg, 0.62 mmol) were dissolved in anhydrous THE and the reaction mixture cooled to 0° C., whilst stirring under N.sub.2. DIAD (257 μl, 1.31 mmol) was then added dropwise and the reaction mixture allowed to stir over the weekend. Reaction crude was concentrated under reduced pressure, dissolved in EtOAc (40 ml) and washed with water (35 ml) and brine (35 ml). Organic phase was dried and concentrated under reduced pressure. Crude material was purified by column chromatography with a gradient of 0 to 50% EtOAc/cyclohexane and subsequently with a gradient of 0 to 5% MeOH/DCM when required product eluted. Product fractions were combined and concentrated under reduced pressure to afford the title compound (129 mg, 34%)

(402) LCMS Method: 1, RT: 4.89 min, MI: 613 [M+1]

Synthesis of N—((R)-2-amino-1-phenyl-ethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 210)

(403) ##STR00527##

(404) In a round bottom flask fitted with magnetic stirrer and reflux condenser, to a solution of N—[(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-phenyl-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (129 mg, 0.21 mmol) in EtOH (6 ml) was added hydrazine monohydrate (51 μl, 1.05 mmol) and the solution was heated at reflux for 5 hours. Reaction crude was allowed to cool down to r.t. As the reaction mixture cooled, some 2,3-dihydro-phthalazine-1,4-dione precipitated out. The reaction mixture was then filtered and the filtrate was passed through a 5 g SCX cartridge. The SCX cartridge was flushed with MeOH and the product eluted using 2 M ammonia in MeOH solution. Eluent was concentrated under reduced pressure to give 72 mg of an oily solid. This solid was further purified by reverse phase mass-directed preparative HPLC using LCMS Method 7. Product fractions were concentrated in the Genevac™ to afford the title compound (4 mg, 4%).

(405) LCMS Method: 1, RT: 2.74 min, MI: 484 [M+1]

General Synthesis of 3-(3-aralkyl-6-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-63 (Scheme 017)

(406) ##STR00528##

(407) Commercially available 5-bromo-2-chloro-3-nitro-pyridine of formula F-1d was reacted with Cs.sub.2CO.sub.3 and the required amine 1 in methanol at reflux to yield the aralkyl-(5-bromo-3-nitro-pyridin-2-yl)-amine derivatives of general formula F-59. Intermediate F-60 was prepared following the same procedure as for intermediate F-3 in Scheme 001. Intermediates F-61 and F-62 were prepared following the same procedure as for intermediates F-6 and F-5, respectively, in Scheme 002-A. Compounds of general formula F-62 were treated with trimethylboroxine and Pd(PPh.sub.3).sub.4 to afford the final compounds of general formula F-63.

(408) The above synthesis (Scheme 017) is illustrated by the preparation of N—[(S)-1-(4-chloro-phenyl)-ethyl]-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 211) described below.

Synthesis of N—[(S)-1-(4-chloro-phenyl)-ethyl]-3-[6-methyl-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 211)

(409) ##STR00529##

(410) In a round bottom flask fitted with magnetic stirrer and reflux condenser, 3-[6-bromo-3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-N—[(S)-1-(4-chloro-phenyl)-ethyl]-propionamide (150 mg, 0.26 mmol) was dissolved in K.sub.3PO.sub.4 aqueous solution (0.5 ml) and dioxane (3 ml). Mixture was degassed with N.sub.2 for 30 min, then Pd(PPh.sub.3).sub.4 (15 mg, 0.01 mmol) and trimethylboroxine (36 mg, 0.28 mmol) were added in. This mixture was heated at 80° C. under N.sub.2 overnight. Further 0.28 mmol of trimethylboroxine and an additional 0.01 mmol of Pd(PPh.sub.3).sub.4 were added in and stirring was continued for 3 hours at 90° C. Reaction was allowed to cool down to r.t. Reaction mixture was filtered through Celite® and eluted with EtOAc. Filtrate was washed with water and brine, filtered through a silicone treated filter paper and concentrated under reduced pressure. Crude material was purified by reverse phase mass-directed preparative HPLC using LCMS Method 6. Required product fractions were concentrated in the Genevac™ to afford the title compound (27 mg, 21%).

(411) The following compounds of general formula F-63 were prepared according to the general synthesis shown in Scheme 017:

(412) TABLE-US-00014 Example Amine 1 Amine 2 Characterisation 211 0 LCMS Method: 1, RT: 4.97 min, MI: 517 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.21 (d 1H), 7.72 (d 1H), 7.19-7.06 (m 8H), 6.61 (d 1H), 5.58 (d 1H), 5.41 (d 1H), 5.01-4.94 (m 1H), 3.15-3.01 (m 2H), 2.88-2.76 (m 2H), 2.50 (s 3H), 1.38 (d 3H) 212 LCMS Method: 1, RT: 4.59 min, MI: 513 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 8.34 (d 1H), 8.14 (d 1H), 7.82 (d 1H), 7.31-7.26 (m 4H), 7.16 (d 2H), 6.77 (d 2H), 5.50 (s 2H), 4.87-4.79 (m 1H), 3.69 (s 3H), 3.06-2.97 (m 2H), 2.77-2.64 (m 2H), 2.42 (s 3H), 1.29 (d 3H) 213 LCMS Method: 1, RT: 4.45 min, MI: 451 [M + 1] .sup.1H-NMR, Method 1: (DMSO) 7.81 (m 1H), 7.31-7.21 (m 6H), 7.13 (tt 2H), 5.45 (s 2H), 4.90-4.83 (m 1H), 3.08-2.95 (m 2H), 2.78-2.65 (m 2H), 2.43 (s 3H), 1.31 (d 3H)

General Synthesis of N-(1-acyl-piperidin-4-ylmethyl)-3-(3-aralkyl-3H-imidazo[4,5-b]pyridin-2-yl)-propionamide of General Formula F-66 and F66a (Scheme 018)

(413) ##STR00536##

(414) Intermediates F-2 and F-3 were prepared as in Scheme 001. Intermediate F-6 was prepared as in Scheme 002-A. Intermediate F-64 was prepared following the same procedure as for intermediate F-5 in scheme 002-A, using 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester as the required amine. Compounds of general formula F-64 were treated with TFA to afford the deprotected analogues of general formula F-65. This was reacted with the required acid chloride or sulphonyl chloride to afford the final compounds of general formula F-66 and F-66a.

(415) F-1 could be any of the following intermediates:

(416) ##STR00537##

(417) The above synthesis (Scheme 018) is illustrated by the preparation of N-(1-methanesulfonyl-piperidin-4-ylmethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 214) described below.

Synthesis of N-piperidin-4-ylmethyl-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide

(418) ##STR00538##

(419) In a round bottom flask fitted with magnetic stirrer, 4-({3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (461 mg, 0.82 mmol) was dissolved in DCM (4 ml) and TFA (2 ml) was added in. This mixture was allowed to stir at r.t. overnight. Solvent was concentrated under reduced pressure to afford the title compound (380 mg, 100%).

(420) LCMS Method: 1, RT: 2.51 min, MI: 462 [M+1]

Synthesis of N-(1-methanesulfonyl-piperidin-4-ylmethyl)-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (Ex. 214)

(421) ##STR00539##

(422) In a round bottom flask fitted with magnetic stirrer, N-piperidin-4-ylmethyl-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide (126 mg, 0.27 mmol) was dissolved in DCM (3 ml) under N.sub.2. To this solution was added NEt.sub.3 (49 μl, 0.35 mmol) and methanesulphonyl chloride (23 μl, 0.30 mmol). This mixture was stirred overnight at r.t. Reaction crude was extracted with brine and organic phase was filtered through a silicone treated filter paper and concentrated under reduced pressure to give the crude product. This was purified by reverse phase mass-directed preparative HPLC using LCMS Method 5 or 6. Product fractions were concentrated in the Genevac™ to afford the title compound (25 mg, 17%).

(423) The following compounds of general formula F-66 and F66a were prepared according to the general synthesis shown in Scheme 018:

(424) TABLE-US-00015 Example SM Amine Chloride Characterisation 214 F-1a 0 LCMS Method: 1, RT: 3.89 min, MI: 540 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.38 (dd 1H), 7.96 (dd 1H), 7.28-7.24 (m 3H), 7.17-7.15 (m 2H), 6.43 (t 1H), 5.53 (s 2H), 3.71 (d 2H), 3.15-3.11 (m 4H), 2.84 (t 2H), 2.73 (s 3H), 2.50 (td 2H), 1.70-1.66 (m 2H), 1.57-1.50 (m 1H), 1.31-1.20 (m 2H) 215 F-1a LCMS Method: 1, RT: 3.87 min, MI: 530 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.36 (dd 1H), 7.94 (dd 1H), 7.25-7.22 (m 3H), 7.15-7.13 (m 2H), 6.48 (t 1H), 5.53 (s 2H), 4.50 (d 1H), 4.10 (d 1H), 3.21-2.90 (m 5H), 2.82 (t 2H), 2.43 (t 1H), 2.06 (bs 2H), 1.70-1.58 (m 2H), 1.13-0.99 (m 2H), 0.92 (bs 2H), 0.71 (dd 2H) 216 F-1a LCMS Method: 1, RT: 3.57 min, MI: 504 [M + 1] .sup.1H-NMR, Method 1: (CDCl.sub.3) 8.37 (dd 1H), 7.94 (dd 1H), 7.26-7.23 (m 3H), 7.15-7.13 (m 2H), 6.48 (t 1H), 5.53 (s 2H), 4.52 (dt 1H), 3.67 (dt 1H), 3.21-3.10 (m 3H), 3.05-2.98 (m 1H), 2.91-2.81 (m 3H), 2.39 (td 1H), 2.02 (s 3H), 1.66-1.58 (m 3H), 1.08-0.97 (m 2H)
Autotaxin (ATX) Activity
Quanta Red Assay

(425) Measuring ATX activity using an enzyme coupled Quanta Red assay (Thermo Scientific—Pierce Protein Research Products, Product #15159) was determined as follows. 8 μL human recombinant ATX (final concentration 0.8 μg/mL) in 1× Assay buffer containing 50 mM Tris-HCl (pH 8.0), 5 mM CaCl.sub.2 was added to an opaque black flat-bottom 384-well plate (Corning, #3575) containing 2 μL test compound in 40% DMSO (4% final DMSO concentration). 10 μL of Quanta Red, Horseradish peroxidase (HRP), Choline Oxidase (CO), Rac-1-Palmitoyl-glycero-3-phosphocholine solution (final concentration 1:250 for Quanta Red, 0.5 units/ml HRP, 0.5 units/ml CO, 15 NM Rac-1-Palmitoyl-glycero-3-phosphocholine) in 1× assay buffer (as described previously) was added to each well to start the reaction and the plate was incubated at room temperature for 2 hours. The reaction was stopped after 2 hours with a 20 μL addition of Quanta Red Stop solution (1:20 dilution in distilled water). The above-described mixture with DMSO alone was used as a positive control whereas that with DMSO alone without ATX was taken as a negative control.

(426) For each test compound, ten concentrations were measured covering a range of 6.1 nM to 120 μM to determine IC.sub.50 values. The top concentration was decreased to 1.2 μM when a test compound's IC.sub.50 value was evaluated in low nanomolar range. Fluorescence was determined in a BMG Labtech Pherastar plus plate reader (λ emission=540 nm, λ excitation=590 nm). Data were analysed using Excel fit software. IC.sub.50 values were determined in duplicate.

(427) TABLE-US-00016 TABLE 1 ATX activity (Quanta Red assay) Example Activity Structure Name  1  68 nM 3-(3-Benzyl-3H- imidazo[4,5-b]pyridin- 2-yl)-N-((S)-1-phenyl- ethyl)-propionamide  3  855 nM 3-(3-Benzyl-3H- imidazo[4,5-b]pyridin- 2-yl)-N-thiophen-2- ylmethyl-propionamide  4 2631 nM 3-(3-Benzyl-3H- imidazo[4,5-b]pyridin- 2-yl)-N-((R)-1-phenyl- ethyl)-propionamide  5  854 nM 3-(3-Benzyl-3H- imidazo[4,5-b]pyridin- 2-yl)-N-(2-methyl- benzyl)-propionamide  6  476 nM 0 N-(3- Trifluoromethoxy- benzyl)-3-[3-(3- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  7   1 nM N-((R)-2-Hydroxy-1- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  8   1 nM N-((1R,2S)-2- Hydroxy-indan-1-yl)- 3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  9   1 nM N-((1R,2R)-2- Hydroxy-indan-1-yl)- 3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  10   2 nM N-[4-(3- Dimethylamino- propoxy)-benzyl]-3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  11   2 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- difluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  12   2 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- trifluoromethyl- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  13   2 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  14   2 nM N-(4-Methoxy- benzyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  15   2 nM N-[1-(4-Fluoro- phenyl)-2-hydroxy- ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  16   3 nM 0 3-[3-(4-Bromo- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide  17   3 nM N-[(S)-1-(4-Bromo- phenyl)-ethyl]-3-[3- (3,4-difluoro-benzyl)- 3H-imidazo[4,5- b]pyridin-2-yl]- propionamide  18   3 nM N-(4-Chloro-benzyl)- 3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  19   4 nM N-[4-(2- Dimethylamino- ethoxy)-benzyl]-3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  20   3 nM N-[2-Hydroxy-1-(4- trifluoromethoxy- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  21   5 nM 3-[3-(4-Bromo- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- chloro-phenyl)-ethyl]- propionamide  22   4 nM N-(4- Trifluoromethoxy- benzyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  23   4 nM N-[2-Hydroxy-1-(4- trifluoromethyl- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  24   4 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(3- fluoro-4-methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  25   4 nM N-(S)-Indan-1-yl-3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  26   4 nM 0 N-[4-(3- Dimethylamino- propoxy)-benzyl]-3-[6- methyl-3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  27   4 nM N-(3-Fluoro-4- methoxy-benzyl)-3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  28   5 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((R)-2- hydroxy-1-phenyl- ethyl)-propionamide  29   5 nM N-((S)-1-Pyridin-2-yl- ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  30   5 nM N-(4-Fluoro-benzyl)-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  31   6 nM N-(4-Dimethylamino- benzyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  32   6 nM N-[2-Hydroxy-1-(4- trifluoromethoxy- phenyl)-ethyl]-3-[3-(4- trifluoromethyl- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  33   6 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[2-hydroxy-1- (4-trifluoromethoxy- phenyl)-ethyl]- propionamide  34   6 nM N-(1-Pyridin-4-yl- ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  35   7 nM N-[1-(4-Chloro- phenyl)-2-hydroxy- ethyl]-3-[3-(3,4- difluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  36   7 nM 0 N-((S)-2-Hydroxy-2- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  37   7 nM N-((R)-2-Hydroxy-2- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  38   9 nM N-(S)-1,2,3,4- Tetrahydro- naphthalen-1-yl-3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  39   7 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[2-hydroxy-1- (4-trifluoromethoxy- phenyl)-ethyl]- propionamide  40   1 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  41  10 nM N-((1S,2R)-2- Hydroxy-1-methyl-2- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  42  11 nM N-Cyclohexylmethyl- 3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  43  11 nM 4-(1-{3-[3-(4- Trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- ethyl)-piperidine-1- carboxylic acid tert- butyl ester  44  12 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-(3- thiophen-2-ylmethyl- 3H-imidazo[4,5- b]pyridin-2-yl)- propionamide  45  17 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- morpholin-4-yl- phenyl)-ethyl]- propionamide  46  18 nM 0 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((1R,2S)-2- hydroxy-indan-1-yl)- propionamide  47  19 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-propionamide  48  19 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[1-(4-fluoro- phenyl)-3-hydroxy- propyl]-propionamide  49  21 nM N-[(R)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  50  22 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-propionamide  51  22 nM 4-({3-[3-(4- Trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- methyl)-piperidine-1- carboxylic acid tert- butyl ester  52  29 nM N-(3-Fluoro-4- methoxy-benzyl)-3-[6- methyl-3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  53  38 nM N-(4-Methoxy- benzyl)-3-[6-methyl-3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  54  40 nM (S)-3-({3-[3-(4- Trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- methyl)-piperidine-1- carboxylic acid tert- butyl ester  55  40 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(S)-indan-1-yl- propionamide  56  45 nM 00 N-[1-(Tetrahydro- pyran-4-yl)-ethyl]-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  57  58 nM 01 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(4- trifluoromethoxy- benzyl)-propionamide  58  61 nM 02 N-(4-Dimethylamino- benzyl)-3-[3-(4-fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  59  63 nM 03 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((1R,2R)-2- hydroxy-indan-1-yl)- propionamide  60  89 nM 04 N-((S)-1-Cyclopropyl- ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  61  100 nM 05 3-[6-Bromo-3-(4- fluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- chloro-propionimide)]  62  125 nM 06 N-(Tetrahydro-pyran- 4-ylmethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  63  139 nM 07 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(4- dimethylamino- benzyl)-propionamide  64  144 nM 08 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-2- hydroxy-1-phenyl- ethyl)-propionamide  65  155 nM 09 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-2- hydroxy-2-phenyl- ethyl)-propionamide  66  162 nM 0 (R)-3-({3-[3-(4- Trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- methyl)-piperidine-1- carboxylic acid tert- butyl ester  67  169 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((R)-2- hydroxy-2-phenyl- ethyl)-propionamide  68  212 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-pyridin- 2-yl-ethyl)- propionamide  69  214 nM N-Thiazol-2-yl-3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  70  242 nM 3-[6-Bromo-3-(4- fluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- chloro-propionimide)]  71  243 nM N-Cyclohexylmethyl- 3-[3-(3,4-difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  72  247 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-pyridin- 2-yl-ethyl)- propionamide  73  267 nM N-[1,3,4]Thiadiazol-2- yl-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  74  339 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(2-methoxy-4- trifluoromethoxy- benzyl)-propionamide  75  424 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-pyridin-2- ylmethyl-propionamide  76  500 nM 0 3-[3-(4-Benzyloxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- chloro-phenyl)-ethyl]- propionamide  77  714 nM N-(4-Methyl-thiazol-2- yl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  78  800 nM N-Oxazol-2-yl-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  79  94 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- fluoro-benzyl)-5- methyl-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  80  844 nM 3-[3-(4-Benzyloxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide  81 1482 nM N-(5-Methyl-thiazol-2- yl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  82  987 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-pyridin-4- ylmethyl-propionamide  83   2 nM N-[(S)-1-(4-Bromo- phenyl)-ethyl]-3-[3-(4- fluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  84   3 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- methoxy-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  85   4 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-p-tolyl- ethyl)-propionamide  86   5 nM 0 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-phenyl- ethyl)-propionamide  87   6 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-phenyl- ethyl)-propionamide  88   6 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide  89   8 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-phenyl- propyl)-propionamide  90   9 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-p-tolyl- ethyl)-propionamide  91  14 nM 3-[7-Fluoro-1-(4- methoxy-benzyl)-1H- benzoimidazol-2-yl]- N-(4-methoxy-benzyl)- propionamide  92  17 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-phenyl- ethyl)-propionamide  93  15 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-phenyl- propyl)-propionamide  94  25 nM N-(4-Fluoro-benzyl)-3- [3-(4-fluoro-benzyl)- 3H-imidazo[4,5- b]pyridin-2-yl]- propionamide  95  26 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide  96  22 nM 0 N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-3-[3-(4- methoxy-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  97  40 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(4-methoxy- benzyl)-propionamide  98  45 nM N-(4-Methoxy- benzyl)-3-[3-(3- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide  99  48 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((S)-1-methyl- 1-phenyl-butyl)- propionamide 100  50 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(4-methoxy- benzyl)-propionamide 101  55 nM 3-[6-Fluoro-3-(2- methoxy-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(4-methoxy- benzyl)-propionamide 102  568 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(3-methyl- benzyl)-propionamide 103  57 nM N-(4-Methoxy- benzyl)-3-[3-(4- methyl-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 104  69 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-methyl-N-((S)- 1-phenyl-ethyl)- propionamide 105  88 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(1-methyl-1H- indol-5-ylmethyl)- propionamide 106  98 nM 0 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(2-methyl- benzyl)-propionamide 107  102 nM N-(3,4-Difluoro- benzyl)-3-[3-(4- methoxy-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 108  180 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(2-p-tolyl- ethyl)-propionamide 109  185 nM 3-[3-(4-Fluoro- benzyl)-6-methyl-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(4-methoxy- benzyl)-propionamide 110  262 nM 3-[3-(3-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(4-methoxy- benzyl)-propionamide 111  406 nM 3-(3-Benzyl-3H- imidazo[4,5-b]pyridin- 2-yl)-N- cyclohexylmethyl- propionamide 112 1060 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-((R)-1-phenyl- ethyl)-propionamide 113 1503 nM N-Isopropyl-3-[3-(4- methoxy-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 114  301 nM N-(2-Fluoro-benzyl)-3- [3-(4-methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 115  650 nM 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-(3-methyl- benzyl)-propionamide 116  778 nM 0 3-[3-(4-Methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[2-(4- methoxy-phenyl)- ethyl]-propionamide 117  373 nM N-(3-Fluoro-benzyl)-3- [3-(4-methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 118  726 nM N-(4-Methoxy- benzyl)-3-[3-(3- methyl-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 119  631 nM N-(4-Fluoro-benzyl)-3- [3-(4-methoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-methyl- propionamide 120  292 nM N-(4- Trifluoromethoxy- benzyl)-3-[3-(2- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 121  269 nM 3-[3-(4-Fluoro- benzyl)-5-methyl-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide 122   3 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 123   3 nM N-((R)-2-Hydroxy-1- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 124   8 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 125   9 nM N-{(S)-1-[4-(4- Methyl-piperazin-1- yl)-phenyl]-ethyl}-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 126  11 nM 0 N-[2-Hydroxy-1-(4- trifluoromethoxy- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 127  14 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N-((S)-1-phenyl- propyl)-propionamide 128  17 nM N-[4-(3- Dimethylamino- propoxy)-benzyl]-3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 129  20 nM N-(4-Chloro-benzyl)- 3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 130  21 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N-((S)-1-phenyl- ethyl)-propionamide 131  23 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N-((S)-1-p-tolyl- ethyl)-propionamide 132  52 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide 133  52 nM N-(4-Fluoro-benzyl)-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-propionamide 134  133 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N-((S)-1-phenyl- butyl)-propionamide 135 1568 nM 4-({3-[3-(4- Trifluoromethoxy- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]- propionylamino}- methyl)-piperidine-1- carboxylic acid tert- butyl ester 136  115 nM 0 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-c]pyridin- 2-yl]-N-(1-methyl-1- phenyl-ethyl)- propionamide 137  10 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-3-[1-(4- trifluoromethoxy- benzyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl]-propionamide 138  10 nM 3-[1-(4-Chloro- benzyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide 139  13 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-3-[5- fluoro-1-(4- trifluoromethoxy- benzyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl]-propionamide 140  13 nM 3-[1-(4-Fluoro- benzyl)-1H- pyrrolo[2,3-b]pyridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide 141  14 nM 3-[1-(4-Chloro- benzyl)-5-fluoro-1H- pyrrolo[2,3-b]byridin- 2-yl]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- propionamide 142   1 nM N-((R)-2-Hydroxy-1- phenyl-ethyl)-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylsulfanyl]- acetamide 143   1 nM 2-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylsulfanyl]-N-((R)-2- hydroxy-1-phenyl- ethyl)-acetamide 144   2 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylsulfanyl]- acetamide 145   2 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylsulfanyl]- acetamide 146   3 nM 0 2-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylsulfanyl]-N-[(S)-1- (4-fluoro-phenyl)- ethyl]-acetamide 147   3 nM 2-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylsulfanyl]-N-[(S)-1- (4-morpholin-4-yl- phenyl)-ethyl]- acetamide 148  10 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5- b]pyridine-2-sulfinyl]- acetamide (diastereomer 1) 149  178 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5- b]pyridine-2-sulfinyl]- acetamide (diastereomer 2) 150 2884 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5- b]pyridine-2-sulfonyl]- acetamide 151   3 nM N-((R)-2-Hydroxy-1- phenyl-ethyl)-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yloxy]-acetamide 152   5 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yloxy]-acetamide 153  39 nM 2-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yloxy]-N-[(S)-1-(4- fluoro-phenyl)-ethyl]- acetamide 154  11 nM N-((R)-2-Hydroxy-1- phenyl-ethyl)-2-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylsulfanyl]- propionamide 155  254 nM N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-3-[3-(4- hydroxy-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 156  704 nM 00 N-[(S)-1-(4-Fluoro- phenyl)-ethyl]-3-[3-(4- isobutoxy-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 157  10 nM 01 1-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- fluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl]-urea 158  17 nM 02 1-[(S)-1-(4-Bromo- phenyl)-ethyl]-3-[3- (3,4-difluoro-benzyl)- 3H-imidazo[4,5- b]pyridin-2-ylmethyl]- urea 159  42 nM 03 1-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl]-3-[(S)-1- (4-methoxy-phenyl)- ethyl]-urea 160  80 nM 04 1-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl]-3-[(S)-1- (4-fluoro-phenyl)- ethyl]-urea 161  115 nM 05 1-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl]-3-((S)-1- phenyl-ethyl)-urea 162  209 nM 06 1-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl]-3-((R)-2- hydroxy-1-phenyl- ethyl)-urea 163  309 nM 07 1-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl]-3-[(S)-1- (4-morpholin-4-yl- phenyl)-ethyl]-urea 164  957 nM 08 [3-(4-Fluoro-benzyl)- 3H-imidazo[4,5- b]pyridin-2-ylmethyl]- carbamic acid (S)-1-(4- fluoro-phenyl)-ethyl ester 165  514 nM 09 1-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl]-3-[(S)-1- (3-methoxy-phenyl)- ethyl]-urea 166  336 nM 0 [(S)-1-(4-Fluoro- phenyl)-ethyl]- carbamic acid 3-(4- fluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-ylmethyl ester 167   1 nM N-{(S)-1-[4-(4- Methyl-piperazin-1- yl)-phenyl]-ethyl}-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 168   1 nM N-{(S)-1-[4-((R)-3- Dimethylamino- pyrrolidin-1-yl)- phenyl]-ethyl}-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 169   1 nM N-{(S)-1-[4-((S)-3- Dimethylamino- pyrrolidin-1-yl)- phenyl]-ethyl}-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 170   2 nM N-[(S)-1-(4- [1,4]Diazepan-1-yl- phenyl)-ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 171   2 nM N-{(S)-1-[4-((cis)-3,5- Dimethyl-piperazin-1- yl)-phenyl]-ethyl}-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 172   2 nM N-{(S)-1-[4-((S)-3- Ethyl-piperazin-1-yl)- phenyl]-ethyl}-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 173   3 nM N-{(S)-1-[4-(1- Methyl-piperidin-4- ylamino)-phenyl]- ethyl}-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 174   2 nM N-{(S)-1-[4-((R)-3- Methyl-piperazin-1- yl)-phenyl]-ethyl}-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 175   3 nM N-{(S)-1-[4-((S)- Pyrrolidin-3-ylamino)- phenyl]-ethyl}-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 176   3 nM 0 N-{(S)-1-[4-((S)-3- Methyl-piperazin-1- yl)-phenyl]-ethyl}-3- [3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 177   3 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-(3- dimethylamino- pyrrolidin-1-ylmethyl)- phenyl]-ethyl}- propionamide 178   3 nM N-[(S)-1-(4-Azepan-1- yl-phenyl)-ethyl]-3-[3- (4-fluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 179   5 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-(3- trifluoromethyl- piperazin-1-yl)- phenyl]-ethyl}- propionamide 180   6 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- pyrrolidin-1-yl- phenyl)-ethyl]- propionamide 181   7 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-(4- hydroxymethyl- piperidin-1-yl)- phenyl]-ethyl}- propionamide 182   8 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-(4- methyl-piperazin-1- ylmethyl)-phenyl]- ethyl}-propionamide 183  10 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- pyrrolidin-1-yl- phenyl)-ethyl]- propionamide 184  12 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-((S)- 3-methyl-piperazin-1- yl)-phenyl]-ethyl}- propionamide 185  13 nM 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- morpholin-4-yl- phenyl)-ethyl]- propionamide 186  13 nM 0 3-[3-(4-Fluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- piperidin-1-yl-phenyl)- ethyl]-propionamide 187  15 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- piperidin-1-yl-phenyl)- ethyl]-propionamide 188  15 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-((R)- 3-methyl-piperazin-1- yl)-phenyl]-ethyl}- propionamide 189  16 nM 3-[6-Methyl-3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-((S)- pyrrolidin-3-ylamino)- phenyl]-ethyl}- propionamide 190  20 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-{(S)-1-[4-((R)- 3-hydroxy-pyrrolidin- 1-yl)-phenyl]-ethyl}- propionamide 191  25 nM N-[(S)-1-(4- [1,4]Diazepan-1-yl- phenyl)-ethyl]-3-[6- methyl-3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 192  56 nM N-{(S)-1-[4-((S)-3- Methyl-piperazin-1- yl)-phenyl]-ethyl}-3- [6-methyl-3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 193  83 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- piperazin-1-yl-phenyl)- ethyl]-propionamide 194   1 nM (R)-Cyclohexyl-{3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- acetic acid 195   1 nM (R)-3-Phenyl-2-{3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- propionic acid 196   2 nM 0 (R)-3-Phenyl-2-{3-[3- (4-trifluoromethyl- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- propionic acid 197   5 nM (R)-2-{3-[3-(4- Difluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}-3- phenyl-propionic acid 198  37 nM (R)-2-{3-[3-(3,4- Difluoro-benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}-3- phenyl-propionic acid 199  71 nM (S)-3-Phenyl-2-{3-[3- (4-trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- propionic acid 200  471 nM (S)-3-(4-Hydroxy- phenyl)-2-{3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]- propionylamino}- propionic acid 201  598 nM (R)-2-(3-{3-[(S)-1-(4- Fluoro-phenyl)-ethyl]- 3H-imidazo[4,5- b]pyridin-2-yl}- propionylamino)-3- phenyl-propionic acid 202  819 nM (R)-3-Phenyl-2-[3-(3- thiophen-2-ylmethyl- 3H-imidazo[4,5- b]pyridin-2-yl)- propionylamino]- propionic acid 203   2 nM N-((R)-1- Hydroxymethyl-2- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 204  89 nM N-((S)-1- Hydroxymethyl-2- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 205  188 nM N-[(S)-1- Hydroxymethyl-2-(4- hydroxy-phenyl)- ethyl]-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 206   3 nM 0 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- morpholin-4-ylmethyl- phenyl)-ethyl]- propionamide 207  25 nM N-[(S)-1-(4- Diethylaminomethyl- phenyl)-ethyl]-3-[3- (3,4-difluoro-benzyl)- 3H-imidazo[4,5- b]pyridin-2-yl]- propionamide 208  80 nM 3-[3-(3,4-Difluoro- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-N-[(S)-1-(4- dimethylaminomethyl- phenyl)-ethyl]- propionamide 209   3 nM N-((R)-2-Mercapto-1- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 210   3 nM N-((R)-2-Amino-1- phenyl-ethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 211   7 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[6- methyl-3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 212   7 nM N-[(S)-1-(4-Methoxy- phenyl)-ethyl]-3-[6- methyl-3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 213  17 nM N-[(S)-1-(4-Chloro- phenyl)-ethyl]-3-[3-(4- fluoro-benzyl)-6- methyl-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 214  30 nM N-(1-Methanesulfonyl- piperidin-4-ylmethyl)- 3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 215  81 nM N-(1- Cyclopropanecarbonyl- piperidin-4-ylmethyl)- 3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide 216  495 nM 0 N-(1-Acetyl-piperidin- 4-ylmethyl)-3-[3-(4- trifluoromethoxy- benzyl)-3H- imidazo[4,5-b]pyridin- 2-yl]-propionamide

(428) TABLE-US-00017 TABLE 2 Additional compounds tested for ATX activity (Quanta Red Assay): Example Activity Structure Name 217  29 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-(4- chloro-benzyl)-propionamide 218  23 nM N-(4-Chloro-benzyl)-3-[3-(4-methoxy-benzyl)-3H- imidazo[4,5-b]pyridin-2-yl]-propionamide 219  89 nM N-(4-Fluoro-benzyl)-3-[3-(4-methoxy-benzyl)-3H- imidazo[4,5-b]pyridin-2-yl]-propionamide 220  125 nM 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2- yl]-N-(4-methyl-benzyl)-propionamide 221  154 nM 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2- yl]-N-[2-(4-methylsulfanyl-phenyl)-ethyl]-propionamide 222  193 nM N-(4-Methoxy-benzyl)-3-[3-(4-methoxy-benzyl)-3H- imidazo[4,5-b]pyridin-2-yl]-propionamide 223  324 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-(4- fluoro-benzyl)-propionamide 224  685 nM N-(4-Fluoro-benzyl)-3-(3-thiophen-2-ylmethyl-3H- imidazo[4,5-b]pyridin-2-yl)-propionamide 225  708 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-[2-(4- ethoxy-phenyl)-ethyl]-propionamide 226  807 nM 0 N-Benzyl-3-(3-thiophen-2-ylmethyl-3H-imidazo[4,5- b]pyridin-2-yl)-propionamide 227 3828 nM N-(4-Fluoro-phenyl)-3-[3-(4-methoxy-benzyl)-3H- imidazo[4,5-b]pyridin-2-yl]-propionamide 228 8811 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-butyl- propionamide 229  466 nM 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2- yl]-N-(2-m-tolyl-ethyl)-propionamide 230  688 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-[2-(4- methylsulfanyl-phenyl)-ethyl]-propionamide 231  200 nM N-(3-Chloro-benzyl)-3-[3-(4-methoxy-benzyl)-3H- imidazo[4,5-b]pyridin-2-yl]-propionamide 232  596 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-(3- chloro-benzyl)-propionamide 233  539 nM N-[2-(4-Ethoxy-phenyl)-ethyl]-3-[3-(4-methoxy- benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide 234  720 nM N-Benzo[1,3]dioxol-5-ylmethyl-3-[3-(4-methoxy- benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide 235  627 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N-(4- methyl-benzyl)-propionamide

(429) TABLE-US-00018 TABLE 3 Commercially available compounds tested for Autotaxin activity (Quanta Red assay) Example Activity Structure Name 236 406 nM 0 N-Benzyl-3-[3-(4-methoxy-benzyl)-3H- imidazo[4,5-b]pyridin-2-yl]-propionamide 237 227 nM 3-[3-(4-Methoxy-benzyl)-3H-imidazo[4,5- b]pyridin-2-yl]-N-phenethyl-propionamide 238 473 nM 3-(3-Benzyl-3H-imidazo[4,5-b]pyridin-2-yl)-N- (4-methoxy-benzyl)-propionamide
In Vivo Data
ATX 4T1 Orthotopic, Metastatic Breast Cancer Mouse Model
Procedure

(430) On day −1 dosing of the test compound by gavage (100 mg/kg of test compound in 1% methylcellulose solution, twice daily with the second dose 8 hours after the first and assuming a mouse weight of 20 g) was commenced on female BALB/c mice 6 weeks of age (Charles River). The test compound (Example F93) was dosed for 15 days (day −1 to day 14)

(431) On day 1 4T1 cells (10.sup.5 in 10 μl of PBS) were injected into the fat pad of the 4.sup.th mammary gland of the mice. Before injection, cells were stored at room temperature for a period that did not exceed 2 hours at which time a new batch of cell suspension was prepared. At day 15 animals were anaesthetised and primary tumours were surgically removed. Primary tumours were weighed, fixed with paraformaldehyde (PEA 4%) for 48 hours, dehydrated for 24 hours in 70% ethanol and embedded in paraffin. Mice were then monitored for an additional 3-week period. At this time they were sacrificed. Re-grown primary tumours were collected, weighed, fixed with PFA, dehydrated with 70% ethanol and embedded in paraffin as described above.

(432) Bone marrow cells from both hind limbs of each animal were flushed with PBS, suspended in RPMI 1640 medium containing 10% FBS supplemented with 6-thioguanine (10 μg/mL) and seeded on a well of a 6-well culture plate. After a two-week incubation period at 37° C., tumour colonies were stained with crystal violet and counted. The levels of disseminated tumour cells in bone were expressed as the number of colonies per well.

(433) At the time of animal sacrifice, lungs were inflated with PFA prior to removal, then fixed with PFA for 48 hours, dehydrated with ethanol and embedded in paraffin as described above for primary tumour samples. 5 um sections were cut every 50 um through the lungs and the number and total volume of the metastases was determined using the assumption that the metastases were spherical.
The results are summarised in FIGS. 1 to 3. In which:
FIG. 1 shows total volume of lung metastases for Example 40 compared to the vehicle, in the 4T1 orthotopic metastatic breast cancer model.
FIG. 2 shows the number of lung metastases for Example 40 compared to the vehicle, in the 4T1 orthotopic metastatic breast cancer model.
FIG. 3 shows the effect on bone metastatic colony formation in the presence of Example 40 compared to the vehicle, in the 4T1 orthotopic metastatic breast cancer model.

REFERENCES

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