| (11) | EP 2 590 974 B1 |
(12) | EUROPEAN PATENT SPECIFICATION |
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(54) | TETRAHYDRO-PYRIDO-PYRIMIDINE DERIVATIVES TETRAHYDRO-PYRIDO(2,3-D)PYRIMIDINS-DERIVATE DÉRIVÉS DE TETRAHYDRO-PYRIDO(2,3-D)PYRIMIDINE |
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Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
SUMMARY OF THE INVENTION
Y is selected from O or NR3;
R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
-C(O)-R4
wherein
R4 is selected from C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C1-C8-alkyl, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C8-alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C1-C8-alkyl, hydroxy, C1-C8-alkoxy, amino, N-C1-C8-alkyl-amino or N,N-di-C1-C8-alkyl-amino,
wherein 'C1-C8-alkyl' in N-C1-C8-alkyl-amino and N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein 'C3-C12-cycloalkyl' in C3-C12-cycloalkyl and C3-C12-cycloalkyl-C1-C8-alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
R2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
R3 is selected from H, C1-C4-alkyl or halo-C1-C4-alkyl; and
m is selected from 0 or 1.
DESCRIPTION OF THE DRAWINGS
Figure 1 discloses the X-ray Powder Diffraction Pattern of Example 1 citrate salt
Figure 2 discloses the X-ray Powder Diffraction Pattern of Example 1 fumarate salt
Figure 3 discloses the X-ray Powder Diffraction Pattern of Example 1 napadisylate salt
Figure 4 discloses the X-ray Powder Diffraction Pattern of Example 67 phosphate salt
Figure 5 discloses the: X-ray Powder Diffraction Pattern of Example 67 HCl salt
Figure 6 discloses the X-ray Powder Diffraction Pattern of Example 67 hippurate salt
Figure 7 discloses the X-ray Powder Diffraction Pattern of Example 1 anhydrous form
Figure 8 discloses the X-ray Powder Diffraction Pattern of Example 1 trihydrate
Figure 9 discloses the X-ray Powder Diffraction Pattern of Example 67 anhydrous form
DETAILED DESCRIPTION OF THE INVENTION
R4 is selected from C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, C3-C12-cycloalkyl, heteroaryl, C1-C8-alkoxy or N,N-di-C1-C8-alkyl-amino, wherein 'C1-C8-alkyl' in N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein 'C3-C12-cycloalkyl' in C3-C12-cycloalkyl may be unsubstituted or substituted by 1-3 substituents independently selected from oxo, halogen, C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from oxo, halogen, C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from halogen, C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkyl-carbonyl;
wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states.
R4 is selected from heterocyclyl, C4-C8-cycloalkyl or heteroaryl;
wherein 'C3-C12-cycloalkyl' may be unsubstituted or substituted by 1-3 substituents independently selected from fluoro, C1-C4-alkyl, hydroxyl, C1-C4-alkoxy;
wherein 'heterocyclyl' is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from oxo, halogen, C1-C4-alkyl, hydroxyl, C1-C4-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from C1-C4-alkyl, hydroxyl;
wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states.
R4 is selected from heterocyclyl;
wherein 'heterocyclyl' is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from oxo, halogen, C1-C4-alkyl, hydroxyl, C1-C4-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states.
R4 is selected from C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkoxy or N,N-di-C1-C8-alkyl-amino,
wherein 'C1-C8-alkyl' in N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy.
R4 is selected from C1-C8-alkyl.
R2 is selected from 3-pyridyl or 5-pyrimidinyl; each of which is substituted by 1-2 substituents independently selected from fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy or amino, wherein one substituents is located in the para position relative to the point of connection of R2 to the core of the compound and R4 is selected from heterocyclyl;
wherein 'heterocyclyl' is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from oxo, halogen, C1-C4-alkyl, hydroxyl, C1-C4-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states.
R2 is selected from 3-pyridyl or 5-pyrimidinyl; each of which is substituted by 1-2 substituents independently selected from fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy or amino, wherein one substituents is located in the para position relative to the point of connection of R2 to the core of the compound and R4 is selected from C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkoxy or N,N-di-C1-C8-alkyl-amino,
wherein 'C1-C8-alkyl' in N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy.
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{(S)-3-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
2-Methoxy-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-nicotinonitrile;
2-Methoxy-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
1-{((S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
1-{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
2-Amino-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Amino-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
(S)-(3-(6-(5-Fluoro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(5-Fluoro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-2-Methoxy-5-(4-(1-(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
2-Methoxy-5-(4-(1-(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
(S)-5-(4-(1-(Cyclopentanecarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxynicotinonitrile;
5-((4-(1-(Cyclopentanecarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxynicotinonitrile;
(2,4-Dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(2,4-Dimethyl-oxazol-5-yl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
(3-Methoxy-cyclobutyl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(3-Methoxy-cyclobutyl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
({(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
({3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
1-((4-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
1-((4-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanone;
5-{((S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-1H-pyridin-2-one;
5-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-1 H-pyridin-2-one;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi n-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid i n-4-yl oxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi n-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi n-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanone;
(4,4-Difluoro-cyclohexyl)-{(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(4,4-Difluoro-cyclohexyl)-(3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
2-Methoxy-5-{4-[(S)-1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
5-{4-[(S)-1-(2,4-Dimethyl-oxazole-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
5-{4-[1-(2,4-Dimethyl-oxazole-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
5-{4-[(S)-1-(2,2-Dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
5-{4-[1-(2,2-Dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
Isoxazol-3-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Isoxazol-3-yl-(3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Isoxazol-5-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Isoxazol-5-yl-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
2-Methoxy-5-{4-[(S)-1-(thiazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(thiazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(1-methyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
(2,2-Dimethyl-tetrahyd ro-pyran-4yl)-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(2,2-Dimethyl-tetrahydro-pyran-4yl)-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(1,1-Dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(1,1-Dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(S)-(2,4-Dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(2,4-Dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1 H-pyrazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1 H-pyrazol-5-yl)methanone;
4-(((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
4-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanone;
(S)-(1H-Imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(1 H-Imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
5-(((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
5-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanone;
(S)-(1,3-Dimethyl-1 H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(1,3-Dimethyl-1 H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanone;
(S)-(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone;
(3-((6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1 H-imidazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanone;
{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanone;
{(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
(S)-(3-(6-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)azetidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
{(S)-3-[6-(2-Methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(2-Methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
[(S)-3-(6-Quinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone;
[3-((6-Quinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-1-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-one;
1-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-one;
1-{((S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
1-{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
2-Methoxy-5-[4-((S)-1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitrile;
2-Methoxy-5-[4-(1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitrile;
(S)-6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
6-((6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
(S)-6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
6-((6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
(S)-1-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
1-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-2-Methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
2-Methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
(S)-1-(4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidine-1-carbonyl)piperidin-1-yl)ethanone;
1-((4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidine-1-carbonyl)piperidin-1-yl)ethanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanone;
((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanone;
((1s,4R)-4-Hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
((1s,4R)-4-Hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
((1r,4S)-4-Hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
((1r,4S)-4-Hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1 H-imidazol-4-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4, 3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(S)-1-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
1-((3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
(S)-(3-(6-(5-Chloro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(5-Chloro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(Tetrahydro-pyran-4-yl)-{(S)-3-{6-(5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanone;
(Tetrahydro-pyran-4-yl)-{3-(6-(5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanone;
(S)-(4-Hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
4-Hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(S)-N-(2-Hydroxyethyl)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-methylpyrrolidine-1-carboxamide;
N-(2-Hydroxyethyl)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-methylpyrrolidine-1-carboxamide;
(S)-1-(4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)piperazin-1-yl)ethanone;
1-((4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)piperazin-1-yl)ethanone;
(S)-2-Methoxy-5-(4-(1-(morpholine-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
2-Methoxy-5-(4-(1-(morpholine-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
1-((4-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
1-((4-{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{(S)-3-[6-(6-Methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone; or
{3-[6-(6-Methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone.
General reaction processes:
"Protecting group":
â– a compound of the formula (I) as defined herein, as pharmaceutical / for use as pharmaceutical;
â– a compound of the formula (I) as defined herein, as medicament / for use as medicament;
â– a compound of the formula (I) as defined herein, for use in therapy;
■a compound of the formula (I) as defined herein, for the prevention and/or treatment of conditions, diseases or disorders which are mediated by the activity of the Pl3K enzymes, preferably by the activity of the PI3Kδ isoform;
■the use of a compound of formula (I) as defined herein, for the manufacture of a medicament for the prevention and/or treatment of conditions, diseases or disorders which are mediated by the activity of the Pl3K enzymes, preferably by the activity of the PI3Kδ isoform;
■the use of a compound of formula (I) as defined herein, for the prevention and/or treatment of conditions, diseases or disorders which are mediated by the activity of the Pl3K enzymes, preferably by the activity of the PI3Kδ isoform;
■the use of a compound of formula I as defined herein for the inhibition of the PI3K, enzymes, preferably of the PI3Kδ isoform ;
â– the use of a compound of formula (I) as defined herein, for the treatment of a disorder or disease selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection, cancers eg of hematopoietic origin or solid tumors.
â– the use of a compound of formula (I) as defined herein, for the treatment of a disorder or disease selected from antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell-mediated hyperacute, acute and chronic transplant rejection and cancers of haematopoietic origin including but not limited to multiple myeloma; ; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Walden stroem disease.
â–
â– the use of a compound of formula (I) as defined herein, for the treatment of a disorder or disease selected from rheumatoid arthritis (RA), pemphigus vulgaris (PV), idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), acquired hemophilia type A (AHA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjögren's syndrome (SS), ANCA-associated vasculitides, cryoglobulinemia, chronic autoimmune urticaria (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, transplant rejection and cancers of haematopoietic origin.
■a method of modulating the activity of the Pl3K enzymes, preferably the PI3Kδ isoform, in a subject, comprising the step of administering to a subject a therapeutically effective amount of a compound of formula I as definded herein;
■a method for the treatment of a disorder or disease mediated by the Pl3K enzymes, preferably by the PI3Kδ isoform. comprising the step of administering to a subject a therapeutically effective amount of a compound of formula (I) as definded herein;
■a method for inhibition of the Pl3K enzymes, preferably the PI3Kδ isoform, in a cell, comprising contacting said cell with an effective amound of a compound of formula I as defined herein.
â– a pharmaceutical composition comprising (i.e. containing or consisting of) a compound as defined herein and one or more carriers / excipients;
â– a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as defined herein, and one or more pharmaceutically acceptable carriers / excipients.
â– a combination in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula I and one or more therapeutically active agents, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic agent, e.g. as indicated below;
â– a combined pharmaceutical composition, adapted for simultaneous or sequential administration, comprising a therapeutically effective amount of a compound of formula (I) as defined herein; therapeutically effective amount(s) of one or more combination partners e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic agent, e.g. as indicated below; one or more pharmaceutically acceptable excepients;
â– a combined pharmaceutical composition as defined herein (i) as pharmaceutical, (ii) for use in the treatment of a disease mediated by the Pl3K enzymes, (iii) in a method of treatment of a disease mediated by the Pl3K enzymes.
Experimental details:
Abbreviations:
LCMS Methods used:
Purification method:
Preparative reverse phase Gilson HPLC
X-ray Powder Diffraction
Instrumentation:
Method X1 | |
Instrument | Bruker AXS, D8 Advance |
Irradiation | CuKα (30 kV, 40 mA) |
Detector | PSD (Vantec) detector |
Scan range | 2°-40° (2 theta value) |
Method X2 | |
Instrument | Bruker D8 GADDS Discover |
Irradiation | CuKα (40 kV, 40 mA) |
Detector | HI-STAR Area detector |
Scan range | 6°-40° (2 theta value) |
Preparation of intermediate compounds
Intermediate 1: 5-Bromo-2-methoxy-3-trifluoromethyl-pyridine
Intermediate 2: 1-((S)-3-Hydroxy-pyrrolidin-1-yl)-propan-1-one
Intermediate 3: ((S)-3-Hydroxy-pyrrolidin-1-yl)-(tetrahydro-pyran-4-yl)-methanone
Intermediate 4: [(S)-1-(Tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester
Intermediate 5: (S)-3-Amino-pyrrolidin-1-yl-(tetrahydro-pyran-4-yl)-methanone
Intermediate 6: 3-(4-Acetyl-piperazine-1-carbonyl)-1-methyl-3H-imidazol-3-ium iodide
Intermediate 7: (S)-3-(5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester
Aternative sythesis for intermediate 7:
(S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester
Alternative synthesis for (S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 8: 6-(2,4-Dimethoxy-pyrimidin-5-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Intermediate 9: 2-Amino-5-[4-((S)-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]nicotinonitrile
Imidodicarbonic acid, 2-[5-bromo-3-(cyano)-2-pyridinyl]-, 1,3-bis(1,1-dimethylethyl) ester
Intermediate 10: (S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 11: (S)-3-[6-(5-Cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 12: (S)-3-[6-(5-Fluoro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 13: (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 14: 4-Methoxy-6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Intermediate 15: 6-(5-Chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Intermediate 16: 4-Methoxy-6-(5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Intermediate 17: 6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol
Intermediate 18: 6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol
Intermediate 19: 6-(5-Trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol
Intermediate 20: (S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 21: (S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester
Intermediate 22: (S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester
Alternative synthesis for intermediate 22:
Intermediate 23: (S)-3-(5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester
Alternative synthesis for intermediate 23:
Intermediate 24: (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester
Alternative synthesis for intermediate 24:
Intermediate 25: (S)-3-[6-(5-Cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester
Preparation of examples
a) N-BOC deprotection is performed under customary BOC deprotection conditions using among the possible acid preferably trifluoro-actetic acid and organic solvent preferably CH2Cl2. The reaction is preferably performed at room temperature. b) Reaction of compound of general formula IX with an acid chloride of formula R4C(O)Cl or carboxylic acid of formula R4C(O)OH using general methods i - v as decribed in Scheme 1, step e. Those skilled in the art will appreciate that there are many known ways of preparing amides. For example, see Mantalbetti, C.A.G.N and Falque, V., Amide bond formation and peptide coupling, Tetrahedron, 2005, 61(46), pp10827-10852 and references cited therein. The examples provided herein are thus not intended to be exhaustive, but merely illustrative.
c) Removal of the benzyl protecting group is performed using standard methodology as described in "Protecting groups in Organic Synthesis" by T.W. Greene and P. Wutz, 3rd edition, 1999, John Wiley and Sons. Typical conditions comprise of 1.0 eq. of compound of general formula X (8.0 eq. of ammonium formate and 20% (w/w) palladium hydroxide Pd(OH)2/C (catalyst) heated under reflux in methanol. d) Buchwald-Hartwig cross coupling between compound of general formula XI and compounds of general formula R2-X where X=Bromo or lodo is performed under customary Buchwald-Hartwig conditions using such a ligand such as X-Phos or 2-di-t-butylphosphino-2'-(N,N-dimethylamino)biphenyl with a palladium catalyst such as Pd2(dba)3 or Pd2(dba)3.CHCl3 or Pd(OAc)2, preferably Pd2(dba)3 with X-Phos, base such as preferably Cs2CO3 or preferably tert-BuONa, and organic solvent such as preferably dioxane or preferably THF. The reaction is preferably stirred at a temperature of approximately 80-150°C, preferably 120°C. The reaction may preferably be carried out under an inert gas such as nitrogen or argon.
Example 1: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone
Synthesis of Example 1 - Method 1a (according to Scheme 8)
4-Chloro-6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol
6'-Methoxy-5'-methyl-4-oxo-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-3-carboxylic acid methyl ester
6'-Methoxy-5'-methyl-2,3,5,6-tetrahydro-[1,3']bipyridinyl-4-one
Synthesis of Example 1 - Method 1b (according to Scheme 1)
Step 3
6-(6-Methoxy-5-methyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Step 2
(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester
Step 1
Crystallization of Example 1 by heating and cooling in acetonitrile
2-Theta in deg | Intensity in % |
7.5 | 56 |
10.9 | 12.5 |
11.7 | 25.1 |
14.3 | 23.8 |
15.1 | 100 |
15.8 | 40.9 |
16.7 | 22.1 |
17.7 | 65.1 |
18.9 | 28.9 |
20.5 | 24.7 |
21.8 | 26 |
22.5 | 28.3 |
23.3 | 31.3 |
24.2 | 76.1 |
24.6 | 51.8 |
25.0 | 41.3 |
25.6 | 20.4 |
26.2 | 20.8 |
27.0 | 14.2 |
28.0 | 17.5 |
29.1 | 16.1 |
32.8 | 14 |
34.6 | 11.4 |
Crystallization of trihydrate form of Example 1 by slurry in water
2-Theta in deg | Intensity in % |
6.6 | 24.3 |
8.9 | 7.9 |
13.3 | 100 |
14.5 | 18.3 |
15.0 | 12.6 |
16.5 | 12.4 |
17.5 | 15.7 |
17.7 | 17.2 |
18.2 | 9.8 |
20.0 | 10.7 |
21.6 | 11.7 |
22.6 | 20.3 |
23.8 | 11.4 |
24.4 | 15.2 |
26.7 | 26.5 |
27.5 | 18.7 |
27.8 | 16.6 |
29.2 | 9.8 |
33.3 | 9 |
33.9 | 7.6 |
35.7 | 8.2 |
38.8 | 7 |
Preparation of citrate salt of Example 1
2-Theta in deg | Intensity in % |
5.7 | 62 |
11.5 | 100 |
12.1 | 4 |
14.3 | 4 |
15.4 | 12 |
17.2 | 21 |
17.9 | 31 |
19.3 | 25 |
20.2 | 37 |
20.7 | 8 |
21.9 | 5 |
23.3 | 11 |
23.9 | 36 |
25.5 | 28 |
27.0 | 5 |
27.7 | 6 |
29.8 | 8 |
30.3 | 7 |
Preparation of fumarate salt of Example 1
2-Theta in deg | Intensity in % |
6.0 | 100 |
6.5 | 12 |
9.8 | 8 |
12.3 | 10 |
13.1 | 14 |
15.6 | 22 |
17.7 | 16 |
19.1 | 21 |
19.7 | 27 |
23.9 | 40 |
24.7 | 6 |
24.9 | 10 |
25.2 | 5 |
26.4 | 11 |
27.0 | 4 |
Preparation of napadisylate salt of Example 1
2-Theta in deg | Intensity in % |
4.3 | 100 |
8.5 | 3 |
9.4 | 6 |
12.2 | 12 |
12.9 | 12 |
13.5 | 37 |
15.0 | 26 |
15.6 | 12 |
16.0 | 11 |
17.7 | 28 |
18.9 | 23 |
19.3 | 11 |
20.0 | 11 |
20.8 | 3 |
21.2 | 5 |
22.0 | 9 |
23.0 | 41 |
24.5 | 39 |
26.5 | 20 |
Example 2 |
|
Rt(1) (min.) | MS: [M+H]+ |
471.3 | 1.21 | ||
Name: {(S)-3-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase method C | |||
Prepared using process step 3 of method 1 b from intermediate 8 and tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 1.50-1.86 (m, 4H) 2.20-2.45 (m, 2H) 2.70-2.87 (m, 1H) 2.96-2.99 (m, 2H) 3.35-4.14 (m, 18H) 5.69-5.85 (m, 1H) 7.96 (m, 1H) 8.58 (m, 1H) |
Example 3 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.42 | 465.2 | ||
Name: 2-Methoxy-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using process steps 2-3 of method 1 b from intermediate 11 and tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.50-1.64 (m, 4H) 2.10-2.31 (m, 2H) 2.62-2.77 (m, 1H) 2.87-2.95 (m, 2H) 3.29-3.96 (m, 13H) 4.08-4.21 (m, 2H) 5.58-5.73 (m, 1H) 8.06-8.09 (m, 1H) 8.23-8.27 (m, 1H) 8.60-8.64 (m, 1H) |
Example 4 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.27 | 414.2 | ||
Name: 1-{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one | |||
Purification method: Reverse phase method A | |||
Prepared using process steps 2-3 of method 1b from intermediate 10 and propionyl chloride | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 1.10-1.20 (m, 3H) 2.19-2.49 (m, 4H) 3.02-3.08 (m, 2H) 3.45-3.52 (m, 2H) 3.56-3.68 (m, 2H) 3.72-3.90 (m, 2H) 3.91 (s, 3H) 3.99 (s, 3H) 4.07-4.12 (m, 2H) 5.75-5.78 (m, 1H) 6.89-7.01 (m, 1H) 7.44-7.46 (m, 1H) 8.60-8.62 (m, 1H) |
Example 5 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.25 | 470.2 | ||
Name: {(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using process steps 2-3 of method 1b from intermediate 10 and tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 1.56-1.68 (m, 2H) 1.88-2.00 (m, 2H) 2.20-2.38 (m, 2H) 2.53-2.70 (m, 1H) 3.05-3.10 (m, 2H) 3.39-3.54 (m, 4H) 3.59-3.82 (m, 4H) 3.91 (s, 3H) 3.99 (s, 3H) 4.01-4.10 (m, 4H) 5.62-5.78 (m, 1H) 6.89-6.90 (m, 1H) 7.40-7.43 (m, 1H) 8.60-8.65 (m, 1H) |
Example 6 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.10 | 450.2 | ||
Name: 2-Amino-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Prepared using process step 3 of method 1 b from intermediate 9 and tetrahydro-pyran-4-carbonyl chloride | |||
Purification method: | 1- Normal phase chromatography CH2Cl2 / MeOH as solvent | ||
2- Reverse phase method A | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 1.45-1.75 (m, 2H) 1.86-2.02 (m, 2H) 2.20-2.40 (m, 2H) 2.50-2.75 (m, 1H) 3.02-3.09 (m, 2H) 3.38-4.20 (m, 12H) 4.96 (s, 1H) 5.70-5.78 (m, 1H) 7.39 (m, 1H) 8.13-8.14 (m, 1H) 8.62-8.64 (m, 1H) |
Example 7 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.41 | 458.1 | ||
Name: {(S)-3-[6-(5-Fluoro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Biotage 11g KP-NH cartridge eluting with Heptane / EtOAc 100/0 to 0/100 | |||
Prepared using process steps 2-3 of method 1b from intermediate 12 and tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, CDCl3, 298K) δ ppm 1.56-1.74 (m, 2H) 1.87-2.02 (m, 2H) 2.19-2.42 (m, 2H) 2.51-2.74 (m, 1H) 3.01-3.09 (m, 2H) 3.39-4.20 (m, 15H) 5.70-5.79 (m, 1H) 7.13-7.20 (m, 1H) 7.63-7.69 (m, 1H) 8.59-8.66 (m, 1H) |
Example 8 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.35 | 425.1 | ||
Name: 2-Methoxy-5-{4-[(S)-1-(2-methoxy-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using process steps 2-3 of method 1b from intermediate 11 and methoxy acetyl chloride | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.11-2.32 (m, 2H) 2.88-2.95 (m, 2H) 3.26-3.32 (m, 3H) 3.46-3.84 (m, 6H) 3.91-3.95 (m, 3H) 3.98-4.08 (m, 2H) 4.13-4.19 (m, 2H) 5.59-5.71 (m, 1H) 8.07-8.10 (m, 1H) 8.25-8.28 (m, 1H) 8.61-8.62 (m, 1H) |
Example 9 |
|
Rt(8) (min.) | MS: [M+H]+ |
3.79 | 449.1 | ||
Name: 5-[4-((S)-1-Cyclopentanecarbonyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-2-methoxy-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using process steps 2-3 of method 1b from intermediate 11 and cyclopentanecarbonyl chloride |
Example 10: (2,4-Dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone
Step 1
Example 11 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.57 | 436.2 | ||
Name: Furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using furan-3-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.30-2.45 (m, 2H) 2.93-3.05 (m, 2H) 3.45-3.54 (m, 2H) 3.72-4.21 (m, 9H) 5.79-5.86 (m, 1H) 6.78-6.82 (m, 1H) 7.37-7.44 (m, 1H) 7.56-7.61 (m, 1H) 7.61-7.69 (m, 1H) 8.01-8.12 (m, 1H) 8.54-8.62 (m, 1H) |
Example 12 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.36 | 437.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.30-2.39 (m, 1H) 2.41-2.50 (m, 1H) 2.95-3.03 (m, 2H) 3.45-3.52 (m, 2H) 3.76-4.32 (m, 9H) 5.79-5.94 (m, 1H) 7.40 (br. s., 1H) 7.62-7.66 (m, 1H) 7.75-7.82 (m, 1H) 8.34-8.40 (m, 1H) 8.56-8.61 (m, 1H) |
Example 13 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.13 | 450.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[ 4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 3-methyl-3H-imidazole-4-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.30-2.45 (m, 2H) 2.93-3.05 (m, 2H) 3.43-3.55 (m, 2H) 3.74-4.24 (m, 12H) 5.82 (br. s., 1H) 7.35-7.56 (m, 2H) 7.66 (m, 1H) 7.76 (br. s., 1H) 8.55-8.60 (m, 1H) |
Example 14 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.49 | 451.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 2-methyl-oxazole -4-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.27-2.43 (m, 2H) 2.43-2.50 (m, 3H) 2.95-3.02 (m, 2H) 3.45-3.53 (m, 2H) 3.72-4.33 (m, 9H) 5.78-5.89 (m, 1H) 7.37-7.43 (m, 1H) 7.61-7.67 (m, 1H) 8.25-8.31 (m, 1H) 8.57-8.60 (m, 1H) |
Example 15 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.53 | 454.2 | ||
Name: (3-Methoxy-cyclobutyl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 3-methoxy-cyclobutanecarboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 1.99-2.55 (m, 9H) 2.78-2.95 (m, 1 H), 2.95-3.02 (m, 2H) 3.20-3.23 (m, 3H) 3.47-3.52 (m, 2H) 3.52-4.10 (m, 10H) 5.73-5.81 (m, 1H) 7.38-7.42 (m, 1) 7.63-7.67 (m, 1H) 8.57 (s, 1H) |
Example 16 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.41 | 437.2 | ||
Name: ({(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using oxazole-4-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.29-2.37 (m, 1H) 2.37-2.44 (m, 1H) 2.94-3.03 (m, 2H) 3.45-3.53 (m, 2H) 3.75-4.38 (m, 9H) 5.79-5.89 (m, 1H) 7.38-7.42 (m, 1H) 7.62-7.66 (m, 1H) 8.19-8.26 (m, 1H) 8.44-8.48 (m, 1H) 8.56-8.61 (m, 1H) |
Example 17 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.35 | 495.2 | ||
Name: 1-(4-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone | |||
Purification method: Reverse phase method A | |||
Prepared using 1-acetyl-piperidine-4-carboxylic acid | |||
1H NMR ((400 MHz, methanol-d4, 298K) δ ppm 1.49-1.89 (m, 4H) 2.06-2.13 (m, 3H) 2.18 (s, 3H) 2.23-2.43 (m, 2H) 2.61-2.93 (m, 2H) 2.95-3.04 (m, 2H) 3.15-3.25 (m, 1H) 3.42-3.53 (m, 2H) 3.55-4.12 (m, 10H) 4.46-4.59 (m, 1H) 5.74-5.86 (m, 1H) 7.38-7.45 (m, 1H) 7.62-7.67 (m, 1H) 8.56-8.61 (m, 1H) |
Example 18 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.47 | 451.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 4-methyl-oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.29-2.47 (m, 5H) 2.95-3.3.03 (m, 2H) 3.45-3.52 (m, 2H) 3.73-4.30 (m, 9H) 5.79-5.90 (m, 1H) 7.41 (m, 1H) 7.65 (br.s., 1H) 8.19-8.24 (m, 1H) 8.55-8.61 (m, 1H) |
Example 19 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.25 | 463.1 | ||
Name: 5-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-1H-pyridin-2-one | |||
Purification method: Reverse phase method A | |||
Prepared using 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.19 (s, 3H) 2.30-2.40 (m, 2H) 2.95-3.05 (m, 2H) 3.45-3.55 (m, 2H) 3.74-4.22 (m, 9H) 5.73-5.85 (m, 1H) 6.50-6.56 (m, 1H) 7.39-7.45 (m, 1H) 7.60-7.70 (m, 1H) 7.78-7.90 (m, 2H) 8.50-8.60 (m, 1H) |
Example 20 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.22 | 450.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 1-methyl-1H-imidazole-4-carboxylic acid | |||
1H NMR (400 MHz, methanol-d4, 298K) δ ppm 2.17 (s, 3H) 2.28-2.41 (m, 2H) 2.94-3.02 (m, 2H) 3.45-3.52 (m, 2H) 3.73-4.35 (m, 12H) 5.80-5.85 (m, 1H) 7.38-7.43 (m, 1H) 7.60-7.69 (m, 3H) 8.55-8.61 (m, 1H) |
Example 21 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.23 | 453.1 | ||
Name: {(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone | |||
Purification method: Normal phase chromatography with EtOAc / MeOH as solvent | |||
Prepared using intermediate 10 and method 1b of process step 2 of example 1 followed by process step 1 of example 10 using oxazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.10 - 2.37 (m, 2 H) 2.81 - 2.99 (m, 2 H) 3.46 - 4.27 (m, 14 H) 5.58 - 5.77 (m, 1 H) 7.08 - 7.20 (m, 1 H) 7.30 - 7.42 (m, 1 H) 8.43 - 8.54 (m, 1 H) 8.55 - 8.69 (m, 2 H) |
Example 22 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.18 | 453.1 | ||
Name: {(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 10 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 373K) δ ppm 2.22 - 2.42 (m, 2 H) 2.80-3.00 (m, 2 H) 3.50 - 4.30 (m, 14 H) 5.63 - 5.83 (m, 1 H) 7.06 - 7.09 (m, 1 H) 7.38 - 7.40 (m, 1 H) 7.69 (s, 1 H) 8.40 (s, 1 H) 8.57 (s, 1 H) |
Example 23 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.3 | 467.2 | ||
Name: {(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 10 and process step 2, method 1 b of example 1 followed by process step 1 of example 10 using 2-methyl-oxazole -4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.11 - 2.36 (m, 2 H) 2.40 - 2.44 (m, 3 H) 2.81 - 2.97 (m, 2 H) 3.40 - 4.28 (m, 14 H) 5.62 - 5.78 (m, 1 H) 7.11 - 7.21 (m, 1 H) 7.29 - 7.41 (m, 1 H) 8.42 - 8.52 (m, 1 H) 8.59 - 8.67 (m, 1 H) |
Example 24 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.38 | 498.3 | ||
Name: {(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 10 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 2,2-dimethyl-tetrahydro-pyran-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.97 - 1.24 (m, 6 H) 1.28 - 1.58 (m, 4 H) 2.08 - 2.34 (m, 2 H) 2.72 - 2.97 (m, 3 H) 3.43 - 4.12 (m, 16 H) 5.55 - 5.76 (m, 1 H) 7.14 - 7.20 (m, 1 H) 7.31- 7.37 (m, 1 H) 8.59 - 8.64 (m, 1 H) |
Example 25 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.32 | 481.2 | ||
Name: {(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 10 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 2,2-dimethyl-tetrahydro-pyran-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.11 - 2.48 (m, 8 H) 2.83 - 2.98 (m, 2 H) 3.43 - 4.18 (m, 14 H) 5.56 - 5.89 (m, 1 H) 7.12-7.20 (m, 1 H) 7.32-7.40 (m, 1 H) 8.57-8.67 (m, 1 H) |
Example 26 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.57 | 504.3 | ||
Name: (4,4-Difluoro-cyclohexyl)-{(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 10 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 4,4-difluoro-cyclohexanecarboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.49 - 2.35 (m, 10 H) 2.61 - 2.67 (m, 1 H) 2.84 - 2.99 (m, 2 H) 3.42 - 3.83 (m, 12 H) 4.00 - 4.19 (m, 2 H) 5.57 - 5.78 (m, 1 H) 7.11 - 7.25 (m, 1 H) 7.29 - 7.43 (m, 1 H) 8.52 - 8.68 (m, 1 H) |
Example 27 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.46 | 479.2 | ||
Name: 2-Methoxy-5-{4-[(S)-1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 11 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using (tetrahydro-pyran-4-yl)-acetic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.11-1.28 (m, 2H) 1.49-1.64 (m, 2H) 1.87-1.99 (m, 1H) 2.07-2.29 (m, 4H) 2.86-2.95 (m, 2H) 3.19-3.30 (m, 2H) 3.42-3.88 (m, 8H) 3.90-3.96 (m, 3H) 4.09-4.19 (m, 2H) 5.57-5.70 (m, 1H) 8.07-8.11 (m, 1H) 8.22-8.28 (m, 1H) 8.58-8.65 (m, 1H) |
Example 28 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.51 | 476.2 | ||
Name: 5-{4-[(S)-1-(2,4-Dimethyl-oxazole-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 11 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 2,4-dimethyl-oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.16-2.46 (m, 5H) 2.30 (s, 3H) 2.85-2.96 (m, 2H) 3.50-4.20 (m, 8H) 3.92 (s, 3H) 5.64-5.80 (m, 1H) 8.04-8.12 (m, 1H) 8.22-8.30 (m, 1H) 8.62 (s, 1H) |
Example 29 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.58 | 493.2 | ||
Name: 5-{4-[(S)-1-(2,2-Dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 11 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 2,2-dimethyl-tetrahydro-pyran-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.00-1.24 (m, 6H) 1.28-1.73 (m, 4H) 2.10-2.34 (m, 2H) 2.62-2.97 (m, 3H) 3.43-3.84 (m, 8H) 3.94 (s, 3H) 4.09-4.20 (m, 2H) 5.58-5.75 (m, 1H) 8.05-8.11 (m, 1H) 8.20-8.29 (m, 1H) 8.59-8.65 (m, 1H) |
Example 30 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.55 | 451.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 5-methyl-oxazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.10-2.32 (m, 2H) 2.13 (s, 3H) 2.52.2.54 (m, 3H) 2.85-2.93 (m, 2H) 3.42-3.50 (m, 2H) 3.61-4.22 (m, 6H) 3.81 (s, 3H) 5.64-5.72 (m, 1H) 7.41-7.45 (m, 1H) 7.67-7.71 (m, 1H) 8.27-8.33 (m, 1H) 8.59-8.64 (m, 1H) |
Example 31 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.53 | 451.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 5-methyl-isoxazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.10-2.31(m, 2H) 2.14 (s, 3H) 2.54-2.59 (m, 3H) 2.83-2.97 (m, 2H) 3.41-3.53 (m, 2H) 3.59-4.15 (m, 6H) 3.81 (s, 3H) 5.65-5.73 (m, 1H) 7.40-7.48 (m, 1H) 7.67-7.74 (m, 1H) 8.56-8.66 (m, 1H) 8.83-8.95 (m, 1H) |
Example 32 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.53 | 451.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 3-methyl-isoxazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.08-2.37 (m, 8H) 2.82-2.95 (m, 2H) 3.40-3.53 (m, 2H) 3.55-4.16 (m, 9H) 5.65-5.75 (m, 1H) 7.41-7.48 (m, 1H) 7.68-7.73 (m, 1H) 8.57-8.65 (m, 1H) 9.28-9.40 (m, 1H) |
Example 33 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.59 | 437.2 | ||
Name: Isoxazol-3-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using isoxazole-3-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.13 (m, 3H) 2.21-2.31 (m, 2H) 2.86-2.94 (m, 2H) 3.43-3.50 (m, 2H) 3.66-4.15 (m, 9H) 5.67-5.73 (m, 1H) 6.84-6.91 (m, 1H) 7.42-7.46 (m, 1H) 7.67-7.74 (m, 1H) 8.57-8.64 (m, 1H) 9.05-9.13 (m, 1H) |
Example 34 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.5 | 437.2 | ||
Name: Isoxazol-5-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using isoxazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.08-2.16 (m, 3H) 2.19-2.36 (m, 2H) 2.85-2.95 (m, 2H) 3.42-3.49 (m, 2H) 3.66-4.23 (m, 9H) 5.66-5.78 (m, 1H) 7.06-7.13 (m, 1H) 7.41-7.46 (m, 1H) 7.68-7.74 (m, 1H) 8.59-8.64 (m, 1H) 8.73-8.79 (m, 1H) |
Example 35 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.5 | 464.1 | ||
Name: 2-Methoxy-5-{4-[(S)-1-(thiazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 11 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using thiazole-4-carboxylic acid | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 2.30-2.37 (m, 2H) 3.07-3.12 (m, 2H) 3.46-3.53 (m, 2H) 3.81-4.43 (m, 9H) 5.80-5.85 (m, 1H) 7.55-7.59 (m, 1H) 8.09-8.13 (m, 1H) 8.18-8.23 (m, 1H) 8.63-8.69 (m, 1H) 8.75-8.85 (m, 1H) |
Example 36 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.35 | 461.2 | ||
Name: 2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 11 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 1-methyl-1H-imidazole-4-carboxylic acid | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 2.24-2.47 (m, 2H) 3.03-3.17 (m, 2H) 3.45-3.58 (m, 2H) 3.87-4.20 (m, 12H) 5.75-5.85 (m, 1H) 7.54-7.60 (m, 1H) 7.73-7.90 (m, 2H) 8.09-8.14 (m, 1H) 8.61-8.68 (m, 1H) |
Example 37 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.47 | 461.2 | ||
Name: 2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 11 and process step 2, method 1 b of example 1 followed by process step 1 of example 10 using 1-methyl-1H-pyrazole-3-carboxylic acid | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 2.24-2.41 (m, 2H) 3.07-3.14 (m, 2H) 3.44-3.58 (m, 2H) 3.74-4.44 (m, 12H) 5.77-5.86 (m, 1H) 6.78-6.84 (m, 1H) 7.33-7.39 (m, 1H) 7.54-7.59 (m, 1H) 8.08-8.14 (m, 1H) 8.63-8.70 (m, 1H) |
Example 38 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.58 | 482.3 | ||
Name: (2,2-Dimethyl-tetrahydro-pyran-4yl)-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 2,2-dimethyl-tetrahydro-pyran-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.02-1.21 (m, 6H) 1.27-1.71 (m, 4H) 2.08-2.32 (m, 5H) 2.67-2.94 (m, 3H) 3.41-4.08 (m, 13H) 5.60-5.73 (m, 1H) 7.41-7.46 (m, 1H) 7.65-7.72 (m, 1H) 8.58-8.65 (m, 1H) |
Example 39 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.60 | 556.1 | ||
Name: (1,1-Dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.90 - 2.37 (m, 6 H) 2.72 - 3.27 (m, 7 H) 3.43 - 3.81 (m, 6 H) 3.89 - 3.97 (m, 3 H) 4.13 - 4.20 (m, 2 H) 5.61 - 5.75 (m,1 H) 7.80 - 7.86 (m, 1 H) 8.15 - 8.22 (m, 1 H) 8.60 - 8.65 (m, 1 H) |
Example 40 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.77 | 519.2 | ||
Name: (2,4-Dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 2,4-dimethyl-oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.13-2.45 (m, 8H) 2.89-2.96 (m, 2H) 3.54-4.21 (m, 11H) 5.64-5.79 (m, 1H) 7.81-7.85 (m, 1H) 8.218-8.22 (m.,1H) 8.61-8.65 (m, 1H) |
Example 41 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.69 | 507.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-5-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using thiazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.15-2.42 (m, 2H) 2.88-2.97 (m, 2H) 3.53-3.61 (m, 2H) 3.67-4.11 (m, 7 H) 4.15-4.24 (m, 2H) 5.67-5.79 (m, 1H) 7.81-7.88 (m, 1H) 8.18-8.23 (m, 1H) 8.35-8.45 (m, 1H) 8.60-8.66 (m, 1H) 9.22-9.29 (m, 1H) |
Example 42 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.74 | 504.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-2H-pyrazol-3-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 2-methyl-2H-pyrazole-3-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.15-2.35 (m, 2H) 2.88-2.97 (m, 2H) 3.51 - 4.13 (m, 12 H) 4.13-4.25 (m, 2H) 5.63-5.74 (m, 1H) 6.63-6.74 (m, 1H) 7.43-7.52 (m, 1H) 7.81-7.89 (m, 1H) 8.17-8.25 (m, 1H) 8.57-8.67 (m, 1H) |
Example 43 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.47 | 507.2 | ||
Name: 4-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-pyrrolidin-2-one | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 5-oxo-pyrrolidine-3-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.10-2.43 (m, 4H) 2.89-2.96 (m, 2H) 3.35-3.79 (m, 9H) 3.90-3.94 (m, 3H) 4.15-4.20 (m, 2H) 5.60-5.73 (m, 1H) 7.53-7.62 (m, 1H) 7.81-7.87 (m, 1H) 8.17-8.22 (m, 1H) 8.60-8.64 (m, 1H) |
Example 44 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.63 | 501.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-pyridin-3-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using nicotinic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.11-2.37 (m, 2H) 2.87-2.99 (m, 2H) 3.51-4.13 (m, 9H) 4.13-4.29 (m, 2H) 5.60-5.75 (m, 1H) 7.43-7.53 (m, 1H) 7.81-8.04 (m, 2H) 8.17-8.28 (m, 1H) 8.53-8.82 (m, 3H) |
Example 45 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.36 | 490.2 | ||
Name: (1H-Imidazol-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 1H-imidazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.12-2.35 (m, 2H) 2.87-2.95 (m, 2H) 3.60-4.31 (m, 11H) 5.63-5.76 (m, 1H) 7.57-7.65 (m, 1H) 7.70-7.78 (m, 1H) 7.80-7.85 (m, 1H) 8.16-8.21 (m, 1H) 8.61-8.65 (m, 1H) |
Example 46 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.47 | 507.2 | ||
Name:5-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-pyrrolidin-2-one | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 5-oxo-pyrrolidine-2-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.78-2.40 (m, 6H) 2.89-2.97 (m, 2H) 3.43-3.86 (m, 6H) 3.90-3.94 (m, 3H) 4.15-4.20 (m, 2H) 4.30-4.45 (m, 1H) 5.60-5.75 (m, 1H) 7.70-7.89 (m, 2H) 8.16-8.22 (m, 1H) 8.61-8.63 (m, 1H) |
Example 47 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.61 | 501.2 | ||
Name:{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-pyridin-4-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using isonicotinic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.12-2.36 (m, 2H) 2.86-2.99 (m, 2H) 3.46-3.81 (m, 5H) 3.84-4.13 (m, 4H) 4.14-4.28 (m, 2H) 5.59-5.74 (m, 1H) 7.44-7.56 (m, 2H) 7.82-7.91 (m, 1H) 8.18-8.27 (m, 1H) 8.52-8.72 (m, 3H) |
Example 48 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.62 | 518.2 | ||
Name: (1,3-Dimethyl-1H-pyrazol-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 1,3,-dimethyl-1H-pyrazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.13-2.35 (m, 5H) 2.89-2.97 (m, 2H) 3.53-4.06 (m, 12H) 4.14-4.22 (m, 2H) 5.64-5.72 (m, 1H) 7.80-7.88 (m, 1H) 7.99-8.11 (m, 1H) 8.16-8.22 (m, 1H) 8.58-8.66 (m, 1H) |
Example 49 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.51 | 490.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1H-pyrazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 1H-pyrazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.12-2.39 (m, 2H) 2.87-2.97 (m, 2H) 3.43-4.11 (m, 9H) 4.12-4.22 (m, 2H) 5.63-5.79 (m, 1H) 7.78-7.94 (m, 2H) 8.10-8.25 (m, 3H) 8.59-8.68 (m, 1H) |
Example 51 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.72 | 506.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-[1,3,4]oxadiazol-2-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 5-methyl-[1,3,4]oxadiazole-2-carboxylic acid |
Example 52 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.71 | 502.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-pyrazin-2-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using pyrazine-2-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.15-2.36 (m, 2H) 2.87-2.97 (m, 2H) 3.52-3.64 (m, 2H) 3.66-4.11 (m, 7H) 4.12-4.24 (m, 2H) 5.67-5.75 (m, 1H) 7.81-7.87 (m, 1H) 8.17-8.25 (m, 1H) 8.56-8.80 (m, 3H) 8.97-9.02 (m, 1H) |
Example 53 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.45 | 504.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 13 and process step 2, method 1b of example 1 followed by process step 1 of example 10 using 1-methyl-1 H-imidazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.07 - 2.36 (m, 2 H) 2.82 - 3.05 (m, 2 H) 3.20 - 4.43 (m, 14 H) 5.60 - 5.74 (m, 1 H) 7.59 - 7.72 (m, 2 H) 7.78 - 7.87 (m, 1 H) 8.14 - 8.21 (m, 1 H) 8.59 - 8.66 (m, 1 H) |
Example 54: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanone
Example 55 | Structure | Rt(1) (min.) | MS: [M+H]+ |
|
|||
1.77 | 507.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanone | |||
Purification method: Flash chromatography on Biotage amino silica gel eluting with cyclohexane/EtOAc 100/0 to 0/100 | |||
Prepared using thiazole-4-carboxylic acid | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 2.29-2.40 (m, 2H) 3.05-3.12 (m, 2H) 3.49-3.56 (m, 2H) 3.80-4.45 (m, 9H) 5.80-5.86 (m, 1H) 7.60-7.62 (m, 1H) 8.04-8.18 (m, 1H) 8.21 - 8.25 (m, 1H) 8.64-8.68 (m, 1H) 8.79-8.84 (m, 1H) |
Example 56: {(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone
6-(5-Chloro-6-methoxy-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester
Example 57: {(S)-3-[6-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone
(S)-tert-butyl 3-(6-(6-(bis(tert-butoxycarbonyl)amino)-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylate
Imidodicarbonic acid, 2-[5-bromo-3-(trifluoromethyl)-2-pyridinyl]-, 1,3-bis(1,1-dimethylethyl) ester
Example 58: {3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-azetidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone
3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-azetidine-1-carboxylic acid tert-butyl ester
3-(5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-azetidine-1-carboxylic acid tert-butyl ester
3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-azetidine-1-carboxylic acid tert-butyl ester
Example 59: {(S)-3-[6-(2-Methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone
Step 4
(Tetrahydro-pyran-4-yl)-[(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-methanone
Step 3
[(S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydropyran-4-yl)-methanone
Step 2
6-Benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Step 1
Example 60 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.27 | 460.2 | ||
Name: [(S)-3-(6-Quinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 3-bromo-quinoline | |||
1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 1.60-1.72 (m, 3H) 1.89-2.04 (m, 2H) 2.24-2.46 (m, 2H) 2.53-2.73 (m, 1H) 3.08-3.21 (m, 2H) 3.39-3.52 (m, 2H) 3.67-4.11 (m, 8H) 4.20-4.40 (m, 2H) 5.73-5.83 (m, 1H) 7.47-7.62 (m, 3H) 7.73-7.80 (m, 1H) 8.02-8.14 (m, 1H) 8.62-8.68 (m, 1H) 8.86-8.91 (m, 1H). |
Example 61 |
|
Rt(7) (min.) | MS: [M+H]+ |
1.17 | 508.7 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using intermediate 1 | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.50-1.66 (m, 4H) 2.07-2.46 (m, 2H) 2.60-2.80 (m, 1H) 2.88-2.97 (m, 2H) 3.30-3.95 (m, 13H) 4.08-4.23 (m, 2H) 5.59-5.74 (m, 1H) 7.79-7.85 (m, 1H) 8.16-8.23 (m, 1H) 8.60-8.65 (m, 1H) |
Example 62 |
|
Rt(1) (min.) | MS: [M+H]+ |
2.11 | 494.2 | ||
Name: 1-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-3,3-dimethyl-butan-1-one | |||
Purification method: Reverse phase method A | |||
Prepared using step 2 of example 59 and 3,3-dimethyl-butyryl chloride followed by steps 3-4 of example 59 using intermediate 1 | |||
1H NMR (400 MHz, CDCl3, 298K) δ ppm 1.00-1.12 (m, 9H) 2.13-2.35 (m, 4H) 3.08-3.15 (m, 2H) 3.45-3.93 (m, 6H) 4.02 (s, 3H) 4.03-4.15 (m, 2H) 5.72-5.79 (m, 1H) 7.57-7.62 (m, 1H) 8.03-8.07 (m, 1H) 8.64-8.69 (m, 1H) |
Example 63: 1-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one
Step 3
1-[(S)-3-(5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one
Step 2
1-[(S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one
Step 1
Example 64 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.46 | 409.2 | ||
Name: 2-Methoxy-5-[4-((S)-1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitrile | |||
Purification method: Reverse phase method A | |||
Prepared using step 3 of example 59 and 5-bromo-2-methoxynicotinonitrile | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 0.95-1.02 (m, 3H) 2.10-2.35 (m, 5H) 2.89-2.98 (m, 2H) 3.40-3.90 (m, 5H) 3.93 (s, 3H) 4.16 (s, 2H) 5.58-5.71 (m, 1H) 8.08-8.10 (m, 1H) 8.24-8.28 (m, 1H) 8.61 (m, 1H). |
Example 65: 6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyridin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Example 66: 6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyrimidin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
Example 67: 1-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one
Alternative synthesis for example 67
Crystallization of Example 67 by heating in acetonitrile/water
2-Theta in deg | Intensity in % |
7.9 | 31 |
9.6 | 88 |
11.5 | 29 |
13.4 | 8 |
15.2 | 7 |
15.9 | 100 |
16.8 | 57 |
17.6 | 9 |
18.7 | 20 |
20.0 | 8 |
20.6 | 40 |
22.0 | 32 |
22.4 | 53 |
22.7 | 26 |
23.4 | 17 |
23.9 | 23 |
24.5 | 41 |
25.1 | 20 |
25.8 | 13 |
26.7 | 31 |
Preparation of phosphate salt of Example 67
2-Theta in deg | Intensity in % |
5.2 | 51 |
9.8 | 56 |
10.3 | 19 |
11.6 | 100 |
14.9 | 14 |
15.5 | 48 |
15.9 | 11 |
16.6 | 65 |
19.5 | 54 |
20.7 | 62 |
21.5 | 10 |
22.1 | 21 |
23.3 | 57 |
25.8 | 18 |
26.4 | 29 |
27.2 | 20 |
28.2 | 13 |
Preparation of hydrochloride salt of Example 67
2-Theta in deg | Intensity in % |
5.6 | 100 |
11.0 | 18 |
11.3 | 42 |
11.8 | 12 |
14.7 | 33 |
17.1 | 13 |
18.7 | 19 |
19.4 | 29 |
22.0 | 23 |
22.6 | 28 |
23.1 | 50 |
23.7 | 28 |
24.9 | 29 |
25.5 | 15 |
Preparation of hippurate salt of Example 67
2-Theta in deg | Intensity in % |
5.2 | 76 |
7.5 | 100 |
10.3 | 60 |
10.9 | 63 |
11.8 | 9 |
13.1 | 16 |
16.1 | 44 |
16.7 | 26 |
17.7 | 49 |
18.4 | 38 |
21.2 | 49 |
23.2 | 74 |
24.2 | 67 |
26.2 | 28 |
Example 68 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.26 | 507.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.48-1.67 (m, 4H) 1.88-2.35 (m, 2H) 2.59-2.87 (m, 3H) 3.26-4.03 (m, 15H) 4.56-4.83 (m, 1H) 6.82-6.92 (m, 1H, N-H) 7.86-7.90 (m, 1H) 8.26--8.32 (m, 1H) 8.37-8.42 (m, 1H) |
Example 69 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.06 | 464.2 | ||
Name: 2-Methoxy-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-ylamino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using intermediate 25 and tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 1.59-1.86 (m, 4H) 2.07-2.47 (m, 2H) 2.75-2.98 (m, 3H) 3.44-4.13 (m, 15H) 4.64-5.24 (m, 1H, signal masked by water peak) 7.94-7.99 (m, 1H) 8.20-8.26 (m, 1H) 8.33-8.39 (m, 1H) |
Example 70: 1-(4-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone
Example 71 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.40 | 535.3 | ||
Name: (2,2-Dimethyl-tetrahydro-pyran-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using 2,2-dimethyl-tetrahydro-pyran-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.05-1.20 (m, 6H) 1.30-1.58 (m, 4H) 1.86-2.35 (m, 2H) 2.70-2.90 (m, 3H) 3.34-4.03 (m, 13H) 4.55-4.80 (m, 1H) 6.67-6.76 (m, 1H, N-H) 7.86-7.89 (m, 1H) 8.26-8.31 (m, 1H) 8.32-8.37 (m, 1H) |
Example 72 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.22 | 490.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-oxazol-5-yl-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.89-2.39 (m, 2H) 2.78-2.86 (m, 2H) 3.50-4.20 (m, 11H) 4.65-4.84 (m, 1H) 6.75-6.83 (m, 1H, N-H) 7.75-7.83 (m, 1H) 7.86-7.92 (m, 1H) 8.26-8.32 (m, 1H) 8.35-8.38 (m, 1H) 8.55-8.60 (m, 1H) |
Example 73 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.38 (Isomer 1) | 535.2 (Isomer 1) | ||
Example 74 |
|
1.48 (Isomer 2) | 535.2 (Isomer 2) |
Cis/trans not assigned | |||
Name: ((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1R,4R)-4-methoxycyclohexyl)methanone | |||
((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1R,4S)-4-methoxycyclohexyl)methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using 4-methoxy-cyclohexanecarboxylic acid (mixture of cis/trans) | |||
1H NMR (Isomer 1 cis/trans not assigned) (400 MHz, DMSO-d6, 298K) δ ppm 1.04-1.47 (m, 4H) 1.64-2.45 (m, 7H) 2.77-2.86 (m, 2H) 3.00-3.77 (m, 10H) 3.87-4.03 (m, 5H) 4.53-4.80 (m, 1H) 6.67-6.78 (m, 1H, N-H) 7.85-7.91 (m, 1H) 8.26-8.32 (m, 1H) 8.33-8.38 (m, 1H) | |||
1H NMR (Isomer 2 cis/trans not assigned) (400 MHz, DMSO-d6, 298K) δ ppm 1.32-1.48 (m, 4H) 1.55-2.50 (m, 7H) 2.78-2.84 (m, 2H) 3.01-3.77 (m, 10H) 3.87-4.03 (m, 5H) 4.53-4.80 (m, 1H) 6.67-6.78 (m, 1H, N-H) 7.85-7.91 (m, 1H) 8.26-8.32 (m, 1H) 8.33-8.38 (m, 1H) |
Example 75 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.18 (Isomer 1) | 521.2 (Isomer 1) | ||
521.2 (Isomer 2) | |||
Example 76 |
|
1.29 (Isomer 2) | |
Cis/trans not assigned | |||
Name: ((1S,4R)-4-hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone | |||
((1R,4S)-4-hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using 4-hydroxy-cyclohexanecarboxylic acid (mixture of cis/trans) | |||
1H NMR (Isomer 1 cis/trans not assigned) (400 MHz, DMSO-d6, 298K) δ ppm 1.06-1.44 (m, 4H) 1.57-2.86 (m, 9H) 3.01-3.76 (m, 7H) 3.88-4.03 (m, 5H) 4.50-4.78 (m, 2H) 6.68-6.78 (m, 1H, N-H) 7.86-7.91 (m, 1H) 8.26-8.32 (m, 1H) 8.33-8.39 (m, 1H) | |||
1 H NMR (Isomer 1 cis/trans not assigned) (400 MHz, DMSO-d6, 298K) δ ppm 1.28-1.52 (m, 4H) 1.59-2.85 (m, 9H) 3.03-3.83 (m, 8H) 3.88-4.03 (m, 5H) 4.55-4.79 (m, 1H) 6.68-6.77 (m, 1H, N-H) 7.85-7.91 (m, 1H) 8.26-8.32 (m, 1H) 8.33-8.39 (m, 1H) |
Example 77 |
|
Rt(1) (min.) | MS: [M+H]+ |
0.89 | 449.2 | ||
Name:-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using intermediate 20 and 1-methyl-1H-imidazole-4-carboxylic acid | |||
1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 2.07-2.44 (m, 5H) 2.86-2.95 (m, 2H) 3.44-4.43 (m, 14H) 4.77-4.87 (m, 1H) 7.44-7.48 (m, 1H) 7.60-7.70 (m, 2H) 7.72-7.79 m, 1H) 8.32-8.41 (m, 1H) |
Example 78 |
|
Rt(1) (min.) | MS: [M+H]+ |
0.99 | 436.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-oxazol-5-yl-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using intermediate 20 and oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.95-2.35 (m, 5H) 2.74-2.83 (m, 2H) 3.35-4.20 (m, 11H) 4.62-4.83 (m, 1H) 6.73-6.81 (m, 1H) 7.44-7.49 (m, 1H) 7.75-7.85 (m, 2H) 8.33-8.38 (m, 1H) 8.54-8.59 (m, 1H) |
Example 79 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.01 | 436.2 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-oxazol-4-yl-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using intermediate 20 and oxazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.93-2.35 (m, 5H) 2.75-2.82 (m, 2H) 3.38-4.27 (m, 11H) 4.61-4.78 (m, 1H) 6.74-6.80 (m, 1H) 7.45-7.49 (m, 1H) 7.78-7.84 (m, 1H) 8.32-8.37 (m, 1H) 8.47-8.53 (m, 1H) 8.61-8.66 (m, 1H) |
Example 80 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.18 | 481.3 | ||
Name: (2,2-Dimethyl-tetrahydro-pyran-4-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using intermediate 20 and 2,2-dimethyl-tetrahydro-pyran-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.05-1.22 (m, 6H) 1.30-1.58 (m, 4H) 1.90-2.29 (m, 5H) 2.75-2.85 (m, 3H) 3.35-3.77 (m, 7H) 3.82 (s, 3H) 3.87-3.97 (m, 3H) 4.54-4.79 (m, 1H) 6.66-6.75 (m, 1H) 7.47 (d, 1H) 7.81 (d, 1H) 8.35 (d, 1H) |
Example 81: 1-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one
Example 82 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.13 | 473.2 | ||
Name: {(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using intermediate 21 and tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 1.58-1.87 (m, 4H) 2.04-2.45 (m, 2H) 2.73-2.96 (m, 3H) 3.39-4.14 (m, 15H) 4.71-4.90 (m, 1H) 7.67-7.74 (m, 1H) 7.88-7.93 (m, 1H) 8.34-8.39 (m, 1H) |
Example 83 |
|
Rt(7) (min.) | MS: [M+H]+ |
0.86 | 453.6 | ||
Name: {(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Reverse phase HPLC Method A then Method C | |||
Prepared using intermediate 20 and tetrahydro-pyran-4-carbonyl chloride | |||
1H NMR (400 MHz, MeOD-d6, 298K) δ ppm 1.57-1.88 (m, 4H) 2.04-2.45 (m, 5H) 2.73-2.96 (m, 3H) 3.37-4.12 (m, 15H) 4.73-4.88 (m, 1H) 7.45-7.48 (m, 1H) 7.73-7.77 (m, 1H) 8.36-8.39 (m, 1H) |
Example 84: (Tetrahydro-pyran-4-yl)-{(S)-3-(6-(5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanone
Example 85: {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone
Example 86 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.71 | 509.2 | ||
Name: -{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-morpholin-4-yl-methanone | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using morpholine 4-carbonyl chloride | |||
1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 2.21-2.31 (m, 2H) 3.03 (t, 2H) 3.23-3.42 (m, 4H) 3.48-3.81 (m, 9H) 3.82-3.88 (m, 1H) 3.99 (s, 3H) 4.17 (s, 2H) 5.72-5.77 (m, 1H) 7.79 (d, 1H) 8.13 (d, 1H) 8.59 (s, 1H) |
Example 87: (4-Hydroxy-piperidin-1-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone
Example 88 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.58 | 497.2 | ||
Name: (S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid (2-hydroxy-ethyl)-methyl-amide | |||
Purification method: Reverse phase HPLC Method A | |||
Prepared using 2-methylamino-ethanol | |||
1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 2.20-2.32 (m, 2H) 2.97 (s, 3H) 2.98-3.06 (t, 2H) 3.27-3.38 (m, 1H) 3.40-3.80 (m, 8H) 3.82-3.89 (m, 1H) 3.98 (s, 3H) 4.18 (s, 2H) 5.71-5.76 (m, 1H) 7.78 (d, 1H) 8.14 (d, 1H) 8.58 (s, 1H) |
Example 89: 1-(4-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperazin-1-yl)-ethanone
Example 90: (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid methyl ester
Example 91: {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yll-oxazol-4-yl-methanone
Step 2
6-(6-Methoxy 5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride
Step 1
Example 92 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.58 | 549.2 | ||
Name: 1-(4-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone | |||
Purification method: Reverse phase method A | |||
Prepared using 1-acetyl-piperidine-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.21 - 1.77 (m, 4 H) 1.92 - 2.02 (m, 3 H) 2.08 - 2.36 (m, 2 H) 2.42 - 2.80 (m, 2 H) 2.88 - 2.98 (m, 2H) 3.00 - 3.18 (m, 1 H) 3.39 - 4.24 (m, 13 H) 5.60 - 5.74 (m, 1 H) 7.80 - 7.87 (m, 1 H) 8.15 - 8.22 (m, 1 H) 8.59 - 8.65 (m, 1 H) |
Example 93 |
|
Rt(1) (min.) | MS: [M+H]+ |
1.37 | 504.1 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using 3-methyl-3H-imidazole-4-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ pm 2.14 - 2.38 (m, 2 H) 2.78 - 3.08 (m, 2 H) 3.44 - 4.04 (m, 12 H) 4.08 - 4.27 (m, 2 H) 5.66 - 5.73 (m, 1 H) 7.32 - 7.57 (m, 1 H) 7.70 - 7.97 (m, 2 H) 8.13 - 8.28 (m, 1 H) 8.56 - 8.69 (m, 1 H) | |||
Example 94 |
|
Rt(1) (min.) | MS: [M+H]+ |
0.95 | 490.9 | ||
Name: {(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone | |||
Purification method: Reverse phase method A | |||
Prepared using oxazole-5-carboxylic acid | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.28 - 2.43 (m, 2 H) 2.86 - 3.00 (m, 2 H) 3.39 - 4.27 (m, 11 H) 5.60 - 5.85 (m, 1 H) 7.72 - 7.91 (m, 2 H) 8.15 - 8.30 (m, 1 H) 8.53 - 8.68 (m, 2 H) |
Example 95 | Structure | Rt(3) (min.) | MS: [M+H]+ |
|
|||
1.39( | 440.1 | ||
Name: {(S)-3-[6-(6-Methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone | |||
Purification method: Flash-chromatography on silica gel with CH2Cl2 / MeOH | |||
Prepared using 1-benzyl-1-methyl-4-oxo-piperidinium iodide (Ref: Tortolani, R.; Org. Lett., Vol. 1, No 8, 1999) and 2-methoxypyridine | |||
1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.48-1.65 (m, 4H) 2.05-2.30 (m, 2H) 2.59-2.78 (m, 1H) 2.85-2.93 (m, 2H) 3.25-4.11 (m, 15H) 5.59-5.73 (m, 1H) 6.73-6.79 (m, 1H) 7.53-7.59 (m, 1H) 7.86-7.89 (m, 1H) 8.58-8.64 (m, 1H). |
Biological evaluation
Biological assays
1 Determination of enzymatic PI3K alpha and PI3K delta isoform inhibition
1.1 Test of lipid kinase activity
1.912 mL of HEPES assay buffer
8.33 µl of 3 mM stock of ATP giving a final concentration of 5 µM per well
1 µl of [33P]ATP on the activity date giving 0.05 µCi per well
30 µl of 1 mg/mL PI stock giving a final concentration of 6 µg/mL per well
5 µl of 1 M stock MgCl2 giving a final concentration of 1 mM per well
200 µl of 1M TRIS HCl pH7.5 (10 mM in final)
60 µl of 1 M MgCl2 (3 mM in final)
500 µl of 2M NaCl (50 mM in final)
100 µl of 10% CHAPS (0.05% in final)
200 µl of 100mM DTT (1 mM in final)
18.94 mL of nanopure water
200 µl of 1 mg/mL I-alpha-Phosphatidylinositol (Liver Bovine, Avanti Polar Lipids Cat. No. 840042C MW=909.12) prepared in 3% OctylGlucoside (10 µg/mL in final)
9.8 mL of 'buffer'
6.7 µl of 3 mM stock of ATP giving a final concentration of 1 µM per well 10 mL of 'buffer'
10 nM PI3K alfa EMV B1075
25 nM beta EMV BV949
10 nM delta EMV BV1060
150 nM gamma EMV BV950
1.2 Generation of gene constructs
PI3Kα BV-1052 p85(iSH2)-Gly linker-p110a(D20aa)-C-term His tag
PI3Kα BV-1075 p85(iSH2)-12 XGly linker-p110a(D20aa)-C-term His tag
PI3Kβ BV-949 p85(iSH2)-Gly linker-p110b(full-length)-C-term His tag
PI3Kδ BV-1060 p85(iSH2)-Gly linker-p110d(full-length)-C-term His tag
PI3Ky BV-950 p110a(D144aa)-C-term His tag
1.3 Protein expression and purification
Methods to generate recombinant baculovirus and protein for PI3K isoforms:
PI3K alpha Purification Protocol For HTS (BV1052)
PI3K beta Purification Protocol For HTS (BV949)
PI3K gamma Purification Protocol For HTS (BV950)
PI3K delta Purification Protocol For HTS (BV1060)
2. Cellular assays
2.1 Phosphoinositide-3 kinase (PI3K)-mediated Akt 1/2 (S473) phosphorylation in Rat-1 cells
2.2 Determination of murine B cell activation
3 Determination of antibody production to sheep red blood cells (SRBC).
Preparation of spleen cell suspensions:
Plaque forming assay:
References:
Biological data
Enzymatic Assay
Example | PI3K alpha (uM) | PI3K delta (uM) |
1 | 2.0378 | 0.015 |
2 | 3.391 | 0.009 |
3 | 2.386 | 0.015 |
4 | 1.764 | 0.033 |
5 | 0.749 | 0.020 |
6 | 0.987 | 0.044 |
7 | 1.973 | 0.013 |
8 | 2.494 | 0.027 |
9 | 2.906 | 0.009 |
10 | 0.668 | 0.009 |
11 | 1.199 | 0.011 |
12 | 0.952 | 0.012 |
13 | 1.802 | 0.013 |
14 | 1.832 | 0.013 |
15 | 1.631 | 0.014 |
16 | 1.684 | 0.016 |
17 | 7.678 | 0.017 |
18 | 0.871 | 0.033 |
19 | 3.056 | 0.033 |
20 | 1.839 | 0.048 |
21 | 0.320 | 0.008 |
22 | 0.580 | 0.008 |
23 | 0.129 | 0.010 |
24 | 0.374 | 0.009 |
25 | 0.820 | 0.026 |
26 | 0.368 | 0.021 |
27 | 3.410 | 0.040 |
28 | 1.214 | 0.004 |
29 | 2.585 | 0.011 |
30 | 2.831 | 0.040 |
31 | 3.024 | 0.021 |
32 | 2.036 | 0.023 |
33 | 1.967 | 0.018 |
34 | 1.648 | 0.014 |
35 | 4.232 | 0.049 |
36 | 4.103 | 0.025 |
37 | 7.021 | 0.031 |
38 | 3.306 | 0.016 |
39 | 0.434 | 0.009 |
40 | 0.260 | 0.006 |
41 | 0.515 | 0.014 |
42 | 0.863 | 0.013 |
43 | 0.728 | 0.016 |
44 | 1.189 | 0.016 |
45 | 0.860 | 0.018 |
46 | 0.803 | 0.027 |
47 | 0.656 | 0.025 |
48 | 0.518 | 0.029 |
49 | 0.388 | 0.034 |
51 | 0.912 | 0.044 |
52 | 1.024 | 0.046 |
53 | 0.504 | 0.006 |
54 | 0.384 | 0.005 |
55 | 0.661 | 0.005 |
56 | 0.860 | 0.013 |
57 | 0.590 | 0.025 |
58 | 3.060 | 0.030 |
59 | 9.100 | 0.028 |
60 | 3.333 | 0.045 |
61 | 0.589 | 0.012 |
62 | 0.489 | 0.023 |
63 | 0.791 | 0.051 |
64 | 2.331 | 0.032 |
65 | 0.738 | 0.023 |
66 | 1.280 | 0.014 |
67 | 0.262 | 0.023 |
68 | 0.043 | 0.007 |
69 | 0.056 | 0.003 |
70 | 0.121 | 0.006 |
71 | 0.057 | 0.003 |
72 | 0.093 | 0.004 |
73 | 0.054 | 0.004 |
74 | 0.113 | 0.004 |
75 | 0.118 | 0.004 |
76 | 0.106 | 0.007 |
77 | 1.290 | 0.044 |
78 | 0.384 | 0.012 |
79 | 0.781 | 0.017 |
80 | 0.430 | 0.016 |
81 | 0.651 | 0.02 |
82 | 0.066 | 0.003 |
83 | 0.432 | 0.017 |
84 | 0.058 | 0.009 |
85 | 0.569 | 0.021 |
86 | 1.330 | 0.020 |
87 | 0.452 | 0.012 |
88 | 1.336 | 0.034 |
89 | 1.189 | 0.029 |
90 | 1.991 | 0.038 |
91 | 0.924 | 0.011 |
92 | 2.545 | 0.009 |
93 | 0.872 | 0.024 |
94 | 1.714 | 0.021 |
95 | 0.757 | 0.053 |
Cellular Assays
Example | Cell PI3Kδ / IC50 [umol I-1] | mCD86 / IC50 CD86 [nmol I-1] |
1 | 0.153 | 94.9 |
5 | 0.455 | 125 |
20 | 0.2538 | 120 |
28 | 0.268 | 71.6 |
65 | 0.191 | 570 |
67 | 0.047 | 48.3 |
68 | 0.053 | 14.9 |
71 | 0.035 | 24.7 |
81 | 0.246 | 86.5 |
82 | 0.116 | 46.2 |
SRBC Assay
Plaques/spleen | |
Example 1 10mg/kg bid | 12608 ± 4986 |
Vehicle (0.5% CMC 0.5%Tween80) | 168363 ± 49142 |
The following are further embodiments of the invention:
Embodiment 1: A tetrahydro-pyrido-pyrimidine derivative of the formula (I) and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof,
wherein
Y is selected from O or NR3;
R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
-C(O)-R4
wherein
R4 is selected from C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C1-C8-alkyl, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C8-alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C1-C8-alkyl, hydroxy, C1-C8-alkoxy, amino, N-C1-C8-alkyl-amino or N,N-di-C1-C8-alkyl-amino,
wherein 'C1-C8-alkyl' in N-C1-C8-alkyl-amino and N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein 'C3-C12-cycloalkyl' in C3-C12-cycloalkyl and C3-C12-cycloalkyl-C1-C8-alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
R2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
R3 is selected from H, C1-C4-alkyl or halo-C1-C4-alkyl; and
m is selected from 0 or 1.
Embodiment 2: A compound according to embodiment 1, of the formula (Ib) and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof,
wherein
R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
-C(O)-R4
wherein
R4 is selected from C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C1-C8-alkyl, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C8-alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C1-C8-alkyl, hydroxy, C1-C8-alkoxy, amino, N-C1-C8-alkylamino or N,N-di-C1-C8-alkyl-amino,
wherein 'C1-C8-alkyl' in N-C1-C8-alkyl-amino and N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein `C3-C12-cycloalkyl' in C3-C12-cycloalkyl and C3-C12-cycloalkyl-C1-C8-alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
R2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl.
Embodiment 3: A compound according to embodiments 1 or 2, of the formula (Ib')
and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof.
Embodiment 4: A compound according to embodiment 1, of the formula (Ic) and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof,
wherein
R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
-C(O)-R4
wherein
R4 is selected from C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-oxy, heterocydyl-C1-C8-alkyl, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C8-alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C1-C8-alkyl, hydroxy, C1-C8-alkoxy, amino, N-C1-C8-alkylamino or N,N-di-C1-C8-alkyl-amino,
wherein 'C1-C8-alkyl' in N-C1-C8-alkyl-amino and N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein 'C3-C12-cycloalkyl' in C3-C12-cycloalkyl and C3-C12-cycloalkyl-C1-C8-alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
R2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl.
Embodiment 5: A compound according to embodiments 1 or 4, of the formula (Ic')
and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof.
Embodiment 6: A compound according to embodiment 1, of the formula (Id) and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof,
wherein
R4 is selected from C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C1-C8-alkyl, C3-C12-cycloalkyl, C3-C12-cydoalkyl-C1-C8-alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C1-C8-alkyl, hydroxy, C1-C8-alkoxy, amino, N-C1-C8-alkyl-amino or N,N-di-C1-C8-alkyl-amino, wherein 'C1-C8-alkyl' in N-C1-C8-alkyl-amino and N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein `C3-C12-cycloalkyl' in C3-C12-cycloalkyl and C3-C12-cydoalkyl-C1-C8-alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heterocyclyl' is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states; and
R2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl.
Embodiment 7: A compound according to embodiment 1, of the formula (Ie) and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof,
wherein
R4 is selected from C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C1-C8-alkyl, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C8-alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C1-C8-alkyl, hydroxy, C1-C8-alkoxy, amino, N-C1-C8-alkyl-amino or N,N-di-C1-C8-alkyl-amino, wherein 'C1-C8-alkyl' in N-C1-C8-alkyl-amino and N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein 'C3-C12-cycloalkyl' in C3-C12-cycloalkyl and C3-C12-cycloalkyl-C1-C8-alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heterocyclyl' is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states; and
R2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl.
Embodiment 8: A compound according to embodiment 1, of the formula (Id')
and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof.
Embodiment 9: A compound according to embodiment 1, of the formula (Ie')
and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof.
Embodiment 10: A compound according to any one of embodiments 1 to 9, wherein R2 is selected from naphthyl, pyridyl or pyrimidinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl.
Embodiment 11: A compound according to any one of embodiments 1 to 10, wherein
R1, if present, is -C(O)-R4, wherein
R4 is selected from heterocyclyl, C4-C8-cycloalkyl or heteroaryl;
wherein `C3-C12-cycloalkyl' may be unsubstituted or substituted by 1-3 substituents independently selected from fluoro, C1-C4-alkyl, hydroxyl, C1-C4-alkoxy;
wherein 'heterocyclyl' is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from oxo, halogen, C1-C4-alkyl, hydroxyl, C1-C4-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from C1-C4-alkyl, hydroxyl;
wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states.
Embodiment 12: A compound according to any one of embodiments 1 to 10, wherein
R1, if present, is -C(O)-R4,and
R4 is selected from C1-C8-alkyl, C1-C8-alkoxy-Ci-C8-alkyl, C1-C8-alkoxy or N,N-di-C1-C8-alkyl-amino,
wherein 'C1-C8-alkyl' in N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy.
Embodiment 13:. A compound of the formula (I) as defined in anyone of embodiments 1 to 12 in form of a salt selected from
Embodiment 14: A compound of the formula (I) as defined in anyone of embodiments 1 to 13, for use as pharmaceutical.
Embodiment 15: A combination comprising a therapeutically effective amount of a compound of formula (I) as defined in anyone of embodiments 1 to 13, and one or more therapeutically active agents.
Embodiment 16: Use of a compound of formula (I) as defined in anyone of embodiments 1 to 13, for the manufacture of a medicament for the treatment of a diseases or disorders which are mediated by the activity of the PI3K enzymes, preferably by the activity of the PI3Kδ isoform.
Embodiment 17: A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in anyone of embodiments 1 to 13, and one or more pharmaceutically acceptable carriers.
Embodiment 18: A method of modulating the activity of the PI3K enzymes, preferably of the PI3Kδ isoform , in a subject, comprising the step of administering to a subject a therapeutically effective amount of a compound of formula (I) as defined in anyone of embodiments 1 to 13.
Embodiment 19: A method for the treatment of a disorder or a disease mediated by the PI3K enzymes, preferably by the PI3Kδ isoform , comprising the step of administering to a subject a therapeutically effective amount of a compound of formula (I) as defied defined in anyone of embodiments 1 to 13.
Embodiment 20: A method according to embodiment 19, wherein the disorder or a disease is selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection; antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell-mediated hyperacute, acute and chronic transplant rejection and cancers of haematopoietic origin including but not limited to multiple myeloma; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Walden stroem disease.
Embodiment 21: A method according to embodiment 19, wherein the disorder or a disease is selected from rheumatoid arthritis (RA), pemphigus vulgaris (PV), idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), acquired hemophilia type A (AHA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjögren's syndrome (SS), ANCA-associated vasculitides, cryoglobulinemia, chronic autoimmune urticaria (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, transplant rejection and cancers of haematopoietic origin.
Embodiment 22: Use of a compound of formula (I) as defined in anyone of embodiments 1 to 13, for the treatment of a disorder or a disease in a subject mediated by the activity of the PI3K enzymes, preferably by the activity of the PI3Kδ isoform.
Embodiment 23: Use of a compound of formula (I) as defined in anyone of embodiments 1 to 13, for the treatment of a disorder or disease selected from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection; antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren`s syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, AMR (antibody-mediated transplant rejection), B cell-mediated hyperacute, acute and chronic transplant rejection and cancers of haematopoietic origin including but not limited to multiple myeloma; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Walden stroem disease.
Embodiment 24. Use of a compound of formula (I) as defined in anyone of embodiments 1 to 13, for the treatment of a disorder or disease selected from rheumatoid arthritis (RA), pemphigus vulgaris (PV), idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune hemolytic anemia (AIHA), acquired hemophilia type A (AHA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjögren's syndrome (SS), ANCA-associated vasculitides, cryoglobulinemia, chronic autoimmune urticaria (CAU), allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), goodpasture's syndrome, transplant rejection and cancers of haematopoietic origin.
Embodiment 25: A process or method for the manufacture of a compound of the formula (I) according to embodiment 1,
comprising the steps of method A:
b) deprotecting the compound of formula (E),
wherein PG2 represents a suitable protectiong group and R1, Y and m are as defined for a compound of formula (I)
c) followed by reaction with
R2-Hal,
wherein R2 is as defined for a compound of formula (I) and Hal represents halogen, under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst, in the presence of a base, in an organic solvent;
d) deprotecting PG1 from the compound of formula (C),
wherein PG1 represents a suitable protecting group, and the other substituents are as defined above,
e) followed by coupling reaction with
R1-Act,
wherein when R1 is -C(O)-R4, wherein R4 is as defined for a compound of formula (I), and Act represents an activating group or a hydroxy group, the coupling reaction is an amide, urea or carbamic ester formation, or;
wherein when R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl and Act represents halogen, the coupling reaction is carried out in the presence of an amine base or alternatively, the reaction is carried out under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst in the presence of a base;
d) deprotecting the compound of formula (D),
wherein PG1 represents a suitable protecting group, and the other substituents are as defined above
e) followed by coupling reaction with
R1-Act,
wherein when R1 is -C(O)-R4, wherein R4 is as defined for a compound of formula (I), and Act represents an activating group or a hydroxy group, the coupling reaction is an amide, urea or carbamic ester formation, or;
wherein when R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl and Act represents halogen, the coupling reaction is carried out in the presence of an amine base or alternatively, the reaction is carried out under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst in the presence of a base;
wherein compound of formula (D) is prepared comprising the step of
b) deprotecting PG1 from the compound of formula (C),
wherein PG1 represents a suitable protecting group, and the other substituents are as defined above,
c) followed by coupling reaction with
R2-Hal,
wherein R2 is as defined for a compound of formula (I) and Hal represents halogen, under customary Buchwald-Hartwig conditions using a ligand with a palladium catalyst, in the presence of a base, in an organic solvent;
wherein the compound of formula (C) is prepared as described above;
Y is selected from O or NR3;
R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
-C(O)-R4
wherein
R4 is selected from C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C1-C8-alkyl, C3-C12-cycloalkyl, C3-C12-cycloalkyl-C1-C8-alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C1-C8-alkyl, hydroxy, C1-C8-alkoxy, amino, N-C1-C8-alkylamino or N,N-di-C1-C8-alkyl-amino,
wherein `C1-C8-alkyl' in N-C1-C8-alkyl-amino and N,N-di-C1-C8-alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C1-C4-alkoxy;
wherein 'C3-C12-cycloalkyl' in C3-C12-cycloalkyl and C3-C12-cycloalkyl-C1-C8-alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' is selected from oxiranyl, aziridinyl, oxetanyl, thiethanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl or oxepanyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl;
wherein 'heterocyclyl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
wherein 'heteroaryl' is selected from
furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl; each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-C1-C8-alkyl-carbonyl; wherein 'heteroaryl' can be attached at a heteroatom or a carbon atom and where the N and/or S heteroatoms can also optionally be oxidized to various oxidation states;
R2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, cyano, nitro, C1-C8-alkyl, halo-C1-C8-alkyl, hydroxy-C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, amino, N-C1-C8-alkyl-amino, N,N-di-C1-C8-alkyl-amino, C1-C8-alkyl-carbonyl, halo-C1-C8-alkyl-carbonyl, hydroxy-C1-C8-alkyl-carbonyl or C1-C8-alkoxy-Cl-C8-alkyl-carbonyl;
R3 is selected from H, C1-C4-alkyl or halo-C1-C4-alkyl; and
m is selected from 0 or 1.
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{(S)-3-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
2-Methoxy-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
1-{((S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
1-{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
2-Amino-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Amino-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
(S)-(3-(6-(5-Fluoro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(5-Fluoro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-2-Methoxy-5-(4-(1-(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
2-Methoxy-5-(4-(1-(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
(S)-5-(4-(1-(Cyclopentanecarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxynicotinonitrile;
5-((4-(1-(Cyclopentanecarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxynicotinonitrile;
(2,4-Dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(2,4-Dimethyl-oxazol-5-yl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
(3-Methoxy-cyclobutyl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(3-Methoxy-cyclobutyl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
({(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
({3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
1-((4-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
1-((4-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanone;
5-{((S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-1H-pyridin-2-one;
5-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-1H-pyridin-2-one;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanone;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanone;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanone;
(4,4-Difluoro-cyclohexyl)-{(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(4,4-Difluoro-cyclohexyl)-{3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
2-Methoxy-5-{4-[(S)-1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
5-{4-[(S)-1-(2,4-Dimethyl-oxazole-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
5-{4-[1-(2,4-Dimethyl-oxazole-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
5-{4-[(S)-1-(2,2-Dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
5-{4-[1-(2,2-Dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitrile;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanone;
Isoxazol-3-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Isoxazol-3-yl-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Isoxazol-5-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
Isoxazol-5-yl-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
2-Methoxy-5-{4-[(S)-1-(thiazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(thiazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
2-Methoxy-5-{4-[1-(1-methyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile;
(2,2-Dimethyl-tetrahydro-pyran-4yl)-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(2,2-Dimethyl-tetrahydro-pyran-4yl)-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(1,1-Dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(1,1-Dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone;
(S)-(2,4-Dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(2,4-Dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluorom ethyl) pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-5-yl)methanone;
4-(((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
4-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanone;
(S)-(1H-Imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(1H-Imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
5-(((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
5-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanone;
(S)-(1,3-Dimethyl-1H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(1,3-Dimethyl-1H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanone;
(S)-(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone;
(3-((6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1 H-imidazol-4-yl)methanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanone; {3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1 H-pyrazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanone;
{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanone;
{(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
(S)-(3-(6-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)azetidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
{(S)-3-[6-(2-Methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
{3-[6-(2-Methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone;
[(S)-3-(6-Quinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone;
[3-((6-Quinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-1-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-one;
1-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-one;
1-{((S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
1-{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one;
2-Methoxy-5-[4-((S)-1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitrile;
2-Methoxy-5-[4-(1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitrile;
(S)-6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
6-((6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
(S)-6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
6-((6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;
(S)-1-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
1-((3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-2-Methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
2-Methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
(S)-1-(4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidine-1-carbonyl)piperidin-1-yl)ethanone;
1-((4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidine-1-carbonyl)piperidin-1-yl)ethanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanone;
((S)-3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanone;
((1s,4R)-4-Hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
((1s,4R)-4-Hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
((1r,4S)-4-Hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
((1r,4S)-4-Hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanone;
(S)-1-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
1-((3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one;
(S)-(3-(6-(5-Chloro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(5-Chloro-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone;
(Tetrahydro-pyran-4-yl)-{(S)-3-{6-(5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanone;
(Tetrahydro-pyran-4-yl)-{3-{6-(5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanone;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanone;
(S)-(4-Hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
4-Hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanone;
(S)-N-(2-Hydroxyethyl)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-methylpyrrolidine-1-carboxamide;
N-(2-Hydroxyethyl)-3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-methylpyrrolidine-1-carboxamide;
(S)-1-(4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)piperazin-1-yl)ethanone;
1-((4-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)piperazin-1-yl)ethanone;
(S)-2-Methoxy-5-(4-(1-(morpholine-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
2-Methoxy-5-(4-(1-(morpholine-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile;
(S)-(3-(6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
(3-((6-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanone;
1-((4-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
1-((4-{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperidin-1-yl)-ethanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanone;
{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanone;
{(S)-3-[6-(6-Methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone; and
{3-[6-(6-Methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone.
a) citrate, fumarate or napadisylate; or
b) phosphate, hydrochloride or hippurate.
Y aus O oder NR3 ausgewählt ist;
R1 ausgewählt ist aus Phenyl, Pyridyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, 1,2,3-Triazinyl, 1,2,4-Triazinyl, 1,3,5-Triazinyl,
oder
-C(O)-R4,
wobei
R4 aus C1-C8-Alkyl, Halo-C1-C8-alkyl, Hydroxy-C1-C8-alkyl, C1-C8-Alkoxy-C1-C8-alkyl, C1-C8-Alkylsulfonyl-C1-C8-alkyl, Heterocyclyl, Heterocyclyloxy, Heterocyclyl-C1-C8-alkyl, C3-C12-Cycloalkyl, C3-C12-Cycloalkyl-C1-C8-alkyl, Heteroaryl, Heteroaryloxy, Heteroaryl-C1-C8-alkyl, Hydroxy, C1-C8-Alkoxy, Amino, N-C1-C8-Alkylamino oder N,N-di-C1-C8-Alkylamino ausgewählt ist,
wobei "C1-C8-Alkyl" in N-C1-C8-Alkylamino und N,N-di-C1-C8-Alkylamino unsubstituiert oder durch Halogen, Hydroxy oder C1-C4-Alkoxy substituiert sein kann;
wobei "C3-C12-Cycloalkyl" in C3-C12-Cycloalkyl und C3-C12-Cycloalkyl-C1-C8-alkyl unsubstituiert oder durch 1 bis 5 Substituenten substituiert sein kann, die unabhängig aus Oxo, Halogen, C1-C8-Alkyl, Halo-C1-C8-alkyl, Hydroxy-C1-C8-alkyl, Hydroxyl, C1-C8-Alkoxy, C1-C8-Alkoxy-C1-C8-alkyl, Amino, N-C1-C8-Alkylamino, N,N-di-C1-C8-Alkylamino, C1-C8-Alkylcarbonyl, Halo-C1-C8-alkylcarbonyl, Hydroxy-C1-C8-alkylcarbonyl oder C1-C8-Alkoxy-C1-C8-alkylcarbonyl ausgewählt sind;
wobei "Heterocyclyl" aus Oxiranyl, Aziridinyl, Oxetanyl, Thiethanyl, Azetidinyl, Pyrrolidinyl, Tetrahydrofuranyl, Tetrahydrothiophenyl, 2,3-Dihydrofuranyl, 2,5-Dihydrofuranyl, 2,3-Dihydrothiophenyl, 1-Pyrrolinyl, 2-Pyrrolinyl, 3-Pyrrolinyl, Tetrahydropyranyl, Piperidinyl, Tetrahydrothiopyranyl, Morpholinyl, Thiomorpholinyl, Piperazinyl, Azepanyl, Thiepanyl oder Oxepanyl ausgewählt ist; wobei jedes davon unsubstituiert oder durch 1 bis 5 Substituenten substituiert ist, die unabhängig aus Oxo, Halogen, C1-C8-Alkyl, Halo-C1-C8-alkyl, Hydroxy-C1-C8-alkyl, Hydroxyl, C1-C8-Alkoxy, C1-C8-Alkoxy-C1-C8-alkyl, Amino, N-C1-C8-Alkylamino, N,N-di-C1-C8-alkylamino, C1-C8-Alkylcarbonyl, Halo-C1-C8-alkylcarbonyl, Hydroxy-C1-C8-alkylcarbonyl oder C1-C8-Alkoxy-C1-C8-alkylcarbonyl ausgewählt sind;
wobei "Heterocyclyl" an ein Heteroatom oder ein Kohlenstoffatom angehaftet sein kann, und wobei die N- und/oder S-Hetereoatome optional auch zu diversen Oxidationszuständen oxidiert sein können;
wobei "Heteroaryl" ausgewählt ist aus
Furanyl, Thiophenyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Thiazolyl, Isothiazolyl, Oxazolyl, Isoxazolyl, 1,2,5-Oxadiazolyl, 1,2,4-Oxadiazolyl, 1,2,3-Oxadiazolyl, 1,3,4-Oxadiazolyl, 1,2,5-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,3-Thiadiazolyl, 1,3,4-Thiadiazolyl, 1,2,3-Triazolyl, 1,2,4-Triazolyl, 1,2,5-Triazolyl, Pyridyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, 1,2,3-Triazinyl, 1,2,4-Triazinyl oder 1,3,5-Triazinyl; wobei jedes davon unsubstituiert oder durch 1 bis 5 Substituenten substituiert ist, die unabhängig aus Halogen, C1-C8-Alkyl, Halo-C1-C8-alkyl, Hydroxy-C1-C8-alkyl, Hydroxyl, C1-C8-Alkoxy, C1-C8-Alkoxy-C1-C8-alkyl, Amino, N-C1-C8-Alkylamino, N,N-di-C1-C8-alkylamino, C1-C8-Alkylcarbonyl, Halo-C1-C8-alkylcarbonyl, Hydroxy-C1-C8-alkylcarbonyl oder C1-C8-Alkoxy-C1-C8-alkylcarbonyl ausgewählt sind; wobei "Heteroaryl" an ein Heteroatom oder ein Kohlenstoffatom angehaftet sein kann, und wobei die N- und/oder S-Heteroatome optional auch zu diversen Oxidationszuständen oxidiert sein können;
R2 aus Phenyl, Naphthyl, Pyridyl, Pyrimidinyl, Pyrazinyl, Pyridazinyl, Chinolinyl oder Isochinolinyl ausgewählt ist, wobei jedes davon unsubstituiert oder durch 1 bis 5 Substituenten substituiert ist, die unabhängig aus Halogen, Cyano, Nitro, C1-C8-Alkyl, Halo-C1-C8-alkyl, Hydroxy-C1-C8-alkyl, Hydroxyl, C1-C8-Alkoxy, C1-C8-Alkoxy-C1-C8-alkyl, Amino, N-C1-C8-Alkylamino, N,N-di-C1-C8-alkylamino, C1-C8-Alkylcarbonyl, Halo-C1-C8-alkylcarbonyl, Hydroxy-C1-C8-alkylcarbonyl oder C1-C8-Alkoxy-C1-C8-alkylcarbonyl ausgewählt sind;
R3 aus H, C1-C4-Alkyl oder Halo-C1-C4-alkyl ausgewählt ist; und
m aus 0 oder 1 ausgewählt ist.
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
{(S)-3-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
{3-[6-(2,4-Dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
2-Methoxy-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Methoxy-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
1- {((S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-on;
1- {3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-on;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy] -pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
2-Amino-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Amino-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
(S)-(3-(6-(5-Fluor-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(3-((6-(5-Fluor-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(S)-2-Methoxy-5-(4-(1-(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitril;
2-Methoxy-5-(4-(1-(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitril;
(S)-5-(4-(1-(Cyclopentancarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxynicotinonitril;
5-((4-(1-(Cyclopentancarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxynicotinonitril;
(2,4-Dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
(2,4-Dimethyl-oxazol-5-yl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
Furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
Furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
Furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
Furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon;
(3-Methoxy-cyclobutyl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
(3-Methoxy-cyclobutyl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
({(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanon;
({3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanon;
1-((4-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon;
1-((4-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanon;
5-{((S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-1H-pyridin-2-on;
5-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-1H-pyridin-2-on;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanon;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanon;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanon;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanon;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanon;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanon;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanon;
{(S)-3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanon;
{3-[6-(5,6-Dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanon;
(4,4-Difluor-cyclohexyl)-{(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
(4,4-Difluor-cyclohexyl)-{3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
2-Methoxy-5-{4-[(S)-1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Methoxy-5-{4-[1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
5-{4-[(S)-1-(2,4-Dimethyl-oxazol-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitril;
5-{4-[1-(2,4-Dimethyl-oxazol-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitril;
5-{4-[(S)-1-(2,2-Dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitril;
5-{4-[1-(2,2-Dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinonitril;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-Pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-Pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanon;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanon;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon;
{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon;
Isoxazol-3-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
Isoxazol-3-yl-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
Isoxazol-5-yl-{(S)-3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanol;
Isoxazol-5-yl-{3-[6-(6-Methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
2-Methoxy-5-{4-[(S)-1-(thiazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Methoxy-5-{4-[1-(thiazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Methoxy-5-{4-[1-(1-methyl-1H-pyrazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazol-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
2-Methoxy-5-{4-[1-(1-methyl-1H-pyrazol-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitril;
(2,2-Dimethyl-tetrahydro-pyran-4yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
(2,2-Dimethyl-tetrahydro-pyran-4yl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
(1,1-Dioxo-hexahydro-Ilambda*6*-thiopyran-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
(1,1-Dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{3-[6-(6-methoxy-5-trifluormethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon;
(S)-(2,4-Dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
(2,4-Dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-5-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-5-yl)methanon;
4-(((S)-3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on;
4-((3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanon;
(S)-(1H-Imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
(1H-Imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
5-(((S)-3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on;
5-((3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanon;
(S)-(1,3-Dimethyl-1H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
(1,3-Dimethyl-1H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanon;
{(S)-3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanon;
{(S)-3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanon;
{3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanon;
{(S)-3-[6-(5-Chlor-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
{3-[6-(5-Chlor-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
(S)-(3-(6-(6-Amino-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(3-((6-(6-Amino-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)azetidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
{(S)-3-[6-(2-Methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-l-yl}-(tetrahydro-pyran-4-yl)-methanon;
{3-[6-(2-Methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon;
[(S)-3-(6-Chinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanon;
[3-((6-Chinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(S)-1-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-on;
1-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-on;
1-(((S)-3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl-propan-1-on;
1-{3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-on;
2-Methoxy-5-[4-((S)-1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitril;
2-Methoxy-5-[4-(1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitril;
(S)-6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin;
6-((6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin;
(S)-6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin;
6-((6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin;
(S)-1-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-on;
1-((3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-on;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(S)-2-Methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitril;
2-Methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitril;
(S)-1-(4-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-carbonyl)piperidin-1-yl)ethanon;
1-((4-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-carbonyl)piperidin-1-yl)ethanon;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon;
((S)-3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanon; (3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanon;
((S)-3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanon; (3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanon;
((1s,4R)-4-Hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
((1s,4R)-4-Hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
((1r,4S)-4-Hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
((1r,4S)-4-Hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanon;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanon;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanon;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon;
(S)-1-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-on;
1-((3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-on;
(S)-(3-(6-(5-Chlor-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(3-((6-(5-Chlor-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(3-((6-(6-Methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon;
(Tetrahydro-pyran-4-yl)-{(S)-3-{6-(5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanon;
(Tetrahydro-pyran-4-yl)-{3-{6-(5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanon;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanon;
(S)-(4-Hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
4-Hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon;
(S)-N-(2-Hydroxyethyl)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-methylpyrrolidin-1-carboxamid;
N-(2-Hydroxyethyl)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-methylpyrrolidin-1-carboxamid;
(S)-1-(4-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)piperazin-1-yl)ethanon;
1-((4-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)piperazin-1-yl)ethanon;
(S)-2-Methoxy-5-(4-(1-(morpholin-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitril;
2-Methoxy-5-(4-(1-(morpholin-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitril;
(S)-(3-(6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanon;
(3-((6-(6-Methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanon;
1-((4-{(S)-3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon;
1-((4-{3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon;
{(S)-3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon;
{3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon;
{(S)-3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanon;
{3-[6-(6-Methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanon;
{(S)-3-[6-(6-Methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; und
{3-[6-(6-Methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon.
a) Citrat, Fumarat oder Napadisylat; oder
b) Phosphat, Hydrochlorid oder Hippurat.
• Y est choisi parmi 0 ou NR3 ;
• R1 est choisi parmi phényle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, 1,2,3-triazinyle, 1,2,4-triazinyle, 1,3,5-triazinyle, ou
• -C(O)-R4
où :
- R4 est choisi parmi alkyle en C1-C8, halo-alkyle en C1-C8, hydroxy-alkyle en C1-C8, alcoxy en C1-C8-alkyle en C1-C8, alkyl en C1-C8-sulfonyl-alkyle en C1-C8, hétérocyclyle, hétérocyclyl-oxy, hétérocyclyl-alkyle en C1-C8, cycloalkyle en C3-C12, cycloalkyl en C3-C12-alkyle en C1-C8, hétéroaryle, hétéroaryl-oxy, hétéroaryl-alkyle en C1-C8, hydroxy, alcoxy en C1-C8, amino, N-alkyl en C1-C8-amino ou N,N-di-(alkyl en C1-C8)-amino ;
- où « alkyl en C1-C8 » dans N-alkyl en C1-C8-amino et N,N-di-(alkyl en C1-C8)-amino peut être non substitué ou substitué par halogène, hydroxy ou alcoxy en C1-C4 ;
- où « cycloalkyle en C3-C12 » dans cycloalkyle en C3-C12 et cycloalkyl en C3-C12-alkyle en C1-C8 peut être non substitué ou substitué par 1-5 substituants indépendamment choisis parmi oxo, halogène, alkyle en C1-C8, halo-alkyle en C1-C8, hydroxy-alkyle en C1-C8, hydroxyle, alcoxy en C1-C8, alcoxy en C1-C8-alkyle en C1-C8, amino, N-alkyl en C1-C8-amino, N,N-di-(alkyl en C1-C8)-amino, alkyl en C1-C8-carbonyle, halo-alkyl en C1-C8-carbonyle, hydroxy-alkyl en C1-C8-carbonyle ou alcoxy en C1-C8-alkyl en C1-C8-carbonyle ;
- où « hétérocyclyle » est choisi parmi oxiranyle, aziridinyle, oxétanyle, thiéthanyle, azétidinyle, pyrrolidinyle, tétrahydrofuranyle, tétrahydrothiophényle, 2,3-dihydrofuranyle, 2,5-dihydrofuranyle, 2,3-dihydrothiophényle, 1-pyrrolinyle, 2-pyrrolinyle, 3-pyrrolinyle, tétrahydropyranyle, pipéridinyle, tétrahydrothiopyranyle, morpholinyle, thiomorpholinyle, pipérazinyle, azépanyle, thiépanyle ou oxépanyle ; dont chacun est non substitué ou substitué par 1-5 substituants indépendamment choisis parmi oxo, halogène, alkyle en C1-C8, halo-alkyle en C1-C8, hydroxy-alkyle en C1-C8, hydroxyle, alcoxy en C1-C8, alcoxy en C1-C8-alkyle en C1-C8, amino, N-alkyl en C1-C8-amino, N,N-di- (alkyl en C1-C8)-amino, alkyl en C1-C8-carbonyle, halo-alkyl en C1-C8-carbonyle, hydroxy-alkyl en C1-C8-carbonyle ou alcoxy en C1-C8-alkyl en C1-C8-carbonyle ;
- où « hétérocyclyle » peut être attaché à un hétéroatome ou à un atome de carbone et où les hétéroatomes N et/ou S peuvent également facultativement être oxydés à divers états d'oxydation ;
- où « hétéroaryle » est choisi parmi furanyle, thiophényle, pyrrolyle, imidazolyle, pyrazolyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle, 1,2,5-oxadiazolyle, 1,2,4-oxadiazolyle, 1,2,3-oxadiazolyle, 1,3,4-oxadiazolyle, 1,2,5-thiadiazolyle, 1,2,4-thiadiazolyle, 1,2,3-thiadiazolyle, 1,3,4-thiadiazolyle, 1,2,3-triazolyle, 1,2,4-triazolyle, 1,2,5-triazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, 1,2,3-triazinyle, 1,2,4-triazinyle ou 1,3,5-triazinyle ; dont chacun est non substitué ou substitué par 1-5 substituants indépendamment choisis parmi halogène, alkyle en C1-C8, halo-alkyle en C1-C8, hydroxy-alkyle en C1-C8, hydroxyle, alcoxy en C1-C8, alcoxy en C1-C8-alkyle en C1-C8, amino, N-alkyl en C1-C8-amino, N,N-di-(alkyl en C1-C8)-amino, alkyl en C1-C8-carbonyle, halo-alkyl en C1-C8-carbonyle, hydroxy-alkyl en C1-C8-carbonyle ou alcoxy en C1-C8-alkyl en C1-C8-carbonyle ;
- où « hétéroaryle » peut être attaché à un hétéroatome ou à un atome de carbone et où les hétéroatomes N et/ou S peuvent également facultativement être oxydés à divers états d'oxydation ;
• R2 est choisi parmi phényle, naphtyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, quinolinyle ou isoquinolinyle, dont chacun est non substitué ou substitué par 1-5 substituants indépendamment choisis parmi halogène, cyano, nitro, alkyle en C1-C8, halo-alkyle en C1-C8, hydroxy-alkyle en C1-C8, hydroxyle, alcoxy en C1-C8, alcoxy en C1-C8-alkyle en C1-C8, amino, N-alkyl en C1-C8-amino, N,N-di-(alkyl en C1-C8)-amino, alkyl en C1-C8-carbonyle, halo-alkyl en C1-C8-carbonyle, hydroxy-alkyl en C1-C8-carbonyle ou alcoxy en C1-C8-alkyl en C1-C8-carbonyle ;
• R3 est choisi parmi H, alkyle en C1-C4 ou halo-alkyle en C1-C4 ; et
• m est choisi parmi 0 ou 1.
R2 est choisi parmi naphtyle, pyridyle ou pyrimidinyle ;
dont chacun est non substitué ou substitué par 1-3 substituants indépendamment choisis parmi halogène, cyano, nitro, alkyle en C1-C8, halo-alkyle en C1-C8, hydroxy-alkyle en C1-C8, hydroxyle, alcoxy en C1C8, alcoxy en C1-C8-alkyle en C1-C8, amino, N-alkyl en C1-C8-amino, N,N-di-(alkyl en C1-C8)-amino, alkyl en C1-C8-carbonyle, halo-alkyl en C1-C8-carbonyle, hydroxy-alkyl en C1-C8-carbonyle ou alcoxy en C1-C8-alkyl en C1-C8-carbonyle.
R1, s'il est présent, représente -C(O)-R4, où :
R4 est choisi parmi hétérocyclyle, cycloalkyle en C4-C8 ou hétéroaryle ;
• où « cycloalkyle en C3-C12 » peut être non substitué ou substitué par 1-3 substituants indépendamment choisis parmi fluoro, alkyle en C1-C4, hydroxyle, alcoxy en C1-C4 ;
• où « hétérocyclyle » est choisi parmi pyrrolidinyle, tétrahydropyranyle, pipéridinyle, tétrahydrothiopyranyle, morpholinyle ou pipérazinyle ; dont chacun est non substitué ou substitué par 1-3 substituants indépendamment choisis parmi oxo, halogène, alkyle en C1-C4, hydroxyle, alkyl en C1-C4-carbonyle ;
• où « hétérocyclyle » peut être attaché à un hétéroatome ou à un atome de carbone et où les hétéroatomes N et/ou S peuvent également facultativement être oxydés à divers états d'oxydation ;
• où « hétéroaryle » est choisi parmi furanyle, imidazolyle, pyrazolyle, thiazolyle, oxazolyle, isoxazolyle, 1,3,4-oxadiazolyle, pyridyle, pyrazinyle ; dont chacun est non substitué ou substitué par 1-3 substituants indépendamment choisis parmi alkyle en C1-C4, hydroxyle ;
• où « hétéroaryle » peut être attaché à un hétéroatome ou à un atome de carbone et où les hétéroatomes N et/ou S peuvent également facultativement être oxydés à divers états d'oxydation.
• R1, s'il est présent, représente -C(O)-R4 ; et
• R4 est choisi parmi alkyle en C1-C8, alcoxy en C1-C8-alkyle en C1-C8, alcoxy en C1-C8 ou N,N-di-(alkyl en C1-C8)-amino,
• où « alkyle en C1-C8 » dans N,N-di-(alkyl en C1-C8-amino peut être non substitué ou substitué par halogène, hydroxy ou alcoxy en C1-C4.
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la {(S)-3-[6-(2,4-diméthoxy-pyrimidin-5-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la {3-[6-(2,4-diméthoxy-pyrimidin-5-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• le 2-méthoxy-5-{4-[(S)-1-(tétrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-méthoxy-5-{4-[1-(tétrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• la 1-{(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one ;
• la 1-{3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one ;
• la {(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la {3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• le 2-amino-5-{4-[(S)-1-(tétrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-amino-5-{4-[1-(tétrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• la (S)-(3-(6-(5-fluoro-6-méthoxypyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (3-(6-(5-fluoro-6-méthoxypyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• le (S)-2-méthoxy-5-(4-(1-(2-méthoxyacétyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile ;
• le 2-méthoxy-5-(4-(1-(2-méthoxyacétyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl) nicotinonitrile ;
• le (S)-5-(4-(1-(cyclopentanecarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-méthoxynicotinonitrile ;
• le 5-(4-(1-(cyclopentanecarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-méthoxynicotinonitrile ;
• la (2,4-diméthyl-oxazol-5-yl)-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la (2,4-diméthyl-oxazol-5-yl)-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la furan-3-yl-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la furan-3-yl-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la furan-3-yl-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la furan-3-yl-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-3H-imidazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-3H-imidazol-4-yl)-méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-méthyl-oxazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-méthyl-oxazol-4-yl)-méthanone ;
• la (3-méthoxy-cyclobutyl)-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la (3-méthoxy-cyclobutyl)-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la ({(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-méthanone ;
• la ({3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-méthanone ;
• la 1-(4-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-pipéridin-1-yl)-éthanone ;
• la 1-(4-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-pipéridin-1-yl)-éthanone ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-méthyl-oxazol-5-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(4-méthyl-oxazol-5-yl)-méthanone ;
• la 5-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-1H-pyridin-2-one ;
• la 5-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-1H-pyridin-2-one ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-méthyl-1H-imidazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-méthyl-1H-imidazol-4-yl)-méthanone ;
• la {(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-méthanone ;
• la {3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-méthanone ;
• la {(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-méthanone ;
• la {3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-méthanone ;
• la {(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-méthyl-oxazol-4-yl)-méthanone ;
• la {3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-méthyl-oxazol-4-yl)-méthanone ;
• la {(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-diméthyl-tétrahydro-pyran-4-yl)-méthanone ;
• la {3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,2-diméthyl-tétrahydro-pyran-4-yl)-méthanone ;
• la {(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-diméthyl-oxazol-5-yl)-méthanone ;
• la {3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2,4-diméthyl-oxazol-5-yl)-méthanone ;
• la (4,4-difluoro-cyclohexyl)-{(S)-3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la (4,4-difluoro-cyclohexyl)-{3-[6-(5,6-diméthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• le 2-méthoxy-5-{4-[(S)-1-(2-tétrahydro-pyran-4-yl-acétyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-méthoxy-5-{4-[1-(2-tétrahydro-pyran-4-yl-acétyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 5-{4-[(S)-1-(2,4-diméthyl-oxazole-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-méthoxy-nicotinonitrile ;
• le 5-{4-[1-(2,4-diméthyl-oxazole-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-méthoxy-nicotinonitrile ;
• le 5-{4-[(S)-1-(2,2-diméthyl-tétrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-méthoxy-nicotinonitrile ;
• le 5-{4-[1-(2,2-diméthyl-tétrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-méthoxy-nicotinonitrile ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-méthyl-oxazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-méthyl-oxazol-4-yl)-méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-méthyl-isoxazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(5-méthyl-isoxazol-4-yl)-méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-isoxazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-isoxazol-4-yl)-méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-isoxazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-isoxazol-4-yl)-méthanone ;
• l'isoxazol-3-yl-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• l'isoxazol-3-yl-t3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• l'isoxazol-5-yl-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• l'isoxazol-5-yl-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• le 2-méthoxy-5-{4-[(S)-1-(thiazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-méthoxy-5-{4-[1-(thiazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-méthoxy-5-{4-[(S)-1-(1-méthyl-1H-pyrazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-méthoxy-5-{4-[1-(1-méthyl-1H-pyrazole-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-méthoxy-5-{4-[(S)-1-(1-méthyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• le 2-méthoxy-5-{4-[1-(1-méthyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinonitrile ;
• la (2,2-diméthyl-tétrahydro-pyran-4yl)-{(S)-3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la (2,2-diméthyl-tétrahydro-pyran-4yl)-{3-[6-(6-méthoxy-5-méthyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la (1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{(S)-3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la (1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-méthanone ;
• la (S)-(2,4-diméthyloxazol-5-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• la (2,4-diméthyloxazol-5-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-méthyl-1H-pyrazol-5-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-méthyl-1H-pyrazol-5-yl)méthanone ;
• la 4-((S)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one ;
• la 4-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)méthanone ;
• la (S)-(1H-imidazol-4-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• la (1H-imidazol-4-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• la 5-((S)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one ;
• la 5-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pyrrolidin-2-one ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)méthanone ;
• la (S)-(1,3-diméthyl-1H-pyrazol-4-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• la (1,3-diméthyl-1H-pyrazol-4-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-méthyl-1,3,4-oxadiazol-2-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-méthyl-1,3,4-oxadiazol-2-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-méthyl-1H-imidazol-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-méthyl-1H-imidazol-4-yl)méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-méthyl-1H-pyrazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-méthyl-1H-pyrazol-4-yl)-méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-méthanone ;
• la {3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-méthanone ;
• la {(S)-3-[6-(5-chloro-6-méthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la {3-[6-(5-chloro-6-méthoxy-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la (S)-(3-(6-(6-amino-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (3-(6-(6-amino-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)azétidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la {(S)-3-[6-(2-méthoxy-pyrimidin-5-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la {3-[6-(2-méthoxy-pyrimidin-5-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ;
• la [(S)-3-(6-quinolin-3-yl-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tétrahydro-pyran-4-yl)-méthanone ;
• la [3-(6-quinolin-3-yl-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tétrahydro-pyran-4-yl)-méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (S)-1-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-diméthylbutan-1-one ;
• la 1-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-diméthylbutan-1-one ;
• la 1-{(S)-3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one ;
• la 1-{3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-one ;
• le 2-méthoxy-5-[4-((S)-1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitrile ;
• le 2-méthoxy-5-[4-(1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-nicotinonitrile ;
• la (S)-6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidine ;
• la 6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-4-(1-(pyridin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidine ;
• la (S)-6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidine ;
• la 6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-4-(1-(pyrimidin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidine ;
• la (S)-1-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one ;
• la 1-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• le (S)-2-méthoxy-5-(4-(1-(tétrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile ;
• le 2-méthoxy-5-(4-(1-(tétrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile ;
• la (S)-1-(4-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino) pyrrolidine-1-carbonyl)pipéridin-1-yl)éthanone ;
• la 1-(4-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidine-1-carbonyl)pipéridin-1-yl)éthanone ;
• la (2,2-diméthyltétrahydro-2H-pyran-4-yl)((S)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la (2,2-diméthyltétrahydro-2H-pyran-4-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)méthanone ;
• la ((S)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1S,4R)-4-méthoxycyclohexyl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1S,4R)-4-méthoxycyclohexyl)méthanone ;
• la ((S)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1R,4S)-4-méthoxycyclohexyl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)((1R,4S)-4-méthoxycyclohexyl)méthanone ;
• la ((1S,4R)-4-hydroxycyclohexyl)((S)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la ((1S,4R)-4-hydroxycyclohexyl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la ((1R,4S)-4-hydroxycyclohexyl)((S)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la ((1R,4S)-4-hydroxycyclohexyl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-méthyl-1H-imidazol-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-méthyl-1H-imidazol-4-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl) (oxazol-5-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-4-yl)méthanone ;
• la (2,2-diméthyltétrahydro-2H-pyran-4-yl)((S)-3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la (2,2-diméthyltétrahydro-2H-pyran-4-yl)(3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)méthanone ;
• la (S)-1-(3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one ;
• la 1-(3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-one ;
• la (S)-(3-(6-(5-chloro-6-méthoxypyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (3-(6-(5-chloro-6-méthoxypyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-méthylpyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tétrahydro-2H-pyran-4-yl)méthanone ;
• la (tétrahydro-pyran-4-yl)-{(S)-3-{6-(5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-méthanone ;
• la (tétrahydro-pyran-4-yl)-{3-{6-(5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-méthylpipérazin-1-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-méthylpipérazin-1-yl)méthanone ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)méthanone ;
• la (S)-(4-hydroxypipéridin-1-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• la 4-(hydroxypipéridin-1-yl)(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)méthanone ;
• le (S)-N-(2-hydroxyéthyl)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-méthylpyrrolidine-1-carboxamide ;
• le N-(2-hydroxyéthyl)-3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)-N-méthylpyrrolidine-1-carboxamide ;
• la (S)-1-(4-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pipérazin-1-yl)éthanone ;
• la 1-(4-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carbonyl)pipérazin-1-yl)éthanone ;
• le (S)-2-méthoxy-5-(4-(1-(morpholine-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile ;
• le 2-méthoxy-5-(4-(1-(morpholine-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinonitrile ;
• la (S)-(3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)méthanone ;
• la (3-(6-(6-méthoxy-5-(trifluorométhyl)pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)méthanone ;
• la 1-(4-{(S)-3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-pipéridin-1-yl)-éthanone ;
• la 1-(4-{3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-pipéridin-1-yl)-éthanone ;
• la {(S)-3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-3H-imidazol-4-yl)-méthanone ;
• la {3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-méthyl-3H-imidazol-4-yl)-méthanone ;
• la {(S)-3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-méthanone ;
• la {3-[6-(6-méthoxy-5-trifluorométhyl-pyridin-3-yl)-5,6,7,8-tétrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-méthanone ;
• la {(S)-3-[6-(6-méthoxy-pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone ; et
• la {3-[6-(6-méthoxy-pyridin-3-yl)-5,6,7,8-tétrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tétrahydro-pyran-4-yl)-méthanone.
a) citrate, fumarate ou napadisylate ; ou
b) phosphate, chlorhydrate ou hippurate.
REFERENCES CITED IN THE DESCRIPTION
Patent documents cited in the description
Non-patent literature cited in the description