Tetrahydro-pyrido-pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9499536-B2
Application number	US-201414151796-A
Country	US
Kind code	B2
Filing date	Jan 9, 2014
Priority date	Jul 6, 2010
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The invention relates to substituted tetrahydro-pyrido-pyrimidine derivatives of the formula (I),

wherein Y, R 1 , R 2 and m are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of the PI3K enzymes.

First claim

What is claimed is:

1. A method of ameliorating a disease or disorder in a subject in need of such therapy, wherein the disease or disorder is selected from the group consisting of lymphocytic leukemia, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma, lymphomas, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Walden stroem disease and rheumatoid arthritis, wherein the method comprises the step of administering to a subject a therapeutically effective amount of 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 NR 3 ;
R 1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
—C(O)—R 4

wherein
R 4 is selected from C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkyl-sulfonyl-C 1 -C 8 -alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl, heteroaryl, heteroaryl-oxy, heteroaryl-C 1 -C 8 -alkyl, hydroxy, C 1 -C 8 -alkoxy, amino, N—C 1 -C 8 -alkyl-amino or N,N-di-C 1 -C 8 -alkyl-amino,
wherein ‘C 1 -C 8 -alkyl’ in N-C 1 -C 8 -alkyl-amino and N,N-di-C 1 -C 8 -alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy;
wherein ‘C 3 -C 12 -cycloalkyl’ in C 3 -C 12 -cycloalkyl and C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by 1-5 substituents independently selected from oxo, halogen, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -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, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -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, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -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;

R 2 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, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl;
R 3 is selected from H, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl; and
m is selected from 0 or 1.

2. The method of claim 1 , wherein the disease or disorder is rheumatoid arthritis.

3. The method of claim 1 , wherein the compound is represented by formula (Id′)

and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof.

4. The method of claim 1 , wherein the compound is represented by formula (Ie′)

and/or tautomers and/or N-oxides and/or pharmaceutically acceptable salts thereof.

5. The method of claim 1 , wherein
R 2 is selected from naphthyl, pyridyl or pyrimidinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from halogen, cyano, nitro, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, hydroxy-C 1 -C 8 -alkyl, hydroxyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino, C 1 -C 8 -alkyl-carbonyl, halo-C 1 -C 8 -alkyl-carbonyl, hydroxy-C 1 -C 8 -alkyl-carbonyl or C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl-carbonyl.

6. The method of claim 1 , wherein
R 1 is —C(O)—R 4 , wherein
R 4 is selected from heterocyclyl, C 4 -C 8 -cycloalkyl or heteroaryl;
wherein ‘C 3 -C 12 -cycloalkyl’ may be unsubstituted or substituted by 1-3 substituents independently selected from fluoro, C 1 -C 4 -alkyl, hydroxyl, C 1 -C 4 -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, C 1 -C 4 -alkyl, hydroxyl, or C 1 -C 4 -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, or pyrazinyl; each of which is unsubstituted or substituted by 1-3 substituents independently selected from C 1 -C 4 -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.

7. The method of claim 1 , wherein
R 1 is —C(O)—R 4 , and
R 4 is selected from C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy or N,N-di-C 1 -C 8 -alkyl-amino,
wherein ‘C 1 -C 8 -alkyl’ in N,N-di-C 1 -C 8 -alkyl-amino may be unsubstituted or substituted by halogen, hydroxy or C 1 -C 4 -alkoxy.

8. The method of claim 1 , the compound is selected from the group consisting of
{(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)-methano

Assignees

• Cooke Nigel Graham
• Zecri Frédèric
• Soldermann Nicolas
• Wolf Romain
• Hebach Christina
• Hoegenauer Klemens
• Hollingworth Gregory John
• Von Matt Anette
• Strang Ross Sinclair
• Smith Alexander Baxter
• Fernandes Gomes Dos Santos Paulo
• Graveleau Nadege
• Stowasser Frank
• Tufilli Nicola
• Novartis Ag

Inventors

• Cooke Nigel Graham
• Zecri Frédèric
• Soldermann Nicolas
• Wolf Romain
• Hebach Christina
• Hoegenauer Klemens
• Hollingworth Gregory John
• Von Matt Anette
• Strang Ross Sinclair
• Smith Alexander Baxter
• Fernandes Gomes Dos Santos Paulo
• Graveleau Nadege
• Stowasser Frank
• Tufilli Nicola

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title