Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives

Patent metadata

Field	Value
Publication number	US-9763952-B2
Application number	US-201514976998-A
Country	US
Kind code	B2
Filing date	Dec 21, 2015
Priority date	Dec 22, 2011
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The invention relates to dihydro-benzo-oxazine and dihydro-pyrido-oxazine compounds of the formula (I) and/or pharmaceutically acceptable salts and/or solvates thereof,

wherein Y, V, W, U, Q, R 1 , R 5 , R 7 and R 30 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

The invention claimed is:

1. A method of inhibiting the activity of PI3Kδ isoform in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound according Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
Y is selected from O or NH;
V is selected from CR 5 or N;
W is selected from CH 2 , or O;
U is selected from N or CH;
Q is selected from N or CR 6 ;
wherein U and Q are not both N;
R 1 is selected from phenyl, pyridyl, pyrimininyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
—X—R 4
wherein X is selected from C(O), S(O) 2 or CH 2
and
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, cyano-C 1 -C 8 -alkyl, N,N-di-C 1 -C 4 -alkyl-amino-C 1 -C 8 -alkyl, C 1 -C 4 -alkyl-sulfonyl-C 1 -C 8 -alkyl, phenyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkyl-oxy, 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 in 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 in C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by 1-5 substituents selected from halogen, hydroxy or C 1 -C 4 -alkoxy;
wherein ‘heterocyclyl’ is a 3 to 7 membered saturated or partially unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, each of which is unsubstituted or substituted by 1-5 substituents 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 a 3 to 7 membered fully unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, or pyrazolo[1,5-a]pyrimidine or imidazo[2,1-b]thiazole, each of which is unsubstituted or substituted by 1-5 substituents 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 6 is selected from hydrogen, halogen, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-sulfinyl, C 1 -C 4 -alkyl-sulfanyl, halo-C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, N,N-di-C 1 -C 8 -alkyl-amino;
R 7 is selected from hydrogen, halogen, cyano, nitro, C 1 -C 4 -alkyl, halo-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, N(R 8 ) 2 -sulfonyl, C 1 -C 4 -alkyl-sulfonyl, C 1 -C 4 -alkyl-sulfonyl-amino, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl, amino, N—C 1 -C 8 -alkyl-amino, or N,N-di-C 1 -C 8 -alkyl-amino;
or R 6 and R 7 , together are CH═CH—CH═CH,
wherein R 8 is independently selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or two R 8 together with the nitrogen they are attached to form a 4 to 7 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O, S, which is unsubstituted or substituted by 1-3 substituents selected from C 1 -C 4 -alkyl;

R 5 is independently selected from H, D, F or C 1 -C 2 -alkyl;
R 30 is independently selected from H, D or F.

2. A method of ameliorating a disorder or a disease selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), myasthenia gravis (MG), Sjögren's syndrome (SS) transplant rejection, lymphoctic leukemia, non-Hodgkin lymphoma, and lymphomas comprising administering to a subject suffering from the disease or disorder a therapeutically effective amount of a compound according Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
Y is selected from O or NH;
V is selected from CR 5 or N;
W is selected from CH 2 , or O;
U is selected from N or CH;
Q is selected from N or CR 6 ;
wherein U and Q are not both N;
R 1 is selected from phenyl, pyridyl, pyrimininyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
or
—X—R 4
wherein X is selected from C(O), S(O) 2 or CH 2
and
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, cyano-C 1 -C 8 -alkyl, N,N-di-C 1 -C 4 -alkyl-amino-C 1 -C 8 -alkyl, C 1 -C 4 -alkyl-sulfonyl-C 1 -C 8 -alkyl, phenyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-C 1 -C 8 -alkyl, C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkyl-oxy, 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 in 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 in C 3 -C 12 -cycloalkyl-C 1 -C 8 -alkyl may be unsubstituted or substituted by 1-5 substituents selected from halogen, hydroxy or C 1 -C 4 -alkoxy;
wherein ‘heterocyclyl’ is a 3 to 7 membered saturated or partially unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, each of which is unsubstituted or substituted by 1-5 substituents 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 a 3 to 7 membered fully unsaturated monocyclic ring system containing 1 to 3 heteroatoms selected from N, O or S, or pyrazolo[1,5-a]pyrimidine or imidazo[2,1-b]thiazole, each of which is unsubstituted or substituted by 1-5 substituents 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 6 is selected from hydrogen, halogen,

Assignees

• Caravatti Giorgio
• Chamoin Sylvie
• Furet Pascal
• Hogenauer Klemens
• Hurth Konstanze
• Kammertoens Karen
• Lewis Ian
• Moebitz Henrik
• Smith Alexander Baxter
• Soldermann Nicolas
• Wolf Romain
• Zecri Frederic
• Novartis Ag

Inventors

• Caravatti Giorgio
• Chamoin Sylvie
• Furet Pascal
• Hogenauer Klemens
• Hurth Konstanze
• Kammertoens Karen
• Lewis Ian
• Moebitz Henrik
• Smith Alexander Baxter
• Soldermann Nicolas
• Wolf Romain
• Zecri Frederic

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title