Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

Patent metadata

Field	Value
Publication number	US-RE46856-E
Application number	US-200715398916-A
Country	US
Kind code	E1
Filing date	Dec 5, 2007
Priority date	Dec 5, 2006
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

This invention relates to novel 2,3-dihydroimidazo[1,2-c]quinazoline compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions for phosphotidylinositol-3-kinase (PI3K) inhibition and treating diseases associated with phosphotidylinositol-3-kinase (PI3K) activity, in particular treating hyperproliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

First claim

What is claimed is:

1. A compound having the formula:

or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:
R 1 is —(CH 2 ) n —(CHR 4 )—(CH 2 ) m —N(R 5 )(R 5′ );
R 2 is a heteroaryl optionally substituted with 1, 2 or 3 R 6 groups;
R 3 is alkyl or cycloalkyl;
R 4 is hydrogen, hydroxy or alkoxy;
R 5 and R 5′ may be the same or different and are independently, hydrogen, alkyl, cycloalkylalklyl, or alkoxyalkyl or R 5 and R 5′ may be taken together with the nitrogen atom to which they are bound to form a 3-7 membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6′ groups, or R 4 and R 5 may be taken together with the atoms to which they are bound to form a 5-6 membered nitrogen containing heterocyclic ring optionally containing 1 or more nitrogen, oxygen or sulfur atoms and which may be optionally substituted with 1 or more R 6′ groups;
each occurrence of R 6 may be the same or different and is independently halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, alkyl-OR 7 , alkyl-SR 7 , alkyl-N(R 7 )(R 7′ ), alkyl-COR 7 , —CN, —COOR 7 , —CON(R 7 )(R 7′ ), —OR 7 , —SR 7 , —N(R 7 )(R 7′ ), or —NR 7 COR 7 each of which may be optionally substituted with 1 or more R 8 groups;
each occurrence of R 6′ may be the same or different and is independently alkyl, cycloalkylalklyl, or alkyl-OR 7 ;
each occurrence of R 7 and R 7′ may be the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;
each occurrence of R 8 is independently nitro, hydroxy, cyano, formyl, acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl;
n is an integer from 1-4 and m is an integer from 0-4 with the proviso that when R 4 and R 5 are taken together with the atoms to which they are bound to form a 3-7 membered nitrogen containing ring, n+m≤4.

2. The compound of claim 1 , wherein R 2 is a nitrogen containing heteroaryl optionally substituted with 1, 2 or 3 R 6 groups.

3. The compound of claim 1 , wherein R 5 and R 5′ are independently alkyl.

4. The compound of claim 1 , wherein R 5 and R 5′ are taken together with the nitrogen atom to which they are bound to form a 5-6 membered nitrogen containing heterocyclic ring containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6′ groups.

5. The compound of claim 1 , wherein R 4 is hydroxy.

6. The compound of claim 1 , wherein R 4 and R 5 are taken together with the atoms to which they are bound to form a 5-6 membered nitrogen containing heterocyclic ring optionally containing 1 or more nitrogen, oxygen or sulfur atoms and which may be optionally substituted with 1 or more R 6′ groups.

7. The compound of claim 1 , wherein R 3 is methyl.

8. The compound of claim 1 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

9. The compound of claim 2 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

10. The compound of claim 1 , having the formula:

11. The compound of claim 10 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

12. The compound of claim 11 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

13. The compound of claim 1 having the formula:

14. The compound of claim 13 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

15. The compound of claim 14 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

16. The compound of claim 1 having the formula:

17. The compound of claim 16 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

18. The compound of claim 17 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

19. The compound of claim 1 having the formula:

20. The compound of claim 19 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

21. The compound of claim 20 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

22. The compound of claim 19 , wherein R 5′ is alkyl.

23. The compound of claim 1 having the formula:

24. The compound of claim 23 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan or thiophene, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

25. The compound of claim 24 , wherein R 2 is pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole, in each case unsubstituted or substituted with 1, 2 or 3 R 6 groups.

26. The compound of claim 23 , wherein R 5′ is alkyl.

27. The compound according to claim 1 , wherein said compound is selected from:
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]isonicotinamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-y

Assignees

• Bayer Ip Gmbh

Inventors

• Hentemann Martin
• Wood Jill
• Scott William
• Michels Martin
• Campbell Ann-Marie
• Bullion Ann-Marie
• Rowley Bruce R
• Redman Aniko

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title