3-aryl-2-((arylamino)methyl)quinazolin-4-(3H)-ones
The invention relates to novel quinazolinone compounds and their use as inhibitors of PI3 kinases, for example, PI3Kδ, for treating and/or preventing diseases, disorder, and conditions associated with modulating PI3 kinase activity. Novel 3 -aryl-2-((arylamino)methyl)quinazolin-4(3H)-one derivatives and pharmaceutically acceptable salts or solvates thereof and their use for the treatment or prevention of diseases, disorders, and conditions associated with the activity of one or more PI3 kinase, such as PI3Kδ, are disclosed.
1. A method of inhibiting a PI3 kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein
X 1 is selected from N, CH, CF, CCF 3 , CCHF 2 , and CCH 2 F;
X 2 is N or CH;
R 1 is (CX 3A X 4A ) s —(O) v —(CX 3B X 4B ) t —(O) w —(CX 3C X 4C ) u —(O) x —X 5 ;
X 3A , X 3B , X 3C , X 4A , X 4B , and X 4C are each independently selected from H and F;
X 5 is selected from H, F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 CHF 2 , and OCH 2 CH 2 F;
s, t, and u are each independently selected from 0, 1, 2, 3, 4, 5, 6, and 7;
v, w, and x are each independently selected from 0 and 1;
R 2 is Cl or F;
each X 6 is independently (CX 7A X 8A ) e —(O) h —(CX 7B X 8B ) f —(O) i —(CX 7C X 8C ) g —(O) j —X 9 ;
X 7A , X 7B , X 7C , X 8A , X 8B , and X 8C are each independently selected from H and F;
X 9 is selected from H, F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 CHF 2 , and OCH 2 CH 2 F;
e, f, and g are each independently selected from 0, 1, 2, 3, 4, 5, 6, and 7;
h, i, and j are each independently selected from 0 and 1; and
z is selected from 0, 1, and 2,
provided that when X 1 and X 2 are each N and z is 0, then R 1 comprises at least one F atom; and that when X 1 and X 2 are each N and R 2 is Cl, then z is 1 or 2 and X 9 is selected from CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CF 3 , OCH 2 CHF 2 , and OCH 2 CH 2 F, and
provided that R 1 does not contain a total number of more than 8 atoms of carbon and oxygen and R 1 does not contain adjacent oxygen atoms, and that each X 6 does not contain a total number of more than 8 atoms of carbon and oxygen and X 6 does not contain adjacent oxygen atoms.
2. The method of claim 1 , wherein the compound is of Formula Ia:
or a pharmaceutically acceptable salt or solvate thereof.
3. The method of claim 1 , wherein R 2 is F.
4. The method of claim 1 , wherein X 1 is N and X 2 is N or CH.
5. The method of claim 1 , wherein X 1 is CH, CF, or CCF 3 and X 2 is N or CH.
6. The method of claim 1 , wherein the sum of v+w+x≦2.
7. The method of claim 1 , wherein the sum of s+t+u≦6.
8. The method of claim 1 , wherein X 5 is H, CF 3 , CHF 2 , or CH 2 F.
9. The method of claim 1 , wherein z is 0 or 1.
10. The method of claim 9 , wherein
11. The method of claim 1 , wherein the sum of h+i+j≦2.
12. The method of claim 11 , wherein h is 1; i is 0; and j is 0.
13. The method of claim 1 , wherein the sum of e+f+g≦6.
14. The method of claim 1 , wherein X 9 is CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F,OCH 2 CF 3 , OCH 2 CHF 2 , or OCH 2 CH 2 F.
15. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.
16. The method of claim 1 , wherein the PI3 kinase is PI3Kα, PI3Kβ, PI3Kγ, or PI3Kδ.
17. The method of claim 1 , wherein the PI3 kinase is PI3Kδ.