Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors
Provided are isotopologues of isoquinolinone and quinazolinone compounds of formula (AB′) that modulate PI3 kinase activity, processes for the preparation of the compounds, pharmaceutical compositions comprising the compounds, and methods of treatment of diseases and disorders using the compounds or pharmaceutical compositions.
1. A compound of Formula (AB′):
or a pharmaceutically acceptable salt thereof, wherein
R is C 1 -C 3 alkyl optionally substituted with one or more deuterium or halogen;
X is CY 5d or N;
Y 1 is hydrogen or deuterium;
Y 2 , Y 3 , and Y 4 are each independently hydrogen or deuterium;
Y 5a , Y 5b , Y 5c , and Y 5d are each independently hydrogen or deuterium;
Y 6a , Y 6b , Y 7a , Y 7b , and Y 8 are each independently hydrogen, deuterium, halogen, or C 1 -C 3 alkyl, wherein each instance of the C 1 -C 3 alkyl is independently optionally substituted with one or more deuterium or halogen;
Z is a pyrazolyl optionally substituted with one or more deuterium, halogen, or C 1 -C 3 alkyl, wherein each instance of the C 1 -C 3 alkyl is independently optionally substituted with one or more deuterium or halogen; and
at least one of R, Y 1 , Y 2 , Y 3 , Y 4 , Y 5a , Y 5b , Y 5c , Y 5d , Y 6a , Y 6b , Y 7a , Y 7b , Y 8 , and Z is or comprises a deuterium;
provided that, when Y 6a , Y 6b , Y 7a , Y 7b , and Y 8 are all deuterium, at least one of R, Y 1 , Y 2 , Y 3 , Y 4 , Y 5a , Y 5b , Y 5c , Y 5d , and Z is or comprises a deuterium.
2. The compound of claim 1 , wherein the compound is a compound of Formula (AB), (A′), (A), (B′), or (B):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein Y 5a is deuterium; Y 5b is deuterium; Y 5c is deuterium; Y 5a , Y 5b , and Y 5c are all hydrogen; or Y 5a , Y 5b , and Y 5c are all deuterium.
4. The compound of claim 1 , wherein Y 6a , Y 6b , Y 7a , Y 7b , and Y 8 are all hydrogen; Y 6a , Y 6b , Y 7a , Y 7b and Y 8 are all deuterium; or one or more of Y 6a , Y 6b , Y 7a , Y 7b , and Y 8 are C 1 -C 3 alkyl, wherein each instance of the C 1 -C 3 alkyl is independently optionally substituted with one or more deuterium or halogen.
5. The compound of claim 1 , wherein Z is a 4-pyrazolyl.
6. The compound of claim 1 , wherein Z is substituted with one or more C 1 -C 3 alkyl, wherein each instance of the C 1 -C 3 alkyl is independently optionally substituted with one or more deuterium or halogen.
7. The compound of claim 6 , wherein Z is substituted with one or two methyl, wherein each instance of the methyl is independently optionally substituted with one or more deuterium or halogen.
8. The compound of claim 1 , wherein the compound is a compound of Formula (A-I), (A-II), (A-III), (B-I), (B-II), or (B-III):
or a pharmaceutically acceptable salt thereof, wherein
Y 9a and Y 9b are each independently hydrogen, deuterium, or C 1 -C 3 alkyl, wherein each instance of the C 1 -C 3 alkyl is independently optionally substituted with one or more deuterium or halogen; and
Y 10 is hydrogen or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl itself is optionally substituted with one or more deuterium or halogen.
9. The compound of claim 8 , wherein Y 9 a and Y 9b are each independently hydrogen or deuterium; or Y 9a and Y 9b are both C 1 -C 3 alkyl, wherein each instance of the C 1 -C 3 alkyl is independently optionally substituted with one or more deuterium or halogen.
10. The compound of claim 8 , wherein Y 10 is C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl itself is optionally substituted with one or more deuterium or halogen.
11. The compound of claim 10 , wherein Y 10 is —CD 3 .
12. The compound of claim 1 , wherein R is C 1 -C 3 alkyl optionally substituted with one or more deuterium.
13. The compound of claim 12 , wherein R is —CD 3 .
14. The compound of claim 1 , wherein Y 1 is deuterium.
15. The compound of claim 1 , wherein Y 2 is deuterium; Y 3 is deuterium; Y 4 is deuterium; Y 2 , Y 3 , and Y 4 are all hydrogen; or Y 2 , Y 3 , and Y 4 are all deuterium.
16. The compound of claim 1 , wherein the compound is a compound of Formula (A-I-a), (A-I-b), (A-II-a), (B-I-a), (B-I-b), or (B-II-a):
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , which is selected from any one of the compounds in Tables 1 to 74, or a pharmaceutically acceptable salt thereof.
18. The compound of claim 8 , wherein one of Y 9a and Y 9b is hydrogen or deuterium, and the other is C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl itself is optionally substituted with one or more deuterium or halogen.
19. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
22. A method of inhibiting a PI3K in a subject, comprising administering a therapeutically effective amount of a compound of claim 1 to the subject.