Substituted quinazolinones for inhibiting PI3K
The present invention relates to novel quinazolinone derivatives inhibiting PI3K; a method for preparing the derivatives; and a pharmaceutical composition for treating hematologic neoplasms or liver diseases, containing the quinazolinone derivatives, wherein the novel quinazolinone derivatives according to the present invention have a beneficial effect in the treatment of hematologic neoplasms or liver diseases. Particularly, the quinazolinone derivatives inhibit PI3Kδ with high selectivity compared to that of a conventional anticancer drug of PI3Kδ inhibitors, thereby significantly reducing immunotoxicity, or simultaneously inhibit PI3Kδ and PI3Kγ, thereby enabling the treatment of autoimmune diseases, and anticancer therapy for blood cancer and the like. These targeted drugs have reduced side effects. The present invention provides a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, wherein X is —H, halogen, —CH 3 , or —NH 2 ; and Y is C 1-2 linear alkyl or C 3-4 cycloalkyl.
1. A compound of Formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
X is hydrogen, halo, or methyl; and
Y is C 3-4 cycloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is fluoro; and
Y is cyclopropyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is methyl; and
Y is cyclopropyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is fluoro; and
Y is cyclobutyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is chloro; and
Y is cyclobutyl.
6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
X is hydrogen, halo, or methyl; and
Y is C 3-4 cycloalkyl.
7. A method for inhibiting a kinase activity in a patient, comprising administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
X is hydrogen, halo, or methyl; and
Y is C 3-4 cycloalkyl,
wherein the kinase is at least one selected from the group consisting of phosphoinositide 3-kinase alpha, phosphoinositide 3-kinase beta, phosphoinositide 3-kinase gamma, and phosphoinositide 3-kinase delta.
8. The method of claim 7 , wherein the patient has a disease selected from the group consisting of a hematological malignancy, a liver disease, and an autoimmune disease.
9. The method of claim 8 , wherein the hematological malignancy is selected from the group consisting of leukemia and lymphoma.
10. The method of claim 8 , wherein the liver disease is selected from the group consisting of hepatic adenoma, hepatic steatosis, hepatitis, hepatocirrhosis, insulin hypersensitivity, liver cancer, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.
11. The method of claim 7 , wherein the compound selectively inhibits phosphoinositide 3-kinase delta activity in the patient.
12. A method for treating a hematological malignancy, comprising administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
X is hydrogen, halo, or methyl; and
Y is C 3-4 cycloalkyl.
13. The method of claim 12 , wherein the hematological malignancy is selected from the group consisting of leukemia and lymphoma.