2,4-bis(nitrogen-containing group)-substituted pyrimidine compound, preparation method and use thereof
Provided are a 2, 4-di-(nitrogen containing group) substituted pyrimidine compound represented by a general formula (I), a pharmaceutically acceptable salt and a stereoisomer thereof, a preparation method thereof, and a use thereof in preparation of anti-tumor drugs. The compound having a structural feature shown in the general formula (I) can selectively suppress activity of mutant epidermal growth factor receptors (EGFR), including single-mutant EGFR (T790M) and double-mutant EGFR (including L858R/T790M and ex19del/T790M), and can suppress activity of single gain-of-function mutant EGFR (including L858R and ex19del) as well. The compound has a weak suppression effect on wild-type EFGR and a very high selectivity, and thus it has a potential to be used in preparation of drugs for treating EGFR mutant tumors, especially non-small cell lung cancer (NSCLC) comprising a T790M EGFR mutation.
1. A 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound of formula III or a pharmaceutically acceptable salt or a stereoisomer thereof:
wherein
R 1 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted methyl, halo-substituted C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C1-C3 alkoxy-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, C1-C3 alkylamino-substituted C1-C4 alkyl, halogen, nitro, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio, cyano, amino, C1-C3 alkyl-substituted amino, and carboxyl;
R 2 and R 3 are each independently selected from the group consisting of H and C1-C6 alkyl;
R 4 is selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl-substituted C1-C4 alkyl, and C1-C3 alkoxy-substituted C1-C4 alkoxy;
R 5 is selected from the group consisting of groups below:
R 15 is selected from the group consisting of H and C1-C6 alkyl;
R 16 and R 17 are each independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 alkoxy;
Z is selected from the group consisting of C, N, and O, and when Z is O, R 8 does not exist;
m is selected from 0, 1, or 2;
n is selected from 1, 2, or 3;
p is selected from 1, 2, 3, 4, 5, or 6;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted methyl, benzyl, phenyl, methylsulfonyl, halo-substituted C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C1-C3 alkoxy-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, C1-C3 alkylamino-substituted C1-C4 alkyl, amino, C1-C3 alkyl-substituted amino, hydroxyl, and C1-C6 alkoxy;
X 1 is selected from the group consisting of N, and C—R 9 ;
R 9 is selected from the group consisting of H, C1-C6 alkyl, halo-substituted C1-C6 alkyl, halogen, cyano, and amino;
X 2 is C—R 10 ;
R 10 is selected from the group consisting of H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted methyl, and halo-substituted C1-C6 alkyl;
X 3 is N;
X 4 , X 5 , and X 6 are each independently selected from the group consisting of N, and C—R 11 ;
R 11 is selected from the group consisting of H, C1-C6 alkyl, hydroxyl-substituted C1-C4 alkoxy, C1-C3 alkoxy-substituted C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-substituted methyl, halo-substituted C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C1-C3 alkoxy-substituted C1-C4 alkyl; amino-substituted C1-C4 alkyl, C1-C3 alkylamino-substituted C1-C4 alkyl, halogen, nitro, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio, cyano, amino, C1-C3 alkyl-substituted amino, C1-C3 alkyl-substituted amido group, and carboxyl;
G is selected from the group consisting of following groups:
R 12 and R 13 are each independently selected from the group consisting of H, and C1-C6 alkyl;
R 14 is selected from the group consisting of H, C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, C1-C3 alkylamino-substituted C1-C4 alkyl, and heterocycle-substituted C1-C4 alkyl; and
if R 1 is selected from the group consisting of H, halogen, and cyano, R 4 is C1-C6 alkoxy, G is
and R 11 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, and halo-substituted C1-C6 alkyl, then R 10 is not selected from any one in the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, and halo-substituted C1-C6 alkyl.
2. The 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 , wherein
X 5 and X 6 are each independently selected from the group consisting of N and CH;
X 4 is C—R 11 ; and
R 11 is defined as in claim 1 .
3. The 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 , wherein
X 1 and X 2 are each CH;
X 4 is defined as in claim 1 ;
X 5 and X 6 are each CH; and
R 1 , R 2 , R 3 , R 4 , R 5 , and G are each defined as in claim 1 .
4. The 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 , wherein
X 1 and X 2 are each CH;
X 5 and X 6 are each CH;
X 4 is C—R 11 ;
R 11 is selected from the group consisting of C1-C6 alkoxy, halogen, and cyano;
R 1 , R 2 , and R 3 are each H;
R 4 is a methoxy group;
R 5 is a following group:
and
G is a following group:
5. The 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 , wherein
R 1 is selected from the group consisting of H, F, Cl, Br, methyl, trifluoromethyl, methoxy, cyano, hydroxyl, and dimethylamino;
R 2 and R 3 are each H;
R 4 is selected from the group consisting of H, methoxy, ethoxy, methyl, ethyl, OH, and methoxyethoxy;
R 12 and R 13 are each H; and
R 14 is selected from the group consisting of H, C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, C1-C3 alkylamino-substituted C1-C4 alkyl, and heterocycle-substituted C1-C4 alkyl.
6. The 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 , wherein R 5 is selected from the group consisting of following groups:
7. The 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 , wherein said compound is selected from the group consisting of following compounds:
8. A pharmaceutical composition for treatment of a tumor, comprising the 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 as an active component, and a pharmaceutically acceptable carrier, wherein said tumor is non-small-cell lung cancer with T790M EGFR mutation.