Pyrimidine compounds, compositions, and medicinal applications thereof
The present disclosure relates to a class of pyrimidine compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates thereof. The present disclosure also relates to a process of preparation of these pyrimidine compounds, pharmaceutical compositions containing them, and medicinal applications thereof.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 1 is —(C(R 4 ) 2 )R 5 ;
X is —NH;
n is 0;
R 5 is phenyl substituted with 0 or 1 R 5′ ;
R 2 is phenyl substituted with at least one R 7 and 0, 1, or 2 R 8 ; and
R 3 is pyrazolyl substituted with 0, 1, 2, or 3 R 12 ;
each R 5′ is independently alkyl, haloalkyl, heterocycloalkyl, halo, hydroxy, or alkoxy;
R 7 is
R 8 is fluoro;
Y is —C(═O)—;
R 9 , R 9′ , and R 9″ are hydrogen;
R 10 is hydrogen; and
each R 12 is independently methyl, iso-propyl, tert-butyl, hydroxyethyl, methoxyethyl, trifluoromethyl, trifluoroethyl, chloro, cyano, morpholinyl, or cyclopropyl.
2 . The compound of claim 1 , wherein each R 5′ is independently methyl, ethyl, tert-butyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, fluoro, chloro, hydroxy, methoxy, ethoxy, fluoromethyl, difluoromethyl, or trifluoromethyl.
3 . The compound of claim 2 , wherein each R 5′ is independently methyl, morpholinyl, fluoro, chloro, methoxy, fluoromethyl, difluoromethyl, or trifluoromethyl.
4 . The compound of claim 3 , wherein R 2 is substituted with 1 or 2 R 8 .
5 . The compound of claim 3 , wherein R 2 is substituted with 0 R 8 .
6 . The compound of claim 4 , wherein R 3 is unsubstituted.
7 . The compound of claim 4 , wherein R 3 is substituted with at least 1 R 12 .
8 . The compound of claim 7 , wherein R 3 is substituted with at least 2 R 12 .
9 . The compound of claim 8 , wherein each R 12 is independently methyl, hydroxyethyl, methoxyethyl, trifluoroethyl, or chloro.
10 . The compound of claim 9 , wherein each R 12 is independently methyl or chloro.
11 . The compound of claim 3 , wherein R 5′ is fluoromethyl, difluoromethyl, or trifluoromethyl.
12 . The compound of claim 10 , wherein R 12 is methyl.
13 . The compound of claim 1 , wherein the compound is of Formula I-A, Formula I-B, Formula I-C, Formula I-D, Formula I-E, Formula I-F, or Formula I-G:
or a pharmaceutically acceptable salt or stereoisomer thereof.
14 . The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt or stereoisomer thereof.
15 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
16 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer comprises an EGFR mutation.
17 . The method of claim 16 , wherein the cancer is bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, or non-small cell lung cancer.
18 . The method of claim 16 , wherein the EGFR mutation comprises a substitution in exon 18, a deletion in exon 19, a substitution in exon 20, an insertion in exon 20, a mutation in the extracellular domain, or a substitution in exon 21.
19 . The method of claim 18 , wherein the EGFR mutation is selected from del19/T790M EGFR, L858R/T790M EGFR, L858R EGFR, L861Q EGFR, G719X EGFR, 763insFQEA EGFR, 767insTLA EGFR, 769insASV EGFR, 769insGE EGFR, 770insSVD EGFR, 770insNPG EGFR, 770insGT EGFR, 770insGF EGFR, 770insG EGFR, 771insH EGFR, 771insN EGFR, 772insNP EGFR, 773insNPH EGFR, 773insH EGFR, 773insPH EGFR, EGFRvii, EGFRviii, A767_dupASV EGFR, 773insAH EGFR, M766_A767insAI EGFR, and any combination thereof.
20 . The compound of claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt or stereoisomer thereof.