Cycloalkyl and hetero-cycloalkyl inhibitors, preparation methods therefor, and use thereof
Cycloalkyl and hetero-cycloalkyl inhibitors, preparation methods therefor, and the use thereof are described. Compounds of the present invention have a structure represented by formula (I). Further disclosed are preparation methods for said compounds, and the use of said compounds as KRAS G12C inhibitors. The compounds have an excellent ability to selectively inhibit KRAS G12C , improved pharmacodynamic and pharmacokinetic performance, and reduced toxic side effects.
1. A compound of formula (I), and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein:
A and B are N;
X is selected from 4-14 membered saturated or unsaturated heterocyclyl, wherein said saturated or unsaturated heterocyclyl may optionally be substituted by one or more R 8 ;
Y is O;
L is bond;
Z is bond;
W is bond;
R 1 is —C(O)C(R A ) C(R B ) p ;
R A is absent, or is independently selected from hydrogen, deuterium, fluorine, cyano or C 1 -C 3 alkyl;
R B is independently selected from hydrogen, deuterium, cyano or C 1 -C 3 alkyl;
p is an integer of 1 or 2;
R 2 is —(CH 2 ) n R 7 , where H in CH 2 is optionally substituted;
R 7 is selected from substituted C 3 -C 20 cycloalkyl or substituted 4-20 membered heterocyclyl; wherein “substituted” refers to substitution with one or more groups selected from the group consisting of C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, and amino; and the C 1 -C 18 alkyl or deuterated C 1 -C 18 alkyl is substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, amino, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 and NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl;
n is 1, 2, or 3;
m is an integer of 0, 1, 2 or 3;
R 3 is independently selected from the group consisting of hydrogen, deuterium, oxygen, C 1 -C 3 alkyl and C 1 -C 3 haloalkyl;
R 4 is selected from group consisting of substituted or unsubstituted C 6 -C 14 aryl and substituted or unsubstituted 5-14 membered heteroaryl;
R 5 is independently selected from substituted or unsubstituted group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, amino, hydroxyl, 4-20 membered heterocyclyl;
R 8 is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, or CNCH 2 —;
wherein, the above “substituted” refers to be substituted with one or more groups selected from the group consisting of hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, C 1 -C 18 haloalkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, C 1 -C 18 haloalkoxy, C 6 -C 14 aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclyl, halogen, nitro, hydroxy, cyano, ester, amino, amido, sulfonamido and ureido.
2. The compound, and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 , wherein it has a structure represented by formula (VIII):
R 11 and R 12 are the same or different, and each independently selected from hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl;
ring A is a substituted or unsubstituted C 3 -C 20 cycloalkyl or a substituted or unsubstituted 4-20 membered heterocyclyl; and
L 1 is C 1 -C 18 alkyl, or deuterated C 1 -C 18 alkyl;
Q is C 3 -C 7 cycloalkyl, 4-7 membered heterocyclyl, NHR 9 or NR 9 R 10 ; R 9 and R 10 are each independently C 1 -C 3 alkyl.
3. A compound is selected from the group consisting of:
or a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
4. A pharmaceutical composition comprises one or more of the compound, the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 1 ; and a pharmaceutically acceptable carrier.
5. The compound, and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 2 , wherein R 4 is
6. The compound, and the stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof of claim 2 , wherein the compound is selected from the group consisting of: