ATR inhibitor and application thereof
Disclosed are a compound as an ATR inhibitor and an application in preparing a drug as an ATR inhibitor. In particular, disclosed is a compound represented by formula (I) or an isomer or pharmaceutically acceptable salt thereof.
1. A compound of formula (I), or a tautomer or a pharmaceutically acceptable salt thereof,
wherein,
n is 1, 2, 3 or 4;
Z 1 , Z 2 , and Z 3 are each independently selected from the group consisting of CH and N, and at least one of Z 1 , Z 2 and Z 3 is N;
T 1 and T 2 are each independently selected from the group consisting of C(R 2 ) and N;
ring A is selected from the group consisting of 5-6 membered heteroaryl;
R 1 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are optionally substituted by 1, 2 or 3 R;
R 2 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , COOH and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
R is each independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R′;
R′ is each independently selected from the group consisting of F, Cl, Br, I, OH and NH 2 ;
the 5-6 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms or heteroradicals independently selected from the group consisting of —NH—, —O—, —S— and N;
provided that the compound of formula (I) is not:
(3R)-3-methyl-4-[6-(pyridin-3-yl)-2-[1H-pyrrolo[2,3-b]pyridin-4-yl]pyrimidin-4-yl]morpholine,
(R)-4-(2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)-3-methylmorpholine, or
(R)-5-(6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)pyridin-2-amine.
2. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, R is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et and —O—CH 3 .
3. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, R 1 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl, wherein the C 1-3 alkyl, C 1-3 alkoxy and cyclopropyl are optionally substituted by 1, 2 or 3 R.
4. The compound according to claim 3 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, R 1 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , Et, —CH 2 OH, —O—CH 3 ,
5. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, R 2 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , COOH, CH 3 , Et and —CH 2 —OH.
6. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, ring A is selected from the group consisting of pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and pyridyl.
7. The compound according to claim 6 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, ring A is selected from the group consisting of
8. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, the structural unit
is selected from the group consisting of
9. The compound according to claim 8 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, the structural unit
is selected from the group consisting of
10. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, the structural unit
is selected from the group consisting of
11. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein, the structural unit
is selected from the group consisting of
12. The compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein the compound is selected from
wherein,
T 1 , and T 2 are each independently selected from the group consisting of C(R 2 ) and N;
and R 1 , R 2 , Z 1 , Z 2 and Z 3 are defined as in claim 1 .
13. The compound according to claim 12 , or the tautomer or the pharmaceutically acceptable salt thereof, wherein the compound is selected from
wherein,
R 1 , R 2 , Z 1 , Z 2 , and Z 3 are defined as in claim 12 .
14. A compound or a tautomer or a pharmaceutically acceptable salt thereof, selected from
15. A method for treating an ATR associated disease, comprising administering the compound of formula (I) according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the ATR associated disease is a solid tumor or a hematologic tumor,
wherein, in the compound of formula (I),
Z 1 , Z 2 and Z 3 are not N at the same time.
16. A method for treating an ATR associated disease, comprising administering the compound according to claim 14 , or the tautomer or the pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the ATR associated disease is a solid tumor or a hematologic tumor.
17. A pharmaceutical composition comprising the compound according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof.
18. The compound of formula (I) according to claim 1 , or the tautomer or the pharmaceutically acceptable salt thereof,
wherein,
n is 1, 2, 3 or 4;
Z 1 , Z 2 , and Z 3 are each independently selected from the group consisting of CH and N, and at least one of Z 1 , Z 2 and Z 3 is N;
T 1 and T 2 are each independently selected from the group consisting of C(R 2 ) and N;
R 2 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , COOH and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
R is each independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 alkyl and C 1-3 alkoxy are optionally substituted by 1, 2 or 3 R′;
R′ is each independently selected from the group consisting of F, Cl, Br, I, OH and NH 2 ; and
ring A is selected from the group consisting of pyrazolyl, isoxazolyl, oxazolyl, imidazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl; and
R 1 is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are optionally substituted by 1, 2 or 3 R;
or
the structural unit
is selected from the group consisting of
19. A method for treating an ATR associated disease, comprising administering the compound of formula (I) according to claim 18 , or the tautomer or the pharmaceutically acceptable salt thereof to a subject in need thereof; wherein the ATR associated disease is a solid tumor or a hematologic tumor;
wherein, in the compound of formula (I),
Z 1 , Z 2 and Z 3 are not N at the same time.