Azaindole derivative and use thereof as FGFR and C-Met inhibitor
A series of pyrazolopymidine derivatives, and use thereof in the preparation of a medicament for treating disease associated with FGFR and c-Met. The pyrazolopymidine derivative is a compound represented by formula (I), a tautomer, or a pharmaceutically acceptable salt thereof.
1. A compound represented by formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof,
wherein,
X 1 , X 2 and X 3 are respectively independently selected from CH, C(CH 3 ) and N;
T is selected from CH and N;
R 1 and R 4 are F;
R 2 is
R 3 is H or
R 5 is selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl, wherein the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl are optionally substituted by 1, 2 or 3 R b ;
ring B is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R 6 ;
R 6 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, COOH, C 1-3 alkyl and C 1-3 heteroalkyl, wherein the C 1-3 alkyl and C 1-3 heteroalkyl are optionally substituted by 1, 2 or 3 R c ;
alternatively, two R 6 connected to adjacent carbon atoms and the C atoms to which they are connected together form a 4-6 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 R c ;
L is selected from single bond and —(CR d R e ) m —;
m is selected from 1, 2, 3 and 4;
R b is respectively independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, COOH, C 1-3 alkyl, C 1-3 heteroalkyl and 4-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 heteroalkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R;
R c is respectively independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and CH 3 CH 2 ;
alternatively, two R c connected to the same carbon atom and the C atom to which they are connected together form a 4-6 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 R;
R d and R e are respectively independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and CH 3 CH 2 ;
R is selected from F, Cl, Br, I, OH, CN, NH 2 , CN, COOH, CH 3 , CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, CF 3 , CHF 2 , CH 2 F, CH 3 O and
wherein the C 1-6 heteroalkyl, C 1-3 heteroalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl respectively independently contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from —NH—, —O—, —S—, —C(═O)—, S(═O)—, S(═O) 2 —, and N;
or a compound having any of the following structures, a tautomer thereof or a pharmaceutically acceptable salt thereof,
2. The compound the, tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein R b is respectively independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, COOH, CH 3 , CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, CF 3 , CHF 2 , CH 2 F,
or, the L is selected from a single bond, —CH 2 —, —CH 2 CH 2 .
3. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein R 5 is selected from H, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-C(═O)—, C 1-3 alkyl-S(═O) 2 —, C 1-3 alkyl-S(═O) 2 —C 1-3 alkyl-, C 1-3 alkylamino, cyclohexyl, piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridyl, azetidinyl, oxebutanyl, pyrrolidinyl and piperazinyl, wherein C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl-C(═O)—, C 1-3 alkyl-S(═O) 2 —, C 1-3 alkyl-S(═O) 2 —C 1-3 alkyl-, C 1-3 alkylamino, cyclohexyl, piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridyl, azetidinyl, oxebutanyl, pyrrolidinyl and piperazinyl are optionally substituted by 1, 2 or 3 R b .
4. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein, R 2 and R 3 are respectively independently
or, R 5 is selected from H, CH 3 , CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, C(R b ) 3 , CH(R b ) 2 , CH 2 (R b ),
5. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein R 5 is selected from H, CH 3 , CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, CF 3 , CHF 2 , CH 2 F,
6. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein the R 6 is respectively independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, COOH, CH 3 , CH 2 CH 3 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH and
wherein the CH 3 , CH 2 CH 3 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH and
are optionally substituted by 1, 2 or 3 R e .
7. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 6 , wherein the R 6 is respectively independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, COOH, CH 3 , CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, CF 3 , CHF 2 , CH 2 F and
8. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein the two R c connected to the same carbon atom are linked together to form piperidinyl optionally substituted by 1, 2 or 3 R.
9. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 8 , wherein the two R c connected to the same carbon atom are linked together to form
10. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein the ring B is selected from phenyl, pyrazolyl, imidazolyl, pyridyl and pyrazinyl, wherein the phenyl, pyrazolyl, imidazolyl, pyridyl and pyrazinyl are optionally substituted by R 6 , and the number of R 6 is 1, 2 or 3.
11. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 10 , wherein the ring B is selected from
12. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein the ring B is selected from
13. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein the moiety
is selected from H, CH 3 , CH 3 CH 2 , CH 3 CH 2 CH 2 , (CH 3 ) 2 CH, CF 3 , CHF 2 , CH 2 F,
14. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , wherein the moiety
is selected from
15. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 , which is selected from
wherein,
T 1 , T 2 , T 3 and T 4 are respectively independently selected from C(R 6 ) and N;
T, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined in claim 1 .
16. The compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 15 , which is selected from
wherein,
R 1 , R 2 , R 3 , R 4 , R 5 and L are as defined in claim 15 .
17. A compound, tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
18. A method of treating a disease associated with FGFR and c-Met in a subject, comprising administering the compound, the tautomer thereof or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject; wherein the disease associated with FGFR and c-Met is non-small cell lung cancer, multiple myeloma, renal cell carcinoma, breast cancer, liver cancer, bile duct epithelial cancer, thyroid cancer, brain cancer, bladder cancer, hemangioma, biliary tract cancer or gastric cancer.