Spiro aromatic ring compound and application thereof
Provided is a compound of formula I or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substituent, polymorph, prodrug, or metabolite thereof. Also provided is a method for preparing the compound of formula I. The compound of formula I has higher inhibitory activity against SHP2, and thus can be used to prevent or treat a disease related to SHP2.
1. A compound of Formula:
or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, solvate, isotope-substituted derivative, polymorph, prodrug or metabolite thereof, wherein:
X 1 and X 2 are independently selected from a bond, CR a R b or NR c ;
X 3 is selected from a bond, CR a R b , NR c , S or o;
R a , R b and R c are independently selected from H, halogen, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-6 alkoxyl;
X 4 is N or CH;
R 1 , R 2 , R 3 , and R 4 are independently selected from H, —OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 1-6 alkoxyl; and R 1 , R 2 , R 3 , and R 4 cannot be —OH or —NH 2 simultaneously;
ring A is selected from substituted or unsubstituted 5 to 10-membered heteroaryl, wherein the heteroaryl comprises 1-3 heteroatoms selected from: N, O, S or P;
ring C is
X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from N or CR d ; and at most 3 of X 5 , X 6 , X 7 , X 8 and X 9 are N simultaneously;
X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 and X 17 are independently selected from N or CR d ; and at most 5 of X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 and X 17 are N simultaneously;
X 18 , X 19 , X 20 and X 21 are independently selected from N or CR d , and at most 3 of X 18 , X 19 , X 20 and X 21 are N simultaneously;
R 6 and R 8 are independently selected from —NH 2 , —CN, —OH, —NO 2 , halogen, unsubstituted or halogenated C 1-6 alkyl, or unsubstituted or halogenated C 1-6 alkoxyl; and
R d is selected from H, halogen, unsubstituted or halogenated C 1-6 alkyl, or unsubstituted or halogenated C 1-6 alkoxyl;
n is any integer from 1 to 3; and
wherein the term “substituted” refers to one or more hydrogen atoms on the group are substituted by a substituent selected from: halogen, —OH, —NO 2 , —NH 2 , —N(unsubstituted or halogenated C 1-6 alkyl) 2 , —CN, unsubstituted or halogenated C 1-8 alkyl, unsubstituted or halogenated C 1-8 alkoxyl, unsubstituted or halogenated C 1-8 alkoxyl-C 1-8 alkyl, unsubstituted or halogenated C 3-8 cycloalkyl-C 1-8 alkyl, unsubstituted or halogenated C 1-6 alkyl carbonyl, unsubstituted or halogenated C 1-6 alkoxyl carbonyl, hydroxamic acid group, unsubstituted or halogenated C 1-6 alkyl thiol, —S(O) 2 N (unsubstituted or halogenated C 1-6 alkyl) 2 , —S(O) 2 (unsubstituted or halogenated C 1-6 alkyl), —N(unsubstituted or halogenated C 1-6 alkyl)S(O) 2 N (unsubstituted or halogenated C 1-6 alkyl) 2 , —S(O)N (unsubstituted or halogenated C 1-6 alkyl) 2 , —S(O)(unsubstituted or halogenated C 1-6 alkyl), —N(unsubstituted or halogenated C 1-6 alkyl)S(O)N (unsubstituted or halogenated C 1-6 alkyl) 2 , or —N(unsubstituted or halogenated C 1-6 alkyl)S(O)(unsubstituted or halogenated C 1-6 alkyl).
2. The compound of claim 1 , wherein the ring C is
3. The compound of claim 1 , wherein the ring C is
4. The compound of claim 1 , wherein the ring C is
5. The compound of claim 1 , wherein the ring A is
6. The compound of claim 1 , wherein the ring A is
7. The compound of claim 1 , wherein the ring A is
8. The compound of claim 1 , wherein the ring A is
9. The compound of claim 1 , wherein the ring A is
10. The compound of claim 1 , wherein the ring A is
11. The compound of claim 1 , wherein the compound is:
12. A pharmaceutical composition comprising:
(i) an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereoisomer, tautomer, solvate, isotope-substituted derivative, polymorph, prodrug or metabolite thereof; and
(ii) a pharmaceutically acceptable carrier.