Novel Heterocyclic Derivatives Useful as SHP2 Inhibitors

Abstract

The present invention provides a compound of formula I, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, the present invention provides a pharmaceutical composition comprising the said compound.

##STR00001##

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: ##STR00252## Wherein, ring A is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00253## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted or unsubstituted; ring B is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; T is absent, O, NR.sub.1 or CR.sub.1R.sub.2; each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; or R.sub.I and R.sub.2 together with the carbon atom to which they are both attached form CO or C═NR.sub.5; p is 0, 1, 2, 3 or 4; each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; or R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR.sub.5, and each of the ring systems is independently optionally substituted or unsubstituted; each of R.sub.5 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; q is 0, 1, 2, 3 or 4; W is absent, O, S or —C(R.sub.W).sub.2-; and each of R.sub.W is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-6alkyl, —CO—OC.sub.1-6alkyl, —C.sub.1-6alkylene-O—C.sub.1-6alkoxy, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when ring C is absent, Y.sub.5 is CR.sub.5aR.sub.5b, NR.sub.5a or O, and Y.sub.6 is CR.sub.6aR.sub.6b, NR.sub.6a or O; when ring C is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring; i) Y.sub.5 is CR.sub.5a or N, and Y.sub.6 is CR.sub.6a or N, when the “” in the term “Y.sub.5Y.sub.6” represents a single bond; or ii) Y.sub.5 is C, and Y.sub.6 is C, when the “” in the term “Y.sub.5Y.sub.6” represents a double bond; each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; each of R.sub.6a and R.sub.6b is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; each of R.sub.a is independently selected from hydrogen, deuterium, halogen, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, —C.sub.1-6alkoxy, —C.sub.1-6alkyl, —C.sub.3-8cycloalkyl, —C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene-O—C.sub.1-6alkyl, —C.sub.1-6alkylene-(3-10 membered heterocyclic), —C.sub.1-6alkylene-(5-10 membered heteroaryl), —C.sub.1-6alkylene—CO—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene—NR.sub.a1—CO—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene—NR.sub.a1—CO—C.sub.1-6alkyl, —CO—NR.sub.a1R.sub.a2, —CO—CO—NR.sub.a1R.sub.a2, —C.sub.3-10carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C.sub.1-6alkyl, —CO—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —CO—NR.sub.a1-(3-10 membered heterocyclic), —CO—NR.sub.a1-(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C.sub.1-6alkylene—CO—OR.sub.a1, —O—C.sub.1-6alkylene—CO—NR.sub.a1R.sub.a2, —O—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —O—C.sub.3-10carbocyclic, —O-(3-10 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-6alkyl, —NR.sub.a1—CO—NR.sub.a1R.sub.a2, —NR.sub.a1—CO-(5-10 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-8cycloalkyl,—NR.sub.a1—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-6alkylene-(3-10 membered heterocyclic), —NR.sub.a1—C.sub.1-6alkylene-(5-10 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-6alkyl, —S—C.sub.1-6alkyl, —SONR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-6alkyl, —SO.sub.2—C.sub.1-6alkyl, —PO(C.sub.1-6alkyl).sub.2, —PO(C.sub.1-6alkoxy).sub.2,−3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n iso, 1, 2, 3, 4, 5 or 6; or two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; or R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted; each of R.sub.a1 and R.sub.a2 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein ring A is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

3. The compound or pharmaceutically acceptable salt thereof of claim 1 or claim 2, wherein ring A is a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein ring A is a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

5. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein ring A is ##STR00254## represents a single bond or a double bond; X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene—C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl, —O—C.sub.1-6alkylene-C.sub.1-6alkoxy, —O—C.sub.5-8aryl or —O—C.sub.1-6alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ; X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or a 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X.sub.6 is O, S, CO or NR.sub.X6, or C(R.sub.X6).sub.2; each of R.sub.X6 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X5 and R.sub.X6 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted.

6. The compound or pharmaceutically acceptable salt thereof of claim 5, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

7. The compound or pharmaceutically acceptable salt thereof of claim 5 or claim 6, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-7, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-8, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-9, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-10, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene-C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-11, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene-C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-12, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2,CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-4alkyl, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene-C.sub.3-6cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-13, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene-C.sub.3-6cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

15. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-14, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene—C.sub.3-6cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-15, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-16, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-17, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-18, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl, —O—C.sub.1-6alkylene-C.sub.1-6alkoxy, —O—C.sub.5-8aryl or —O—C.sub.1-6alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

20. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-19, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl,—O—C.sub.1-6alkylene-C.sub.1-6alkyl, —O—C.sub.5-8aryl or —O—C.sub.1-6alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

21. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-20, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl, —O—C.sub.1-3alkylene-C.sub.1-3alkyl, —O—C.sub.5-6aryl or —O—C.sub.1-3alkylene-C.sub.5-6aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-21, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl, —O—C.sub.1-3alkylene-C.sub.1-3alkyl, —O—C.sub.5-6aryl or —O—C.sub.1-3alkylene-C.sub.5-6aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

23. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-22, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, -S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl, —O—C.sub.1-3alkylene—C.sub.1-3alkyl, —O—C.sub.5-6aryl or —O—C.sub.1-3alkylene-C.sub.5-6aryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

24. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-23, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-24, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

26. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-25, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, an 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

27. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-26, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

28. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-27, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

29. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-28, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

30. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-29, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

31. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-30, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

32. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-31, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

33. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-32, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

34. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-33, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

35. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-34, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

36. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-35, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or -C.sub.1-3alkoxy.

37. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-36, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

38. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-37, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

39. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-38, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

40. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-39, wherein R.sub.X4 and R.sub.X5together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

41. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-40, wherein R.sub.X4 and R.sub.X5together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

42. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-41, wherein R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

43. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-42, wherein X.sub.6 is O, S, CO or NR.sub.X6, or C(R.sub.X6).sub.2; each of R.sub.X6 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

44. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-43, wherein X.sub.6 is O, S, CO or NR.sub.X6, or C(R.sub.X6).sub.2; each of R.sub.X6 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

45. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-44, wherein X.sub.6 is O, S, CO or NR.sub.X6, or C(R.sub.X6).sub.2; each of R.sub.X6 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

46. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-45, wherein X.sub.6 is O, S, CO or NR.sub.X6, or C(R.sub.X6).sub.2; each of R.sub.X6 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

47. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-46, wherein X.sub.6 is O, S, CO or NR.sub.X6, or C(R.sub.X6).sub.2; each of R.sub.X6 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

48. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-47, wherein R.sub.X5 and R.sub.X6 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

49. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-48, wherein R.sub.X5 and R.sub.X6 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

50. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-49, wherein R.sub.X5 and R.sub.X6 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

51. The compound or pharmaceutically acceptable salt thereof of any one of claims 5-50, wherein ring A is selected from ##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261##

52. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-51, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00262## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted or unsubstituted.

53. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-52, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00263## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted or unsubstituted.

54. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-53, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00264## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.

55. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-54, wherein ring B is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2,3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3, 4, 5 or 6heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

56. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-55, wherein ring B is a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 3-10 membered carbocyclic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2,3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

57. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-56, wherein ring B is a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, a 7 membered carbocyclic ring, a 8 membered carbocyclic ring, a 9 membered carbocyclic ring, a 10 membered carbocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, a 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

58. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-57, wherein ring B is ##STR00265## Y.sub.1 is N or CR.sub.Y1, R.sub.Y1 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —OH, —CN, —N—(C.sub.1-6alkyl).sub.2, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —N—(C.sub.1-6alkyl).sub.2, alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.Y1and R.sub.Y2together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when the “” in the term “Y.sub.3Y.sub.4” represents a single bond, Y.sub.3 is NR.sub.Y3 or C(R.sub.Y3).sub.2, and Y.sub.4 is CO, C(R.sub.Y4).sub.2 or NR.sub.Y4; when the “” in the term “Y.sub.3Y.sub.4” represents a double bond, Y.sub.3 is N or CR.sub.Y3, and Y.sub.4 is N or CR.sub.Y4; R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH —CO—C.sub.3-8heterocyclic ring, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl, —C.sub.1-6alkyl substituted with —OH, or —C.sub.1-6alkoxy; or R.sub.Y3 and R.sub.Y4together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted.

59. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-58, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, I, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

60. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-59, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, I, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

61. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-60, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, I, —NH.sub.2, —OH, —CN, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

62. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-61, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, I, —NH.sub.2, —OH, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

63. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-62, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

64. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-63, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

65. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-64, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

66. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-65, wherein Y.sub.2 is N or CR.sub.Y2; Rye is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

67. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-66, wherein R.sub.Y1 and R.sub.Y2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

68. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-67, wherein R.sub.Y1 and R.sub.Y2 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

69. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-68, wherein R.sub.Y1and R.sub.Y2together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

70. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-69, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH, —C.sub.1-6alkylene—OH, —CO—C.sub.3-8heterocyclic ring, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl, —C.sub.1-6alkyl substituted with —OH or —C.sub.1-6alkoxy.

71. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-70, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH, —C.sub.1-6alkylene—OH, —CO—C.sub.3-8heterocyclic ring, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl, —C.sub.1-3alkyl substituted with —OH or —C.sub.1-3alkoxy.

72. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-71, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-3alkyl, carboxyl, —COO—C.sub.1-3alkyl, —NH—C.sub.1-3alkylene—OH, —C.sub.1-3alkylene—OH, —CO—C.sub.3-8heterocyclic ring, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl, —C.sub.1-3alkyl substituted with —OH or —C.sub.1-3alkoxy.

73. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-72, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C.sub.1-3alkyl, —NH—C.sub.1-3alkylene—OH, —C.sub.1-3alkylene—OH, —CO—C.sub.3-8heterocyclic ring, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, ethyl substituted with —OH, methoxy, ethoxy, propoxy or isopropoxy.

74. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-73, wherein R.sub.Y3 and R.sub.Y4together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

75. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-74, wherein R.sub.Y3 and R.sub.Y4 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

76. The compound or pharmaceutically acceptable salt there of any one of claims 1-75, wherein R.sub.Y3 and R.sub.Y4together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

77. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-75, wherein ring B is selected from ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271##

78. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-77, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

79. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-78, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-3alkyl, —N(C.sub.1-3alkyl).sub.2, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

80. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-79, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

81. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-80, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

82. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-81, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO or C═NR.sub.5.

83. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-82, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO.

84. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-83, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form C═NR.sub.5.

85. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-84, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

86. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-85, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-3alkyl, —N(C.sub.1-3alkyl).sub.2, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

87. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-86, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

88. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-87, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

89. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-88, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

90. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-89, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

91. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-90, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, 9 membered heterocyclic ring, 10 membered heterocyclic ring, 5 membered heteroaromatic ring, 6 membered heteroaromatic ring, 7 membered heteroaromatic ring, 8 membered heteroaromatic ring, 9 membered heteroaromatic ring, 10 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

92. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-91, wherein each of R.sub.5 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

93. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-92, wherein each of R.sub.5 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

94. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-93, wherein each of R.sub.5 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy

95. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-94, wherein W is absent, —O, —S or —C(R.sub.W).sub.2-; and each of R.sub.W is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-6alkyl, —CO—OC.sub.1-6alkyl, —C.sub.1-6alkylene-O—C.sub.1-6alkoxy, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

96. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-95, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-3alkyl, —CO—OC.sub.1-3alkyl, —C.sub.1-3alkylene-O—C.sub.1-3alkoxy, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

97. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-96, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkylene-O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

98. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-97, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkylene-O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

99. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-98, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkylene-O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

100. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-99, wherein ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

101. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-100, wherein ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

102. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-101, wherein ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

103. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-102, wherein ring C is selected from ##STR00272##

104. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-103, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

105. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-104, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

106. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-105, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

107. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-106, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

108. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-107, wherein each of RY.sub.6, and R.sub.6b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

109. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-108, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

110. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-109, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

111. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-110, wherein each of Rha and R.sub.6b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

112. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-111, wherein each of R.sub.a is independently hydrogen, deuterium, F, Cl, Br, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, —C.sub.1-3alkoxy,—C.sub.1-4alkyl, —C.sub.3-6cycloalkyl, —C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene-O—C.sub.1-6alkyl, —C.sub.1-3alkylene-(3-8 membered heterocyclic), —C.sub.1-3alkylene-(5-8 membered heteroaryl), —C.sub.1-3alkylene—CO—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene—NR.sub.a1—CO—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene—NR.sub.a1—CO—C.sub.1-3alkyl, —CO—NR.sub.a1R.sub.a2, —CO—CO—NR.sub.a1R.sub.a2, —C.sub.3-8carbocyclic, −5-8 membered heteroaryl, −3-8 membered heterocyclic, —CO—C.sub.1-3alkyl, —COO—C.sub.1-3alkyl, —CO—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —CO—NR-(3-8 membered heterocyclic), —CO—NR-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C.sub.1-3alkylene—CO—OR.sub.a1, —O—C.sub.1-3alkylene—CO—NR.sub.a1R.sub.a2, —O—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —O—C.sub.3-8carbocyclic, —O-(3-8 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-3alkyl, —NR.sub.a1—CO—NR.sub.a1R.sub.a2, —NR.sub.a1—CO-(5-8 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-6cycloalkyl,—NR.sub.a1—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-3alkylene-(3-8 membered heterocyclic), —NR.sub.a1—C.sub.1-3alkylene-(5-8 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-3alkyl, —S—C.sub.1-3alkyl, —SONR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-3alkyl, —SO.sub.2—C.sub.1-3alkyl, —PO(C.sub.1-3alkyl).sub.2, —PO(C.sub.1-3alkoxy).sub.2, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

113. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-112, wherein each of R.sub.a is independently hydrogen, deuterium, F, Cl, Br, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, butyl, isobutyl, —C.sub.3-6cycloalkyl,-C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene-O—C.sub.1-6alkyl, —C.sub.1-3alkylene—CO—OR.sub.a1, —C.sub.1-3alkylene-(3-8 membered heterocyclic), —C.sub.1-3alkylene-(5-8 membered heteroaryl), —C.sub.1-3alkylene—CO—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene—NR.sub.a1—CO—NR.sub.a1R.sub.a2, —CO—NR.sub.a1R.sub.a2, —CO—CO—NR.sub.a1R.sub.a2, —C.sub.3-8carbocyclic, −5-8 membered heteroaryl, −3-8 membered heterocyclic, —CO—C.sub.1-3alkyl, —COO—C.sub.1-3alkyl, —CO—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —CO—NR-(3-8 membered heterocyclic), —CO—NR-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C.sub.1-3alkylene—CO—OR.sub.a1, —O—C.sub.1-3alkylene—CO—NR.sub.a1R.sub.a2, —O—C.sub.1-3alkylene-NR.sub.a1R.sub.a2, —O—C.sub.3-8carbocyclic, —O-(3-8 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-3alkyl, -NL1—CO—NR.sub.a1R.sub.a2, -NL1—CO-(5-8 membered heteroaryl), -NLI—CO—C.sub.3-6cycloalkyl,—NR.sub.a1—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-3alkylene-(3-8 membered heterocyclic), —NR.sub.a1—C.sub.1-3alkylene-(5-8 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-3alkyl, —S—C.sub.1-3alkyl, —SONR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-3alkyl, −50.sub.2—C.sub.1-3alkyl, —PO(C.sub.1-3alkyl).sub.2, —PO(C.sub.1-3alkoxy).sub.2, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

114. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-113, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

115. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-114, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

116. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-115, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

117. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-116, R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

118. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-117, R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, -C.sub.1-3alkyl or —C.sub.1-3alkoxy.

119. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-118, R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

120. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-116, R.sub.a and R.sub.w with the atom to which they are both attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 5 membered heteroaryl ring, a 6 membered heteroaryl ring, a 5 membered heterocyclic ring or a 6 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

121. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-120, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted -C.sub.1-6alkyl.

122. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-121, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

123. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-122, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

124. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-123, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

125. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-124, wherein the compound is of Formula II: ##STR00273## X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SF.sub.S, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene—C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X.sub.3 is N, S, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl, —O—C.sub.1-6alkylene-C.sub.1-6alkoxy, —O—C.sub.5-8aryl or —O—C.sub.1-6alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ; X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl,-C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; represents a single bond or a double bond; G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00274## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted or unsubstituted; Y.sub.1 is N or CR.sub.Y1, R.sub.Y1 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.Y1 and R.sub.Y2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when the “” in the term “Y.sub.3Y.sub.4” represents a single bond, Y.sub.3 is NR.sub.Y3 or C(R.sub.Y3).sub.2, and Y.sub.4 is CO, C(R.sub.Y4).sub.2 or NR.sub.Y4; when the “” in the term “Y.sub.3Y.sub.4” represents a double bond, Y.sub.3 is N or CR.sub.Y3, and Y.sub.4 is N or CR.sub.Y4; R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH , —C.sub.1-6alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.Y3 and R.sub.Y4together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; T is absent, O, NR.sub.1 or CR.sub.1R.sub.2; each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; or R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO or C═NR.sub.5; p is 0, 1, 2 or 3; each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; or R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR.sub.5, and each of the ring systems is independently optionally substituted or unsubstituted; each of R.sub.5 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; q is 0, 1, 2, 3 or 4; W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-6alkyl, —CO—OC.sub.1-6alkyl, C.sub.1-6alkoxy, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when ring C is absent, Y.sub.5 is CR.sub.5aR.sub.5b, NR.sub.5a or O, and Y.sub.6 is CR.sub.6aR.sub.6b, NR.sub.6a or O; when ring C is a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring; i) Y.sub.5 is CR.sub.5a or N, and Y.sub.6 is CR.sub.6a or N, when the “” in the term “Y.sub.5Y.sub.6” represents a single bond; or ii) Y.sub.5 is C, and Y.sub.6 is C, when the “” in the term “Y.sub.5Y.sub.6” represents a double bond; each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; each of R.sub.6a and R.sub.6b is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; each of R.sub.a is independently hydrogen, deuterium, halogen, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, —C.sub.1-6alkoxy, —C.sub.1-6alkyl, —C.sub.3-8cycloalkyl,-C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene-O—C.sub.1-6alkyl, —C.sub.1-6alkylene-(3-10 membered heterocyclic), —C.sub.1-6alkylene-(5-10 membered heteroaryl), —C.sub.1-6alkylene—CO—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene—NR.sub.a1—CO—NR.sub.a1R.sub.a2, —C.sub.1,.sub.6alkylene—NR.sub.a1—CO—C.sub.1-6alkyl, —CO—NR.sub.a1R.sub.a2, —CO—CO—NR.sub.a1R.sub.a2, —C.sub.3-10carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C.sub.1-6alkyl, —CO—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —CO—NR.sub.a1-(3-10 membered heterocyclic), —CO—NR.sub.a1-(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C.sub.1-6alkylene—CO—OR.sub.a1, —O—C.sub.1-6alkylene—CO—NR.sub.a1R.sub.a2, —O—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —O—C.sub.3-10carbocyclic, —O-(3-10 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-6alkyl, —NR.sub.a1—CO—NR.sub.a1R.sub.a2, —NR.sub.a1—CO-(5-10 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-8cycloalkyl,—NR.sub.a1—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-6alkylene-(3-10 membered heterocyclic), —NR.sub.a1—C.sub.1-6alkylene-(5-10 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-6alkyl, —S—C.sub.1-6alkyl, —SONR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-6alkyl, —PO(C.sub.1-6alkyl).sub.2, —PO(C.sub.1-6alkoxy).sub.2, −3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; each of R.sub.a1 and R.sub.a2 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

126. The compound or pharmaceutically acceptable salt thereof of claim 125, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

127. The compound or pharmaceutically acceptable salt thereof of claim 122 or claim 126, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

128. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-127, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

129. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-128, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

130. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-129, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

131. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-130, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SFS, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene-C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

132. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-131, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene-C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

133. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-132, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene—C.sub.3-6cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

134. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-133, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene-C.sub.3-6cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

135. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-134, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene-C.sub.3-6cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

136. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-135, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

137. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-137, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

138. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-137, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

139. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-138, wherein X.sub.3 is N, S, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl,—O—C.sub.1-6alkylene-C.sub.1-6alkoxy, —O—C.sub.5-8aryl or —O—C.sub.1-6alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

140. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-139, wherein X.sub.3 is N, S, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl, —O—C.sub.1-6alkylene-C.sub.1-6alkoxy, —O—C.sub.5-8aryl or —O—C.sub.1-6alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

141. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-140, wherein X.sub.3 is N, S, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl, —O—C.sub.1-3alkylene-C.sub.1-3alkoxy, —O—C.sub.5-8aryl or —O—C.sub.1-6alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

142. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-141, wherein X.sub.3 is N, S, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, -S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl or —O—C.sub.1-3alkylene—C.sub.1-3alkoxy, −0—C.sub.5-8aryl or —O—C.sub.1-3alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

143. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-142, wherein X.sub.3 is N, S, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, -S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl or —O—C.sub.1-3alkylene-C.sub.1-3alkoxy, —O—C.sub.5-8aryl or —O—C.sub.1-3alkylene-C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

144. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-143, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

145. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-144, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

146. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-145, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

147. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-146, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

148. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-147, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

149. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-148, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

150. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-149, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

151. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-150, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

152. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-151, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

153. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-152, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

154. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-153, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

155. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-154, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

156. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-155, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

157. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-156, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

158. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-157, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

159. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-158, wherein X.sub.5 is N, S, NR.sub.X5, C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

160. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-159, wherein R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

161. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-160, wherein R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

162. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-161, wherein R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

163. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-162, wherein ring A is selected from ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279##

164. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-163, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, ##STR00280## —NR.sub.G—SO.sub.2—, —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted or unsubstituted.

165. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-164, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00281## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted or unsubstituted.

166. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-165, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00282## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.

167. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-166, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.s-maryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

168. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-167, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

169. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-168, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

170. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-169, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

171. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-170, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

172. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-171, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

173. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-172, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

174. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-173, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

175. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-174, R.sub.Y1 and R.sub.Y2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

176. The compound or pharmaceutically acceptable salt thereof of any one of claims 122-172, R.sub.Y1 and R.sub.Y2 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

177. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-176, R.sub.Y1 and R.sub.Y2 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

178. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-177, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH, —C.sub.1-6alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

179. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-178, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH, —C.sub.1-6alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

180. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-179, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-3alkyl, carboxyl, —COO—C.sub.1-3alkyl, —NH—C.sub.1-3alkylene—OH, —C.sub.1-3alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

181. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-180, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C.sub.1-3alkyl, —NH—C.sub.1-3alkylene—OH, —C.sub.1-3alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

182. The compound or pharmaceutically acceptable salt thereof of any one claims 125-181, wherein R.sub.Y3 and R.sub.Y4together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

183. The compound or pharmaceutically acceptable salt thereof of any one claims 125-182, wherein R.sub.Y3 and R.sub.Y4 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

184. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-183, wherein R.sub.Y3 and R.sub.Y4together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

185. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-184, wherein ring B is selected from ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287##

186. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-185, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

187. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-186, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-3alkyl, —N(C.sub.1-3alkyl).sub.2, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

188. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-187, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

189. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-188, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

190. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-189, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO or C═NR.sub.5.

191. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-190, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO.

192. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-191, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form C═NR.sub.5.

193. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-192, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

194. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-193, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-3alkyl, —N(C.sub.1-3alkyl).sub.2, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

195. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-194, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

196. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-195, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

197. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-196, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or a 5-12 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

198. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-197, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

199. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-198, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

200. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-199, wherein each of R.sub.5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

201. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-200, wherein each of R.sub.5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

202. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-201, wherein each of R.sub.5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy

203. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-202, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-6alkyl, —CO—OC.sub.1-6alkyl, —C.sub.1-6alkyl-O—C.sub.1-6alkoxy, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

204. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-203, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-3alkyl, —CO—OC.sub.1-3alkyl, —C.sub.1-3alkyl—O—C.sub.1-3alkoxy, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

205. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-204, wherein W is absent, —O, —S or —C(R.sub.W).sub.2-; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkyl—O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

206. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-205, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkyl—O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

207. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-206, wherein W is absent, —O, —S or —C(R.sub.W).sub.2-; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkyl—O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

208. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-207, wherein ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

209. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-208, wherein ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

210. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-209, wherein ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, a 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

211. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-210, wherein ring C is selected from ##STR00288##

212. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-211, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

213. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-212, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

214. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-213, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

215. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-214, wherein each of R.sub.sa and R.sub.5b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

216. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-215, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

217. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-216, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

218. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-217, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

219. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-218, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

220. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-219, wherein each of R.sub.a is independently selected from hydrogen, deuterium, F, Cl, Br, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, —C.sub.1-3alkoxy, —C.sub.1-3alkyl, —C.sub.3-6cycloalkyl, —C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene-O—C.sub.1-6alkyl, —C.sub.1-3alkylene—CO—OR.sub.a1, —C.sub.1-3alkylene-(3-8 membered heterocyclic), —C.sub.1-3alkylene-(5-8 membered heteroaryl), —C.sub.1-3alkylene—CO—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene-NR.sub.a1—CO—C.sub.1-3alkyl, —CO—NR.sub.a1R.sub.a2, —CO—CO—NR.sub.a1R.sub.a2, —C.sub.3-8carbocyclic, −5-10 membered heteroaryl, −3-8 membered heterocyclic, —CO—C.sub.1-3alkyl, —COO—C.sub.1-3alkyl, —CO—C.sub.1-3alkylene-NR.sub.a1R.sub.a2, —CO—NR.sub.a1-(3-8 membered heterocyclic), —CO—NR.sub.a1-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C.sub.1-3alkylene-CO—OR.sub.a1, —O—C.sub.1-3alkylene-CO—NR.sub.a1R.sub.a2, —O—C.sub.1-3alkylene-NR.sub.a1R.sub.a2, —O—C.sub.3-8carbocyclic, −0-(3-8 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-3alkyl, —NR.sub.a1—CO—NR.sub.a1R.sub.a2, —NR.sub.a1—CO-(5-8 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-6cycloalkyl, —NR.sub.a1—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-3alkylene-(3-8 membered heterocyclic), —NR.sub.a1—C.sub.1-3alkylene-(5-8 membered heteroaryl), —NR.sub.a1—SO.sub.2 C.sub.1-.sub.3alkyl, —S—C.sub.1-3alkyl, —SO.sub.2NR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-3alkyl, —SO.sub.2C.sub.1-3alkyl, —PO(C.sub.1-3alkyl).sub.2, —PO(C.sub.1-3alkoxy).sub.2, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

221. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-220, wherein each of R.sub.a is independently selected from hydrogen, deuterium, F, Cl, Br, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, —C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-NR.sub.a2, —C.sub.1-3alkylene-O—C.sub.1-6alkyl, —C.sub.1-3alkylene-CO—OR.sub.a1, —C.sub.1-3alkylene-(3-8 membered heterocyclic), —C.sub.1-3alkylene-(5-8 membered heteroaryl), —C.sub.1-3alkylene—NR.sub.a1—C—NR.sub.a1R.sub.a2, —CO—NR.sub.a1R.sub.a2, —C.sub.3-8carbocyclic, −3-8 membered heterocyclic, —CO—C.sub.1-3alkyl, —COO—C.sub.1-3alkyl, —CO—C.sub.1-3alkylene-NR.sub.a1R.sub.a2, —CO—NR.sub.a1-(3-8 membered heterocyclic), —CO-NR.sub.a1-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C.sub.1-3alkylene-CO—OR.sub.a1, —O—C.sub.1-3alkylene-CO—NR.sub.a1R.sub.a2, —O—C.sub.1-3alkylene-NR.sub.a1R.sub.a2, —O—C.sub.3-8carbocyclic, −O-(3-8 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-3alkyl, -NIU-00-(5-8 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-6cycloalkyl,—NR.sub.a1—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-3alkylene-(3-8 membered heterocyclic), —NR.sub.a1—C.sub.1-3alkylene-(5-8 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-3alkyl, —S—C.sub.1-3alkyl, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-3alkyl, —SO.sub.2C.sub.1-3alkyl, —PO(C.sub.1-3alkyl).sub.2, —PO(C.sub.1-3alkoxy).sub.2, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

222. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-221, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

223. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-222, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

224. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-223, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

225. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-224, wherein each of R.sub.a1 and R.sub.a2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted -C.sub.1-6alkyl.

226. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-225, wherein each of R.sub.a1 and R.sub.a2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

227. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-226, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

228. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-227, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

229. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-228, wherein the compound is of Formula II-a: ##STR00289## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5; G, R.sub.Y1, R.sub.Y3, T, R.sub.3, R.sub.4, W, Y.sub.5; Y.sub.6, R.sub.a, p, q and n are as defined in claims 125-228.

230. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-229, wherein the compound is of Formula II-b ##STR00290## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5; G, R.sub.Y1, R.sub.Ya, T, R.sub.3, R.sub.4, W, Y.sub.5; Y.sub.6, R.sub.a, p, q and n are as defined in claims 125-228.

231. The compound or pharmaceutically acceptable salt thereof of any one of claims 125-230, wherein the compound is of Formula II-c ##STR00291## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5; G, R.sub.Y1, R.sub.Y2, R.sub.Ya, T, R.sub.3, R.sub.4, W, Y.sub.5; Y.sub.6, R.sub.a, p, q and n are as defined in claims 125-228.

232. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-124, wherein the compound is of Formula III: ##STR00292## X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxyl; X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —SF.sub.5, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene—C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, halogen, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl,-C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl or —O—C.sub.1-6alkylene-C.sub.1-6alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted ; X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; X.sub.5 is N, NR.sub.X5 C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; or R.sub.X4 and R.sub.X5together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; represents a single bond or a double bond; G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, —NR.sub.G—SO.sub.2—, ##STR00293## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—, each of R.sub.G is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted or unsubstituted; Y.sub.1 is N or CR.sub.Y1, R.sub.Y1 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; Y.sub.2 is N or CR.sub.Y2, R.sub.Y2 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; when the “” in the term “Y.sub.3Y.sub.4” represents a single bond, Y.sub.3 is NR.sub.Y3, and Y.sub.4 is CO; when the “” in the term “Y.sub.3Y.sub.4” represents a double bond, Y.sub.3 is N or CR.sub.Y3, and Y.sub.4 is N or CR.sub.Y4; R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH ,-C.sub.1-6alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxyl; T is absent, O, NR.sub.1 or CRIR.sub.2; each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; or R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO or C═NR.sub.5; p is 0, 1, 2 or 3; each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; or R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form a 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR.sub.5, and each of the ring systems is independently optionally substituted or unsubstituted; each of R.sub.5 is selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy; q is 0, 1, 2, 3 or 4; W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-6alkyl, —CO—OC.sub.1-6alkyl, —C.sub.1-6alkyl-O—C.sub.16alkoxy, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the ring systems is independently optionally substituted or unsubstituted; when ring C is absent, Y.sub.5 is CR.sub.5aR.sub.5b, NR.sub.5a or O, and Y.sub.6 is CR.sub.6aR.sub.6b, NR.sub.6a or O; when ring C is 5-12 membered aromatic ring, 5-12 membered heteroaromatic ring or 5-12 membered heterocyclic ring; i) Y.sub.5 is CR.sub.5a or N, and Y.sub.6 is CR.sub.6a or N, when the “” in the term “Y.sub.5Y.sub.6” represents a single bond; or ii) Y.sub.5 is C, and Y.sub.6 is C, when the “” in the term “Y.sub.5Y.sub.6” represents a double bond; each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; each of R.sub.6. and R.sub.6b is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl; each of R.sub.a is independently hydrogen, deuterium, halogen, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, —C.sub.1-6alkoxy, —C.sub.1-6alkyl, —C.sub.3-8cycloalkyl,-C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene-O—C.sub.1-6alkyl, —C.sub.1-6alkylene—CO—OR.sub.a1, —C.sub.1-6alkylene-(3-10 membered heterocyclic), —C.sub.1-6alkylene-(5-10 membered heteroaryl), —C.sub.1-6alkylene—CO—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene.sup.-NR.sub.a1—CO—NR.sub.a1R.sub.a2, —C.sub.1-6alkylene—NR.sub.a1—CO—C.sub.1-6alkyl, —CO—NR.sub.a1R.sub.a2, —COO—C.sub.1-6alkyl, —CO—CO—NR.sub.a1R..sub.2, —C.sub.3-10carbocyclic, −5-10 membered heteroaryl, −3-10 membered heterocyclic, —CO—C.sub.1-6alkyl, —CO—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —CO—NR.sub.a1-(3-10 membered heterocyclic), —CO—NR.sub.a1-(3-10 membered heterocyclic), —CO-(3-10 membered heterocyclic), —O—C.sub.1-6alkylene—CO—OR.sub.a1, —O—C.sub.1-6alkylene—CO—NR.sub.a1R.2,—O—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —O—C.sub.3-10carbocyclic, —O-(3-10 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-6alkyl, —NR.sub.a1—CO—NR.sub.a1R..sub.2, —NR—CO-(5-10 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-8cycloalkyl,—NR.sub.a1—C.sub.1-6alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-6alkylene-(3-10 membered heterocyclic), —NR.sub.a1—C.sub.1-6alkylene-(5-10 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-6alkyl, —S—C.sub.1-6alkyl, —SONR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-6alkyl, —SO.sub.2C.sub.1-6alkyl, —PO(C.sub.1-6alkyl).sub.2, —PO(C.sub.1-6alkoxy).sub.2, −3-10 membered heterocyclic or −5-10 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6; or two adjacent R.sub.a can be joined together to form a 6-membered aryl ring, 5-membered heteroaryl ring, 6-membered heteroaryl ring, −3-6 membered heterocyclic or -3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted; or R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring or 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted; each of R.sub.a1and R.sub.ae is independently selected from hydrogen, deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

233. The compound or pharmaceutically acceptable salt thereof of claim 232, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

234. The compound or pharmaceutically acceptable salt thereof of claim 232 or claim 233, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

235. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-234, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

236. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-235, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

237. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-236, wherein X.sub.1 is N, S, NR.sub.X1, C(R.sub.X1).sub.2, or CR.sub.X1; each of R.sub.X1 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CONH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

238. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-237, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene-C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

239. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-238 wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —CO—C.sub.1-6alkyl, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-8cycloalkyl, —NH—C.sub.3-8cycloalkyl, —C.sub.1-6alkylene-(3-8 membered heterocyclyl), —NHCO-(5-12 membered heterocyclyl), —NH—C.sub.1-6alkylene—C.sub.3-8cycloalkyl or 3-8 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

240. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-239, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-4alkyl, —C.sub.1-3alkoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene-C.sub.3-6cycloalkyl or 3-6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

241. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-240, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene-C.sub.3-6cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

242. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-241, wherein X.sub.2 is N, S, NR.sub.X2, C(R.sub.X2).sub.2, CR.sub.X2 or CO; each of R.sub.X2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, —CO—C.sub.1-3alkyl, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —SF.sub.5, —NHCO—C.sub.3-6cycloalkyl, —NH—C.sub.3-6cycloalkyl, —C.sub.1-3alkylene-(3-6 membered heterocyclyl), —NHCO-(5-10 membered heterocyclyl), —NH—C.sub.1-3alkylene-C.sub.3-6cycloalkyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic or 6 membered heterocyclic, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, -oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

243. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-242, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

244. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-243, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

245. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-244, wherein R.sub.X1 and R.sub.X2 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

246. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-245, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl or —O—C.sub.1-6alkylene-C.sub.1-6alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

247. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-246, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, C.sub.3-8cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-6alkyl, 3-12 membered heterocyclyl, —O—C.sub.3-8cycloalkyl or —O—C.sub.1-6alkylene-C.sub.1-6alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

248. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-247, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, —C.sub.1-3alkyl,—C.sub.1-3alkoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, -S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl or —O—C.sub.1-3alkylene—C.sub.1-3alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

249. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-248, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl or —O—C.sub.1-3alkylene-C.sub.1-3alkyl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

250. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-249, wherein X.sub.3 is N, S, O, NR.sub.X3, C(R.sub.X3).sub.2 or CR.sub.X3; each of R.sub.X3 is independently selected from hydrogen, deuterium, F, Cl, Br, carboxyl, —NO.sub.2, —NH.sub.2, —CN, —CONH.sub.2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C.sub.3-6cycloalkyl, C.sub.5-8aryl, —S—C.sub.1-3alkyl, 3-10 membered heterocyclyl, —O—C.sub.3-6cycloalkyl or —O—C.sub.1-3alkylene —C.sub.1-3alkyl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

251. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-250, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

252. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-251, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

253. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-252, wherein R.sub.X2 and R.sub.X3 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N or O, and each of the ring systems is independently optionally substituted or unsubstituted.

254. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-253, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

255. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-254, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NHCO-(5-12 membered heterocyclyl) or 5-12 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

256. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-255, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl,—C.sub.1-3alkoxy, —NHCO-(5-10 membered heterocyclyl) or 5-10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

257. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-256, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

258. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-257, wherein X.sub.4 is N, S, NR.sub.X4, C(R.sub.X4).sub.2 or CR.sub.X4; each of R.sub.X4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NHCO-(5-10 membered heterocyclyl), 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, oxo, ═O, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

259. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-258, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

260. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-259, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

261. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-260, wherein R.sub.X3 and R.sub.X4 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

262. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-261, wherein X.sub.5 is N, S, NR.sub.X5 C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

263. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-262, wherein X.sub.5 is N, S, NR.sub.X5 C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

264. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-263, wherein X.sub.5 is N, S, NR.sub.X5 C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

265. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-264, wherein X.sub.5 is N, S, NR.sub.X5 C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

266. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-265, wherein X.sub.5 is N, S, NR.sub.X5C(R.sub.X5).sub.2 or CR.sub.X5; each of R.sub.X5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted with 1, 2 or 3 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

267. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-266, wherein R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

268. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-267, wherein R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

269. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-268, wherein R.sub.X4 and R.sub.X5 together with the ring to which they are attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring or a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

270. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-269, wherein ring A is selected from ##STR00294## ##STR00295## ##STR00296## ##STR00297##

271. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-270, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, ##STR00298## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independent selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy, and each of which is independently optionally substituted or unsubstituted.

272. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-271, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, ##STR00299## —C(R.sub.G).sub.2— or —SO.sub.2—NR.sub.G—; each of R.sub.G is independent selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl or —C.sub.1-3alkoxy, and each of which is independently optionally substituted or unsubstituted.

273. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-272, wherein G is selected from absent, S, —SO—, —SO.sub.2—, O, —CO—, —NR.sub.G—, ##STR00300## —C(R.sub.G).sub.2— or −502—NR.sub.G—; each of R.sub.G is independent selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, and each of which is independently optionally substituted or unsubstituted.

274. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-273, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, -C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, -C.sub.1-6alkyl or —C.sub.1-6alkoxy.

275. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-274, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

276. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-275, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

277. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-276, wherein Y.sub.1 is N or CR.sub.Y1; R.sub.Y1 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

278. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-277, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

279. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-278, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-6alkyl, —C.sub.1-6alkoxy, —NH—C.sub.1-6alkyl, —N—(C.sub.1-6alkyl).sub.2, —C.sub.1-6 alkenyl, —C.sub.3-8cycloalkyl or —C.sub.5-10aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

280. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-279, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —C.sub.1-3alkyl, —C.sub.1-3alkoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

281. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-280, wherein Y.sub.2 is N or CR.sub.Y2; R.sub.Y2 is selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —NH—C.sub.1-3alkyl, —N—(C.sub.1-3alkyl).sub.2, —C.sub.1-3alkenyl, —C.sub.3-6cycloalkyl or —C.sub.5-8aryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

282. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-281, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH , —C.sub.1-6alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

283. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-282, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-6alkyl, carboxyl, —COO—C.sub.1-6alkyl, —NH—C.sub.1-6alkylene—OH ,-C.sub.1-6alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

284. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-283, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, —C.sub.1-3alkyl, carboxyl, —COO—C.sub.1-3alkyl, —NH—C.sub.1-3alkylene—OH ,—C.sub.1-3alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

285. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-284, wherein R.sub.Y3 and R.sub.Y4 are independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —OH, —CN, methyl, ethyl, propyl, isopropyl, carboxyl, —COO—C.sub.1-3alkyl, —NH—C.sub.1-3alkylene—OH ,—C.sub.1-3alkylene—OH, —CONH.sub.2 or −5-8 membered heteroaryl, and each of which is independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents, and the said each substituents is independently selected from deuterium, F, Cl, Br, I, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

286. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-285, wherein ring B is selected from ##STR00301##

287. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-286, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

288. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-287, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-3alkyl, —N(C.sub.1-3alkyl).sub.2, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

289. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-288 wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

290. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-289, wherein each of R.sub.1 and R.sub.2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

291. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-290, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO or C═NR.sub.5.

292. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-291, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form CO.

293. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-292, wherein R.sub.1 and R.sub.2 together with the carbon atom to which they are both attached form C═NR.sub.5.

294. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-293, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-6alkyl, —N(C.sub.1-6alkyl).sub.2, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

295. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-294, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —NH—C.sub.1-3alkyl, —N(C.sub.1-3alkyl).sub.2, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted

296. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-295 wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

297. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-296, wherein each of R.sub.3 and R.sub.4 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; —NH—C.sub.1-3alkyl; —N(C.sub.1-3alkyl).sub.2; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

298. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-297, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form 3-12 membered heterocyclic ring or 5-12 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

299. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-298, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring or C═NR.sub.5; and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

300. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-299, wherein R.sub.3 and R.sub.4 together with the carbon atom to which they are both attached form 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, 9 membered heterocyclic ring, 10 membered heterocyclic ring, 5 membered heteroaromatic ring, 6 membered heteroaromatic ring, 7 membered heteroaromatic ring, 8 membered heteroaromatic ring, 9 membered heteroaromatic ring, 10 membered heteroaromatic ring or C═NR.sub.5, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

301. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-300, wherein each of R.sub.5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

302. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-301, wherein each of R.sub.5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

303. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-302, wherein each of R.sub.5 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

304. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-303, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-6alkyl, —CO—OC.sub.1-6alkyl, —C.sub.1-6alkyl-O—C.sub.1-6alkoxy, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

305. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-304, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —CO—C.sub.1-3alkyl, —CO—OC.sub.1-3alkyl, —C.sub.1-3alkyl—O—C.sub.1-3alkoxy, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl

306. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-305, wherein W is absent, —O, —S or —C(R.sub.W).sub.2-; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkyl—O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

307. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-306, wherein W is absent, —O, —S or —C(R.sub.W).sub.2—; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkyl—O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

308. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-307, wherein W is absent, —O, —S or —C(R.sub.W).sub.2-; and each of R.sub.W is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN;—OH; —NO.sub.2; carboxyl; —CO—C.sub.1-3alkyl; —CO—OC.sub.1-3alkyl; —C.sub.1-3alkyl—O—C.sub.1-3alkoxy; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

309. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-308, wherein ring C is absent, a 5-12 membered aromatic ring, a 5-12 membered heteroaromatic ring or a 5-12 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

310. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-309, wherein ring C is absent, a 5-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

311. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-310, wherein ring C is absent, a 5 membered aromatic ring, a 6 membered aromatic ring, a 7 membered aromatic ring, an 8 membered aromatic ring, a 9 membered aromatic ring, a 10 membered aromatic ring, a 5 membered heteroaromatic ring, a 6 membered heteroaromatic ring, a 7 membered heteroaromatic ring, an 8 membered heteroaromatic ring, a 9 membered heteroaromatic ring, a 10 membered heteroaromatic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 7 membered heterocyclic ring, an 8 membered heterocyclic ring, a 9 membered heterocyclic ring, a 10 membered heterocyclic ring, and each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the ring systems is independently optionally substituted or unsubstituted.

312. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-311, wherein ring C is selected from ##STR00302##

313. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-312, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

314. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-313, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

315. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-314, wherein each of R.sub.5a and R.sub.5b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

316. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-315, wherein each of R.sub.Ya and R.sub.5b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

317. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-316, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted —C.sub.1-6alkyl.

318. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-317, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

319. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-318, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

320. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-319, wherein each of R.sub.6a and R.sub.6b is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

321. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-320, wherein each of R.sub.a is independently selected from hydrogen, deuterium, F, Cl, Br, —NR.sub.a1R.sub.a2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, —C.sub.1-3alkoxy,—C.sub.1-4alkyl, —C.sub.3-6cycloalkyl, —C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene-O—C.sub.1-6alkyl, —C.sub.1-3alkylene—CO—OR.sub.a1, —C.sub.1-3alkylene-(3-8 membered heterocyclic), —C.sub.1-3alkylene-(5-8 membered heteroaryl), —C.sub.1-3alkylene—CO—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene—NR.sub.a1—CO—NR.sub.a1R.sub.a2, —C.sub.1-3alkylene—NR.sub.a1—CO—C.sub.1-3alkyl, —CO—NR.sub.a1R.sub.a2, —CO—CO—NR.sub.a1R.sub.a2, —C.sub.3-8carbocyclic, −3-8 membered heterocyclic, —CO—C.sub.1-3alkyl, —COO—C.sub.1-3alkyl, —CO—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —CO—NR.sub.a1-(3-8 membered heterocyclic), —CO—NR.sub.a1-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C.sub.1-3alkylene-CO—OR.sub.a1, —O—C.sub.1-3alkylene-CO—NR.sub.a1R.sub.a2, .sup.-0 .sup.-C.sub.1-3alkylene-NR.sub.a1R.sub.a2, —O—C.sub.3-8carbocyclic, —O-(3-8 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-3alkyl, —NR.sub.a1—CO—NR.sub.a1R.sub.a2, —NR.sub.a1—CO-(5-8 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-6cycloalkyl,—NR.sub.a1—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-3alkylene-(3-8 membered heterocyclic), —NR.sub.a1—C.sub.1-3alkylene-(5-8 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-3alkyl, —SONR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO—C.sub.1-3alkyl, —SO.sub.2C.sub.1-3alkyl, —PO(C.sub.1-3alkyl).sub.2, —PO(C.sub.1-3alkoxy).sub.2, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

322. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-321, wherein each of R.sub.a is independently selected from hydrogen, deuterium, F, Cl, Br, —NR.sub.a1R..sub.2, —CN, —OH, —NO.sub.2, oxo, ═O, carboxyl, methoxy, ethoxy, propoxy, isopropoxy methyl, ethyl, propyl, isopropyl, butyl, isobutyl, —C.sub.3-6cycloalkyl,-C.sub.1-3alkylene.sup.-NR.sub.a1R.sub.a2, —C.sub.1-3alkylene-(3-8 membered heterocyclic), —C.sub.1-3alkylene-(5-8 membered heteroaryl), -.sub.3alkylene.sup.-CO.sup.-NR.sub.a1R.sub.a2, -.sub.3alkylene.sup.-NR.sub.a1.sup.-CO.sup.-NR.sub.a1R.sub.a2, —CO—NR.sub.a1R.sub.a2, —CO—CO—NR.sub.a1R.sub.a2, —C.sub.3-8carbocyclic, −3-8 membered heterocyclic, —CO—C.sub.1-3alkyl, —CO—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —CO—NR.1-(3-8 membered heterocyclic), —CO—NR.sub.a1-(3-8 membered heterocyclic), —CO-(3-8 membered heterocyclic), —O—C.sub.1-3alkylene-CO—OR.sub.a1, —O—C.sub.1-3alkylene—CO—NR.sub.a1R.sub.a2, —O—C.sub.1-3alkylene-NR.sub.a1R.sub.a2, —O—C.sub.3-8carbocyclic, —O-(3-8 membered heterocyclic), —NR.sub.a1—CO—C.sub.1-3alkyl, —NR.sub.a1—CO-(5-8 membered heteroaryl), —NR.sub.a1—CO—C.sub.3-6cycloalkyl,—NR.sub.a1—C.sub.1-3alkylene—NR.sub.a1R.sub.a2, —NR.sub.a1—C.sub.1-3alkylene-(3-8 membered heterocyclic), —NR.sub.a1—C.sub.1-3alkylene-(5-8 membered heteroaryl), —NR.sub.a1—SO.sub.2C.sub.1-3alkyl, —SONR.sub.a1R.sub.a2, —SO.sub.2NR.sub.a1R.sub.a2, —SO.sub.2C.sub.1-3alkyl, —PO(C.sub.1-3alkyl).sub.2, —PO(C.sub.1-3alkoxy).sub.2, −3-8 membered heterocyclic or −5-8 membered heteroaryl; each of which is independently optionally substituted; and n is 0, 1, 2, 3, 4, 5 or 6.

323. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-322, wherein each of R.sub.a1and R.sub.ae is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-6alkoxy, or substituted or unsubstituted

324. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-323, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

325. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-324, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3-6 membered heterocyclic ring or a 3-6 membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

326. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-325, wherein two adjacent R.sub.a can be joined together to form a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a 3 membered heterocyclic ring, a 4 membered heterocyclic ring, a 5 membered heterocyclic ring, a 6 membered heterocyclic ring, a 3 membered carbocyclic ring, a 4 membered carbocyclic ring, a 5 membered carbocyclic ring, a 6 membered carbocyclic ring, wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S, and each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S, each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

327. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-326, R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, halogen, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-6alkyl or —C.sub.1-6alkoxy.

328. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-327, R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

329. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-328, R.sub.a and R.sub.w with the atom to which they are both attached form a 3-10 membered aromatic ring, a 3-10 membered heteroaromatic ring or a 3-10 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

330. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-329, R.sub.a and R.sub.w with the atom to which they are both attached form a 5 membered aromatic ring, a 6 membered aromatic ring, a 5 membered heteroaryl ring, a 6 membered heteroaryl ring, a 5 membered heterocyclic ring or a 6 membered heterocyclic ring; each of the heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; each of the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of the ring systems is independently optionally substituted with deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, —C.sub.1-3alkyl or —C.sub.1-3alkoxy.

331. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-330, wherein each of R.sub.a1 and R.sub.a2 is independently selected from hydrogen, deuterium, F, Cl, Br, —NH.sub.2, —CN, —OH, —NO.sub.2, carboxyl, substituted or unsubstituted —C.sub.1-3alkoxy, or substituted or unsubstituted —C.sub.1-3alkyl.

332. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-331, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with halogen, NH.sub.2, CN, OH, NO.sub.2, carboxyl, C.sub.1-3alkyl or C.sub.1-3alkoxy.

333. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-332, wherein each of R.sub.a1and R.sub.a2 is independently selected from hydrogen; deuterium; F; Cl; Br; —NH.sub.2; —CN; —OH; —NO.sub.2; carboxyl; methoxy; ethoxy; propoxy; isopropoxy; —C.sub.1-3alkoxy substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; methyl; ethyl; propyl; isopropyl; —C.sub.1-3alkyl substituted with F, Cl, Br, NH.sub.2, CN, OH, NO.sub.2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.

334. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-333, wherein the compound is of Formula III-a: ##STR00303## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5; G, R.sub.Y3, T, R.sub.3, R.sub.4, W, Y.sub.5; Y.sub.6, R.sub.a, p, q and n are as defined in claims 232-333.

335. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-334, wherein the compound is of Formula III-b: ##STR00304## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5; G, R.sub.Y3, T, R.sub.3, R.sub.4, W, Y.sub.5; Y.sub.6, R.sub.a, p, q and n are as defined in claims 232-334.

336. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-335, wherein the compound is of Formula III-c: ##STR00305## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, G, R.sub.Y3, T, R.sub.3, R.sub.4, W, Y.sub.5, Y.sub.6, R.sub.a, p, q and n are as defined in claims 232-335.

337. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-336, wherein the compound is of Formula III-d: ##STR00306## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5; G, R.sub.Y3, T, R.sub.3, R.sub.4, W, Y.sub.5; Y.sub.6, R.sub.a, p, q and n are as defined in claims 232-336.

338. The compound or pharmaceutically acceptable salt thereof of any one of claims 232-337, wherein the compound is of Formula III-e: ##STR00307## Wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, G, R.sub.Ya, T, R.sub.3, R.sub.4, W, Y.sub.5, Y.sub.6, R.sub.a, p, q and n are as defined in claims 232-337.

339. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-338, wherein the compound is selected from TABLE-US-00012 1 ethyl (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5--2- carboxylate 2 (S)-1′-(5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 3 (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazine-2-carboxylic acid 4 (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylplyrazine-2-carboxamide 5 ethyl (S)-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2-amino-3-chloropyridin- 4-yl)thio)-5-methylpyrazine-2-carboxylate 6 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2 4′-piperidin]-1-amine 7 (S)-1′-(6-amino-5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 8 (S)-1′-(4-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrimidin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 9 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 10 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-(methylamino)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 11 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-(dimethylamino)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 12 (S)-1′-(6-amino-5-(thiazol-4-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 13 (S)-1′-(6-amino-5-(thiazol-2-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 14 (S)-1′-(6-amino-5-(quinolin-3-ylthio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 15 (S)-5-amino-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-3-carbonitrile 16 (S)-1′-(5-((2-ammo-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-N-methyl-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine 17 (S)-1′-(5-((3,5-dichloropyridin-4-yl)thio)pyrazin-2-yl)-5,6,7-trifluoro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine 18 (S)-1-amino-1′-(2-((2-cyanopyridin-3-yl)thio)pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-4-carbonitrile 19 (S)-1′-(5-((3-chloro-2-methoxypyridin-4-yl)thio)pyrazin-2-yl)-6-(methylthio)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 20 (S)-1-(5-((5-(4-amino-2-(tert-butyl)-4,6-dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-1′- yl)pyrazin-2-yl)thio)-2-chlorophenyl)ethan-1-one 21 (S)-1′-(5-((3-chloro-2-(isopropylamino)pyridin-4-yl)thio)pyrazin-2-yl)-6-(methylsulfonyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 22 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7,7-d2-5-amine 23 (S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(2,3-dichlorophenyl)-5- methylpyrazin-2-yl)methanol 24 (S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2-amino-3-chloropyridin-4- yl)thio)-5-methylpyrazin-2-yl)methanol 25 (S)-1′-(3-bromo-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 26 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazine-2-carbonitrile 27 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazine-2-carboxamide 28 (S)-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(2,3- dichlorophenyl)-5-methylpyrazin-2-ol 29 (S)-1′-(6-amino-3-bromo-5-((2,3-dichlorophenyl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 30 (S)-5-amino-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-((2,3- dichlorophenyl)thio)pyrazine-2-carbonitrile 31 (S)-5-amino-3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-((2,3- dichlorophenyl)thio)pyrazine-2-carboxamide 32 (S)-1′-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 33 (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)pyridin-3-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 34 (S)-1′-(4-((2-amino-3-chloropyridin-4-yl)thio)phenyl)-5,7-dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidin]-5-amine 35 (S)-1′-(4-((2-amino-3-chloropyridin-4-yl)thio)isoquinolin-1-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 36 (S)-6-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-3-(2,3- dichlorophenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 37 (S)-6-(1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2,3-dichlorophenyl)- 5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 38 (S)-6-(1-amino-5,6,7-trifluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methyl-3-(5- methylthiophen-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 39 (S)-2-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-5-(2,3- dichlorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 40 (S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2-amino-3- chloropyridin-4-yl)thio)-3-methylpyrimidin-4(3H)-one 41 (S)-1′-(6-amino-5-((4-chlorothiazol-2-yl)thio)pyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 42 (S)-1-amino-1′-(5-((4-amino-5-bromopyrimidin-2-yl)thio)-1-methyl-6-oxo-1,6-dihydropyridin-2- yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 43 (S)-6-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-((3-chloro-2- methoxypyridin-4-yl)thio)-1-methylpyridin-2(1H)-one 44 (S)-1-amino-1′-(4-(6-bromonaphthalen-2-yl)thiazol-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-6-carbonitrile 45 (S)-1′-(6-amino-5-(2-chloro-3-methylphenyl)pyrazin-2-yl)-6-bromo-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 46 (S)-1′-(5-(3-amino-2-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-1,6-diamine 47 (S)-1′-(6-amino-5-(2-chloro-3-methylphenyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-1,6-diamine 48 (S)-1′-(6-(5-chlorothiophen-2-yl)pyridazin-3-yl)-5-methyl-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 49 (S)-1′-(6′-chloro-[3,3′-bipyridazin]-6-yl)-5-methyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1- amine 50 (S)-1′-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 51 (R)-1′-(5-(2,3-dichloro-5-methoxyphenyl)pyridin-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]- 2-amine 52 (S)-6′-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1′-methyl-2′-oxo-1′,2′- dihydro-[3,3′-bipyridine]-2-carbonitrile 53 (S)-6′-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1′-methyl-2′-oxo-1′,2′- dihydro-[3,3′-bipyridine]-2-carboxamide 54 (S)-1′-(4-(3-methoxyphenyl)cyclohexyl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]- 5-amine 55 (S)-1-amino-1′-(6-((3-amino-2-chlorophenyl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carbonitrile 56 1-(5-((5-((1S)-1-amino-6-(methylsulfmyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin- 2-yl)thio)-2-chlorophenyl)ethan-1-one 57 (S)-1′-(5-(pyrimidin-2-ylthio)pyrazin-2-yl)-6-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 58 (S)-6-bromo-5-fluoro-1′-(5-(quinolin-4-ylthio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine 59 (S)-6-(4-amino-4,6-dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-1′-yl)-3-(3- (trifluoromethyl)pyridin-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 60 (S)-2-(1-amino-6-chloro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3,5- dichloropyridin-4-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 61 (S)-1′-(7-(5-chloropyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-3-amine 62 (S)-1′-(7-(3-chloropyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1H,3H-spiro[phenalene-2,4′- piperidin]-1-amine 63 (R)-1′-(3-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3,4-dihydro-1H- spiro[naphthalene-2,4′-piperidin]-3-amine 64 (S)-6-amino-2-(1-amino-7-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methyl-5- phenylpyrimidin-4(3H)-one 65 (S)-1-amino-1′-(4-amino-6-oxo-5-(pyridazin-3-ylthio)-1,6-dihydropyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-7-carbonitrile 66 (S)-1-amino-1′-(1-methyl-6-oxo-5-(pyrazin-2-yl)-1,6-dihydropyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-7-carbonitrile 67 (S)-2-(1-amino-6-chloro-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((4- isopropylphenyl)thio)pyrimidin-4(3H)-one 68 (S)-4-amino-6-(1-amino-6-bromo-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(2- chloro-3-methylphenyl)-1-methylpyridin-2(1H)-one 69 (S)-6-(4-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-4-amino-3-(4- (trifluoromethyl)phenyl)pyridin-2(1H)-one 70 (S)-6′-(1-amino-4-hydroxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2′-oxo-1′,2′-dihydro- [3,3′-bipyridine]-2-carbonitrile 71 (S)-1′-(3-bromo-5-(1H-indol-6-yl)-6-methylpyrazin-2-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 72 (S)-3-(4-amino-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-5-methyl-6-(2- oxoindolin-7-yl)pyrazine-2-carbonitrile 73 (S)-1′-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 74 (S)-1′-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thio)pyridin-3-yl)-6-chloro-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 75 (S)-1′-(4-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 76 (S)-1′-(5-((2,3-dichlorophenyl)thio)thiazol-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-7-amine 77 (R)-1′-(4-((3-chloropyridin-4-yl)thio)thiazol-2-yl)spiro[indoline-2,4′-piperidin]-3-amine 78 (R)-1′-(2-(7-chloro-1H-indol-1-yl)thiazol-4-yl)-2,3-dihydrospiro[indene-1,4′-piperidin]-2-amine 79 (R)-1′-(2-((2-(trifluoromethyl)phenyl)thio)thiazol-5-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3- amine 80 (S)-(5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)(2,3- dichlorophenyl)methanone 81 (S)-2-(1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(indolin-1-yl)-3-methyl- 3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 82 (S)-1′-(5-((1,2,3,4-tetrahydroquinolin-8-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[b]naphthalene-2,4′-piperidin]-1-amine 83 (S)-1′-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-1-amine 84 1′-(5-((3-amino-2-chlorophenyl)thio)-6-methylpyrazin-2-yl)-1-methyl-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 85 (R)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)-1H-indol-4-yl)-3H-spiro[benzofuran-2,4′- piperidin]-3-amine 86 (S)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)isoquinolin-3-yl)-5,6-dibromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 87 (S)-4-((5-(5-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-aminopyrazin-2- yl)thio)-3-chloro-1-methylpyridin-2(1H)-one 88 (S)-5-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-2-((2,3-dichlorophenyl)thio)- 6-(hydroxymethyl)pyridin-3-ol 89 (S)-6-bromo-1′-(5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 90 (S)-1′-(7-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl)-6-bromo-1,3- dihydrospiroindene-2,4′-piperidin]-1-amine 91 (S)-1′-(8-((2-amino-3-chloropyridin-4-yl)thio)pyrido[4,3-d]pyrimidin-5-yl)-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 92 (S)-3-(5-(1-amino-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyridin-2-yl)-4,5- dichlorophenol 93 (S)-1-amino-1′-(5-(5-methylthiophen-2-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]- 6-ol 94 (S)-1′-(5-(1H-indol-7-yl)pyrazin-2-yl)-5-ethyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 95 (S)-1′-(5-(cyclohex-1-en-1-yl)pyrazin-2-yl)-5-isopropyl-1,3-dihydrospiro[indene-2,4′-piperidin]- 1-amine 96 (S)-N-(1-amino-1′-(5-(2-(trifluoromethyl)phenyl)pyrimidin-2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-6-yl)methanesulfonamide 97 (S)-1′-(5-((4-(trifluoromethyl)pyrimidin-5-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-7-amine 98 (S)-1′-(5-((2-chloropyridin-3-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[c]pyridine-6,4′- piperidin]-5-amine 99 (S)-4-((5-(5-amino-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)-3-chlorobenzoic acid 100 (S)-1′-(5-((3-(trifluoromethyl)pyrazin-2-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-7-amine 101 (S)-1′-(5-((3-chloropyridazin-4-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[d]pyrimidine- 6,4′-piperidin]-7-amine 102 (S)-4-((5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyrazine-6,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)-3-chlorobenzamide 103 (S)-(1-amino-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-6-yl)dimethylphosphine oxide 104 (S)-1-amino-1′-(6-amino-5-((3-chloro-2-(dimethylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-5-carboxylic acid 105 ethyl (S)-1-amino-1′-(5-((3-chloro-2-(methylamino)pyridin-4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-5-carboxylate 106 (S)-1′-(5-((3-(morpholinomethyl)phenyl)thio)pyrazin-2-yl)-6-(trifluoromethyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 107 (S)-6-bromo-5-fluoro-1′-(5-((3-(pentafluoro-16-sulfanyl)phenyl)thio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 108 (S)-N-(3-((5-(1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2- yl)thio)phenyl)cyclopropanecarboxamide 109 (S)-6-(6-amino-1-bromo-4H,6H-spiro[cyclopenta[c]thiophene-5,4′-piperidin]-1′-yl)-3-(m-tolyl)- 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 110 (S)-2-(1-amino-5,6,7-trifluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(3-ethylphenyl)-3- methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 111 (R)-1′-(3-(3-(tert-butyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3,4-dihydro-1H- spiro[naphthalene-2,4′-piperidin]-3-amine 112 (S)-2-(3-amino-1,3-dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-1′-yl)-5- (3-isopropylphenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 113 (S)-1-amino-1′-(3-(3-chloro-2-morpholinopyridin-4-yl)-4-oxo-4,5-dihydro-1H- pyrrolo[3,2-c]pyridin-6-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 114 (S)-1′-(7-(3-chloro-2-(cyclobutylamino)pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta[a]naphthalene-2,4′-piperidin]-3-amine 115 (S)-1′-(3-(3-chloro-2-(cyclopropylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N6- methyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1,6-diamine 116 (S)-5-amino-1′-(3-(3-chloro-2-(pyrrolidin-1-yl)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2- fluoro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine]-3-carboxamide 117 1-(4-(6-((S)-4-amino-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-3-chloropyridin-2-yl)pyrrolidin-3-ol 118 (S)-1′-(3-(3-chloro-2-((cyclopropylmethyl)amino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- N6,N6-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-1,6-diamine 119 (S)-1′-(3-(2-amino-6-chloropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-(tert-butyl)-4,6- dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-4-amine 120 (S)-2-chloro-1′-(3-(1,3-dihydroisobenzofuran-5-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-6-amine 121 (S)-3-chloro-1′-(3-((2-chlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 122 (S)-1′-(3-(3-chloro-2-(ethylamino)pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[b]thiophene-5,4′-piperidin]-4-amine 123 (R)-1′-(7-(methyl(pyridin-4-yl)amino)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-3H- spiro[furo[2,3-b]pyridine-2,4′-piperidin]-3-amine 124 (R)-1′-(3-((3-chloropyridin-4-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-6,7- dihydrospiro[cyclopenta[b]pyridine-5,4′-piperidin]-6-amine 125 (S)-2-methoxy-1′-(3-(1-phenylvinyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 126 (R)-1-(3-benzyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1′,3′-dihydrospiro[piperidine-4,2′- pyrrolo[2,3-b]pyridin]-3′-amine 127 (S)-(6-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)(phenyl)methanone 128 (4S)-1′-(3-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′-piperidin]-4-amine 129 1-(6-((S)-5-amino-2-methoxy-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1-phenylethan-1-ol 130 (S)-1′-(3-((2,3-dichloropyridin-4-yl)oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 131 (S)-6-bromo-1′-(3-(5-(3,4-difluorophenyl)-3,4-dihydroquinolin-1(2H)-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 132 (S)-6-amino-2-(1-amino-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(4- cyclopropoxyphenyl)-3-methylpyrimidin-4(3H)-one 133 (S)-N-(1-amino-1′-(4-amino-5-((4-(methylthio)phenyl)thio)-6-oxo-1,6-dihydropyrimidin-2-yl)- 1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)acetamide 134 (S)-2-(1-amino-6-(methylamino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(4- (benzyloxy)phenyl)-3-methylpyrimidin-4(3H)-one 135 (S)-2-(7-acetyl-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-(benzo[d][1,3]dioxol- 4-ylthio)pyrimidin-4(3H)-one 136 4-amino-6-((1S)-1-amino-7-(1-hydroxyethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- (4-(difluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one 137 (S)-1-amino-1′-(4-amino-6-oxo-5-(4-phenoxyphenyl)-1,6-dihydropyridin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-4-carbonitrile 138 (S)-6-(1-amino-4-hydroxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(4- cyclohexylphenyl)-1-methylpyridin-2(1H)-one 139 (S)-3-([1,1′-biphenyl]-4-yl)-6-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′- yl)pyridin-2(1H)-one 140 (S)-6-amino-2-(1-amino-6-(2-oxopiperidin-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- methyl-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4(3H)-one 141 (S)-1-(1-amino-1′-(4-amino-5-((4-cyanophenyl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2- yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-6-yl)urea 142 (S)-4-amino-6-(1-amino-6-chloro-5-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1- methyl-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)pyridin-2(1H)-one 143 (S)-6-(1-amino-6-(trifluoromethyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-(4-(2- methoxyethoxy)phenyl)-1-methylpyridin-2(1H)-one 144 (S)-6-amino-2-(1-amino-6-(piperidine-1-carbonyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)- 3-methyl-5-(quinolin-8-ylthio)pyrimidin-4(3H)-one 145 (S)-6-amino-2-(1-amino-6-morpholino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3-methyl- 5-((4-nitrophenyl)thio)pyrimidin-4(3H)-one 146 (S)-6-amino-2-(5-amino-3-nitro-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-3- methyl-5-(quinolin-8-ylthio)pyrimidin-4(3H)-one 147 (S)-6-(5-amino-3-(4-methylpiperazin-1-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-1-methyl-3-(naphthalen-1-ylthio)pyridin-2(1H)-one 148 (S)-2-(1-amino-6-(1H-pyrrol-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-((2,2- difluorobenzo[d][1,3]dioxol-4-yl)thio)pyrimidin-4(3H)-one 149 (S)-7-(5-(1-amino-6-(1H-imidazol-1-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6- (hydroxymethyl)-3-methylpyrazin-2-yl)isoindolin-1-one 150 (S)-3-(1-amino-6-(ethylamino)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(1H-indol-5-yl)- 5-methylpyrazine-2-carboxamide 151 (S)-N-(1-amino-1′-(3-bromo-5-(1H-indol-6-yl)-6-methylpyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-6-yl)cyclopropanecarboxamide 152 (S)-4-(6-amino-5-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-3- methylpyrazin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 153 (S)-3-(1-amino-5-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-5-methyl-6-(2- oxoindolin-7-yl)pyrazine-2-carbonitrile 154 (S)-N-(5-(1-amino-7-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2- hydroxyethyl)amino)-3-methylpyrazin-2-yl)benzenesulfonamide 155 (S)-1′-(6-methyl-3-(1H-pyrazol-5-yl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 156 (S)-2-(3-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-6-(8- chlorochroman-7-yl)-5-methylpyrazin-2-yl)propan-2-ol 157 (S)-6-chloro-1′-(5-(7-chloro-2,3-dihydrobenzofuran-6-yl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 158 (S)-4-bromo-1′-(5-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 159 (S)-1-amino-1′-(6-cyano-5-(1H-indazol-7-yl)pyrazin-2-yl)-5-fluoro-1,3-dihydrospiro[indene-2,4′- piperidine]-6-carboxamide 160 (S)-1′-(5-(1H-indol-3-yl)-6-iodopyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-5-amine 161 (R)-6-(5-(7′-amino-7′,8′-dihydro-5′H-spiro[piperidine-4,6′-quinolin]-1-yl)-3-vinylpyrazin-2- yl)isoindolin-1-one 162 (R)-1-(4-(5-(6-amino-6,7-dihydrospiro[cyclopenta[b]pyridine-5,4′-piperidin]-1′-yl)-3- ethylpyrazin-2-yl)-3,3-difluoroindolin-1-yl)ethan-1-one 163 (S)-1′-(5-(3-methyl-1H-indazol-6-yl)-6-phenylpyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-5-amine 164 (S)-1′-(5-(1H-benzo[d][1,2,3]triazol-6-yl)-6-cyclopropylpyrazin-2-yl)-6-((tetrahydro-2H-pyran- 4-yl)oxy)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 165 (S)-1-amino-1′-(3-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 166 (S)-1′-(3-(1H-benzo[d]imidazol-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 167 (S)-1-(6-(1-amino-5-chloro-6-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one 168 (1-(6-((S)-1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)methanol 169 1-(6-((1S)-1-amino-6-(methylsulfinyl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-5-fluoro-1,2,3,4-tetrahydroquinoline-6-carbonitrile 170 (S)-6-chloro-1′-(3-(2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5-methyl-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 171 (S)-5-(6-(1-amino-4-methoxy-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H-pyrazolo[3,4- b]pyrazin-3-yl)-N-(2-methoxyethyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxamide 172 (S)-1-amino-5-fluoro-1′-(3-(6-(piperazin-1-yl)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile 173 (S)-2-(1-(6-(1-amino-6-(methylthio)-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylic acid 174 (S)-1′-(6-(aminomethyl)-5-(2,3-dichloropyridin-4-yl)pyrazin-2-yl)-6-(1H-imidazol-1-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 175 (1S)-1-amino-1′-(5-(2,3-dichloropyridin-4-yl)-3-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-6- methylpyrazin-2-yl)-N,N-dimethyl-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carboxamide 176 (S)-1′-(8-(2-amino-3-chloropyridin-4-yl)-7-methylimidazo[1,2-c]pyrimidin-5-yl)-5-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]-1-amine 177 (S)-1′-(5-(1-methyl-1H-indol-2-yl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-3,3-d2- 1-amine 178 (S)-1-(6-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one 179 (S)-1′-(3-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5-amine 180 (3-((S)-1-amino-6-fluoro-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((R)-1- methylisoindolin-2-yl)pyrazin-2-yl)methanol 181 (S)-1′-(3-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclopenta[c]pyridine-6,4′-piperidin]-5,5-d2-7-amine 182 (S)-4-(difluoromethyl)-1′-(5-methyl-6-((R)-2-methyl-3,4-dihydro-1,5-naphthyridin-1(2H)- yl)pyridin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine 183 (S)-1′-(8-(2-chloro-3-(isopropyl(methyl)amino)phenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)- 2,3,6,8-tetrahydrospiro[indeno[5,6-b][1,4]dioxine-7,4′-piperidin]-6-amine 184 (S)-1-(5-amino-1′-(8-((5-chloro-1-methylindolin-6-yl)thio)imidazo[1,5-a]pyridin-5-yl)-2,3,5,7- tetrahydro-1H-spiro[cyclopenta[b]pyrrolo[3,2-e]pyridine-6,4′-piperidin]-1-yl)ethan-1-one

340. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-339 and at least one pharmaceutically acceptable excipient.

341. The pharmaceutical composition of claim 340, wherein, the compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10.

342. A combination pharmaceutical product comprising the compound or a pharmaceutically acceptable salt thereof of any of claims 1-339, together with one or more other therapeutically active agents.

343. Use of the compound or a pharmaceutically acceptable salt thereof of any one of claim 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342 for the preparation of a medicament.

344. The use of claim 343, wherein the medicament is used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.

345. Use, in the manufacture of a medicament for use as an inhibitor of SHP2, of at least one compound or a pharmaceutically acceptable salt thereof any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342.

346. Use of the compound or a pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342 for the preparation of a medicament in the treatment of diseases or conditions mediated by the activity of SHP2.

347. The use of claim 346, wherein the diseases or conditions mediated by the activity of SHP2 is cancer.

348. The use of claim 346, wherein the diseases or conditions mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.

349. A method for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease, comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claims 340 or 341, or the combination pharmaceutical product of claim 342, wherein the disease is cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.

350. A method for inhibiting the activity of SHP2 level, comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, or the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342.

351. A method for preventing or treating a disease, lessening a disease symptoms, delaying the progression or onset of a disease, comprising administering to the patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342, wherein the disease is mediated by the activity of SHP2.

352. The method of claim 351, wherein the disease mediated by the activity of SHP2 is cancer.

353. The method of claim 351, wherein the disease mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.

354. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 342 for use in preventing or treating a disease, lessening a disease symptom, delaying the progression or onset of a disease, wherein the disease is cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.

355. The compound or the pharmaceutically acceptable slat thereof any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 339, for use in inhibiting the activity of SHP2.

356. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-339, the pharmaceutical composition of claim 340 or 341, or the combination pharmaceutical product of claim 339 for use in preventing or treating a disease, lessening a disease symptom, delaying the progression or onset of a disease, wherein the disease is mediated by the activity of SHP2.

357. The compound or the pharmaceutically acceptable salt thereof, the pharmaceutical composition, or the combination pharmaceutical product of claim 356, wherein the disease mediated by the activity of SHP2 is cancer.

358. The compound or the pharmaceutically acceptable salt thereof, the pharmaceutical composition, or the combination pharmaceutical product of claim 356, wherein the disease mediated by the activity of SHP2 is selected from Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.

Description

EXAMPLES

[0551] The following Examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:

TABLE-US-00002 DMF N,N-Dimethylformamide EA Ethyl acetate Hex Hexane MeOH Methanol DCM Dichloromethane DCE 1,2-Dichloroethane EtOH Ethanol t-BuOH tert-Butanol iPrOH Propan-2-ol CD.sub.3I Iodomethane-d3 LiHMDS Lithium bis(trimethylsilyl)amide THF Tetrahydrofuran Ti(OEt).sub.4 Titanium ethoxide NMP 1-Methyl-2-pyrrolidinone DIPEA N,N-Diisopropylethylamine (Boc).sub.2O Di-tert-butyl dicarbonate LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide PPA Polyphosphoric acids TEA Triethylamine PPh.sub.3 Triphenylphosphane Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene BINAP 2,2′-Bis(diphenylphosphanyl)-1,1′-binaphthalene DavePhos 2′-(dicyclohexylphosphanyl)-N,N-dimethyl-[1,1′-biphenyl]-2-amine Pd(OAc).sub.2 Palladium diacetate Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl.sub.2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl.sub.2•CH.sub.2Cl.sub.2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex BOP Benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate PyBOP Benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate K.sub.4Fe(CN).sub.6•3H.sub.2O Potassium ferrocyanide trihyrate Cy.sub.3PH•BF.sub.4 Tricyclohexylphosphonium tetrafluoroborate t-BuOK Potassium tert-butoxide NaOEt Sodium ethoxide NCS N-Chlorosuccinimide NBS N-Bromosuccinimide NIS N-Iodosuccinimide TFA 2,2,2-Trifluoroacetic acid RT Room temperature min minute(s) h hour(s) aq aqueous sat saturated TLC Thin layer chromatography Prep - TLC Preparative thin layer chromatography

Intermediate A1

[0552] ##STR00055##

[0553] A mixture of 3-chloro-4-iodopyridin-2-amine (25.55 g, 100.41 mmol), methyl 3-mercaptopropanoate (12.72 g, 105.85 mmol), Pd.sub.2(dba).sub.3 (0.96 g, 1.05 mmol), XantPhos (1.21 g, 2.09 mmol) and DIPEA (26.01 g, 201.25 mmol) in 1,4-dioxane (80 mL) was stirred for 18 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA (80 mL), filtered and concentrated under reduced pressure. The residue was diluted with EA (50 mL) and Hex (250 mL), the resulting suspension was stirred for 10 min and filtered. The filter cake was collected. The filtration was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluting with EA:Hex=1:1, v/v). The product was combined with the filter cake to give compound A1-1 (21.62 g). MS: 247 [M+1].sup.+.

[0554] Sodium (2.48 g, 107.83 mmol) was dissolved in EtOH (200 mL) and added to a suspension of compound A1-1 (21.62 g, 87.63 mmol) in EtOH (100 mL) dropwise at 0° C. The resulting mixture was allowed to warm to RT and stirred for 2 h. The mixture was diluted with EtOH (20 mL) and DCM (200 mL), stirred for another 20 min, filtered and washed with DCM (30 mL). The filter cake was collected and dried in an high vacuum oven to afford intermediate A1 (12.72 g). MS: 161 [M−Na+2H].sup.+.

[0555] The following compounds were synthesized using the above procedure with the corresponding starting materials.

##STR00056##

Intermediate A2

[0556] ##STR00057##

[0557] To a −80° C. solution of 2,6-dibromonaphthalene (994 mg, 3.48 mmol) in THF (20 mL) under nitrogen atmosphere was added n-BuLi (2.5 M, 1.60 mL, 4.00 mmol) dropwise. The resulting mixture was stirred for 50 min at −80° C. Then triisopropyl borate (789 mg, 4.20 mmol) was added and the resulting mixture was allowed to warm to RT and stirred for 16 h. Hydrochloric acid (1 M, 10.00 mL) was added and stirred for 1 h. The reaction mixture was diluted with brine. The layers were separated and the organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give intermediate A2 (922 mg) as an off—white solid.

[0558] The following compound was synthesized using the above procedure with 2-bromo-5-chlorothiophene.

##STR00058##

Intermediate B1

[0559] ##STR00059##

[0560] To a 0° C. mixture of 3-bromo-6-chloropyrazin-2-amine (511 mg, 2.45 mmol) in DMF (5 mL) under nitrogen atmosphere was added NaH (60%, 153 mg, 3.83 mmol). The resulting mixture was allowed to warm to RT and stirred for 30 min. Then CH.sub.3I (453 mg, 3.19 mmol) was added and the resulting mixture was stirred for 1 h at RT. The reaction mixture was quenched with brine (50 mL) and extracted with EA (80 mL). The organic layer was washed with brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give intermediate B1 (503 mg) as a brown solid which was used in next step without further purification. MS: 222 [M+1].sup.+.

[0561] The following compounds were synthesized using with corresponding starting materials.

##STR00060##

Intermediate B2

[0562] ##STR00061##

[0563] A mixture of 6-chloropyridin-2(1H)-one (5.03 g, 38.83 mmol), CH.sub.3I (8.49 g, 66.86 mmol), K.sub.2CO.sub.3 (8.99 g, 65.05 mmol) and EtOH (25 mL) in a sealed tube was stirred for 17 h at 70° C. After cooling to RT, the reaction mixture was poured into water (200 mL) and extracted with EA (2 A 100 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound B2-1 (4.35 g) as a yellow solid. MS: 144 [M+1].sup.+. Following procedures of WO 2007146824, intermediate B2 was prepared from compound B2-1.

Intermediate C1

[0564] ##STR00062##

[0565] To a −70° C. solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (26.02 g, 101.18 mmol) in THF (100 mL) under nitrogen atmosphere was added LDA (2 M, 65.00 mL, 130.00 mmol) dropwise. The resulting mixture was stirred for 1 h at -70° C. Then (bromomethyl)benzene (17.98 g, 105.12 mmol) was added and the resulting mixture was stirred for 30 min. The reaction mixture was quenched by the addition of brine (100 mL) dropwise. The layers were separated and the organic layer was washed with brine (1×80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound C1-1 (38.05 g, crude) as a yellow oil. MS: 348 [M+1].sup.+.

[0566] A mixture of compound C1-1 (38.05 g, 0.11 mol) and PPA (50.00 g) was stirred for 1.5 hat 130° C. After cooling to RT, the reaction mixture was poured into ice/water and the pH value of the resulting mixture was adjusted to 9 with NaOH. (Boc).sub.2O (40.12 g, 0.18 mol) was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was extracted with EA (3×150 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give compound C1-2 (10.00 g). MS: 302 [M+1].sup.+.

[0567] A mixture of compound C1-2 (10.00 g, 0.033 mol) and (R)-(+)-2-methyl-2-propanesulfinamide (8.33 g, 0.069 mol) in Ti(OEt).sub.4 (50 mL) was stirred for 2 h at 120° C. The reaction mixture was poured into water (100 mL) and diluted with EA (300 mL). The resulting mixture was filtered through a pad of Celite, the filtrate was separated and the organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound C.sub.1-3 (18.49 g, crude) as a yellow oil. MS: 405 [M+1].sup.+.

[0568] To a −50° C. solution of compound C.sub.1-3 (18.49 g, 0.046 mol) in THF (100 mL) was added BH.sub.3 /THF (1 M, 125.00 mL, 0.13 mol) dropwise. The resulting mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was quenched by the addition of brine dropwise. The layers were separated and the organic layer was washed with brine (1×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound C1-4 (8.06 g) as a yellow oil. MS: 407 [M+1].sup.+.

[0569] A mixture of compound C1-4 (8.06 g, 0.020 mol) and HCl/EA (4 M, 20.00 mL, 80.00 mmol) in DCM (120 mL) was stirred for 1 h at RT. Another portion of HCl/EA (4 M, 10.00 mL, 40.00 mmol) was added and stirred for 1.5 h at RT. The reaction mixture was filtered followed by EA (50 mL) wash. The filter cake was collected, dried under high vacuum to give intermediate C1 (4.57 g) as a white solid. MS: 203 [M+1].sup.+.

[0570] The following compounds were synthesized using the above procedure or modified procedure with the corresponding starting materials.

##STR00063##

Intermediate C2

[0571] ##STR00064##

[0572] A solution of 2,2′-azanediylbis(ethan-l-ol) (198.15 g, 1.88 mol), K.sub.2CO.sub.3 (520.95 g, 3.77 mol) and (bromomethyl)benzene (386.79 g, 2.26 mol) in acetonitrile (2000 mL) was stirred at 90° C. for 2.5 h. After cooling to RT, the reaction mixture was filtered followed by EA (2×100mL) wash. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:10, v/v) to give compound C2-1 (89.44 g) as a colorless oil. MS: 196 [M+H].sup.+.

[0573] To a 0° C. solution of compound C2-1 (30.66 g, 0.16 mol) in toluene (300 mL) was added tribromophosphane (69.13 g, 0.26 mol) dropwise. The resulting mixture was stirred at 105° C. for 16 h. After cooling to RT, the volatiles were removed under reduce pressure. The residue was diluted with water (300 mL), and the pH value was adjusted to 9 with NaOH. The resulting mixture was extracted with EA (3×150 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated under reduced pressure to give compound C2-2 (41.58 g) which was used in next step without any further purification. MS: 320 [M+H].sup.+.

[0574] To a 0° C. solution of compound C2-2 (1.70 g, 12.77 mmol) in DMF (20 mL) under nitrogen atmosphere was added NaH (60% dispersion in mineral oil, 982 mg, 24.55 mmol) in three portions, and the mixture was heated to 60° C., stirred for 1 h at this temperature. Then N-benzyl-2-bromo-N-(2-bromoethypethan-l-amine (4.54 g, 14.14 mmol) was added and stirred at 60° C. for another 1 h. After cooling to RT, the reaction mixture was quenched with water (80 mL), extracted with EA (3×80 mL). The combined organic layers were washed with water (3×80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA) to give compound C2-3 (1.14 g). MS: 293 [M+H].sup.+.

[0575] To a 0° C. solution of compound C2-3 (1.05 g, 3.59 mmol) in DCE (10 mL) was added 1-chloroethyl carbonochloridate (903 mg, 6.32 mmol) dropwise. The resulting mixture was stirred at RT for 1.5 h. The volatiles were removed under reduced pressure and the residue was dissolved in MeOH (20 mL), stirred at 80° C. for 4 h. The volatiles were removed under reduced pressure and dissolved in DCM (20 mL). DIPEA (1.33 g, 10.32 mmol) and (Boc).sub.2O (1.38 g, 6.32 mmol) were added. The resulting solution was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:1, v/v) to give compound C2-4 (438 mg). MS: 303 [M+H].sup.+.

[0576] Intermediate C2 was synthesized in the manner similar to intermediate C1, except compound C1-2 was replaced with compound C2-4.

Intermediate C3

[0577] ##STR00065##

[0578] To a -78° C. solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (2.83 g, 11.00 mmol) in THF (50 mL) was added LDA (2 M, 6.00 mL, 12.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 1 h at this temperature. Then 2-chloro-5-(chloromethyl)thiazole (in 3 mL THF, 1.69 g, 10.06 mmol) was added dropwise and stirred for 1 h. The reaction mixture was quenched with brine (50 mL), extracted with EA (2×30 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:20, v/v) to give compound C3-1 (1.15 g). MS: 389 [M+H].sup.+.

[0579] To a −78° C. solution of compound C3-1 (900 mg, 2.31 mmol) in THF (50 mL) was added LDA (2 M, 3.00 mL, 6.00 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 30 min at this temperature, and quenched with brine (30 mL). The resulting mixture was extracted with EA (2×30 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound C3-2 (832 mg). MS: 343 [M+1].sup.+.

[0580] Compound C3-4 was synthesized in the manner similar to intermediate C1-4, except compound C1-2 was replaced with compound C3-2.

[0581] A suspension of compound C3-4 (2.50 g, 5.58 mmol), TEA (2 mL) and Pd/C (10%, 690 mg) in MeOH (50 mL) was stirred for 24 h at 40° C. under hydrogen atmosphere. The resulting mixture was filtered, and an additional portion of Pd/C (10%, 1.32 g) was added to the filtration. The resulting mixture was stirred for another 16 h at 50° C. under hydrogen atmosphere. The resulting mixture was filtered, the filtration was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:1, v/v) to give intermediate C3 (1.28 g). MS: 414 [M+H].sup.+.

Intermediate C4

[0582] ##STR00066##

[0583] To a −30° C. solution of compound C1-4 (695 mg, 1.71 mmol) in DMF (6 mL) was added LiHMDS (1 M, 2.10 mL, 2.10 mmol) dropwise. The resulting mixture was stirred for 1.5 h at this temperature. Then CH.sub.3I (496 mg, 3.49 mmol) was added dropwise. The resulting mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (EA:Hex=2:5, v/v) to give compound C4-1 (232 mg) as a yellow solid. MS: 421 [M+1].sup.+.

[0584] A mixture of compound C4-1 (232 mg, 0.55 mmol) and HCl/EA (4 M, 2.00 mL, 8.00 mmol) in EA (5 mL) was stirred for 1.5 h at RT. The reaction mixture was filtered. The filter cake was collected, dried under high vacuum to give intermediate C4 (50 mg) as a white solid. MS: 217 [M+1].sup.+.

[0585] Following procedures of WO2018172984, the following intermediates were prepared with corresponding starting materials.

##STR00067##

Intermediate C5

[0586] ##STR00068## ##STR00069##

[0587] To a solution of 2,3-dibromopyridine (47.38 g, 0.20 mol) in THF (300 ml) was added isopropylmagnesium chloride (2 M solution in THF, 110 mL) dropwise at RT under nitrogen atmosphere. The reaction mixture was stirred for 1.5 h, and C5-1 (46.93 g in 130 mL THF, 0.22 mol) was added at RT. The reaction mixture was stirred for 1 h and quenched with brine (300 mL), and then the mixture was filtered. The filtrate was separated and the organic layer was collected. The aqueous layer was extracted with EA (1×200 mL).The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give C5-2 (87.67 g) which was used without any further purification. MS: 371 (M+H).sup.+.

[0588] To a solution of C5-2 (64.77 g, 17.45 mmol) in DCM (500 mL) was added Dess-Martin (90.12 g, 21.25 mmol) below 30° C. The resulting mixture was stirred for 4 h, and then saturated sodium bicarbonate solution (500 mL) and saturated sodium carbonate solution (300 mL) were added. The organic layer was collected and washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was added to the solution of EA (60 mL) and Hex (300 mL) and stirred for 27 h. The mixture was filtered, and the filter cake was collected to give C5-3 (30.57 g) as an off-white solid. MS: 369 (M+H) +.

[0589] To a −30° C. solution of C5-3 (10.16 g, 27.52 mmol) in THF (80 mL) were added LiHMDS (1 M solution in THF, 31.00 mL) and CD.sub.3I under nitrogen atmosphere. The resulting mixture was allowed to warm to RT and stirred for 20 h. The reaction mixture was quenched with brine (80 mL), and the organic layer was collected. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA:Hex=1:5, v/v) to give C5-4 (8.40 g). MS: 386 (M+H).sup.+.

[0590] A mixture of C5-4 (8.40 g, 21.74 mmol), Cs.sub.2CO.sub.3 (7.04 g, 21.61 mmol), pivalic.sub..ucid (672 mg, 6.58 mmol), Pd(OAc).sub.2 (248 mg, 1.10 mmol) and Cy.sub.3PHBF.sub.4 (809 mg, 2.20 mmol) in 1,3,5-mesitylene (40 mL) was stirred for 16 h at 140° C. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA:Hex=1:1, v/v) to give C5-5 (3.80 g). MS:305 (M+H) +.

[0591] A mixture of C5-5 (3.80 g, 12.48 mmol) and (R)-(+)-2-Methyl-2-propanesulfinamide (3.03 g, 25.00 mmol) in Ti(OEt).sub.4 (38 mL) was stirred for 2 h at 100° C. After cooling to RT, the reaction mixture was diluted with EA (200 mL) and water (40 mL). The resulting mixture was filtered through a pad of Celite followed by EA (40 mL) wash. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give C5-6 (5.50 g). MS: 408 (M+H) +.

[0592] To a −40° C. solution of C5-6 (5.40 g, 13.25 mmol) in THF (50 mL) was added BH.sub.3 (1 M solution in THF, 40.00 mL). The resulting mixture was allowed to warm to RT and stirred for 3 h. The reaction mixture was quenched with MeOH (150 mL) and stirred at 80° C. for 20 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica chromatography (eluting with EA:Hex=1:1, v/v) to give C5-7 (3.78 g). MS: 410 (M+H) +.

[0593] To solution of C5-7 (3.70 g, 9.03 mmol) in EA (40 mL) was added HCl (4 M solution in EA, 15 mL), and stirred at RT for 17 h. The resulting mixture was filtered followed by EA (10 *2 mL) wash, and then the filter cake was concentrated under reduced pressure to give C5 (3.30 g) as a white solid. MS: 206 (M+H).sup.+.

Examnle 1

[0594] ##STR00070##

[0595] A solution of propane-1,2-diamine (11.00 mL, 129.11 mmol) in EtOH (220 mL) was cooled to 0° C. Diethyl 2-oxomalonate (20.00 mL, 131.15 mmol) was added to the solution dropwise. Then the cooling bath was removed. The solution was allowed to warmed to RT and stirred for 1 h. The clear solution had become a thick mixture. The mixture was warmed to reflux temperature and stirred for 24 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure to give compound 1-1 (27.12 g, crude) as a solid. MS: 183 [M+1].sup.+.

[0596] To a 0° C. solution of compound 1-1 (27.12 g, crude) in DMF (100 mL) under nitrogen atmosphere was added NBS (21.30 g, 0.12 mol). The resulting mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was diluted with brine (100 mL) and EA (400 mL). The organic layer was separated, washed with water (2×100 mL) and brine (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:100, v/v) to give compound 1-2 (7.75 g) as a yellow solid. MS: 261 [M+1].sup.+. .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ12.72 (brs, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.44 (s, 3H), 1.28 (t, J=7.1 Hz, 1H).

[0597] To a solution of PPh.sub.3 (31.03 g, 80.18 mmol) in 1,4-dioxane (280 mL) was added NCS (10.77 g, 80.66 mmol). The resulting mixture was stirred for 30 min at RT. Compound 1-2 (6.96 g, 26.66 mmol) was added, the resulting mixture was warmed to 100° C. and stirred for 1 h. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:5, v/v) to give compound 1-3 (6.66 g) as a yellow oil. MS: 279 [M+1].sup.+.

[0598] A mixture of compound 1-3 (1.19 g, 4.26 mmol), (2,3-dichlorophenyl)boronic acid (1.21 g, 6.34 K.sub.2CO.sub.3 (2.42 g, 17.51 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (0.44 g, 0.54 mmol) in CH.sub.3CN/H.sub.2O (15 mL/1 mL) was stirred for 2.5 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA (50 mL) and washed with brine (2×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:30, v/v) to give compound 1-4 (0.67 g). MS: 345 [M+1].sup.+.

[0599] A mixture of compound 1-4 (0.67 g, 1.94 mmol), intermediate Cl (0.64 g, 2.33 mmol) and K.sub.2CO.sub.3 (2.70 g, 19.54 mmol) in CH.sub.3CN (15 mL) was stirred for 24 h at 100° C. After cooling to RT, the reaction mixture was diluted with EA (60 mL) and water (100 mL). The organic layer was separated, the aqueous layer was extracted with EA (1×50 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:50, v/v) to give example 1 (468 mg) as a yellow solid. MS: 511 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ7.65 (dd, J=7.9, 1.6 Hz, 1H), 7.47-7.34 (m, 3H), 7.29-7.14 (m, 3H), 4.40 (q, J=7.1 Hz, 2H), 4.02-3.91 (m, 3H), 3.41-3.37 (m, 1H), 3.32-3.30 (m, 1H), 3.19-3.15 (m, 1H), 2.85-2.81 (m, 1H), 2.27 (s, 3H), 1.94-1.82 (m, 2H), 1.62-1.55 (m, 1H), 1.46 (m, 1H), 1.39 (t, J=7.1 Hz, 3H).

[0600] The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

TABLE-US-00003 Ex No. Chemical Name Structure MS & .sup.1HNMR 2 (S)-1′-(5-(2,3- dichlorophenyl)-6- methylpyrazin-2-yl)-5,7- dihydrospiro[cyclo- penta[b]pyridine-6,4′- piperidin]-5-amine [00071] MS: 440 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.34 (d, J = 4.6 Hz, 1H), 8.05 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.61 (dd, J = 8.0, 1.5 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.32-7.25 (m, 2H), 4.38-4.33 (m, 2H), 4.03 (s, 1H), 3.29-3.22 (m, 3H), 2.96-2.90 (m, 1H), 2.19 (s, 3H), 1.96- 1.80 (m, 2H), 1.68-1.62 (m, 1H), 1.46- 1.39 (m, 1H).

Example 3

[0601] ##STR00072##

[0602] A mixture of example 1 (302 mg, 0.59 mmol) and LiOH (81 mg, 3.38 mmol) in MeOH/H.sub.2(20 mL/3 mL) was stirred for 4 h at 60° C. After cooling to RT, MeOH was removed under reduced pressure. The residue was dissolved in brine (50 mL), extracted with EA (3×40 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give example 3 (258 mg) as a light yellow solid. MS: 483 [M+1].sup.+.

[0603] Example 4

##STR00073##

[0604] A solution of example 3 (60 mg, 0.12 mmol), (Boc).sub.2O (0.50 mL, 2.18 mmol) and DIPEA (1.00 mL, 6.05 mmol) in DCM was stirred for 1 h at 40° C. The reaction solution was concentrated under reduced pressure to give compound 4-1 (0.39 g, crude), which was used in next step without further purification. MS: 583 [M+1].sup.+.

[0605] A solution of compound 4-1 (0.39 g, crude), NH.sub.4Cl (466 mg, 8.71 mmol), PyBOP (194 mg, 0.37 mmol) and DIPEA (0.50 mL, 3.03 mmol) in NMP (8 mL) was stirred for 2 h at 80° C. The reaction solution was diluted with EA (40 mL) and washed with brine (3×30 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 4-2 (0.37 g, crude) as a yellow oil, which was used in next step without further purification. MS: 582 [M+1].sup.+.

[0606] A mixture of compound 4-2 (0.37 g, crude) and HCl/EA (4 M, 3.00 mL, 12.00 mmol) in DCM (20 mL) was stirred for 2.5 h at RT. The reaction mixture was diluted with brine (50 mL) and the pH value was taken to 9 with NH.sub.3H.sub.2O (25%). The resulting mixture was extracted with DCM (1×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:10, v/v) to give example 4 (9 mg) as a light yellow solid. MS: 482 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ7.66 (d, J=9.4 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.48-7.29 (m, 5H), 4.39 (s, 1H), 4.13-4.00 (m, 2H), 3.39-3.35 (m, 1H), 3.31-3.28 (m, 1H), 3.24-3.12 (m, 2H), 2.29 (s, 3H), 2.03-1.88 (m, 2H), 1.73-1.62 (m, 2H).

Example 5

[0607] ##STR00074##

[0608] A mixture of intermediate A1 (504 mg, 2.76 mmol), compound 1-3 (769 mg, 2.75 mmol), Pd.sub.2(dba).sub.3 (127 mg, 0.14 mmol), XantPhos (144 mg, 0.25 mmol) and DIPEA (1.10 g, 8.51 mmol) in 1,4-dioxane (20 mL) was stirred for 3 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was quenched with brine (100 mL), extracted with EA (1×60 mL), the organic layer dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound 5-1 (489 mg) as a yellow solid. MS: 359 [M+1].sup.+.

[0609] Example 5 was synthesized in the manner similar to example 1, except compound 1-4 was replaced with compound 5-1. MS: 525 1M+11.sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ7.63 (d, J=5.5 Hz, 1H), 7.47-7.34 (m, 1H), 7.26-7.19 (m, 3H), 5.91 (d, J=5.5 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 4.06-3.98 (m, 2H), 3.97 (s, 1H), 3.43-3.35 (m, 2H), 3.18-3.14 (m, 1H), 2.85-2.81 (m, 1H), 2.49 (s, 3H), 1.96-1.76 (m, 2H), 1.64-1.57 (m, 1H), 1.48-1.42 (m, 1H), 1.39 (t, J=8.0 Hz, 3H).

[0610] The following examples were synthesized using the above procedure or modified procedure with the corresponding starting materials.

TABLE-US-00004 EX No Chemical Name Structure MS & .sup.1HNMR 6 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)-6-methyl- pyrazin-2-yl)-1,3-di- hydrospiro[indene-2,4′- piperidin]-1-amine [00075] MS: 453 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.16 (s, 1H), 7.60- 7.32 (m, 5H), 5.80 (s, 1H), 4.46-4.25 (m, 3H), 3.46-3.35 (m, 2H), 3.23- 3.08 (m, 2H), 2.45 (s, 3H), 1.89-1.57 (m, 4H). 7 (S)-1′-(6-amino-5- ((2,3-dichlorophenyl) thio)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyridine- 6,4′-piperidin]-5- amine [00076] MS: 473 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.36 (d, J = 4.7 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.62 (s, 1H), 7.37-7.22 (m, 2H), 7.13 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.33 (d, J = 13.4 Hz, 2H), 4.05 (s, 1H), 3.29-3.17 (m, 3H), 2.94 (d, J = 16.5 Hz, 1H), 1.98-1.75 (m, 2H), 1.70- 1.57 (m, 1H), 1.48-1.37 (m, 1H). 8 (S)-1′-(4-amino-5- ((2-amino-3-chloro- pyridin-4-yl)thio) pyrimidin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′- piperidin]-5-amine [00077] MS: 455 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.41 (d, J = 4.4 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 5.5 Hz, 1H), 7.31 (dd, J = 7.6, 5.2 Hz, 1H), 6.03 (d, J = 5.5 Hz, 1H), 4.62 (t, J = 13.3 Hz, 2H), 4.19 (s, 1H), 3.24 (m, 3H), 3.09-2.95 (m, 1H), 1.92-1.63 (m, 2H), 1.63- 1.42 (m, 2H). 9 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)pyridin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyridine- 6,4′-piperidin]-5- amine [00078] MS: 439 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.38 (d, J = 4.5 Hz, 1H), 8.21 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.72-7.55 (m, 2H), 7.38-7.26 (m, 1H), 6.97 (d, J = 9.0 Hz, 1H), 5.92 (d, J = 5.5 Hz, 1H), 4.43-4.26 (m, 2H), 4.10 (s, 1H), 3.32-3.19 (m, 3H), 3.03-2.91 (m, 1H), 1.98-1.79 (m, 2H), 1.70-1.60 (m, 1H), 1.54-1.44 (m, 1H). 10 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)-6-(methyl- amino)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyridine- 6,4′-piperidin]-5- amine [00079] MS: 469 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.36 (d, J = 4.3 Hz, 1H), 7.83 (d, J = 10.6 Hz, 1H), 7.73- 7.71,7.51-7.49 (m, 1H), 7.59 (dd, J = 9.9, 4.4 Hz, 1H), 7.29 (dd, J = 7.4, 5.2 Hz, 1H), 5.89-5.84 (m, 1H), 4.45- 4.13 (m, 2H), 4.06 (s, 1H), 3.31-3.13 (m, 3H), 3.07 (s, 1H), 2.88 (s, 3H), 2.00-1.77 (m, 2H), 1.67-1.63 (m, 1H), 1.47-1.43 (m, 1H). 11 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)-6-(dimethyl- amino)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyri- dine-6,4′-piperidin]- 5-amine [00080] MS: 483 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.36 (d, J = 4.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.72- 7.50 (m, 1H), 7.64-7.57 (m, 1H), 7.29 (dd, J = 7.5, 5.2 Hz, 1H), 5.89- 5.84 (m, 1H), 4.36 (t, J = 15.0 Hz, 2H), 4.07 (s, 1H), 3.31-3.16 (m, 3H), 3.10 (s, 3H), 3.06 (s, 1H), 2.88 (s, 3H), 1.98-1.77 (m, 2H), 1.71-1.57 (m, 1H), 1.71-1.44 (m, 1H). 12 (S)-1′-(6-amino-5- (thiazol-4-ylthio)pyr- azin-2-yl)-5,7-dihy- drospiro[cyclopenta [b]pyridine-6,4′-pi- peridin]-5-amine [00081] MS: 412 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 9.00 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 4.3 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.53 (s, 1H), 7.40- 7.34 (m, 1H), 7.20 (d, J = 2.0 Hz, 1H), 4.40-4.23 (m, 3H), 3.28-3.06 (m, 4H), 1.90-1.79 (m, 2H), 1.68-1.56 (m, 2H). 13 (S)-1′-(6-amino-5- (thiazol-2-ylthio)pyr- azin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′-pi- peridin]-5-amine [00082] MS: 412 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.41 (d, J = 4.7 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 3.4 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J = 3.4 Hz, 1H), 7.32 (dd, J = 7.5, 5.2 Hz, 1H), 4.45-4.29 (m, 2H), 4.17 (s, 1H), 3.31-3.20 (m, 3H), 3.08-2.96 (m, 1H), 1.97-1.78 (m, 2H), 1.70- 1.59 (m, 1H), 1.55-1.44 (m, 1H). 14 (S)-1′-(6-amino-5- (quinolin-3-ylthio) pyrazin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′- piperidin]-5-amine [00083] MS: 456 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.69 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 4.6 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 7.1 Hz, 2H), 7.33 (dd, J = 7.4, 5.2 Hz, 1H), 4.34 (t, J = 11.8 Hz, 2H), 4.17 (s, 1H), 3.30-3.19 (m, 3H), 3.08-2.95 (m, 1H), 1.92-1.82 (m, 2H) , 1.64 (d, J = 12.5 Hz, 1H), 1.51 (d, J = 12.2 Hz, 1H). 15 (S)-5-amino-1′-(5- ((2-amino-3-chloro- pyridin-4-yl)thio)pyr- idin-2-yl)-5,7-di- hydrospiro[cyclopenta [b]pyridine-6,4′-pi- peridine]-3-carboni- trile [00084] MS: 464 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.20 (d, J = 2.3 Hz, 1H), 7.74 (s, 1H), 7.67-7.56 (m, 2H), 7.45 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 5.91 (d, J = 5.6 Hz, 1H), 4.37-4.27 (m, 2H), 4.07 (s, 1H), 3.29- 3.19 (m, 3H), 2.98-2.93 (m, 1H), 1.95-1.85 (m, 2H), 1.79-1.74 (m, 1H), 1.63-1.60 (m, 1H). 16 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)pyrazin-2-yl)- N-methyl-1,3-di- hydrospiro[indene- 2,4′-piperidin]-1- amine [00085] MS: 453 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.36 (s, 1H), 8.31 (s, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.38-7.21 (m, 3H), 5.96 (d, J = 5.6 Hz, 1H), 4.37-4.27 (m, 1H), 4.25-4.16 (m, 1H), 3.86 (s, 1H), 3.53-3.39 (m, 2H), 3.09 (dd, J = 38.1, 15.9 Hz, 2H), 2.56 (s, 3H), 2.00- 1.92 (m, 1H),1.60-1.51 (m, 2H), 1.37-1.29 (m, 1H). 17 (S)-1′-(5-((3,5-dichloro- pyridin-4-yl)thio) pyrazin-2-yl)-5,6, 7-trifluoro-1,3-di- hydrospiro[indene-2, 4′-piperidin]-1-amine [00086] MS: 512 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.54 (s, 2H), 8.19- 8.05 (m, 2H), 7.06-6.97 (m, 1H), 4.33-3.97 (m, 3H), 3.46-3.34 (m, 2H), 3.09 (d, J = 16.3 Hz, 1H), 2.90 (d, J = 16.2 Hz, 1H), 1.95-1.84 (m, 1H), 1.76-1.60 (m, 2H), 1.59-1.46 (m, 1H). 18 (S)-1-amino-1′-(2- ((2-cyanopyridin-3- yl)thio)pyrimidin-5- yl)-1,3-dihydrospiro [indene-2,4′-piper- idine]-4-carbonitrile [00087] MS: 440 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.52 (s, 2H), 7.87- 7.82 (m, 2H), 7.80-7.76 (m, 2H), 7.56-7.52 (m, 2H), 3.91-3.68 (m, 3H), 3.28-3.08 (m, 4H), 1.86-1.78 (m, 2H), 1.76-1.63 (m, 2H). 19 (S)-1′-(5-((3-chloro- 2-methoxypyridin- 4-yl)thio)pyrazin-2- yl)-6-(methylthio)- 1,3-dihydrospiro [indene-2,4′-piperidin]- 1-amine [00088] MS: 500 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.30 (s, 1H), 8.26 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 4.43 (d, J = 13.8 Hz, 1H), 4.31 (d, J = 13.9 Hz, 1H), 4.13 (s, 1H), 3.28- 3.21 (m, 1H), 3.11 (dd, J = 33.5, 15.9 Hz, 3H), 2.60 (s, 3H), 1.94-1.74 (m, 4H), 1.40 (s, 9H). 20 (S)-1-(5-((5-(4-amino- 2-(tert-butyl)-4, 6-dihydrospiro[cyclo- penta[b]thiophene- 5,4′-piperidin]-1′- yl)pyrazin-2-yl)thio)- 2-chlorophenyl) ethan-1-onez [00089] MS: 527 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.30 (s, 1H), 8.26 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 4.43 (d, J = 13.8 Hz, 1H), 4.31 (d, J = 13.9 Hz, 1H), 4.13 (s, 1H), 3.28- 3.21 (m, 1H), 3.20-3.01 (m, 3H), 2.60 (s, 3H), 1.94-1.74 (m, 4H), 1.45- 1.36 (s, 9H). 21 (S)-1′-(5-((3-chloro- 2-(isopropylamino) pyridin-4-yl)thio) pyrazin-2-yl)-6-(methyl- sulfonyl)-1,3-di- hydrospiro[indene- 2,4′-piperidin]-1- amine [00090] MS: 559 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ 8.37 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.81-7.74 (m, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.65 (d, J = 5.7 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.91 (d, J = 5.5 Hz, 1H), 4.28-4.18 (m, 1H), 4.13 (s, 1H), 3.66-3.56 (m, 5H), 3.40- 3.37 (m, 1H), 3.15 (s, 3H), 1.88-1.82 (m, 2H), 1.72-1.67 (m, 2H), 1.27 (d, J = 6.5 Hz, 6H). 22 (S)-1′-(5-((2-amino- 3-chloropyridin-4- yl)thio)pyrazin-2-yl)- 5,7-dihydrospiro [cyclopenta[b]pyri- dine-6,4′-piperidin]- 7,7-d2-5-amine [00091] MS: 442 [M + 1].sup.+. .sup.1HNMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.35 (d, 1H), 8.29 (s, 1H), 7.70 (d, 1H), 7.67 (d, 1H), 7.20 (dd, 1H), 6.34 (s, 2H), 5.83 (d, 1H), 4.31 (d, 2H), 3.98 (s, 1H), 3.30-3.20 (m, 2H), 3.15 (s, 2H), 1.85-1.67 (m, 2H), 1.57 (d, 1H), 1.22 (d, 1H).

Example 23

[0611] ##STR00092##

[0612] To a 0° C. solution of example 1 (132 mg, 0.26 mmol) in THF (8 mL) under nitrogen atmosphere was added LiBH.sub.4 (2M/THF, 0.30 mL, 0.60 mmol). The resulting mixture was stirred for 16 h at 70° C. After cooling to RT, the reaction mixture was quenched with brine (50 mL), extracted with EA (3×40 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:16, v/v) to give example 23 (11 mg). MS: 469 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ7.63 (dd, J=7.9, 1.3 Hz, 1H), 7.50-7.39 (m, 2H), 7.37-7.24 (m, 4H), 4.69 (s, 2H), 4.29 (s, 1H), 3.80-3.58 (m, 2H), 3.26-2.96 (m, 4H), 2.26 (s, 3H), 3.01-1.89 (m, 2H), 1.74-1.59 (m, 2H).

[0613] The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

TABLE-US-00005 EX No Chemical Name Structure MS & .sup.1HNMR 24 (S)-(3-(1-amino-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-6-((2- amino-3-chloropyridin-4-yl) thio)-5-methylpyrazin-2- yl)methanol [00093] MS: 483 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 7.62 (d, J = 5.5 Hz, 1H), 7.54- 7.50 (m, 1H), 7.39-7.36 (m, 3H), 5.93 (d, J = 5.5 Hz, 1H), 4.68 (s, 2H), 4.38 (s, 1H), 4.14- 3.85 (m, 4H), 3.21-3.14 (m, 2H), 2.51 (s, 3H), 1.76-1.72 (m, 2H), 1.64-1.57 (m, 2H).

Example 25

[0614] ##STR00094##

[0615] To a 0° C. solution of example 2 (0.57 g, 1.29 mmol) in DCM (20 mL) was added NBS (0.35 g, 1.97 mmol). The resulting mixture was stirred for 4 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:30, v/v) to give example 25 (451 mg). MS: 518 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.34 (d, J=4.5 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.65 (dd, J=8.0, 1.5 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.36-7.32 (m, 1H), 7.29-7.25 (m, 1H), 4.09-4.07 (m, 1H), 3.97-3.92 (m, 2H), 3.25-3.16 (m, 3H), 2.95-2.89 (m, 1H), 2.68 (s, 3H), 2.03-1.99 (m, 2H), 1.70-1.65 (m, 1H), 1.51-1.47 (m, 1H).

Example 26 & Example 27

[0616] ##STR00095##

[0617] A mixture of example 25 (155 mg, 0.30 mmol), K.sub.4Fe(CN).sub.6.3H.sub.2O (156 mg, 0.37 mmol), DBU (242 mg, 1.59 mmol) and Pd(PPh.sub.3).sub.4 (39 mg, 0.034 mmol) in t-BuOH/H.sub.2O (6 mL/6 mL) was stirred for 3.5 h at 100° C. under nitrogen atmosphere. After cooling to RT, the resulting mixture was quenched with brine (50 mL) and extracted with EA (2×30 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 26 (19 mg) and example 27 (25 mg).

[0618] Example 26: MS: 465 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.39 (d, J=4.7 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.66 (dd, J=8.0, 1.4 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.35 (dd, J=7.6, 1.4 Hz, 1H), 7.32-7.28 (m, 1H), 4.55-4.49 (m, 2H), 4.18 (s, 1H), 3.52-3.43 (m, 2H), 3.26-3.24 (m, 1H), 3.04-2.99 (m, 1H), 2.29 (s, 3H), 2.03-1.91 (m, 2H), 1.76-1.66 (m, 1H), 1.60-1.54 (m, 1H).

[0619] Example 27: MS: 483 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.42 (d, J=4.5 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.62 (dd, J=7.3, 2.3 Hz, 1H), 7.47-7.37 (m, 2H), 7.32 (dd, J=7.5, 5.2 Hz, 1H), 4.24 (s, 1H), 4.13-3.97 (m, 2H), 3.39-3.33 (m, 1H), 3.29-3.20 (m, 2H), 3.09-2.99 (m, 1H), 2.26 (s, 3H), 2.02-1.87 (m, 2H), 1.66-1.50 (m, 2H).

Example 28

[0620] ##STR00096##

[0621] A mixture of example 25 (64 mg, 0.12 mmol) and HCl/EA (4 M, 4 mL) was stirred for 1 h at RT. The reaction mixture was filtered followed by EA wash. The solid was dissolved in EA (20 mL) and washed with NH.sub.3H.sub.2O (10%, 20 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure and dried under high vacuum for 2 h to give example 28 (17 mg) as a yellow solid. MS: 456 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.37 (d, J=4.7 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.67 (dd, J=8.0, 1.4 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.38-7.34 (m, 1H), 7.32-7.28 (m, 1H), 4.11 (s, 1H), 4.04-3.99 (m, 2H), 3.28-3.21 (m, 3H),2.98-2.93 (m, 1H) , 2.27 (s, 3H), 2.10-1.98 (m, 2H), 1.73-1.67(d, J=11.9 Hz, 2H).

Example 29 & Example 30 & Example 31

[0622] ##STR00097##

[0623] A mixture of 1,2-dichloro-3-iodobenzene (575 mg, 3.13 mmol), sodium 3-amino-5-chloropyrazine-2-thiolate (813 mg, 2.98 mmol), Pd.sub.2(dba).sub.3 (134 mg, 0.15 mmol), XantPhos (176 mg, 0.30 mmol) and DIPEA (1.41 g, 10.92 mmol) in 1,4-dioxane (20 mL) was stirred for 3 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give compound 29-1 (0.41 g). MS: 306 [M+1].sup.+.

[0624] To a 0° C. solution of compound 29-1 (0.40 g, 1.31 mmol) in DCM (20 mL) was added NBS (0.32 g, 1.80 mmol). The resulting mixture was stirred for 17 h at RT. The reaction mixture was diluted with EA (50 mL) and brine (100 mL). The aqueous layer was separated, extracted with EA (1×50 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 29-2 (0.43 g) as a brown solid.

[0625] A mixture of compound 29-2 (0.43 g, 1.11 mmol), intermediate C2 (0.43 g, 1.38 mmol) and K.sub.2CO.sub.3 (1.60 g, 11.58 mmol) in CH.sub.3CN (20 mL) was stirred for 5 h at 100° C. After cooling to RT, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give example 29 (191 mg) an a brown solid. MS: 551 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.35 (d, J=4.6 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.35 (dd, J=8.0, 1.2 Hz, 1H), 7.28 (dd, J=7.5, 5.2 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.77 (dd, J=8.0, 1.2 Hz, 1H), 4.14-3.95 (m, 3H), 3.28-3.12 (m, 3H), 2.91 (d, J=16.5 Hz, 1H), 2.08-1.93 (m, 2H), 1.70-1.59 (m, 1H), 1.50-1.42 (m, 1H).

[0626] A mixture of example 29 (173 mg, 0.31 mmol), K.sub.4Fe(CN).sub.6.3H.sub.2O (168 mg, 0.40 mmol), DBU (240 mg, 1.58 mmol) and Pd(PPh.sub.3).sub.4 (35 mg, 0.030 mmol) in t-BuOH/H.sub.2O (1/1, 16 mL) was stirred for 16 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:12, v/v) to give example 30 (117 mg) as a yellow solid. MS: 498 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.37 (d, J=4.9 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.42-7.38 (m, 1H), 7.34-7.27 (m, 1H), 7.23-7.11 (m, 1H), 6.89-6.86, 6.68-6.65 (m, 1H), 4.55-4.43 (m, 1H), 4.38-4.26 (m, 1H), 4.15-3.99 (m, 1H), 3.65 (t, J=6.9 Hz, 1H), 3.25-3.12 (m, 2H), 3.02-2.91 (m, 1H), 2.13-1.81 (m, 2H), 1.65-1.59 (m, 1H), 1.50-1.42 (m, 1H).

[0627] A mixture of example 30 (105 mg, 0.21 mmol) in sulfuric acid (98%, 5 mL) was stirred for 16 h at 80° C. After cooling to RT, the reaction mixture was poured into water and the pH value was taken to 10 with NH.sub.3H.sub.2O (25%). The resulting mixture was extracted with EA (2×50 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 31 (30 mg). MS: 516 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.36 (d, J=4.6 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.36 (dd, J=8.0, 1.1 Hz, 1H), 7.29 (dd, J=7.5, 5.2 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.81 (dd, J=8.0, 1.1 Hz, 1H), 4.07 (s, 1H), 3.99 (d, J=13.7 Hz, 2H), 3.30-3.17 (m, 3H), 2.93 (d, J=16.5 Hz, 1H), 2.03-1.86 (m, 2H), 1.64-1.55 (m, 1H), 1.46-1.40 (m, 1H).

Example 32

[0628] ##STR00098##

[0629] Compound 32-1 was synthesized in the manner of compound 5-1, except compound 1-3 was replaced with 6-chloro-3-iodopyridin-2-amine.

[0630] A mixture of compound C2-6 (351 mg, 0.86 mmol) and TFA (1 mL) in DCM (20 mL) was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. Compound 32-1 (200 mg, 0.70 mmol), Pd(OAc).sub.2 (33 mg, 0.15 mmol), DavePhos (65 mg, 0.17 mmol), t-BuOK (1.21 g, 10.78 mmol) and toluene (30 mL) was added. The resulting mixture was stirred for 18 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with water (100 mL) and extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 32-2 (0.37 g) as a brown solid. MS: 558 [M+1].sup.+.

[0631] A mixture of compound 32-2 (0.37 g, 0.66 mmol) and HCl/EA (4 M, 3.00 mL, 12.00 mmol) in DCM (20 mL) was stirred for 30 min at RT. The resulting mixture was diluted with water (50 mL) and the pH value was adjusted to 9 with NH.sub.3H.sub.2O (25%). The resulting mixture was extracted with DCM (1×50 mL), the organic layer dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 32 (10 mg). MS: 454 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.43 (dd, J=13.1, 4.3 Hz, 1H), 7.96-7.88 (m, 1H), 7.60 (d, J=5.2 Hz, 1H), 7.43-7.29 (m, 2H), 6.24 (d, J=8.5 Hz, 1H), 6.01 (d, J=5.2 Hz, 1H), 4.42-4.15 (m, 3H), 3.26-3.08 (m, 4H), 1.86-1.77 (m, 2H), 1.59-1.43 (m, 2H).

Example 33

[0632] ##STR00099##

[0633] A mixture of compound C2-6 (552 mg, 1.35 mmol) and TFA (2.50 mL) in DCM (30 mL) was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. 2-Bromo-5-iodopyridine (354 mg, 1.25 mmol), Pd.sub.2(dba).sub.3 (66 mg, 0.072 mmol), BINAP (86 mg, 0.14 mmol), t-BuOK (3204 mg, 28.55 mmol) and toluene (20 mL) was added. The resulting mixture was stirred for 21 h at 100° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA (50 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give compound 33-1 (392 mg) as a yellow solid. MS: 463 [M+1].sup.+.

[0634] A mixture of compound 33-1 (184 mg, 0.40 mmol), intermediate Al (80 mg, 0.44 mmol), Pd.sub.2(dba).sub.3 (41 mg, 0.045 mmol), XantPhos (55 mg, 0.095 mmol) and DIPEA (193 mg, 1.49 mmol) in 1,4-dioxane (20 mL) was stirred for 16 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:12, v/v) to give compound 33-2 (127 mg). MS: 543 [M+1].sup.+.

[0635] A mixture of compound 33-2 (127 mg, 0.23 mmol) and HCl/EA (4 M, 3.00 mL, 12.00 mmol) in DCM (20 mL) was stirred for 1.5 h at RT. The reaction mixture was diluted with water (50 mL) and the pH value was adjusted to 9 with NH.sub.3H.sub.2O (25%). The resulting mixture was extracted with DCM (2×50 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 33 (28 mg). MS: 439 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.45-8.34 (m, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.67-7.54 (m, 2H), 7.53-7.44 (m, 1H), 7.37-7.25 (m, 1H), 5.95 (d, J=5.5 Hz, 1H), 4.11 (s, 1H), 3.93-3.75 (m, 2H), 3.28-3.10 (m, 3H), 3.01-2.83 (m, 1H), 2.07-1.84 (m, 2H), 1.76-1.66 (m, 1H), 1.57-1.45 (m, 1H).

Example 34

[0636] ##STR00100##

[0637] 1-Bromo-4-fluorobenzene (3.69 g, 21.09 mmol), intermediate C2 (0.95 g, 3.04 mmol), K.sub.2CO.sub.3 (5.21 g, 37.70 mmol) and NMP (6 mL) was added to a 15 mL sealed tube. The resulting mixture was stirred for 6.5 h at 140° C. An additional batch of 1-bromo-4-fluorobenzene (1.22 g, 6.97 mmol) was added and the resulting mixture was stirred for 18 h at 160° C. After cooling to RT, the reaction mixture was poured into water (50 mL) and extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:15, v/v) to give compound 34-1 (249 mg) as a brown oil. MS: 358 [M+1].sup.+.

[0638] A mixture of compound 34-1 (120 mg, 0.33 mmol), intermediate Al (65 mg, 0.36 mmol), Pd.sub.2(dba).sub.3 (61 mg, 0.067 mmol), XantPhos (83 mg, 0.14 mmol) and DIPEA (303 mg, 2.34 mmol) in 1,4-dioxane (10 mL) was stirred for 18 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give example 34 (47 mg). MS: 438 [M+1].sup.+..sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.47 (d, J=4.6 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.56 (d, J=5.5 Hz, 1H), 7.43 (d, J=8.7 Hz, 2H), 7.39-7.33 (m, 1H), 7.13 (d, J=8.7 Hz, 2H), 5.88 (d, J=5.5 Hz, 1H), 4.31 (s, 1H), 3.87-3.74 (m, 2H), 3.27-3.02 (m, 4H), 2.02-1.91 (m, 2H), 1.73-1.60 (m, 2H).

[0639] The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

TABLE-US-00006 EX No Chemical Name Structure MS & .sup.1HNMR 35 (S)-1′-(4-((2-amino- 3-chloropyridin-4- yl)thio)isoquinolin-1- yl)-1,3-dihydrospiro [indene- 2,4′-piperidin]-1-amine [00101] MS: 488 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 8.38 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.47-7.32 (m, 5H), 5.63 (d, J = 5.6 Hz, 1H), 4.48 (s, 1H), 4.06-3.87 (m, 2H), 3.52-3.37 (m, 2H), 3.21 (d, J = 7.5 Hz, 1H), 2.25-2.06 (m, 2H), 1.89-1.83 (m, 1H), 1.79-1.72 (m, 1H).

Example 36

[0640] ##STR00102##

[0641] To a solution of 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (10.00 g, 62.28 mmol) in EtOH (200 mL) was added hydrazine hydrate (80%, 52.00 mL) at RT. The resulting mixture was stirred for 4 h at 80° C. After cooling to RT, the reaction mixture was concentrated to about 100 mL under reduced pressure and filtered. The filtered cake was washed with EtOH (2×50 mL). The filtered cake was collected and dried in a high vacuum oven to give compound 36-1 (5.56 g) as a light yellow solid. MS: 157 [M+1].sup.+.

[0642] A mixture of compound 36-1 (5.56 g, 35.61 mmol) and 4-methoxybenzaldehyde (7.02 g, 51.56 mmol) in MeOH was stirred for 6 h at 70° C. After cooling to RT, the reaction mixture was filtered and the filtered cake was washed with MeOH. The filtered cake was collected and dried under high vacuum to give compound 36-2 (5.78 g) as a yellow solid. MS: 275 [M+1].sup.+.

[0643] A mixture of compound 36-2 (2.03 g, 7.40 mmol), 2,3-dichlorobenzaldehyde (1.36 g, 7.77 mmol) and piperidine (0.77 g, 9.04 mmol) in DMF/iPrOH (20 mL/10 mL) was stirred for 18 h at 85° C. After cooling to RT, the reaction mixture was diluted with EA (200 mL) and washed with brine (2×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound 36-3 (2.40 g) as a light yellow solid. MS: 431 [M+1].sup.+.

[0644] A mixture of compound 36-3 (197 mg, 0.46 mmol) and BOP (649 mg, 1.47 mmol) in DMF (17 mL) was stirred for 10 min at RT. Then DBU (748 mg, 4.91 mmol) and C2 (229 mg, 0.73 mmol) was added and stirred for 20 h at RT. The reaction mixture was diluted with EA (100 mL) wad washed with brine (3×100 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:8, v/v) to give compound 36-4 (210 mg). MS: 615 [M+1].sup.+.

[0645] A mixture of compound 36-4 (210 mg, 0.34 mmol) and TFA (15 mL) was stirred for 1.5 h at 100° C. The reaction mixture was diluted with water (100 mL) and the pH value was taken to 10 with NH.sub.3H.sub.2O (25%). The resulting mixture was extracted with DCM (2×50 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give example 36 (21 mg). MS: 496 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.38 (d, J=4.7 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.65 (dd, J=7.9, 1.5 Hz, 1H), 7.46 (dd, J=7.6, 1.5 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.31 (dd, J=7.4, 5.2 Hz, 1H), 4.14 (s, 1H), 3.68-3.58 (m, 2H), 3.55 (s, 3H), 3.29-3.12 (m, 3H), 3.01-2.90 (m, 1H), 2.15-1.96 (m, 2H), 1.74-1.65 (m, 1H), 1.57-1.45 (m, 1H).

[0646] The following example was synthesized using the above procedure or modified procedure with the corresponding starting materials.

TABLE-US-00007 EX No Chemical Name Structure MS & .sup.1HNMR 37 (S)-6-(1-amino-6-fluoro- 1,3-dihydrospiro[indene- 2,4′-piperidin]- 1′-yl)-3-(2,3-dichloro phenyl)-5-methyl-1,5- dihydro-4H- pyrazolo[3,4- d]pyrimidin-4-one [00103] MS: 513 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 7.65 (dd, J = 7.9, 1.7 Hz, 1H), 7.45 (dd, J = 7.6, 1.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.26 (dd, J = 8.2, 5.1 Hz, 1H), 7.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.03-6.93 (m, 1H), 4.10 (s, 1H), 3.63-3.55 (m, 2H), 3.54 (s, 3H), 3.25-3.09 (m, 3H), 2.88-2.79 (m, 1H), 2.10-1.95 (m, 2H), 1.72- 1.65 (m, 1H), 1.57-1.49 (m, 1H). 38 (S)-6-(1-amino-5,6,7- trifluoro-1,3- dihydrospiro[indene- 2,4′-piperidin]-1′-yl)-5- methyl-3-(5- methylthiophen- 2-yl)-1,5-dihydro-4H- pyrazolo[3,4-d] pyrimidin-4-one [00104] MS: 501 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 8.22 (d, J = 3.6 Hz, 1H), 7.10-6.99 (m, 1H), 6.81 (d, J = 3.5 Hz, 1H), 4.28 (s, 1H), 3.59 (s, 3H), 3.57-3.43 (m, 2H), 3.26-3.15 (m, 4H), 2.54 (s, 3H), 1.92-1.76 (m, 4H).

Example 39

[0647] ##STR00105## ##STR00106##

[0648] A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.53 g, 13.46 mmol), (4-methoxyphenyl)methanol (2.00 mL) and t-BuOK/THF (1 M, 53.00 mL, 53.00 mmol) in 1,4-dioxane (20 mL) was stirred for 2 h at RT. The reaction mixture was quenched with sat.aq.NH.sub.4Cl and extracted with EA (2×100 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 39-1 (4.22 g) as a light yellow solid which was used in next step without further purification. MS: 290 [M+1].sup.+.

[0649] A mixture of compound 39-1 (4.22 g, 14.57 mmol) and NBS (2.96 g, 16.63 mmol) in DMF (35 mL) was stirred for 20 min at RT. The reaction mixture was diluted with sat.aq.Na.sub.2SO.sub.3 (200 mL), extracted with EA (2×100 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 39-2 (4.76 g) as a brown solid which was used in next step without further purification. MS: 368 [M+1].sup.+.

[0650] A mixture of compound 39-2 (4.76 g, 12.91 mmol), (Boc).sub.2O (2.97 g, 13.61 mmol), DIPEA (5.05 g, 39.07 mmol) in DMF (40 mL) was stirred for 16 h at RT. To the mixture was added DMAP (52 mg, 0.43 mmol) and stirred for another 1 h at 40° C. The reaction mixture purified by silica gel chromatography (eluting with EA:Hex=1:30, v/v) to give compound 39-3 (2.82 g) as a white solid. MS: 468 [M+1].sup.+.

[0651] A mixture of compound 39-3 (500 mg, 1.07 mmol), (2,3-dichlorophenyl)boronic acid (215 mg, 1.13 mmol), K.sub.2CO.sub.3 (606 mg, 4.38 mmol) and Pd(dppf)C.sub.2 (102 mg, 0.14 mmol) in THF/H.sub.2O (5.0 mL/0.5 mL) was stirred for 3 h at 90° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with brine (50 mL), extracted with EA (2×50 mL). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give compound 39-4 (380 mg). MS: 534 [M+1].sup.+.

[0652] A mixture of compound 39-4 (241 mg, 0.56 mmol), C2 (210 mg, 0.67 mmol) and K.sub.2CO.sub.3 (1903 mg, 13.77 mmol) in NMP (15 mL) was stirred for 23 h at 140° C. After cooling to RT, the reaction mixture was diluted with EA (100 mL) and washed with brine (3×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:10, v/v) to give compound 39-5 (39 mg) as a brown solid. MS: 601 [M+1].sup.+.

[0653] A mixture of compound 39-5 (38 mg, 0.063 mmol) and TFA (2 mL) in DCM (10 mL) was stirred for 1 h at RT. The reaction mixture was diluted with brine (50 mL) and the pH value was taken to 10 with NH.sub.3H.sub.2O (25%). The resulting mixture was extracted with DCM (2×30 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:6, v/v) to give example 39 (12 mg). MS: 481 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.43 (d, J=4.7 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.42 (dd, J=7.8, 1.5 Hz, 2H), 7.33 (dd, J=7.5, 5.2 Hz, 1H), 7.28-7.21 (m, 1H), 6.87 (s, 1H), 4.28-4.18 (m, 2H), 4.16 (s, 1H), 3.31-3.20 (m, 3H), 3.05-2.94 (m, 1H), 1.98-1.82 (m, 2H), 1.65-1.58 (m, 1H), 1.51-1.45 (m, 1H).

Example 40

[0654] ##STR00107##

[0655] A mixture of 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (0.50 g, 3.54 mmol) and PyBOP (5.62 g, 10.80 mmol) in DMF (15 mL) was stirred for 10 min at RT. Then DBU (5.62 g, 36.92 mmol) and Cl (1.39 g, 5.05 mmol) was added and stirred for 3 h at RT. The reaction mixture was diluted with EA (100 mL) wad washed with brine (3×100 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:5, v/v) to give compound 40-1 (1135 mg) as a yellow oil. MS: 326 [M+1].sup.+.

[0656] A mixture of compound 40-1 (1.13 g, 3.47 mmol) and NIS (859 mg, 3.82 mmol) in DMF (10 mL) was stirred for 17 h at RT. The reaction mixture was diluted with EA (200 mL) and washed sat.aq.Na.sub.2SO.sub.3 with EA (2×80 mL) and sat.aq.NH.sub.4Cl (1×80 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:8, v/v) to give compound 40-2 (828 mg). MS: 452 [M+1].sup.+.

[0657] A mixture of compound 40-2 (103 mg, 0.23 mmol), intermediate Al (48 mg, 0.26 mmol), Pd.sub.2(dba).sub.3 (21 mg, 0.023 mmol), XantPhos (25 mg, 0.043 mmol) and DIPEA (103 mg, 0.80 mmol) in 1,4-dioxane (10 mL) was stirred for 15 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was filtered through Kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by Prep—TLC (eluting with MeOH:DCM=1:10, v/v) to give example 40 (12 mg). MS: 484 [M+1].sup.+..sup.1HNMR (400 MHz, methanol-d.sub.4) δ7.62 (d, J=5.5 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.45-7.32 (m, 3H), 6.19 (d, J=5.5 Hz, 1H), 4.42 (s, 1H), 3.80-3.63 (m, 2H), 3.47 (s, 3H), 3.30-3.09 (m, 4H), 2.11-1.89 (m, 2H), 1.75 (d, J=12.9 Hz, 1H), 1.66 (d, J=13.2 Hz, 1H).

Example 41

[0658] ##STR00108##

[0659] A mixture of 2,4-dichlorothiazole (1.54 g, 10.00 mmol), sodium 3-amino-5-chloropyrazine-2-thiolate -(2.77 g, 15.10 mmol) and K.sub.2CO.sub.3 (2.92 g, 21.10 mmol) in DMF (15 mL) was stirred for 3 h at 75° C. After cooling to RT, the reaction mixture was diluted with EA (50 mL) and water (50 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:5, v/v) to give compound 41-1 (281 mg) as a yellow solid. MS: 279 [M+1].sup.+.

[0660] To a solution of intermediate C3 (288 mg, 0.70 mmol) in DCM (17 mL) was added TFA (2 mL), and stirred for 1.5 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in NMP (5 mL), 41-1 (232 mg, 1.19 mmol) and K.sub.2CO.sub.3 (1.18 g, 8.52 mmol) was added. The resulting mixture was stirred for 16 h at 95° C. After cooling to RT, the reaction mixture was diluted with water (30 mL) and EA (30 mL). The aqueous layer was separated and extracted with EA (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 41-2 (272 mg) as a red oil. MS: 556 [M+1-1].sup.+.

[0661] A mixture of compound 41-2 (254 mg, 0.43 mmol) and HC1/1, 4-dioxane (4M, 1 mL) in DCM was stirred for 30 min at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:8, v/v) to give 41 (34 mg) as a yellow solid. MS: 452 [M+1-1].sup.+..sup.1HNMR (400 MHz, methanol-d.sub.4) δ9.01 (s, 1H), 7.63 (s, 1H), 7.26 (s, 1H), 4.50-4.28 (m, 3H), 3.46-3.35 (m, 1H), 3.31-3.21 (m, 2H), 3.19-3.09 (m, 1H), 2.00-1.76 (m, 4H).

Example 42

[0662] ##STR00109##

[0663] A mixture of compound B2-1 (192 mg, 1.34 mmol), (S)-1-amino-1,3-dihydrospiro [indene-2,4′-piperidine]-6-carbonitrile dihydrochloride (406 mg, 1.35 mmol), K.sub.2CO.sub.3 (2132 mg, 15.43 mmol) and NMP (8 mL) was stirred for 1.5 h at 140° C. After cooling to RT, the reaction mixture was diluted with water (20 mL) and extracted with EA (2 A 50 mL). The combined organic layers were washed with brine (1 b 100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:10, v/v) to give compound 42-1 (202 mg) as a brown oil. MS: 335 [M+1].sup.+.

[0664] A mixture of compound 42-1 (202 mg, 0.60 mmol), NIS (167 mg, 0.74 mmol) and THF (8 mL) was stirred for 19 h at RT. The reaction mixture was diluted with brine (50 mL) and extracted with EA (2 2 50 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:20, v/v) to give compound 42-2 (79 mg) as a yellow solid. MS: 461 [M+1].sup.+.

[0665] A mixture of compound 42-2 (79 mg, 0.17 mmol), sodium 4-amino-5-bromopyrimidine-2-thiol (57 mg, 0.25 mmol), Pd.sub.2(dba).sub.3 (15 mg, 0.016 mmol), XantPhos (21 mg, 0.036 mmol) and DIPEA (75 mg, 0.58 mmol) in 1,4-dioxane (8 mL) was stirred for 2 h at 90° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:10, v/v) to give example 42 (15 mg) as a yellow solid. MS: 538 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.02 (s, 1H), 7.93 7.76 (m, 2H), 7.70 7.64 (m, 1H), 7.50 (d, J=7.5 Hz, 1H), 6.18 (d, J=8.0 Hz, 1H), 4.29 (s, 1H), 3.62 (s, 3H), 3.46 3.36 (m, 2H), 3.30 3.15 (m, 4H), 2.06 1.90 (m, 2H), 1.77 1.67 (m, 2H).

[0666] The following compound was synthesized in the similar manner of example 42.

TABLE-US-00008 EX No Chemical Name Structure MS & .sup.1HNMR 43 (S)-6-(1-amino-6- bromo-1,3-dihydrospiro [indene-2,4′-piperidin]-1′- yl)-3-((3-chloro-2- methoxypyridin- 4-yl)thio)-1- methylpyridin- [00110] MS: 561 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 7.93 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 5.5 Hz, 1H), 7.69 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.35 (d, J = 5.5 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 4.39 (s, 1H), 3.98 2(1H)-one (s, 3H), 3.62 (s, 3H), 3.21-2.90 (m, 6H), 2.10-1.95 (m, 2H), 1.79- 1.64 (m, 2H).

Example 44

[0667] ##STR00111##

[0668] Solution of 2,4-dibromothiazole (202 mg, 0.83 mmol), (S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-6-carbonitrile dihydrochloride (382 mg, 1.27 mmol) and TEA (1609 mg, 15.90 mmol) in DMF (8 mL) was stirred for 30 h at 90° C. The reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 44-1 (243 mg) as a light yellow solid. MS: 389 [M+1].sup.+.

[0669] A mixture of intermediate A2 (420 mg, 1.67 mmol), compound 44-1 (135 mg, 0.53 mmol), Pd(PPh.sub.3).sub.4 (127 mg, 0.11 mmol), Na.sub.2CO.sub.3 (1120 mg, 10.57 mmol), THF (20 mL) and H.sub.2O (2 mL) was stirred for 16 h at 90° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with brine (100 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:50, v/v) to give the crude product and was further purified by Prep—TLC (MeOH:DCM=1:40, v/v) to give example 44 (20 mg) as an off-white solid. MS: 515 [M+1].sup.+..sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.36 (s, 1H), 7.91 7.79 (m, 4H), 7.72 7.68 (m, 1H), 7.60 7.45 (m, 3H), 7.21 7.13 (m, 1H), 4.31 (s, 1H), 4.20 3.94 (m, 3H), 3.47 3.36 (m, 2H), 3.08 (m, 1H), 1.94 1.81 (m, 2H), 1.75 1.63 (m, 2H).

Example 45

[0670] ##STR00112##

[0671] A mixture of 1-bromo-2-chloro-3-methylbenzene (2.89 g, 14.06 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.43 g, 21.38 mmol), Pd(dppf)C.sub.2CH.sub.2C.sub.2 (1.21 g, 1.65 mmol), Na.sub.2CO.sub.3 (5.56 g, 52.46 mmol) in 1,4-dioxane (30 mL) was stirred for 22 hat 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:4, v/v) to give the compound 45-1 (2.17 g).

[0672] A mixture of compound 45-1 (1.00 g, 3.96 mmol), 3-bromo-6-chloropyrazin-2-amine (1.03 g, 4.94 mmol), Pd(dppf)C.sub.2CH.sub.2Cl.sub.2 (0.84 g, 1.15 mmol), K.sub.2CO.sub.3 (2.37 g, 17.15 mmol), CH.sub.3CN (40 mL) and H.sub.2O (4 mL) was stirred for 2 h at 110° C. under nitrogen atmosphere. After cooling to RT, the reaction mixture was diluted with EA and filtered through a pad of Celite. The filtrate was washed with brine, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:15, v/v) to give the compound 45-2 (2.17 g). MS: 254 [M+1].sup.+.

[0673] A mixture of compound 45-2 (102 mg, 0.40 mmol), (S)-6-bromo-1,3-dihydrospiro[indene-2,4′-piperidin]-1-amine dihydrochloride (205 mg, 0.42 mmol), K.sub.2CO.sub.3 (1562 mg, 11.30 mmol) and CH.sub.3CN (20 mL) was stirred for 16 h at 100° C. After cooling to RT, the reaction mixture was diluted with EA (50 mL) filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:12, v/v) to give example 45 (89 mg) as a yellow solid. MS: 498 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ7.61 (s, 1H), 7.49-7.43 (m, 2H), 7.38 (d, J=7.0 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.23 (dd, J=10.8, 7.9 Hz, 2H), 4.24 (t, J=13.6 Hz, 2H), 4.17 (s, 1H), 3.25-3.10 (m, 3H), 2.92 (d, J=16.2 Hz, 1H), 2.46 (s, 3H), 1.92-1.74 (m, 2H), 1.65-1.47 (m, 2H).

[0674] The following examples were synthesized in the similar manner of example 45.

TABLE-US-00009 EX No Chemical Name Structure MS & .sup.1HNMR 46 (S)-1′-(5-(3-amino-2- (trifluoromethyl)phenyl) pyrimidin-2-yl)-1,3- dihydrospiro[indene-2,4′- piperidine]-1,6-diamine [00113] MS: 455 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 8.63 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H) 7.12 (d, J = 8.0 Hz, 2H), 6.89-6.72 (m, 3H), 4.68-4.53 (m, 2H), 4.23 (s, 1H), 3.44-3.37 (m, 2H), 3.09-3.03 (m, 2H), 1.76-1.61 (m, 4H). 47 (S)-1′-(6-amino-5-(2- chloro-3-methylphenyl) pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′- piperidine]-1,6-diamine [00114] MS: 435 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 7.46 (s, 1H), 7.38 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.24-7.18 (m, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.74 (dd, J = 8.0, 2.0 Hz, 1H), 4.35- 4.07 (m, 3H), 3.28-3.09 (m, 2H), 3.07-2.90 (m, 2H), 2.45 (s, 3H), 1.88- 1.73 (m, 2H), 1.70-1.56 (m, 2H). 48 (S)-1′-(6-(5- chlorothiophen- 2-yl)pyridazin-3-yl)-5- methyl-1,3-dihydrospiro [indene-2,4′- piperidin]-1-amine [00115] MS: 411 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 7.83 (d, J = 9.7 Hz, 1H), 7.42-7.31 (m, 3H), 7.21 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 4.45-4.36 (m, 1H), 4.33 (s, 1H), 4.26-4.15 (m, 1H), 3.45- 3.34 (m, 2H), 3.17 (s, 2H), 2.38 (s, 3H), 1.95-1.84 (m, 1H), 1.83-1.70 (m, 2H), 1.68-1.56 (m, 1H). 49 (S)-1′-(6′-chloro-[3,3′- bipyridazin]-6-yl)-5- methyl-1,3-dihydrospiro [indene-2,4′- piperidin]-1-amine [00116] MS: 407 [M + 1].sup.+. .sup.1HNMR (400 MHz, methanol - d.sub.4) δ 8.63 (d, J = 9.1 Hz, 1H), 8.43 (d, J = 9.7 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.46 (d, J = 9.7 Hz, 1H), 7.19 (s, 1H), 7.18-7.11 (m, 2H), 4.50 (d, J = 13.8 Hz, 1H), 4.40-4.35 (m, 1H), 4.28-4.25 (m, 1H), 3.48- 3.43 (m, 2H), 3.18-3.11 (m, 2H), 2.37 (s, 3H), 1.94-1.78 (m, 4H).

Example 50

[0675] ##STR00117## ##STR00118##

[0676] A solution of compound C1-4 (1.90 g, 4.67 mmol) and TFA (6.00 mL) in DCM (20 mL) was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. 3,5-Dichloropyrazine-2-carbonitrile (818 mg, 4.70 mmol), DMSO (8 mL) and DIPEA (6.56 g, 50.76 mmol) was added and stirred for 1 h at 70° C. The reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:2, v/v) to give compound 50-1 (1.81 g). MS: 444 [M+1].sup.+.

[0677] A mixture of compound 50-1 (1.81 g, 4.08 mmol), (4-methoxybenzyl)hydrazine hydrochloride (0.94 g, 4.98 mmol), TEA (4.60 g, 45.46 mmol) and EtOH (20 mL) was stirred for 18 h at 90° C. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EA (100 mL), washed with sat.aq.NH.sub.4Cl (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under high vacuum to give compound 50-2 (2.19 g) as a yellow solid. MS: 560 [M+1].sup.+.

[0678] A solution of compound 50-2 (1.58 g, 2.82 mmol), tert-butyl nitrite (0.36 g, 3.49 mmol) and CH.sub.2I.sub.2 (1.60 g, 5.97 mmol) in CH.sub.3CN (30 mL) was stirred for 1.5 h at 90° C. The reaction mixture was diluted with brine (150 mL), MeOH (20 mL) and extracted with EA (2×100 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. To the obtained red solid was added EA (20 mL), filtered and the filter cake was collected. The crude 50-3 (1.02 g) was used in next step without further purification. MS: 567 [M+1].sup.+.

[0679] A mixture of compound 50-3 (236 mg, 0.42 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (62 mg, 0.46 mmol), Pd2(dba)3 (77 mg, 0.084 mmol), BINAP (59 mg, 0.094 mmol) and t-BuONa (121 mg, 1.26 mmol) in toluene (10 mL) was stirred for 16 h at 90° C. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with MeOH:DCM=1:20, v/v) to give the crude product and was further purified by Prep TLC (MeOH:DCM=1:20, v/v) to give compound 50-4 (45 mg) as a yellow solid. MS: 573 [M+1].sup.+.

[0680] A mixture of compound 50-4 (34 mg, 0.059 mmol), TFA (3.0 mL), H.sub.2SO.sub.4 (98%, 0.2 mL) and anisole (0.5 mL) was stirred for 4 h at 90° C. The pH value of the reaction mixture was adjusted to 9 with sat.aq.Na.sub.2CO.sub.3. The resulting mixture was extracted with EA (2×20 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4 and concentrated reduced pressure. The residue was purified by Prep TLC (MeOH:DCM=1:10, v/v) to give example 50 (3 mg) as a light yellow solid. MS: 453 [M+1].sup.+.

Example 51

[0681] ##STR00119##

[0682] A mixture of 1-bromo-3-chloro-5-methoxybenzene (2.05 g, 9.26 mmol), 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (733 mg, 2.27 mmol) and DMF (15 mL) was stirred for 18 h at 50° C. The reaction mixture was quenched with water (15 mL) and extracted with EA (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 51-1 (2.60 g) as a white solid.

[0683] A mixture of 5-bromo-2-chloropyridine (100 mg, 0.52 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (145 mg, 0.57 mmol), Pd(dppf)C.sub.2 (19 mg, 0.026 mmol) and CH.sub.3COOK (153 mg, 1.56 mmol) in 1,4-dioxane (10 mL) was stirred for 2.5 h at 90° C. under nitrogen atmosphere. To the resulting mixture was added compound 51-1 (148 mg, 0.58 mmol), Pd(dppf)C.sub.2 (21 mg, 0.029 mmol), CH.sub.3COOK (154 mg, 1.57 mmol). The resulting mixture was stirred for 16 h at 70° C. After cooling to RT, the reaction mixture was diluted with water (20 mL) and extracted with EA (2×15 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with EA:Hex=1:10, v/v) to give the compound 51-2 (28 mg). MS: 288 [M+1].sup.+.

[0684] Example 51 was synthesized in the similar manner of example 1, except compound 1-4 was replaced with compound 51-2. MS: 454 [M+1].sup.+..sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.16 (d, J=2.3 Hz, 1H), 7.68 (dd, J=8.9, 2.5 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.43-7.29 (m, 3H), 7.14 (d, J=2.9 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 6.89 (d, J=2.9 Hz, 1H), 4.59 (s, 1H), 4.47-4.33 (m, 2H), 3.86 (s, J=7.9 Hz, 3H), 3.26-3.06 (m, 3H), 3.00-2.89 (m, 1H), 1.93-1.72 (m, 4H).

Example 52 & Example 53

[0685] ##STR00120##

[0686] Example 52 was prepared following procedures of example 51 from intermediate B2. MS: 442 [M+1].sup.+..sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.04 (dd, J=8.1, 1.5 Hz, 1H), 7.79-7.66 (m, 2H), 7.28 (t, J=7.9 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.28 (d, J=7.9 Hz, 1H), 4.20 (s, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.58 (t, J=6.0 Hz, 1H), 3.28-3.22 (m, 1H), 3.13-2.99 (m, 3H), 2.93-2.84 (m, 1H), 2.10-1.96 (m, 2H), 1.75-1.64 (m, 2H).

[0687] A solution of example 52 (10 mg, 0.023 mmol), KOH (40 mg, 0.71 mmol) in MeOH (2 mL) and H.sub.2O (2 mL) was stirred for 4 h at 100° C. The reaction mixture was diluted with water (5 mL), extracted with EA (2×5 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the example 53 (7 mg) as a yellow solid. MS: 460 [M+1].sup.+. .sup.1HNMR (400 MHz, methanol-d.sub.4) δ8.57 (d, J=4.7 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.75-7.68 (m, 1H), 7.66-7.54 (m, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.33-7.26 (m, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.19 (d, J=7.7 Hz, 1H), 4.27 (s, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 3.27-3.17 (m, 2H), 3.07-2.93 (m, 4H), 1.81-1.63 (m, 4H).

Example 54

[0688] ##STR00121##

[0689] To a −80° C. solution of 1-bromo-3-chloro-5-methoxybenzene (2.24 g, 10.11 mmol) in THF (50 mL) under nitrogen atmosphere was added n-BuLi (2.5 M, 7.40 mL, 18.50 mmol) dropwise. The resulting mixture was stirred for 40 min at −80° C. Then 1,4-dioxaspiro[4.5]decan-8-one (dissolved in 9 mL THF, 1.62 g, 10.37 mmol) was added dropwise and the resulting mixture was stirred for 40 min. The reaction mixture was quenched with brine (10 mL), diluted with water (100 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 54-1 (3.73 g) as a yellow oil.

[0690] A suspension of compound 54-1 (3.72 g, 13.25 mmol), Pd/C (Pd 10%, H.sub.2O 54.55%, 6.07 g) in MeOH (50 mL) was stirred for 2 h at RT under hydrogen atmosphere. The reaction mixture was filtered through a Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in acetone (60 mL) and HCl (aq, 2M, 20 mL) was added. The resulting mixture was stirred for 1 h at 60° C. The reaction mixture was diluted with water (50 mL) and extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give compound 54-2 (1.82 g) as a white solid. .sup.1H NMR (400 MHz, d-DMSO) 6 7.17 (t, J=8.1 Hz, 1H), 6.86-6.79 (m, 2H), 6.76-6.69 (m, 1H), 3.70 (s, 3H), 3.04-2.89 (m, 1H), 2.57-2.44 (m, 2H), 2.29-2.19 (m, 2H), 2.06-1.97 (m, 2H), 1.89-1.74 (m, 2H).

[0691] A solution of intermediate C2-6 (115 mg, 0.28 mmol), TFA (2 mL) and DCM (10 mL) was stirred for 1 h at RT. To the resulting mixture was added compound 54-2 (57 mg, 0.28 mmol), TsOH (5 mg) and NaBH(OAc).sub.3 (120 mg, 0.57 mmol). The resulting mixture was stirred for 3 days at RT. The reaction mixture was diluted with brine (30 mL) and extracted with DCM (2×30 mL), the organic layers combined, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by Prep—TLC (MeOH:DCM=1:15, v/v) to give compound 54-3 (30 mg) as a white solid. MS: 496 [M+1].sup.+.

[0692] A mixture of compound 54-3 (30 mg, 0.061 mmol) and HCl/EA (4 M, 1.00 mL, 4.00 mmol) in EA (10 mL) was stirred for 2.0 h at RT. The reaction mixture was diluted with water (20 mL) and the pH value was taken to 9 with NH.sub.3H.sub.2O (25%). The resulting mixture was extracted with EA (2×20 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give example 54 (8 mg) as a brown solid. MS: 392 [M+1].sup.+.

[0693] The following compounds were synthesized using the above procedure or modified procedure with the corresponding starting materials.

TABLE-US-00010 MS: EX Chemical Name Structure [M + 1].sup.+ 55 (S)-1-amino-1′-(6-((3-amino-2-chloro phenyl)thio)-1,2,4-triazin-3-yl)-1,3- dihydrospiro[indene-2,4′-piperidine]-6- carbonitrile [00122] 464 56 1-(5-((5-((1S)-1-amino-6-(methylsulfinyl)- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)pyrazin-2-yl)thio)-2- chlorophenyl)ethan-1-one [00123] 527 57 (S)-1′-(5-(pyrimidin-2-ylthio) pyrazin-2-yl)-6-(trifluoromethyl)- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1-amine [00124] 459 58 (S)-6-bromo-5-fluoro-1′-(5-(quinolin- 4-ylthio)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine [00125] 536 59 (S)-6-(4-amino-4,6-dihydrospiro [cyclopenta[b]thiophene-5,4′-piperidin]- 1′-yl)-3-(3-(trifluoromethyl)pyridin- 4-yl)-1,5-dihydro-4H-pyrazol[3,4- d]pyrimidin-4-one [00126] 488 60 (S)-2-(1-amino-6-chloro-5-methoxy- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-5-(3,5- dichloropyridin-4-yl)-3-methyl- 3,7-dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one [00127] 559 61 (S)-1′-(7-(5-chloropyridin-2-yl)-5H- pyrrolo[2,3-b]pyrazin-3-yl)-1,3- dihydrospiro[cyclopenta] naphthalene-2,4′-piperidin]- 3-amine [00128] 481 62 (S)-1′-(7-(3-chloropyridin-2-yl)-5H- pyrrolo[2,3-b]pyrazin-3-yl)-1H,3H- spiro[phenalene-2,4′-piperidin]- 1-amine [00129] 481 63 (R)-1′-(3-(2-methylpyridin-3-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-3,4- dihydro-1H-spiro[naphthalene-2,4′- piperidin]-3-amine [00130] 426 64 (S)-6-amino-2-(1-amino-7-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-3-methyl-5-phenylpyrimidin- 4(3H)-one [00131] 480 65 (S)-1-amino-1′-(4-amino-6-oxo-5- (pyridazin-3-ylthio)-1,6- dihydropyrimidin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-7-carbonitrile [00132] 447 66 (S)-1-amino-1′-(1-methyl-6-oxo-5- (pyrazin-2-yl)-1,6-dihydropyrimidin- 2-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-7-carbonitrile [00133] 414 67 (S)-2-(1-amino-6-chloro-5-methoxy- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-5-((4- isopropylphenyl)thio) pyrimidin-4(3H)-one [00134] 511 68 (S)-4-amino-6-(1-amino-6-bromo-5- fluoro-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-3-(2-chloro- 3-methylphenyl)-1-methylpyridin- 2(1H)-one [00135] 545 69 (S)-6-(4-acetyl-1-amino-1,3-dihydrospiro [indene-2,4′-piperidin]-1′- yl)-4-amino-3-(4-(trifluoromethyl) phenyl)pyridin-2(1H)-one [00136] 497 70 (S)-6′-(1-amino-4-hydroxy-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-2′-oxo- 1′,2′-dihydro-[3,3′- bipyridine]-2-carbonitrile [00137] 414 71 (S)-1′-(3-bromo-5-(1H-indol-6-yl)-6- methylpyrazin-2-yl)-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-4-amine [00138] 495 72 (S)-3-(4-amino-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-1′-yl)-5-methyl-6- (2-oxoindolin-7-yl)pyrazine-2- carbonitrile [00139] 458 73 (S)-1′-(5-amino-6-((2-amino-3-chloro pyridin-4-yl)thio)-1,2,4-triazin-3-yl)- 5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-5-amine [00140] 456 74 (S)-1′-(5-amino-6-((2-amino-3-chloro pyridin-4-yl)thio)pyridin-3-yl)-6- chloro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine [00141] 487 75 (S)-1′-(4-amino-5-((2-amino-3-chloro pyridin-4-yl)thio)pyridin-2-yl)-5,7- dihydrospiro[cyclopena[b] pyridine-6,4′-piperidin]-5-amine [00142] 454 76 (S)-1′-(5-((2,3-dichlorophenyl)thio) thiazol-2-yl)-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′- piperidin]-7-amine [00143] 463 77 (R)-1′-(4-((3-chloropyridin-4-yl)thio) thiazol-2-yl)spiro[indoline-2,4′- piperidin]-3-amine [00144] 430 78 (R)-1′-(2-(7-chloro-1H-indol-1-yl) thiazol-4-yl)-2,3-dihydrospiro [indene-1,4′-piperidin]- 2-amine [00145] 435 79 (R)-1′-(2-((2-(trifluoromethyl) phenyl)thio)thiazol-5-yl)-3H- spiro[benzofuran-2,4′- piperidin]-3-amine [00146] 464 80 (S)-(5-(1-amino-1,3-dihydrospiro [indene-2,4′-piperidin]-1′- yl)pyrazin-2-yl)(2,3- dichlorophenyl)methanone [00147] 453 81 (S)-2-(1-amino-6-fluoro-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-(indolin-1-yl)-3- methyl-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one [00148] 485 82 (S)-1′-(5-((1,2,3,4-tetrahydroquinolin- 8-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[b] naphthalene-2,4′- piperidin]-1-amine [00149] 494 83 (S)-1′-(5-((2-amino-3-chloropyridin- 4-yl)thio)pyrazin-2-yl)-1,3- dihydrospiro[cyclopenta[a] naphthalene-2,4′-piperidin]-1- amine [00150] 489 84 1′-(5-((3-amino-2-chlorophenyl)thio)- 6-methylpyrazin-2-yl)-1-methyl-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine [00151] 466 85 (R)-1′-(7-((2-amino-3-chloropyridin- 4-yl)thio)-1H-indol-4-yl)-3H-spiro [benzofuran-2,4′-piperidin]-3- amine [00152] 478 86 (S)-1′-(7-((2-amino-3-chloropyridin- 4-yl)thio)isoquinolin-3-yl)-5,6- dibromo-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine [00153] 644 87 (S)-4-((5-(5-acetyl-1-amino-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-3- aminopyrazin-2-yl)thio)-3-chloro- 1-methylpyridin-2(1H)-one [00154] 511 88 (S)-5-(1-amino-6-bromo-1,3-dihydro spiro[indene-2,4′- piperidin]-1′-yl)-2-(2,3- dichlorophenyl)thio)-6-(hydroxy methyl)pyridin-3-ol [00155] 480 89 (S)-6-bromo-1′-(5-(2,3-dichlorophenyl)- 6-methylimidazo[1,5-a]pyrazin-8- yl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine [00156] 556 90 (S)-1′-(7-((2-amino-3-chloropyridin- 4-yl)thio)-[1,2,5]thiadiazolo[3,4-c] pyridin-4-yl)-6-bromo-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine [00157] 574 91 (S)-1′-(8-((2-amino-3-chloropyridin- 4-yl)thio)pyrido[4,3-d]pyrimidin-5-yl)- 6-bromo-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine [00158] 568 92 (S)-3-(5-(1-amino-6-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)pyridin-2-yl)-4,5-dichlorophenol [00159] 470 93 (S)-1-amino-1′-(5-(5-methylthiophen- 2-yl)pyrazin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-6-ol [00160] 393 94 (S)-1′-(5-(1H-indol-7-yl)pyrazin-2-yl)- 5-ethyl-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine [00161] 424 95 (S)-1′-(5-(cyclohex-1-en-1-yl)pyrazin- 2-yl)-5-isopropyl-1,3-dihydrospiro [indene-2,4′-piperidin]-1- amine [00162] 403 96 (S)-N-(1-amino-1′-(5-(2- (trifluoromethyl)phenyl)pyrimidin- 2-yl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-6-yl) methanesulfonamide [00163] 518 97 (S)-1′-(5-((4-(trifluoromethyl) pyrimidin- 5-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[c] pyridine-6,4′-piperidin]-7-amine [00164] 460 98 (S)-1′-(5-((2-chloropyridin-3-yl)thio) pyrazin-2-yl)-5,7-dihydrospiro[cyclo penta[c]pyridine-6,4′-piperidin]-5- amine [00165] 425 99 (S)-4-((5-(5-amino-5,7-dihydrospiro [cyclopenta[d]pyrimidine-6,4′- piperidin]-1′-yl)pyrazin-2-yl)thio)- 3-chlorobenzoic acid [00166] 469 100 (S)-1′-(5-((3-(trifluoromethyl)pyrazin- 2-yl)thio)pyrazin-2-yl)-5,7- dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-7-amine [00167] 460 101 (S)-1′-(5-((3-chloropyridazin-4-yl)thio) pyrazin-2-yl)-5,7-dihydrospiro [cyclopenta[d]pyrimidine-6,4′- piperidin]-7-amine [00168] 427 102 (S)-4-((5-(5-amino-5,7-dihydrospiro [cyclopenta[b]pyrazine-6,4′- piperidin]-1′-yl)pyrazin-2-yl)thio)- 3-chlorobenzamide [00169] 468 103 (S)-(1-amino-1′-(5-((3-chloro-2- (methylamino)pyridin-4-yl)thio)pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-6-yl)dimethylphosphine oxide [00170] 529 104 (S)-1-amino-1′-(6-amino-5-((3-chloro- 2-(dimethylamino)pyridin-4-yl)thio) pyrazin-2-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-5-carboxylic acid [00171] 526 105 ethyl (S)-1-amino-1′-(5-((3-chloro-2- (methylamino)pyridin-4-yl)thio)pyrazin-2- yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-5-carboxylate [00172] 525 106 (S)-1′-(5-((3-(morpholinomethyl) phenyl)thio)pyrazin-2-yl)-6- (trifluoromethyl)-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine [00173] 556 107 (S)-6-bromo-5-fluoro-1′-(5-((3-(penta fluoro-16-sulfanyl)phenyl)thio)pyrazin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine [00174] 611 108 (S)-N-(3-((5-(1-amino-6-(methylthio)- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1′-yl)pyrazin-2-yl)thio)phenyl) cyclopropanecarboxamide [00175] 518 109 (S)-6-(6-amino-1-bromo-4H,6H-spiro [cyclopenta[c]thiophene-5,4′- piperidin]-1′-yl)-3-(m-tolyl)-1,5- dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one [00176] 511 110 (S)-2-(1-amino-5,6,7-trifluoro-1,3- dihydrospiro[indene-2,4′-piperidin]-1′- yl)-5-(3-ethylphenyl)-3-methyl-3,7- dihydro-4H-pyrrolo[2,3-d] pyrimidin-4-one [00177] 508 111 (R)-1′-(3-(3-(tert-butyl)phenyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-3,4- dihydro-1H-spiro[naphthalene-2,4′- piperidin]-3-amine [00178] 467 112 (S)-2-(3-amino-1,3-dihydrospiro [cyclopenta[a]naphthalene-2,4′- piperidin]-1′-yl)-5-(3- isopropylphenyl)-3,7-dihydro-4H- pyrrolo[2,3-d]pyrimidin-4-one [00179] 504 113 (S)-1-amino-1′-(3-(3-chloro-2- morpholinopyridin-4-yl)-4-oxo-4,5- dihydro-1H-pyrrolo[3,2-c]pyridin-6- yl)-5-fluoro-1,3-dihydrospiro [indene-2,4′-piperidine]- 6-carbonitrile [00180] 574 114 (S)-1′-(7-(3-chloro-2-(cyclobutylamino) pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-3- yl)-1,3-dihydrospiro[cyclopenta [a]naphthalene-2,4′-piperidin]- 3-amine [00181] 550 115 (S)-1′-(3-(3-chloro-2-(cyclopropylamino) pyridin-4-yl)-1H-pyrazolo[3,4-b] pyrazin-6-yl)-N6-methyl-1,3-dihydrospiro [indene-2,4′-piperidine]-1,6- diamine [00182] 516 116 (S)-5-amino-1′-(3-(3-chloro-2- (pyrrolidin-1-yl)pyridin-4-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-2-fluoro-5,7- dihydrospiro[cyclopenta[b]pyridine- 6,4′-piperidine]-3-carboxamide [00183] 563 117 1-(4-(6-((S)-4-amino-2-chloro-4,6- dihydrospiro[cyclopenta[d]thiazole-5,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-3-chloropyridin-2-yl) pyrrolidin-3-ol [00184] 558 118 (S)-1′-(3-(3-chloro-2-((cyclopropyl- methyl)amino)pyridin-4-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-N6,N6- dimethyl-1,3-dihydrospiro[indene- 2,4′-piperidine]-1,6-diamine [00185] 544 119 (S)-1′-(3-(2-amino-6-chloropyridin- 4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 2-(tert-butyl)-4,6-dihydrospiro [cyclopenta[b]thiophene-5,4′- piperidin]-4-amine [00186] 509 120 (S)-2-chloro-1′-(3-(1,3-dihydroiso- benzofuran-5-yl)-1H-pyrazolo[3,4-b] pyrazin-6-yl)-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-6-amine [00187] 480 121 (S)-3-chloro-1′-(3-((2-chlorophenyl) thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-5-amine [00188] 498 122 (S)-1′-(3-(3-chloro-2-(ethylamino)pyridin- 4-yl)-1H-pyrazolo[3,4-b]pyrazin- 6-yl)-4,6-dihydrospiro[cyclopenta [b]thiophene-5,4′-piperidin]-4-amine [00189] 481 123 (R)-1′-(7-(methyl(pyridin-4-yl)amino)- 5H-pyrrolo[2,3-b]pyrazin-3-yl)-3H- spiro[furo[2,3-b]pyridine-2,4′- pipendin]-3-amine [00190] 429 124 (R)-1′-(3-((3-chloropyridin-4-yl) amino)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 6,7-dihydrospiro[cyclopenta[b] pyridine-5,4′-piperidin]-6-amine [00191] 448 125 (S)-2-methoxy-1′-(3-(1-phenylvinyl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-4,6- dihydrospiro[cyclopenta[d]thiazole- 5,4′-piperidin]-4-amine [00192] 460 126 (R)-1-(3-benzyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)-1′,3′-dihydrospiro [piperidine-4,2′-pyrrolo[2,3-b] pyridin]-3′-amine [00193] 413 127 (S)-(6-(6-amino-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′-piperidin]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3- yl)(phenyl)methanone [00194] 432 128 (4S)-1′-(3-(1-phenylethyl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-4,6-dihydrospiro [cyclopenta[d]thiazole-5,4′- piperidin]-4-amine [00195] 432 129 1-(6-((S)-5-amino-2-methoxy-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4- b]pyrazin-3-yl)-1-phenylethan-1-ol [00196] 472 130 (S)-1′-(3-((2,3-dichloropyridin-4-yl) oxy)-1H-pyrazolo[3,4-b]pyrazin-6-yl)- 5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-5-amine [00197] 483 131 (S)-6-bromo-1′-(3-(5-(3,4-difluorophenyl)- 3,4-dihydroquinolin-1(2H)-yl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine [00198] 642 132 (S)-6-amino-2-(1-amino-6-bromo-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-(4-cyclopropoxyphenyl)-3- methylpyrimidin-4(3H)-one [00199] 536 133 (S)-N-(1-amino-1′-(4-amino-5-((4- (methylthio)phenyl)thio)-6-oxo-1,6- dihydropyrimidin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-6-yl)acetamide [00200] 523 134 (S)-2-(1-amino-6-(methylamino)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-(4-(benzyloxy)phenyl)-3- methylpyrimidin-4(3H)-one [00201] 522 135 (S)-2-(7-acetyl-1-amino-1,3-dihydrospiro [indene-2,4′-piperidin]-1′-yl)-5- (benzo[d][1,3]dioxol-4-ylthio) pyrimidin-4(3H)-one [00202] 491 136 4-amino-6-((1S)-1-amino-7-(1- hydroxyethyl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-1′-yl)-3-(4- (difluoromethoxy)phenyl)-1- methylpyridin-2(1H)-one [00203] 511 137 (S)-1-amino-1′-(4-amino-6-oxo-5-(4- phenoxyphenyl)-1,6-dihydropyridin- 2-yl)-1,3-dihydrospiro[indene-2,4′- piperidine]-4-carbonitrile [00204] 504 138 (S)-6-(1-amino-4-hydroxy-1,3-dihydrospiro [indene-2,4′-piperidin]-1′-yl)-3- (4-cyclohexylphenyl)-1-methylpyridin- 2(1H)-one [00205] 484 139 (S)-3-([1,1′-biphenyl]-4-yl)-6-(1- amino-4-methoxy-1,3-dihydrospiro [indene-2,4′-piperidin]-1′-yl) pyridin-2(1H)-one [00206] 478 140 (S)-6-amino-2-(1-amino-6-(2-oxopiperidin- 1-yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-3-methyl-5-(4- (trifluoromethoxy)phenyl)pyrimidin- 4(3H)-one [00207] 583 141 (S)-1-(1-amino-1′-(4-amino-5-((4- cyanophenyl)thio)-1-methyl-6-oxo-1,6- dihydropyrimidin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-6-yl)urea [00208] 517 142 (S)-4-amino-6-(1-amino-6-chloro-5- fluoro-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1-methyl-3-(4- (tetrahydro-2H-pyran-4-yl)phenyl)pyridin- 2(1H)-one [00209] 537 143 (S)-6-(1-amino-6-(trifluoromethyl)-1,3- dihydrospiro[indene-2,4′-piperidin]-1′- yl)-3-(4-(2-methoxyethoxy)phenyl)-1- methylpyridin-2(1H)-one [00210] 528 144 (S)-6-amino-2-(1-amino-6-(piperidine-1- carbonyl)-1,3-dihydrospiro[indene- 2,4′-piperidin]-1′-yl)-3-methyl-5- (quinolin-8-ylthio)pyrimidin-4(3H)-one [00211] 596 145 (S)-6-amino-2-(1-amino-6-morpholino- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-3-methyl-5-((4-nitrophenyl)thio) pyrimidin-4(3H)-one [00212] 564 146 (S)-6-amino-2-(5-amino-3-nitro-5,7- dihydrospiro[cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-3-methyl-5-(quinolin-8- ylthio)pyrimidin-4(3H)-one [00213] 531 147 (S)-6-(5-amino-3-(4-methylpiperazin-1- yl)-5,7-dihydrospiro[cyclopenta[b] pyridine-6,4′-piperidin]-1′-yl)-1- methyl-3-(naphthalen-1-ylthio) pyridin-2(1H)-one [00214] 567 148 (S)-2-(1-amino-6-(1H-pyrrol-1-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-5-((2,2-difluorobenzo[d][1,3] dioxol-4-yl)thio)pyrimidin-4(3H)-one [00215] 550 149 (S)-7-(5-(1-amino-6-(1H-imidazol-1- yl)-1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-6-(hydroxymethyl)-3- methylpyrazin-2-yl)isoindolin-1-one [00216] 522 150 (S)-3-(1-amino-6-(ethylamino)-1,3- dihydrospiro[indene-2,4′-piperidin]-1′- yl)-6-(1H-indol-5-yl)-5-methylpyrazine-2- carboxamide [00217] 496 151 (S)-N-(1-amino-1′-(3-bromo-5-(1H- indol-6-yl)-6-methylpyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 6-yl)cyclopropanecarboxamide [00218] 571 152 (S)-4-(6-amino-5-(1-amino-4-methoxy- 1,3-dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-3-methylpyrazin-2-yl)-1,3- dihydro-2H-benzo[d]imidazol-2-one [00219] 472 153 (S)-3-(1-amino-5-methoxy-1,3- dihydrospiro [indene-2,4′-piperidin]-1′-yl)- 5-methyl-6-(2-oxoindolin-7-yl)pyrazine- 2-carbonitrile [00220] 481 154 (S)-N-(5-(1-amino-7-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-6-((2-hydroxyethyl)amino)-3- methylpyrazin-2-yl)benzenesulfonamide [00221] 539 155 (S)-1′-(6-methyl-3-(1H-pyrazol-5-yl)- 5-(1H-pyrrolo[2,3-b]pyridin-4-yl) pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta [b]pyridine-6,4′-piperidin]-5-amine [00222] 478 156 (S)-2-(3-(5-amino-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′-piperidin]- 1′-yl)-6-(8-chlorochroman-7-yl)-5- methylpyrazin-2-yl)propan-2-ol [00223] 520 157 (S)-6-chloro-1′-(5-(7-chloro-2,3- dihydrobenzofuran-6-yl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine [00224] 467 158 (S)-4-bromo-1′-(5-(3-(1-methyl-1H- pyrazol-5-yl)phenyl)pyrazin-2-yl)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine [00225] 515 159 (S)-1-amino-1′-(6-cyano-5-(1H-indazol- 7-yl)pyrazin-2-yl)-5-fluoro-1,3- dihydrospiro [indene-2,4′-piperidine]-6- carboxamide [00226] 483 160 (S)-1′-(5-(1H-indol-3-yl)-6-iodopyrazin- 2-yl)-5,7-dihydrospiro[cyclopenta [b]pyridine-6,4′-piperidin]-5-amine [00227] 523 161 (R)-6-(5-(7′-amino-7′,8′-dihydro-5′H- spiro[piperidine-4,6′-quinolin]-1-yl)- 3-vinylpyrazin-2-yl)isoindolin-1-one [00228] 453 162 (R)-1-(4-(5-(6-amino-6,7-dihydrospiro [cyclopenta[b]pyridine-5,4′-piperidin]- 1′-yl)-3-ethylpyrazin-2-yl)-3,3- difluoroindolin-1-yl)ethan-1-one [00229] 505 163 (S)-1′-(5-(3-methyl-1H-indazol-6-yl)- 6-phenylpyrazin-2-yl)-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′- piperidin]-5-amine [00230] 488 164 (S)-1′-(5-(1H-benzo[d][1,2,3]triazol- 6-yl)-6-cyclopropylpyrazin-2-yl)-6- ((tetrahydro-2H-pyran-4-yl)oxy)-1,3- dihydrospiro[indene-2,4′- piperidin]-1-amine [00231] 538 165 (S)-1-amino-1′-(3-((l-methyl-1H- imidazol-2-yl)thio)-1H-pyrazolo[3,4-b] pyrazin-6-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carbonitrile [00232] 458 166 (S)-1′-(3-(1H-benzo[d]imidazol-1-yl)- 1H-pyrazolo[3,4-b]pyrazin-6-yl)-6- bromo-1,3-dihydrospiro[indene-2,4′- piperidin]-1-amine [00233] 515 167 (S)-1-(6-(1-amino-5-chloro-6-methoxy- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-3,4-dihydro-1,5- naphthyridin-2(1H)-one [00234] 531 168 (1-(6-((S)-1-amino-6-(methylthio)-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5- naphthyridin-4-yl)methanol [00235] 529 169 1-(6-((1S)-1-amino-6-(methylsulfinyl)-1,3- dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-5- fluoro-1,2,3,4-tetrahydroquinoline- 6-carbonitrile [00236] 557 170 (S)-6-chloro-1′-(3-(2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-5-methyl-1,3- dihydrospiro[indene-2,4′-piperidin]- 1-amine [00237] 487 171 (S)-5-(6-(1-amino-4-methoxy-1,3- dihydrospiro[indene-2,4′-piperidin]- 1′-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N- (2-methoxyethyl)-5,6,7,8-tetrahydro-1,5- naphthyridine-2-carboxamide [00238] 584 172 (S)-1-amino-5-fluoro-1′-(3-(6-(piperazin- 1-yl)-3,4-dihydro-1,5-naphthyridin- 1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin- 6-yl)-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carbonitrile [00239] 580 173 (S)-2-(1-(6-(1-amino-6-(methylthio)- 1,3-dihydrospiro[indene-2,4′- piperidin]-1′-yl)-1H-pyrazolo[3,4-b] pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin- 5-yl)thiazole-4-carboxylic acid [00240] 625 174 (S)-1′-(6-(aminomethyl)-5-(2,3- dichloropyridin-4-yl)pyrazin-2-yl)-6- (1H-imidazol-1-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine [00241] 521 175 (1S)-1-amino-1′-(5-(2,3-dichloropyridin- 4-yl)-3-(2-(hydroxymethyl)pyrrolidine- 1-carbonyl)-6-methylpyrazin-2-yl)-N,N- dimethyl-1,3-dihydrospiro[indene- 2,4′-piperidine]-6-carboxamide [00242] 638 176 (S)-1′-(8-(2-amino-3-chloropyridin-4- yl)-7-methylimidazo[1,2-c]pyrimidin- 5-yl)-5-fluoro-1,3-dihydrospiro[indene- 2,4′-piperidin]-1-amine [00243] 478 177 (S)-1′-(5-(1-methyl-1H-indol-2-yl) pyrazin-2-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-3,3-d2-1- amine [00244] 410 178 (S)-1-(6-(5-amino-5,7-dihydrospiro [cyclopenta[b]pyridine-6,4′- piperidin]-1′-yl)-1H-pyrazolo [3,4-b]pyrazin-3-yl)-1,2,3,4- tetrahydro-6H-pyrido[1,2-a] pyrimidin-6-one [00245] 470 179 (S)-1′-(3-(2,3,4,5-tetrahydro-1H- benzo[b]azepin-1-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-5,7- dihydrospiro[cyclo penta[c]pyridine-6,4′-piperidin]-5- amine [00246] 467 180 (3-((S)-1-amino-6-fluoro-1,3-dihydro spiro[indene-2,4′-piperidin]-1′-yl)-6- ((R)-1-methylisoindolin-2-yl) pyrazin-2-yl)methanol [00247] 460 181 (S)-1′-(3-(6,7-dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-1H-pyrazolo [3,4-b]pyrazin-6-yl)-5,7-dihydrospiro [cyclopenta[c]pyridine-6,4′- piperidin]-5,5-d2-7-amine [00248] 443 182 (S)-4-(difluoromethyl)-1′-(5-methyl- 6-((R)-2-methyl-3,4-dihydro-1,5- naphthyridin- 1(2H)-yl)pyridin-3-yl)-1,3-dihydrospiro [indene-2,4′-piperidin]-1-amine [00249] 470 183 (S)-1′-(8-(2-chloro-3-(isopropyl(methyl) amino)phenyl)-[1,2,4]triazolo[4,3-c] pyrimidin-5-yl)-2,3,6,8-tetrahydrospiro [indeno[5,6-b][1,4]dioxine- 7,4′-piperidin]-6-amine [00250] 561 184 (S)-1-(5-amino-1′-(8-((5-chloro-1- methylindolin-6-yl)thio)imidazo[1,5- a]pyridin-5-yl)-2,3,5,7-tetrahydro-1H- spiro[cyclopenta[b]pyrrolo[3,2-e] pyridine-6,4′-piperidin]-1-yl) ethan-1-one [00251] 601

Example A.

Phosphatase Assay (Single Dose Inhibition)

Assay Protocol:

[0694] For single dose inhibition assays using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as a substrate, SHP2 samples (diluted to 0.5 nM in reaction buffer) were incubated with dPEG8 peptide for 30 min in reaction buffer[60 mM 3,3-dimethyl glutarate (pH7.2), 75 mM NaCl, 75 mM KCl, and 1 mM EDTA, 0.05% Tween 20, 2mM dithiothreitol (DTT) ] to active the PTP. DMSO [0.5% (v/v)] or compounds (20nM) were added to the mixture and incubated for 30 min at room temperature. Reactions were initiated by the addition of DiFMUP (12 μM; total reaction volume of 100 μL), and the fluorescence (excitation at 340 nm, emission at 450 nm) of the resulting solutions was measured on a 2104-0020 EnVision Xcite Multilabel Reader (PerkinElmer) after 30min. The experiment is carried out in triplicate. The value for the control sample (DMSO) was set to 100%, and the values for the compound-treated samples were expressed as activity relative to the control sample. The inhibition of SHP2 by compounds of the invention were shown in table 1.

TABLE-US-00011 Example SHP2 inhibition(%)  1@0.02 μM 82  2@0.02 μM 80  3@0.02 μM 81  4@0.02 μM 89  5@0.02 μM 84  6@0.02 μM 89  8@0.02 μM 68 15@0.02 μM 64 19@0.02 μM 61 21@0.02 μM 68 23@0.02 μM 85 24@0.02 μM 87 25@0.02 μM 78 26@0.02 μM 67 27@0.02 μM 79 28@0.02 μM 74 29@0.02 μM 68 30@0.02 μM 80 31@0.02 μM 82 32@0.02 μM 75 33@0.02 μM 70 36@0.02 μM 88 37@0.02 μM 68 38@0.02 μM 53 39@0.02 μM 78 40@0.02 μM 68 45@0.02 μM 78 47@0.02 μM 56 50@0.02 μM 86