DRAK2 INHIBITOR, AND PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Provided are a compound as represented by formula I serving as a DRK2 inhibitor, or a stereoisomer or optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof. Further provided are a preparation method for the compound, a pharmaceutical composition thereof, and the use thereof as a Drak2 inhibitor and in the preparation of a drug for preventing and/or treating a Drak2-related disease.

##STR00001##

Claims

1. A compound of formula I, or a stereoisomer or optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, ##STR00391## wherein, X.sub.1 is selected from N and CR.sub.m1; X.sub.2 is selected from N and CR.sub.m2; X.sub.3 is selected from N and CR.sub.m3; X.sub.5 is selected from N and CR.sub.m3; L is selected from: bond, O, S, NR.sub.m4, C(O) and C(O)NR.sub.m4; ring A and ring B are each independently selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, and 5-12 membered heteroaryl; wherein the C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, and 5-12 membered heteroaryl are optionally substituted with 1 to 3 R; each R.sub.m is independently selected from: H, D, halogen, cyano, hydroxyl, carboxyl, S(O).sub.tR.sub.m5, C(O)R.sub.m5, C(O)OR.sub.m5, C(O)NR.sub.m6R.sub.m7, S(O).sub.tNR.sub.m6R.sub.m7, C(O)NR.sub.m8S(O).sub.tNR.sub.m6R.sub.m7, (CH.sub.2).sub.qS(O).sub.tR.sub.m5, (CH.sub.2).sub.qC(O)R.sub.m5, (CH.sub.2).sub.qC(O)OR.sub.m5, (CH.sub.2).sub.qC(O)NR.sub.m6R.sub.m7, (CH.sub.2).sub.q(CH.sub.2).sub.qS(O).sub.tNR.sub.m6R.sub.m7, C(O)NR.sub.m8S(O).sub.tNR.sub.m6R.sub.m7, (CH.sub.2).sub.qR.sub.m9, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; alternatively, two R.sub.m located on adjacent ring atoms together with their adjacent ring atoms form a C3-C12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the C3-C12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with 1 to 3 R; R.sub.n is selected from: H, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, and C(O)R.sub.p; wherein, R.sub.p is selected from: NH.sub.2, C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C2-C15 alkenyl, C2-C15 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; R.sub.m1, R.sub.m2, R.sub.m3, and R.sub.m3 are each independently selected from: H, cyano, halogen, C(O)NH.sub.2, carboxyl, S(O).sub.2NH.sub.2, C(O)OC1-C6 alkyl and S(O).sub.2C1-C6 alkyl; R.sub.m4 is selected from: H and C1-C6 alkyl; R.sub.m5 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; R.sub.m6, R.sub.m7, R.sub.m8, and R.sub.m9 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, and 5-12 membered heteroaryl; or, R.sub.m6 and R.sub.m7 together with the N atom to which they are adjacent form a 3-12 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, or 5-12 membered heteroaryl is optionally substituted with 1-3 R; the H atoms in (CH.sub.2).sub.q are optionally substituted with R; R is selected from: H, D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, oxo-(?O), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, and OC.sub.1-4 alkylene-phenyl; t is 0, 1 or 2; q is 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6.

2. The compound of claim 1, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein the compound has a structure of formula II ##STR00392## wherein, X.sub.1, X.sub.2, X.sub.3, X.sub.5, ring A, ring B, R.sub.m, R.sub.p, and n are as defined in claim 1; particularly, X.sub.1, X.sub.2, X.sub.3, X.sub.5, ring A, ring B, and R.sub.m are as defined in claim 8; n is as defined in claim 1; ##STR00393## is defined as Rn of claim 8; more particularly, ##STR00394## is as defined in claim 8.

3. The compound of claim 1, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein the compound has a structure of formula III ##STR00395## wherein, X.sub.4 is selected from: N and CR.sub.m10; wherein R.sub.m10 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; or, R.sub.m6 and R.sub.m7 together with the N atom to which they are adjacent form a 3-12 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; R is selected from: H, D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, preferably is H; R, X.sub.1, X.sub.2, X.sub.3, X.sub.5, ring A, R.sub.m, R.sub.p, and n are as defined in claim 1; particularly, X.sub.1, X.sub.2, X.sub.3, X.sub.5, ring A, and R.sub.m are as defined in claim 8; n is as defined in claim 1; ##STR00396## is defined as Rn of claim 8; more particularly, ##STR00397## is as defined in claim 8.

4. The compound of any one of claims 1 to 3, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein, the compound has a structure of formula IV ##STR00398## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each independently selected from: H, D, halogen, cyano, hydroxyl, carboxyl, S(O).sub.tR.sub.m5, C(O)R.sub.m5, C(O)OR.sub.m5, C(O)NR.sub.m6R.sub.m7, S(O).sub.tNR.sub.m6R.sub.m7, C(O)NR.sub.m8S(O).sub.tNR.sub.m6R.sub.m7, (CH.sub.2).sub.qS(O).sub.tR.sub.m5, (CH.sub.2).sub.qC(O)R.sub.m5, (CH.sub.2).sub.qC(O)OR.sub.m5, (CH.sub.2).sub.qC(O)NR.sub.m6R.sub.m7, (CH.sub.2).sub.q(CH.sub.2).sub.qS(O).sub.tNR.sub.m6R.sub.m7, C(O)NR.sub.m8S(O).sub.tNR.sub.m6R.sub.m7, (CH.sub.2).sub.qR.sub.m9, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; or, R.sub.1 and R.sub.2, or R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5 together with the C atoms to which they are adjacent form a 5-6-membered heterocyclyl, wherein the 5-6-membered heterocyclyl is optionally substituted with 1 to 3 R; R is selected from: H, D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, preferably is H; t, q, R, R.sub.m5, R.sub.m6, R.sub.m7, R.sub.m8, R.sub.m9, X.sub.1, X.sub.2, X.sub.3, X.sub.5 and R.sub.p are as defined in claim 1. particularly, X.sub.1, X.sub.2, X.sub.3, and X.sub.5 are as defined in claim 8; R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are defined as Rm of claim 8; ##STR00399## R is defined as Rn of claim 8; more particularly, ##STR00400## is as defined in claim 8.

5. The compound of any one of claims 1 to 4, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein the compound has a structure of formula A ##STR00401## wherein R.sup.6 is selected from: H, D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, preferably is H; R.sub.7 is selected from: C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl is 5-12 membered heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of: D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, oxo-(?O), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are as defined in claim 4; particularly, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are defined as Rm of claim 8; ##STR00402## is defined as Rn of claim 8;

6. The compound of any one of claims 1 to 4, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein the compound has a structure of formula B ##STR00403## wherein R.sub.7 is selected from: C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl is 5-12 membered heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of: D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, oxo-(?O), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; R.sub.8 and R.sub.9 are each independently selected from: H, S(O).sub.2NR.sub.11R.sub.12, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, and 5-12 membered heteroaryl; or, R.sub.8 and R.sub.9 together with the N atom to which they are adjacent form a 3-12 membered heterocyclyl, preferably 5-6 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 5-6 membered heterocyclyl, C6-C10 aryl, or 5-12 membered heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C3-C12 cycloalkyl, C1-C6 alkyl-C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C1-C6 alkyl-3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; R.sub.11 and R.sub.12 are each independently selected from: H, C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; particularly, X.sub.1 and X.sub.2 are as defined in claim 8; ##STR00404## is defined as Rn of claim 8; ##STR00405## is formamide, ##STR00406## ##STR00407## ##STR00408##

7. The compound of any one of claims 1 to 4, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein, the compound has a structure of formula C ##STR00409## wherein, R.sub.10 is selected from: H, cyano, and CONH.sub.2; R.sub.7 is selected from: C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of: D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, oxo-(?O), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; particularly, ##STR00410## is defined as Rn of claim 8.

8. The compound of claim 1, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein the compound satisfies one or more of the following conditions, (1) X.sub.1 is N or CH; (2) X.sub.2 is N or CH; (3) X.sub.3 is N, CC(?O)NH.sub.2 or CCN; (4) X.sub.5 is N or CH; (5) L is bond or NH; (6) ring A is C6-C10 aryl, or 3-12 membered heterocyclyl; wherein the 3-12 membered heterocyclyl is preferably 5-7 membered heterocyclyl, and more preferably 6-membered heterocyclyl; preferably, ring A is phenyl, ##STR00411## the substituents on ring A is defined as R.sub.m of claim 1; (7) ring B is 5-12 membered heteroaryl or C3-C12 cycloalkyl, preferably 5-membered heteroaryl or 6-membered cycloalkyl; preferably, ring B is ##STR00412## the substituents on ring B is defined as R of claim 1; (8) R.sub.m is methoxy, F, Cl, cyano, hydroxyl, carboxyl, formamide, ##STR00413## ##STR00414## ##STR00415## (9) R.sub.n is ##STR00416## acetyl, isobutyryl, ##STR00417## cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyl carbonyl, cyclohexyl carbonyl, phenyl carbonyl, cyclopropyl methylene carbon 1 cyclobutyl methylene carbonyl, cyclopentyl methylene carbonyl, cyclohexyl methylene carbonyl, or ##STR00418## or R.sub.n is H; particularly, ##STR00419##

9. The compound of any one of claims 1 to 8, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein Rn is selected from: C(O)R.sub.p; wherein R.sub.p is selected from: C1-C15 alkyl; wherein the C1-C15 alkyl is optionally substituted with 1, 2, or 3 R; R is selected from: C3-C12 cycloalkyl; wherein the C3-C12 cycloalkyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: C1-C6 alkyl, halogenated C1-C6 alkyl, C6-C10 aryl substituted with halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C6-C10 aryl substituted with halogenated C1-C6 alkoxy, and C(O)C1-C6 alkyl; or, Rn is selected from: OR.sub.p; wherein R.sub.p is selected from: C1-C15 alkyl; wherein C1-C15 alkyl is optionally substituted with 1, 2, or 3 R; R is selected from: C1-C15 alkylamino; the C1-C15 alkylamino is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C6-C10 aryl substituted with halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C6-C10 aryl substituted with halogenated C1-6 alkoxy, C(O)C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, and S(O).sub.2C1-C6 alkyl; or ##STR00420## is selected form ##STR00421## wherein R.sub.m is as defined in claim 1; or, ring B selected from ##STR00422## the substituents on ring B is defined as R of claim 1; or, Rm is selected from: ##STR00423## or, Rn is selected from: ##STR00424## ##STR00425## or, n is 0.

10. The compound of claim 1, wherein the compound has a structure of formula D: ##STR00426## R.sub.p is as described in claim 1; L.sub.2 is selected from: bond, C1-C15 alkylene, C1-C15 alkylene-O, C1-C15 alkylene-NH, C3-C12 cycloalkylene, 3-12 membered heterocyclylene, C6-C10 arylene and 5-12 membered heteroarylene; wherein the C1-C15 alkylene, C1-C15 alkylene-O, C1-C15 alkylene-NH, C3-C12 cycloalkylene, 3-12 membered heterocyclylene, C6-C10 arylene and 5-12 membered heteroarylene are optionally substituted with 1 to 3 substituents selected from the group consisting of: D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, oxo-(?O), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; R.sub.11 is selected from: H, C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of: D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, oxo-(?O), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered heterocyclyl substituted with C1-C6 alkyl, C6-C10 aryl, 5-12 membered heteroaryl and 5-12 membered heteroaryl substituted with C1-C6 alkyl.

11. The compound of claim 1, wherein the compound has a structure of formula E: ##STR00427## Ring A, R.sub.m, R.sub.p and n are as described in claim 1; preferably, ring A is 5-10-membered heteroaryl, preferably 5 membered heteroaryl, or 9-10 membered heteroaryl; more preferably, ring A is selected from pyrazole, furan, thiophene, thiazole, benzene ring, pyridine, pyrimidine, pyrazine, indole, indazole, benzopyrazole, pyrrolo [2,3-b] pyridine.

12. A compound of formula I, or a stereoisomer or optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, ##STR00428## wherein, X is selected from 0 and CH.sub.2; X.sub.1 is selected from N and CR.sub.m1; X.sub.2 is selected from N and CR.sub.m2; X.sub.3 is selected from N and CR.sub.m3; X.sub.5 is selected from N and CR.sub.m3; L is selected from: bond, O, S, NR.sub.m4, C(O) and C(O)NR.sub.m4; ring A and ring B are each independently selected from: C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, and 5-12 membered heteroaryl; wherein the C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, and 5-12 membered heteroaryl are optionally substituted with 1-3 R; each R.sub.m is independently selected from: H, D, halogen, cyano, hydroxyl, carboxyl, S(O).sub.tR.sub.m5, C(O)R.sub.m5, C(O)OR.sub.m5, C(O)NR.sub.m6R.sub.m7, S(O).sub.tNR.sub.m6R.sub.m7, C(O)NR.sub.m8S(O).sub.tNR.sub.m6R.sub.m7, (CH.sub.2).sub.qS(O).sub.tR.sub.m5, (CH.sub.2).sub.qC(O)R.sub.m5, (CH.sub.2).sub.qC(O)OR.sub.m5, (CH.sub.2).sub.qC(O)NR.sub.m6R.sub.m7, (CH.sub.2).sub.q(CH.sub.2).sub.qS(O).sub.tNR.sub.m6R.sub.m7, C(O)NR.sub.m8S(O).sub.tNR.sub.m6R.sub.m7, (CH.sub.2).sub.qR.sub.m9, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; or, two R.sub.m on adjacent ring atoms together with the ring atoms to which they are adjacent form a C3-C12 cycloalkyl or a 3-12 membered heterocyclyl, wherein the C3-C12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with 1 to 3 R; R.sub.n is selected from: H, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, and C(O)R.sub.p; wherein R.sub.p is selected from: NH.sub.2, C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C2-C15 alkenyl, C2-C15 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C15 alkyl, C1-C15 alkoxy, C1-C15 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1-3 R; R.sub.m1, R.sub.m2, R.sub.m3, and R.sub.m3 are each independently selected from: H, cyano, halogen, C(O)NH.sub.2, carboxyl, S(O).sub.2NH.sub.2, C(O)OC1-C6 alkyl and S(O).sub.2C1-C6 alkyl; R.sub.m4 is selected from: H and C1-C6 alkyl; R.sub.m5 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; R.sub.m6, R.sub.m7, R.sub.m8, and R.sub.m9 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, and 5-12 membered heteroaryl; or, R.sub.m6 and R.sub.m7 together with the N atom to which they are adjacent form a 3-12 membered heterocyclyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, or 5-12 membered heteroaryl is optionally substituted with 1 to 3 R; the H atoms in (CH.sub.2).sub.q are optionally substituted with R; R is selected from: H, D, halogen, cyano, hydroxyl, carboxyl, NH.sub.2, oxo-(?O), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl and 5-12 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl or 5-12 membered heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C(O)OC1-C6 alkyl, S(O).sub.2C1-C6 alkyl, OC.sub.1-4alkylene-phenyl; t is 0, 1 or 2; q is 1, 2, 3, 4, 5 or 6; n is 1, 2, 3, 4, 5 or 6.

13. The compound of claim 1, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, wherein the compound is selected from: ##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435## ##STR00436## ##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482##

14. A pharmaceutical composition, comprising the compound of any one of claims 1 to 13, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug, or the solvate thereof; and pharmaceutically acceptable carriers.

15. A use of the compound of any one of claims 1 to 13, or the stereoisomer or optical isomer, the pharmaceutically acceptable salt, the prodrug or the solvate thereof, or the pharmaceutical composition of claim 14 in the preparation of a drug for treating or preventing a disease associated with the activity or expression of Drak2 kinase, or in the preparation of a drug for inhibiting the activity of Drak2 kinase. preferably, the disease is cancer, autoimmune disease, metabolic disease, or motor neurodegenerative disease; wherein, the cancer is preferably selected from: malignant lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, non Hodgkin lymphoma, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, basal cell carcinoma, breast cancer, brain cancer, adrenal cancer, renal cancer, nephroblastoma, stomach cancer, gastrointestinal stromal cancer, pituitary adenoma, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colon cancer, rectal cancer, small intestine cancer, duodenal carcinoma, retinoblastoma, choroidal melanoma, ampullary cancer, bladder cancer, peritoneal cancer, parathyroid carcinoma, non sinus cancer, small cell lung cancer, non small cell lung cancer, astrocytoma, esophageal cancer, glioma, neuroblastoma, malignant soft tissue tumor, malignant bone tumor, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, tumors with unknown primary sites, carcinoma of penis, oral cancer, lip cancer, pharyngeal cancer, epithelial ovarian cancer, ovarian genital carcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, vaginal cancer, Paget's disease, tonsil cancer, anal cancer, rhabdomyosarcoma, Kaposi sarcoma, sarcoma, tongue cancer, laryngeal cancer, pleural cancer, thymic cancer, and combinations thereof; wherein the non-small cell lung cancer is preferably lung adenocarcinoma, or lung squamous cell carcinoma; the autoimmune disease is preferably selected from: inflammatory colitis, Crohn's disease, psoriasis, idiopathic dermatitis, alopecia areata, vitiligo, eczema, lupus, Sjogren's syndrome, amyotrophic lateral sclerosis, Behcet's disease, multiple sclerosis, asthma, macular degeneration, complications caused by organ transplantation, urticaria, infections and allergies, arthritis, encephalitis, viral meningitis, and combinations thereof; the metabolic disease is preferably selected from diabetes, and the diabetes is preferably type I diabetes or type II diabetes, more preferably is type II diabetes; the motor neurodegenerative disease is preferably selected from amyotrophic lateral sclerosis, motor neuron disease, and Lou Gehrig's disease.

Description

EXAMPLE

[0248] As used herein, all temperatures were represented by ? C., unless otherwise specified.

[0249] As used herein, percentages for yield were all mass percentages.

[0250] As used herein, all portions were by volume, and all percentages were by volume, unless otherwise specified.

[0251] In this article, the preparative chromatography of PTLC or TLC (thin layer chromatography) was carried out on a 20?20 cm plate (500 ?m thick silica gel); Biotage rapid chromatography system was used for silica gel chromatography.

[0252] In this article, .sup.1H NMR (hydrogen spectrum) was performed using a Bruker Ascend?400 spectrometer at 400 MHz, 298? K, and the chemical shift (ppm) of residual protons in deuterated reagents was given as a reference: ? (Chemical shift) for CDCl.sub.3 was 7.26 ppm, ? for CD.sub.3OD was 3.31 ppm, ? for DMSO-d6 was 2.50 ppm.

[0253] In this article, in LCMS (liquid chromatography-mass spectrometry) testing, Agilent Technologies 1200 series or 6120 quadrupole spectrometers were used for liquid chromatography. For liquid chromatography, the mobile phase consists of acetonitrile (A), water (B), and 0.01% formic acid. The eluent gradient is 5-95% A for 6.0 minutes, 60-95% A for 5.0 minutes, 80-100% A for 5.0 minutes, and 85-100% A for 10 minutes, a SBC1850 mm?4.6 mm?2.7 ?m capillary column is used; mass spectrometry (MS) is determined by electrospray ionization mass spectrometry (ESI).

[0254] As used herein, the analysis conditions for high-performance liquid chromatography (HPLC)-mass spectrometry (MS) were as follows: [0255] LC1 column: SB-C18 50 mm?4.6 mm?2.7 sum; [0256] Temperature: 50? C. [0257] Eluent: acetonitrile/water from 5:95 to 95:5 (the above ratio was by volume)+0.01% formic acid, 6 minutes; [0258] Flow: 1.5 mL/min, Injection: 5 ?L; [0259] Detection: PDA detector, 200-600 nm; [0260] MS: Quality range 150-750 amu; Positive ion spray ionization. [0261] LC2 column: SB-C18 50 mm?4.6 mm?2.7 ?m; [0262] Temperature: 50? C. [0263] Eluent: Acetonitrile/water from 5:95 to 95:5 (the above ratio was by volume)+0.05% TFA (trifluoroacetic acid) gradient, over 3.00 minutes; [0264] Flow: 1.5 mL/min, Injection: 5 ?L [0265] Detection: PDA detector, 200-600 nm; [0266] MS: Quality range 150-750 amu; Positive ion spray ionization. [0267] LC3 column: SB-C18 50 mm?4.6 mm?2.7 ?m; [0268] Temperature: 50? C. [0269] Eluent: Acetonitrile/water from 10:90 to 98:2 (the above ratio was by volume)+0.05% TFA gradient, over 3.75 minutes; [0270] Flow rate: 1.0 mL/min, Injection: 10 ?L [0271] Detection: PDA detector, 200-600 nm; [0272] MS: Quality range 150-750 amu; Positive ion spray ionization.

[0273] As used herein, the meaning of each abbreviation was as follows: [0274] AcOH=acetic acid; Alk represents an alkyl group; AR represents an aryl group; Boc=tert-butoxycarbonyl; CH.sub.2Cl.sub.2=dichloromethane; DBU=1,8-diazabicyclo [5.4.0] undecyl-7-ene; DCM=dichloromethane; DEAD=Diethyl azodicarboxylate; DMF=N, N-dimethylformamide; DMSO=dimethyl sulfoxide; EA=ethyl acetate; Et=Ethyl; EtOAc=ethyl acetate; EtOH=ethanol; HOAc=acetic acid; LiOH=lithium hydroxide; Me=methyl; MeCN=acetonitrile; MeOH=methanol; MgSO.sub.4=magnesium sulfate; NaCl=sodium chloride; NaOH=sodium hydroxide; Na.sub.2SO.sub.4=sodium sulfate; PE=petroleum ether; Ph=phenyl; PG=protecting group; TFA=trifluoroacetic acid; THF=tetrahydrofuran; Ts=p-toluene sulfonyl group; rt=room temperature; h=hour; min=minute; bs=broad peak; s=single peak; d=bimodal; dd=double double peak; t=triple peak; m=multiple peak.

General Method

Method 1

Method A

[0275] ##STR00119## ##STR00120## [0276] S1) Under appropriate alkaline conditions (such as but not limited to potassium acetate, etc.), selecting appropriate solvents (such as but not limited to Dioxane, etc.), and at an appropriate temperature (such as but not limited to 80? C.), under the catalysis with appropriate coupling catalysts (such as but not limited to Pd (dppf).sub.2), reacting compound (A-1) with corresponding boron ester or boric acid compounds (A-1a) (such as but not limited to Pinacolboronates) to obtain compound (A-2); [0277] S2) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting suitable solvent (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at an appropriate temperature (such as but not limited to 80? C.), under the catalysis with an appropriate coupling catalyst (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting compound (A-2) with the corresponding aryl halide compound (A-2a) (such as but not limited to 2,6-dibromopyrazine) to obtain compound (A-3); [0278] S3) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting appropriate solvents (such as but not limited to Dioxane, etc.), and at appropriate temperatures (such as but not limited to 60? C.), under the catalysis with appropriate coupling catalysts (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting the compound (A-3) with the corresponding boric acid or boron ester compounds (A-3a) to obtain compound (A-4); [0279] S4) Under appropriate alkaline conditions (such as but not limited to cesium carbonate, etc.), selecting appropriate solvents (such as but not limited to toluene, etc.), and at an appropriate temperature (such as but not limited to 110? C.), selecting appropriate ligand (such as but not limited to BINAP, etc.), under the catalysis with appropriate coupling catalysts (such as but not limited to Pd.sub.2(dba).sub.3), reacting compound (A-4) with corresponding nitrogen-containing compound (A-4a) to obtain compound (A-5-1); [0280] S5) Selecting appropriate solvents (such as but not limited to tetrahydrofuran, etc.), selecting appropriate acids (such as but not limited to 1M hydrochloric acid), and making compound (A-5-2) undergo deprotecting reaction to obtain compound (A-5); [0281] S6) Selecting suitable solvent (such as but not limited to dichloromethane, etc.), selecting suitable base (such as but not limited to triethylamine), and reacting compound (A-5) with corresponding acyl chloride (A-5a) to obtain compound (A);

Method B

[0282] ##STR00121## ##STR00122## [0283] S1) Under appropriate alkaline conditions (such as but not limited to potassium acetate, etc.), selecting appropriate solvents (such as but not limited to Dioxane, etc.), and at an appropriate temperature (such as but not limited to 80? C.), under the catalysis with appropriate coupling catalysts (such as but not limited to Pd (dppf).sub.2), reacting compound (A-1) with corresponding boron ester or boric acid compounds (A-1a) (such as but not limited to Pinacolboronates) to obtain compound (A-2); [0284] S2) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting suitable solvent (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at an appropriate temperature (such as but not limited to 80? C.), under the catalysis with an appropriate coupling catalyst (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting compound (A-2) with the corresponding aryl halide compound (A-2a) (such as but not limited to 2,6-dibromopyrazine) to obtain compound (A-3); [0285] S3) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), appropriate solvents (such as but not limited to Dioxane, etc.), and at appropriate temperatures (such as but not limited to 60? C.), under the catalysis with appropriate coupling catalysts (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting the compound (A-3) with the corresponding boric acid or boron ester compounds (A-3a) to obtain compound (A-4); [0286] S4) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting appropriate solvents (such as but not limited to DMSO, etc.), and at an appropriate temperature (such as but not limited to 110? C.), selecting appropriate ligand (such as but not limited to L-proline, etc.), under the catalysis with appropriate coupling catalysts (such as but not limited to cuprous iodide), reacting compound (A-4) with corresponding nitrogen-containing compound ammonia under pipe sealing condition to obtain compound (A-5); [0287] S5) Selecting suitable solvent (such as but not limited to dichloromethane, etc.), selecting suitable base (such as but not limited to triethylamine), and reacting compound (A-5) with corresponding acyl chloride (A-5a) to obtain compound (A);

Method 2

[0288] ##STR00123## ##STR00124## [0289] S1) Under appropriate alkaline conditions (such as but not limited to potassium acetate, etc.), selecting appropriate solvents (such as but not limited to Dioxane, etc.), and at appropriate temperatures (such as but not limited to 80? C.), under the catalysis with appropriate coupling catalysts (such as but not limited to Pd (dppf).sub.2), reacting compound (B-1) with corresponding boron ester or boric acid compounds (B-1a) (such as but not limited to pinacolboronates) to obtain compound (B-2); [0290] S2) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting appropriate solvents (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at appropriate temperatures (such as but not limited to 80? C.), under the catalysis with appropriate coupling catalysts (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting compound (B-2) with the corresponding aryl halide compound (B-2a) to obtain compound (B-3); [0291] S3) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting suitable solvent (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at an appropriate temperature (such as but not limited to 60? C.), under the catalysis with an appropriate coupling catalyst (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting compound (B-3) with the corresponding boric acid or boron ester compound (B-3a) to obtain compound (B-4); [0292] S4) Under appropriate alkaline conditions (such as but not limited to cesium carbonate, etc.), selecting appropriate solvents (such as but not limited to DMSO, etc.), and at an appropriate temperature (such as but not limited to 110? C.), selecting appropriate ligand (such as but not limited to L-proline, etc.), under the catalysis with appropriate coupling catalysts (such as but not limited to cuprous iodide), reacting compound (B-4) with corresponding nitrogen-containing compound ammonia under pipe sealing condition to obtain compound (B-5); [0293] S5) Selecting suitable solvent (such as but not limited to dichloromethane), selecting suitable base (such as but not limited to triethylamine), and reacting compound (B-5) with corresponding acyl chloride (B-5a) to obtain compound (B-6); [0294] S6) Selecting appropriate solvents (such as but not limited to a mixed solvent of tetrahydrofuran and water, etc.), appropriate bases (such as but not limited to lithium hydroxide), and making compound (B-6) undergo hydrolytic reaction to obtain carboxyl compound (B-7); [0295] S7) Selecting suitable solvent (such as but not limited to DMF), selecting suitable base (such as but not limited to DIEA), suitable coupling reagents (such as but not limited to EDCI+HOBT), and reacting compound (B-7) with corresponding amine (B-7a) to obtain compound (B-8);

Method 3

[0296] ##STR00125## ##STR00126## [0297] S1) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting suitable solvent (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at an appropriate temperature (such as but not limited to 80? C.), under the catalysis with an appropriate coupling catalyst (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting compound (C-1) with the corresponding aryl halide compound (C-1a) to obtain compound (C-2); [0298] S2) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting suitable solvent (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at an appropriate temperature (such as but not limited to 60? C.), under the catalysis with an appropriate coupling catalyst (such as but not limited to tetrakis(triphenylphosphine)palladium), reacting compound (C-2) with corresponding boric acid or boron ester compounds (C-2a) to obtain compound (C-3); [0299] S3) Under appropriate alkaline conditions (such as but not limited to cesium carbonate, etc.), selecting appropriate solvents (such as but not limited to toluene, etc.), at appropriate temperatures (such as but not limited to 110? C.), selecting appropriate ligands (such as but not limited to BINAP), and under the catalysis with appropriate coupling catalysts (such as but not limited to Pd.sub.2(dba).sub.3), reacting compound (C-3) with corresponding nitrogen-containing compound (C-3a) to obtain compound (C-4); [0300] S4) Selecting appropriate solvents (such as but not limited to tetrahydrofuran, etc.), selecting appropriate acids (such as but not limited to 1M hydrochloric acid), and making compound (C-4) undergo deprotecting reaction to obtain compound (C-5); [0301] S5) Selecting suitable solvent (such as but not limited to dichloromethane), selecting suitable base (such as but not limited to triethylamine), and reacting compound (C-5) with corresponding acyl chloride (C-5a) to obtain compound (C-6); [0302] S6) Selecting appropriate solvents (such as but not limited to tert butanol, etc.), selecting appropriate bases (such as but not limited to sodium tert-butoxide, etc.), and making compound (C-6) undergo hydrolytic reaction to obtain amide compound (C-7);

Method 4

[0303] ##STR00127## ##STR00128## [0304] S1) Under appropriate alkaline conditions (such as but not limited to potassium acetate, etc.), selecting appropriate solvents (such as but not limited to DMF, etc.), and at appropriate temperatures (such as but not limited to 25? C.), reacting compound (D-1) with the corresponding compounds D-1a (such as but not limited to benzyl bromide, benzyl chloride, MOMCl, SEMCl, etc.) to obtain compound (D-2) with phenolic hydroxyl groups being protected; [0305] S2) Under appropriate alkaline conditions (such as but not limited to potassium acetate, etc.), selecting appropriate solvents (such as but not limited to Dioxane, etc.), and at appropriate temperatures (such as but not limited to 80? C.), under the catalysis with appropriate coupling catalysts (such as but not limited to Pd(dppf).sub.2), reacting compound (D-2) with the corresponding boron ester or boronic acid compounds (D-2a) (such as but not limited to pinacol borate) to obtain compound (D-3); [0306] S3) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), selecting suitable solvent (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at an appropriate temperature (such as but not limited to 80? C.), under the catalysis with an appropriate coupling catalyst (such as but not limited to Pd(PPh.sub.3).sub.4), reacting compound (D-3) with the corresponding aryl halide compound (D-4) to obtain compound (D-5); S4) Under appropriate alkaline conditions (such as but not limited to potassium carbonate, etc.), [0307] selecting suitable solvent (such as but not limited to a mixed solvent of Dioxane and water, etc.), and at an appropriate temperature (such as but not limited to 60? C., under the catalysis with an appropriate coupling catalyst (such as but not limited to Pd(PPh.sub.3).sub.4), reacting compound (D-5) with the corresponding boronic acid or boron ester compounds (D-6) to obtain compound (D-7); [0308] S5) Under appropriate alkaline conditions (such as but not limited to sodium carbonate, etc.), selecting appropriate solvents (such as but not limited to toluene, etc.), at appropriate temperatures (such as but not limited to 110? C.), selecting appropriate ligands (such as but not limited to BINAP), and under the catalysis with appropriate coupling catalysts (such as but not limited to Pd.sub.2(dba).sub.3), and reacting compound D-7 with the corresponding nitrogen-containing compound D-7a) to obtain compound D-8; [0309] S6) Selecting appropriate solvents (such as but not limited to tetrahydrofuran, etc.), selecting appropriate acids (such as but not limited to 1M hydrochloric acid), making compound (D-8) to undergo deprotecting reaction to obtain compound D-9; [0310] S7) Selecting suitable solvent can be selected (such as but not limited to DMF), selecting suitable base (such as but not limited to DIEA), selecting suitable coupling reagents (such as but not limited to EDCI+HOBT), and reacting compound (D-9) with the corresponding acid (D-9a) to obtain compound (D-10); [0311] S8) Selecting appropriate solvents (such as but not limited to methanol, etc.), selecting appropriate catalyzer (such as but not limited to PdC), and making compound (D-10) to undergo deprotecting reaction to obtain phenolic hydroxyl compounds (D-11); [0312] S9) Selecting suitable solvent (such as but not limited to acetonitrile), selecting suitable base (such as but not limited to cesium carbonate etc.), and reacting compound (D-11) with the corresponding compounds D-12 with active leaving group (such as but not limited to Oms, C1, Br, OTS, etc.) to obtain compound D;

[0313] In the above reaction steps, the solvent, reaction temperature, reaction time, and catalyst, etc. can be selected according to specific reactants.

[0314] Raw materials and intermediates are commercially available, or prepared using known steps, or using methods well-known in the art.

Example 1: Preparation of N-(5-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiophen-3-yl) pentanamide (A1) (Method A)

[0315] ##STR00129## ##STR00130##

Step 1: 3,4-dimethoxyphenyl Boronic Acid Pinacol Ester (A1-1)

[0316] 3,4-Dimethoxybromobenzene (910 mg, 4.20 mmol), potassium acetate (1.03 g, 10.50 mmol), 1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(154 mg, 0.21 mmol), Bis(pinacolato)diboron (1.28 g, 5.00 mmol) and, 1,4-dioxane (20 mL) were added successively to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. for 5 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was filtered, and the filter cake was washed with ethyl acetate. The reaction solution and the washing solution were combined, and spin dried to obtain 3,4-dimethoxyphenyl boronic acid pinacol ester (A1-1, crude, 4.20 mmol), which was directly used in the next reaction without any purification.

Step 2: 2-bromo-6-(3,4-dimethoxyphenyl) pyrazine (A1-2)

[0317] 2,6-Dibromopyrazine (1.0 g, 4.2 mmol), 3,4-dimethoxyphenyl boronic acid pinacol ester (A1-1, crude, 4.20 mmol), potassium carbonate (1.38 g, 10.00 mmol), Tetrakis(triphenylphosphine)palladium (243 mg, 0.21 mmol), 1,4-dioxane (40 mL), and water (10 mL) were added successively to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. for 5 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and re-dissolved with ethyl acetate (50 mL). The organic phase was extracted successively with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-bromo-6-(3,4-dimethoxyphenyl) pyrazine (A1-2, 900 mg, 72.6%). .sup.1HNMR (400 MHz, CDCl3) ? 8.92 (s, 1H), 8.55 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.60 (dd, J=8.4, 2.1 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 3.98 (s, 3H).

Step 3: 2-(4-bromothiophen-2-yl)-6-(3,4-dimethoxyphenyl) pyrazine (A1-3)

[0318] 2-bromo-6-(3,4-dimethoxyphenyl) pyrazine (A1-2, 488 mg, 1.65 mmol), (4-bromothiophen-2-yl) boronic acid (377 mg, 1.82 mmol), tetrakis(phosphorus)palladium (38 mg, 0.033 mmol), potassium carbonate (524 mg, 3.79 mmol), 1,4-dioxane (16 mL), and water (2.5 mL) were successively added to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. for 4 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and then added with dichloromethane (30 mL) and water (10 mL), and fractioned. The aqueous phase was extracted with dichloromethane (20 mL*2), and the organic phases were combined, washed with saturated salt water (20 mL*1), dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-(4-bromothiophen-2-yl)-6-(3,4-dimethoxyphenyl) pyrazine (A1-3, 463 mg, 74.4%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.89 (s, 1H), 8.78 (s, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.67 (dd, J=8.4, 2.0 Hz, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.40 (d, J=1.1 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.04 (s, 3H), 3.99 (s, 3H).

Step 4: N-(5-(6-(3,4-dimethoxyphenyl) pyrazin-2yl) thiazol-3yl)-1,1-diphenylimine (A1-4)

[0319] 2-(4-bromothiophen-2-yl)-6-(3,4-dimethoxyphenyl) pyrazine (A1-3, 106 mg, 0.28 mmol), benzophenone imine (76.4 mg, 0.42 mmol), 1.1-binaphthyl-2.2-diphenyl phosphine (17.4 mg, 0.028 mmol), Tris(dibenzylideneacetone)dipalladium (12.8 mg, 0.014 mmol), cesium carbonate (136.8 mg, 0.42 mmol), and toluene (10 mL) were sequentially added to a reaction flask. The mixture was reacted under nitrogen protection at 110? C. for 16 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford N-(5-(6-(3,4-dimethoxyphenyl) pyrazin-2yl) thiazol-3yl)-1,1-diphenylimine (A1-4, 59 mg, 43.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.82 (d, J=9.7 Hz, 1H), 8.56 (s, 1H), 7.82 (d, J=7.3 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H), 7.65 (dd, J=8.4, 1.9 Hz, 1H), 7.57-7.49 (m, 1H), 7.43 (dt, J=9.2, 5.8 Hz, 5H), 7.29 (m, 3H), 7.20 (d, J=1.3 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H).

Step 5: 5-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl)thiazol-3-amine Hydrochloride (A1-5)

[0320] N-(5-(6-(3,4-dimethoxyphenyl) pyrazin-2yl) thiazol-3yl)-1,1-diphenylimine (A1-4, 59 mg, 0.12 mmol) was dissolved in tetrahydrofuran (10 mL), to the reaction solution was added 1M concentrated hydrochloric acid (0.5 mL) dropwise and the mixture was reacted at room temperature for 4 hours. White solid precipitated. The solid was collected by filtration, and dried to obtain 5-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl)thiazol-3-amine hydrochloride (A1-5, 34 mg, 78.5%). 1H NMR (400 MHz, CDCl3) ? 8.83 (s, 1H), 8.74 (s, 1H), 7.77 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.38 (s, 1H), 4.05 (s, 3H), 3.99 (s, 3H).

Step 6: N-(5-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiophen-3-yl) pentanamide (A1)

[0321] 5-(6-(3,4-Dimethoxyphenyl) pyrazin-2-yl)thiazol-3-amine hydrochloride (A1-5, 32 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), and the solution was cooled under an ice water bath and added with triethylamine (18.5 mg, 0.183 mmol). Additionally, pentanoyl chloride (14.9 mg, 0.123 mmol) was taken and dissolved in dichloromethane (0.5 mL) and the resulting mixture was slowly dropped into the above reaction system. Upon addition, the reaction system was warmed to room temperature and reacted for 16 hours. LCMS detection showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford N-(5-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiophen-3-yl) pentanamide (A1, 19 mg, 53.1%). 1H NMR (400 MHz, DMSO) ? 10.39 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.80 (dd, J=8.4, 1.9 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 3.83 (d, J=19.3 Hz, 3H), 2.32 (t, J=7.4 Hz, 2H), 1.69-1.51 (m, 2H), 1.41-1.29 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Compounds A2-A34 of Examples 2-34 were Prepared Using Experimental Steps Similar to Those in Example 1 Above, and Compounds A1-A34 were Summarized in Table 1.

TABLE-US-00001 TABLE 1 Ex- Com- MS(cald) am- pound [M + H].sup.+/ ple No. Structure MS (found) Name and characterization 1 A1 [00131] 398.15/N/A (HNMR) N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide .sup.1H NMR (400 MHz, DMSO) ? 10.39 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.80 (dd, J = 8.4, 1.9 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.83 (d, J = 19.3 Hz, 3H), 2.32 (t, J = 7.4 Hz, 2H), 1.69-1.51 (m, 2H), 1.41-1.29 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 2 A2 [00132] 314.09/N/A (HNMR) 5-(6-(3,4-dimethoxyphenyl)pyrazin- 2-yl)thiophen-3-amine hydrochloride .sup.1H NMR (400 MHz, CDCl3) ? 8.83 (s, 1H), 8.74 (s, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.38 (s, 1H), 4.05 (s, 3H), 3.99 (s, 3H). 3 A3 [00133] 356.10/356.34 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 4 A4 [00134] 384.13/384.76 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)isobutyramide 5 A5 [00135] 398.15/398.86 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pivalamide 6 A6 [00136] 382.11/382.46 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclopropanecarboxamide 7 A7 [00137] 396.13/396.20 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclobutanecarboxamide 8 A8 [00138] 410.15/410.49 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclopentanecarboxamide 9 A9 [00139] 424.16/424.33 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclohexanecarboxamide 10 A10 [00140] 418.11/418.37 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)benzamide 11 A11 [00141] 398.15/398.43 N-(5-(4-(3,4- dimethoxyphenyl)pyrimidin-2- yl)thiophen-3-yl)pentanamide 12 A12 [00142] 398.15/397.97 N-(5-(6-(2,3- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 13 A13 [00143] 398.15/398.66 N-(5-(6-(2,5- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 14 A14 [00144] 396.13/396.63 N-(5-(6-(2,5- dimethoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclobutanecarboxamide 15 A15 [00145] 400.08/399.94 N-(5-(6-(4-chloro-3- methoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclobutanecarboxamide 16 A16 [00146] 402.10/401.94 N-(5-(6-(4-chloro-3- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 17 A17 [00147] 400.08/399.87 N-(5-(6-(3-chloro-4- methoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclobutanecarboxamide 18 A18 [00148] 398.15/398.24 N-(5-(6-(3,5- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 19 A19 [00149] 402.10/401.91 N-(5-(6-(3-chloro-4- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 20 A20 [00150] 393.13/N/A (HNMR) N-(5-(6-(4-cyano-3- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide .sup.1H NMR (400 MHz, DMSO) ? 10.40 (s, 1H), 9.30 (s, 1H), 9.16 (s, 1H), 8.03-7.87 (m, 4H), 7.73 (s, 1H), 4.08 (s, 3H), 2.32 (t, J = 7.4 Hz, 2H), 1.68- 1.54 (m, 2H), 1.37-1.31 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 21 A21 [00151] 393.13/393.60 N-(5-(6-(3-cyano-4- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 22 A22 [00152] 391.12/N/A (HNMR) N-(5-(6-(3-cyano-4- methoxyphenyl)pyrazin-2- yl)thiophen-3- yl)cyclobutanecarboxamide .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.83 (s, 2H), 8.38 (d, J = 2.0 Hz, 1H), 8.30 (dd, J = 8.8, 2.0 Hz, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 4.05 (s, 3H), 3.28- 3.17 (m, 1H), 2.54-2.38 (m, 2H), 2.36-2.21 (m, 2H), 2.13-1.97 (m, 2H). 23 A23 [00153] 382.11/N/A (HNMR) N-(5-(6-(benzo[d][1,3]dioxol-5- yl)pyrazin-2-yl)thiophen-3- yl)pentanamide .sup.1H NMR (400 MHz, DMSO) ? 10.39 (s, 1H), 9.09 (d, J = 9.6 Hz, 1H), 8.98 (s, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.83-7.66 (m, 3H), 7.12 (d, J = 8.1 Hz, 1H), 6.14 (s, 2H), 2.32 (t, J = 7.4 Hz, 2H), 1.67-1.54 (m, 2H), 1.37- 1.28 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 24 A24 [00154] 380.10/N/A (HNMR) N-(5-(6-(benzo[d][1,3]dioxol-5- yl)pyrazin-2-yl)thiophen-3- yl)cyclobutanecarboxamide .sup.1H NMR (400 MHz, DMSO) ? 10.24 (s, 1H), 9.08 (s, 1H), 8.96 (s, 1H), 7.89 (s, 1H), 7.76 (dd, J = 18.8, 11.4 Hz, 3H), 7.12 (d, J = 8.1 Hz, 1H), 6.14 (s, 2H), 3.22 (dd, J = 16.5, 8.3 Hz, 1H), 2.27 (dd, J = 27.4, 17.4 Hz, 2H), 2.13 (d, J = 8.9 Hz, 2H), 2.01- 1.80 (m, 2H). 25 A25 [00155] 439.14/ N/A (HNMR) 2-(6-(4- (cyclobutanecarboxamido)thiophen- 2-yl)pyrazin-2-yl)-4,5- dimethoxybenzamide .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.78 (s, 1H), 8.64 (s, 1H), 7.70 (d, J = 29.4 Hz, 3H), 7.27 (s, 1H), 7.16 (s, 1H), 4.01 (d, J = 4.3 Hz, 6H), 3.17-3.09 (m, 1H), 2.45-2.35 (m, 2H), 2.28- 2.19 (m, 2H), 2.10-1.97 (m, 2H). 26 A26 [00156] 441.15/441.70 4,5-dimethoxy-2-(6-(4- pentanamidothiophen-2-yl)pyrazin- 2-yl)benzamide 27 A27 [00157] 374.11/ N/A N-(5-(6-(3,4- difluorophenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide .sup.1H NMR (400 MHz, CDCl3) ? 8.86 (s, 1H), 8.84 (s, 1H), 8.07-7.95 (m, 1H), 7.91-7.83 (m, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.46 (s, 1H), 7.34 (dd, J = 18.2, 8.5 Hz, 1H), 2.41 (t, J = 7.6 Hz, 2H), 1.81-1.73 (m, 2H), 1.51- 1.40 (m, 2H), 1.06-0.94 (m, 3H). 28 A28 [00158] 372.09/ N/A N-(5-(6-(3,4- difluorophenyl)pyrazin-2- yl)thiophen-3- yl)cyclobutanecarboxamide 1H NMR (400 MHz, CDC13) 8 8.86 (s, 1H), 8.84 (s, 1H), 8.07-7.97 (m, 1H), 7.85 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 3.24-3.16 (m, 1H), 2.52-2.38 (m, 2H), 2.38-2.22 (m, 2H), 2.13-1.99 (m, 2H). 29 A29 [00159] 412.16/412.20 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)hexanamide 30 A30 [00160] 426.18/426.20 N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)heptanamide 31 A31 [00161] 396.13/396.10 2-cyclopropyl-N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 32 A32 [00162] 410.15/410.20 2-cyclobutyl-N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 33 A33 [00163] 424.16/424.20 2-cyclopentyl-N-(5-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 34 A34 [00164] 372.11/372.10 N-(5-(6-(3-fluoro-4- hydroxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide

Example 35: Preparation of N-(5-(6-(4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)pyrazin-2-yl) thiophen-3-yl) pentanamide (A35) (Method B)

[0322] ##STR00165##

Step 1: 3-(2-Methoxy-4-borate-phenyl)oxetan-3-ol (A35-1)

[0323] 3-(4-bromo-2-methoxyphenyl) oxetan-3-ol (400 mg, 1.54 mmol), potassium acetate (379 mg, 3.86 mmol), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57 mg, 0.08 mmol), and bis(pinacolato)diboron (471 mg, 1.85 mmol) were added to 1,4-dioxane (15 mL) and the mixture was reacted under nitrogen protection at 80? C. for 5 hours. TLC monitoring showed that the reaction was complete. The reaction solution was filtered and the filter cake was washed with ethyl acetate. The reaction solution and the washing solution were combined, and spin dried to obtain 3-(2-methoxy-4-borate-phenyl)oxetan-3-ol (A35-1, crude, 1.54 mmol in theory), which was directly used in the next reaction without any purification.

Step 2: 3-(4-(6-bromopyrazin-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-2)

[0324] 3-(2-Methoxy-4-borate-phenyl)oxetan-3-ol (A35-1, crude, 1.54 mmol), potassium carbonate (512 mg, 3.70 mmol), 2,6-dibromopyrazine (551 mg, 2.32 mmol), and tetrakis(triphenylphosphine)palladium (89 mg, 0.08 mmol) were added to 1,4-dioxane/water (4:1, 15 mL) and the mixture was reacted under nitrogen protection at 80? C. for 5 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with 45 mL of water and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated salt water (20 mL*1), dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 3-(4-(6-bromopyrazin-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-2, 310 mg, 59.6%). MS (ESI) m/z: calcd 337.01 (M+H.sup.+). found 337.00.

Step 3: 3-(4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl) oxetan-3-ol (A35-3)

[0325] 3-(4-(6-bromopyrazin-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-2, 310 mg, 0.92 mmol), (4-bromothiophen-2-yl) boronic acid (191 mg, 0.93 mmol), tetrakis(triphenylphosphine)palladium (55 mg, 0.05 mmol) and potassium carbonate (305 mg, 2.21 mmol) were added to 1,4-dioxane/water (4:1, 15 mL) and the mixture was reacted under nitrogen protection at 60? C. for 0.5 hour. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with water (45 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated saline (20 mL*1), dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography to afford 3-(4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl) oxetan-3-ol (A35-3, 160 mg, 41.6%). MS (ESI) m/z: calcd 419.29 (M+H). found 419.00.

Step 4: 3-(4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl) oxetan-3-ol (A35-4)

[0326] 3-(4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl) oxetan-3-ol (A35-3, 160 mg, 0.38 mmol), cuprous iodide (15 mg, 0.08 mmol), L-proline (35 mg, 0.31 mmol), dimethyl sulfoxide (3 mL), and ammonia (25% wt, 360 mg, 2.57 mmol) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 10 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with 20 mL of water, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated ammonium chloride (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain 3-(4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl) oxetan-3-ol (A35-4, crude, theoretical 0.38 mmol), which was directly used in the next reaction step without any purification.

Step 5: N-(5-(6-(4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)pyrazin-2-yl) thiophen-3-yl) pentanamide (A35)

[0327] 3-(4-(6-(4-Aminothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl) oxetan-3-ol (A35-4, crude, 0.38 mmol) was dissolved in dichloromethane (10 mL). The solution was cooled under an ice water bath, and added with triethylamine (117 mg, 1.16 mmol). Pentanoyl chloride (93 mg, 0.77 mol) was taken and dissolved in dichloromethane (0.5 mL) and the resulting mixture was slowly dropped into the above reaction system. Upon addition, the reaction continued for 1 hour under an ice water bath. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford N-(5-(6-(4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)pyrazin-2-yl) thiophen-3-yl) pentanamide (A35, 32 mg, 19.1%). MS (ESI) m/z: calcd 440.16 (M+H.sup.+). found 440.10 .sup.1H NMR (400 MHz, DMSO) ? 10.39 (s, 1H), 9.19 (s, 1H), 9.06 (s, 1H), 7.89 (d, J=1.4 Hz, 1H), 7.76 (dd, J=13.5, 7.3 Hz, 2H), 7.72 (d, J=1.3 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 5.97 (s, 1H), 5.02 (d, J=6.9 Hz, 2H), 4.67 (d, J=6.9 Hz, 2H), 3.94 (d, J=6.9 Hz, 3H), 2.36-2.29 (m, 2H), 1.64-1.56 (m, 2H), 1.38-1.30 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Compounds A36-A45 of Examples 36-45 were Prepared Using Experimental Steps Similar to Those in Example 35 Above, and Compounds A35-A45 were Summarized in Table 2.

TABLE-US-00002 TABLE 2 MS(cald) Compound [M + H].sup.+/ Example No. Structure MS (found) Name and characterization 35 A35 [00166] 440.16/440.40 N-(5-(6-(4-(3-hydroxyoxetan-3- yl)-3-methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 36 A36 [00167] 451.14/451.20 N-(5-(6-(4-(3-hydroxyisoxazol- 5-yl)-3-methoxyphenyl)pyrazin- 2-yl)thiophen-3-yl)pentanamide 37 A37 [00168] 451.14/451.20 N-(5-(6-(3-methoxy-4-(5-oxo- 4,5-dihydroisoxazol-3- yl)phenyl)pyrazin-2-yl)thiophen- 3-yl)pentanamide 38 A38 [00169] 402.12/402.30 N-(5-(6-(3-fluoro-4-hydroxy-5- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 39 A39 [00170] 452.13/No MS signal (HNMR) N-(5-(6-(3-methoxy-4-(5-oxo- 2,5-dihydro-1,2,4-oxadiazol-3- yl)phenyl)pyrazin-2-yl)thiophen- 3-yl)pentanamide .sup.1H NMR (400 MHz, DMSO) ? 10.76 (s, 1H), 9.29 (d, J = 4.3 Hz, 2H), 8.16 (d, J = 1.4 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 6.52 (s, 1H), 4.00 (s, 3H), 2.35- 2.32 (m, 2H), 1.20-1.16 (m, 2H), 1.09-1.03 (m, 2H), 0.91 (t, J = 8.0 Hz, 3H). 40 A40 [00171] 416.10/416.30 N-(5-(6-(4- (methylsulfonyl)phenyl)pyrazin- 2-yl)thiophen-3-yl)pentanamide 41 A41 [00172] 372.11/372.10 N-(5-(6-(4-fluoro-3- hydroxyphenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 42 A42 [00173] 446.11/446.00 N-(5-(6-(3-methoxy-4- (methylsulfonyl)phenyl)pyrazin- 2-yl)thiophen-3-yl)pentanamide 43 A43 [00174] 444.10/444.10 2-cyclopropyl-N-(5-(6-(3- methoxy-4- (methylsulfonyl)phenyl)pyrazin- 2-yl)thiophen-3-yl)acetamide 44 A44 [00175] 458.11/458.10 2-cyclobutyl-N-(5-(6-(3- methoxy-4- (methylsulfonyl)phenyl)pyrazin- 2-yl)thiophen-3-yl)acetamide 45 A45 [00176] 460.13/460.10 N-(5-(6-(3-methoxy-4- (methylsulfonyl)phenyl)pyrazin- 2-yl)-2-methylthiophen-3- yl)pentanamide

Example 46: Preparation of 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-N-(1H-tetrazol-5-yl) benzamide (B4)

[0328] ##STR00177## ##STR00178##

Step 1: 3-methoxy-4-methoxycarbonylphenyl Boronic Acid Pinacol Ester (B4-1)

[0329] Methyl 4-Bromo-2-methoxybenzoate (10 g, 40.8 mmol), potassium acetate (10.1 g, 103 mmol), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.51 g, 2.06 mmol), bis(pinacolato)diboron (12.44 g, 49.0 mmol) and 1,4-dioxane (100 mL) were successively added to a reaction flask and the mixture was reacted under nitrogen protection at 80? C. for 5 hours. TLC monitoring showed that the reaction was complete. The reaction solution was dried by rotary dryer directly, and purified by column chromatography to afford 3-methoxy-4-methoxycarbonylphenyl boronic acid pinacol ester (B4-1, 11.0 g, 92.3%). .sup.1H NMR (400 MHz, CDCl3) ? 7.78 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.40 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 1.37 (s, 12H).

Step 2: methyl 2-methoxy-4-(6-bromopyrazin-2-yl) benzoate (B4-2)

[0330] 2,6-dibromopyrazine (11.6 g, 48.8 mmol), 3-methoxy-4-methoxycarbonylphenyl boronic acid pinacol ester (B4-1, 11.0 g, 37.6 mmol), potassium carbonate (13.52 g, 98.0 mmol), tetrakis(triphenylphosphine)palladium(2.37 g, 2.05 mmol), 1,4-dioxane (120 mL), and water (10 mL) were added successively to a reaction flask. The mixture was reacted under nitrogen protection at 100? C. for 5 hours, and TLC monitoring showed that the reaction was complete. The most of 1,4-dioxane was removed by rotary evaporation, the residue was added with water (50 mL), and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain methyl 2-methoxy-4-(6-bromopyrazin-2-yl) benzoate (B4-2, 6.67 g, 54.7%). MS (ESI) m/z: calcd 323.00 (M+H.sup.+). found 322.90: .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.00 (s, 1H), 8.68 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.59 (dd, J=8.1, 1.6 Hz, 1H), 4.05 (s, 3H), 3.95 (s, 3H).

Step 3: methyl 2-methoxy-4-(6-bromothiophen-2-yl) pyrazin-2-yl)benzoate (B4-3)

[0331] Methyl 2-methoxy-4-(6-bromopyrazin-2-yl) benzoate (B4-2, 6.67 g, 20.8 mmol), (4-bromothiophen-2-yl) boronic acid (4.30 g, 20.8 mmol), tetrakis(triphenylphosphorus)palladium (1.3 g, 0.86 mmol), potassium carbonate (10.25 g, 74.3 mmol), 1,4-dioxane (120 mL), and water (2.5 mL) were successively added to a reaction flask. The mixture was reacted under nitrogen protection at 60? C. for 0.5 hour, and TLC monitoring showed that the reaction was complete. The most of 1,4-dioxane was removed by rotary evaporation, the residue was added with dichloromethane (60 mL) and water (30 mL), and fractioned. The organic phases were combined, washed with saturated salt water (30 mL*1), dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain methyl 2-methoxy-4-(6-bromothiophen-2-yl) pyrazin-2-yl)benzoate (B4-3, 3.96 g, 47.3%). MS (ESI) m/z: calcd 404.98 (M+H.sup.+). found 404.90: .sup.1H NMR (400 MHz, CDCl3) ? 8.97 (s, 1H), 8.90 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.82 (s, 1H), 7.68 (d, J=6.5 Hz, 1H), 7.44 (s, 1H), 6.98 (s, 1H), 4.08 (s, 3H), 3.96 (s, 3H).

Step 4: methyl 2-methoxy-4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)benzoate (B4-4)

[0332] Methyl 2-methoxy-4-(6-bromothiophen-2-yl) pyrazin-2-yl)benzoate (B4-3, 400 mg, 0.99 mmol), cuprous iodide (47 mg, 0.25 mmol), L-proline (57 mg, 0.50 mmol), dimethyl sulfoxide (25 mL), and ammonia (25% wt, 1.0 g, 5.92 mmol) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 10 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with water (100 mL), and extracted with ethyl acetate (40 mL*3). The organic phases were combined, washed with saturated ammonium chloride (40 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain methyl 2-methoxy-4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)benzoate (B4-4, 450 mg crude, theoretical 0.99 mmol), which was directly used in the next reaction without any purification. MS (ESI) m/z: calcd 342.08 (M+H.sup.+). found 342.10.

Step 5: methyl 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)benzoate (B1)

[0333] Methyl 2-methoxy-4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)benzoate (B4-4, 450 mg crude, theoretical 0.99 mmol) was dissolved in dichloromethane (5 mL). The solution was cooled under an ice water bath, and added with triethylamine (666 mg, 6.59 mmol). Additionally, pentanoyl chloride (318 mg, 2.64 mmol) was taken and dissolved in dichloromethane (1 mL) and the resulting mixture was slowly dropped into the above system. Upon addition, the reaction was warmed to room temperature and reacted for 0.5 hour. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain methyl 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)benzoate (B1, 295 mg, 70.0%). MS (ESI) m/z: calcd 426.14 (M+H.sup.+). found 426.10. .sup.1H NMR (400 MHz, DMSO) ? 10.42 (s, 1H), 9.27 (s, 1H), 9.13 (s, 1H), 7.91 (d, J=3.2 Hz, 2H), 7.85 (s, 2H), 7.74 (s, 1H), 3.98 (s, 3H), 3.84 (s, 3H), 2.32 (t, J=7.4 Hz, 2H), 1.67-1.54 (m, 2H), 1.39-1.30 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Step 6: 2-Methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)benzoic Acid (B2)

[0334] Methyl 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)benzoate (B1, 295 mg, 0.69 mmol), lithium hydroxide monohydrate (146 mg, 3.48 mmol), tetrahydrofuran (4 mL) and water (2 mL) 50 were added successively to a reaction flask and the mixture was reacted at room temperature for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was evaporated by rotary dryer to remove tetrahydrofuran, diluted by adding 5 mL of water, acidified to pH=3-4 using 1M hydrochloric acid and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed successively with water and saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)benzoic acid (B2, 258 mg, 90.4%). MS (ESI) m/z: calcd 412.13 (M+H.sup.+). found 412.10.

Step 7: 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-N-(1H-tetrazol-5-yl) benzamide (B4)

[0335] 2-Methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)benzoic acid (B4-6, 258 mg, 0.63 mmol), 5-aminotetrazole (56 mg, 0.66 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (241 mg, 1.26 mmol), 1-hydroxybenzotriazole (170 mg, 1.26 mmol), N,N-diisopropylethylamine (324 mg, 2.51 mmol), and N, N-dimethylformamide (5 mL) were sequentially added to a reaction flask and the mixture was reacted at room temperature for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed successively with water and saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-N-(1H-tetrazol-5-yl) benzamide (B4, 115 mg, 38.3%). MS (ESI) m/z: calcd 477.15 (M?H.sup.+). found 477.10: .sup.1H NMR (400 MHz, DMSO) ? 10.40 (s, 1H), 9.29 (s, 1H), 9.13 (s, 1H), 8.05-7.82 (m, 3H), 7.73 (d, J=1.3 Hz, 1H), 4.05 (s, 3H), 2.36-2.26 (m, 2H), 1.64-1.57 (m, 2H), 1.44-1.28 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Examples 47-121 (Compounds B1-B78) are Prepared Using Experimental Steps Similar to Those in Example 46 Above, and Compounds B1-B78 are Summarized in Table 3.

[0336]

TABLE-US-00003 TABLE 3 MS(calcd) Ex- Com- [M + H].sup.+/ am- pound MS ple No. Structure (found) Name and characterization 46 B1 [00179] 426.14/ 426.10 Methyl 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzoate 46 B2 [00180] 412.13/ 412.00 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzoic acid 47 B3 [00181] 411.14/ 410.96 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 46 B4 [00182] 479.15/ 477.10 (?) 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide 48 B5 [00183] 477.16/ 477.10 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H- imidazol-2-yl) benzamide 49 B6 [00184] 438.14/ 438.10 4-(6-(4- (cyclohexanecarboxamido) thiophen-2-yl)pyrazin-2-yl)-2- methoxybenzoic acid 50 B7 [00185] 518.15/ 518.00 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(N,N- dimethylsulfamoyl)benzamide 51 B8 [00186] 494.12/ 494.20 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(thiazol-2- yl)benzamide 52 B9 [00187] 465.14/ 464.80 2-methoxy-4-(6-(4- butyramidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide 53 B10 [00188] 437.11/ 435.10 (?) 2-methoxy-4-(6-(4- acetamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide 54 B11 [00189] 451.12/ 449.10 (?) 2-methoxy-4-(6-(4- propionamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide 55 B12 [00190] 477.14/ 475.10 (?) 2-methoxy-4-(6-(4-(2- cyclopropylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(1H- tetrazol-5-yl)benzamide 2- -4-(6-(4-(2- -2- -2- )-N- (1H- -5- 56 B13 [00191] 503.12/ No MS signals (HNMR) 2-methoxy-4-(6-(4-(2-(furan-2- yl)acetamido)thiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.74 (s, 1H), 9.29 (s, 1H), 9.16 (s, 1H), 7.93 (d, J = 14.2 Hz, 4H), 7.75 (s, 1H), 7.59 (s, 1H), 6.43 (s, 1H), 6.31 (s, 1H), 5.97 (d, J = 16.9 Hz, 1H), 4.07 (s, 3H), 3.75 (s, 2H). 57 B14 [00192] 519.18/ No MS signals (HNMR) 2-methoxy-4-(6-(4-(2- cyclohexylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(1H- tetrazol-5-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.40 (s, 1H), 9.28 (s, 1H), 9.12 (s, 1H), 7.93 (d, J = 12.5 Hz, 3H), 7.75 (s, 1H), 5.93 (d, J = 14.2 Hz, 1H), 4.08 (s, 3H), 2.21 (d, J = 6.8 Hz, 2H), 1.71-1.61 (m, 5H), 1.27-1.17 (m, 6H). 58 B15 [00193] 493.17/ 493.10 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(1-methyl- 1H-tetrazol-5-yl)-benzamide 59 B16 [00194] 493.17/ 493.20 2-methoxy-4-(6-(4- hexanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide 60 B17 [00195] 507.18/ No MS signals (HNMR) 2-methoxy-4-(6-(4- heptanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.41 (s, 1H), 9.29 (s, 1H), 9.13 (s, 1H), 7.93 (d, J = 13.1 Hz, 3H), 7.74 (s, 1H), 4.07 (s, 3H), 2.39- 2.27 (m, 2H), 1.66-1.58 (m, 2H), 1.36-1.25 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H), 0.92-0.84 (m, 2H). 61 B18 [00196] 521.20/ 519.10 (?) 2-methoxy-4-(6-(4- octanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide 62 B19 [00197] 535.22/ No MS signals (HNMR) 2-methoxy-4-(6-(4- nonanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.41 (s, 1H), 9.30 (s, 1H), 9.14 (s, 1H), 7.90 (dd, J = 28.4, 11.5 Hz, 4H), 7.74 (s, 1H), 4.06 (s, 3H), 2.39-2.26 (m, 2H), 1.68- 1.57 (m, 2H), 1.34-1.23 (m, 10H), 0.87 (s, 3H). 63 B20 [00198] 549.23/ No MS signals (HNMR) 2-methoxy-4-(6-(4- decanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.40 (s, 1H), 9.29 (s, 1H), 9.13 (s, 1H), 7.93 (d, J = 13.4 Hz, 4H), 7.74 (s, 1H), 4.06 (s, 3H), 2.35- 2.28 (m, 2H), 1.66-1.58 (m, 2H), 1.30-1.24 (m, 10H), 1.18 (t, J = 7.3 Hz, 2H), 0.87 (t, J = 6.4 Hz, 3H) 64 B21 [00199] 563.25/ No MS signals (HNMR) 2-methoxy-4-(6-(4- undecanamidothiophen-2- yl)pyrazin-2-yl)-N-(1H-tetrazol- 5-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.41 (s, 1H), 9.29 (s, 1H), 9.13 (s, 1H), 7.91 (dd, J = 22.8, 11.0 Hz, 4H), 7.74 (s, 1H), 4.06 (s, 3H), 2.35-2.28 (m, 2H), 1.61 (s, 2H), 1.30-1.24 (m, 14H), 0.86 (s, 3H). 65 B22 [00200] 549.18/ 549.20 methyl 4-(2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamido)-1- methyl-1H-imidazole-2- carboxylate 66 B23 [00201] 479.14/ 479.10 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(1,3,4- oxadiazol-2-yl)benzamide 67 B24 [00202] 495.12/ 495.10 2-methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(1,3,4- thiadiazol-2-yl)benzamide 68 B25 [00203] 491.15/ 491.10 2-methoxy-4-(6-(4-(2- cyclopropylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(1-methyl- 1H-tetrazol-5-yl)benzamide 69 B26 [00204] 505.17/ 505.30 2-methoxy-4-(6-(4-(2- cyclobutylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(1-methyl- 1H-tetrazol-5-yl)benzamide 70 B27 [00205] 519.18/ 519.10 2-methoxy-4-(6-(4-(2- cyclopentylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(1-methyl- 1H-tetrazol-5-yl)benzamide 71 B28 [00206] 533.20/ 533.20 2-methoxy-4-(6-(4-(2- cyclohexylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(1-methyl- 1H-tetrazol-5-yl)benzamide 72 B29 [00207] 481.18/ 481.20 N-(5-(6-(3-methoxy-4- (morpholine-4- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 73 B30 [00208] 467.20/ 467.10 N-(5-(6-(3-methoxy-4- (morpholinomethyl)phenyl) pyrazin-2-yl)thiophen-3- yl)pentanamide 74 B31 [00209] 479.17/ 479.20 2-cyclopropyl-N-(5-(6-(3- methoxy-4-(morpholine-4- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 75 B32 [00210] 493.18/ 493.30 2-cyclobutyl-N-(5-(6-(3- methoxy-4-(morpholine-4- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 76 B33 [00211] 507.20/ 507.20 2-cyclopentyl-N-(5-(6-(3- methoxy-4-(morpholine-4- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 77 B34 [00212] 465.19/ 465.2 2-cyclopropyl-N-(5-(6-(3- methoxy-4- (morpholinomethyl)phenyl) pyrazin-2-yl)thiophen-3- yl)acetamide 78 B35 [00213] 479.20/ 479.20 2-cyclobutyl-N-(5-(6-(3- methoxy-4- (morpholinomethyl)phenyl) pyrazin-2-yl)thiophen-3- yl)acetamide 79 B36 [00214] 493.22/ 493.20 2-cyclopentyl-N-(5-(6-(3- methoxy-4- (morpholinomethyl)phenyl) pyrazin-2-yl)thiophen-3- yl)acetamide 80 B37 [00215] 494.21/ 494.20 N-(5-(6-(3-methoxy-4-(4- methylpiperazine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 81 B38 [00216] 492.20/ 492.20 2-cyclopropyl-N-(5-(6-(3- methoxy-4-(4-methylpiperazine- 1-carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 82 B39 [00217] 506.21/ 506.10 2-cyclobutyl-N-(5-(6-(3- methoxy-4-(4-methylpiperazine- 1-carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 83 B40 [00218] 520.23/ 520.20 2-cyclopentyl-N-(5-(6-(3- methoxy-4-(4-methylpiperazine- 1-carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 84 B41 [00219] 521.19/ 521.20 2-methoxy-N-(3-methoxy-1- methyl-1H-pyrazol-4-yl)-4-(6- (4-pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 85 B42 [00220] 519.17/ 519.10 4-(6-(4-(2- cyclopropylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-(3-methoxy-1-methyl-1H- pyrazol-4-yl)benzamide 86 B43 [00221] 533.19/ 533.10 4-(6-(4-(2- cyclobutylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-(5-methoxy-1-methyl-1H- pyrazol-4-yl)benzamide 87 B44 [00222] 547.20/ 547.30 4-(6-(4-(2- cyclopentylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-(5-methoxy-1-methyl-1H- pyrazol-4-yl)benzamide 88 B45 [00223] 505.18/ 505.30 2-(bicyclo[1.1.1]pentan-1-yl)-N- (5-(6-(3-methoxy-4- (morpholine-4- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 89 B46 [00224] 477.13/ 477.20 4-(6-(4-(2- cyclopropylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-(1,3,4-oxadiazol-2- yl)benzamide 90 B47 [00225] 577.29/ 577.20 N-(5-(6-(3-methoxy-4-(4-(1- methylpiperidin-4- yl)piperazine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 91 B48 [00226] 507.20/ 507.30 2-cyclopropyl-N-(5-(6-(3- methoxy-4-(4- methoxypiperidine-1 - carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 92 B49 [00227] 521.21/ 521.30 2-cyclobutyl-N-(5-(6-(3- methoxy-4-(4- methoxypiperidine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 93 B50 [00228] 575.27/ 575.40 2-cyclopropyl-N-(5-(6-(3- methoxy-4-(4-(1- methylpiperidin-4- yl)piperazine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 94 B51 [00229] 589.29/ 589.30 2-cyclobutyl-N-(5-(6-(3- methoxy-4-(4-(1- methylpiperidin-4- yl)piperazine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 95 B52 [00230] 603.30/ 603.40 2-cyclopentyl-N-(5-(6-(3- methoxy-4-(4-(1- methylpiperidin-4- yl)piperazine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 96 B53 [00231] 509.21/ 509.20 N-(5-(6-(3-methoxy-4-(4- methoxypiperidine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)pentanamide 97 B54 [00232] 535.23/ 535.30 2-cyclopentyl-N-(5-(6-(3- methoxy-4-(4- methoxypiperidine-1- carbonyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide 98 B55 [00233] 496.23/ 496.30 N-(2-(dimethylamino)ethyl)-2- methoxy-N-methyl-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 99 B56 [00234] 494.21/ 494.30 4-(6-(4-(2- cyclopropylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(2- (dimethylamino)ethyl)-2- methoxy-N-methylbenzamide 100 B57 [00235] 508.23/ 508.20 4-(6-(4-(2- cyclobutylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(2- (dimethylamino)ethyl)-2- methoxy-N-methylbenzamide 101 B58 [00236] 522.25/ 522.30 4-(6-(4-(2- cyclopentylacetamido)thiophen- 2-yl)pyrazin-2-yl)-N-(2- (dimethylamino)ethyl)-2- methoxy-N-methylbenzamide 102 B59 [00237] 522.25/ 522.40 2-methoxy-N-methyl-N-(1- methylpiperidin-4-yl)-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 103 B60 [00238] 520.23/ 520.30 4-(6-(4-(2- cyclopropylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-methyl-N-(1-methylpiperidin- 4-yl)benzamide 104 B61 [00239] 548.26/ 548.30 4-(6-(4-(2- cyclopentylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-methyl-N-(1-methylpiperidin- 4-yl)benzamide 105 B62 [00240] 491.14/ 491.20 4-(6-(4-(2- cyclobutylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-(1,3,4-oxadiazol-2- yl)benzamide 106 B63 [00241] 534.25/ 534.40 4-(6-(4-(2- cyclobutylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-methyl-N-(1-methylpiperidin- 4-yl)benzamide 107 B64 [00242] 505.16/ 505.10 4-(6-(4-(2- cyclopentylacetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy- N-(1,3,4-oxadiazol-2- yl)benzamide 108 B65 [00243] 522.25/ 522.20 2-methoxy-N-methyl-N-(1- methylpiperidin-4-yl)-4-(6-(5- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 109 B66 [00244] 522.25/ 522.30 2-methoxy-N-methyl-N-(1- methylpiperidin-4-yl)-4-(2-(4- pentanamidothiophen-2- yl)pyrimidin-4-yl)benzamide 110 B67 [00245] 522.25/ 522.20 2-methoxy-N-methyl-N-(1- methylpiperidin-4-yl)-4-(6-(5- pentanamidothiophen-3- yl)pyrazin-2-yl)benzamide 111 B68 [00246] 550.28/ 550.20 N-(1-isopropylpiperidin-4-yl)-2- methoxy-N-methyl-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 112 B69 [00247] 548.26/ 548.30 N-(1-cyclopropylpiperidin-4- yl)-2-methoxy-N-methyl-4-(6- (4-pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 113 B70 [00248] 590.23/ 590.10 2-methoxy-N-methyl-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(1-(2,2,2- trifluoroethyl)piperidin-4- yl)benzamide 114 B71 [00249] 588.27/ 588.20 2-methoxy-N-methyl-N-(1-(1- methyl-1H-pyrazol-4- yl)piperidin-4-yl)-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 115 B72 [00250] 586.25/ 586.30 2-methoxy-N-methyl-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)-N-(1- (pyrimidin-2-yl)piperidin-4- yl)benzamide 116 B73 [00251] 510.23/ 510.40 2-fluoro-N-methyl-N-(1- methylpiperidin-4-yl)-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 117 B74 [00252] 528.22/ 528.20 2,6-difluoro-N-methyl-N-(1- methylpiperidin-4-yl)-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 118 B75 [00253] 547.27/ 547.50 N-cyclopropyl-2-methoxy-N-(1- methylpiperidin-4-yl)-4-(6-(4- pentanamidothiophen-2- yl)pyridin-2-yl)benzamide 119 B76 [00254] 548.26/ 548.40 N-cyclopropyl-2-methoxy-N-(1- methylpiperidin-4-yl)-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 120 B77 [00255] 588.27/ 588.40 2-methoxy-N-(1-methyl-1H- pyrazol-4-yl)-N-(1- methylpiperidin-4-yl)-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide 121 B78 [00256] 574.28/ 574.40 N-cyclopropyl-N-(1- cyclopropylpiperidin-4-yl)-2- methoxy-4-(6-(4- pentanamidothiophen-2- yl)pyrazin-2-yl)benzamide

Example 122: Preparation of 3-(4-(cyclobutylformamido) thiophen-2-yl)-5-(3,4-dimethoxyphenyl) isonicotinamide (C1)

[0337] ##STR00257## ##STR00258##

Step 1: 3-Bromo-5-(3,4-dimethoxyphenyl)isonicotinonitrile (C1-1)

[0338] 3,5-dibromo-4-cyanopyridine (1.5 g, 5.73 mmol), 3,4-dimethoxyphenylboronic acid (1.15 g, 6.30 mmol), tetrakis(triphenylphosphine)palladium(132 mg, 0.12 mmol), potassium carbonate (1.82 g, 13.17 mmol), 1,4-dioxane (20 mL), and water (5 mL) were added to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. for 14 hours, and TLC monitoring showed that the reaction was complete. The most of 1,4-dioxane was removed by rotary evaporation, the residue was diluted by adding 25 mL of water, and extracted with dichloromethane (15 mL*3). The organic phases were combined, washed with saturated salt water (15 mL*1), dried over anhydrous sodium sulfate, and purified by column chromatography after rotary drying to obtain 3-bromo-5-(3,4-dimethoxyphenyl)isonicotinonitrile (C1-1, 676 mg, 37.0%). .sup.1H NMR (400 MHz, DMSO) ? 9.01 (s, 1H), 8.89 (s, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.26 (dd, J=8.3, 2.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H).

Step 2: 3-(4-bromothiophen-2-yl)-5-(3,4-dimethoxy) isonicotinonitrile (C1-2)

[0339] 3-Bromo-5-(3,4-dimethoxyphenyl)isonicotinonitrile (C1-1, 470 mg, 0.48 mmol), (4-bromothiophen-2-yl) boronic acid (335.1 mg, 1.62 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 0.029 mmol), potassium carbonate (610 mg, 4.42 mmol), 1,4-dioxane (10 mL), and water (2.5 mL) were added to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. for 14 hours, and TLC monitoring showed that the reaction was complete. The most of 1,4-dioxane was removed by rotary evaporation, the residue was diluted by adding water (15 mL), and extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated salt water (5 mL*1), dried over anhydrous sodium sulfate, and purified by column chromatography after rotary drying to obtain 3-(4-bromothiophen-2-yl)-5-(3,4-dimethoxy) isonicotinonitrile (C1-2, 190.5 mg, 30.8%). .sup.1H NMR (400 MHz, DMSO) ? 8.94 (s, 1H), 8.90 (s, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.77 (d, J=1.4 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.29 (dd, J=8.3, 2.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H).

Step 3: 3-(3,4-Dimethoxyphenyl)-5-(4-((diphenylmethylene) amino) thiophen-2-yl) isonicotinonitrile (C1-3)

[0340] 3-(4-bromothiophen-2-yl)-5-(3,4-dimethoxy) isonicotinonitrile (C1-2, 100 mg, 0.238 mmol), benzophenone imine (64.83 mg, 0.358 mmol), 1.1-binaphthyl-2.2-diphenyl phosphine (29.70 mg, 0.048 mmol), tris(dibenzylideneacetone)dipalladium (21.84 mg, 0.024 mmol), sodium tert-butoxide (68.76 mg, 0.715 mmol), and toluene (5 mL) were sequentially added to a reaction flask. The mixture was reacted under nitrogen protection at 100? C. for 16 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford 3-(3,4-Dimethoxyphenyl)-5-(4-((diphenylmethylene) amino) thiophen-2-yl) isonicotinonitrile (C1-3, 110 mg, 92.1%). .sup.1H NMR (400 MHz, CDCl3) ? 8.72 (s, 1H), 8.69 (s, 1H), 7.82 (d, J=6.2 Hz, 2H), 7.47-7.40 (m, 10H), 6.82 (d, J=3.5 Hz, 1H), 6.77 (s, 1H), 6.65 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H).

Step 4: 3-(4-aminothiophen-2-yl)-5-(3,4-dimethoxyphenyl) isonicotinonitrile Hydrochloride (C1-4)

[0341] 3-(3,4-Dimethoxyphenyl)-5-(4-((diphenylmethylene) amino) thiophen-2-yl) isonicotinonitrile (C1-3, 110 mg, 0.219 mmol) was dissolved in dichloromethane. Two drops of concentrated hydrochloric acid were added and the mixture was reacted at room temperature for 4 hours. White solid precipitated, the reaction solution was filtered and the solid was collected, and dried to obtain 3-(4-aminothiophen-2-yl)-5-(3,4-dimethoxyphenyl) isonicotinonitrile hydrochloride (C.sub.1-4, 47 mg, 57.4%). MS (ESI) m/z: calcd 338.09 (M+H.sup.+). found 338.10.

Step 5: N-(5-(4-cyano-5-(3,4-dimethoxyphenyl) pyridin-3-yl) thiophen-3-yl) cyclobutylformamide (C2)

[0342] 3-(4-aminothiophen-2-yl)-5-(3,4-dimethoxyphenyl) isonicotinonitrile hydrochloride (C.sub.1-4, 30 mg, 0.08 mmol) was dissolved in 3 mL of dichloromethane. The system was cooled under an ice water bath, and added with triethylamine (40.4 mg, 0.40 mmol). Additionally, cyclobutylcarbonyl chloride (11.61 mg, 0.098 mmol) was taken and dissolved in dichloromethane (0.5 mL) and the resulting mixture was slowly dropped into the reaction system. Upon addition, the reaction was warmed to room temperature and reacted for 3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford N-(5-(4-cyano-5-(3,4-dimethoxyphenyl) pyridin-3-yl) thiophen-3-yl) cyclobutylformamide (C2, 32 mg, 95%). .sup.1H NMR (400 MHz, CDCl3) ? 8.88 (s, 1H), 8.75 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.19 (dd, J=8.3, 2.0 Hz, 1H), 7.14 (d, J=1.9 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 3.99 (s, 6H), 3.25-3.13 (m, 1H), 2.51-2.37 (m, 2H), 2.31-2.25 (m, 2H).

Step 6: 3-(4-(cyclobutylformamido) thiophen-2-yl)-5-(3,4-dimethoxyphenyl) isonicotinamide (C1)

[0343] N-(5-(4-cyano-5-(3,4-dimethoxyphenyl) pyridin-3-yl) thiophen-3-yl) cyclobutylformamide (C2, 2 mg, 0.0048 mmol), sodium tert-butoxide (1.68 mg, 0.015 mmol), and tert butanol (3 mL) were added to a reaction flask, heated to 50? C. and reacted for 2 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched by adding ice water (10 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed successively with saturated salt water, dried over anhydrous sodium sulfate, and spin-dried to obtain 3-(4-(cyclobutylformamido) thiophen-2-yl)-5-(3,4-dimethoxyphenyl) isonicotinamide (C1, 1.8 mg,). .sup.1H NMR (400 MHz, CDCl3) ? 8.74 (s, 1H), 8.64 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.12 (d, J=1.5 Hz, 1H), 7.09 (dd, J=8.0, 1.7 Hz, 1H), 6.97 (d, J=8.3 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.20-3.12 (m, 1H), 2.44-2.36 (m, 2H), 2.28-2.20 (m, 2H).

Example 123-124 were Prepared Using Experimental Steps Similar to Those in Example 122 Above, and Compounds C1-C4 were Summarized in Table 4.

TABLE-US-00004 TABLE 4 MS(calcd) [M + H].sup.+/ Compound MS Example No. Structure (found) Name and characterization 122 C1 [00259] 438.14/ N/A (HNMR) 3-(4- (cyclobutanecarboxamido)thiophen- 2-yl)-5-(3,4- dimethoxyphenyl)isonicotinamide .sup.1H NMR (400 MHz, CDCl3) ? 8.74 (s, 1H), 8.64 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.12 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 8.0, 1.7 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.20-3.12 (m, 1H), 2.44-2.36 (m, 2H), 2.28-2.20 (m, 2H). 122 C2 [00260] 420.13/ N/A (HNMR) N-(5-(4-cyano-5-(3,4- dimethoxyphenyl)pyridin-3- yl)thiophen-3- yl)cyclobutanecarboxamide .sup.1H NMR (400 MHz, CDCl3) ? 8.88 (s, 1H), 8.75 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.19 (dd, J = 8.3, 2.0 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.99 (s, 6H), 3.25-3.13 (m, 1H), 2.51- 2.37 (m, 2H), 2.28 (dd, J = 17.3, 8.6 Hz, 2H). 123 C3 [00261] 440.16/ N/A (HNMR) 3-(3,4-dimethoxyphenyl)-5-(4- pentanamidothiophen-2- yl)isonicotinamide .sup.1H NMR (400 MHz, CDCl3) ? 8.74 (s, 1H), 8.64 (s, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.27 (s, 1H), 7.12 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.36 (t, J = 7.5 Hz, 2H), 1.76-1.71 (m, 2H), 1.45-1.39 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). 124 C4 [00262] 422.15 N/A (HNMR) N-(5-(4-cyano-5-(3,4- dimethoxyphenyl)pyridin-3- yl)thiophen-3-yl)pentanamide .sup.1H NMR (400 MHz, CDCl3) ? 8.89 (s, 1H), 8.75 (s, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.19 (dd, J = 8.2, 1.9 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.99 (s, 6H), 2.40 (t, J = 7.6 Hz, 2H), 1.79-1.74 (m, 2H), 1.49-1.40 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H).

Example 125: Preparation of N-(4-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) amino) cyclohexyl) cyclobutylformamide (D2)

[0344] ##STR00263##

Step 1: N.SUP.1.-(6-(3,4-Dimethoxyphenyl) pyrazin-2-yl) cyclohexan-1,4-diamine (D1)

[0345] 2-bromo-6-(3,4-dimethoxyphenyl) pyrazine (A1-2, 50 mg, 0.17 mmol), 1,4-cyclohexanediamine (97 mg, 0.85 mmol), sodium tert-butoxide (33 mg, 0.34 mmol), 1,1-binaphthyl-2.2-diphenyl phosphine (10.6 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (7.3 mg, 0.008 mmol), and toluene (10 mL) were sequentially added to a reaction flask. The mixture was reacted under nitrogen protection at 110? C. for 4 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, spin-dried to remove solvent and purified by column chromatography to afford N.sup.1-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) cyclohexan-1,4-diamine (D1, 25 mg, 45.0%). .sup.1H NMR (400 MHz, DMSO) ? 8.23 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.96 (d, J=7.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.04 (dt, J=13.9, 7.0 Hz, 2H), 2.05 (s, 2H), 1.87 (s, 2H), 1.26 (s, 4H).

Step 2: N-(4-((6-(3,4-dimethoxyphenyl) pyrazin-2-yl) amino) cyclohexyl) cyclobutylformamide (D2)

[0346] N.sup.1-(6-(3,4-Dimethoxyphenyl) pyrazin-2-yl) cyclohexan-1,4-diamine (D1, 14 mg, 0.043 mmol) was dissolved in dichloromethane (5 mL) and then cyclobutylcarbonyl chloride (6.1 mg, 0.051 mmol) was added. The mixture was reacted at room temperature for 2 hours. TLC monitoring showed that the reaction was complete. The reaction system was quenched by adding water (10 mL) and fractioned. The aqueous phase was extracted again with dichloromethane (5 mL). The organic phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and purified by column chromatography after rotary drying to obtain N-(4-((6-(3,4-dimethoxyphenyl) pyrazin-2-yl) amino) cyclohexyl) cyclobutylformamide (D2, 8 mg, 45.3%). MS (ESI) m/z: calcd 411.23 (M+H.sup.+). found 411.57: .sup.1H NMR (400 MHz, CDCl3) ? 8.26 (s, 1H), 7.80 (s, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.55 (dd, J=8.3, 1.9 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 5.20 (d, J=7.6 Hz, 1H), 4.70 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.37-3.26 (m, 1H), 3.03-2.94 (m, 1H), 2.34-2.31 (m, 4H), 2.21-2.07 (m, 4H), 1.93-1.86 (m, 1H), 1.35-1.22 (m, 4H), 0.96-0.77 (m, 2H).

Example 126: Preparation of 3-(2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-yl)-1,1-diethylurea (D4)

[0347] ##STR00264## ##STR00265##

Step 1: 6-(3,4-Dimethoxyphenyl) pyrazin-2-nitrile (D4-1)

[0348] 2-bromo-6-(3,4-dimethoxyphenyl) pyrazine (A1-2, 520 mg, 1.76 mmol), cuprous cyanide (189 mg, 2.11 mmol), and N-methylpyrrolidone (14 mL) were added successively to a reaction flask and the mixture was reacted at 180? C. for 1 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (70 mL) and extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed successively with water and saturated salt water, dried over anhydrous sodium sulfate to obtain 6-(3,4-dimethoxyphenyl) pyrazin-2-nitrile (D4-1, 268 mg, 63.1%). .sup.1H NMR (400 MHz, DMSO) ? 9.58 (s, 1H), 9.09 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.16 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).

Step 2: 6-(3,4-Dimethoxyphenyl) pyrazin-2-formamide (D4-2)

[0349] 6-(3,4-Dimethoxyphenyl) pyrazin-2-nitrile (D4-1, 268 mg, 1.11 mmol) was dissolved in trifluoroacetic acid/concentrated sulfuric acid (4/1, 10 mL) and reacted at 50? C. for 3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled under an ice water bath, and alkalized to pH=8-11 using 2 M sodium hydroxide solution. Solid precipitates were observed; the reaction solution was filtered, and the solid was collected and dried to obtain 6-(3,4-dimethoxyphenyl) pyrazin-2-formamide (D4-2, 201 mg, 69.8%). .sup.1H NMR (400 MHz, DMSO) ? 9.44 (s, 1H), 9.04 (s, 1H), 8.48 (s, 1H), 8.07-7.87 (m, 3H), 7.12 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H).

Step 3: 6-(3,4-Dimethoxyphenyl) pyrazin-2-thioamide (D4-3)

[0350] 6-(3,4-Dimethoxyphenyl) pyrazin-2-formamide (D4-2, 201 mg, 0.775 mmol), lawesson's reagent (188 mg, 0.465 mmol), and acetonitrile (10 mL) were added to a reaction flask and the mixture was reacted at 80? C. for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, spin-dried and purified by column chromatography to afford 6-(3,4-dimethoxyphenyl) pyrazin-2-thioamide (D4-3, 157 mg, 73.5%). .sup.1H NMR (400 MHz, DMSO) ? 10.41 (s, 1H), 10.18 (s, 1H), 9.44 (d, J=6.2 Hz, 2H), 8.09-7.83 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H).

Step 4: methyl 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carboxylate (D4-4)

[0351] 6-(3,4-Dimethoxyphenyl) pyrazin-2-thioamide (D4-3, 142 mg, 0.52 mmol), methyl bromopyruvate (140 mg, 0.62 mmol), and methanol (15 mL) were added successively to a reaction flask and the mixture was reacted at 70? C. for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature. Solid precipitates were observed; the reaction solution was filtered, and the solid was collected and dried to obtain methyl 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carboxylate (D4-4, 82 mg, 44.1%). .sup.1H NMR (400 MHz, DMSO) ? 9.42 (s, 1H), 9.20 (s, 1H), 8.80 (s, 1H), 7.87 (dd, J=8.5, 1.9 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 3.92 (s, 6H), 3.87 (s, 3H).

Step 5: 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carboxylic Acid (D4-5)

[0352] Methyl 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carboxylate (D4-4, 80 mg, 0.224 mmol), lithium hydroxide monohydrate (47 mg, 1.12 mmol), and tetrahydrofuran/water (3/1, 4 mL) were added successively to a reaction flask and the mixture was reacted at 40? C. for 2 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled under an ice water bath, acidified with 2 M hydrochloric acid, and adjusted to pH=3-4. Solid precipitates were observed; the reaction solution was filtered, and the solid was collected and dried to obtain 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carboxylic acid (D4-5, 75.0 mg, 97.5%). .sup.1H NMR (400 MHz, DMSO) ? 9.41 (s, 1H), 9.19 (s, 1H), 8.70 (s, 1H), 7.87 (dd, J=8.4, 1.9 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H).

Step 6: Tert-Butyl 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carbamate (D3)

[0353] 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carboxylic acid (D4-5, 50.0 mg, 0.146 mmol), triethylamine (44.3 mg, 0.438 mmol), and tert butanol (5 mL) were added successively to a reaction flask and diphenyl azidophosphate (80.1 mg, 0.292 mmol, diluted with 0.5 mL tert butanol) was added dropwise. Upon addition, the reaction system was heated to 85? C. and reacted for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford tert-butyl 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) 50 thiazol-4-carbamate (D3, 25 mg, 41.3%). .sup.1H NMR (400 MHz, CDCl3) ? 9.20 (s, 1H), 9.02 (s, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.73-7.61 (m, 2H), 7.47 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 1.59 (s, 9H).

Step 7: 3-(2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-yl)-1,1-diethylurea (D4)

[0354] Tert-Butyl 2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-carbamate (D3, 18 mg, 0.043 mmol) and hydrogen chloride ethyl acetate solution (3 M, 5 mL) were sequentially added to a reaction flask, and the mixture was reacted at room temperature for 1 hour. Solid precipitates were observed, and the solid was collected by filtration and transferred to a reaction flask. Dichloromethane (2 mL) and triethylamine (27.3 mg, 0.27 mmol) were added. Additionally, N,N-diethylchloroformamide (14.9 mg, 0.11 mmol) was taken and dissolved in dichloromethane (0.5 mL) and added dropwise to the above system. Upon addition, the reaction was carried out at room temperature for 2 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford 3-(2-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiazol-4-yl)-1,1-diethylurea (D4, 0.8 mg, 4.5%). MS (ESI) m/z: calcd 414.15 (M+H.sup.+). found 414.10: .sup.1H NMR (400 MHz, CDCl3) ? 9.16 (s, 1H), 9.01 (s, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.70 (dd, J=8.3, 1.9 Hz, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.46 (q, J=7.2 Hz, 4H), 1.31 (t, J=7.2 Hz, 6H).

Example 127: Preparation of 2-methoxy-4-(4-(4-Pentamidothiophen) pyrimidin-2-yl)-N-methyl-N-(1-methylpiperidin-4-yl) benzamide (D5)

[0355] ##STR00266## ##STR00267##

Step 1: 2-bromo-4-(4-bromothiophen-2-yl) pyrimidine (D5-1)

[0356] 2,4-dibromopyrimidine (100 mg, 0.42 mmol), (4-bromothiophen-2-yl) boronic acid (87 mg, 0.42 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.021 mmol), potassium carbonate (87 mg, 0.63 mmol), 1,4-dioxane (1.6 mL), and water (0.4 mL) were added sequentially. The mixture was reacted under nitrogen protection at 80? C. for 4 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain 2-bromo-4-(4-bromothiophen-2-yl) pyrimidine (D5-1, 90 mg, 67.0%). MS (ESI) m/z: calcd 318.85 (M+H.sup.+). found 318.90.

Step 2: methyl 4-(4-(4-bromothiophen-2-yl) pyrimidin-2-yl)-2-methoxybenzoate (D5-2)

[0357] 2-bromo-4-(4-bromothiophen-2-yl) pyrimidine (D5-1, 90 mg, 0.28 mmol), 3-methoxy-4-methoxycarbonylphenylborate pinacol ester (B4-1, 98 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (32 mg, 0.028 mmol), potassium carbonate (58 mg, 0.42 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) were added. The mixture was reacted under nitrogen protection at 80? C. for 2 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to obtain methyl 4-(4-(4-bromothiophen-2-yl) pyrimidin-2-yl)-2-methoxybenzoate (D5-2, 101 mg, 88.9%). .sup.1H NMR (400 MHz, DMSO) ? 9.00 (d, J=5.3 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 8.04 (d, J=6.7 Hz, 2H), 7.84 (d, J=8.0 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H).

Step 3: methyl 4-(4-(4-aminothiophen-2-yl) pyrimidin-2-yl)-2-methoxybenzoate (D5-3)

[0358] Methyl 4-(4-(4-bromothiophen-2-yl) pyrimidin-2-yl)-2-methoxybenzoate (D5-2, 100 mg, 0.247 mmol), cuprous iodide (9.4 mg, 0.049 mmol), L-proline (11.4 mg, 0.10 mmol), dimethyl sulfoxide (2 mL), and ammonia (25% wt, 200 mg, 1.48 mmol) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with water (10 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated ammonium chloride (5 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain methyl 4-(4-(4-aminothiophen-2-yl) pyrimidin-2-yl)-2-methoxybenzoate (D5-3, 105 mg crude, theoretical 0.247 mmol), which was directly used in the next reaction without any purification. MS (ESI) m/z: calcd 342.08 (M+H.sup.+). found 342.10.

Step 4: methyl 2-Methoxy-4-(4-(4-pentamidothiophen-2-yl) pyrimidin-2-yl) benzoate (D5-4)

[0359] Methyl 4-(4-(4-aminothiophen-2-yl) pyrimidin-2-yl)-2-methoxybenzoate (D5-3, 105 mg crude, theoretical 0.247 mmol) was dissolved in dichloromethane (5 mL). The reaction system was cooled under an ice water bath, and added with triethylamine (31 mg, 0.31 mmol). Additionally, pentanoyl chloride (56 mg, 0.46 mmol) was taken and dissolved in dichloromethane (1 mL) and the resulting mixture was slowly dropped into the reaction system. Upon addition, the reaction was warmed to room temperature and reacted for 0.5 hour. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain methyl 2-methoxy-4-(4-(4-pentamidothiophen-2-yl) pyrimidin-2-yl) benzoate (D5-4, 67 mg, 63.8%). MS (ESI) m/z: calcd 426.14 (M+H.sup.+). found 426.10.

Step 5: 2-Methoxy-4-(4-(4-pentamidothiophen-2-yl) pyrimidin-2-yl)benzoic Acid (D5-5)

[0360] Methyl 2-methoxy-4-(4-(4-pentamidothiophen-2-yl) pyrimidin-2-yl) benzoate (D5-4, 67 mg, 0.158 mmol), lithium hydroxide monohydrate (33 mg, 0.786 mmol), tetrahydrofuran (4 mL) and water (1 mL) were added successively to a reaction flask and the mixture was reacted at room temperature for 16 hours. TLC monitoring showed that the reaction was complete. Tetrahydrofuran was removed by rotary evaporation, the residue was diluted with water (5 mL), acidified to pH=3-4 using saturated citric acid and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed successively with water and saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-methoxy-4-(4-(4-pentamidothiophen-2-yl) pyrimidin-2-yl)benzoic acid (D5-5, 56 mg, 86.1%). MS (ESI) m/z: calcd 412.13 (M+H.sup.+). found 412.10.

Step 6: 2-Methoxy-4-(4-(4-pentamidothiophen) pyrimidin-2-yl)-N-methyl-N-(1-methylpiperidin-4-yl) benzamide (D5)

[0361] 2-Methoxy-4-(4-(4-pentamidothiophen-2-yl) pyrimidin-2-yl)benzoic acid (D5-5, 10 mg, 0.024 mmol), 1-methyl-4-(methylamino) piperidine (4.7 mg, 0.036 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.3 mg, 0.048 mmol), 1-hydroxybenzotriazole (6.6 mg, 0.048 mmol), N, N-diisopropylethylamine (9.4 mg, 0.073 mmol), and N,N-dimethylformamide (1 mL) were sequentially added to a reaction flask and the mixture was reacted at room temperature for 5 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (5 mL*3). The organic phase phases were combined, washed successively with water and saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-methoxy-4-(4-(4-pentamidothiophen) pyrimidin-2-yl)-N-methyl-N-(1-methylpiperidin-4-yl) benzamide (D5, 5 mg, 39.4%). MS (ESI) m/z: calcd 522.25 (M+H.sup.+). found 522.40: .sup.1H NMR (400 MHz, DMSO) ? 10.42 (s, 1H), 8.92 (dd, J=5.3, 2.2 Hz, 1H), 8.16-8.06 (m, 2H), 8.01 (dd, J=5.6, 1.4 Hz, 1H), 7.84 (dd, J=5.3, 2.6 Hz, 1H), 7.78 (dd, J=3.2, 1.3 Hz, 1H), 7.38 (dd, J=10.3, 8.2 Hz, 1H), 3.93 (s, 3H), 3.52 (d, J=8.0 Hz, 2H), 3.19 (d, J=12.6 Hz, 2H), 2.99 (s, 1H), 2.92-2.79 (m, 3H), 2.66 (d, J=7.1 Hz, 3H), 2.32 (t, J=7.4 Hz, 2H), 2.08-1.77 (m, 4H), 1.60 (dt, J=15.0, 7.5 Hz, 2H), 1.34 (dq, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 128: Preparation of N-(5-(6-(4-(methylsulfonyl) piperazin-1-yl) pyrazin 2-yl) thiophen-3-yl) pentanamide (D6)

[0362] ##STR00268##

Step 1: Tert butyl 4-(6-bromopyrazin-2-yl) piperazin-1-carboxylate (D6-1)

[0363] 1-tert butyl carboxylate piperazine (300 mg, 1.61 mmol), 2,6-dibromopyrazine (460 mg, 1.93 mmol), potassium carbonate (445 mg, 3.22 mmol), and dimethyl sulfoxide (9 mL) were added, and the mixture was reacted under nitrogen protection for 5 hours at 120? C. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with 50 mL of water and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated salt water (20 mL*1), dried over anhydrous sodium sulfate and spin-dried to obtain Tert butyl 4-(6-bromopyrazin-2-yl) piperazin-1-carboxylate (D6-1, 250 mg, 45.2%). MS (ESI) m/z: calcd 343.07 (M+H). found 343.10.

Step 2: Tert butyl 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (D36-2)

[0364] Tert butyl 4-(6-bromopyrazin-2-yl) piperazin-1-carboxylate (250 mg, 0.73 mmol), (4-bromothiophen-2-yl) boronic acid (200 mg, 0.97 mmol), tetrakis(triphenylphosphine)palladium (42 mg, 0.036 mmol), potassium carbonate (242 mg, 1.75 mmol) and 1,4-dioxane/water (4:1, 15 mL) were successively added to a reaction flask, and the mixture was reacted under nitrogen protection at 60? C. for 0.5 hour. TLC monitoring showed that the reaction was complete. The reaction solution was added with water (25 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography to afford tert butyl 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (D6-2, 105 mg, 33.8%). 1H NMR (400 MHz, DMSO) ? 8.46 (s, 1H), 8.26 (s, 1H), 7.91 (d, J=1.3 Hz, 1H), 7.81 (d, J=1.3 Hz, 1H), 3.64-3.60 (m, 4H), 3.48-3.45 (m, 4H), 1.44 (s, 9H).

Step 3: Tert butyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (D6-3)

[0365] Tert butyl 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (105 mg, 0.25 mmol), cuprous iodide (10 mg, 0.052 mmol), L-proline (23 mg, 0.2 mmol), dimethyl sulfoxide (2 mL), and ammonia (25% wt, 59 mg, 1.69 mmol) were sequentially added to a sealed tube, and the reaction system was sealed and reacted at 80? C. for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with water (10 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated ammonium chloride (5 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain tert butyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (D6-3, 90 mg, theoretical 0.25 mmol), which was directly used in the next reaction without any purification. MS (ESI) m/z: calcd 362.16 (M+H). found 362.10.

Step 4: Tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (D6-4)

[0366] Tert butyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (D6-3, 90 mg, theoretical 0.25 mmol) was dissolved in dichloromethane (5 mL). The reaction system was cooled under an ice water bath, and added with triethylamine (76 mg, 0.75 mmol). Additionally, pentanoyl chloride (60 mg, 0.498 mmol) was taken and dissolved in dichloromethane (0.5 mL) and the resulting mixture was slowly dropped into the above reaction system. The reaction system was reacted under ice water bath for 1 hour. TLC monitoring that the reaction was complete. The reaction solution was purified by column chromatography to afford tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (D6-4, 65 mg, 58.3%). MS (ESI) m/z: calcd 446.21 (M+H.sup.+). found 446.30.

Step 5: N-(5-(6-(piperazin-1-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide (D6-5)

[0367] Tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) piperazin-1-carboxylate (65 mg, 0.146 mmol) was dissolved in methanol (1 mL). To the system then was added with hydrogen chloride methanol solution (3 M, 1 mL), and the reaction was carried out at room temperature for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin dried without any treatment to afford N-(5-(6-(piperazin-1-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide (D6-5, theoretical 0.146 mmol). MS (ESI) m/z: calcd 346.21 (M+H.sup.+). found 346.30.

Step 6: N-(5-(6-(4-(methylsulfonyl) piperazin-1-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide (D6)

[0368] N-(5-(6-(piperazin-1-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide (D6-5, theoretical 0.146 mmol) was dissolved in dichloromethane (5 mL). The reaction system was cooled under an ice water bath, and added with triethylamine (73 mg, 0.72 mmol). Additionally, methanesulfonyl chloride (25 mg, 0.22 mmol) was taken and dissolved in dichloromethane (0.5 mL) and the resulting mixture was slowly dropped into the above system. Upon addition, the reaction was warmed to room temperature and reacted for 0.5 hour. TLC monitoring that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford N-(5-(6-(4-(methylsulfonyl) piperazin-1-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide (D6, 21 mg, 34.0%). MS (ESI) m/z: calcd 423.55 (M+H.sup.+). found 424.30; 1H NMR (400 MHz, DMSO) ? 10.31 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.69 (d, J=1.4 Hz, 1H), 7.62 (s, 1H), 3.77 (s, 4H), 3.26 (d, J=4.9 Hz, 4H), 2.92 (s, 3H), 2.31-2.27 (m, 2H), 1.58 (d, J=7.4 Hz, 2H), 1.35-1.30 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 129: Preparation of N-(5-(6-(1-(methylsulfonyl) piperidin-4-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide (D7)

[0369] ##STR00269## ##STR00270##

Step 1: Tert butyl 4-(6-bromopyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-1)

[0370] N-Boc-1,2,5,6-tetrahydropyridin-4-boronic acid pinacol ester (500 mg, 1.62 mmol), 2,6-dibromopyrazine (385 mg, 1.62 mmol), sodium carbonate (429 mg, 4.05 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (60 mg, 0.082 mmol), and 1,4-dioxane/water (5:1, 12 mL) were sequentially added to a reaction flask. The reaction was carried out at 100? C. for 5 hours under nitrogen protection. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain tert butyl 4-(6-bromopyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-1, 310 mg, 56.3%). .sup.1H NMR (400 MHz, DMSO) ? 8.88 (s, 1H), 8.72 (s, 1H), 6.88 (s, 1H), 4.10 (d, J=2.3 Hz, 2H), 3.60-3.49 (m, 2H), 2.54 (d, J=1.7 Hz, 2H), 1.43 (s, 9H).

Step 2: Tert butyl 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-2)

[0371] Tert butyl 4-(6-bromopyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-1, 220 mg, 0.647 mmol), (4-bromothiophen-2-yl) boronic acid (134 mg, 0.647 mmol), tetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol), potassium carbonate (214 mg, 1.75 mmol) and 1,4-dioxane/water (5:1, 6 mL) were successively added to a reaction flask, and the mixture was reacted under nitrogen protection at 60? C. for 0.5 hour. TLC monitoring showed that the reaction was complete. The reaction solution was added with water (25 mL) and extracted with ethyl acetate (20 mL*3). The organic phase phases were combined, washed with saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain tert butyl 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-2, 158 mg, 57.8%). .sup.1H NMR (400 MHz, DMSO) ? 9.12 (s, 1H), 8.78 (s, 1H), 8.07 (d, J=1.4 Hz, 1H), 7.89 (d, J=1.4 Hz, 1H), 6.90 (s, 1H), 4.12 (s, 2H), 3.66-3.52 (m, 3H), 2.62 (s, 2H), 1.44 (s, 9H).

Step 3: Tert butyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-3)

[0372] Tert butyl 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-2, 158 mg, 0.375 mmol), cuprous iodide (14 mg, 0.074 mmol), L-proline (17 mg, 0.148 mmol), dimethyl sulfoxide (2 mL), and ammonia (25% wt, 315 mg, 2.25 mmol) were sequentially added to a sealed tube, and the reaction system was sealed and reacted at 80? C. for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with water (10 mL), and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated ammonium chloride (5 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain tert butyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-3, theoretical 0.375 mmol), which was directly used in the next reaction without any purification. MS (ESI) m/z: calcd 359.15 (M+H.sup.+). found 359.10.

Step 4: Tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-4)

[0373] Tert butyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-3, theoretical 0.375 mmol) was dissolved in dichloromethane (5 mL). The reaction system was cooled under an ice water bath, and added with triethylamine (73 mg, 0.72 mmol). Additionally, pentanoyl chloride (134 mg, 1.11 mmol) was taken and dissolved in dichloromethane (0.5 mL) and the resulting mixture was slowly dropped into the above system. Upon addition, the reaction system was warmed to room temperature and reacted for 0.5 hour. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-4, 35 mg, 21.1%). MS (ESI) m/z: calcd 443.20 (M+H.sup.+). found 443.10.

Step 5: Tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)piperidin-1-carbonate (D7-5)

[0374] Tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-carboxylate (D7-4, 35 mg, 0.079 mmol) was dissolved in methanol (2 mL), the solution was added palladium carbon (35 mg), and the reaction was carried out at room temperature under hydrogen atmosphere (1 atm) for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was filtered to remove palladium carbon and spin-dried to afford tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)piperidin-1-carbonate (D7-5, 35 mg, 100%). MS (ESI) m/z: calcd 445.22 (M+H.sup.+). found 445.20.

Step 6: N-(5-(6-(piperidin-4-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide hydrochloride (D7-6)

[0375] Tert butyl 4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)piperidin-1-carbonate (D7-5, 35 mg, 0.079 mmol) was dissolved in methanol (4 mL), the solution was added with hydrogen chloride methanol solution (3 M, 4 mL), and the mixture was reacted at room temperature for 1 hour. LCMS detection showed that the reaction was complete. The reaction solution was spin-dried and used directly in the next reaction to afford N-(5-(6-(piperidin-4-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide hydrochloride (D7-6, 30 mg, 100%). MS (ESI) m/z: calcd 345.17 (M+H.sup.+). found 345.10.

Step 7: N-(5-(6-(1-(methylsulfonyl) pyridin-4-yl) pyrazin-2yl) thiophen-3-yl) pentanamide (D7)

[0376] N-(5-(6-(piperidin-4-yl) pyrazin-2-yl) thiophen-3-yl) pentanamide hydrochloride (D7-6, 30 mg, 0.079 mmol) was dissolved in dichloromethane (5 mL). The solution was added with triethylamine (24 mg, 0.238 mmol) and cooled under an ice water bath. Additionally, methylsulfonyl chloride (13.6 mg, 0.119 mmol) was taken and dissolved in dichloromethane (2 mL) and the resulting mixture was slowly dropped into the above system. Upon addition, the reaction system was warmed to room temperature and reacted for 0.5 hour. LCMS detection showed that the reaction was complete. The reaction solution was directly spin-dried and purified by column chromatography to afford N-(5-(6-(1-(methylsulfonyl) pyridin-4-yl) pyrazin-2yl) thiophen-3-yl) pentanamide (D7, 1.6 mg, 4.8%). MS (ESI) m/z: calcd 423.14 (M+H.sup.+). found 423.10: .sup.1H NMR (400 MHz, DMSO) ? 10.35 (s, 1H), 8.94 (s, 1H), 8.51 (d, J=3.7 Hz, 1H), 7.81 (d, J=1.4 Hz, 1H), 7.66 (d, J=1.3 Hz, 1H), 3.70 (d, J=11.9 Hz, 2H), 3.01-2.83 (m, 5H), 2.34-2.28 (m, 2H), 2.08-2.01 (m, 2H), 1.88-1.77 (m, 2H), 1.63-1.55 (m, 2H), 1.38-1.30 (m, 2H), 1.24 (s, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 130 was Prepared Using Experimental Steps Similar to Those in Examples 125-129 Above, and Compounds D1-D9 were Summarized in Table 5.

TABLE-US-00005 TABLE 5 MS(calcd) Compound [M + H].sup.+/ Example No. Structure MS (found) Name and characterization 125 D1 [00271] 329.19/N/A (HNMR) N.sup.1-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)cyclohexane-1,4-diamine .sup.1H NMR (400 MHz, DMSO) ? 8.23 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 7.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.04 (dt, J = 13.9, 7.0 Hz, 2H), 2.05 (s, 2H), 1.87 (s, 2H), 1.26 (s, 4H). 125 D2 [00272] 411.23/411.57 N-(4-((6-(3,4- dimethoxyphenyl)pyrazin-2- yl)amino)cyclohexyl) cyclobutanecarboxamide 126 D3 [00273] 415.14/No MS signals (HNMR) tert-butyl (2-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiazol-4-yl)carbamate .sup.1H NMR (400 MHz, CDCl3) ? 9.20 (s, 1H), 9.02 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.73-7.61 (m, 2H), 7.47 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 1.59 (s, 9H). 126 D4 [00274] 414.15/414.10 3-(2-(6-(3,4- dimethoxyphenyl)pyrazin-2- yl)thiazol-4-yl)-1,1-diethylurea 127 D5 [00275] 522.25/522.40 2-methoxy-N-methyl-N-(1- methylpiperidin-4-yl)-4-(4-(4- pentanamidothiophen-2- yl)pyrimidin-2-yl)benzamide 128 D6 [00276] 424.14/424.30 N-(5-(6-(4- (methylsulfonyl)piperazin-1 - yl)pyrazin-2-yl)thiophen-3- yl)pentanamide 129 D7 [00277] 423.14/423.10 N-(5-(6-(1- (methylsulfonyl)piperidin-4- yl)pyrazin-2-yl)thiophen-3- yl)pentanamide 130 D8 [00278] 421.13/421.10 N-(5-(6-(1-(methylsulfonyl)- 1,2,3,6-tetrahydropyridin-4- yl)pyrazin-2-yl)thiophen-3- yl)pentanamide
Examples 131-152 (Compounds B79-100) were Prepared Using Experimental Steps Similar to Those in Example 46 Above, and Compounds B79-100 were Summarized in Table 6.

TABLE-US-00006 TABLE 6 MS(calcd) [M + H].sup.+/ Compound MS Example No. Structure (found) Name and characterization 131 B79 [00279] 453.15/ 453.30 4-(6-(4-(2- cyclopropylacetamido)thiophen-2- yl)pyrazin-2-yl)-N,2-dimethoxy-N- methylbenzamide .sup.1H NMR (400 MHz, DMSO) ? 10.34 (s, 1H), 9.23 (s, 1H), 9.10 (s, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 1.3 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 3.94 (s, 3H), 3.49 (s, 3H), 3.26 (s, 3H), 2.22 (d, J = 7.0 Hz, 2H), 1.13- 1.03 (m, 1H), 0.56-0.44 (m, 2H), 0.30-0.17 (m, 2H). 132 B80 [00280] 503.14/ 503.30 4-(6-(4-(2-(bicyclo[1.1.1]pentan-1- yl)acetamido)thiophen-2-yl)pyrazin- 2-yl)-2-methoxy-N-(1,3,4-oxadiazol- 2-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 12.05 (s, 1H), 10.34 (s, 1H), 9.25 (s, 1H), 9.12 (s, 1H), 8.11 (d, J = 0.9 Hz, 1H), 7.90 (d, J = 1.4 Hz, 1H), 7.88-7.83 (m, 2H), 7.73 (d, J = 1.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H), 1.78 (s, 4H), 1.24 (s, 2H), 1.19-1.17 (m, 1H). 133 B81 [00281] 467.17/ 467.30 4-(6-(4-(2- cyclobutylacetamido)thiophen-2- yl)pyrazin-2-yl)-N,2-dimethoxy-N- methylbenzamide .sup.1H NMR (400 MHz, DMSO) ? 10.37 (s, 1H), 9.23 (s, 1H), 9.09 (s, 1H), 7.89 (d, J = 1.4 Hz, 1H), 7.87- 7.79 (m, 2H), 7.71 (d, J = 1.3 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 3.94 (s, 3H), 3.50 (s, 3H), 3.25 (s, 3H), 2.43 (d, J = 7.6 Hz, 2H), 2.08 (dt, J = 19.4, 7.5 Hz, 2H), 1.94-1.70 (m, 4H), 1.27-1.22 (m, 1H). 134 B82 [00282] 550.24/ 550.00 2-methoxy-N-methyl-4-(6-(4-(2- (3-methyloxetan-3-yl) acetamido)thiophen-2-yl)pyrazin- 2-yl)-N-(1-methylpiperidin-4- yl)benzamide 135 B83 [00283] 570.23/ 570.40 4-(6-(4-(2-(3,3- difluorocyclobutyl)acetamido) thiophen-2-yl)pyrazin-2- yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide 136 B84 [00284] 546.25/ 546.30 N-(5-(6-(3-methoxy-4-(methyl(1- methylpiperidin-4- yl)carbamoyl)phenyl)pyrazin-2- yl)thiophen-3-yl)spiro[2.3] hexane-1-carboxamide .sup.1H NMR (400 MHz, DMSO) ? 10.61 (s, 1H), 9.24 (d, J = 10.0 Hz, 1H), 9.10 (d, J = 2.3 Hz, 1H), 7.92 (dd, J = 3.8, 1.3 Hz, 1H), 7.85 (t, J = 7.4 Hz, 2H), 7.69 (s, 1H), 7.35 (t, J = 7.5 Hz, 1H), 4.48-4.35 (m, 1H), 3.93 (d, J = 2.5 Hz, 3H), 3.11 (d, J = 97.3 Hz, 2H), 2.85 (d, J = 29.2 Hz, 3H), 2.61 (d, J = 46.9 Hz, 3H), 2.33 (s, 2H), 2.05-1.95 (m, 2H), 1.83 (d, J = 11.5 Hz, 3H), 1.73 (dd, J = 8.1, 5.4 Hz, 1H), 1.63 (s, 2H), 1.47 (s, 1H), 1.27 (dd, J= 14.8, 11.1 Hz, 2H), 1.10 (t, J = 4.7 Hz, 1H), 1.00 (dd, J = 8.2, 4.2 Hz, 1H). 137 B85 [00285] 678.26/ 678.30 2-methoxy-N-methyl-N-(1- methylpiperidin-4-yl)-4-(6- (4-(2-(1-(4-(trifluoromethyl) phenyl)cyclobutyl) acetamido)thiophen-2-yl)pyrazin- 2-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.23 (s, 1H), 9.22 (d, J = 10.2 Hz, 1H), 9.05 (d, J = 2.1 Hz, 1H), 7.83 (t, J = 7.1 Hz, 2H), 7.76 (s, 1H), 7.71-7.58 (m, 3H), 7.44 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 4.43-4.28 (m, 1H), 3.92 (d, J = 2.8 Hz, 3H), 3.16 (s, 1H), 2.87 (d, J = 7.9 Hz, 4H), 2.81-2.61 (m, 3H), 2.44-2.30 (m, 3H), 2.22 (s, 1H), 2.07 (s, 2H), 1.82 (d, J = 10.8 Hz, 4H), 1.60 (s, 2H), 1.46-1.34 (m, 1H), 1.25 (d, J = 6.0 Hz, 1H). 138 B86 [00286] 562.28/ N/A 4-(6-(4-(2-(1- ethylcyclobutyl)acetamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.89 (s, 1H), 9.26 (d, J = 10.3 Hz, 1H), 9.16 (d, J = 2.2 Hz, 1H), 7.95 (dd, J = 3.5, 1.3 Hz, 1H), 7.84 (dd, J = 14.9, 8.4 Hz, 3H), 7.42-7.30 (m, 1H), 4.49-4.31 (m, 1H), 3.92 (t, J = 9.5 Hz, 3H), 3.23-3.11 (m, 1H), 2.96 (s, 1H), 2.88 (s, 3H), 2.79-2.63 (m, 3H), 2.31 (d, J = 16.7 Hz, 2H), 2.25-2.20 (m, 1H), 2.12 (s, 2H), 1.92-1.74 (m, 6H), 1.67 (dd, J = 14.6, 7.1 Hz, 2H), 1.45 (s, 1H), 1.28-1.21 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 139 B87 [00287] 604.29/ 604.30 4-(6-(4-(2-(3-acetyl-2,2- dimethylcyclobutyl)acetamido) thiophen-2-yl)pyrazin- 2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.43 (d, J = 8.8 Hz, 1H), 9.24 (d, J = 9.6 Hz, 1H), 9.10 (s, 1H), 7.85 (dd, J = 14.7, 7.0 Hz, 3H), 7.71 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 4.51- 4.35 (m, 1H), 3.93 (d, J = 2.0 Hz, 3H), 3.04 (d, J = 9.0 Hz, 2H), 3.00- 2.62 (m, 6H), 2.45-2.10 (m, 6H), 2.08-1.96 (m, 3H), 1.96-1.73 (m, 4H), 1.36-1.19 (m, 5H), 0.90 (d, J = 51.9 Hz, 3H). 140 B88 [00288] 549.26/ 549.30 4-(6-(4-(2-amino-2- cyclobutylacetamido)thiophen-2- yl)pyrazin-2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 11.38 (d, J = 15.9 Hz, 1H), 9.24 (d, J = 9.2 Hz, 1H), 9.13 (d, J = 2.6 Hz, 1H), 8.11-7.96 (m, 1H), 7.85 (dd, J = 12.6, 4.4 Hz, 3H), 7.38 (dd, J = 10.1, 8.0 Hz, 1H), 4.74-4.56 (m, 1H), 3.99-3.95 (m, 1H), 3.94 (s, 3H), 3.34 (dd, J = 32.7, 12.0 Hz, 1H), 3.23-3.10 (m, 1H), 2.97 (t, J = 12.5 Hz, 1H), 2.88 (s, 1H), 2.81 (d, J = 12.6 Hz, 1H), 2.75 (d, J = 8.4 Hz, 2H), 2.64 (d, J = 23.1 Hz, 3H), 2.28-2.08 (m, 3H), 2.08-1.95 (m, 2H), 1.95-1.72 (m, 5H), 1.72-1.61 (m, 1H). 141 B89 [00289] 536.23/ 536.30 2-methoxy-N-methyl-N-(1- methylpiperidin-4-yl)-4-(6-(4-(2- (oxetan-3-yl)acetamido)thiophen-2- yl)pyrazin-2-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 9.22 (dd, J = 11.2, 6.6 Hz, 2H), 8.35 (dd, J = 3.6, 1.2 Hz, 1H), 7.86 (dd, J = 13.3, 5.2 Hz, 2H), 7.74 (s, 1H), 7.38 (dd, J = 11.6, 8.0 Hz, 1H), 4.64 (t, J = 12.0 Hz, 1H), 3.98 (d, J = 9.6 Hz, 1H), 3.95 (s, 3H), 3.71 (dd, J = 9.7, 4.6 Hz, 1H), 3.60-3.45 (m, 4H), 3.25-3.11 (m, 1H), 3.09-2.94 (m, 1H), 2.84 (d, J = 29.7 Hz, 3H), 2.73-2.56 (m, 5H), 2.32 (q, J = 9.7 Hz, 1H), 2.07 (dd, J = 22.2, 14.3 Hz, 2H), 1.95-1.65 (m, 2H). 142 B90 [00290] 552.24/ 552.20 4-(6-(4-(2-(3- fluorocyclobutyl)acetamido) thiophen-2-yl)pyrazin- 2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.44 (s, 1H), 9.24 (d, J = 8.8 Hz, 1H), 9.11 (d, J = 2.9 Hz, 1H), 7.88 (dt, J = 13.2, 5.8 Hz, 2H), 7.72 (s, 1H), 7.38 (dd, J = 11.3, 8.0 Hz, 1H), 4.62 (s, 1H), 3.94 (s, 3H), 3.53 (d, J = 11.3 Hz, 2H), 3.10 (d, J = 7.4 Hz, 2H), 2.99 (s, 1H), 2.84 (d, J = 29.7 Hz, 3H), 2.67 (s, 3H), 2.48 (d, J = 8.1 Hz, 2H), 2.40-2.27 (m, 2H), 2.24-2.13 (m, 2H), 2.09-1.95 (m, 2H), 1.91-1.79 (m, 2H), 1.71 (d, J = 12.5 Hz, 1H). 143 B91 [00291] 576.26/ 576.40 4-(6-(4-(2-(3- acetylcyclobutyl)acetamido) thiophen-2-yl)pyrazin- 2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.40 (d, J = 14.9 Hz, 1H), 9.24 (d, J = 9.5 Hz, 1H), 9.10 (s, 1H), 7.94- 7.80 (m, 3H), 7.71 (s, 1H), 7.36 (t, J = 7.7 Hz, 1H), 4.46 (s, 1H), 3.94 (d, J = 2.0 Hz, 3H), 3.21-3.12 (m, 2H), 2.89 (s, 3H), 2.70-2.60 (m, 3H), 2.39-2.20 (m, 6H), 2.05 (d, J = 15.2 Hz, 3H), 1.87 (dd, J = 20.7, 11.6 Hz, 4H), 1.69 (s, 2H), 1.48 (s, 2H). 144 B92 [00292] 598.26/ 598.40 4-(6-(4-(2-(3-(1,1- difluoroethyl)cyclobutyl)acetamido) thiophen-2-yl)pyrazin-2-yl)-2- methoxy-N-methyl-N-(1- methylpiperidin-4-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.40 (s, 1H), 9.24 (d, J = 9.8 Hz, 1H), 9.09 (d, J = 2.0 Hz, 1H), 7.91- 7.79 (m, 3H), 7.71 (s, 1H), 7.35 (t, J = 7.5 Hz, 1H), 4.41 (s, 1H), 3.93 (d, J = 2.4 Hz, 3H), 3.23-3.17 (m, 1H), 3.04 (s, 1H), 2.89 (s, 3H), 2.70-2.58 (m, 3H), 2.43-2.32 (m, 5H), 2.15 (dd, J = 19.7, 8.2 Hz, 4H), 1.83 (s, 3H), 1.65 (s, 2H), 1.49 (d, J = 18.6 Hz, 3H). 145 B93 [00293] 546.25/ 546.40 4-(6-(4-(2- cyclobutylacetamido)thiophen-2- yl)pyrazin-2-yl)-2-methoxy-N- methyl-N-(2-methyl-2-azaspiro [3.3]heptan-6-yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.38 (s, 1H), 9.23 (d, J = 7.4 Hz, 1H), 9.09 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.87-7.79 (m, 2H), 7.71 (d, J = 1.4 Hz, 1H), 7.32 (t, J = 8.3 Hz, 1H), 4.87-4.76 (m, 1H), 3.92 (d, J = 5.0 Hz, 3H), 3.87 (d, J = 8.2 Hz, 1H), 3.20 (s, 1H), 3.06 (s, 1H), 3.01 (d, J = 3.4 Hz, 1H), 2.92 (d, J = 6.8 Hz, 3H), 2.78- 2.64 (m, 3H), 2.43 (d, J = 7.6 Hz, 2H), 2.35-2.26 (m, 2H), 2.17 (s, 1H), 2.12-2.05 (m, 3H), 2.05-1.95 (m, 2H), 1.85-1.80 (m, 1H), 1.80- 1.69 (m, 2H). 146 B94 [00294] 549.26/ 549.50 4-(6-(4-(2-(1- aminocyclobutyl)acetamido) thiophen-2-yl)pyrazin- 2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 11.08 (d, J = 14.7 Hz, 1H), 9.26 (d, J = 9.5 Hz, 1H), 9.10 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 4.9, 1.2 Hz, 1H), 7.87 (dd, J = 13.1, 7.0 Hz, 2H), 7.78 (d, J = 1.1 Hz, 1H), 7.39 (dd, J = 12.3, 7.8 Hz, 1H), 4.66 (t, J = 12.2 Hz, 1H), 3.95 (s, 3H), 3.60-3.11 (m, 4H), 3.02-2.83 (m, 4H), 2.76-2.57 (m, 4H), 2.39-2.08 (m, 6H), 2.04- 1.75 (m, 4H). 147 B95 [00295] 548.26/ 548.40 4-(6-(4-(2- cyclobutylpropanamido)thiophen- 2-yl)pyrazin-2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 10.35 (s, 1H), 9.24 (d, J = 10.2 Hz, 1H), 9.09 (d, J = 2.2 Hz, 1H), 8.00- 7.79 (m, 3H), 7.73 (s, 1H), 7.35 (t, J = 7.4 Hz, 1H), 4.37 (s, 1H), 3.93 (d, J = 2.7 Hz, 3H), 3.19 (s, 1H), 2.92 (s, 1H), 2.90-2.62 (m, 6H), 2.44 (s, 3H), 2.33 (s, 1H), 2.25 (s, 2H), 2.09 (s, 4H), 1.92 (s, 1H), 1.62 (s, 2H), 1.44 (s, 1H), 1.02 (d, J = 5.8 Hz, 3H). 148 B96 [00296] 560.26/ N/A 4-(6-(4-(2- cyclobutylacetamido)thiophen-2- yl)pyrazin-2-yl)-N-(1- cyclopropylpiperidin-4-yl)-2- methoxy-N-methylbenzamide .sup.1H NMR (400 MHz, DMSO) ? 10.37 (s, 1H), 9.24 (d, J = 12.2 Hz, 1H), 9.09 (d, J = 3.7 Hz, 1H), 7.94- 7.79 (m, 3H), 7.71 (s, 1H), 7.39- 7.31 (m, 1H), 4.39 (s, 1H), 3.93 (s, 3H), 3.22-3.17 (m, 1H), 3.05 (s, 1H), 2.93 (s, 1H), 2.86 (s, 2H), 2.73-2.63 (m, 3H), 2.31 (d, J = 18.9 Hz, 2H), 2.08 (s, 2H), 1.98 (d, J = 11.3 Hz, 1H), 1.89-1.81 (m, 2H), 1.72 (d, J = 8.9 Hz, 2H), 1.61 (s, 2H), 1.48 (s, 2H), 0.45-0.21 (m, 4H). 149 B97 [00297] 572.26/ 572.50 4-(6-(4-(2- cyclobutylacetamido)thiophen-2- yl)pyrazin-2-yl)-N-(2-cyclopropyl- 2-azaspiro[3.3]heptan-6-yl)-2- methoxy-N-methylbenzamide .sup.1H NMR (400 MHz, DMSO) ? 10.38 (s, 1H), 9.23 (d, J = 7.3 Hz, 1H), 9.10 (d, J = 4.0 Hz, 1H), 7.91- 7.88 (m, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H), 7.35-7.30 (m, 1H), 4.89-4.83 (m, 1H), 3.93 (d, J = 4.6 Hz, 3H), 3.00 (d, J = 30.4 Hz, 3H), 2.74-2.62 (m, 4H), 2.43 (d, J = 7.5 Hz, 2H), 2.34-2.32 (m, 1H), 2.11-2.05 (m, 2H), 1.91-1.82 (m, 2H), 1.78-1.69 (m, 2H), 1.51-1.41 (m, 2H), 1.30-1.21 (m, 3H), 0.79- 0.62 (m, 4H). 150 B98 [00298] 439.14/ 439.50 4-(6-(4-(2- cyclobutylacetamido)thiophen-2- yl)pyrazin-2-yl)-N-hydroxy-2- methoxybenzamide .sup.1H NMR (400 MHz, DMSO) ? 10.74 (s, 1H), 10.37 (s, 1H), 9.29- 9.05 (m, 3H), 7.95-7.81 (m, 3H), 7.72 (dd, J = 11.3, 4.5 Hz, 2H), 3.97 (d, J = 11.4 Hz, 3H), 2.78-2.63 (m, 1H), 2.43 (d, J = 7.6 Hz, 2H), 2.14- 1.98 (m, 2H), 1.92-1.66 (m, 4H). 151 B99 [00299] 564.24/ N/A 4-(6-(4-(2-(3- fluorocyclobutyl)acetamido) thiophen-2-yl)pyrazin-2-yl)-2- methoxy-N-methyl-N-(2-methyl-2- azaspiro[3.3]heptan-6-yl)benzamide .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.85 (s, 1H), 8.80 (s, 1H), 7.67 (ddd, J = 20.0, 14.0, 7.2 Hz, 4H), 7.33 (d, J = 5.0 Hz, 1H), 4.09-4.02 (m, 1H), 3.95 (d, J = 12.3 Hz, 3H), 3.73-3.59 (m, 2H), 3.43-3.32 (m, 2H), 3.20- 3.05 (m, 3H), 2.91-2.78 (m, 3H), 2.69-2.61 (m, 1H), 2.58-2.50 (m, 3H), 2.41-2.36 (m, 2H), 2.28-2.21 (m, 2H), 2.00-1.92 (m, 2H), 1.86- 1.78 (m, 2H). 152 B100 [00300] 562.28/ 562.70 4-(6-(4-(2-cyclobutyl-2- methylpropanamido)thiophen-2- yl)pyrazin-2-yl)-2-methoxy-N- methyl-N-(1-methylpiperidin-4- yl)benzamide .sup.1H NMR (400 MHz, DMSO) ? 9.64 (s, 1H), 9.23 (d, J = 10.3 Hz, 1H), 9.04 (d, J = 1.9 Hz, 1H), 8.08 (s, 1H), 7.83 (dd, J = 20.7, 15.4 Hz, 3H), 7.38-7.29 (m, 1H), 4.44-4.32 (m, 1H), 3.93 (d, J = 2.7 Hz, 3H), 3.24-3.12 (m, 2H), 2.89 (s, 3H), 2.72-2.65 (m, 3H), 2.36-2.20 (m, 3H), 2.14-2.04 (m, 2H), 1.68-1.56 (m, 3H), 1.48-1.38 (m, 1H), 1.32- 1.21 (m, 4H), 1.16 (s, 6H).

Example 155: Preparation of 2-cyclopropyl-N-(5-(6-(3-methoxy-4-(N-methyl-N-(1-methylpiperidin-4-yl) sulfamoyl) phenyl) pyrazin-2-yl) thiophene-3-yl) acetamide (B103)

[0377] ##STR00301## ##STR00302##

Step 1: 4-bromo-2-methoxybenzenesulfonyl Chloride (B103-1)

[0378] Cuprous chloride (20 mg, 0.20 mmol) was dissolved in water (30 mL), and the reaction system was cooled to 0-10? C. under iced-water bath. Dichlorosulfoxide (8.0 g, 67.24 mmol) was slowly added dropwise to the reaction system and the reaction system was naturally returned to room temperature and reacted for 16 hours to form a stable system A. 2-Methoxy-4-bromoaniline (3.0 g, 14.85 mmol) was dissolved in acetic acid (15 mL), and the system was cooled to around 10? C. under ice water bath. In addition, sodium nitrite (1.12 g, 16.23 mmol) was taken and dissolved in water (5 mL) and then added dropwise to the reaction system. Upon addition, the reaction continued at 0? C. for 1 hour to form a stable system B. The stable system A was cooled to 0-10? C., and the stable system B was slowly added to A. Upon addition, the mixture was naturally warmed to room temperature and continued to react for 16 hours. TLC detection showed that the reaction was complete. The reaction was extracted with ethyl acetate (50 mL*3), and the organic phase were combined and washed with saturated saline (50 mL*1), dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography to afford 4-bromo-2-methoxybenzenesulfonyl chloride (B103-1, 671 mg, 15.8%). .sup.1H NMR (400 MHz, CDCl3) ? 7.84 (d, J=8.4 Hz, 1H), 7.30-7.27 (m, 2H), 4.09 (s, 3H).

Step 2: 4-bromo-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-2)

[0379] 4-bromo-2-methoxybenzenesulfonyl chloride (B103-1, 200 mg, 0.7 mmol) was dissolved in dichloromethane (8 mL), and 1-methyl-4-(methylamino) piperidine (99 mg, 0.77 mmol), and triethylamine (142 mg, 1.40 mmol) were sequentially added to the above reaction system. The reaction was carried out at room temperature for 14 hours, and TLC detection showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain 4-bromo-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-2, 264 mg, 100%). MS (ESI) m/z: calcd 377.05 (M+H.sup.+). found 377.40.

Step 3: (3-Methoxy-4-(N-methyl-N-(1-methylpiperidin-4-yl) aminosulfonyl) phenyl) boronic Acid (B103-3)

[0380] 4-bromo-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-2, 264 mg, 0.70 mmol) and triisopropyl borate (396 mg, 2.10 mmol) were added to tetrahydrofuran (20 mL), and the mixture was cooled to ?78? C., and n-butyl lithium (0.84 mL, 2.10 mmol, 2.5 M in THF) was slowly added dropwise. Upon addition, the reaction was naturally warmed to room temperature and reacted for another 14 hours, and LCMS detected that the reaction was complete. An appropriate amount of water (1 mL) was added to the system to quench the reaction, and the reaction was filtered to remove most of the inorganic salts, spin-dried, and then used directly in the next reaction without any purification. MS (ESI) m/z: calcd 343.14 (M+H.sup.+). found 343.60.

Step 4: 4-(6-bromopyrazine 2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-4)

[0381] (3-Methoxy-4-(N-methyl-N-(1-methylpiperidin-4-yl) aminosulfonyl) phenyl) boronic acid (B103-3, crude, theoretical 0.70 mmol), 2,6-dibromopyrazine (200 mg, 0.84 mmol), and tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol) were added to 1,4-dioxane/water (4:1, 10 mL), and the mixture reacted under nitrogen protection at 80? C. for 5 hours. LCMS monitored that the reaction is complete. The reaction solution was directly spin dried and purified by column chromatography to obtain 4-(6-bromopyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-4, 216 mg, 47.9%). MS (ESI) m/z: calcd 455.07 (M+H.sup.+). found 454.90.

Step 5: 4-(6-(4-bromothiophene-2-yl) pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-5)

[0382] 4-(6-bromopyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-4, 216 mg, 0.48 mmol), (4-bromothiophene-2-yl) boronic acid (98.5 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol) and potassium carbonate (158 mg, 1.14 mmol) were added to 1,4-dioxane/water (4:1, 10 mL), and the mixture reacted under nitrogen protection at 60? C. for 0.5 hour. TLC detected the completion of reaction. The reaction solution was directly spin-dried and purified by column chromatography to obtain 4-(6-(4-bromothiophene-2-yl) pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-5, 182 mg, 71.4%). MS (ESI) m/z: calcd 537.06 (M+H). found 536.90.

Step 6: 4-(6-(4-aminothiophene-2-yl) pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-6)

[0383] 4-(6-(4-bromothiophene-2-yl) pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-5, 182 mg, 0.34 mmol), cuprous iodide (13 mg, 0.07 mmol), L-proline (16 mg, 0.14 mmol), dimethyl sulfoxide (2 mL), and ammonia (25% wt, 286 mg, 2.04 mmol) were sequentially added to the sealed tube, and the reaction was sealed and reacted at 80? C. for 10 hours. LCMS monitored that the reaction was complete. The reaction solution was cooled to room temperature, added with 20 mL of water, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated ammonium chloride (10 mL*2), dried with anhydrous sodium sulfate, and spin-dried to obtain 4-(6-(4-aminothiophene-2-yl) pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-6, crude, theoretical 0.34 mmol), which was directly used in the next reaction without any purification. MS (ESI) m/z: calcd 474.16 (M+H). found 474.10.

Step 7: 2-cyclopropyl-N-(5-(6-(3-methoxy-4-(N-methyl-N-(1-methylpiperidin-4-yl) sulfamoyl) phenyl) pyrazin-2-yl) thiophene-3-yl) acetamide (B103)

[0384] 4-(6-(4-aminothiophene-2-yl) pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzenesulfonamide (B103-6, crude, theoretical 0.17 mmol) was added to DMF (3 mL). The flask was sequentially added with cyclopropyl acetic acid (25.4 mg, 0.25 mmol), EDCI (65 mg, 0.34 mmol), HOBT (46 mg, 0.34 mmol), and DIEA (109 mg, 0.84 mmol), and the mixture was reacted at room temperature for 14 hours. LCMS detection showed that the reaction was complete. The reaction solution was diluted with sufficient water and extracted with ethyl acetate (20 mL*3), and the ethyl acetate phases were combined, washed with saturated ammonium chloride (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography to afford 2-cyclopropyl-N-(5-(6-(3-methoxy-4-(N-methyl-N-(1-methylpiperidin-4-yl) sulfamoyl) phenyl) pyrazin-2-yl) thiophene-3-yl) acetamide (B103, 25 mg, 26.4%). MS (ESI) m/z: calcd 556.20 (M+H.sup.+). found 556.00. .sup.1H NMR (400 MHz, DMSO) ? 10.35 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 8.01-7.86 (m, 4H), 7.75 (t, J=2.4 Hz, 1H), 4.03 (s, 3H), 3.64-3.57 (m, 1H), 2.85-2.74 (m, 5H), 2.22 (d, J=7.0 Hz, 2H), 2.12 (s, 3H), 1.89 (t, J=11.0 Hz, 2H), 1.76-1.66 (m, 2H), 1.36 (d, J=13.0 Hz, 2H), 1.29-1.20 (m, 1H), 0.55-0.46 (m, 2H), 0.26-0.17 (m, 2H).

Examples 153-157 (Compounds B101-105) were Prepared Using Experimental Steps Similar to Those in Example 155 Above, and Compounds B101-105 were Summarized in Table 7.

TABLE-US-00007 TABLE 7 MS(calcd) Compound [M + H].sup.+/ Example No. Structure MS (found) Name and characterization 153 B101 [00303] 544.20/ N/A 2-cyclobutyl-N-(5-(6-(4-(N-(2- (dimethylamino)ethyl)-N- methylsulfamoyl)-3- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.38 (s, 1H), 9.28 (d, J = 9.5 Hz, 1H), 9.15 (s, 1H), 8.00-7.86 (m, 4H), 7.72 (d, J = 1.3 Hz, 1H), 4.06 (s, 3H), 2.82 (d, J = 5.7 Hz, 3H), 2.62-2.55 (m, 2H), 2.43 (d, J = 7.6 Hz, 2H), 2.31 (d, J = 7.6 Hz, 2H), 2.29 (s, 6H), 2.09-2.04 (m, 2H), 1.88-1.81 (m, 2H), 1.79-1.72 (m, 2H), 1.69-1.61 (m, 1H). 154 B102 [00304] 530.18/ 530.80 2-cyclopropyl-N-(5-(6-(4-(N-(2- (dimethylamino)ethyl)-N- methylsulfamoyl)-3- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.35 (s, 1H), 9.27 (s, 1H), 9.19 (d, J = 27.1 Hz, 1H), 8.02-7.87 (m, 4H), 7.75 (d, J = 1.3 Hz, 1H), 4.10- 4.02 (m, 3H), 3.28-3.19 (m, 2H), 2.83 (s, 3H), 2.58 (s, 2H), 2.28 (s, 6H), 2.22 (d, J = 7.0 Hz, 2H), 1.14- 1.03 (m, 1H), 0.58-0.45 (m, 2H), 0.30-0.18 (m, 2H). 155 B103 [00305] 556.20/ 556.00 2-cyclopropyl-N-(5-(6-(3-methoxy-4- (N-methyl-N-(1-methylpiperidin-4- yl)sulfamoyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.35 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 8.01-7.86 (m, 4H), 7.75 (t, J = 2.4 Hz, 1H), 4.03 (s, 3H), 3.64-3.57 (m, 1H), 2.85-2.74 (m, 5H), 2.22 (d, J = 7.0 Hz, 2H), 2.12 (s, 3H), 1.89 (t, J = 11.0 Hz, 2H), 1.76-1.66 (m, 2H), 1.36 (d, J = 13.0 Hz, 2H), 1.29-1.20 (m, 1H), 0.55-0.46 (m, 2H), 0.26-0.17 (m, 2H). 156 B104 [00306] 570.21/ 569.90 2-cyclobutyl-N-(5-(6-(3-methoxy-4- (N-methyl-N-(1-methylpiperidin-4- yl)sulfamoyl)phenyl)pyrazin-2- yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.38 (s, 1H), 9.27 (s, 1H), 9.14 (s, 1H), 8.00-7.84 (m, 4H), 7.72 (d, J = 1.3 Hz, 1H), 4.10-4.01 (m, 3H), 2.78 (s, 3H), 2.75 (d, J = 7.5 Hz, 2H), 2.43 (d, J = 7.6 Hz, 2H), 2.31 (d, J = 7.6 Hz, 1H), 2.12 (s, 3H), 2.10-2.04 (m, 2H), 1.91-1.83 (m, 3H), 1.77-1.65 (m, 4H), 1.39-1.32 (m, 2H), 1.28-1.22 (m, 2H). 157 B105 [00307] 529.15/ 529.00 2-cyclobutyl-N-(5-(6-(3-methoxy-4- (morpholinosulfonyl)phenyl)pyrazin- 2-yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.37 (s, 1H), 9.28 (s, 1H), 9.15 (s, 1H), 8.05-7.84 (m, 4H), 7.72 (d, J = 1.2 Hz, 1H), 4.04 (d, J = 11.8 Hz, 3H), 3.70-3.56 (m, 4H), 3.22-3.07 (m, 4H), 2.69 (dq, J = 15.2, 7.8 Hz, 1H), 2.43 (d, J = 7.5 Hz, 2H), 2.15- 2.03 (m, 2H), 1.93-1.80 (m, 2H), 1.80-1.67 (m, 2H).

Example 158: Preparation of 2-cyclopropyl-N-(5-(6-(4-(1-methylpiperidin-4-carbonyl)-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) pyrazine-2-yl) thiophene-3-yl) acetamide (E2)

[0385] ##STR00308## ##STR00309##

Step 1: 7-bromo-3,4-dihydro-2H-benzo[b] [1,4]oxazine (E2-1)

[0386] 2-Amino-5-bromophenol (500 mg, 2.66 mmol), 1,2-dibromoethane (1 g, 5.32 mmol), potassium carbonate (735 mg, 5.32 mmol), and acetonitrile (35 mL) were taken and placed sequentially in a reaction flask and the mixture was reacted at 80? C. for 16 hours. LCMS monitoring showed that the reaction was completed. The reaction solution was concentrated, added with water and extracted with ethyl acetate. The aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to afford 7-bromo-3,4-dihydro-2H-benzo[b] [1,4]oxazine (E2-1, 190 mg, 33.4%). MS (ESI) m/z: calcd 216.1 (M+H). found 216.10.

Step 2: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b] [1,4] oxazine (E2-2)

[0387] 7-bromo-3,4-dihydro-2H-benzo[b] [1,4]oxazine (E2-1, 190 mg, 0.89 mmol), bis(pinacolato)diboron (271 mg, 1.07 mmol), potassium acetate (218 mg, 2.22 mmol), Pd (dppf).sub.2Cl.sub.2 (33 mg, 0.05 mmol), and 1,4-dioxane (10 mL) were taken and placed sequentially in a reaction flask. The mixture was reacted at 80? C. for 6 hours under nitrogen protection. LCMS monitoring showed that the reaction was complete. The reaction solution was filtered, and the solid was washed with ethyl acetate. The filtrate was subjected to concentration. The residue was purified by column chromatography to afford 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine (E2-2, 243 mg, 100%) MS (ESI) m/z: calcd 262.15, (M+H). found 262.10.

Step 3: 7-(6-bromopyrazin-2-yl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine (E2-3)

[0388] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine (E2-2, 243 mg, 0.93 mmol), 2,6-dibromopyrazine (266 mg, 1.12 mmol), potassium carbonate (309 mg, 2.24 mmol), Pd (dppf).sub.2 (54 mg, 0.05 mmol), and 1,4-dioxane:water=4:1 (15 mL) were taken and placed sequentially in a reaction flask. The mixture was reacted at 80? C. for 6 hours under nitrogen protection. LCMS monitoring showed that the reaction was completed. The reaction solution was diluted with water and extracted with EA, and the aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to afford 7-(6-bromopyrazine 2-yl)-3,4-dihydro-2H-benzo [b][1,4] oxazine (E2-3, 120 mg, 44.12%). MS (ESI) m/z: calcd 292.00 (M+H). found 293.90.

Step 4: 7-(6-(4-bromothiophene-2-yl) pyrazine-2-yl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine (E2-4)

[0389] 7-(6-bromopyrazin-2-yl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine (E2-3, 120 mg, 0.41 mmol), (4-bromothiophene-2-yl) boronic acid (85 mg, 0.41 mmol), potassium carbonate (136 mg, 0.98 mmol), Pd(PPh.sub.3).sub.4 (24 mg, 0.02 mmol), and 1,4-dioxane:water=4:1 (10 mL) were taken and added sequentially in a reaction flask. The mixture was reacted at 60? C. for 40 min under nitrogen protection. LCMS monitoring showed that the reaction was completed. The reaction solution was extracted with water and EA and the aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to afford 7-(6-(4-bromothiophene-2-yl) pyrazine-2-yl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine (E2-4, 85 mg, 55.19%). MS (ESI) m/z: calcd 373.99 (M+H). found 376.00.

Step 5: 1-methylpiperidin-4-carbonyl chloride (E2-5)

[0390] 1-Methylpiperidin-4-carboxylic acid (150 mg, 1.05 mmol) was taken and placed in a flask. Dichloromethane (10 mL) was added and oxalyl chloride (266 mg, 2.10 mmol) was added slowly dropwise. Upon addition, N,N-dimethylformamide (0.5 mL) was added dropwise and the resulting solution was reacted at room temperature for 3 hours. The reaction solution was spin-dried directly to obtain 1-methylpiperidin-4-carbonyl chloride (E2-5, 167 mg, 99.82%).

Step 6: (7-(6-(4-bromothiophene-2-yl) pyrazin-2-yl)-2,3-dihydro-4H-benzo [b] [1,4] oxazin-4-yl) (1-methylpiperidin-4-yl) ketone (E2-6)

[0391] 7-(6-(4-bromothiophene-2-yl) pyrazine-2-yl)-3,4-dihydro-2H-benzo [b] [1,4] oxazine (E2-4, 85 mg, 0.23 mmol), 1-methylpiperidin-4-carbonyl chloride (E2-5, 55 mg, 0.34 mmol), and 1,2-dichloroethane (8 mL) were taken and added sequentially to a reaction flask. The mixture was reacted at 85? C. for 2 hours, and LCMS monitoring showed that the reaction was complete. The reaction solution was diluted with water and extracted with DCM, and the aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate, and concentrated to afford (7-(6-(4-bromothiophene-2-yl) pyrazin-2-yl)-2,3-dihydro-4H-benzo [b] [1,4]oxazin-4-yl) (1-methylpiperidin-4-yl) ketone (E2-6, 60 mg, 53.1%). MS (ESI) m/z: calcd 499.07 (M+H). found 501.20.

Step 7: (7-(6-(4-aminothiophene-2-yl) pyrazin-2-yl)-2,3-dihydro-4H-benzo [b] [1,4] oxazin-4-yl) (1-methylpiperidin-4-yl) ketone (E2-7)

[0392] (7-(6-(4-bromothiophene-2-yl) pyrazin-2-yl)-2,3-dihydro-4H-benzo [b] [1,4] oxazin-4-yl) (1-methylpiperidin-4-yl) ketone (E2-6, 60 mg, 0.12 mmol), cuprous iodide (5 mg, 0.03 mmol), L-proline (6 mg, 0.18 mmol), potassium carbonate (25 mg, 0.18 mmol), dimethyl sulfoxide (4 mL), and ammonia (42 mg, 1.2 mmol) were taken and added sequentially to a sealed tube, and the mixture was reacted at 80? C. for 10 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was added with water and extracted with EA, and the aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated to afford crude product (7-(6-(4-aminothiophene-2-yl) pyrazin-2-yl)-2,3-dihydro-4H-benzo [b] [1,4]oxazin-4-yl) (1-methylpiperidin-4-yl) ketone (E2-7, 20 mg, 38.5%). MS (ESI) m/z: calcd 436.17 (M+H). found 436.30.

Step 8: 2-cyclopropyl-N-(5-(6-(4-(1-methylpiperidin-4-carbonyl)-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) pyrazin-2-yl) thiophen-3-yl) acetamide (E2)

[0393] 1-Methylenecyclopropanoic acid (7 mg, 0.07 mmol), EDCI (18 mg, 0.09 mmol), HOBT (12 mg, 0.09 mmol), N, N-dimethylformamide (5 mL) were taken and placed in a reaction flask and the mixture was reacted at room temperature for 5 minutes. Then, the reaction was added with N, N-diisopropylethylamine (30 mg, 0.23 mmol), and (7-(6-(4-aminothiophene-2-yl) pyrazin-2-yl)-2,3-dihydro-4H-benzo [b] [1,4] oxazin-4-yl) (1-methylpiperidin-4-yl) ketone (E2-7, 20 mg, 0.05 mmol), and then reacted overnight at room temperature. MS detection showed that the reaction was complete. The reaction solution was added with water and extracted with EA, and the aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to afford 2-cyclopropyl-N-(5-(6-(4-(1-methylpiperidin-4-carbonyl)-3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) pyrazin-2-yl) thiophen-3-yl) acetamide (E2, 5.18 mg, 21.7%). MS (ESI) m/z: calcd 518.21 (M+H). found 518.50. 1H NMR (400 MHz, DMSO) ? 10.33 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 7.89 (d, J=1.4 Hz, 1H), 7.79-7.71 (m, 3H), 4.38-4.31 (m, 2H), 4.01-3.93 (m, 2H), 2.92-2.79 (m, 3H), 2.22 (d, J=7.1 Hz, 2H), 2.20 (s, 2H), 2.12 (d, J=7.0 Hz, 1H), 2.02-1.92 (m, 2H), 1.82-1.65 (m, 4H), 1.11-1.05 (m, 1H), 0.52-0.43 (m, 2H), 0.23-0.19 (m, 1H), 0.14-0.08 (m, 1).

Example 159 was Prepared Using Experimental Steps Similar to Those in Example 158 Above to Afford Compound E1, See Table 8.

[0394]

TABLE-US-00008 TABLE 8 MS(calcd) Compound [M + H].sup.+/ Example No. Structure MS (found) Name and characterization 158 E2 [00310] 518.21/ 518.50 2-cyclopropyl-N-(5-(6-(4-(1- methylpiperidin-4-carbonyl) -3,4- dihydro-2H-benzo[b][1,4]oxazin-7- yl)pyrazine-2-yl) thiophene-3-yl) acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.33 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 7.89 (d, J = 1.4 Hz, 1H), 7.79-7.71 (m, 3H), 4.38-4.31 (m, 2H), 4.01-3.93 (m, 2H), 2.92-2.79 (m, 3H), 2.22 (d, J = 7.1 Hz, 2H), 2.20 (s, 2H), 2.12 (d, J = 7.0 Hz, 1H), 2.02-1.92 (m, 2H), 1.82-1.65 (m, 4H), 1.11-1.05 (m, 1H), 0.52-0.43 (m, 2H), 0.23-0.19 (m, 1H), 0.14-0.08 (m, 1H). 159 E1 [00311] 532.23/ 532.4 2-cyclobutyl-N-(5-(6-(4-(1- methylpiperidine-4-carbonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-7- yl)pyrazin-2-yl)thiophen-3- yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.36 (s, 1H), 9.11 (s, 1H), 9.01 (s, (dd, J = 17.2, 4.7 Hz, 3H), 4.42- 1H), 7.88 (d, J = 1.4 Hz, 1H), 7.71 4.30 (m, 2H), 4.05-3.91 (m, 2H), 2.94-2.79 (m, 3H), 2.74-2.65 (m, 1H), 2.43 (d, J = 7.6 Hz, 2H), 2.20 (s, 3H), 2.14-2.03 (m, 2H), 2.03- 1.93 (m, 2H), 1.89-1.80 (m, 2H), 1.80-1.69 (m, 4H), 1.38-1.29 (m, 2H).

Example 160: Preparation of 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl) pyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzamide (F1)

[0395] ##STR00312##

Step 1: methyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl-2-methoxybenzoate (F1-1)

[0396] Methyl 4-(6-(4-bromothiophen-2-yl) pyrazine-2-yl-2-methoxybenzoate (B4-3, 200 mg, 0.49 mmol), cuprous iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), and potassium carbonate (102 mg, 0.74 mmol) were added to dimethyl sulfoxide (4 mL) followed by the addition of ammonia (1 mL). The tube was sealed, and heated to 80? C. and stirred for 8 hours. After TLC confirmed completion of the reaction, the reaction was poured into water and extracted with ethyl acetate. The organic phase was washed three times with deionized water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate to obtain methyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl-2-methoxybenzoate (F1-1, 150 mg, 89%). MS (ESI) m/z: calcd 342.08 (M+H). found 342.1.

Step 2: methyl 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxybenzoate (F1-2)

[0397] Methyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl-2-methoxybenzoate (F1-1, 148 mg, 0.43 mmol) was dissolved in dichloromethane (10 mL). The solution was added with triethylamine (53 mg, 0.52 mmol) and phenyl chloroformate (75 mg, 0.48 mmol) and the mixture was stirred at room temperature for 4 hours. LCMS monitoring showed that the reaction was completed. The reaction solution was washed for three times by adding water; the organic phase was dried over anhydrous sodium sulfate and concentrated. The product and cyclobutylamine (34 mg, 0.48 mmol) were added to N,N-dimethylformamide (8 ml), followed by the addition of N,N-diisopropylethylamine (181 mg, 1.4 mmol). The mixture was stirred at room temperature for 4 hours. LCMS monitoring showed that the reaction was completed. The reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was washed three times with deionized water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate. The residue was purified by column chromatography to afford methyl 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxybenzoate (F1-2, 75 mg, 39.5%). MS (ESI) m/z: calcd 439.14 (M+H). found 349.3.

Step 3: 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxybenzoic Acid (F1-3)

[0398] Methyl 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxybenzoate (F1-2, 75 mg, 0.17 mmol) was added to a mixed solvent of tetrahydrofuran and water (8 mL, 2 mL). Then the mixture was added with lithium hydroxide (29 mg, 0.69 mmol), and stirred at room temperature for 16 hours. LCMS monitoring showed that the reaction was completed. The reaction solution was adjusted to weak acidity with 2M HCl and extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to afford 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxybenzoic acid (F1-3, 40 mg, 55.3%). MS (ESI) m/z: calcd 425.12, (M+H). found 452.2.

Step 4: 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzamide (F1-4)

[0399] 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxybenzoic acid (F1-3, 40 mg, 0.094 mmol) and 1-methyl-4 (methylamino) piperidine (15 mg, 0.12 mmol), and o-(7-aza-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) were added to dichloromethane. The mixture was then added with N, N-diisopropylethylamine (49 mg, 0.38 mmol) and stirred at room temperature for 1 hour. TLC detection showed that the reaction was completed. The reaction solution was washed with water and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to afford 4-(6-(4-(3-cyclobutylurea) thiophen-2-yl-pyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzamide (F1, 25 mg, 49.8%). MS (ESI) m/z: calcd 535.24, (M+H). found 535.4. .sup.1H NMR (400 MHz, DMSO) ? 9.21 (d, J=10.7 Hz, 1H), 9.10 (d, J=2.6 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J=8.2 Hz, 3H), 7.40 (s, 1H), 7.34 (t, J=7.3 Hz, 1H), 6.51 (d, J=7.8 Hz, 1H), 4.21-4.07 (m, 1H), 3.93 (d, J=2.7 Hz, 3H), 3.16 (s, 1H), 2.95-2.61 (m, 6H), 2.22-2.17 (m, 2H), 2.09-1.94 (m, 4H), 1.92-1.75 (m, 4H), 1.69-1.54 (m, 4H).

Example 161: Preparation of (S)-4-(6-(4-(4-amino-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl) benzamide (G1)

[0400] ##STR00313## ##STR00314##

Step 1: Methyl 2-Methoxy-4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiophen-2-yl) pyrazin-2-ylbenzoate (G1-1)

[0401] Methyl 4-(6-(4-bromothiophen-2-yl) pyrazin-2-ylmethoxybenzoate (B4-3, 200 mg, 0.49 mmol), bis(pinacolato)diboron (150 mg, 0.59 mmol), Pd (dppf).sub.2Cl.sub.2 (18 mg, 0.02 mmol), potassium acetate (121 mg, 1.23 mmol), and dioxane (10 mL) were placed sequentially into a reaction flask. The mixture was reacted at 80? C. for 6 hours under nitrogen protection. MS monitoring showed that the reaction was completed. The reaction solution was filtered. The solid was washed with ethyl acetate and the filtrate was concentrated and purified by column chromatography to afford methyl 2-methoxy-4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiophen-2-yl) pyrazin-2-ylbenzoate (G1-1, 197 mg, 89.8%). MS (ESI) m/z: calcd 453.16 (M+H). found 453.50.

Step 2: (5-(6-(3-methoxy-4-(methoxycarbonyl) phenyl) pyrazin-2-yl) thiophen-3-yl) boronic Acid (G1-2)

[0402] 2-Methoxy-4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiophen-2-yl) pyrazin-2-ylbenzoate (G1-1,197 mg, 0.44 mmol), sodium periodate (189 mg, 0.88 mmol), sodium acetate (171 mg, 2.21 mmol), and tetrahydrofuran:water=3:1 (10 mL) were sequentially added to a reaction flask and the mixture was reacted at room temperature for 14 hours. LCMS detection showed that the reaction was completed. The reaction solution was filtered and the solid was collected, washed with water and dried to afford yellow product (5-(6-(3-methoxy-4-(methoxycarbonyl) phenyl) pyrazin-2-yl) thiophen-3-yl) boronic acid (G1-2, 110 mg, 67.6%). MS (ESI) m/z: calcd 371.08 (M+H). found 371.30.

Step 3: methyl 4-(6-(4-hydroxythiophen-2-yl)pyrazin-2-yl)-2-methoxybenzoate (G1-3)

[0403] To a flask containing (5-(6-(3-methoxy-4-(methoxycarbonyl) phenyl) pyrazin-2-yl) thiophen-3-yl) boronic acid (G1-2, 110 mg, 0.30 mmol) was added tetrahydrofuran (10 mL). The reaction was placed in an ice bath and added slowly with hydrogen peroxide (35%, 230 mg, 2.37 mmol), followed by the addition of a 2 mol/L sodium hydroxide solution (5 mg). Upon addition, the ice bath was removed and the reaction was carried out at room temperature for 14 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was filtered and the solid was collected, washed with water and dried to afford methyl 4-(6-(4-hydroxythiophen-2-yl)pyrazin-2-yl)-2-methoxybenzoate (G1-3, 54 mg, 48.9%). MS (ESI) m/z: calcd 342.07 (M+H). found 343.30.

Step 4: butyl (R)-4-((tert butoxycarbonyl) amino)-3-methylmethane sulfonate (G1-4)

[0404] (R)-(4-hydroxy-2-methylbutyl) carbamate (100 mg, 0.49 mmol) was taken and placed in a flask. Dichloromethane (10 mL) was added and the reaction was placed in an ice bath. Then the reaction was added with triethylamine (149 mg, 1.47 mmol) and slowly added with methylsulfonyl chloride (68 mg, 0.59 mmol). Upon addition, the ice bath was removed and the reaction was carried out at room temperature for 30 min. LCMS monitoring showed that the reaction was completed. The reaction was quenched with water and extracted with dichloromethane, and the aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to afford butyl (R)-4-((tert butoxycarbonyl) amino)-3-methyl methanesulfonate (Gi-4, 131 mg, 94.93%). MS (ESI) m/z: calcd 282.13 found 282.40.

Step 5: methyl (S)-4-(6-(4-(4-(tert butoxycarbonyl) amino)-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl-2-methoxybenzoate (G1-5)

[0405] Methyl 4-(6-(4-hydroxythiophen-2-yl)pyrazin-2-yl)-2-methoxybenzoate (G1-3, 54 mg, 0.16 mmol), butyl (R)-4-((tert butoxycarbonyl) amino)-3-methyl methanesulfonate (G1-4, 53 mg, 0.19 mmol), cesium carbonate (103 mg, 0.32 mmol), and N, N-dimethylformamide (10 mL) were sequentially added to a flask and the mixture was reacted at 100? C. for 14 hours. MS monitoring showed that the reaction was completed. The reaction solution was added with water and extracted with ethyl acetate. The aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to afford methyl (S)-4-(6-(4-(4-(tert butoxycarbonyl) amino)-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl-2-methoxybenzoate (G1-5, 40 mg, 48.2%). MS (ESI) m/z: calcd 528.21 (M+H). found 528.40.

Step 6: (S)-4-(6-(4-(4-(tert butoxycarbonyl) amino)-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl-2-methoxybenzoic Acid (A1-06)

[0406] Methyl (S)-4-(6-(4-(4-(tert butoxycarbonyl) amino)-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl-2-methoxybenzoate (G1-5, 40 mg, 0.08 mmol), lithium hydroxide (13 mg, 0.31 mmol) and tetrahydrofuran:water=4:1 (10 mL) were sequentially added to a reaction flask and the mixture was reacted at room temperature for 14 hours. MS monitoring showed that the reaction was completed. The reaction solution was adjusted to around pH 6 with citric acid, added with water, and extracted with ethyl acetate. The aqueous phase was extracted again. The organic phase was combined, washed with saturated salt water, dried over anhydrous sodium sulfate, and concentrated to obtain crude (S)-4-(6-(4-(4-(tert butoxycarbonyl) amino)-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl-2-methoxybenzoic acid (G1-6, 45 mg). MS (ESI) m/z: calcd 514.19 (M+H). found 514.40.

Step 7: Tert-butyl (S)-(4-(5-(6-(3-methoxy-4-(methyl (1-methylpiperidin-4-ylcarbamoyl) phenyl) pyrazin-2-yl) thiophen-3-yl-oxy)-2-methylbutyl) carbamate (G1-7)

[0407] (S)-4-(6-(4-(4-(tert butoxycarbonyl) amino)-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl-2-methoxybenzoic acid (G1-6, 45 mg, 0.09 mmol) was mixed with 2-(7-aza-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (67 mg, 0.18 mmol) and dichloromethane (10 mL). The mixture was reacted at room temperature for 5 min and then added with 1-methyl-4-(methylamino) piperidine (14 mg, 0.11 mmol), and N, N-diisopropylethylamine (45 mg, 0.35 mmol). The resulting solution was reacted at room temperature for 2 hours. LCMS detection showed that the reaction was completed. The reaction solution was added with water and extracted with DCM, and the aqueous phase was extracted again. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography to afford tert-butyl (S)-(4-(5-(6-(3-methoxy-4-(methyl (1-methylpiperidin-4-ylcarbamoyl) phenyl) pyrazin-2-yl) thiophen-3-yl-oxy)-2-methylbutyl) carbamate (G1-7, 21 mg, 38.2%). MS (ESI) m/z: calcd 624.31, (M+H). found 624.50.

Step 8: (S)-4-(6-(4-(4-amino-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl)benzamide (G1)

[0408] Tert-butyl (S)-(4-(5-(6-(3-methoxy-4-(methyl (1-methylpiperidin-4-ylcarbamoyl) phenyl) pyrazin-2-yl) thiophen-3-yloxy)-2-methylbutyl) carbamate (G1-7, 21 mg, 0.03 mmol) was taken and added with hydrochloric acid ethyl acetate solution (3 mol/L, 3 mL) and ethyl acetate (1 mL). The mixture was reacted at room temperature for 30 min. LCMS monitoring showed that the reaction was complete. The reaction solution was directly dried by rotary evaporation to afford yellow solid product (S)-4-(6-(4-(4-amino-3-methylbutoxy) thiophen-2-yl) pyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidin-4-yl)benzamide hydrochloride (Gi, 12 mg, 66.67%). MS (ESI) m/z: calcd 524.26 (M+H). found 524.50; .sup.1H NMR (400 MHz, DMSO) ? 9.21 (dd, J=15.2, 7.4 Hz, 2H), 8.10 (s, 3H), 7.95-7.74 (m, 3H), 7.46-7.33 (m, 1H), 6.96-6.88 (m, 1H), 4.12-4.06 (m, 1H), 3.94 (s, 3H), 3.65-3.53 (m, 2H), 3.47 (d, J=11.2 Hz, 1H), 3.41-3.23 (m, 2H), 3.23-3.07 (m, 2H), 2.91-2.81 (m, 3H), 2.74-2.67 (m, 3H), 2.59 (d, J=4.6 Hz, 2H), 2.38-2.17 (m, 2H), 2.08-1.96 (m, 1H), 1.95-1.87 (m, 1H), 1.80 (t, J=12.1 Hz, 1H), 1.70-1.56 (m, 2H), 1.02 (d, J=6.7 Hz, 3H).

Examples 162-164 (Compounds A46-A48) were Prepared Using Experimental Steps Similar to Those in Example 35 Above, and Compounds A46-A48 were Summarized in Table 9.

TABLE-US-00009 TABLE 9 MS(calcd) Compound [M + H].sup.+/ Example No. Structure MS (found) Name and characterization 162 A46 [00315] 472.13/ 471.90 2-cyclobutyl-N-(5-(6-(4- (ethylsulfonyl)-3- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.38 (s, 1H), 9.29 (s, 1H), 9.16 (s, 1H), 8.01-7.91 (m, 4H), 7.72 (d, J=1.3 Hz, 1H), 4.10 (s, 3H), 3.44 (q, J=7.4 Hz, 2H), 2.70 (dt, J = 15.2, 7.7 Hz, 2H), 2.43 (d, J = 7.5 Hz, 2H), 2.12-2.04 (m, 2H), 1.94-1.65 (m, 4H), 1.13 (t, J = 7.4 Hz, 3H). 163 A47 [00316] 442.12/ 442.30 2-cyclobutyl-N-(5-(6-(3-methoxy- 4-(methylsulfinyl)phenyl)pyrazin- 2-yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.38 (s, 1H), 9.25 (s, 1H), 9.12 (s, 1H), 8.03 (dd, J = 8.0, 1.3 Hz, 1H), 7.89 (dd, J = 7.8, 1.3 Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 4.02 (s, 3H), 2.79 (s, 3H), 2.70 (dt, J = 15.5, 7.8 Hz, 1H), 2.43 (d, J = 7.6 Hz, 2H), 2.12-2.04 (m, 2H), 1.91-1.68 (m, 4H). 164 A48 [00317] 498.14/ 498.30 2-cyclobutyl-N-(5-(6-(4- (cyclobutylsulfonyl)-3- methoxyphenyl)pyrazin-2- yl)thiophen-3-yl)acetamide

Example 166: Preparation of 2-cyclobutyl-N-(5-(6-(2-(1-methylpiperidin-4-yl) methyl)-2H-indazol-6-yl) pyrazin-2-yl) thiophene-3-yl) acetamide (A50)

[0409] ##STR00318## ##STR00319## ##STR00320##

Step 1: Tert butyl 4-(6-bromo-2H-indazol-2-yl) methyl) piperidin-1-carboxylate (A50-1)

[0410] 6-bromo-1H-indazole (600 mg, 3.04 mmol), tert butyl 4-(hydroxymethyl) piperidin-1-carboxylate (1.0 g, 3.6 mmol), and cesium carbonate (1.98 g, 6.08 mmol) were added to N,N-dimethylformamide (10 ml), and the mixture was heated to 60? C. and stirred for 3 hours. After LCMS and TLC confirmed completion of the reaction, the reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate. The residue was purified by column chromatography to afford tert butyl 4-(6-bromo-2H-indazol-2-yl) methyl) piperidin-1-carboxylate (A50-1, 630 mg, 52.3%). MS (ESI) m/z: calcd 394.11 (M+H). found 338.2.

Step 2: Tert butyl 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2H-indazol-2-ylmethyl) piperidin-1-carboxylate (A50-2)

[0411] Tert butyl 4-(6-bromo-2H-indazol-2-yl) methyl) piperidin-1-carboxylate (A50-1, 630 mg, 1.59 mmol), bis(pinacolato)diboron (487 mg, 1.90 mmol), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58 mg, 0.08 mmol), and potassium acetate (392 mg, 3.98 mmol) were added to dioxane (10 mL), and the mixture was heated to 80? C. under nitrogen protection, and stirred for 14 hours. LCMS and TLC confirmed completion of the reaction, and the crude product was used directly in the next step to afford tert butyl 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2H-indazol-2-ylmethyl) piperidin-1-carboxylate (A50-2, 705 mg Crude, theoretical 1.59 mmol). MS (ESI) m/z: calcd 442.28 (M+H). found 442.5.

Step 3: Tert butyl 4-((6-(6-bromopyrazin-2-yl)-2H-indazol-2-ylmethyl) piperidin-1-carboxylate (A50-3)

[0412] Tert butyl 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2H-indazol-2-ylmethyl) piperidin-1-carboxylate (A50-2, 705 mg Crude, theoretical 1.59 mmol), 2,6-dibromopyrazine (456 mg, 1.90 mmol), tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol), and potassium carbonate (530 mg, 3.80 mmol) were added to a mixed solvent of dioxane/water (12 mL/3 mL), and the mixture was heated to 80? C. under nitrogen protection, and stirred for 8 hours. After MS and TLC confirmed completion of the reaction, the reaction solution was poured into water, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford tert butyl 4-((6-(6-bromopyrazin-2-yl)-2H-indazol-2-ylmethyl) piperidin-1-carboxylate (A50-3, 280 mg, 37.1%). MS (ESI) m/z: calcd 472.13 (M+H). found 374.2.

Step 4: Tert butyl 4-(6-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2H-indazol-2-yl) methylpiperidin-1-carboxylate (A50-4)

[0413] Tert butyl 4-((6-(6-bromopyrazin-2-yl)-2H-indazol-2-ylmethyl) piperidin-1-carboxylate (A50-3, 280 mg, 0.59 mmol), (4-bromothiophen-2-yl) boronic acid (122 mg, 0.59 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) and potassium carbonate (197 mg, 1.44 mmol) were added to dioxane/water (12 mL/3 mL), and the mixture was heated to 60? C. and stirred for 0.5 h under nitrogen protection. After MS and TLC confirmed completion of the reaction, the reaction solution was poured into water, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford tert butyl 4-(6-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2H-indazol-2-yl) methylpiperidin-1-carboxylate (A50-4, 240 mg, 83.0%). MS (ESI) m/z: calcd 554.11 (M+H). found 456.2.

Step 5: Tert butyl 4-(6-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2H-indazol-2-yl) methyl) piperidin-1-carboxylate (A50-5)

[0414] Tert butyl 4-(6-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2H-indazol-2-yl) methylpiperidin-1-carboxylate (A50-4, 240 mg, 0.49 mmol), cuprous iodide (16 mg, 0.10 mmol), L-proline (19 mg, 0.20 mmol), and potassium carbonate (85 mg, 1.18 mmol) were added to dimethyl sulfoxide (4 mL), and the ammonia (1 mL) was added. The tube was sealed, and heated to 80? C. and stirred for 8 hours. TLC confirmed completion of the reaction. The reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate to afford tert butyl 4-(6-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2H-indazol-2-yl) methyl) piperidin-1-carboxylate (A50-5, 220 mg crude, 0.49 mmol theoretical), which was used directly in the next step. MS (ESI) m/z: calcd 491.22 (M+H). found 491.6.

Step 6: Tert butyl 4-(6-(6-(4-(2-cyclobutylacetamido) thiophen-2-yl)pyrazin-2-yl)-2H-indazol-2-yl)methyl)piperidin-1-carboxylate (A50-6)

[0415] Tert butyl 4-(6-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2H-indazol-2-yl) methyl) piperidin-1-carboxylate (A50-5, 220 mg crude, 0.49 mmol theoretical), 2-cyclobutyl acetic acid (62 mg, 0.54 mmol), 1-hydroxybenzotriazole (122 mg, 0.90 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg, 0.90 mmol) were added to dichloromethane (12 mL), and then the mixture was added with N, N-diisopropylethylamine (232 mg, 1.80 mmol) and stirred at room temperature for 4 hours. LCMS and TLC confirmed completion of the reaction. The reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate. The residue was purified by column chromatography to afford tert butyl 4-(6-(6-(4-(2-cyclobutylacetamido) thiophen-2-yl)pyrazin-2-yl)-2H-indazol-2-yl)methyl)piperidin-1-carboxylate (A50-6, 70 mg, 20.4%). MS (ESI) 50 m/z: calcd 586.27 (M+H). found 487.6.

Step 7: 2-cyclobutyl-N-(5-(6-(2-(2-piperidin-4-ylmethyl)-2H-indazol-6-yl) pyrazin-2-yl) thiophen-3-yl) acetamide (A50-7)

[0416] Tert butyl 4-(6-(6-(4-(2-cyclobutylacetamido) thiophen-2-yl)pyrazin-2-yl)-2H-indazol-2-yl)methyl)piperidin-1-carboxylate (A50-6, 70 mg, 0.1 mmol) was dissolved in 2 mL of ethyl acetate. The mixture was added with 4 mL of 3M hydrogen chloride in ethyl acetate and then stirred at room temperature for 10 hours. TLC detection showed that the reaction was completed. The solvent was dried by rotary evaporation to afford 2-cyclobutyl-N-(5-(6-(2-(2-piperidin-4-ylmethyl)-2H-indazol-6-yl) pyrazin-2-yl) thiophen-3-yl) acetamide (A50-7, 90 mg crude product, theoretical 0.1 mmol) and the crude product was directly used in the next step. MS (ESI) m/z: calcd 486.22 (M+H). found 487.5.

Step 8: 2-cyclobutyl-N-(5-(6-(2-(1-methylpiperidin-4-yl) methyl)-2H-indazol-6-yl) pyrazin-2-yl) thiophene-3-yl) acetamide (A50)

[0417] 2-cyclobutyl-N-(5-(6-(2-(2-piperidin-4-ylmethyl)-2H-indazol-6-yl) pyrazin-2-yl) thiophen-3-yl) acetamide (A50-7, 90 mg crude product, theoretical 0.1 mmol), formaldehyde (55 mg, 1.90 mmol) and acetic acid (34.2 mg, 0.57 mmol) were added to methanol (12 mL). After stirring at room temperature for 0.5 hours, the mixture was added with sodium triacetoxyborohydride (196 mg, 0.93 mmol) and stirred at room temperature for 14 hours. After LCMS and TLC confirmed completion of the reaction, the reaction was dried to remove solvent. The residue was added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated to remove ethyl acetate. The residue was purified by column chromatography to afford 2-cyclobutyl-N-(5-(6-(2-(1-methylpiperidin-4-yl) methyl)-2H-indazol-6-yl) pyrazin-2-yl) thiophene-3-yl) acetamide (A50, 20 mg, 39.9%). MS (ESI) m/z: calcd 501.24 (M+H). found 501.40. .sup.1H NMR (400 MHz, DMSO) ? 10.40 (s, 1H), 9.23 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 7.90 (dd, J=5.0, 1.1 Hz, 3H), 7.71 (d, J=1.2 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 2.79-2.69 (m, 2H), 2.69-2.65 (m, 1H), 2.44 (d, J=7.6 Hz, 2H), 2.13 (s, 2H), 2.10-2.05 (m, 1H), 2.02-1.93 (m, 1H), 1.91-1.82 (m, 2H), 1.80 (s, 3H), 1.78-1.69 (m, 2H), 1.45 (d, J=10.8 Hz, 2H), 1.35-1.26 (m, 3H).

Examples 165-168 (Compounds A49-A52) were Prepared Using Experimental Steps Similar to Those in Above Example A50, and Compounds A49-A52 were Summarized in Table 10.

TABLE-US-00010 TABLE 10 MS(calcd) Compound [M + H].sup.+/ Example No. Structure MS (found) Name and characterization 165 A49 [00321] 404.15/ 404.40 2-cyclobutyl-N-(5-(6-(1-methyl- 1H-indazol-6-yl)pyrazin-2- yl)thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.37 (s, 1H), 9.30 (s, 1H), 9.07 (s, 1H), 8.49 (s, 1H), 8.14 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 1.1 Hz, 1H), 7.72 (s, 1H), 4.17 (s, 3H), 2.77-2.65 (m, 1H), 2.44 (d, J = 7.6 Hz, 2H), 2.15-2.03 (m, 2H), 1.94-1.81 (m, 2H), 1.81-1.67 (m, 2H). 166 A50 [00322] 501.24/ 501.40 2-cyclobutyl-N-(5-(6-(2-((1- methylpiperidin-4-yl)methyl)- 2H-indazol-6-yl)pyrazin-2- yl) thiophen-3-yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.40 (s, 1H), 9.23 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 7.90 (dd, J = 5.0, 1.1 Hz, 3H), 7.71 (d, J = 1.2 Hz, 1H), 4.37 (d, J = 7.2 Hz, 2H), 2.79- 2.69 (m, 2H), 2.69-2.65 (m, 1H), 2.44 (d, J = 7.6 Hz, 2H), 2.13 (s, 2H), 2.10-2.05 (m, 1H), 2.02-1.93 (m, 1H), 1.91-1.82 (m, 2H), 1.80 (s, 3H), 1.78-1.69 (m, 2H), 1.45 (d, J = 10.8 Hz, 2H), 1.35-1.26 (m, 3H). 167 A51 [00323] 418.16/ 418.30 2-cyclobutyl-N-(5-(6-(1,3- dimethyl-1H-indazol-6- yl)pyrazin-2-yl)thiophen-3- yl)acetamide .sup.1H NMR (400 MHz, DMSO) ? 10.38 (s, 1H), 9.29 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 7.96 (d, J = 9.5 Hz, 1H), 7.89 (d, J = 9.1 Hz, 2H), 7.72 (s, 1H), 4.08 (s, 3H), 2.73-2.67 (m, 1H), 2.53 (s, 3H), 2.44 (d, J = 7.6 Hz, 2H), 2.16-2.04 (m, 2H), 1.91-1.81 (m, 2H), 1.81-1.70 (m, 2H). 168 A52 [00324] 390.13/ 390.40 N-(5-(6-(1H-indazol-6- yl)pyrazin-2-yl)thiophen-3-yl)-2- cyclobutylacetamide .sup.1H NMR (400 MHz, DMSO) ? 13.35 (s, 1H), 10.38 (s, 1H), 9.22 (s, 1H), 9.06 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.95 (s, 2H), 7.90 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 2.78- 2.64 (m, 1H), 2.44 (d, J = 7.6 Hz, 2H), 2.15-2.03 (m, 2H), 1.92-1.81 (m, 2H), 1.81-1.69 (m, 2H).

Example 169: 2-cyclobutyl-N-(5-(6-(3-methoxy-4-(2-morpholinylethoxy) phenyl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0418] ##STR00325##

Synthesis Method:

[0419] ##STR00326## ##STR00327##

Step 1: 1-Benzyloxy-4-bromo-2-methoxybenzene

[0420] To a solution of 4-bromo-2-methoxyphenol (500 mg) in DMF (10 mL) was added BnBr (450 mg), and potassium carbonate (350 mg). The mixture was reacted at room temperature for 14 hours. TLC detection showed that the reaction was completed. The reaction solution was extracted with ethyl acetate, and washed with water. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1-benzyloxy-4-bromo-2-methoxybenzene (700 mg, yield 97%). LCMS (m/z): 293.1 [M+H].sup.+.

Step 2: 2-(4-(benzyloxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0421] 1-Benzyloxy-4-bromo-2-methoxybenzene (100 mg), potassium acetate (840 mg), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (125 mg), bis(pinacolato)diboron (1100 mg) and 1,4-dioxane (40 mL) were successively added to a reaction flask and the mixture was reacted under nitrogen protection at 80? C. overnight. TLC monitoring showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated, and purified by thin-layer chromatography to obtain the product 2-(4-(benzyloxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.16 g, yield 99%). LCMS (m/z): 341.2 [M+H].sup.+.

Step 3: 2-[4-(benzyloxy)-3-methoxyphenyl]-6-bromopyrazine

[0422] 2-(4-(benzyloxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.16 g), 2,6-dibromopyrazine (1210 mg), potassium carbonate (1130 mg), tetrakis(triphenylphosphine)palladium (198 mg), 1,4-dioxane (16 mL), and water (4 mL) were added successively to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. overnight, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and re-dissolved with ethyl acetate (50 mL). The organic phase was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-[4-(benzyloxy)-3-methoxyphenyl]-6-bromopyrazine (690 mg, yield 48%). LCMS (m/z): 371.1 [M+H].sup.+.

Step 4: 2-[4-(benzyloxy)-3-methoxyphenyl]-6-(4-bromothiophen-2-yl)pyrazine

[0423] 2-[4-(benzyloxy)-3-methoxyphenyl]-6-bromopyrazine (600 mgl), (4-bromothiophen-2-yl) boronic acid (332 mg), tetrakis(triphenylphosphorus)palladium (94 mg), potassium carbonate (537 mg), 1,4-dioxane (16 mL), and water (4 mL) were successively added to a reaction flask. The mixture was reacted under nitrogen protection at 60? C. for 0.5 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, then added with dichloromethane (30 mL) and water (30 mL), and fractioned. The aqueous phase was extracted with dichloromethane (20 mL*2) and the organic phases were combined, washed with saturated salt water (20 mL*1), dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-[4-(benzyloxy)-3-methoxyphenyl]-6-(4-bromothiophen-2-yl)pyrazine (500 mg, yield 69%). LCMS (m/z): 453.1 [M+H].sup.+

Step 5: 5-(6-(4-(benzyloxy)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-amine

[0424] 2-[4-(benzyloxy)-3-methoxyphenyl]-6-(4-bromothiophen-2-yl)pyrazine (250 mg), cuprous iodide (22 mg), L-proline (28 mg), dimethyl sulfoxide (3 mL), and ammonia (25% wt, 1 mL) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 10 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with 20 mL of water, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated ammonium chloride (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain 5-(6-(4-(benzyloxy)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-amine (crude, 200 mg), which was directly used in the next reaction without any purification. LCMS (m/z): 390.1 [M+H].sup.+

Step 6: N-(5-(6-(4-(benzyloxy)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutyl Acetamide

[0425] 5-(6-(4-(benzyloxy)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-amine (crude, 200 mg) was added with DMF (10 mL). The flask was sequentially added with cyclobutyl acetic acid (88 mg), EDCI (246 mg), HOBT (174 mg), and DIEA (332 mg), and the mixture was reacted at room temperature for 14 hours. LCMS detection showed that the reaction was complete. The reaction solution was washed with water and the organic phase was dried over anhydrous sodium sulfate and spin-dried. The residue was purified by column chromatography to obtain N-(5-(6-(4-(benzyloxy)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutyl acetamide (90 mg, yield 36%). LCMS (m/z): 486.2 [M+H].sup.+.

Step 7: 2-Cyclobutyl-N-(5-(6-(4-hydroxy-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0426] To a solution of (5-(6-(4-(benzyloxy)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutyl acetamide (90 mg) in methanol (10 mL) was added palladium carbon (10 mg) and the mixture was reacted at room temperature overnight. MS monitoring showed that the reaction was completed. The reaction solution was filtered and concentrated to afford 2-cyclobutyl-N-(5-(6-(4-hydroxy-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl) acetamide (70 mg, yield 93%). LCMS (m/z): 396.1 [M+H].sup.+.

Step 8: 2-Cyclobutyl-N-(5-(6-(3-methoxy-4-(2-morpholinylethoxy) phenyl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0427] To a mixture of 2-cyclobutyl-N-(5-(6-(4-hydroxy-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl) acetamide (20 mg) in acetonitrile (10 mL) was added cesium carbonate (32 mg) and the mixture was reacted at 75? C. for 2 h. MS monitoring showed that the reaction was completed. The reaction solution was filtered, concentrated and purified by thin layer chromatography to afford 2-cyclobutyl-N-(5-(6-(3-methoxy-4-(2-morpholinylethoxy) phenyl) pyrazin-2-yl) thiophen-3-yl) acetamide (5 mg, yield 20%). LCMS (m/z): 509.2[M+H]+. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 9.16 (s, 1H), 9.00 (s, 1H), 7.89-7.78 (m, 3H), 7.69 (d, J=1.1 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 4.47-4.44 (m, 2H), 4.02 (s, 2H), 3.93 (s, 3H), 3.75 (s, 2H), 3.68-3.52 (m, 4H), 3.28 (s, 2H), 2.69 (dq, J=15.3, 7.7 Hz, 1H), 2.43 (d, J=7.5 Hz, 2H), 2.13-2.01 (m, 2H), 1.94-1.67 (m, 4H).

[0428] Examples 170-198 were prepared using the experimental steps similar to those in Example 169 above.

Example 170: 2-Cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(2-oxotetrahydro-1H-pyrrol-1-yl) ethyl] oxy} phenyl) pyrazin-2-yl] thiophen-3-yl} acetamide

[0429] ##STR00328##

[0430] Yellow solid (2.23 mg), LCMS (ESI): [M+H].sup.+=507.50; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.35 (s, 1H), 9.14 (s, 1H), 8.97 (s, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.83-7.73 (m, 2H), 7.69 (d, J=1.3 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 4.16 (t, J=5.6 Hz, 2H), 3.91 (s, 3H), 3.59 (t, J=5.5 Hz, 2H), 3.52 (t, J=7.0 Hz, 2H), 2.70 (dt, J=15.4, 7.6 Hz, 1H), 2.43 (d, J=7.6 Hz, 2H), 2.24 (t, J=8.1 Hz, 2H), 2.12-2.04 (m, 2H), 1.98-1.69 (m, 6H).

Example 171: 2-Cyclobutyl-N-{5-[6-(4-{[1-hydroxy-2-(3-oxo-1,4-oxazepan-4-yl) ethyl] oxy}-3-methoxyphenyl) pyrazin-2-yl] thiophen-3-yl} acetamide

[0431] ##STR00329##

[0432] Yellow solid (2.86 mg), LCMS (ESI): [M+H].sup.+=539.40: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.44 (s, 1H), 9.10 (s, 1H), 8.98 (s, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.81-7.72 (m, 2H), 7.68 (d, J=1.3 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 5.76 (s, 1H), 4.17 (td, J=11.8, 3.3 Hz, 1H), 3.90 (s, 3H), 3.84 (dd, J=11.3, 4.2 Hz, 1H), 3.59 (t, J=5.6 Hz, 2H), 3.56-3.47 (m, 1H), 3.38 (ddd, J=13.3, 12.8, 3.9 Hz, 3H), 2.67 (dt, J=15.5, 7.8 Hz, 1H), 2.40 (t, J=7.3 Hz, 2H), 2.11-1.99 (m, 2H), 1.89-1.78 (m, 2H), 1.78-1.65 (m, 2H).

Example 172: 2-cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(pyridin-2-yl) ethyl] oxy} phenyl) pyrazin-2-yl] thiophen-3-yl} acetamide

[0433] ##STR00330##

[0434] Yellow solid (2.47 mg), LCMS (ESI): [M+H].sup.+=501.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.36 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 8.53 (d, J=4.8 Hz, 1H), 7.85 (d, J=1.3 Hz, 1H), 7.82-7.65 (m, 4H), 7.41 (d, J=7.8 Hz, 1H), 7.26 (dd, J=7.0, 5.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 4.45 (t, J=6.8 Hz, 2H), 3.85 (s, 3H), 3.25 (t, J=6.7 Hz, 2H), 2.69 (dt, J=15.3, 7.8 Hz, 1H), 2.43 (d, J=7.6 Hz, 2H), 2.15-1.99 (m, 2H), 1.95-1.79 (m, 2H), 1.78-1.66 (m, 2H)

Example 173: 2-cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(4-methylpiperazin-1-yl) ethyl]oxy}phenyl)pyrazin-2-yl] thiophen-3-yl}acetamide

[0435] ##STR00331##

[0436] Yellow solid (2.63 mg), LCMS (ESI): [M+H].sup.+=522.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.36 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 7.85 (d, J=1.3 Hz, 1H), 7.83-7.73 (m, 2H), 7.69 (d, J=1.3 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 4.15 (t, J=5.9 Hz, 2H), 3.89 (s, 3H), 2.80-2.67 (m, 3H), 2.47-2.39 (m, 2H), 2.37 (d, J=20.0 Hz, 3H), 2.17 (s, 3H), 2.14-2.03 (m, 2H), 1.93-1.80 (m, 2H), 1.80-1.66 (m, 2H).

Example 174: 2-cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(pyrazin-2-yl)ethyl]oxy}phenyl)pyrazin-2-yl]thiophen-3-yl} acetamide

[0437] ##STR00332##

[0438] Yellow solid (2.17 mg), LCMS (ESI): [M+H].sup.+=502.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.35 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 8.70 (d, J=1.4 Hz, 1H), 8.61 (dd, J=2.5, 1.6 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.77 (dt, J=5.9, 2.0 Hz, 2H), 7.69 (d, J=1.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 4.47 (t, J=6.5 Hz, 2H), 3.84 (s, 3H), 3.32-3.29 (m, 2H), 2.76-2.63 (m, 1H), 2.43 (d, J=7.6 Hz, 2H), 2.15-2.01 (m, 2H), 1.92-1.80 (m, 2H), 1.80-1.70 (m, 2H).

Example 175: 2-cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(5,6,7,8-tetrahydro [1,2,4] triazolo [1,5-a] pyrazin-7-yl) ethyl] oxy} phenyl) pyrazin-2-yl] thiophen-3-yl} acetamide

[0439] ##STR00333##

[0440] Yellow solid (1.74 mg), LCMS (ESI): [M+H].sup.+=546.40: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.36 (s, 1H), 9.14 (s, 1H), 8.97 (s, 1H), 7.92 (s, 1H), 7.85 (d, J=1.3 Hz, 1H), 7.82-7.75 (m, 2H), 7.69 (d, J=1.3 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 4.28 (t, J=5.5 Hz, 2H), 4.15 (t, J=5.5 Hz, 2H), 3.97-3.79 (m, 5H), 3.19-3.11 (m, 2H), 3.05 (t, J=5.5 Hz, 2H), 2.70 (dt, J=15.6, 7.8 Hz, 1H), 2.43 (d, J=7.6 Hz, 2H), 2.12-2.03 (m, 2H), 1.90-1.80 (m, 2H), 1.78-1.68 (m, 2H).

Example 176: 2-cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]oxy} phenyl) pyrazin-2-yl]thiophen-3-yl} acetamide

[0441] ##STR00334##

[0442] Yellow solid (2.36 mg), LCMS (ESI): [M+H].sup.+=536.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.37 (s, 1H), 9.14 (s, 1H), 8.99 (s, 1H), 7.86 (d, J=1.3 Hz, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.74 (dd, J=8.5, 2.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 4.99 (s, 2H), 4.43 (s, 1H), 4.10 (s, 1H), 3.93 (s, 3H), 3.49 (s, 2H), 3.07 (d, J=50.0 Hz, 4H), 2.86 (s, 3H), 2.70 (dt, J=15.4, 7.8 Hz, 1H), 2.43 (d, J=7.6 Hz, 2H), 2.15-2.01 (m, 2H), 1.96-1.80 (m, 2H), 1.80-1.64 (m, 2H).

Example 177: 2-cyclobutyl-N-(5-{6-[3-methoxy-4-({2-[4-(1-methylhexahydropyridin-4-yl) piperazin-1-yl] ethyl} oxy) phenyl] pyrazin-2-yl} thiophen-3-yl) acetamide

[0443] ##STR00335##

[0444] Yellow solid (2.44 mg), LCMS (ESI): [M+H].sup.+=605.60: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.39 (s, 1H), 9.16 (s, 1H), 9.00 (s, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.81 (d, J=7.2 Hz, 2H), 7.70 (d, J=1.1 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.38 (s, 2H), 3.92 (s, 3H), 3.60-3.34 (m, 6H), 3.30-3.00 (m, 5H), 2.95 (d, J=9.6 Hz, 3H), 2.77 (s, 4H), 2.69 (dd, J=15.4, 7.7 Hz, 2H), 2.43 (d, J=7.6 Hz, 2H), 2.19-1.96 (m, 4H), 1.93-1.56 (m, 6H).

Example 178: 2-cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(6-methyl-2,6-diazaspiro [3.3] hept-2-yl) ethyl] oxy} phenyl) pyrazin-2-yl] thiophen-3-yl} acetamide

[0445] ##STR00336##

[0446] Yellow solid (1.76 mg), LCMS (ESI): [M+H].sup.+=534.60: .sup.1H NMR (400 MHz, DMSO-d6) ? 9.09 (s, 1H), 8.96 (s, 1H), 7.86 (d, J=1.3 Hz, 1H), 7.83-7.74 (m, 2H), 7.68 (d, J=1.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.42 (d, J=23.8 Hz, 6H), 4.24 (s, 4H), 3.93 (s, 3H), 3.62 (s, 2H), 2.80 (s, 3H), 2.72-2.59 (m, 1H), 2.41 (d, J=7.6 Hz, 2H), 2.12-1.98 (m, 2H), 1.92-1.60 (m, 4H).

Example 179: N-{5-[6-(3-methoxy-4-{[2-(morpholin-4-yl) ethyl] oxy} phenyl) pyrazin-2-yl] thiophen-3-yl} pentanamide

[0447] ##STR00337##

[0448] Yellow solid (4.22 mg), LCMS (ESI): [M+H].sup.+=497.70: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.39 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.78 (dd, J=6.4, 2.0 Hz, 2H), 7.70 (d, J=1.3 Hz, 1H), 7.17 (d, J=9.1 Hz, 1H), 4.17 (t, J=5.9 Hz, 2H), 3.91 (d, J=7.2 Hz, 3H), 3.65-3.50 (m, 4H), 2.74 (t, J=5.9 Hz, 2H), 2.32 (t, J=7.4 Hz, 2H), 1.67-1.53 (m, 2H), 1.34 (dq, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 180: N-{5-[6-(4-{[2-(1,1-dioxo-1 ?.SUP.6.-1,4-thiomorpholin-4-yl) ethyl] oxy}-3-methoxyphenyl) pyrazin-2-yl] thiophen-3-yl} pentanamide

[0449] ##STR00338##

[0450] Yellow solid (2.05 mg), LCMS (ESI): [M+H].sup.+=545.70: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.39 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 7.86 (d, J=1.4 Hz, 1H), 7.79 (dd, J=6.8, 2.0 Hz, 2H), 7.70 (d, J=1.4 Hz, 1H), 7.18 (d, J=9.1 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H), 3.90 (s, 3H), 3.10 (d, J=4.0 Hz, 8H), 2.98 (t, J=5.7 Hz, 2H), 2.32 (t, J=7.4 Hz, 2H), 1.60 (dt, J=15.0, 7.5 Hz, 2H), 1.41-1.28 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 181: N-{5-[6-(4-hydroxy-3-methoxyphenyl) pyrazin-2-yl] thiophen-3-yl}pentanamide

[0451] ##STR00339##

[0452] Yellow solid (2.65 mg), LCMS (ESI): [M+H].sup.+=384.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 9.59 (s, 1H), 9.08 (s, 1H), 8.93 (s, 1H), 7.84 (d, J=1.3 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.72-7.66 (m, 2H), 6.95 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 2.31 (t, J=7.4 Hz, 2H), 1.68-1.51 (m, 2H), 1.45-1.27 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 182: N-butyl-5-[6-(3,4-dimethoxyphenyl) pyrazin-2-yl] thiophen-3-formamide

[0453] ##STR00340##

[0454] Yellow solid (3.65 mg), LCMS (ESI): [M+H].sup.+=398.30: .sup.1H NMR (400 MHz, DMSO-d6) ? 9.16 (s, 1H), 9.09 (s, 1H), 8.42-8.31 (m, 2H), 8.29 (d, J=1.3 Hz, 1H), 7.82 (dd, J=8.4, 2.1 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.31-3.21 (m, 2H), 1.58-1.47 (m, 2H), 1.43-1.30 (m, 2H), 0.92 (t, J=7.3 Hz, 3H).

Example 183: 2-Cyclobutyl-N-{5-[6-(4-hydroxy-3-methoxyphenyl) pyrazin-2-yl] thiophen-3-yl} acetamide

[0455] ##STR00341##

[0456] Yellow solid (2.30 mg), LCMS (ESI): [M+Na].sup.+=418.20: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.35 (s, 1H), 9.08 (s, 1H), 8.93 (s, 1H), 7.84 (d, J=1.4 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.68 (td, J=4.5, 2.1 Hz, 2H), 6.95 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 2.43 (d, J=7.6 Hz, 2H), 2.13-2.03 (m, 2H), 1.94-1.66 (m, 4H).

Example 184: 2-Cyclobutyl-N-(5-(6-(3-methoxy-4-((1-methylpiperidin-4-yl) methoxy) phenyl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0457] ##STR00342##

[0458] Yellow solid (4.61 mg), LCMS (ESI): [M+H].sup.+=507.40: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.35 (s, 1H), 9.14 (s, 1H), 8.98 (s, 1H), 7.85 (s, 1H), 7.79 (d, J=5.2 Hz, 2H), 7.69 (s, 1H), 7.18 (s, 1H), 3.97 (d, J=5.5 Hz, 2H), 3.91 (s, 3H), 3.48 (d, J=11.6 Hz, 2H), 3.00 (d, J=12.5 Hz, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.43 (d, J=7.5 Hz, 2H), 2.33 (s, 1H), 2.03 (s, 1H), 1.86 (dd, J=11.1, 6.6 Hz, 4H), 1.77-1.71 (m, 4H), 1.46 (s, 2H).

Example 185: 2-(3,3-difluorocyclobutyl)-N-(5-(6-(3-methoxy-4-(2-morpholinylethoxy) phenyl) pyrazin-2-yl)thiophen-3-yl) acetamide

[0459] ##STR00343##

[0460] Yellow solid (2.56 mg), LCMS (ESI): [M+H].sup.+=545.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.48 (s, 1H), 9.17 (s, 1H), 9.02 (s, 1H), 7.87 (d, J=1.3 Hz, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.71 (d, J=1.2 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 4.44 (s, 2H), 4.02 (s, 2H), 3.93 (s, 3H), 3.73 (s, 4H), 3.27 (s, 4H), 2.78-2.70 (m, 2H), 2.58 (d, J=6.7 Hz, 2H), 2.37 (dd, J=15.4, 5.7 Hz, 2H), 2.04-1.97 (m, 1H).

Example 186: N-(5-(6-(3,4-dimethoxyphenyl) pyrazin-2-yl) thiophen-3-yl) heptanamide

[0461] ##STR00344##

[0462] Yellow solid (2.63 mg), LCMS (ESI): [M+H]+=396.20: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 9.16 (s, 1H), 9.00 (s, 1H), 7.89-7.78 (m, 3H), 7.69 (d, J=1.1 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 3.28 (s, 2H), 2.69 (dq, J=15.3, 7.7 Hz, 1H), 2.13-2.01 (m, 2H), 1.94-1.67 (m, 4H).

Example 187: 2-Cyclobutyl-N-(5-(6-(3-methoxy-4-(2-(1-methyl-1H-pyrazol-4-yl) ethoxy) phenyl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0463] ##STR00345##

[0464] Yellow solid (2.18 mg), LCMS (ESI): [M+H].sup.+=504.40: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.39 (d, J=18.7 Hz, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 7.85 (s, 1H), 7.78 (d, J=6.5 Hz, 2H), 7.69 (s, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.16 (d, J=8.9 Hz, 1H), 4.16 (t, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.79 (s, 3H), 2.89 (t, J=6.8 Hz, 2H), 2.69 (dt, J=15.2, 7.7 Hz, 1H), 2.43 (d, J=7.5 Hz, 2H), 2.08 (d, J=4.7 Hz, 2H), 1.90-1.67 (m, 4H).

Example 188: 2-(3,4-Dimethoxyphenyl)-6-(4-hexylthiophen-2-yl) pyrazine

[0465] ##STR00346##

[0466] Yellow solid (2.35 mg), LCMS (ESI): [M+H]+=383.20: .sup.1H NMR (400 MHz, DMSO-d6) ? 9.07 (d, J=16.6 Hz, 2H), 7.90 (d, J=1.2 Hz, 1H), 7.82-7.74 (m, 2H), 7.38 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.63 (t, J=7.6 Hz, 2H), 1.69-1.58 (m, 2H), 1.34 (d, J=17.5 Hz, 6H), 0.88 (dd, J=9.1, 4.8 Hz, 3H).

Example 189: 2-Cyclobutyl-N-(5-(6-(3-methoxy-4-(2-(pyrrolidin-1-yl) ethoxy) phenyl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0467] ##STR00347##

[0468] Yellow solid (2.40 mg), LCMS (ESI): [M+H].sup.+=493.50: .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.82 (s, 1H), 8.76 (s, 1H), 7.72 (s, 2H), 7.67 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.3 Hz, 1H), 4.39 (t, J=5.3 Hz, 2H), 4.00 (s, 3H), 3.32 (s, 2H), 3.12 (s, 4H), 2.90-2.76 (m, 1H), 2.53 (d, J=7.5 Hz, 2H), 2.27-2.21 (m, 2H), 2.02 (s, 4H), 1.97-1.89 (m, 2H), 1.86-1.77 (m, 2H).

Example 190: 2-Cyclobutyl-N-(5-(6-(4-hydroxy-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0469] ##STR00348##

[0470] Yellow solid (2.40 mg), LCMS (ESI): [M+H].sup.+=525.40: .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.85 (s, 1H), 8.78 (s, 1H), 7.74 (dd, J=7.4, 1.6 Hz, 2H), 7.68-7.61 (m, 2H), 7.41 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.28 (s, 2H), 4.02 (s, 3H), 3.10-2.87 (m, 6H), 2.84 (d, J=7.8 Hz, 1H), 2.82-2.63 (m, 4H), 2.52 (d, J=7.6 Hz, 2H), 2.29-2.20 (m, 2H), 2.06-1.89 (m, 2H), 1.88-1.76 (m, 2H), 1.69-1.59 (m, 2H).

Example 191: 2-Cyclobutyl-N-{5-[6-(3-methoxy-4-{[2-(morpholin-4-yl)-2-oxoethyl] oxy}phenyl) pyrazin-2-yl] thiophen-3-yl} acetamide

[0471] ##STR00349##

[0472] Yellow solid (2.60 mg), LCMS (ESI): [M+H].sup.+=523.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.35 (s, 1H), 9.12 (s, 1H), 8.97 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.9 Hz, 1H), 7.74 (dd, J=8.4, 1.9 Hz, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.65-7.52 (m, 1H), 7.09-7.01 (m, 1H), 4.93 (s, 2H), 3.91 (s, 3H), 3.61 (d, J=10.9 Hz, 4H), 2.69 (dt, J=15.5, 8.0 Hz, 1H), 2.42 (d, J=7.6 Hz, 2H), 2.12-2.00 (m, 2H), 1.91-1.79 (m, 2H), 1.77-1.67 (m, 2H), 1.23 (s, 2H), 0.84 (d, J=7.1 Hz, 1H).

Example 192: 2-Cyclobutyl-N-(5-{6-[3-methoxy-4-({2-[4-(1-methylhexahydropyridin-4-yl) piperazin-1-yl]-2-oxoethyl} oxy) phenyl] pyrazin-2-yl} thiophen-3-yl) acetamide

[0473] ##STR00350##

[0474] Yellow solid (2.20 mg), LCMS (ESI): [M+H]+=619.60: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 9.13 (s, 1H), 8.98 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.09 (d, J=8.5 Hz, 1H), 4.97 (s, 2H), 3.92 (s, 3H), 3.58 (d, J=10.7 Hz, 4H), 2.99 (s, 4H), 2.78 (s, 3H), 2.68 (dd, J=15.4, 7.7 Hz, 2H), 2.42 (d, J=7.6 Hz, 2H), 2.24 (s, 2H), 2.07 (d, J=4.7 Hz, 4H), 1.84 (dt, J=10.9, 7.7 Hz, 4H), 1.74 (dd, J=18.4, 8.8 Hz, 2H), 1.23 (s, 2H).

Example 193: N-{5-[6-(3-methoxy-4-[2-(thiomorpholin-4-yl) ethyl] oxy} phenyl) pyrazin-2-yl] thiophen-3-yl} pentanamide

[0475] ##STR00351##

[0476] Yellow solid (2.31 mg), LCMS (ESI): [M+H].sup.+=513.40: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 9.13 (s, 1H), 8.96 (s, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.80-7.75 (m, 2H), 7.70 (d, J=1.3 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 4.16 (s, 2H), 3.89 (s, 3H), 2.79 (s, 6H), 2.62 (s, 4H), 2.31 (t, J=7.4 Hz, 2H), 1.59 (dt, J=15.0, 7.5 Hz, 2H), 1.40-1.27 (m, 2H), 0.95-0.86 (m, 3H).

Example 194: N-{5-[6-(3-methoxy-4-{[2-(1-oxo-1?4-thiomorpholin-4-yl) ethyl] oxy}phenyl) pyrazin-2-yl] thiophen-3-yl} pentanamide

[0477] ##STR00352##

[0478] Yellow solid (2.25 mg), LCMS (ESI): [M+H].sup.+=529.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.39 (s, 1H), 9.13 (s, 1H), 8.96 (s, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.82-7.75 (m, 2H), 7.70 (d, J=1.3 Hz, 1H), 7.18 (d, J=9.1 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H), 3.89 (s, 3H), 3.04 (t, J=11.1 Hz, 2H), 2.95-2.68 (m, 8H), 2.31 (t, J=7.4 Hz, 2H), 1.59 (dt, J=15.0, 7.5 Hz, 2H), 1.38-1.28 (m, 2H), 0.94-0.87 (m, 3H).

Example 195: N-{5-[6-(3-methoxyphenyl) pyrazin-2-yl] thiophen-3-yl} pentanamide

[0479] ##STR00353##

[0480] Yellow solid (2.56 mg), LCMS (ESI): [M+H].sup.+=368.40: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.39 (s, 1H), 9.15 (s, 1H), 9.05 (s, 1H), 7.88 (d, J=1.4 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.74-7.72 (m, 1H), 7.71 (d, J=1.3 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.11 (dd, J=8.2, 2.0 Hz, 1H), 3.87 (s, 3H), 2.31 (t, J=7.4 Hz, 2H), 1.64-1.52 (m, 2H), 1.33 (dq, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 196: N-{5-[6-(4-amino-3-methoxyphenyl) pyrazin-2-yl] thiophen-3-yl}pentanamide

[0481] ##STR00354##

[0482] Yellow solid (2.71 mg), LCMS (ESI): [M+H].sup.+=383.20: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.37 (s, 1H), 9.02 (s, 1H), 8.84 (s, 1H), 7.81 (d, J=1.3 Hz, 1H), 7.65 (ddd, J=10.0, 8.0, 1.5 Hz, 3H), 6.80 (d, J=8.1 Hz, 1H), 3.90 (s, 3H), 2.30 (t, J=7.4 Hz, 2H), 1.59 (dt, J=15.0, 7.4 Hz, 2H), 1.33 (dq, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 197: N-(5-(6-(3-hydroxyphenyl) pyrazin-2-yl) thiophen-3-yl) pentanamide

[0483] ##STR00355##

[0484] Yellow solid (2.11 mg), LCMS (ESI): [M+H].sup.+=354.10: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.37 (s, 1H), 9.15 (s, 1H), 9.05 (s, 1H), 7.86 (d, J=1.4 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.74-7.72 (m, 1H), 7.71 (d, J=1.3 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.11 (dd, J=8.2, 2.0 Hz, 1H), 2.31 (t, J=7.4 Hz, 2H), 1.64-1.52 (m, 2H), 1.33 (q, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 198: N-{5-[6-(3-cyanophenyl)pyrazin-2-yl]thiophen-3-yl} pentanamide

[0485] ##STR00356##

[0486] Yellow solid (2.19 mg), LCMS (ESI): [M+H].sup.+=363.50: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.41 (s, 1H), 9.25 (s, 1H), 9.13 (s, 1H), 8.63 (t, J=1.5 Hz, 1H), 8.59-8.49 (m, 1H), 8.08-7.98 (m, 1H), 7.91 (d, J=1.4 Hz, 1H), 7.81 (t, J=7.8 Hz, 1H), 7.73 (d, J=1.4 Hz, 1H), 2.32 (t, J=7.4 Hz, 2H), 1.60 (dt, J=15.0, 7.5 Hz, 2H), 1.40-1.29 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 199: 2-Methoxy-N-methyl-N-(2-methyl-2-azaspiro[3.3] heptane-6-yl)-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzamide

[0487] ##STR00357##

Synthesis Method:

[0488] ##STR00358## ##STR00359##

Step 1: methyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2-methoxybenzoate

[0489] 4-(6-(4-bromothiophene-2-yl) pyrazine-2-yl)-2-methoxybenzoate methyl ester (300 mg, synthesized using the same method as Example 46 in WO2023/083330), cuprous iodide (24 mg), L-proline (30 mg), dimethyl sulfoxide (3 mL), and ammonia (25% wt, 1 mL) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 10 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with 20 mL of water, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated ammonium chloride (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried to afford methyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2-methoxybenzoate (crude, 180 mg), which was directly used in the next reaction without any purification. LCMS (ESI): [M+H].sup.+=342.2.

Step 2: Methyl 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzoate

[0490] A solution of methyl 4-(6-(4-aminothiophen-2-yl) pyrazin-2-yl)-2-methoxybenzoate (180 mg crude) in dichloromethane (5 mL) was cooled under an ice water bath, and added with triethylamine (107 mg). Additionally, pentanoyl chloride (112 mg) was taken and dissolved in dichloromethane (1 mL) and the resulting mixture was slowly dropped into the above system. Upon addition, the reaction system was warmed to room temperature for 0.5 hour. TLC monitoring showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain methyl 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzoate (180 mg, yield 80.3%). LCMS (ESI): [M+H].sup.+=426.10.

Step 3: 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzoic Acid

[0491] Methyl 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzoate (180 mg), lithium hydroxide monohydrate (35 mg), tetrahydrofuran (4 mL) and water (2 mL) were added successively to a reaction flask and the mixture was reacted at room temperature for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove tetrahydrofuran, diluted with water (5 mL), acidified to pH=3-4 using saturated citric acid and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed successively with water and saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 2-methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzoic acid (150 mg, yield 86.2%). LCMS (ESI): [M+H].sup.+=412.10.

Step 4: Tert-butyl 6-(2-methoxy-N-methyl-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzamido)-2-azaspiro [3.3] heptane-2-carboxylate

[0492] 2-Methoxy-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzoic acid (25 mg), tert butyl 6-(methylamino)-2-azaspiro [3.3] heptane-2-carboxylate (27.12 mg), HATU (45.6 mg), N,N-diisopropylethylamine (16 mg), and N,N-dimethylformamide (1 mL) were sequentially added to a reaction flask and the mixture was reacted at room temperature for 5 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed successively with water and saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain tert butyl 6-(2-methoxy-N-methyl-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzamido)-2-azaspiro [3.3] heptane-2-carboxylate (25 mg, yield 67.5%). LCMS (ESI): [M+H].sup.+=620.2.

Step 5: 2-Methoxy-N-methyl-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-N-(2-azaspiro [3.3] heptane-6-yl) benzamide

[0493] To a solution of tert butyl 6-(2-methoxy-N-methyl-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzamido)-2-azaspiro [3.3] heptane-2-carboxylate (25 mg) in 10 mL of methanol was added TBAF (31 mg), and the mixture was reacted at room temperature overnight. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated and the crude product was used in the next step. LCMS (ESI): [M+H].sup.+=520.2.

Step 6: 2-Methoxy-N-methyl-N-(2-methyl-2-azaspiro [3.3] heptane-6-yl)-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) benzamide

[0494] To a solution of 2-methoxy-N-methyl-4-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl)-N-(2-azaspiro [3.3] heptane-6-yl) benzamide (21 mg) in 10 mL of methanol was added formaldehyde (12 mg) and then acetic acid (0.2 mL). The mixture was reacted at room temperature for 30 min. Sodium borohydride acetate (16 mg) was added and the mixture was reacted overnight at room temperature. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated, and purified by thin-layer chromatography to afford 3.5 mg product with a yield of 14%. LCMS (ESI): [M+H].sup.+=534.2. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.42 (s, 1H), 9.23 (d, J=6.7 Hz, 1H), 9.10 (d, J=3.6 Hz, 1H), 7.90 (dd, J=4.4, 1.3 Hz, 1H), 7.87-7.81 (m, 2H), 7.72 (d, J=1.1 Hz, 1H), 7.37-7.30 (m, 1H), 3.99 (dd, J=16.9, 8.5 Hz, 4H), 3.93 (d, J=4.9 Hz, 3H), 2.95 (s, 2H), 2.80 (s, 1H), 2.70 (dd, J=13.9, 5.3 Hz, 3H), 2.32 (t, J=7.4 Hz, 2H), 2.01 (dd, J=14.6, 7.0 Hz, 1H), 1.60 (dt, J=15.0, 7.4 Hz, 2H), 1.36-1.30 (m, 2H), 1.29-1.19 (m, 4H), 0.92 (t, J=7.3 Hz, 3H).

[0495] Examples 200-207 and example 223 were prepared using the experimental steps similar to those in Example 199 above.

Example 200: 4-[6-(4-{[(3S)-4-amino-3-methylbutyl] oxy} thiophen-2-yl) pyrazin-2-yl]-2-methoxy-N-methyl-N-(1-methylhexahydropyridin-4-yl) benzamide

[0496] ##STR00360##

[0497] Yellow solid (1.40 mg), LCMS (ESI): [M+H].sup.+=524.50.

Example 201: 4-(6-{4-[(2-cyclobutyl-2-methylpropionyl) amino] thiophen-2-yl} pyrazin-2-yl)-2-methoxy-N-methyl-N-(2-methyl-2-azaspiro [3.3] hept-6-yl) benzamide

[0498] ##STR00361##

[0499] Yellow solid (2.06 mg), LCMS (ESI): [M+H].sup.+=574.40.

Example 202: 4-[6-(4-{[2-(3,3-difluorocyclobutyl) acetyl] amino} thiophen-2-yl) pyrazin-2-yl]-2-methoxy-N-methyl-N-(2-methyl-2-azaspiro [3.3] hept-6-yl) benzamide

[0500] ##STR00362##

[0501] Yellow solid (2.19 mg), LCMS (ESI): [M+H].sup.+=582.30.

Example 203: 4-[6-(4-{[2-(3,3-difluorocyclobutyl)-2-methylpropionyl] amino} thiophen-2-yl) pyrazin-2-yl]-2-methoxy-N-methyl-N-(2-methyl-2-azaspiro [3.3] hept-6-yl) benzamide

[0502] ##STR00363##

[0503] Yellow solid (1.75 mg), LCMS (ESI): [M+H].sup.+=610.70.

Example 204: 4-[6-(4-{[2-(bicyclo [1.1.1] penta-1-yl) acetyl] amino} thiophen-2-yl) pyrazin-2-yl]-2-methoxy-N-(1,3,4-oxadiazol-2-yl) benzamide

[0504] ##STR00364##

[0505] Yellow solid (1.42 mg), LCMS (ESI): [M?H].sup.?=501.30; .sup.1H NMR (400 MHz, DMSO-d6) ? 12.05 (s, 1H), 10.34 (s, 1H), 9.25 (s, 1H), 9.12 (s, 1H), 8.11 (s, 1H), 7.90 (d, J=1.4 Hz, 1H), 7.86 (s, 2H), 7.73 (s, 1H), 7.58 (d, J=8.3 Hz, 1H), 3.91 (s, 3H), 2.33 (d, J=1.9 Hz, 2H), 1.78 (s, 6H), 1.27 (s, 1H).

Example 205: 4-(6-(4-(2-(3-hydroxycyclobutyl) acetylamino) thiophen-2-yl) pyrazin-2-yl)-2-methoxy-N-methyl-N-(2-methyl-2-azaspiro [3.3] heptane-6-yl) benzamide

[0506] ##STR00365##

[0507] Yellow solid (1.57 mg), LCMS (ESI): [M+H].sup.+=562.60; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.40 (d, J=15.8 Hz, 1H), 9.23 (d, J=6.7 Hz, 1H), 9.09 (d, J=3.5 Hz, 1H), 7.90 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.71 (d, J=1.2 Hz, 1H), 7.32 (t, J=7.1 Hz, 1H), 4.91-4.79 (m, 1H), 4.05 (ddd, J=25.6, 21.1, 13.9 Hz, 4H), 3.92 (s, 3H), 3.89-3.85 (m, 2H), 2.95 (s, 2H), 2.81 (d, J=5.0 Hz, 1H), 2.72 (d, J=5.3 Hz, 3H), 2.53 (s, 1H), 2.46 (d, J=9.8 Hz, 1H), 2.43-2.31 (m, 4H), 2.14-1.95 (m, 2H), 1.55 (td, J=10.8, 2.7 Hz, 2H).

Example 206: 2-Methoxy-4-(6-(4-(2-(3-methoxycyclobutyl) acetylamino) thiophen-2-yl) pyrazin-2-yl)-N-methyl-N-(2-methyl-2-azaspiro [3.3] heptane-6-yl) benzamide

[0508] ##STR00366##

[0509] Yellow solid (3.51 mg), LCMS (ESI): [M+H].sup.+=576.70; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.41 (d, J=12.3 Hz, 1H), 9.23 (d, J=6.7 Hz, 1H), 9.10 (d, J=3.6 Hz, 1H), 7.89 (d, J=2.9 Hz, 1H), 7.84 (d, J=7.6 Hz, 2H), 7.71 (s, 1H), 7.35-7.29 (m, 1H), 4.88-4.80 (m, 1H), 3.99 (d, J=6.8 Hz, 1H), 3.93 (d, J=4.3 Hz, 3H), 3.89 (s, 2H), 3.71 (dt, J=14.5, 7.2 Hz, 1H), 3.12 (d, J=4.1 Hz, 3H), 2.95 (s, 2H), 2.81 (s, 1H), 2.75-2.65 (m, 3H), 2.49-2.40 (m, 4H), 2.39-2.32 (m, 2H), 2.19 (dd, J=14.9, 7.5 Hz, 2H), 2.03 (dd, J=16.4, 8.7 Hz, 2H), 1.63-1.52 (m, 2H).

Example 207: 4-(6-(4-(2-(3-(benzyloxy) cyclobutyl) acetylamino) thiophen-2-yl) pyrazin-2-yl)-2-methoxy-N-methyl-N-(2-methyl-2-azaspiro [3.3] heptane-6-yl) benzamide

[0510] ##STR00367##

[0511] Yellow solid (2.21 mg), LCMS (ESI): [M+H].sup.+=652.50; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.42 (d, J=12.5 Hz, 1H), 9.23 (d, J=6.6 Hz, 1H), 9.10 (d, J=3.4 Hz, 1H), 7.92-7.87 (m, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.71 (s, 1H), 7.32 (dt, J=10.3, 5.5 Hz, 5H), 4.91-4.76 (m, 1H), 4.43-4.29 (m, 3H), 4.14-4.04 (m, 2H), 3.97 (d, J=8.6 Hz, 1H), 3.93 (d, J=5.6 Hz, 4H), 3.89 (d, J=7.1 Hz, 2H), 2.95 (s, 2H), 2.81 (d, J=5.0 Hz, 1H), 2.72 (d, J=4.2 Hz, 3H), 2.56 (s, 1H), 2.48-2.38 (m, 4H), 2.12 (ddd, J=31.5, 19.7, 5.9 Hz, 2H), 1.65 (dd, J=19.2, 9.4 Hz, 2H).

Example 208: N-(5-(6-(4-(6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d] pyrimidin-2-yl)-3-methyoxyphenyl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutyl Acetamide

[0512] ##STR00368##

Synthesis Method:

[0513] ##STR00369## ##STR00370## ##STR00371##

Step 1: 6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido [4,3-D] pyrimidine

[0514] 6-Benzyl-2,4-dichloro-5,6,7,8-tetrahydropyridino [4,3-D] pyrimidine (3.7 g) and zinc powder (6.78 g) were dissolved in anhydrous ethanol (20 mL), and then added with ammonia (2.19 g). The mixture was reacted overnight at 80? C. TLC detection showed that the reaction was completed. The reaction solution was filtered and the filter cake was washed with ethyl acetate. The reaction solution and the washing solution were combined and concentrated. The residue was purified by column chromatography to afford 6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido [4,3-D] pyrimidine (1.34 g, yield 42%). LCMS (ESI): [M+H].sup.+=260.0.

Step 2: Tert butyl (4-bromo-3-methoxyphenyl) carbamate

[0515] 4-Bromo-3-methoxyaniline (3 g), di-tert-butyl dicarbonate (6.5 g), and triethylamine (3 g) were dissolved in tetrahydrofuran and the mixture was reacted at 70? C. for 8 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated and purified by column chromatography to afford product tert butyl (4-bromo-3-methoxyphenyl) carbamate (4.3 mg, yield 96%). LCMS (ESI): [M+H].sup.+=302.1.

Step 3: Tert butyl (3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)carbamate

[0516] Tert butyl (4-bromo-3-methoxyphenyl) carbamate (2.5 g), potassium acetate (1.2 g), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (300 mg), bis(pinacolato)diboron (2.5 g) and 1,4-dioxane (40 mL) were successively added to a reaction flask and the mixture was reacted under nitrogen protection at 80? C. for 5 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain tert butyl (3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)carbamate (1.5 g, yield 52%). LCMS (ESI): [M+H].sup.+=350.1.

Step 4: Tert butyl (4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) carbamate

[0517] 6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido [4,3-D] pyrimidine (500 mg), tert butyl (3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)carbamate (1.35 mg), tripotassium phosphate (1.05 g), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg), 1,4-dioxane (40 mL), and water (10 mL) were added successively to a reaction flask. The mixture was reacted under nitrogen protection at 100? C. 14 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and re-dissolved with ethyl acetate (50 mL). The organic phase was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain tert butyl (4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) carbamate (800 mg, yield 93%). LCMS (ESI): [M+H].sup.+=447.1.

Step 5: (4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyaniline

[0518] To a solution of tert butyl (4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) carbamate (800 mg) in methanol (10 mL) was added 3M Hydrogen chloride methanol solution (40 mL). The mixture was reacted at 50? C. for 14 hours. TLC detection showed that the reaction was completed. The reaction solution was concentrated to afford 700 mg crude product, which was directly used in the next step.

Step 6: 6-benzyl-2-(4-bromo-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine

[0519] (4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyaniline (700 mg) was dissolved in water (4 mL) and hydrobromic acid (2 mL), and the mixture was cooled to 0? C. under an ice-salt bath, added dropwise with sodium nitrite (330 mg), and then reacted under an ice-salt bath for 30 minutes. A solution of cuprous bromide (314 mg) in water (2 mL) and hydrobromic acid (2 mL) was added dropwise to the reaction solution, and the mixture was reacted overnight at room temperature. TLC detection showed that the reaction was completed. The reaction solution was diluted with water, and extracted with dichloromethane. The organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain 6-benzyl-2-(4-bromo-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (140 mg, yield 17%). LCMS (ESI): [M+H].sup.+=410.0.

Step 7: 6-benzyl-2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine

[0520] 6-benzyl-2-(4-bromo-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (220 mg), potassium acetate (127 mg), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg), bis(pinacolato)diboron (204 mg) and 1,4-dioxane (40 mL) were successively added to a reaction flask and the mixture was reacted under nitrogen protection at 80? C. overnight. TLC monitoring showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and purified by thin-layer chromatography to obtain the product 6-benzyl-2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (200 mg, yield 83%). LCMS (ESI): [M+H].sup.+=458.1.

Step 8: 6-benzyl-2-(4-(6-bromopyrazin-2-yl)-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine

[0521] 6-benzyl-2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (200 mg), 2,6-dibromopyrazine (160 mg), potassium carbonate (145 mg), tetrakis(triphenylphosphine)palladium (26 mg), 1,4-dioxane (16 mL), and water (4 mL) were added successively to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. overnight, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and re-dissolved with ethyl acetate (50 mL). The organic phase was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 6-benzyl-2-(4-(6-bromopyrazin-2-yl)-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (110 mg, yield 51.4%). LCMS (ESI): [M+H].sup.+=488.0.

Step 9: 6-benzyl-2-(4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine

[0522] 6-benzyl-2-(4-(6-bromopyrazin-2-yl)-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d]pyrimidine (600 mgl), (4-bromothiophen-2-yl) boronic acid (52 mg), tetrakis(triphenylphosphine)palladium (12 mg), potassium carbonate (70 mg), 1,4-dioxane (16 mL), and water (4 mL) were successively added to a reaction flask. The mixture was reacted under nitrogen protection at 60? C. for 0.5 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and added with dichloromethane (30 mL) and water (10 mL), and fractioned. The aqueous phase was extracted with dichloromethane (20 mL*2), and the organic phases were combined, washed with saturated salt water (20 mL*1), dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 6-benzyl-2-(4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d]pyrimidine (120 mg, yield 94%). LCMS (ESI): [M+H].sup.+=569.0.

Step 10: 5-(6-(4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-amine

[0523] 6-benzyl-2-(4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-2-methoxyphenyl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (120 mg), cuprous iodide (8 mg), L-proline (10 mg), dimethyl sulfoxide (3 mL), and ammonia (25% wt, 1.0 mL) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 10 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with 20 mL of water, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated ammonium chloride (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain 5-(6-(4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-amine (crude, 95 mg), which was directly used in the next reaction without any purification.

Step 11: N-(5-(6-(4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutyl Acetamide

[0524] 5-(6-(4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-amine (crude, 95 mg) was added into DCM (10 mL). The flask was sequentially added with cyclobutyl acetic acid (26 mg), EDCI (72 mg), HOBT (51 mg), and DIEA (97 mg), and the mixture was reacted at room temperature for 14 hours. LCMS detection showed that the reaction was complete. The reaction solution was washed with water and the organic phase was dried over anhydrous sodium sulfate and spin-dried. The residue was purified by column chromatography to afford N-(5-(6-(4-(6-benzyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl)-3-methoxyphenyl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutyl acetamide (20 mg, yield 18%). LCMS (ESI): [M+H].sup.+=603.1. .sup.1HNMR (400 MHz, CDCl.sub.3) ? 8.93 (s, 1H), 8.84 (s, 1H), 8.53 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.78-7.72 (m, 2H), 7.67 (d, J=1.2 Hz, 1H), 7.49-7.38 (m, 5H), 4.01 (s, 3H), 3.78 (d, J=34.2 Hz, 4H), 3.16 (s, 2H), 2.99 (s, 2H), 2.82 (dd, J=15.6, 7.9 Hz, 1H), 2.52 (d, J=7.6 Hz, 2H), 2.28-2.21 (m, 2H), 2.01-1.91 (m, 2H), 1.86-1.78 (m, 2H).

Example 209: N-(5-(6-(1H-pyrrolo [2,3-b] pyridin-4-yl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutylacetamide

[0525] ##STR00372##

Synthesis Method:

[0526] ##STR00373## ##STR00374##

Step 1: 4-bromo-1-((2-(trimethylsilyl) ethoxy) methyl)-1H pyrrolo [2,3-b] pyridine

[0527] To a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine (500 mg) in anhydrous tetrahydrofuran (10 mL) was added NaH (121 mg). The reaction was carried out under an ice water bath for 30 minutes, and then added with SEMCl. The reaction was carried out at room temperature for 14 hours. TLC detection showed that the reaction was completed. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain product 4-bromo-1-((2-(trimethylsilyl) ethoxy) methyl)-1H pyrrolo [2,3-b] pyridine (530 mg, yield 64%). LCMS (ESI): [M+H].sup.+=327.1.

Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridine

[0528] 4-bromo-1-((2-(trimethylsilyl) ethoxy) methyl)-1H pyrrolo [2,3-b] pyridine (530 mg), potassium acetate (400 mg), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (60 mg), bis(pinacolato)diboron (500 mg) and 1,4-dioxane (40 mL) were successively added to a reaction flask and the mixture was reacted under nitrogen protection at 80? C. overnight. TLC monitoring showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated, and purified by thin-layer chromatography to obtain the product 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridine (300 mg, yield 49.4%). LCMS (ESI): [M+H].sup.+=375.1.

Step 3: 4-(6-bromopyrazin-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H pyrrolo [2,3-b]pyridine

[0529] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridine (300 mg), 2,6-dibromopyrazine (284 mg), potassium carbonate (266 mg), tetrakis(triphenylphosphine)palladium (46.5 mg), 1,4-dioxane (16 mL), and water (4 mL) were added successively to a reaction flask. The mixture was reacted under nitrogen protection at 80? C. overnight, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and re-dissolved with ethyl acetate (50 mL). The organic phase was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 4-(6-bromopyrazin-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H pyrrolo [2,3-b] pyridine (270 mg, yield 83.1%). LCMS (ESI): [M+H].sup.+=405.1.

Step 4: 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridine

[0530] 4-(6-bromopyrazin-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H pyrrolo [2,3-b] pyridine (270 mgl), (4-bromothiophen-2-yl) boronic acid (150 mg), tetrakis(triphenylphosphine)palladium (40 mg), potassium carbonate (222 mg), 1,4-dioxane (16 mL), and water (mL) were successively added to a reaction flask. The mixture was reacted under nitrogen protection at 60? C. for 0.5 hours, and TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to remove the most of 1,4-dioxane, and then added with dichloromethane (30 mL) and water (10 mL), and fractioned. The aqueous phase was extracted with dichloromethane (20 mL*2), and the organic phases were combined, washed with saturated salt water (20 mL*1), dried over anhydrous sodium sulfate, spin-dried and purified by column chromatography to obtain 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridine (140 mg, yield 43%). LCMS (ESI): [M+H].sup.+=487.1.

Step 5: 5-(6-(1-(2-(trimethylsilyl) ethoxy) methyl)-1H-indolyl-4-yl) pyrazine-2-yl) thiophen-3-amine

[0531] 4-(6-(4-bromothiophen-2-yl) pyrazin-2-yl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridine (140 mg), cuprous iodide (11 mg), L-proline (14 mg), dimethyl sulfoxide (3 mL), and ammonia (25% wt, 1 mL) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 10 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, added with 20 mL of water, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated ammonium chloride (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain 5-(6-(1-(2-(trimethylsilyl) ethoxy) methyl)-1H-indol-4-yl) pyrazine-2-yl) thiophen-3-amine (crude, 95 mg), which was directly used in the next reaction without any purification. LCMS (ESI): [M+H].sup.+=423.1.

Step 6: 2-Cyclobutyl-N-(5-(6-(1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b]pyridin-4-yl) pyrazin-2-yl) thiophen-3-yl) acetamide

[0532] 5-(6-(1-(2-(trimethylsilyl) ethoxy) methyl)-1H-indol-4-yl) pyrazine-2-yl) thiophen-3-amine (crude, 95 mg) was added to DMF (10 mL). The flask was sequentially added with cyclobutyl acetic acid (26 mg), EDCI (72 mg), HOBT (51 mg), and DIEA (97 mg), and the mixture was reacted at room temperature for 14 hours. LCMS detection showed that the reaction was complete. The reaction solution was washed with water and the organic phase was dried over anhydrous sodium sulfate and spin-dried. The residue was purified by column chromatography to afford 2-cyclobutyl-N-(5-(6-(1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrazin-2-yl) thiophen-3-yl) acetamide (60 mg, yield 53%). LCMS (ESI): [M+H].sup.+=520.1.

Step 7: N-(5-(6-(1H-pyrrolo [2,3-b] pyridin-4-yl) pyrazin-2-yl) thiophen-3-yl)-2-cyclobutylacetamide

[0533] To a solution of 2-cyclobutyl-N-(5-(6-(1-((2-(trimethylsilyl) ethoxy) methyl)-1H-pyrrolo [2,3-b] pyridin-4-yl) pyrazin-2-yl) thiophen-3-yl) acetamide (20 mg) in DCM (10 mL) was added TFA (1 mL) and the mixture was reacted overnight at room temperature. The reaction solution was concentrated, then added with ethanol (10 mL) and amine in methanol (2 mL). The mixture was reacted overnight at room temperature. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated and purified by thin-layer chromatography to obtain 3 mg of the product. LCMS (ESI): [M+H].sup.+=390.1. .sup.1H NMR (400 MHz, DMSO-d6) ? 11.95 (s, 1H), 10.39 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H), 8.40 (d, J=5.0 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.80 (d, J=5.1 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.71-7.66 (m, 1H), 7.25 (dd, J=3.4, 1.9 Hz, 1H), 2.70 (dd, J=13.6, 5.9 Hz, 1H), 2.44 (d, J=7.6 Hz, 2H), 2.14-2.02 (m, 2H), 1.91-1.80 (m, 2H), 1.75 (dd, J=17.9, 8.3 Hz, 2H).

[0534] Examples 210-215 and example 224 were prepared using the experimental steps similar to those in Example 209 above.

Example 210: 2-Cyclobutyl-N-(5-{6-[1-(propyl-2-yl) pyrrolo [2,3-b] pyridin-4-yl] pyrazin-2-yl} thiophen-3-yl) acetamide

[0535] ##STR00375##

[0536] Yellow solid (2.05 mg), LCMS (ESI): [M+H].sup.+=432.50; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.40 (s, 1H), 9.26 (s, 1H), 9.16 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.89 (d, J=3.6 Hz, 1H), 7.81 (d, J=5.0 Hz, 1H), 7.75 (t, J=2.7 Hz, 1H), 7.25 (d, J=3.6 Hz, 1H), 5.26-5.13 (m, 1H), 2.81-2.63 (m, 2H), 2.44 (d, J=7.6 Hz, 2H), 2.15-2.02 (m, 2H), 1.94-1.65 (m, 4H), 1.52 (d, J=6.8 Hz, 6H).

Example 211: N-{5-[6-(1-benzylpyrrolo [2,3-b] pyridin-4-yl) pyrazin-2-yl] thiophen-3-yl}-2-cyclobutyl Acetamide

[0537] ##STR00376##

[0538] Yellow solid (2.08 mg), LCMS (ESI): [M+H].sup.+=480.50; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.40 (s, 1H), 9.27 (s, 1H), 9.16 (s, 1H), 8.46 (d, J=5.0 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.85 (dd, J=5.3, 4.4 Hz, 2H), 7.74 (d, J=1.3 Hz, 1H), 7.33-7.22 (m, 6H), 5.58 (s, 2H), 2.79-2.62 (m, 1H), 2.42 (dd, J=15.6, 7.6 Hz, 2H), 2.15-1.97 (m, 2H), 1.97-1.65 (m, 4H).

Example 212: 2-Cyclobutyl-N-{5-[6-(1-cyclopropylindazol-6-yl) pyrazin-2-yl] thiophen-3-yl}acetamide

[0539] ##STR00377##

[0540] Yellow solid (3.77 mg), LCMS (ESI): [M+H].sup.+=430.50; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 9.29 (s, 1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.11 (s, 1H), 8.01 (dd, J=8.5, 1.2 Hz, 1H), 7.92 (dd, J=13.3, 4.9 Hz, 2H), 7.72 (d, J=1.3 Hz, 1H), 3.94-3.85 (m, 1H), 2.79-2.64 (m, 1H), 2.44 (d, J=7.6 Hz, 2H), 2.16-2.01 (m, 2H), 1.92-1.68 (m, 4H), 1.23-1.16 (m, 4H).

Example 213: 2-Cyclobutyl-N-(5-{6-[1-(propyl-2-yl) indazol-6-yl] pyrazin-2-yl} thiophen-3-yl) acetamide

[0541] ##STR00378##

[0542] Yellow solid (3.23 mg), LCMS (ESI): [M+H].sup.+=432.50; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 9.31 (s, 1H), 9.07 (s, 1H), 8.54 (s, 1H), 8.16 (s, 1H), 8.00 (dd, J=8.5, 1.2 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.90 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.3 Hz, 1H), 5.18 (dt, J=13.3, 6.6 Hz, 2H), 2.78-2.63 (m, 2H), 2.44 (d, J=7.6 Hz, 2H), 2.16-2.00 (m, 2H), 1.98-1.67 (m, 4H), 1.55 (d, J=6.6 Hz, 6H).

Example 214: N-[5-(6-{4-[(1-methylhexahydropyridin-4-yl) carbonyl]-3,4-dihydro-2H-benzo [2,1-b] [1,4] oxazinan-7-yl} pyrazine-2-y) thiophene-3-yl] pentanamide

[0543] ##STR00379##

[0544] Yellow solid (2.09 mg), LCMS (ESI): [M+H].sup.+=520.30; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.39 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 7.88 (d, J=1.3 Hz, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.71 (d, J=1.3 Hz, 1H), 4.42-4.28 (m, 2H), 3.96 (s, 3H), 2.93 (s, 3H), 2.30 (dd, J=16.9, 9.4 Hz, 5H), 2.09 (s, 2H), 1.75 (dd, J=35.0, 11.1 Hz, 4H), 1.60 (dt, J=15.0, 7.5 Hz, 2H), 1.34 (dq, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 215: 2-Cyclobutyl-N-(5-{6-[1-(2,2,2-trifluoroethyl) pyrrolo [2,3-b] pyridin-4-yl]pyrazin-2-yl} thiophen-3-yl) acetamide

[0545] ##STR00380##

[0546] Yellow solid (3.19 mg), LCMS (ESI): [M+H].sup.+=472.50; .sup.1H NMR (400 MHz, DMSO-d6) ? 10.40 (s, 1H), 9.28 (s, 1H), 9.18 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 7.92 (dd, J=5.4, 3.2 Hz, 2H), 7.81 (d, J=3.6 Hz, 1H), 7.75 (dd, J=5.7, 1.3 Hz, 1H), 7.36 (d, J=3.6 Hz, 1H), 5.28 (q, J=9.3 Hz, 2H), 2.79-2.60 (m, 1H), 2.43 (d, J=7.6 Hz, 2H), 2.15-2.00 (m, 2H), 1.89-1.79 (m, 2H), 1.79-1.66 (m, 2H).

Example 216: Preparation of N-{5-[6-(1,3-dimethylpyrazol-4-yl) pyrazin-2-yl] thiophen-3-yl}pentanamide

[0547] ##STR00381##

Synthesis Method:

[0548] ##STR00382##

Step 1: 2-Bromo-6-(1,3-dimethylpyrazol-4-yl) pyrazine

[0549] 1,3-dimethyl-1H-pyrazole-4-boronic acid, pinacol ester (200 mg), 2,6-dibromopyrazine (278 mg), and tetrakis(triphenylphosphine)palladium (26 mg) were added to 1,4-dioxane/water (4:1, 12.5 mL) and the mixture was reacted under nitrogen protection at 80? C. for 6 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with sufficient water and extracted with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and spin-dried. The residue was purified by column chromatography to afford 2-bromo-6-(1,3-dimethylpyrazol-4-yl) pyrazine (160 mg, yield 70.2%). .sup.1HNMR (400 MHz, CDCl.sub.3) ? 8.66 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 3.94 (s, 3H), 2.58 (s, 3H).

Step 2: 2-(4-bromothiophen-2-yl)-6-(1,3-dimethylpyrazol-4-yl) pyrazine

[0550] 2-bromo-6-(1,3-dimethylpyrazol-4-yl) pyrazine (160 mg), (4-bromothiophen-2-yl) boronic acid (157 mg), tetrakis(triphenylphosphine)palladium (37 mg), potassium carbonate (210 mg) were added to 1,4-dioxane/water (4:1, 10 mL). The mixture was reacted under nitrogen protection at 60? C. for 2 hours, and LCMS monitoring showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain 2-(4-bromothiophen-2-yl)-6-(1,3-dimethylpyrazol-4-yl) pyrazine (154 mg, yield 72.9%). LCMS (ESI): [M+H].sup.+=334.90.

Step 3: 5-[6-(1,3-dimethylpyrazol-4-yl) pyrazin-2-yl] thiophen-3-amine

[0551] 2-(4-bromothiophen-2-yl)-6-(1,3-dimethylpyrazol-4-yl) pyrazine (154 mg), cuprous iodide (35 mg), L-proline (42 mg), dimethyl sulfoxide (2.5 mL), and ammonia (25% wt, 386 mg) were sequentially added to a sealed tube, and the reaction was sealed and reacted at 80? C. for 14 hours. LCMS detection showed that the reaction was complete. The reaction solution was cooled to room temperature, added with 20 mL of water, and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated ammonium chloride (10 mL*2), dried over anhydrous sodium sulfate, and spin-dried to obtain 5-[6-(1,3-dimethylpyrazol-4-yl) pyrazin-2-yl] thiophen-3-amine (DK415-03, crude, 35 mg), which was directly used in the next reaction without any purification. LCMS (ESI): [M+H].sup.+=272.10.

Step 4: N-{5-[6-(1,3-dimethylpyrazol-4-yl) pyrazin-2-yl] thiophen-3-yl} pentanamide

[0552] 5-[6-(1,3-dimethylpyrazol-4-yl) pyrazin-2-yl] thiophen-3-amine (crude, 35 mg), DCM (5 mL), and triethylamine (26 mg) were sequentially added to a reaction flask. The mixture was cooled under an ice water bath, and added with pentanoyl chloride (24 mg). The reaction was then continued under an ice water bath for 0.5 hours. LCMS detection showed that the reaction was complete. The reaction solution was directly spin dried and purified by column chromatography to obtain N-{5-[6-(1,3-dimethylpyrazol-4-yl) pyrazin-2-yl] thiophen-3-yl} pentanamide (8 mg, yield 17%). LCMS (ESI): [M+H].sup.+=356.20. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.37 (s, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 8.41 (s, 1H), 7.80 (d, J=1.4 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 3.84 (s, 3H), 2.54 (s, 3H), 2.31 (t, J=7.4 Hz, 2H), 1.59 (dt, J=15.0, 7.5 Hz, 2H), 1.40-1.29 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

[0553] Examples 217-222 were prepared using the experimental steps similar to those in Example 216 above.

Example 217: N-{5-[6-(1,3-thiazole-5-yl) pyrazin-2-yl] thiophen-3-yl} pentanamide

[0554] ##STR00383##

[0555] Yellow solid (2.46 mg), LCMS (ESI): [M+H].sup.+=345.30: .sup.1HNMR (400 MHz, DMSO-d6) ? 10.41 (s, 1H), 9.29 (s, 1H), 9.19 (s, 1H), 9.01 (s, 1H), 8.81 (s, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.73 (s, 1H), 2.31 (t, J=7.4 Hz, 2H), 1.68-1.49 (m, 2H), 1.43-1.26 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 218: N-(5-{6-[5-(2-hydroxyethyl) thiophen-2-yl] pyrazin 2-yl} thiophen-3-yl) pentanamide

[0556] ##STR00384##

[0557] Yellow solid (1.96 mg), LCMS (ESI): [M+H].sup.+=388.40: .sup.1HNMR (400 MHz, DMSO-d6) ? 10.39 (s, 1H), 9.02 (s, 1H), 8.87 (s, 1H), 7.83 (dd, J=3.6, 2.7 Hz, 2H), 7.70 (d, J=1.3 Hz, 1H), 7.00 (d, J=3.7 Hz, 1H), 4.89 (t, J=5.2 Hz, 1H), 3.68 (dd, J=11.8, 6.4 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.37-2.26 (m, 2H), 1.60 (dt, J=15.1, 7.4 Hz, 2H), 1.38-1.30 (m, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 219: N-{5-[6-(thiophen-2-yl)pyrazin-2-yl]thiophen-3-yl}pentanamide

[0558] ##STR00385##

[0559] Yellow solid (2.97 mg), LCMS (ESI): [M+H].sup.+=344.20: .sup.1HNMR (400 MHz, DMSO-d6) ? 10.40 (s, 1H), 9.09 (s, 1H), 8.93 (s, 1H), 8.02 (dd, J=3.7, 1.1 Hz, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.80 (dd, J=5.0, 1.0 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.26 (dd, J=5.0, 3.7 Hz, 1H), 2.31 (t, J=7.4 Hz, 2H), 1.69-1.51 (m, 2H), 1.34 (dq, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 220: N-{5-[6-(furyl-2-yl)pyrazin-2-yl]thiophen-3-yl}pentanamide

[0560] ##STR00386##

[0561] Yellow solid (3.95 mg), LCMS (ESI): [M+H].sup.+=328.20: .sup.1HNMR (400 MHz, DMSO-d6) ? 10.38 (s, 1H), 8.93 (s, 1H), 8.91 (s, 1H), 8.51 (dd, J=1.4, 0.8 Hz, 1H), 7.88 (t, J=1.7 Hz, 1H), 7.84 (d, J=1.4 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.14 (dd, J=1.9, 0.8 Hz, 1H), 2.31 (t, J=7.4 Hz, 2H), 1.60 (dt, J=15.0, 7.5 Hz, 2H), 1.34 (dq, J=14.5, 7.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H).

Example 221: N-(5-{6-[4-methoxy-3-(methyldioxo)-?.SUP.6.-thio) phenyl] pyrazin-2-yl}thiophen-3-yl) pentanamide

[0562] ##STR00387##

[0563] Yellow solid (2.14 mg), LCMS (ESI): [M+H].sup.+=446.20.

Example 222: methyl 5-(6-(4-pentamidothiophen-2-yl) pyrazin-2-yl) thiophen-2-carboxylate

[0564] ##STR00388##

[0565] Yellow solid (3.16 mg), LCMS (ESI): [M+H].sup.+=402.40: .sup.1HNMR (400 MHz, DMSO-d6) 10.43 (s, 1H), 9.21 (s, 1H), 9.05 (s, 1H), 8.09 (d, J=4.0 Hz, 1H), 7.90 (dd, J=5.6, 2.7 Hz, 2H), 7.74 (d, J=1.4 Hz, 1H), 3.88 (s, 3H), 2.34-2.29 (m, 2H), 2.04-1.97 (m, 2H), 1.59 (d, J=7.5 Hz, 2H), 1.34 (d, J=7.8 Hz, 3H).

Example 223: 4-(6-{4-[(2-cyclobutyl acetyl) amino]-1,3-thiazole-2-yl} pyrazin-2-yl)-2-methoxy-N-methyl-N-(1-methylhexahydropyridin-4-yl) benzamide

[0566] ##STR00389##

[0567] Yellow solid (1.56 mg), LCMS (ESI): [M+H].sup.+=535.60: .sup.1H NMR (400 MHz, DMSO-d6) ? 11.14 (s, 1H), 9.46 (d, J=10.0 Hz, 1H), 9.18 (d, J=1.6 Hz, 1H), 7.95-7.83 (m, 3H), 7.43-7.31 (m, 1H), 3.94 (d, J=2.4 Hz, 3H), 2.89 (s, 2H), 2.78 (s, 1H), 2.73-2.61 (m, 3H), 2.38-2.19 (m, 4H), 2.17-1.97 (m, 4H), 1.93-1.78 (m, 4H), 1.77-1.47 (m, 6H).

Example 224: 2-cyclobutyl-N-{5-[6-(1-methylpyrazolo[2,3-b] pyridin-4-yl) pyrazin-2-yl]thiophen-3-yl} acetamide

[0568] ##STR00390##

[0569] Yellow solid (2.07 mg), LCMS (ESI): [M+H].sup.+=404.40: .sup.1H NMR (400 MHz, DMSO-d6) ? 10.40 (s, 1H), 9.28 (s, 1H), 9.16 (s, 1H), 8.45 (d, J=5.0 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.84 (d, J=5.1 Hz, 1H), 7.74 (d, J=1.6 Hz, 2H), 7.25 (d, J=3.4 Hz, 1H), 3.91 (s, 3H), 2.77-2.62 (m, 1H), 2.44 (d, J=7.6 Hz, 2H), 2.15-2.02 (m, 2H), 1.92-1.80 (m, 2H), 1.80-1.68 (m, 2H).

Effect Example 1

Drak2 Activity Testing Method

[0570] The activity of Drak2 was detected using the ADP-Glo kinase assay kit from Promega. The reaction for this method was in a 384 white shallow well plate and the total volume of the reaction was 5 ?L. Specifically, including 1 ?L of the compound to be tested (2% DMSO), 2 ?L of Drak2, and 2 ?L of ATP. The reaction buffer system includes 50 mM Na.sub.3PO.sub.4, 0.02% NaN.sub.3, 0.1 mM Na.sub.3VO.sub.4, 5 mM MgCl.sub.2, 0.01% (w/v) BSA, and 50 mM HEPES with pH value of 7.0 (the above reaction buffer system was used to dilute Drak2 and ATP, and the above concentrations were their respective concentrations in the total reaction volume of 5 ?L). After incubating at room temperature for two hours, 5 ?L of ADP Glo termination buffer (reagent in the kit) was added to terminate the kinase reaction and consume the remaining ATP. After one hour of reaction, a kinase detection reagent (reagent in the kit) was added and incubated for half an hour. It not only converted ADP to ATP, but also used a coupled luciferase/luciferin (reagent in the kit) reaction to detect newly synthesized ATP. An Envision multifunctional microplate enzyme-linked immunosorbent assay instrument was used to read the value and detect the effect of the compounds to be tested on Drak2 kinase activity. Envision parameter was set to Aperture, and the specific selection was 384 plate US Luminescence Aperture-In. Background pores without Drak2 and Drak2 full enzyme active pores without compounds were set up in the reaction.

[0571] The IC50 value of the compound inhibiting Drak2 kinase activity was calculated using Graphpad Prism 7.00 software, using the formula: Y=100/(1+10{circumflex over ()}(Log IC50?X)*HillSlope). Activity range: A: <10 nM; B: 11-100 nM; C: 101-1000 nM; D: 1001-10000 nM; E: >10000 nM.

TABLE-US-00011 TABLE 11 Example Compound No. IC50_Drak2 (nM) 1 A1 C 2 A2 D 3 A3 C 4 A4 C 5 A5 C 6 A6 C 7 A7 C 8 A8 C 9 A9 C 10 A10 D 11 A11 E 12 A12 D 13 A13 C 14 A14 D 15 A15 C 16 A16 D 17 A17 C 18 A18 C 19 A19 C 20 A20 C 21 A21 C 22 A22 C 23 A23 C 24 A24 D 25 A25 E 26 A26 D 27 A27 D 28 A28 D 29 A29 C 30 A30 E 31 A31 B 32 A32 B 33 A33 C 34 A34 B 35 A35 B 36 A36 C 37 A37 C 38 A38 D 39 A39 C 40 A40 C 41 A41 C 42 A42 C 43 A43 B 44 A44 B 45 A45 D 46 B1 C 46 B2 B 47 B3 C 46 B4 B 48 B5 C 49 B6 C 50 B7 C 51 B8 D 52 B9 C 53 B10 C 54 B11 C 55 B12 C 56 B13 C 57 B14 C 58 B15 B 59 B16 C 60 B17 D 61 B18 E 62 B19 E 63 B20 E 64 B21 E 65 B22 C 66 B23 B 67 B24 D 68 B25 B 69 B26 B 70 B27 B 71 B28 C 72 B29 B 73 B30 C 74 B31 B 75 B32 B 76 B33 B 77 B34 C 78 B35 C 79 B36 C 80 B37 B 81 B38 B 82 B39 B 83 B40 B 84 B41 C 85 B42 C 86 B43 C 87 B44 C 88 B45 B 89 B46 B 90 B47 B 91 B48 B 92 B49 B 93 B50 B 94 B51 B 95 B52 B 96 B53 B 97 B54 B 98 B55 B 99 B56 A 100 B57 B 101 B58 B 102 B59 A 103 B60 B 104 B61 B 105 B62 B 106 B63 A 107 B64 B 108 B65 C 109 B66 D 110 B67 C 111 B68 A 112 B69 A 113 B70 C 114 B71 B 115 B72 C 116 B73 C 117 B74 C 118 B75 E 119 B76 B 120 B77 B 121 B78 B 122 C1 E 122 C2 D 123 C3 D 124 C4 D 125 D1 E 125 D2 E 126 D3 E 126 D4 D 127 D5 D 128 D6 C 129 D7 D 130 D8 D 131 B79 B 132 B80 B 133 B81 B 134 B82 C 135 B83 B 136 B84 B 137 B85 C 138 B86 C 139 B87 C 140 B88 C 141 B89 C 142 B90 A 143 B91 C 144 B92 B 145 B93 B 146 B94 C 147 B95 B 148 B96 B 149 B97 B 150 B98 A 151 B99 A 152 B100 B 153 B101 B 154 B102 B 155 B103 B 156 B104 B 157 B105 B 158 E2 B 159 E1 B 160 F1 B 161 G1 C 162 A46 C 163 A47 C 164 A48 C 165 A49 B 166 A50 B 167 A51 C 168 A52 B 169 B 170 B 171 B 172 C 173 B 174 B 175 B 176 A 177 B 178 B 179 B 180 B 181 B 182 C 183 B 184 B 185 B 186 A 187 B 188 D 189 A 190 B 191 A 192 B 193 B 194 B 195 B 196 A 197 B 198 C 199 B 200 B 201 D 202 B 203 B 204 C 205 B 206 B 207 B 208 C 209 B 210 C 211 C 212 C 213 C 214 B 215 C 216 A 217 B 218 B 219 B 220 C 221 C 222 C 223 C 224 C

[0572] It can be concluded from the activity data from above table that the compound of the present invention possess Drak2 kinase inhibitory activity.

[0573] All documents mentioned in the present invention are cited as references in this application, just as each document is individually cited as a reference. In addition, it should be understood that, after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.