PYRROLO[2,1-F][1,2,4]TRIAZINE DERIVATIVE AND USE THEREOF

Abstract

The present disclosure provides a compound, which is a compound of Formula (I) or a stereoisomer, a tautomer, a N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound of Formula (I):

##STR00001##

Claims

1. A compound, which is a compound of Formula (I) or a stereoisomer, a tautomer, a N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof: ##STR00058## wherein L.sub.2 is a bond or O; R.sub.1, R.sub.2, R.sub.4, and R.sub.5 are each independently H, F, Cl, Br, CN, NO.sub.2, —OR.sup.b, —NR.sup.cR.sup.d, or C.sub.1-6 alkyl; R.sub.3 is —C(═O)R.sup.a, —C(═O)OR.sup.b, —S(═O).sub.2R.sup.b, —C(═O)NR.sup.cR.sup.d, —OR.sup.b, —NR.sup.cR.sup.d, R.sup.bO—C.sub.1-4 alkylene, R.sup.dR.sup.cN—C.sub.1-4 alkylene, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-4 alkylene, heterocyclyl having 3 to 12 atoms, (heterocyclyl having 3 to 12 atoms)-C.sub.1-4 alkylene, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkylene, heteroaryl having 5 to 10 atoms, or (heteroaryl having 5 to 10 atoms)-C.sub.1-4 alkylene, in which the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-4 alkylene, heterocyclyl having 3 to 12 atoms, (heterocyclyl having 3 to 12 atoms)-C.sub.1-4 alkylene, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkylene, heteroaryl having 5 to 10 atoms and (heteroaryl having 5 to 10 atoms)-C.sub.1-4 alkylene are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, ═O, —OR.sup.b, —NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, R.sup.bO—C.sub.1-4 alkylene, or R.sup.dR.sup.cN—C.sub.1-4 alkylene; R.sup.6 is H or ##STR00059## in which L.sub.1 is N or O; A.sub.1 and A.sub.2 are each independently H, C.sub.1-6 alkyl, C.sub.3-12 carbocyclyl, C.sub.3-12 carbocyclyl-C.sub.1-4 alkylene, heterocyclyl having 3 to 12 atoms, (heterocyclyl having 3 to 12 atoms)-C.sub.1-4 alkylene, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkylene, heteroaryl having 5 to 14 atoms, or (heteroaryl having 5 to 14 atoms)-C.sub.1-4 alkylene, or A.sub.1 and A.sub.2, together with L.sub.1 to which they are attached, form a heterocyclic ring having 3-6 atoms, in which the C.sub.1-6 alkyl, C.sub.3-12 carbocyclyl, C.sub.3-12 carbocyclyl-C.sub.1-4 alkylene, heterocyclyl having 3 to 12 atoms, (heterocyclyl having 3 to 12 atoms)-C.sub.1-4 alkylene, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkylene, heteroaryl having 5 to 14 atoms, (heteroaryl having 5 to 14 atoms)-C.sub.1-4 alkylene, or heterocyclic ring having 3-6 atoms formed by A.sub.1 and A.sub.2 together with L.sub.1 to which they are attached are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R′, provided that A.sub.1 and A.sub.2 are not both H; each R′ is independently H, F, Cl, Br, CN, NO.sub.2, ═O, —OR.sup.b, —NR.sup.cR.sup.d, —S(═O).sub.2R.sup.b, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, heterocyclyl having 3 to 12 atoms, C.sub.6-10 aryl or heteroaryl having 5 to 10 atoms, in which the C.sub.3-8 cycloalkyl, heterocyclyl having 3 to 12 atoms, C.sub.6-10 aryl or heteroaryl having 5 to 10 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, ═O, —OR.sup.b, —NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, R.sup.bO—C.sub.1-4 alkylene or R.sup.dR.sup.cN—C.sub.1-4 alkylene; m is 0, 1, 2 or 3; provided that when R.sub.6 is H, m is not 0, and at least one R′ is C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, heterocyclyl having 3 to 12 atoms, C.sub.6-10 aryl or heteroaryl having 5 to 10 atoms, in which the C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, heterocyclyl having 3 to 12 atoms, C.sub.6-10 aryl heteroaryl having 5 to 10 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, ═O, —OR.sup.b, —NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, R.sup.bO—C.sub.1-4 alkylene or R.sup.dR.sup.cN—C.sub.1-4 alkylene; and R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, or heterocyclyl having 3 to 6 atoms, or R.sup.c and R.sup.d, together with nitrogen to which they are attached, form a heterocyclic ring having 3 to 6 atoms, in which the C.sub.1-6 alkyl and heterocyclic ring having 3 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, CN, OH, NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkylamino.

2. The compound according to claim 1, having a structure of Formula (II): ##STR00060## wherein X is represented by a sub-structural formula below: ##STR00061## ring W is C.sub.3-8 cycloalkyl, heterocyclic ring having 3 to 8 atoms, benzene, or heteroaryl ring having 5 to 6 atoms; each R.sup.w is independently H, F, Cl, Br, CN, NO.sub.2, ═O, —OR.sup.b, —NR.sup.cR.sup.d, —S(═O).sub.2R.sup.b, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; R.sub.7 and R.sub.8 are each independently H, or C.sub.1-6 alkyl; and s is 0, 1, 2 or 3.

3. The compound according to claim 1, having a structure of Formula (III): ##STR00062## wherein Y is C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, heterocyclic ring having 3 to 8 atoms, benzene or heteroaryl ring having 5 to 6 atoms; each R.sup.Y is independently H, F, Cl, Br, CN, NO.sub.2, ═O, —OR.sup.b, —NR.sup.cR.sup.d, —S(═O).sub.2R.sup.b, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; and q is 0, 1, 2 or 3.

4. The compound according to claim 1, wherein R.sub.2, R.sub.4, and R.sub.5 are each independently H.

5. The compound according to claim 1, wherein R.sub.3 is —C(═O)NR.sup.cR.sup.d, OR.sup.b, —NR.sup.cR.sup.d, —S(═O).sub.2R.sup.b, heterocyclyl having 3 to 6 atoms, (heterocyclyl having 3 to 6 atoms)-C.sub.1-4 alkylene, C.sub.6-9 aryl, C.sub.6-9 aryl-C.sub.1-4 alkylene, heteroaryl having 5 to 9 atoms or (heteroaryl having 5 to 9 atoms)-C.sub.1-4 alkylene.

6. The compound according to claim 1, wherein A.sub.1 and A.sub.2 are each independently H, C.sub.1-6 alkyl, C.sub.3-6 carbocyclyl, C.sub.3-6 carbocyclyl-C.sub.1-4 alkylene, heterocyclyl having 3 to 6 atoms, (heterocyclyl having 3 to 6 atoms)-C.sub.1-4 alkylene, C.sub.6-8 aryl, C.sub.6-8 aryl-C.sub.1-4 alkylene, heteroaryl having 5 to 8 atoms, or (heteroaryl having 5 to 8 atoms)-C.sub.1-4 alkylene, or A.sub.1 and A.sub.2, together with L.sub.1 to which they are attached, form a heterocyclic ring having 3 to 6 atoms.

7. The compound according to claim 1, wherein each R′ is independently H, F, Cl, Br, CN, NO.sub.2, ═O, —OR.sup.b, —NR.sub.cR.sub.d, —S(═O)OR.sup.b, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.3-6 cycloalkyl, heterocyclyl having 3 to 6 atoms, C.sub.6-8 aryl or heteroaryl having 5 to 8 atoms, in which the C.sub.3-6 cycloalkyl, heterocyclyl having 3 to 6 atoms, C.sub.6-8 aryl or heteroaryl having 5 to 8 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, ═O, —OR.sup.b, —NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, R.sup.bO—C.sub.1-4 alkylene or R.sup.dR.sup.cN—C.sub.1-4 alkylene.

8. The compound according to claim 1, wherein R.sup.a, R.sup.b, R.sup.c, and R.sup.d are each independently H, methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, C.sub.1-3 haloalkyl, or heterocyclyl having 3 to 6 atoms, or R.sup.c and R.sup.d, together with nitrogen to which they are attached, form a heterocyclic ring having 3 to 6 atoms.

9. The compound according to claim 1, wherein A.sub.1 and A.sub.2 are each independently H, C.sub.1-6 alkyl, C.sub.3-6 carbocyclyl, heterocyclyl having 3 to 6 atoms, C.sub.6-8 aryl, or heteroaryl having 5 to 8 atoms.

10. The compound according to claim 1, wherein R.sub.3 is —C(═O)NR.sup.cR.sup.d, OR.sup.b, —NR.sup.cR.sup.d, —S(═O).sub.2R.sup.b, heterocyclyl having 3 to 6 atoms, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, or phenoxathiinyl, in which the heterocyclyl having 3 to 6 atoms, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, or phenoxathiinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, ═O, —OR.sup.b, —NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, R.sup.bO—C.sub.1-4 alkylene or R.sup.dR.sup.cN—C.sub.1-4 alkylene.

11. The compound according to claim 2, wherein ring W is C.sub.3-6 cycloalkyl, heterocyclyl having 3 to 6 atoms, phenyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, or pyrimidinyl.

12. The compound according to claim 2, wherein R.sup.w is independently H, F, Cl, Br, CN, NO.sub.2, ═O, —OR.sup.b, —NR.sup.cR.sup.d, —S(═O).sub.2R.sup.b, methyl, ethyl, isopropyl, n-propyl, n-butyl or t-butyl or C.sub.1-6 haloalkyl.

13. The compound according to claim 3, wherein ring Y is C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, heterocyclyl having 3 to 6 atoms, phenyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, 3,6-dihydro-2H-pyran or tetrahydro-2H-pyran.

14. The compound according to claim 3, wherein R.sup.Y is independently H, F, Cl, Br, CN, NO.sub.2, ═O, —OR.sup.b, —NR.sup.cR.sup.d, —S(═O).sub.2R.sup.b, methyl, ethyl, isopropyl, n-propyl, n-butyl or t-butyl or C.sub.1-6 haloalkyl.

15. The compound according to claim 2, having a structure of Formula (IV), (V), (VI), (VII), (VIII) or (VIIII): ##STR00063## ##STR00064## wherein V is C.sub.3-8 cycloalkyl, heterocyclic ring having 3 to 8 atoms, benzene or heteroaryl ring having 5 to 6 atoms; R.sup.V is F, Cl, Br, CN, —OH, ═O, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; and p is 0, 1, 2 or 3.

16. A compound, having one of the following structures: ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## or a stereoisomer, a tautomer, a N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.

17. A pharmaceutical composition, comprising an effective amount of the compound according to claim 1.

18. The pharmaceutical composition according to claim 17, further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

19. The pharmaceutical composition according to claim 17, further comprising one or more therapeutic agents selected from other anti-tumor drugs.

20. The pharmaceutical composition according to claim 19, wherein the therapeutic agent is an antimitotic agent, an alkylating agent, an antimetabolic drug, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a protein kinase targeting small molecule inhibitor, and a protein kinase targeting antibody drug.

Description

DESCRIPTION OF EMBODIMENTS

[0356] The following examples are intended to illustrate the present disclosure, instead of limiting the scope of the present disclosure.

PREPARATION EXAMPLES

[0357] In the following preparation examples, the preparation process of the compound of the present disclosure is described in detail by taking some compounds of the present disclosure as examples.

##STR00037##

[0358] Step I.

[0359] Compound 1-A (5.3 g, 28.7 mmol) was dissolved in EtOH (50 mL), and then EtONa (4.7 g, 68.8 mmol) was added to the reaction system. The reaction mixture was heated to reflux for 2 h. The reaction system was diluted with water, and then 2N HCl was added until a large amount of solid was precipitated out. After filtration under suction, the filter cake was washed with water (3*40 mL), and dried to obtain Compound 1-B as a yellow solid. LCMS (M+H).sup.+=212.1.

[0360] Step II

[0361] Compound 1-B (5.9 g, 28 mmol), DIPEA (18 g, 140 mmol), methylamine hydrochloride (5.7 g, 84 mmol) and HOAT (4.5 g, 34 mmol) were dissolved in DMF (60 mL). EDCI (6.4 g, 34 mmol) was added to the reaction system at room temperature, and reacted at 50° C. for 18 h under nitrogen atmosphere. A 1 N NaOH (80 mL) solution was added to the reaction system. The reaction system was extracted with dichloromethane (3*60 mL), dried over anhydrous sodium sulfate, rotary evaporated to dryness, and purified by column chromatography (PE:EA=5:1) to prepare Compound 1-C as ayellow solid. LCMS (M+H).sup.+=225.0.

[0362] Step III

[0363] Compound 1-C (0.7 g, 3.1 mmol) was dissolved in DCE (20 mL), and then SOCl.sub.2 (2.1 g, 15.6 mmol) was added to the reaction system at room temperature. The reaction mixture was heated to 85° C. and reacted for 2 h under microwave. The reaction mixture was evaporated to dryness under reduced pressure and then dissolved in DMF (15 mL). Then formylhydrazine (281 mg, 4.7 mmol) was added to the reaction system. The reaction mixture was heated to 110° C. and reacted for 1 h. The reaction solution was cooled to room temperature. A large amount of solid was precipitated out by adding saturated saline into the reaction system. After filtration, the filter cake was washed with a small amount of water and dried to obtain Compound 1-D as a yellow solid. LCMS (M+H).sup.+=249.0.

[0364] Step IV

[0365] Compound 1-D (300 mg, 1.2 mmol) was dissolved in EtOH (15 mL)/MeOH (5 mL), and then 10% Pd/C (130 mg) was added to the reaction system. The reaction mixture was heated to 70° C. and reacted for 12 h under hydrogen atmosphere. After filtration under suction, the filter cake was washed, and the filtrate was rotary evaporation to dryness to obtain Intermediate A. LCMS (M+H).sup.+=219.0. .sup.1H NMR (400 MHz, DMSO) δ 8.53-8.35 (m, 1H), 7.11 (d, J=1.7 Hz, 1H), 7.04 (dd, J=8.1, 1.7 Hz, 1H), 6.72 (t, J=9.4 Hz, 1H), 5.16 (s, 2H), 4.14-3.95 (m, 2H), 3.76-3.63 (m, 3H), 1.47-1.23 (m, 3H).

##STR00038##

[0366] Step I:

[0367] Compound 2-A (200 mg, 0.9 mmol) was dissolved in formic acid (10 mL), and then solid sodium formate (1.2 g, 18 mmol) wad added. The reaction solution was heated to 70° C., and stirred for 1 h. Most formic acid was removed by concentrated under reduced pressure. The residue was adjusted to pH 9-10 with a saturated aqueous sodium bicarbonate solution, then extracted with dichloromethane (3*40 mL), dried over anhydrous sodium sulfate, rotary evaporated to dryness, and purified by column chromatography (PE:EA=2:1), to prepare Intermediate B as a yellow solid. LCMS: (M+H).sup.+=247.0.

##STR00039##

[0368] Step I:

[0369] Compound 3-A (200 mg, 0.8 mmol) was dissolved in tetrahydrofuran (5 mL), m-chloroperoxybenzoic acid (987 mg, 5.7 mmol) was added in batches in an ice bath, and the reaction solution was heated to 50° C. and stirred for 2 h. m-chloroperoxybenzoic acid (100 mg, 0.57 mmol) was further added in batches in an ice-water bath, and reacted for another 2 h. The solvent was removed by concentration. The residue was diluted with ethyl acetate (30 mL), washed with an aqueous sodium bicarbonate solution and then washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA=3:7) to obtain Compound 3-B as a yellow solid. LCMS (M+H).sup.+=276.0.

[0370] Step II

[0371] Intermediate B (50 mg, 0.2 mmol) was dissolved in THF (5 mL), NaH (20 mg, 0.8 mmol) was added in batches in an ice-water bath, and the reaction solution was heated to 50° C. and stirred for 1 h. After cooling to room temperature, Compound 3-B (56 mg, 0.2 mmol) was added in batches, and reacted at 50° C. for another 12 h. After cooling to room temperature, a 2 N aqueous sodium hydroxide solution (0.5 mL) and methanol (0.5 mL) were added, and reacted at room temperature for 1 h. The reaction solution was concentrated, and the crude product was separated by HPLC to obtain Intermediate C. LCMS: (M+H).sup.+=414.0. .sup.1H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 8.58 (d, J=11.3 Hz, 2H), 8.04 (s, 1H), 7.45-7.31 (m, 2H), 7.01 (dd, J=20.9, 4.6 Hz, 2H), 4.25 (q, J=7.0 Hz, 2H), 3.79 (s, 3H), 1.44 (t, J=6.9 Hz, 3H).

Example 1

[0372] ##STR00040##

[0373] Step I:

[0374] Compound 4-A (200 mg, 1 mmol), DIPEA (332 mg, 2.6 mmol) and 2,2-methylpropan-1-amine (112 mg, 1.3 mmol) were dissolved in acetonitrile (5 mL), and the reaction solution was heated to 60° C. for 12 h. The reaction solution was directly concentrated into a yellow oil, and the crude product was purified by column chromatography (PE:EA=1:1) to obtain Compound 1-1 as a yellow oil. LCMS: (M+H).sup.+=239.0.

[0375] Step II

[0376] Compound 1-1 (98 mg, 0.4 mmol), Intermediate A (60 mg, 0.275 mmol), BINAP (34 mg, 0.055 mmol), Cs.sub.2CO.sub.3 (224 mg, 0.688 mmol) and palladium acetate (6.0 mg, 0.028 mmol) were dissolved in dioxane (10 mL), and the reaction mixture was heated to 100° C., and reacted for 12 h under nitrogen atmosphere. The reaction solution was concentrated, and the crude product was separated by HPLC to obtain Compound 1. LCMS: (M+H).sup.+=421.0. .sup.1H NMR (400 MHz, DMSO) δ 8.59-8.48 (m, 2H), 8.08 (t, J=6.2 Hz, 1H), 7.55-7.47 (m, 1H), 7.37-7.27 (m, 2H), 7.19 (s, 1H), 6.97 (dd, J=4.4, 1.6 Hz, 1H), 6.48 (dd, J=4.3, 2.5 Hz, 1H), 4.24 (q, J=6.9 Hz, 2H), 3.76 (s, 3H), 3.47-3.26 (m, 4H), 1.44 (t, J=6.9 Hz, 3H), 0.97 (s, 9H).

Example 2

[0377] ##STR00041##

[0378] Step L:

[0379] Compound 4-A (250 mg, 1.3 mmol) was dissolved in acetonitrile (5 mL), and cyclohexylamine (160 mg, 1.6 mmol) and DIPEA were added to the reaction system. The mixture was heated to 60° C., reacted for 16 h, and concentrated to remove the solvent. The crude product was purified by column chromatography (PE:EA=1:1) to obtain Compound 2-1 as a yellow solid. LCMS (M+H).sup.+=251.0.

[0380] Step II

[0381] Compound 2-1 (172 mg, 0.7 mmol), Intermediate A (100 mg, 0.5 mmol), BINAP (57 mg, 0.09 mmol), Cs.sub.2CO.sub.3 (374 mg, 1.1 mmol) and palladium acetate (10 mg, 0.05 mmol) were dissolved in dioxane (10 mL), and the reaction mixture was heated to 100° C., and reacted for 12 h under nitrogen atmosphere. The reaction solution was concentrated, and the crude product was separated by HPLC to obtain Compound 2. LCMS: (M+H).sup.+=433.0.

[0382] .sup.1H NMR (400 MHz, DMSO) δ 8.61-8.48 (m, 2H), 7.97 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.37-7.27 (m, 2H), 7.21 (s, 1H), 6.89 (d, J=2.8 Hz, 1H), 6.46 (dd, J=4.3, 2.5 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 4.08 (m, 1H), 3.77 (m, 3H), 1.99 (m, 2H), 1.79 (m, 2H), 1.67 (d, J=14.4 Hz, 1H), 1.45 (t, J=6.9 Hz, 3H), 1.38 (m, 4H), 1.20 (m, 1H).

Example 3

[0383] ##STR00042##

[0384] Step I:

[0385] Compound 4-A (500 mg, 2.7 mmol) was dissolved in NMP (5 mL), and then DIPEA (690 mg, 5.3 mmol) and cyclopentanamine (455 mg, 5.3 mmol) were added to the reaction system. The reaction solution was heated to 120° C. and stirred for 1 h. The reaction system was cooled to room temperature, and then the reaction was quenched with water, extracted with ethyl acetate (3*40 mL), and washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate, and rotary evaporated to dryness. The crude product was purified by column chromatography (PE:EA=1:1) to obtain Compound 3-1 as a yellow solid. LCMS (M+H).sup.+=237.1.

[0386] Step II

[0387] Compound 3-1 (100 mg, 0.4 mmol), Intermediate A (139 mg, 0.6 mmol), BINAP (53 mg, 0.09 mmol) and Cs.sub.2CO.sub.3 (346 mg, 1 mmol) were dissolved in dioxane (10 mL). Palladium acetate (10 mg, 0.04 mmol) was added to the reaction system at room temperature, and the reaction was continued at 110° C. for 18 h under nitrogen atmosphere. The solvent was removed by concentration and the crude product was separated by HPLC to obtain Compound 3. LCMS (M+H).sup.+=419.0. .sup.1H NMR (400 MHz, DMSO) δ 8.54 (t, J=4.1 Hz, 2H), 8.02 (d, J=7.3 Hz, 1H), 7.50 (s, 1H), 7.31 (dd, J=12.5, 4.1 Hz, 2H), 7.20 (s, 1H), 6.90 (dd, J=4.3, 1.3 Hz, 1H), 6.46 (dd, J=4.1, 2.6 Hz, 1H), 4.53 (dd, J=13.8, 7.0 Hz, 1H), 4.25 (q, J=6.9 Hz, 2H), 3.78 (d, J=11.1 Hz, 3H), 2.03 (d, J=2.6 Hz, 2H), 1.76 (s, 2H), 1.63 (d, J=19.8 Hz, 4H), 1.44 (t, J=6.9 Hz, 3H).

Example 4

[0388] ##STR00043##

[0389] Step I:

[0390] Compound 4-A (500 mg, 2.7 mmol) was dissolved in NMP (5 mL), and then DIPEA (690 mg, 5.3 mmol) and tetrahydro-2H-pyran-4-amine (540 mg, 5.3 mmol) were added to the reaction system. The reaction solution was heated to 120° C. and stirred for 1 h. The reaction system was cooled to room temperature, and then the reaction was quenched with water, extracted with ethyl acetate (3*40 mL), and washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate, and rotary evaporated to dryness. The crude product was purified by column chromatography (PE:EA=1:1) to obtain Compound 4-1 as a yellow solid. LCMS (M+H).sup.+=253.0.

[0391] Step II

[0392] Compound 4-1 (100 mg, 0.4 mmol), Intermediate A (130 mg, 0.6 mmol), BINAP (50 mg, 0.08 mmol) and Cs.sub.2CO.sub.3 (324 mg, 1 mmol) were dissolved in dioxane (10 mL). Palladium acetate (9 mg, 0.04 mmol) was added to the reaction system at room temperature, and the reaction was continued at 110° C. for 18 h under nitrogen atmosphere. The solvent was removed by concentration and the crude product was separated by HPLC to obtain Compound 4. LCMS (M+H).sup.+=435.0. .sup.1H NMR (400 MHz, DMSO) δ 8.59-8.44 (m, 2H), 8.04 (d, J=7.7 Hz, 1H), 7.51 (s, 1H), 7.39-7.29 (m, 2H), 7.24 (s, 1H), 6.89 (d, J=4.2 Hz, 1H), 6.54-6.41 (m, 1H), 4.41-4.29 (m, 1H), 4.24 (q, J=6.9 Hz, 2H), 3.94 (d, J=8.1 Hz, 2H), 3.80-3.73 (m, 3H), 3.46 (t, J=11.6 Hz, 2H), 1.92 (d, J=10.9 Hz, 2H), 1.63 (qd, J=12.3, 4.5 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).

Example 5

[0393] ##STR00044##

[0394] Step I:

[0395] Compound 4-A (300 mg, 1.6 mmol) was dissolved in NMP (5 mL), and then DIPEA (414 mg, 3.2 mmol) and 4-methoxycyclohexan-1-amine (414 mg, 3.2 mmol) were added to the reaction system. The reaction solution was heated to 120° C. and stirred for 1 h. The reaction system was cooled to room temperature, and then the reaction was quenched with water, extracted with ethyl acetate (3*40 mL), and washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate, and rotary evaporated to dryness. The crude product was purified by column chromatography (PE:EA=1:1) to obtain Compound 5-1 as a yellow solid. LCMS (M+H).sup.+=281.0.

[0396] Step II

[0397] Compound 5-1 (120 mg, 0.4 mmol), Intermediate A (139 mg, 0.6 mmol), BINAP (53 mg, 0.09 mmol) and Cs.sub.2CO.sub.3 (346 mg, 1 mmol) were dissolved in dioxane (10 mL). Palladium acetate (10 mg, 0.04 mmol) was added to the reaction system at room temperature, and the reaction was continued at 110° C. for 18 h under nitrogen atmosphere. The solvent was removed by concentration and the crude product was separated by HPLC to obtain Compound 5. LCMS (M+H).sup.+=463.0. .sup.1H NMR (400 MHz, DMSO) δ 8.58-8.46 (m, 2H), 7.98 (d, J=7.8 Hz, 1H), 7.52-7.46 (m, 1H), 7.35-7.26 (m, 2H), 7.23 (s, 1H), 6.88 (dd, J=4.4, 1.6 Hz, 1H), 6.46 (dd, J=4.3, 2.5 Hz, 1H), 4.24 (q, J=6.9 Hz, 2H), 4.17-4.00 (m, 1H), 3.78 (d, J=10.3 Hz, 3H), 3.25 (d, J=11.5 Hz, 3H), 3.22-3.07 (m, 1H), 2.05 (dd, J=29.4, 10.0 Hz, 4H), 1.51-1.37 (m, 5H), 1.28 (dd, J=23.0, 10.2 Hz, 2H).

Example 6

[0398] ##STR00045##

[0399] Step I:

[0400] Compound 4-A (100 mg, 0.8 mmol) was dissolved in NMP (5 mL), and then DIPEA (200 mg, 1.5 mmol) and Compound 6-1 (160 mg, 0.85 mmol) were added to the reaction system. The reaction solution was heated to 120° C. and stirred for 1 h. The reaction system was cooled to room temperature, and then the reaction was quenched with water, extracted with ethyl acetate (3*30 mL), and washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate, and rotary evaporated to dryness. The crude product was purified by column chromatography (PE:EA=1:1) to obtain Compound 6-2 as a yellow solid. LCMS (M+H).sup.+=281.1.

[0401] Step II

[0402] Compound 6-2 (70 mg, 0.25 mmol), Intermediate A (55 mg, 0.25 mmol), BINAP (31 mg, 0.05 mmol) and Cs.sub.2CO.sub.3 (204 mg, 0.6 mmol) were dissolved in dioxane (10 mL). Palladium acetate (6 mg, 0.03 mmol) was added to the reaction system at room temperature, and the reaction was continued at 110° C. for 18 h under nitrogen atmosphere. The solvent was removed by concentration and the crude product was separated by HPLC to obtain Compound 6. LCMS (M+H).sup.+=463.0. .sup.1H NMR (400 MHz, DMSO) δ 8.59-8.48 (m, 2H), 8.00 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 1H), 7.39-7.25 (m, 2H), 7.20 (s, 1H), 6.92 (dd, J=4.3, 1.5 Hz, 1H), 6.45 (dd, J=4.3, 2.5 Hz, 1H), 4.24 (q, J=6.9 Hz, 2H), 4.14 (s, 1H), 4.10-4.00 (m, 1H), 3.75 (d, J=11.9 Hz, 3H), 1.87-1.58 (m, 6H), 1.43 (q, J=6.9 Hz, 5H), 1.15 (s, 3H).

Example 7

[0403] ##STR00046##

[0404] Step I:

[0405] Compound 4-A (20 mg, 0.16 mmol) was dissolved in NMP (3 mL), and then DIPEA (40 mg, 0.3 mmol) and Compound 7-1 (32 mg, 0.17 mmol) were added to the reaction system. The reaction solution was heated to 120° C. and stirred for 1 h. The reaction system was cooled to room temperature, and then the reaction was quenched with water, extracted with ethyl acetate (3*30 mL), and washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate, and rotary evaporated to dryness. The crude product was purified by column chromatography (PE:EA=1:1) to obtain Compound 7-2 as a yellow solid. LCMS (M+H).sup.+=281.1.

[0406] Step II

[0407] Compound 7-2 (28 mg, 0.1 mmol), Intermediate A (33 mg, 0.15 mmol), BINAP (13 mg, 0.02 mmol) and Cs.sub.2CO.sub.3 (82 mg, 0.25 mmol) were dissolved in dioxane (10 mL). Palladium acetate (3 mg, 0.01 mmol) was added to the reaction system at room temperature, and the reaction was continued at 110° C. for 18 h under nitrogen atmosphere. The solvent was removed by concentration and the crude product was separated by HPLC to obtain Compound 7. LCMS (M+H).sup.+=463.0. .sup.1H NMR (400 MHz, DMSO) δ 8.52 (d, J=9.5 Hz, 2H), 7.91 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.37-7.27 (m, 2H), 7.21 (s, 1H), 6.88 (dd, J=4.3, 1.5 Hz, 1H), 6.47 (dd, J=4.3, 2.5 Hz, 1H), 4.38 (s, 1H), 4.24 (q, J=7.0 Hz, 2H), 4.11 (s, 1H), 3.77 (s, 3H), 3.32 (s, 2H), 1.90 (s, 2H), 1.65 (d, J=4.4 Hz, 2H), 1.55 (dd, J=19.1, 11.2 Hz, 4H), 1.45 (t, J=6.9 Hz, 3H), 1.19 (d, J=7.6 Hz, 3H).

Example 8

[0408] ##STR00047##

[0409] Step L:

[0410] Compound 4-A (300 mg, 1.6 mmol) was dissolved in NMP (5 mL), and then DIPEA (414 mg, 3.2 mmol) and piperidine (389 mg, 3.2 mmol) were added to the reaction system. The reaction solution was heated to 120° C. and stirred for 1 h. The reaction system was cooled to room temperature, and then the reaction was quenched with water, extracted with ethyl acetate (3*30 mL), and washed with saturated saline. The organic phase was dried over anhydrous sodium sulfate, and rotary evaporated to dryness. The crude product was purified by column chromatograph (PE:EA=2:1) to obtain Compound 8-1 as a yellow solid. LCMS (M+H).sup.+=237.0.

[0411] Step II

[0412] Compound 8-1 (100 mg, 0.4 mmol), Intermediate A (139 mg, 0.6 mmol), BINAP (53 mg, 0.09 mmol) and Cs.sub.2CO.sub.3 (346 mg, 1 mmol) were dissolved in dioxane (10 mL). Palladium acetate (10 mg, 0.04 mmol) was added to the reaction system at room temperature, and the reaction was continued at 110° C. for 18 h under nitrogen atmosphere. The solvent was removed by concentration and the crude product was separated by HPLC to obtain Compound 8. LCMS (M+H).sup.+=419.0. .sup.1H NMR (400 MHz, DMSO) δ 8.58-8.44 (m, 2H), 7.62 (dd, J=2.5, 1.5 Hz, 1H), 7.37-7.27 (m, 2H), 7.20 (s, 1H), 6.87 (dd, J=4.6, 1.5 Hz, 1H), 6.56 (dd, J=4.6, 2.6 Hz, 1H), 4.24 (q, J=6.9 Hz, 2H), 3.95 (d, J=5.1 Hz, 4H), 3.77 (s, 3H), 1.78-1.59 (m, 6H), 1.44 (t, J=6.9 Hz, 3H).

Example 9

[0413] ##STR00048##

[0414] Step I:

[0415] Compound 2-1 (50 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL), and then NCS (45.5 mg, 0.3 mmol) was added in batches. The reaction solution was heated to 70° C., stirred for 12 h, and concentrated under reduced pressure. The crude product was purified by HPLC to obtain Compound 9-1 as a white solid. LCMS (M+H).sup.+=285.0. .sup.1H NMR (400 MHz, DMSO) δ 8.62 (d, J=8.0 Hz, 1H), 7.12 (d, J=4.7 Hz, 1H), 6.72 (d, J=4.6 Hz, 1H), 4.04 (s, 1H), 2.08 (s, 1H), 1.92 (s, 2H), 1.76 (s, 2H), 1.64 (d, J=12.2 Hz, 1H), 1.35 (t, J=9.8 Hz, 3H), 1.16 (d, J=12.3 Hz, 1H).

[0416] Step II

[0417] Compound 9-1 (15 mg, 0.05 mmol), BINAP (12 mg, 0.05 mmol), Intermediate A (12 mg, 0.05 mmol) and cesium carbonate (43 mg, 0.13 mmol) were dissolved in dioxane (5 mL), and palladium acetate (1 mg, 0.005 mmol) was added under nitrogen atmosphere. The reaction system was heated to 100° C., and reacted for 12 h under nitrogen atmosphere. The solvent was removed by concentration under reduced pressure and the crude product was separated by HPLC to obtain Compound 9. LCMS (M+H).sup.+=467.0. .sup.1H NMR (400 MHz, DMSO) δ 8.61 (d, J=8.4 Hz, 1H), 8.53 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.33 (dd, J=12.6, 7.6 Hz, 3H), 7.00 (d, J=4.6 Hz, 1H), 6.56 (d, J=4.6 Hz, 1H), 4.26 (q, J=6.8 Hz, 2H), 4.09 (m, 1H), 3.77 (m, 3H), 1.99 (m, 2H), 1.79 (m, 2H), 1.67 (d, J=12.7 Hz, 1H), 1.46 (d, J=6.9 Hz, 3H), 1.37 (m, 3H), 1.23 (m, 2H).

Example 10

[0418] ##STR00049##

[0419] Step I.

[0420] Compound 2-1 (50 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL), and NCS (45.5 mg, 0.3 mmol) was added in batches. The reaction solution was heated to 70° C., stirred for 12 h, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC to obtain Compound 10-1 as a white solid. LCMS (M+H).sup.+=285.0. .sup.1H NMR (400 MHz, DMSO) δ 7.73 (d, J=2.9 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.75 (d, J=2.9 Hz, 1H), 4.17-3.98 (m, 1H), 1.90 (dd, J=12.3, 3.3 Hz, 2H), 1.72 (dd, J=9.2, 3.9 Hz, 2H), 1.64-1.55 (m, 1H), 1.54-1.45 (m, 2H), 1.36 (td, J=12.0, 3.3 Hz, 2H), 1.20 (td, J=11.9, 3.4 Hz, 1H).

[0421] Step II

[0422] Compound 10-1 (15 mg, 0.05 mmol), BINAP (6 mg, 0.01 mmol), Intermediate A (12 mg, 0.05 mmol), and cesium carbonate (43 mg, 0.13 mmol) were dissolved in dioxane (5 mL), and then palladium acetate (1 mg, 0.005 mmol) was added. The reaction solution was heated to 100° C., and reacted for 12 h under nitrogen atmosphere. The solvent was removed by concentration under reduced pressure and the crude product was separated by HPLC to obtain Compound 10. LCMS (M+H).sup.+=467.0. .sup.1H NMR (400 MHz, DMSO) δ 8.52 (d, J=15.9 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.40-7.24 (m, 3H), 6.66-6.54 (m, 2H), 4.24 (q, J=7.0 Hz, 2H), 4.13 (s, 1H), 3.76 (m, 3H), 1.97 (m, 2H), 1.73 (m, 2H), 1.60 (m, 1H), 1.50 (d, J=12.2 Hz, 2H), 1.43 (t, J=6.9 Hz, 3H), 1.41-1.35 (m, 1H), 1.23 (m, 2H).

Example 11

[0423] ##STR00050##

[0424] Step I.

[0425] Compound 2 (40 mg, 0.09 mmol) was dissolved in acetonitrile (3 mL). NBS (16.5 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), and then slowly added dropwise to the reaction system in an ice-water bath. The reaction solution was reacted for 1 h under normal temperature. The solvent was removed by concentration, and the crude product was purified by HPLC to obtain Compound 11. LCMS (M+H).sup.+=511.0. .sup.1H NMR (400 MHz, DMSO) δ 8.66 (d, J=8.4 Hz, 1H), 8.54 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.37 (m, 3H), 7.03 (d, J=4.6 Hz, 1H), 6.62 (d, J=4.6 Hz, 1H), 4.26 (q, J=6.9 Hz, 2H), 4.09 (s, 1H), 3.79 (d, J=10.6 Hz, 3H), 1.99 (m, 2H), 1.79 (m, 2H), 1.67 (d, J=11.6 Hz, 1H), 1.45 (t, J=6.9 Hz, 3H), 1.38 (d, J=5.1 Hz, 4H), 1.19 (m, 1H).

Example 12

[0426] ##STR00051##

[0427] Step I:

[0428] Intermediate C (15 mg, 0.04 mmol) was dissolved in a mixture of dioxane (2 mL) and water (0.5 mL), and then Compound 12-1 (14 mg, 0.07 mmol), potassium carbonate (10 mg, 0.07 mmol) and Pd(dppf)Cl.sub.2 (3 mg, 0.004 mmol) were added. The reaction solution was heated to 100° C. and reacted for 2 h under nitrogen atmosphere. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by HPLC to obtain Compound 12. LCMS: (M+H).sup.+=402.0. .sup.1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.67 (s, 1H), 8.36-8.29 (m, 1H), 7.99 (s, 1H), 7.38 (dd, J=10.3, 1.9 Hz, 2H), 6.99 (s, 1H), 6.93 (d, J=4.7 Hz, 1H), 6.85 (d, J=4.7 Hz, 1H), 4.22 (q, J=6.9 Hz, 2H), 3.80 (s, 3H), 2.83 (s, 2H), 2.65 (d, J=16.7 Hz, 2H), 2.03-1.88 (m, 2H), 1.42 (t, J=6.9 Hz, 3H).

Example 13

[0429] ##STR00052##

[0430] Step I:

[0431] Compound 12 (15 mg, 0.04 mmol) was dissolved in ethyl acetate (3 mL), and then 10% palladium on carbon (10 mg) was added and stirred for 5 h under hydrogen atmosphere at normal temperature. The reaction solution was diluted with ethyl acetate and filtered under suction. The filter cake was washed 3 times with ethyl acetate. The filtrate was combined and concentrated. Then the crude product was separated by HPLC to obtain Compound 13. LCMS: (M+H).sup.+=404.0. .sup.1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.61-8.40 (m, 2H), 7.77 (m, 1H), 7.44-7.30 (m, 2H), 6.86 (d, J=4.6 Hz, 1H), 6.72 (d, J=4.6 Hz, 1H), 4.24 (q, J=6.9 Hz, 2H), 3.78 (s, 3H), 3.57 (d, J=7.5 Hz, 1H), 2.17 (d, J=8.0 Hz, 2H), 1.86-1.64 (m, 6H), 1.45 (t, J=6.9 Hz, 3H).

Example 14

[0432] ##STR00053##

[0433] Step I:

[0434] Intermediate C (28 mg, 0.07 mmol) and Compound 14-1 (28 mg, 0.14 mmol) were dissolved in a mixture of dioxane (2 mL) and water (0.5 mL), and then potassium carbonate (19 mg, 0.14 mmol) and Pd(dppf)Cl.sub.2 (10 mg, 0.014 mmol) were added to the reaction system. The reaction solution was heated to 90° C., and reacted for 18 h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was separated by HPLC to obtain Compound 14. LCMS (M+H).sup.+=416.0. .sup.1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.57 (s, 1H), 8.35 (m, 1H), 7.87 (m, 1H), 7.37 (d, J=10.7 Hz, 2H), 7.12 (m, 1H), 6.89 (d, J=17.5 Hz, 2H), 4.24 (m, 2H), 3.78 (s, 3H), 2.01 (m, 1H), 1.73 (d, J=39.1 Hz, 5H), 1.43 (m, 3H), 1.24 (m, 2H).

Example 15

[0435] ##STR00054##

[0436] Step I:

[0437] Compound 14 (23 mg, 0.05 mmol) was dissolved in a mixture of MeOH (1 mL) and ethyl acetate (1 mL), and the reaction system was reacted for 2 h under hydrogen atmosphere at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was separated by HPLC to obtain Compound 15. LCMS: (M+H).sup.+=418.0. .sup.1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.50 (m, 2H), 7.78 (s, 1H), 7.36 (m, 2H), 6.86 (d, J=4.6 Hz, 1H), 6.67 (d, J=4.6 Hz, 1H), 4.25 (q, J=6.9 Hz, 2H), 3.78 (s, 3H), 3.15 (m, 1H), 2.09 (m, 2H), 1.86 (m, 2H), 1.52 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 1.30 (m, 2H), 1.23 (m, 2H).

Example 16

[0438] ##STR00055##

[0439] Step I:

[0440] Intermediate C (80 mg, 0.19 mmol), Compound 16-1 (80 mg, 0.38 mmol), Pd(dppf)Cl.sub.2 (15 mg, 0.02 mmol) and K.sub.2CO.sub.3 (52 mg, 0.38 mmol) were dissolved in dioxane (6 mL) and H.sub.2O (1 mL). The reaction system was heated to 110° C. and reacted for 8 h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was separated by HPLC to obtain Compound 16. LCMS: (M+H).sup.+=418.0. .sup.1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.95 (s, 1H), 7.38 (m, 2H), 7.19 (m, 1H), 6.92 (dd, J=10.1, 4.8 Hz, 2H), 4.37 (d, J=2.6 Hz, 2H), 4.22 (q, J=6.9 Hz, 2H), 3.88 (t, J=5.4 Hz, 2H), 3.78 (s, 3H), 2.59 (m, 2H), 1.42 (t, J=6.9 Hz, 3H).

Example 17

[0441] ##STR00056##

[0442] Step I:

[0443] Compound 16 (20 mg, 0.05 mmol) was dissolved in a mixture of MeOH (1 mL) and ethyl acetate (1 mL). The reaction system was reacted for 2 h under hydrogen atmosphere at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was separated by HPLC to obtain Compound 17. LCMS: (M+H).sup.+=420.0. .sup.1H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.55 (s, 1H), 8.49 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.37 (m, 2H), 6.88 (d, J=4.6 Hz, 1H), 6.71 (d, J=4.6 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 4.00 (dd, J=11.1, 3.0 Hz, 2H), 3.78 (s, 3H), 3.60 (dd, J=11.7, 9.9 Hz, 2H), 3.45 (m, 1H), 2.01 (d, J=14.9 Hz, 2H), 1.78 (dd, J=12.5, 3.9 Hz, 2H), 1.45 (m, 3H).

Example 18

[0444] ##STR00057##

[0445] Step I:

[0446] Intermediate C (20 mg, 0.05 mmol) and Compound 18-1 (20 mg, 0.10 mmol) were dissolved in a mixture of dioxane (2 mL) and water (0.4 mL), and then potassium carbonate (14 mg, 0.1 mmol) and Pd(dppf)Cl.sub.2 (5 mg, 0.005 mmol) were added to the reaction system. The reaction system was heated to 90° C. and reacted for 18 h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain Compound 18. LCMS (M+H).sup.+=416.0. .sup.1H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.40 (m, 2H), 7.12 (d, J=4.7 Hz, 1H), 6.98 (d, J=4.7 Hz, 1H), 4.23 (q, J=6.9 Hz, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 1.41 (t, J=6.9 Hz, 3H).

Activity Test Examples

[0447] In the following examples, the TTK inhibitory activity and pharmacokinetic properties of the compound of the present disclosure are detected with some compounds of the present disclosure.

Example A: TTK Inhibitory Activity

[0448] The experiment aims to detect the inhibitory activity of the compound of the present disclosure on TTK in vitro.

[0449] Experimental Steps and Methods:

[0450] The TTK kinase reaction system was 10 μL, including 0.5 nM TTK, test compound over a concentration gradient, 10 mM MgCl.sub.2, 2 mM DTT, 7 uM ATP, 0.2 uM Fluorescein-PolyGT (Fluorescein-Poly Glu:Tyr (4:1)), 0.01% Triton X-100, 0.01% BSA, and 50 mM HEPES pH 7.5. The enzyme and the test compound of the present disclosure were added into a 384-well plate, and then a substrate and ATP were added. Then the system was incubated at a constant temperature of 28° C. 30 min after the reaction, 10 μL of a mixed solution of a corresponding antibody and EDTA was added to terminate the reaction, and incubated for 60 min at a constant temperature of 28° C. The data was read on Envision instrument. A curve was plotted with the Log concentration of the inhibitor as the X axis and the inhibition rate as the Y axis, and IC.sub.50 was calculated by Y=Bottom+(Top-Bottom)/(1+(IC.sub.50/X){circumflex over ( )}HillSlope).

[0451] Table 1 shows the experimental data of the TTK inhibitory activity of some compounds of the present disclosure.

TABLE-US-00001 TABLE 1 Compound No. TTK IC.sub.50 (nM) Compound 1 27.0 Compound 2 1.9 Compound 3 8.9 Compound 4 4.0 Compound 5 1.7 Compound 6 3.0 Compound 7 1.1 Compound 10 5.5 Compound 12 8.7 Compound 13 7.1 Compound 14 2.4 Compound 15 4.2 Compound 16 2.0 Compound 17 6.3 Compound 18 2.1

[0452] The experimental results show that the compound of the present disclosure has good TTK inhibitory activity.

[0453] Pharmacokinetic Evaluation of the Compound of the Present Disclosure after Intravenous Injection or Oral Administration in Mice

[0454] This experiment aims to detect the pharmacokinetic properties of the compound of the present disclosure in mice.

[0455] Experimental Steps and Methods:

[0456] The test compound of the present disclosure was dissolved in 1000 DMSO/45% PEG400/45% water, whirled and ultrasonicated, to prepare a clear solution of a corresponding concentration, which was filtered through a microporous membrane filter for later use. Female Balb/c mice of 18-20 g were given the compound in solution by intravenous injection at a dose of is 1 mg/kg. The test compound was dissolved in 10% NMP/10% PEG-15-hydroxystearate/80% water, whirled and ultrasonicated, to prepare a clear solution of a corresponding concentration, which was filtered through a microporous membrane filter for later use. Female Balb/c mice of 18-20 g were given the compound in solution by oral administration at a dose of is 10 mg/kg. Whole blood was collected at certain time points to prepare plasma. The drug concentration was analyzed by LC-MS/MS, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software.

[0457] The experimental results show that the compound of the present disclosure has a large exposure and good absorption in the test animals, and the pharmacokinetic properties are obviously better.

[0458] In the description of the specification, the description with reference to the terms “an embodiment”, “some embodiments”, “example”, “specific example”, or “some example” and so on means that specific features, structures, materials or characteristics described in connection with the embodiment or example are embraced in at least one embodiment or example of the present disclosure. In the present specification, schematic representations of the above terms are not necessarily directed to the same embodiments or examples. Moreover, the described specific features, structures, materials or characteristics may be combined in any suitable manners in one or more embodiments. In addition, where there are no contradictions, the various embodiments or examples described in this specification and features of various embodiments or examples can be combined by those skilled in the art.

[0459] Although the embodiments of the present disclosure have been illustrated and described above, it is to be understood that the above embodiments are exemplary and not to be construed as limiting the present disclosure, and that changes, modifications, substitutions and alterations can be made by those skilled in the art without departing from the scope of the present disclosure.