7-site substituted pyrrole triazine compounds or pharmaceutically acceptable salts thereof, and preparation method thereof and uses thereof

Abstract

The present disclosure relates to 7-substituted pyrrolo[2,1-f][1,2,4]triazine compounds or pharmaceutically acceptable salts thereof, and preparation methods and uses thereof. These compounds show good PI3K inhibitory activity, can effectively inhibit the activity of PI3K kinase, and has significant enhancement and improvement of pharmacokinetic properties, such as bioavailability, due to the introduction of the 7-position group; furthermore, the compounds of the present disclosure exhibit an unpredictable high selectivity and strong inhibitory activity on PI3Kδ, and thus these compounds can be used for treating diseases related to PI3K pathway, especially for anti-cancer or for the treatment of tumors, leukemias and autoimmune diseases. After further optimizing and screening, the compounds are expected to be developed into a new type of anti-tumor drugs.

Claims

1. A 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by a general formula I or a pharmaceutically acceptable salt thereof: ##STR00095## wherein, R.sub.1 is halogen, or C.sub.1-6 alkyl or C.sub.3-8 cycloalkyl which is unsubstituted or substituted with at least one substituent, wherein the substituent is halogen; R.sub.2 is: —C(OH)R.sub.5R.sub.6; —COC.sub.1-6 alkyl; —CN; or, unsubstituted or at least one substituent substituted C.sub.1-6 alkyl, —CH.sub.2NH—C.sub.1-6 alkyl, —CH.sub.2N(C.sub.1-6 alkyl) (C.sub.1-6 alkyl), —CH.sub.2-(saturated heterocyclyl containing 1 to 2 heteroatoms and 3 to 6 carbon atoms), —CH.sub.2-(saturated heterocyclyl containing 1 to 2 heteroatoms and 3 to 6 carbon atoms)-(saturated heterocyclyl containing 1 to 2 heteroatoms and 3 to 6 carbon atoms), —CH.sub.2-(saturated spirocyclic group containing 1 to 2 heteroatoms and 4 to 12 carbon atoms), —CH.sub.2-(saturated bridged ring group containing 1 to 2 heteroatoms and 3 to 12 carbon atoms)-(saturated heterocyclyl containing 1 to 2 heteroatoms and 3 to 6 carbon atoms), or —CH.sub.2-(saturated bridged ring group containing 1 to 2 heteroatoms and 3 to 12 carbon atoms), wherein the substituent is halogen, —N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), —O—C.sub.1-4 alkyl, —CN, —COOH, —CHO, —NHS(O).sub.2—C.sub.1-4 alkyl, —N(C.sub.1-4 alkyl)C(C.sub.1-4 alkyl)(C.sub.1-4 alkyl)—CONH.sub.2, ═O, —OH, —S(O).sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), —S—C.sub.1-4 alkyl, —S(O).sub.2—C.sub.1-4 alkyl, —CO—C.sub.3-6 cycloalkyl, oxetanyl, morpholinyl, C.sub.3-6 cycloalkyl, —C.sub.1-4 alkyl-N(C.sub.1-4 alkyl) (C.sub.1-4 alkyl), C.sub.1-4 alkyl-O—C.sub.1-4 alkyl which is unsubstituted or substituted with at least one methyl, —CONH.sub.2 which is unsubstituted or substituted with at least one methyl, C.sub.1-4 alkyl-CONH.sub.2 which is unsubstituted or substituted with at least one methyl, —COO—C.sub.1-4 alkyl which is unsubstituted or substituted with at least one methyl, —NH.sub.2 which is unsubstituted or substituted with at least one methyl, —NHCO—C.sub.1-4 alkyl which is unsubstituted or substituted with at least one methyl, —CO—C.sub.1-4 alkyl which is unsubstituted or substituted with at least one substituent A, wherein the substituent A is hydroxyl or methyl, or C.sub.1-4 alkyl which is unsubstituted or substituted with at least one substituent B, wherein the substituent B is —NH.sub.2, —OCH.sub.3, —CONH.sub.2, —OH or —CF.sub.3; in R.sub.2, the heteroatom is selected from at least one of N, O and S, R.sub.5 and R.sub.6 are each independently hydrogen or C.sub.1-6 alkyl; R.sub.3 is ##STR00096## wherein R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each independently hydrogen or C.sub.1-6 alkyl which is unsubstituted or substituted with at least one substituent, wherein the substituent is halogen or hydroxyl; R.sub.4 is —NH.sub.2, —NHCONHR.sub.11 or —NHCO.sub.2R.sub.12, wherein R.sub.11 and R.sub.12 are each independently C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl or phenyl which is unsubstituted or substituted with at least one substituent selected from at least one of halogen and —C(O)OR.sub.13, wherein R.sub.13 is C.sub.1-6 alkyl which is unsubstituted or substituted with at least one substituent, and the substituent in the R.sub.13 is halogen.

2. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is halogen, or C.sub.1-4 alkyl or C.sub.3-6 cycloalkyl which is unsubstituted or substituted with at least one substituent.

3. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 2 or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is —Cl, —F, methyl, trifluoromethyl or difluoromethyl.

4. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is: —C(OH)R.sub.5R.sub.6; —COC.sub.1-4 alkyl; —CN; or, unsubstituted or at least one substituent substituted C.sub.1-4 alkyl, —CH.sub.2NH—C.sub.1-4 alkyl, —CH.sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), —X-(saturated four- to six-membered heterocyclyl containing 1 to 2 heteroatoms), —X-(saturated four- to six-membered heterocyclyl containing 1 to 2 heteroatoms)-(saturated four- to six-membered heterocyclyl containing 1 to 2 heteroatoms), —X-(saturated bicyclic spirocyclic group containing 1 to 2 heteroatoms and 4 to 8 carbon atoms), —X-(saturated bicyclic bridged ring group containing 1 to 2 heteroatoms and 3 to 8 carbon atoms)-(saturated four- to six-membered heterocyclyl containing 1 to 2 heteroatoms), or —X-(saturated bicyclic bridged ring group containing 1 to 2 heteroatoms and 3 to 8 carbon atoms), wherein X is CH.sub.2, and wherein the heterocyclyl, spirocyclic group and bridged ring group are connected to X via an N atom, R.sub.5 and R.sub.6 are each independently hydrogen or C.sub.1-4 alkyl.

5. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 4 or a pharmaceutically acceptable salt thereof, wherein the substituent in R.sub.2 is —F, —Cl, —Br, —I, —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2CH(CH.sub.3).sub.2, —CH.sub.2NH.sub.2, —CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2N(CH.sub.3).sub.2, —CH.sub.2OH, —CH.sub.2OCH.sub.3, —CH.sub.2CH.sub.2OH, —C(CH.sub.3).sub.2OH, —C(CH.sub.3)(CF.sub.3)OH, —C(CF.sub.3).sub.2OH, —C(CH.sub.3).sub.2OCH.sub.3, —C(CH.sub.3).sub.2NH.sub.2, —CH.sub.2C(CH.sub.3).sub.2OH, —CH(OH)CH(CH.sub.3).sub.2, —C(CH.sub.3).sub.2CH.sub.2OH, —C(CH.sub.3).sub.2CH.sub.2OCH.sub.3, —CN, —CF.sub.3, —CO.sub.2H, —CHO, —COCH.sub.3, —CO.sub.2CH.sub.3, —CO.sub.2C(CH.sub.3).sub.3, —COCH.sub.2OH, —COC(OH)(CH.sub.3).sub.2, —COCH(OH)CH.sub.3, —CONH.sub.2, —CONHCH.sub.3, —CON(CH.sub.3).sub.2, —CH.sub.2CONH.sub.2, —CH.sub.2CON(CH.sub.3).sub.2, —C(CH.sub.3).sub.2CONH.sub.2, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2, —NHCOCH.sub.3, —N(CH.sub.3)COCH.sub.3, —NHS(O).sub.2CH.sub.3, —N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2, ═O, —OH, —OCH.sub.3, —S(O).sub.2N(CH.sub.3).sub.2, —SCH.sub.3, —S(O).sub.2CH.sub.3, —C(O)-cyclopropyl, cyclopropyl, cyclobutyl, oxetanyl or morpholinyl.

6. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is ##STR00097## Rx and Ry are each —N(CH.sub.3).sub.2, —S(O).sub.2CH.sub.3 or C.sub.1-4 alkyl, wherein the C.sub.1-4 alkyl is unsubstituted or substituted with at least one substituent, the substituent is halogen, hydroxyl, —CONH.sub.2, —CF.sub.3, amino or —OCH.sub.3.

7. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is ##STR00098##

8. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.3 is ##STR00099## and wherein R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are each independently hydrogen or C.sub.1-4 alkyl.

9. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 8 or a pharmaceutically acceptable salt thereof, wherein R.sub.3 is morpholinyl or (S)-3-methylmorpholinyl.

10. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.4 is —NH.sub.2, —NHCONHR.sub.11 or —NHCO.sub.2R.sub.12, wherein R.sub.11 and R.sub.12 are each independently C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl or phenyl which is unsubstituted or substituted with at least one substituent selected from at least one of fluoro, chloro, bromo and —C(O)OR.sub.13, wherein R.sub.13 is C.sub.1-4 alkyl.

11. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 10 or a pharmaceutically acceptable salt thereof, wherein R.sub.11 and R.sub.12 are each independently methyl, ethyl, isopropyl, cyclopropyl, phenyl, -Ph-CO.sub.2Et-p or 4-fluorophenyl.

12. The 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by one of the following general formulas: ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##

13. A method of inhibiting an activity of a PI3K kinase, the method comprising reacting the 7-substituted pyrrolo[2,1-f][1,2,4]triazine compound represented by the general formula I of claim 1 or a pharmaceutically acceptable salt thereof with the PI3K kinase.

14. The method according to claim 13, wherein the PI3K kinase is a PI3Kδ kinase.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) The term “alkyl” described herein refers to a straight alkyl or branched alkyl.

(2) The term “substitute” or the like described herein refers to substituting one or more hydrogen atoms. The halogen herein may be selected from at least one of F, Cl, Br and I, preferably at least one of F and Cl.

(3) The present disclosure will be further described below with reference to the embodiments, but these embodiments are by no means a limitation to the present disclosure. In all examples, .sup.1H NMR was recorded by Brucher AM-400 and GEMINI-300 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm); mass spectra were recorded by MAT-95 mass spectrometer; the silica gel for separation was 200-300 mesh.

Step a: Preparation of ethyl 4-cyano-5-methyl-1H-pyrrole-2-carboxylate (Aa2′)

(4) ##STR00019##

(5) To a solution of compound Aa1′ (1.0 g, 6.5 mmol) and DMF (1.3 mL) in anhydrous acetonitrile (20 mL) in an ice bath was added dropwise chlorosulfonyl isocyanate (0.7 mL, 8.0 mmol), then the mixture was moved to room temperature and reacted overnight. The reaction was quenched with saturated sodium carbonate solution (20 mL), diluted with water, then extracted twice with ethyl acetate (50 mL), the organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude product, which was then purified by chromatographic column (petroleum ether/ethyl acetate: 3/1) to give a white compound (980 mg, 84%).

(6) .sup.1H NMR (300 MHz, CDCl.sub.3) δ10.07 (br s 1H), 7.03 (d, J=2.53 Hz, 1H), 4.34 (q, J=7.13 Hz, 2H), 2.47 (s, 3H), 1.37 (t, J=7.13 Hz, 3H).

Step c: Preparation of ethyl 1-amino-4-cyano-5-methyl-1H-pyrrole-2-carboxylate (Aa3′)

(7) ##STR00020##

(8) To a solution of compound Aa2′ (200 mg, 1.1 mmol), K.sub.2CO.sub.3 (840 mg, 6.0 mmol), NH.sub.4Cl (385 mg, 7.2 mmol), concentrated aqueous ammonia (1.2 mL) and methyltrioctyl ammonium chloride (0.010 mL) in methyl tert-butyl ether (50 mL) in an ice salt bath was added dropwise 5% (mass percentage) sodium hypochlorite solution (12 mL) via a constant pressure dropping funnel, then the mixture was moved to room temperature and reacted for 4 hours. The reaction was quenched with saturated sodium thiosulfate, the methyl tert-butyl ether layer was separated and the aqueous layer was extracted once with ethyl acetate (50 mL), then the organic layers were combined, washed three times with water and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude product. The crude product was purified by chromatographic column (petroleum ether/ethyl acetate: 4/1) to give a colorless liquid (183 mg, 86%), which then solidified after standing.

(9) 1H NMR (300 MHz, CDCl.sub.3) δ 7.01 (s, 1H), 5.46 (s, 2H), 4.30 (q, J=7.13 Hz, 2H), 2.42 (s, 3H), 1.35 (t, J=7.13 Hz, 3H).

Step e: Preparation of 1-amino-4-cyano-5-methyl-1H-pyrrole-2-carboxamide (Aa4′)

(10) ##STR00021##

(11) The compound Aa3′ (800 mg, 4.1 mmol) was dissolved in 100 mL of saturated methanolic ammonia solution or solution of ammonia in methanol, the mixture reacted at 80° C. for 2 days in a sealed tube, then cooled to room temperature, and concentrated to give a yellow solid (680 mg, 100%).

(12) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.01 (br s, 1H), 7.39 br (s, 1H), 7.02 (s, 1H), 6.70 (br s, 2H), 2.27 (s, 3H).

Step b: Preparation of ethyl 4-cyano-5-chloro-1H-pyrrole-2-carboxylate (Aa2″)

(13) ##STR00022##

(14) The compound Aa1″ (2.0 g, 12.2 mmol) was dissolved in chloroform, and N-chlorosuccinimide (2.0 g, 15.0 mmol) was added, then the mixture was stirred overnight at room temperature; the mixture was diluted with water (100 mL), the organic layer was separated and the aqueous layer was extracted twice with chloroform (100 mL), then the organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude product, which was then purified by chromatographic column (petroleum ether/ethyl acetate: 20/1) to give a white solid (510 mg, 22%).

(15) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.68 (s, 1H), 7.09 (d, J=2.8 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).

Step d: Preparation of ethyl 1-amino-4-cyano-5-chloro-1H-pyrrole-2-carboxylate (Aa3″)

(16) ##STR00023##

(17) The compound Aa2″ (300 mg, 1.5 mmol) was dissolved in anhydrous DMF (10 mL), then NaH (60%, dispersed in mineral oil, 75 mg, 1.9 mmol) was added in an ice bath, after continuing stirring the mixture for 30 minutes, O-(2,4-dinitrophenyl)-hydroxylamine (360 mg, 1.8 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Then the reaction solution was poured into water (50 mL), extracted twice with ethyl acetate (50 mL), the organic layers were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (petroleum ether/ethyl acetate: 10/1) to give a white solid (305 mg, 95%).

(18) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.09 (s, 1H), 5.80 (s, 2H), 4.34 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).

Step e: Preparation of 1-amino-4=cyano-5-chloro-1H-pyrrole-2=carboxamide (Aa4″)

(19) ##STR00024##

(20) Using compound Aa3″ (350 mg, 1.6 mmol) as a raw material to perform a preparation process with reference to that of compound Aa4′, a yellow solid (290 mg, 100%) was obtained.

(21) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.12 (br s, 1H), 7.63 (br s, 1H), 7.19 (s, 1H), 6.86 (br s, 2H).

Step f: Synthesis of Compound Aa5

(22) ##STR00025##

(23) A solution of compound Aa4 (1.0 equiv.), N-(5-formyl-4-(trifluoromethyl) pyridyl-2-)pivalamide (1.2 equiv., prepared by our research group) and anhydrous copper chloride (1.0 equiv.) in dimethylsulfoxide was warmed to 100° C. for reaction. After the reaction was completed, the reaction mixture was cooled, poured into water, and extracted three times with ethyl acetate. The organic layers were combined, washed once with saturated brine and dried over anhydrous sodium sulfate, concentrated and then purified by column chromatography (dichloromethane/methanol: 50/1) to give a yellow solid.

(24) ##STR00026##

(25) Compound Aa4′ (600 mg, 3.7 mmol), the corresponding aldehyde (1.2 g, 4.4 mmol), anhydrous copper chloride (490 mg, 3.7 mmol), dimethylsulfoxide (25 mL); to give a yellow solid (1.3 g, 85%).

(26) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.82 (s, 1H), 8.62 (s, 1H), 8.43 (br s, 1H), 7.27 (s, 1H), 2.60 (s, 3H), 1.38 (s, 9H).

(27) ##STR00027##

(28) Compound Aa4″ (200 mg, 1.1 mmol), the corresponding aldehyde (362 mg, 1.3 mmol), anhydrous copper chloride (150 mg, 1.1 mmol), dimethylsulfoxide (15 mL); to give a yellow solid (408 mg, 85%).

(29) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.80 (s, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.36 (s, 1H), 1.38 (s, 9H).

Steps g and h: Synthesis of Compound Aa7

(30) ##STR00028##

(31) To a mixture of compound Aa5 (1.0 equiv.) and 4-dimethylaminopyridine (2.0 equiv.) was added phosphorus oxychloride and refluxed for 10 hours. After the mixture was cooled, the phosphorus oxychloride was removed under reduced pressure, then anhydrous tetrahydrofuran and morpholine were sequentially added, and then the mixture was refluxed for 2 hours. Tetrahydrofuran was distilled off under reduced pressure, water was added, then the mixture was extracted with ethyl acetate and washed once in turn with saturated brine and water, dried over anhydrous sodium sulfate, concentrated and then purified by column chromatography (petroleum ether/ethyl acetate: 4/1) to give a white solid.

(32) ##STR00029##

(33) Compound Aa5′ (1.0 g, 2.4 mmol), 4-dimethylaminopyridine (583 mg, 4.8 mmol), phosphorus oxychloride (20 mL), tetrahydrofuran (100 mL), morpholine (5 mL); to give a white solid (980 mg, 84%).

(34) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.76 (s, 1H), 8.72 (s, 1H), 8.24 (br s, 1H), 6.99 (s, 1H), 4.06 (t, J=4.77 Hz, 4H), 3.84 (t, J=4.73 Hz, 4H), 2.65 (s, 3H), 1.36 (s, 9H).

(35) ##STR00030##

(36) Compound Aa5″ (360 mg, 0.8 mmol), 4-dimethylaminopyridine (200 mg, 1.6 mmol), phosphorus oxychloride (5 mL), tetrahydrofuran (50 mL), morpholine (2 mL); to give a white solid (370 mg, 88%).

(37) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.75 (s, 1H), 8.72 (s, 1H), 8.24 (s, 1H), 7.09 (s, 1H), 4.07 (t, J=4.8 Hz, 4H), 3.86 (t, J=4.8 Hz, 4H), 1.36 (s, 9H).

(38) ##STR00031##

(39) Compound Aa5′ (800 mg, 1.9 mmol), 4-dimethylaminopyridine (466 mg, 3.8 mmol), phosphorus oxychloride (15 mL), tetrahydrofuran (100 mL), (S)-3-methylmorpholine (5 mL); to give a yellow solid (720 mg, 76%).

Step i: Synthesis of Compound Aa8

(40) ##STR00032##

(41) To a suspension of compound Aa7 (1.0 equiv.) and sodium hypophosphite monohydrate (6.7 equiv.) in acetic acid/water/pyridine (v/v/v: 1/1/2) was added Raney nickel, and the mixture was warmed to 60° C. for reaction. The reaction mixture was cooled to room temperature and filtered, extracted with ethyl acetate, washed with 3N hydrochloric acid for three times, concentrated and then purified by column chromatography (dichloromethane/methanol: 50/1) to give a yellow solid.

(42) ##STR00033##

(43) Compound Aa7′ (1.0 g, 1.0 mmol), sodium hypophosphite monohydrate (710 mg, 6.7 mmol), acetic acid/water/pyridine (v/v/v: 1/1/2) (50 mL), Raney nickel (750 mg), to give a yellow solid (232 mg, 47%).

(44) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 10.15 (s, 1H), 8.78 (br s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 7.17 (s, 1H), 4.10 (t, J=4.8 Hz, 8H), 3.84 (t, J=4.8 Hz, 8H), 2.79 (s, 3H), 1.36 (s, 9H).

(45) ##STR00034##

(46) Compound Aa7″ (300 mg, 0.6 mmol), sodium hypophosphite monohydrate (426 mg, 4.0 mmol), acetic acid/water/pyridine (v/v/v: 1/1/2) (25 mL), Raney nickel (450 mg), to give a yellow solid (130 mg, 42%).

(47) ##STR00035##

(48) Compound Aa7′″ (600 mg, 1.2 mmol), sodium hypophosphite monohydrate (852 mg, 8.0 mmol), acetic acid/water/pyridine (v/v/v: 1/1/2) (50 mL), Raney nickel (900 mg), to give a yellow solid (420 mg, 83%).

Step j: Synthesis of Compounds P-(1-9), 12, (29-32), (34-35), (38-43), (45-46)

(49) ##STR00036##

(50) Compound Aa8 (0.2 mmol), sodium cyanoborohydride (0.4 mmol) and the corresponding amine (0.24 mmol) were suspended in methanol (20 mL), acetic acid (0.05 mL) was added, and then the mixture was stirred at room temperature. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (dichloromethane/methanol: 40/1) to give a product.

(51) The resulting product was dissolved in methanol (15 mL), added 10 equivalents of 1M potassium hydroxide solution, and refluxed. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol: 40/1).

(52) ##STR00037##

(53) Yellow solid (38 mg, total yield of two steps: 44%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.62 (s, 1H), 6.80 (s, 1H), 6.73 (s, 1H), 4.90 (br s, 2H), 4.03 (t, J=4.5 Hz, 4H), 3.81 (t, J=4.5 Hz, 4H), 3.50 (s, 2H), 2.48 (s, 3H), 2.28 (s, 6H).

(54) ##STR00038##

(55) Yellow solid (44 mg, total yield of two steps: 45%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.63 (s, 1H), 6.80 (s, 1H), 6.77 (s, 1H), 4.89 (br s, 2H), 4.04 (br s, 4H), 3.87 (s, 2H), 3.82 (br s, 4H), 2.77 (t, J=3.3 Hz, 2H), 2.49 (s, 3H), 2.35 (t, J=6.3 Hz, 2H), 2.23 (s, 6H), 1.80-1.64 (m, 2H).

(56) ##STR00039##

(57) Yellow solid (49 mg, total yield of two steps: 52%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.62 (s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 4.88 (br s, 2H), 4.04 (t, J=3.9 Hz, 4H), 3.91-3.73 (m, 6H), 3.46 (t, J=6.7 Hz, 2H), 3.32 (s, 3H), 2.77 (t, J=6.8 Hz, 2H), 2.49 (s, 3H), 1.89-1.72 (m, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.83, 153.94, 151.95, 151.83, 138.11 (q, J=32.4 Hz), 126.24, 122.95 (q, J=274.3 Hz), 122.44, 121.65, 111.79, 105.21 (q, J=5.5 Hz), 103.35, 71.40, 66.81, 58.71, 47.06, 45.94, 45.66, 29.90, 9.24.

(58) ##STR00040##

(59) Yellow solid (38 mg, total yield of two steps: 38%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.63 (s, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 4.84 (br s, 2H), 4.03 (t, J=4.9 Hz, 4H), 3.82 (t, J=4.8 Hz, 4H), 3.63 (s, 2H), 3.53 (t, J=5.6 Hz, 2H), 3.35 (s, 3H), 2.63 (t, J=5.6 Hz, 2H), 2.48 (s, 3H), 2.33 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 158.77, 153.94, 151.95, 151.77, 138.13 (q, J=32.8 Hz), 127.07, 122.28 (q, J=275.7 Hz), 121.72, 120.25, 111.93, 105.22 (q, J=5.6 Hz), 104.45, 70.60, 66.81, 58.92, 56.06, 54.13, 45.91, 42.68, 9.36.

(60) ##STR00041##

(61) Yellow solid (68 mg, total yield of two steps: 64%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.65 (s, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 4.94-4.88 (m, 2H), 4.06 (t, J=4.6 Hz, 4H), 3.84 (t, J=4.8 Hz, 4H), 3.59 (s, 2H), 3.06 (d, J=10.7 Hz, 2H), 2.51 (s, 3H), 1.97 (t, J=11.3 Hz, 2H), 1.81-1.67 (m, 2H), 1.35-1.25 (m, 3H), 1.19 (s, 6H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.79, 153.93, 151.95, 151.77, 138.12 (q, J=32.3 Hz), 127.33, 122.95 (q, J=274.5 Hz), 121.68, 120.06, 111.82, 105.23 (q, J=6.2 Hz), 104.54, 72.47, 66.81, 54.58, 54.06, 47.40, 45.93, 27.00, 26.84, 9.48.

(62) ##STR00042##

(63) Yellow solid (58 mg, total yield of two steps: 58%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.62 (s, 1H), 6.80 (s, 1H), 6.69 (s, 1H), 4.84 (br s, 2H), 4.03 (t, J=4.8 Hz, 4H), 3.82 (t, J=4.8 Hz, 4H), 3.57 (s, 2H), 2.68-2.45 (m, 8H), 2.41 (q, J=7.2 Hz, 2H), 1.07 (t, J=7.2 Hz, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.78, 153.94, 151.93, 151.79, 138.15 (q, J=32.5 Hz, CF.sub.3C), 127.42, 122.94 (q, J=274.4 Hz, CF.sub.3), 121.71, 119.89, 111.77, 105.23 (q, J=5.5 Hz, CF.sub.3CCH), 104.57, 66.81, 54.42, 52.97, 52.83, 52.28, 45.94, 12.01, 9.45.

(64) ##STR00043##

(65) Yellow solid (55 mg, total yield of two steps: 53%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.64 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 4.99 (br s, 2H), 4.04 (t, J=4.8 Hz, 4H), 3.83 (t, J=4.8 Hz, 4H), 3.56 (s, 2H), 3.09-2.86 (m, 2H), 2.50 (s, 3H), 2.29 (s, 6H), 2.21-2.07 (m, 1H), 2.05-1.93 (m, 2H), 1.87-1.75 (m, 2H), 1.65-1.44 (m, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.88, 153.92, 151.93, 151.77, 138.07 (q, J=32.5 Hz), 127.26, 122.95 (q, J=274.6 Hz), 121.58, 120.29, 111.78, 105.21 (q, J=5.7 Hz), 104.45, 66.80, 62.32, 54.34, 52.93, 45.92, 41.72, 28.29, 9.45.

(66) ##STR00044##

(67) Yellow solid (46 mg, total yield of two steps: 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.62 (s, 1H), 6.81 (s, 2H), 4.87 (br s, 2H), 4.05 (t, J=4.8 Hz, 4H), 3.83 (t, J=4.8 Hz, 4H), 3.70 (s, 2H), 2.85 (s, 4H), 2.78 (s, 4H), 2.49 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.82, 153.96, 152.08, 151.89, 138.16 (q, J=32.3 Hz), 127.58, 122.93 (q, J=274.6 Hz), 121.55, 112.14, 105.29 (q, J=5.4 Hz), 105.03, 66.80, 54.99, 54.49, 45.96, 27.36, 9.47.

(68) ##STR00045##

(69) Yellow solid (79 mg, total yield of two steps: 72%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.62 (s, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 4.84 (br s, 2H), 4.03 (t, J=4.5 Hz, 4H), 3.82 (t, J=4.9 Hz, 4H), 3.60 (s, 2H), 3.24 (t, J=5.0 Hz, 4H), 2.77 (s, 3H), 2.58 (t, J=4.9 Hz, 4H), 2.49 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.83, 153.95, 151.99, 151.95, 138.12 (q, J=32.4 Hz, CF.sub.3C), 127.42, 122.95 (q, J=274.4 Hz, CF.sub.3), 121.57, 119.23, 111.90, 105.25 (q, J=5.5 Hz, CF.sub.3CCH), 104.48, 66.79, 54.26, 52.19, 45.95, 45.84, 34.28, 9.44.

(70) ##STR00046##

(71) To a solution of compound P-9 (160 mg, 0.3 mmol) in chloroform (10 mL) was added methanesulfonic acid (370 μL, 0.3 mmol). After 2 hours of reaction at room temperature, the reaction mixture was diluted with anhydrous ether (50 mL), filtered and dried to give P-9 methane sulfonate (145 mg, 77%) as a yellow compound.

(72) .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.89 (br s, 1H), 8.51 (s, 1H), 7.25 (s, 1H), 7.23 (s, 1H), 4.47 (br s, 2H), 4.02 (t, J=5.0 Hz, 4H), 3.76 (t, J=4.9 Hz, 4H), 3.73 (s, 2H), 3.57-3.47 (m, 2H), 3.30-3.09 (m, 4H), 3.01 (s, 3H), 2.52 (br s, 2H), 2.43 (br s, 6H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 157.47, 153.93, 151.45, 145.46, 138.57 (q, J=33.3 Hz), 129.45, 122.77 (q, J=275.06 Hz), 118.65, 112.36, 111.92, 110.13, 107.64, 66.42, 51.32, 50.27, 46.01, 42.96, 40.23, 35.51, 9.65.

(73) ##STR00047##

(74) Yellow solid (63 mg, total yield of two steps: 53%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.63 (s, 1H), 6.83 (s, 1H), 6.70 (s, 1H), 4.99 (br s, 2H), 4.24-3.98 (m, 4H), 3.96-3.78 (m, 4H), 3.60 (s, 2H), 3.46 (br s, 4H), 2.51 (s, 3H), 2.44 (br s, 4H), 1.47 (s, 9H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.91, 154.77, 153.94, 151.85, 151.72, 138.18 (q, J=32.6 Hz), 127.40, 122.93 (q, J=274.1 Hz), 121.50, 119.51, 111.85, 105.39 (q, J=5.6 Hz), 104.52, 79.65, 66.79, 54.45, 52.74, 45.93, 28.43, 9.45.

(75) ##STR00048##

(76) Yellow solid (45 mg, total yield of two steps: 43%). .sup.1H NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 6.80 (s, 1H), 6.70 (s, 1H), 4.84 (d, J=7.5 Hz, 2H), 4.06-4.00 (m, 4H), 3.95 (d, J=11.4 Hz, 2H), 3.83-3.80 (m, 4H), 3.65 (s, 2H), 3.47 (t, J=7.5 Hz, 2H), 3.36 (t, J=11.7 Hz, 2H), 2.88 (t, J=7.3 Hz, 2H), 2.32-2.16 (m, 2H), 1.71-1.57 (m, 2H), 1.52 (ddd, J=13.2, 3.8, 1.9 Hz, 2H).

(77) ##STR00049##

(78) Yellow solid (40 mg, total yield of two steps: 41%). .sup.1H NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 6.81 (s, 1H), 6.65 (s, 1H), 4.85 (d, J=5.3 Hz, 2H), 4.75 (s, 4H), 4.05-4.00 (m, 4H), 3.82 (t, J=4.9 Hz, 4H), 3.61 (s, 2H), 3.42 (s, 3H), 2.48 (s, 4H).

(79) ##STR00050##

(80) Yellow solid (36 mg, total yield of two steps: 32%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.61 (s, 1H), 6.79 (s, 1H), 6.72 (s, 1H), 4.90 (d, J=5.8 Hz, 2H), 4.02 (t, J=4.7 Hz, 4H), 3.81 (t, J=4.8 Hz, 5H), 3.73-3.68 (m, 4H), 3.57 (s, 2H), 3.00 (d, J=11.1 Hz, 2H), 2.58-2.46 (m, 8H), 2.18 (dq, J=11.2, 5.9, 4.2 Hz, 1H), 2.01 (t, J=11.1 Hz, 2H), 1.82 (d, J=13.4 Hz, 2H), 1.58 (td, J=12.1, 3.6 Hz, 2H).

(81) ##STR00051##

(82) The corresponding amine was synthesized by taking reference to WO2010138589 (A1). Yellow solid (20 mg, total yield of two steps: 18%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 7.74-7.50 (m, 1H), 6.81 (s, 1H), 4.84 (s, 2H), 4.67-4.60 (m, 2H), 4.59-4.51 (m, 2H), 4.32-4.13 (m, 2H), 4.10-3.98 (m, 4H), 3.83 (t, J=4.9 Hz, 4H), 2.92-2.74 (m, 1H), 2.50 (s, 3H), 2.21 (d, J=7.7 Hz, 2H), 2.06-1.97 (m, 4H), 1.00-0.84 (m, 6H).

(83) ##STR00052##

(84) Yellow solid (52 mg, total yield of two steps: 52%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.62 (s, 1H), 6.80 (s, 1H), 6.67 (d, J=1.3 Hz, 1H), 4.84 (d, J=4.0 Hz, 2H), 4.08-3.98 (m, 4H), 3.81 (t, J=4.8 Hz, 4H), 3.62 (s, 2H), 3.37 (dd, J=4.3, 1.5 Hz, 8H), 2.47 (d, J=1.5 Hz, 3H), 2.32 (d, J=1.5 Hz, 3H).

(85) ##STR00053##

(86) The corresponding amine was synthesized by taking reference to WO2010138589 (A1). Yellow solid (75 mg, total yield of two steps: 67%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 7.14 (d, J=5.3 Hz, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 5.54 (d, J=5.3 Hz, 1H), 4.93 (s, 2H), 4.03 (dd, J=5.7, 4.0 Hz, 4H), 3.82 (dd, J=5.7, 4.0 Hz, 4H), 3.58 (s, 2H), 2.59-2.52 (m, 6H), 2.49 (s, 3H), 1.20 (s, 8H).

(87) ##STR00054##

(88) Yellow solid (49 mg, total yield of two steps: 47%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 6.85 (s, 1H), 6.81 (s, 1H), 4.86 (s, 2H), 4.04 (t, J=4.9 Hz, 4H), 3.82 (q, J=4.8, 3.6 Hz, 8H), 3.58 (t, J=5.3 Hz, 4H), 3.28-3.25 (m, 2H), 2.51 (s, 3H), 1.81 (t, J=5.6 Hz, 4H).

(89) ##STR00055##

(90) The corresponding amine was synthesized by taking reference to WO2010138589 (A1). Yellow solid (47 mg, total yield of two steps: 44%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 6.80 (s, 1H), 6.77 (s, 1H), 4.88 (s, 2H), 4.03 (dd, J=5.7, 4.1 Hz, 4H), 3.82 (dd, J=5.6, 4.0 Hz, 4H), 3.75 (d, J=1.5 Hz, 2H), 3.47 (s, 2H), 3.42 (d, J=12.1 Hz, 2H), 3.32 (d, J=10.1 Hz, 1H), 3.20 (d, J=10.2 Hz, 1H), 3.01 (s, 1H), 2.78 (dd, J=9.2, 2.4 Hz, 1H), 2.66 (d, J=2.4 Hz, 2H), 2.50 (s, 3H), 2.24-2.14 (m, 1H), 1.75 (d, J=9.7 Hz, 1H), 1.51 (d, J=9.7 Hz, 1H).

(91) ##STR00056##

(92) Yellow solid (56 mg, total yield of two steps: 51%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 7.62 (s, 1H), 6.82 (s, 1H), 4.97 (s, 2H), 4.74 (t, J=6.3 Hz, 1H), 4.67 (d, J=6.4 Hz, 1H), 4.55-4.44 (m, 2H), 4.26-4.14 (m, 2H), 4.07 (dd, J=5.7, 4.0 Hz, 4H), 4.03-3.87 (m, 2H), 3.86-3.80 (m, 4H), 3.49 (s, 1H), 3.35 (d, J=11.7 Hz, 1H), 2.82-2.62 (m, 1H), 2.51 (s, 3H), 2.21 (t, J=7.6 Hz, 1H), 2.04-1.97 (m, 2H), 0.90-0.82 (m, 1H).

(93) ##STR00057##

(94) The corresponding amine was synthesized by taking reference to WO2010138589(A1). Yellow solid (53 mg, total yield of two steps: 47%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 6.81 (s, 1H), 6.77 (s, 1H), 4.81 (s, 2H), 4.03 (dd, J=5.7, 4.1 Hz, 4H), 3.83-3.81 (m, 4H), 3.72 (d, J=4.7 Hz, 4H), 3.60 (s, 2H), 3.04 (s, 3H), 2.50 (s, 3H), 2.32 (d, J=5.3 Hz, 4H), 1.70 (s, 6H).

(95) ##STR00058##

(96) The corresponding amine was synthesized by taking reference to WO2010138589(A1). Yellow solid (52 mg, total yield of two steps: 48%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J=3.7 Hz, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 4.88 (s, 2H), 4.03 (dq, J=6.3, 2.8, 2.3 Hz, 4H), 3.85-3.79 (m, 4H), 3.59 (s, 2H), 3.34 (s, 2H), 2.67-2.42 (m, 15H), 1.04 (s, 6H).

(97) ##STR00059##

(98) The corresponding amine was synthesized by taking reference to WO2010138589(A1). Yellow solid (52 mg, total yield of two steps: 48%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 6.80 (s, 1H), 4.86 (s, 2H), 4.04 (dd, J=5.7, 4.1 Hz, 4H), 3.84-3.79 (m, 4H), 3.62 (s, 2H), 3.16 (d, J=1.4 Hz, 2H), 3.09-3.04 (m, 2H), 2.48 (d, J=1.5 Hz, 3H), 2.02 (d, J=13.2 Hz, 2H), 1.67 (d, J=8.8 Hz, 2H), 1.45 (s, 2H), 1.08 (s, 6H).

(99) ##STR00060##

(100) The corresponding amine was synthesized by taking reference to WO2013134226. Yellow solid (50 mg, total yield of two steps: 43%). LC-MS m/z: [M+H].sup.+=588.0.

(101) ##STR00061##

(102) The corresponding amine was synthesized by taking reference to WO2013134226. Yellow solid (61 mg, total yield of two steps: 48%). LC-MS m/z: [M+H].sup.+=641.9.

Step j: Synthesis of Compounds P-33, 36, 37

(103) ##STR00062##

(104) Compound Aa8 (0.2 mmol), sodium cyanoborohydride (0.4 mmol) and the corresponding Boc-protected amine (0.24 mmol) were suspended in methanol (20 mL), acetic acid (0.05 mL) was added, and then the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (dichloromethane/methanol: 40/1) to give a product.

(105) The product was dissolved in dichloromethane (10 mL), and 10-fold equivalent of trifluoroacetic acid was added, then the mixture was stirred at room temperature for 2 days, and then evaporated directly after the reaction was completed.

(106) The resulting product was dissolved in methanol (15 mL), and 10 equivalents of 1M potassium hydroxide solution were added, then the mixture was refluxed. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol: 40/1).

(107) ##STR00063##

(108) Yellow solid (52 mg, total yield of two steps: 50%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 6.81 (s, 1H), 6.68 (d, J=3.4 Hz, 1H), 4.83 (s, 2H), 4.03 (t, J=4.8 Hz, 4H), 3.82 (t, J=5.0 Hz, 4H), 3.49 (d, J=3.3 Hz, 2H), 3.36 (s, 2H), 2.47 (d, J=3.4 Hz, 3H), 2.34 (s, 2H), 1.93 (s, 4H), 1.79 (t, J=5.3 Hz, 4H).

(109) ##STR00064##

(110) Yellow solid (50 mg, total yield of two steps: 48%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 6.79 (s, 1H), 6.67 (s, 1H), 4.90 (s, 2H), 4.02 (dd, J=5.7, 4.1 Hz, 4H), 3.84-3.77 (m, 4H), 3.67 (s, 2H), 3.05 (s, 4H), 2.77 (dd, J=6.6, 4.0 Hz, 4H), 2.49 (s, 3H, 1.76-1.69 (m, 4H).

(111) ##STR00065##

(112) Yellow solid (45 mg, total yield of two steps: 46%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J=2.0 Hz, 1H), 6.81 (s, 1H), 6.65 (d, J=3.8 Hz, 1H), 4.80 (s, 2H), 4.03 (q, J=4.1, 3.2 Hz, 4H), 3.82 (t, J=4.8 Hz, 4H), 3.74 (s, 2H), 3.60 (d, J=2.5 Hz, 2H), 3.35 (s, 3H), 3.30 (d, J=8.3 Hz, 2H), 2.51-2.46 (m, 4H).

Step j: Synthesis of Compound P-44

(113) ##STR00066##

(114) Compound Aa8 (0.2 mmol), sodium cyanoborohydride (0.4 mmol) and N-acetyl-2-(4-piperidyl)-2-propylamine (0.24 mmol) were suspended in methanol (20 mL), and acetic acid (0.05 mL) was added, then the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (dichloromethane/methanol: 40/1) to give a product.

(115) The resulting product was dissolved in concentrated hydrochloric acid (10 mL), and refluxed for 7 days. After the reaction was completed, the reaction mixture was neutralized and purified by column chromatography (dichloromethane/methanol: 10/1).

(116) ##STR00067##

(117) N-acetyl-2-(4-piperidyl)-2-propylamine was synthesized by taking reference to WO2014043068. Yellow solid (12 mg, total yield of two steps: 11%). LC-MS m/z: [M+H].sup.+=533.0.

Step j: Synthesis of Compound P-10

(118) ##STR00068##

(119) Compound Aa8″ (0.2 mmol), sodium cyanoborohydride (0.4 mmol) and the corresponding amine (0.24 mmol) were suspended in methanol (20 mL), and acetic acid (0.05 mL) was added, then the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (dichloromethane/methanol: 40/1) to give a product.

(120) The resulting product was dissolved in methanol (15 mL), and 10 equivalents of 1M potassium hydroxide solution were added, then the mixture was refluxed. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol: 40/1).

(121) ##STR00069##

(122) Yellow solid (55 mg, total yield of two steps: 48%). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.63 (d, J=3.1 Hz, 1H), 6.82 (d, J=3.1 Hz, 1H), 6.65 (s, 1H), 4.93 (br s, 1H), 4.83 (s, 2H), 4.56 (d, J=11.3 Hz, 1H), 4.09-3.97 (m, 1H), 3.89-3.74 (m, 2H), 3.72-3.53 (m, 4H), 3.26 (s, 4H), 2.78 (s, 3H), 2.60 (s, 4H), 2.49 (s, 3H), 1.45 (d, J=6.8 Hz, 3H). .sup.13C NMR (126 MHz, Chloroform-d) δ 158.81, 153.66, 152.06, 151.91, 138.12 (q, J=32.3 Hz), 127.41, 122.94 (d, J=274.5 Hz), 121.65, 111.92, 105.26 (d, J=6.7 Hz), 104.58, 71.03, 66.98, 54.26, 52.16, 45.83, 34.28, 15.27, 9.49.

Step j: Synthesis of Compounds P-11, (25-27)

(123) ##STR00070##

(124) Compound Aa8′″ (0.2 mmol), sodium cyanoborohydride (0.4 mmol) and the corresponding amine (0.24 mmol) were suspended in methanol (20 mL), and acetic acid (0.05 mL) was added, then the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (dichloromethane/methanol: 40/1) to give a product.

(125) The resulting product was dissolved in methanol (15 mL), and 10 equivalents of 1M potassium hydroxide solution were added, then the mixture was refluxed. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol: 40/1).

(126) ##STR00071##

(127) Yellow solid (34 mg, total yield of two steps: 30%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.59 (s, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 4.87 (br s, 2H), 4.04 (t, J=4.6 Hz, 4H), 3.83 (t, J=4.7 Hz, 4H), 3.67 (s, 2H), 3.27 (t, J=4.9 Hz, 4H), 2.78 (s, 2H), 2.64 (t, J=5.1 Hz, 4H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 159.02, 153.50, 153.30, 151.82, 138.25 (q, J=32.8 Hz), 122.85 (q, J=274.3 Hz), 120.96, 118.53, 115.86, 112.74, 105.24 (q, J=6.1 Hz), 104.61, 66.69, 53.04, 52.06, 46.00, 45.79, 34.38.

(128) ##STR00072##

(129) White solid (35 mg, yield: 45%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ8.31 (s, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 3.97 (m, 4H), 3.72 (m, 4H), 3.68 (s, 2H), 3.23 (s, 2H), 3.06 (d, 2H), 2.16 (t, 2H), 1.72 (d, 2H), 1.33 (m, 4H), 1.05 (s, 6H).

(130) ##STR00073##

(131) White solid (30 mg, yield: 40%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.32 (s, 1H), 6.94 (s, 1H), 6.83 (s, 1H), 3.97 (m, 4H), 3.72 (m, 4H), 3.55 (br, s, 1H), 3.22 (d, 2H), 2.92 (d, 2H), 2.23 (s, 6H), 2.03 (d, 2H), 1.78 (d, 2H), 1.47 (d, 2H), 1.18 (d, 2H).

(132) ##STR00074##

(133) White solid (38 mg, yield: 42%). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.30 (s, 1H), 6.97 (s, 1H), 6.83 (s, 1H), 4.00 (m, 4H), 3.73 (m, 4H), 3.65 (s, 2H), 3.23 (d, 2H), 2.66 (m, 4H), 1.16 (t, 3H).

Synthesis of Compounds P-13, 14

(134) ##STR00075##

(135) The compound P-12 (500 mg) was dissolved in 40 mL of dichloromethane, added 2.5 mL of trifluoroacetic acid, and then stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure to give an oil. The oil was dissolved by adding 10 mL of methanol, and added diethyl ether (80 mL) to precipitate a solid, which was filtered to give 420 mg of the trifluoroacetate salt of the Boc-deprotected product.

(136) The above obtained salt (calculated by containing one molecule of trifluoroacetic acid, 114 mg, 0.2 mmol), the corresponding acid (1.5 equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (1.5 equiv.), 1-hydroxybenzotriazole (HOBT) (1.5 equiv.) and N, N-diisopropylethylamine (DIPEA) (3 equiv.) were suspended in DMF, then reacted at room temperature. After the reaction was completed, the reaction mixture was diluted with water, and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and then purified by column chromatography (dichloromethane/methanol: 20/1) to give a product.

(137) ##STR00076##

(138) Yellow solid (67 mg, 60%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.65 (s, 1H), 6.84 (s, 1H), 6.68 (s, 1H), 4.91 (s, 2H), 4.53 (br s, 1H), 4.06 (t, J=4.8 Hz, 4H), 3.85 (t, J=4.8 Hz, 4H), 3.79-3.65 (m, 4H), 3.60 (s, 2H), 2.51 (s, 7H), 1.50 (s, 6H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 174.93, 158.85, 153.94, 151.94, 151.92, 138.12 (q, J=32.6 Hz), 127.36, 122.90 (q, J=274.06 Hz), 121.55, 119.38, 111.87, 105.27 (q, J=6.3 Hz), 104.42, 71.53, 66.79, 54.40, 52.96, 45.94, 27.83, 9.44.

(139) ##STR00077##

(140) Yellow solid (55 mg, 50%). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.66 (s, 1H), 6.84 (s, 1H), 6.68 (s, 1H), 4.87 (s, 2H), 4.47 (t, J=6.7 Hz, 1H), 4.07 (t, J=4.8 Hz, 4H), 3.90 (d, J=7.3 Hz, 1H), 3.86 (t, J=4.8 Hz, 4H), 3.82-3.71 (m, 1H), 3.69-3.62 (m, 1H), 3.61 (s, 1H), 3.43 (d, J=5.2 Hz, 2H), 2.58-2.35 (m, 7H), 1.34 (d, J=6.6 Hz, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 173.50, 158.83, 153.95, 151.97, 138.26, 138.13 (d, J=32.8 Hz), 127.37, 122.95 (q, J=274.6 Hz), 121.59, 119.28, 111.89, 105.27, 104.41, 66.79, 64.02, 54.42, 52.70, 52.56, 45.94, 44.87, 42.53, 21.50, 9.44.

Synthesis of Compound P-15

(141) ##STR00078##

(142) To a solution of compound Aa8′ (600 mg, 1.2 mmol) in anhydrous tetrahydrofuran (40 mL) was added 1M methylmagnesium bromide (4.8 mL, 4.8 mmol) in an ice bath under nitrogen protection, and the mixture was moved to room temperature for reaction. After the reaction was completed, the reaction mixture was diluted with 50 mL of water and extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography (dichloromethane/methanol: 40/1) to give a yellow compound (520 mg, 86%).

(143) The above obtained product (400 mg, 0.8 mmol) was dissolved in 15 mL of methanol, and 10 equivalents of 1M potassium hydroxide solution (8 mL) were added, then the mixture was reacted at reflux. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol=40/1) to give a yellow compound (270 mg, 80%).

(144) .sup.1H NMR (300 MHz, CDCl.sub.3). δ 8.59 (s, 1H), 6.80 (s, 1H), 6.75 (s, 1H), 5.14 (q, J=4.8 Hz, 1H), 4.82 (s, 2H), 4.04 (t, J=4.8 Hz, 4H), 3.82 (t, J=4.8 Hz, 4H), 2.53 (s, 3H), 1.99 (br s, 1H), 1.58 (d, J=6.4 Hz, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 158.78, 154.14, 152.05, 151.93, 128.13, 125.24, 111.85, 105.25 (q, J=5.5 Hz), 100.27, 66.80, 63.82, 45.97, 24.52, 9.38.

Synthesis of Compound P-16

(145) ##STR00079##

(146) To a solution of compound Aa8′ (100 mg, 0.2 mmol) in anhydrous dichloromethane (20 mL) was added 1 mL of diethylaminosulfur trifluoride (DAST) in an ice bath under nitrogen protection, and the mixture was moved to room temperature for reaction. After the reaction was completed, 10 mL of ice water was slowly added to quench, then the reaction mixture was diluted with water (50 mL) and extracted twice with dichloromethane (50 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then used directly in the next reaction.

(147) The above obtained product was dissolved in 15 mL of methanol, and 10 equivalents of 1M potassium hydroxide solution (2 mL) were added, then the mixture was reflux. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol=40/1) to give a yellow compound (38 mg, total yield of two steps: 44%).

(148) .sup.1H NMR (300 MHz, CDCl.sub.3). δ 8.63 (s, 1H), 6.86 (t, J=56.4 Hz, 1H), 6.85 (s, 1H), 6.82 (s, 1H), 4.85 (br s, 2H), 4.06 (t, J=4.9 Hz, 4H), 3.84 (t, J=4.8 Hz, 4H), 2.58 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 158.98, 154.52, 152.94, 151.96, 138.17 (q, J=32.6 Hz), 127.09 (t, J=6.3 Hz), 122.88 (q, J=274.3 Hz), 121.13, 117.39 (t, J=25.8 Hz), 112.40 (t, J=233.7 Hz), 112.24, 105.29 (q, J=6.1 Hz), 101.21 (t, J=5.0 Hz), 66.71, 45.96, 9.46.

Synthesis of Compounds P-17,18

(149) ##STR00080##

(150) To a solution of compound P-9 (110 mg, 0.2 mmol) in anhydrous chloroform (10 mL) was added anhydrous triethylamine (30 μL, 0.25 mmol) at −30° C., and a solution of the corresponding chloroformate (0.6 mmol) in chloroform (5 mL) was added dropwise, then the reaction was maintained at this temperature. After the reaction was completed, 10 mL of ice water was slowly added to quench, and dichloromethane (40 mL) was added to dilute. The organic layer was separated, washed once with saturated brine (50 mL) and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (dichloromethane/methanol: 50/1 to give a yellow solid.

(151) ##STR00081##

(152) Yellow solid (55 mg, 45%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.18 (br s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 6.68 (s, 1H), 4.05 (t, J=4.5 Hz, 4H), 3.86 (s, 3H), 3.84-3.78 (m, 4H), 3.62 (s, 2H), 3.25 (s, 4H), 2.78 (s, 3H), 2.59 (s, 4H), 2.50 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 153.87, 153.54, 152.67, 151.39, 150.80, 138.69 (q, J=32.9 Hz, CF.sub.3C), 127.50, 126.60, 122.72 (q, J=275.83 Hz, CF.sub.3), 119.55, 111.79, 109.21 (q, J=5.2 Hz, CF.sub.3CCH), 104.69, 66.70, 54.19, 52.72, 52.18, 45.89, 45.84, 34.22, 9.40.

(153) ##STR00082##

(154) Reference was made to the preparation method of the methane sulfonate of compound P-9. Using compound P-17 (200 mg, 0.3 mmol) as a raw material, the methane sulfonate (190 mg, 81%) of compound P-17 was obtained as a yellow compound.

(155) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.91 (s, 1H), 9.83 (br s, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 7.23 (s, 1H), 4.46 (s, 2H), 4.01 (t, J=4.8 Hz, 4H), 3.82-3.68 (m, 7H), 3.62-3.41 (m, 4H), 3.28-3.04 (m, 4H), 3.00 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 154.58, 154.11, 153.99, 152.04, 151.38, 136.87 (q, J=31.6 Hz, CF.sub.3C), 129.53, 125.47, 123.08 (q, J=274.9 Hz, CF.sub.3), 112.40, 112.00, 108.63 (q, J=6.9 Hz, CF.sub.3CCH), 107.63, 66.41, 52.76, 51.36, 50.31, 46.02, 42.98, 40.23, 35.54, 9.69.

(156) ##STR00083##

(157) Yellow solid (55 mg, 74%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.69 (s, 1H), 8.96 (s, 1H), 8.51 (s, 1H), 7.41 (t, J=7.2 Hz, 2H), 7.36-7.19 (m, 3H), 6.67 (s, 1H), 4.13-3.91 (m, 4H), 3.79 (s, 4H), 3.61 (s, 2H), 3.25 (s, 4H), 2.78 (s, 3H), 2.58 (s, 4H), 2.41 (s, 3H).

Synthesis of Compound P-19

(158) ##STR00084##

(159) In a 10 mL microwave reaction tube, compound P-17 (122 mg, 0.2 mmol), anhydrous calcium chloride (10 mg, 0.09 mmol) and methylamine methanolic solution (2 mL) were added, reacted at 100° C. for 30 minutes under microwave, concentrated and purified by thin layer chromatography (dichloromethane/methanol: 20/1) to gave a white solid (30 mg, 33%).

(160) .sup.1H NMR (400 MHz, CDCl.sub.3). δ 9.37 (s, 1H), 9.06 (br s, 1H), 8.74 (s, 1H), 7.28 (s, 1H), 6.68 (s, 1H), 4.05 (t, J=4.6 Hz, 4H), 3.84 (t, J=4.9 Hz, 4H), 3.61 (s, 2H), 3.25 (br s, 4H), 3.01 (d, J=4.6 Hz, 3H), 2.78 (s, 3H), 2.59 (br s, 4H), 2.50 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 156.42, 153.99 (q, J=13.5 Hz), 151.34, 149.71, 138.66, 138.39, 127.59, 124.36, 122.56 (q, J=274.93 Hz), 119.56, 111.84, 109.33 (q, J=5.4 Hz), 104.70, 66.78, 54.26, 52.23, 45.95, 45.90, 34.27, 26.54, 9.45.

Synthesis of Compound P-20

(161) ##STR00085##

(162) To a solution of compound P-18 (75 mg, 0.1 mmol) in DMF (3 mL) was added cyclopropylamine (1 mL), and the mixture was warmed to 60° C. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted twice with ethyl acetate (50 mL). The organic layers were combined, washed once with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated and then subjected to thin layer chromatography (dichloromethane/methanol: 40/1) to give a yellow compound (26 mg, 40%).

(163) .sup.1H NMR (400 MHz, CDCl.sub.3). δ 9.47 (br s, 1H), 9.09 (br s, 1H), 8.73 (s, 1H), 7.40 (s, 1H), 6.67 (s, 1H), 4.05 (t, J=4.7 Hz, 4H), 3.84 (t, J=4.8 Hz, 4H), 3.61 (s, 2H), 3.25 (t, J=4.7 Hz, 4H), 2.78 (br s, 4H), 2.59 (s, 4H), 2.49 (s, 3H), 0.95-0.78 (m, 2H), 0.71-0.61 (m, 2H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 156.70, 153.93, 153.85, 151.32, 149.81, 138.53 (q, J=33.2 Hz), 127.59, 124.65, 122.57 (q, J=274.7 Hz), 119.57, 111.83, 109.48 (q, J=6.6 Hz), 104.69, 66.77, 54.26, 52.23, 45.95, 45.90, 34.27, 22.58, 9.45, 6.80.

Synthesis of Compounds P-(21-24)

(164) ##STR00086##

(165) To a solution of compound P-9 (1 equiv.) and 1,8-diazacyclo[5.4.0]undec-7-ene (DBU, 6 equiv) in dichloromethane was added the corresponding isocyanate (6 equiv) and reacted at room temperature. After the reaction was completed, the reaction mixture was diluted with water, extracted once with dichloromethane, washed once with saturated brine and dried over anhydrous sodium sulfate, concentrated and then purified by column chromatography (dichloromethane/methanol: 50/1) to give a yellow solid.

(166) ##STR00087##

(167) By using compound P-9 (160 mg, 0.3 mmol) as a starting material, a yellow solid (54 mg, 29%) was obtained. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.62 (s, 1H), 8.71 (s, 1H), 8.08 (s, 1H), 7.45 (d, J=5.7 Hz, 1H), 6.92 (s, 1H), 3.96 (t, J=4.8 Hz, 4H), 3.73 (t, J=4.8 Hz, 4H), 3.56 (s, 2H), 3.18 (t, J=6.8 Hz, 2H), 3.08 (s, 4H), 2.85 (s, 3H), 2.48 (s, 4H), 2.42 (s, 3H), 1.09 (t, J=7.1 Hz, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 154.81, 154.58, 153.78, 151.31, 150.88, 136.71 (q, J=31.8 Hz), 127.20, 124.08, 123.23 (q, J=274.81 Hz), 120.27, 111.34, 108.29 (q, J=6.2 Hz), 106.21, 66.46, 53.80, 52.14, 45.94, 34.44, 34.06, 15.69, 9.67.

(168) ##STR00088##

(169) Reference was made to the preparation method of the methane sulfonate of compound P-9. By using compound P-21 (75 mg, 0.31 mmol) as a raw material, the methane sulfonate (70 mg, 81%) of compound P-21 was obtained as a yellow compound.

(170) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.80 (br s, 1H), 9.65 (s, 1H), 8.72 (s, 1H), 8.11 (s, 1H), 7.44 (br s, 1H), 7.20 (s, 1H), 4.45 (s, 2H), 4.13 (s, 2H), 4.01 (t, J=4.9 Hz, 4H), 3.75 (s, 6H), 3.49 (s, 2H), 3.27-3.03 (m, 7H), 3.00 (s, 3H), 2.37 (s, 3H), 1.09 (t, J=7.0 Hz, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 155.00, 154.56, 153.98, 152.13, 150.91, 136.74 (q, J=31.4 Hz), 129.46, 123.69, 123.29 (q, J=274.3 Hz), 112.39, 111.93, 108.36 (q, J=6.4 Hz), 107.53, 66.41, 51.36, 40.24, 50.30, 46.00, 42.99, 35.51, 34.45, 15.68, 9.69.

(171) ##STR00089##

(172) By using compound P-9 (160 mg, 0.3 mmol) as a starting material, a yellow solid (128 mg, 67%) was obtained. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 9.45 (s, 1H), 8.93 (br s, 1H), 8.74 (s, 1H), 7.30 (s, 1H), 6.67 (s, 1H), 4.10-4.16 (m, 1H), 4.05 (t, J=4.4 Hz, 4H), 3.84 (t, J=4.3 Hz, 4H), 3.61 (s, 2H), 3.25 (t, J=4.5 Hz, 4H), 2.78 (s, 3H), 2.59 (t, J=4.7 Hz, 4H), 2.50 (s, 3H), 1.30 (d, J=6.4 Hz, 6H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 155.16, 154.33, 153.93, 151.41, 149.67, 138.39 (q, J=32.9 Hz), 127.55, 124.19, 122.61 (q, J=274.4 Hz), 119.53, 111.83, 109.53 (q, J=5.6 Hz), 104.66, 66.78, 54.26, 52.23, 45.95, 45.91, 42.21, 34.25, 23.08, 9.45.

(173) ##STR00090##

(174) By using compound P-9 (110 mg, 0.2 mmol) as a starting material, a yellow solid (40 mg, 29%) was obtained. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 11.45 (s, 1H), 9.44 (s, 1H), 8.85 (s, 1H), 7.60 (dd, J=8.9, 4.7 Hz, 2H), 7.35 (s, 1H), 7.07 (t, J=8.2 Hz, 2H), 6.69 (s, 1H), 4.07 (br s, 4H), 3.86 (t, J=5.1 Hz, 4H), 3.63 (s, 2H), 3.26 (s, 4H), 2.79 (s, 3H), 2.60 (s, 4H), 2.52 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 159.29 (d, J=242.9 Hz), 153.74 (d, J=54.9 Hz), 153.50, 151.09, 149.67, 138.93 (q, J=32.9 Hz), 133.94 (q, J=2.9 Hz), 127.67, 125.13, 122.05 (q, J=7.8 Hz), 119.69, 115.66 (q, J=22.6 Hz), 111.82, 109.78, 104.83, 66.78, 54.27, 52.25, 45.96, 45.91, 34.28, 9.47.

(175) ##STR00091##

(176) By using compound P-9 (110 mg, 0.2 mmol) as a starting material, a yellow solid (46 mg, 31%) was obtained. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H), 9.92 (s, 1H), 8.82 (s, 1H), 8.22 (s, 1H), 7.91 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 6.94 (s, 1H), 4.27 (q, J=6.9 Hz, 2H), 3.97 (t, J=4.9 Hz, 4H), 3.82-3.66 (m, 4H), 3.57 (s, 2H), 3.08 (s, 4H), 2.85 (s, 3H), 2.48-2.43 (m, 7H), 1.30 (t, J=7.0 Hz, 3H). .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 165.79, 153.90, 153.79, 152.07, 151.17, 143.65, 136.95 (q, J=32.2 Hz), 130.89, 127.27, 125.30, 123.23 (q, J=274.93 Hz), 124.16, 120.35, 118.45, 111.35, 108.74, 106.31, 66.47, 60.89, 53.80, 52.14, 45.94, 34.07, 14.71, 9.68.

Synthesis of Compound P-28

(177) ##STR00092## ##STR00093##

(178) Step 1: P-28-1 (437.0 mg, 1.0 mmol, for the preparation method thereof, see CN201210177980.3) was dissolved in a mixture of dichloromethane:water (10:1, 20 mL), and then sodium trifluoromethylsulfinate (936.0 mg, 6 mmol) was added, the above system was cooled to 0° C. and 70% aqueous solution of t-butyl hydroperoxide (1.4 mL, 10.0 mmol) was slowly added dropwise. After the dropwise addition was completed, continuing stirring for 30 min; then dimethyl sulfoxide (4.0 mL) was added and warmed to 40° C. to react overnight. The end of the reaction was detected and analyzed by LC-MS. Dichloromethane and water were added and stirred, rested, and the organic phase was separated, dried and concentrated to give a crude product. The crude product was eluated by chromatography with petroleum ether:ethyl acetate (10:1 to 4:1) to give P-28-2 (300 mg). LC-MS: 506.2 (M+1).

(179) Step 2: P-28-2 (300 mg, 0.6 mmol) and phosphorus oxychloride (1.85 g, 11.9 mmol) were added to toluene (20 mL), then N, N-dimethylaniline (215.6 mg, 18.0 mmol) was added and refluxed overnight. After the reaction was completed by TCL analysis, the reaction system was concentrated. Then, ethyl acetate and ice water were added and stirred, and then the ethyl acetate phase was obtained by separation. The ethyl acetate phase was dried and concentrated to give a crude chlorinated compound. The crude chlorinated compound was dissolved in anhydrous tetrahydrofuran (10 mL), morpholine (155.0 mg, 1.8 mmol) was added at 0° C. and the mixture was stirred at room temperature until the raw materials consumed completely, then concentrated to give a crude product, which was used directly in the next step.

(180) Step 3: the crude product obtained from step 2 was dissolved in methanol (20 mL), then added water (1 mL) and sodium hydroxide (237.6 mg) and refluxed until the raw materials were completely disappeared, concentrated, added water, adjusted the pH value to 5-6 to precipitate a solid, dried and used directly in the next step. LC-MS: 477.2 (M+H).sup.+.

(181) Step 4: the crude product from step 3, HBTU (455.0 mg, 1.2 mmol), triethylamine (121 mg, 1.2 mmol) and 2-(4-piperidyl)-2-propanol (Aa9′, 93.2 mg, 0.65 mmol) were added to DMF (10 mL) and reacted at room temperature overnight. The end of the reaction was monitored by LC-MS. The reaction system was poured into ice water and extracted with ethyl acetate. The organic phase was dried, concentrated, and passed through a column (DCM:MeOH=100:1˜40:1) to give P-28-5 (140 mg) as a light-colored solid.

(182) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.48 (s, 1H), 7.79 (d, 1H), 7.65 (d, 1H), 7.34-7.42 (brs, 2H), 6.81 (s, 1H), 6.70 (s, 1H), 5.26 (s, 1H), 4.76 (d, 1H), 4.02 (s, 4H), 3.80 (s, 4H), 1.82-1.95 (m, 2H), 1.47-1.69 (m, 2H), 1.24 (s, 6H). LC-MS: 602.3 (M+1).

(183) Step 5: Under N.sub.2 protection, P-28-5 (100 mg, 0.17 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to −20° C., then BH.sub.3/THF (1N, 1.7 mL, 1.7 mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction system was warmed to 60° C. and reacted for 1 h, and then the reaction system was cooled to −20° C. and concentrated hydrochloric acid (0.8 mL) was added dropwise slowly, and then warmed to 60° C. for reaction after addition. It was detected by LC-MS that all intermediates were converted to the target compounds. The mixture was cooled, and then added ethyl acetate and water for liquid-separating to obtain the aqueous phase. The aqueous phase was adjusted to a pH of about 10 with sodium hydroxide, extracted with DCM, dried and concentrated, and then quickly eluated by a column (DCM:MeOH=100:1 to 40:1) to give P-28 (20 mg).

(184) .sup.1H NMR (300 MHz, CD.sub.3OD) δ: 8.36 (s, 1H), 7.09 (s, 1H), 6.84 (s, 1H), 5.42 (s, 1H), 4.05 (t, 4H), 3.99 (s, 2H), 3.77 (t, 4H), 3.50 (brs, 1H), 2.39 (t, 2H), 1.80 (t, 2H), 1.36˜1.52 (m, 4H), 1.08 (s, 6H), LC-MS: 588.2 (M+1).

(185) The Effect of Compounds on the Kinase Activity of PI3K

(186) Concentration setting for preliminary screening: the compounds to be tested were dissolved in DMSO (dimethyl sulfoxide) to 100 μM or 10 μM as storage solutions; for each one, 2 μL was taken to be added to 48 μL of 1× Reaction Buffer to obtain a 4 μM or 400 nM compound solution containing 4% DMSO. After well mixing, the mixture was diluted with 4% DMSO in 1× Reaction Buffer to obtain a 4 μM or 400 nM compound solution. 5 μL of each diluted solution was taken to be added to a 384-well plate, so that the final concentration of the compound in the final 20 μL of the kinase reaction system was 1 μM and 100 nM or 100 nM and 20 nM, respectively, and containing 1% DMSO.

(187) Concentration setting for IC.sub.50 determination: For different enzymes, 10 μM and 100 μM were selected as the initial concentrations. The compounds to be tested were dissolved in DMSO to 1 mM or 10 mM as working solutions, 1 μL of each working solution was taken to be added to 24 μl of 1× Kinase Buffer A to obtain a 40 μM or 400 μM compound solution containing 4% DMSO. The compound solution was diluted by 4× gradient in sequence, 10 dilution concentrations. 2.5 μL of each diluted solution was taken to be added to a 384-well plate, so that the final concentration of the compound in the final 10 μL of the kinase reaction system was 10 μM, 2.5 μM and 0.625 μM, successively, and containing 1% DMSO.

(188) Experimental Steps: At room temperature, the PI3K kinase was reacted for 30 minutes and then terminated, detection solutions were added to each well, well mixed, and incubated for 2 hours at room temperature, then detected by multifunctional microplate reader (2104 EnVision® Multilabel Reader (Cat: 2104-0010, PerkinElmer)) and the test results were recorded.

Experimental Results

(189) Calculation of the Emission Ratio of Each Well Emission Ratio (ER)=665 nM Emission signal/620 nm Emission signal The average Emission Ratio of 100% inhibition control was recorded as: ER.sub.100% The average Emission Ratio of 0% inhibition control was recorded as: ER.sub.0%

(190) Calculation of the Inhibition Rate The inhibitory rate was calculated by the following formula:
Inhibitory rate=(ER.sub.sample−ER.sub.0%)/(ER.sub.100%−ER.sub.0%)×100%

(191) As shown in Table 1 and Table 2, the compounds in the tables all show good inhibitory effects on PI3K kinase, especially compounds P-5/6/7 show a selective inhibitory effect on PI3Kδ.

(192) TABLE-US-00001 TABLE 1 Inhibitory effect of some compounds on various isoforms of PI3K kinase at specified concentrations IH (%) @ 20 nM IH (%) @ 100 nM Compound α δ β γ P-2 18.72 46.02 4.74 0.62 P-3 6.72 39.81 −0.12 2.94 P-5 −0.60 53.19 14.87 −2.33 P-6 69.72 41.43 11.78 −4.80 P-7 3.60 53.59 3.43 −7.96 P-9 68.90 51.20 12.81 31.41 P-10 80.49 39.74 7.84 32.10 P-11 72.76 50.28 15.82 19.40 P-13 30.49 41.24 2.34 2.16 P-14 24.80 63.28 3.44 6.83 P-17 60.73 64.14 15.98 47.01 P-20 101.92 83.13 57.35 68.29 P-21 89.32 107.21 46.28 74.08 P-22 50.00 46.54 15.08 30.34 P-23 77.87 77.08 32.63 66.96 GDC0941 41.74 56.31 21.13 2.00

(193) TABLE-US-00002 TABLE 2 Inhibitory effects of some compounds on various isforms of PI3K kinase IC.sub.50 (nM) Compound α δ β γ P-2 321.2 36.60 2135 37640 P-5 424.3 19.60 1365 4832 P-6 624.0 35.29 4574 9875 P-7 438.8 27.58 3459 15300 P-9 26.41 23.69 1186 282.8 P-10 104.1 79.66 1769 201.6 P-11 21.29 28.08 1443 247.5 P-14 77.46 85.57 2649 1946 P-17 76.24 75.20 912.5 290.2 P-20 10.79 3.733 124.3 36.55 P-21 21.84 6.224 139.2 37.45 P-22 122.2 29.49 1536 311.2 P-23 18.68 10.09 108.7 47.10 GDC0941 35.42 9.036 324.5 746.1

(194) It can be seen from the tables that compounds P-5, P-6, P-7, etc., have good selectivities for PI3Kδ. GDC0941 is a positive compound with a chemical name of 2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-D]pyrimidine (4-[2-(1H-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine).

(195) Preliminary Pharmacokinetic Test

(196) 1. 14 healthy SD rats, male, weigh 200-220 g, were taken to be randomly divided into 4 groups, 3-4 in each group, and were administered the tested compound P-17 and compound CYH33 (compared with compound P-17, missing a methyl group on 7-position) via intragastric administration (10 mg/kg) and intravenous injection (5 mg/kg) respectively, the specific arrangements are shown in the following table 3:

(197) TABLE-US-00003 Dose Number of Dosage volume Group animals Compound Dose route (mg/kg) (mL/kg) 1 4 CYH33 Intragastric 10 10 administration 2 4 CYH33 intravenous 5 5 3 4 P-17 Intragastric 10 10 administration 4 3 P-17 intravenous 5 5

(198) The rats were fasted for 12 h before experiment, water was taken freely. The rats were fed 2 h after dosing.

(199) 2. Blood Sampling Time Points and Sample Processing

(200) Dosing via intragastric administration: 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h, and 24 h after dosing.

(201) Dosing via intravenous: 5 min, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24 h after dosing.

(202) At the above setting time points, 0.3 ml of venous blood was taken from the retroorbital venous plexus of the rat, and placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 min, then the plasma was separated, and frozen in a refrigerator at −20° C.

(203) 3. Sample Testing and Data Analysis

(204) LC/MS/MS method was used to determine the concentration of the compounds in the plasma of rats.

(205) The non-compartment model of Phoenix 1.3 software (Pharsight Corporation, USA) was used to calculate the pharmacokinetic parameters after dosing.

(206) TABLE-US-00004 TABLE 4 Pharmacokinetic data after intravenous injection of 5 mg/kg of different compounds in rats AUC 0 − t AUC 0 − ∞ MRT T1/2 Cl Vss Treatment ID (h*ng/ml) (h*ng/ml) (h) (h) (l/h/kg) (l/kg) CYH33 5 2847 2850 1.1 0.83 1.75 1.93 6 3645 3655 1.26 0.95 1.37 1.72 7 4142 4172 1.57 1.16 1.2 1.88 Mean 3545 3559 1.308 0.982 1.44 1.843 SD 653 666 0.239 0.168 0.285 0.11 CV % 18.4 18.7 18.3 17.1 19.8 5.9 P-17 5 3698 4188 3.53 2.61 1.19 4.21 6 2564 2672 2.13 1.88 1.87 3.98 7 2711 2845 2.46 1.82 1.76 4.33 Mean 2991 3235 2.706 2.104 1.607 4.175 SD 617 830 0.729 0.44 0.363 0.176 CV % 20.6 25.6 26.9 20.9 22.6 4.2

(207) TABLE-US-00005 TABLE 5 Pharmacokinetic data after intravenous injection of 10 mg/kg of different compounds in rats Tmax Cmax AUC0-t AUC0-∞ MRT T½ F Treatment ID (h) (ng/ml) (h*ng/ml) (h*ng/ml) (h) (h) (%) CYH33 1 1 770 1968 2027 2.41 1.62 36.9 2 1 1743 5959 6360 3.31 1.83 3 0.5 441 1199 1250 2.64 1.7 4 1 372 1351 1360 2.66 0.82 Mean 0.875 831.5 2619 2749 2.76 1.49 SD 0.25 632 2251 2432 0.39 0.46 CV % 28.6 76 86 88.4 14 30.4 P-17 1 4 678 7245 7286 5.82 3.08 95.8 2 2 875 8176 8198 5.55 2.68 3 1 679 3389 4014 4.65 2.6 4 2 833 4122 4993 4.94 2.71 Mean 2.25 766.3 5733 6123 5.24 2.767 SD 1.258 102.8 2334 1948 0.539 0.215 CV % 55.9 13.4 40.7 31.8 10.3 7.8

(208) (ID is the animal number, Tmax is the peak time, Cmax is the peak blood drug concentration, AUC is the area under the curve during medication, MRT is the average residence time, Cl is the drug clearance rate, Vss is the steady-state distribution volume, F is the absolute bioavailability)

(209) As can be seen from the above table, although P-17 differs from CYH33 by one methyl, the steady-state distribution volume Vss, average residence time MRT, half-life T½, and absolute bioavailability F of P-17 have all been improved, especially the absolute bioavailability has been greatly increased (the tested compounds are monomesylates of CYH33 and P17, the structures of the compounds are as follows).

(210) ##STR00094##

(211) The above-mentioned examples are merely illustrative of several embodiments of the present disclosure, which are described specifically and in detail, but it cannot be understood to limit the scope of the present disclosure. It should be noted that, for those ordinary skilled in the art, several variations and improvements may be made without departing from the concept of the present disclosure, and all of which are within the protection scope of the present disclosure. Therefore, the protection scope of the present disclosure shall be defined by the appended claims.