PIPERIDINE DERIVATIVES AS OREXIN RECEPTOR ANTAGONIST

Abstract

The present invention discloses a series of piperidine derivatives as orexin receptor antagonists and compositions thereof, and relates to the application thereof in preparing medications for the treatment of insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, hypersomnia, anxiety, obsessive-compulsive disorder, panic attack, nicotine addiction, or binge eating disorder.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, ##STR00085## wherein: A is selected from an optionally substituted 3-12 membered cyclohydrocarbyl or heterocyclohydrocarbyl or cyclic heterohydrocarbyl; wherein the cyclohydrocarbyl or heterocyclohydrocarbyl or cyclic heterohydrocarbyl is in form of single ring, bicyclic ring, spiro ring, condensed ring or fused ring, and the substituent is selected from the group consisting of F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, a halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, and a halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group; wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; B is selected from C(═O), S(═O) or S(═O).sub.2; X is selected from optionally substituted (CH.sub.2).sub.r1(U).sub.r2(CH.sub.2).sub.r3, wherein the substituent is selected from the group consisting of F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; r.sub.1 and r.sub.3 are independently selected from 0, 1 or 2, r.sub.2 is selected from 0 or 1, and when r.sub.1, r.sub.2 and r.sub.3 are all 0, it means that X is a single bond of linkage; U is selected from halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted CH.sub.2, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent is arbitrary as long as chemical stability is achievable; D and L are independently selected from optionally substituted CH.sub.2, wherein the substituent is selected from F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; T is selected from C or a single bond of linkage, and R.sub.2 and R.sub.3 are none when T is a single bond of linkage; M is selected from C(Y)(R.sub.1a) when Q is selected from C(R.sub.1b)(R.sub.1c), or M is selected from C(R.sub.1b)(R.sub.1c) when Q is selected from C(Y)(R.sub.1a); Y is selected from —(CH.sub.2).sub.r4(G).sub.r5(CH.sub.2).sub.r6—Y.sub.1, wherein Y.sub.1 is selected from —O-E or a structure of formula (Y.sub.2), ##STR00086## G is selected from halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted CH.sub.2, C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, S(═O), S(═O).sub.2, C(═O) or C(═S), wherein the number of substituent is arbitrary as long as chemical stability is achievable; r.sub.4 and r.sub.6 are independently selected from 0, 1 or 2, r.sub.5 is selected from 0 or 1, and when r.sub.4, r.sub.5 and r.sub.6 are all 0, it means the corresponding structure is a single bond of linkage; E is selected from optionally substituted 5-6 membered cyclohydrocarbyl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; each of Y.sub.2a, Y.sub.2b, Y.sub.2c, Y.sub.2d, Y.sub.2e, Y.sub.2f, and Y.sub.2g is selected from optionally substituted CH.sub.2, CH, NH, or is selected from N, O, S, S(═O), S(═O).sub.2, C(═O) or C(═S), and at least one of Y.sub.2a, Y.sub.2b, Y.sub.2c, Y.sub.2d, Y.sub.2e, Y.sub.2f, and Y.sub.2g is optionally substituted CH, CH.sub.2 or NH, wherein the substituent is selected from F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; represents a single bond or a double bond; each of R.sub.1a, R.sub.1b, R.sub.1c, R.sub.2, and R.sub.3 is independently selected from H, F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; or R.sub.2 and R.sub.3 are optionally connected to form a ring; and the compound or the pharmaceutically acceptable salt thereof comprises one or more chiral center.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein A is selected from a structure unit as shown in formula (A.sub.1) or (A.sub.2): ##STR00087## wherein: Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4, and Z.sub.5 are independently selected from halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted CH or CH.sub.2, or C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH or NH, C═N, N, O, S, S(═O), S(═O).sub.2, C(═O)O, C(═O) or C(═S), wherein the number of substituent is arbitrary as long as chemical stability is achievable; V.sub.1, V.sub.2, V.sub.3, V.sub.4, and V.sub.5 are independently selected from halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted CH or CH.sub.2, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH or NH, C═N, C, N, O, S, S(═O), S(═O).sub.2, C(═O)O, C(═O) or C(═S), and at least one of V.sub.1 to V.sub.5 is C or N, wherein the number of substituent is arbitrary as long as chemical stability is achievable; represents a single bond or a double bond; R.sub.4 and R.sub.6 are independently selected from H, F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; R.sub.5 and R.sub.7 are independently selected from optionally substituted 5-6 membered cyclohydrocarbyl or heterocyclic group, while the substituent is selected from F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable; n.sub.4 is selected from 0, 1, 2, 3, 4; and n.sub.6 is selected from 0, 1, 2, 3.

3. The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein the structure unit ##STR00088## is selected from phenyl or pyridyl; ##STR00089## is selected from furyl, thienyl or thiazolyl.

4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein formula (A.sub.2) is selected from a structure of formula (A.sub.21): ##STR00090## wherein the V.sub.1, V.sub.2, V.sub.3, V.sub.4, V.sub.5, R.sub.6, R.sub.7 and n.sub.6 are defined as in claim 2.

5. The compound of claim 4 or the pharmaceutically acceptable salt thereof, wherein A is selected from a structure unit of formula (A.sub.22): ##STR00091## wherein R.sub.6 and R.sub.7 are defined as in claim 2; and n.sub.6a is selected from 0, 1 or 2.

6. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the 5-6 membered cyclohydrocarbyl or heterocyclic group are each independently selected from phenyl, pyridyl, furyl, thienyl, thiazolyl, pyrimidinyl, pyrazolyl, 1,2,3-triazolyl or 1,2,5-triazolyl.

7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein A is selected from: ##STR00092## ##STR00093##

8. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein formula (Y.sub.2) is selected from a structure of formula (Y.sub.21): ##STR00094## wherein Y.sub.2a, Y.sub.2b, Y.sub.2c, Y.sub.2d, Y.sub.2e, Y.sub.2f and Y.sub.2g are defined as in claim 1.

9. The compound of claim 8 or the pharmaceutically acceptable salt thereof, wherein formula (Y.sub.21) is selected from a structure of formula (Y.sub.22) which is optionally substituted: ##STR00095## wherein the substituent is selected from F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable.

10. The compound of claim 9 or the pharmaceutically acceptable salt thereof, wherein Y is selected from optionally substituted ##STR00096##

11. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is selected from —CH.sub.2—O-E or —O-E, wherein E is defined as in claim 1.

12. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein E is selected from a structure unit of formula (E.sub.a): ##STR00097## wherein: E.sub.1, E.sub.2, E.sub.3, and E.sub.4 are independently selected from halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted CH, N; and R.sub.8 and R.sub.9 are independently selected from H, F, Cl, Br, I, CN, ═O, ═S, OH, SH, NH.sub.2, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.1-6 alkyl or heteroalkyl or alkyl hetero group or heteroalkyl hetero group, halogen-substituted, hydroxy-substituted, amino-substituted or unsubstituted C.sub.3-8 cyclic group or heterocyclic group or cyclic hetero group or heterocyclic hetero group, wherein the hetero atom or heteroatom group is independently selected from C.sub.1-6 alkyl substituted, C.sub.3-8 cycloalkyl substituted or unsubstituted C(═O)NH, C(═O)O, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted NH, O, S, C.sub.1-6 alkyl substituted or C.sub.3-8 cycloalkyl substituted or unsubstituted C═NH, C═O, C═S, S(═O) and/or S(═O).sub.2, wherein the number of substituent, heteroatom or heteroatom group is arbitrary as long as chemical stability is achievable.

13. The compound of claim 12 or the pharmaceutically acceptable salt thereof, wherein the structure unit ##STR00098## is defined as phenyl or pyridyl, or is replaced with thienyl or furyl.

14. The compound of claim 12 or the pharmaceutically acceptable salt thereof, wherein Y is selected from: ##STR00099##

15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein U, X, and G are independently selected from NH or N—C.sub.1-6 alkyl.

16. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.1a, R.sub.1b, and R.sub.1c are independently selected from H, methyl, or fluoro.

17. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.2 and R.sub.3 are independently selected from H, methyl, fluoro or cyclopropyl.

18. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R.sub.2 and R.sub.3 together form 3-8 membered cycloalkyl; specifically, R.sub.2 and R.sub.3 together form a cyclopropyl.

19. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein C.sub.1-6 alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, or hexyl, wherein propyl, butyl, pentyl, or hexyl is optionally cyclized or partially cyclized.

20. The compound of claim 1 or the pharmaceutically acceptable salt thereof, which has any of the following structures: ##STR00100## ##STR00101## ##STR00102## ##STR00103##

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A method for treating insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, hypersomnia, anxiety, obsessive-compulsive disorder, panic attack, nicotine addiction, or binge eating disorder wherein comprises the following step: administrating treatment effective dose of a compound of claim 1 or a pharmaceutically acceptable salt thereof to the subjects in need.

Description

EMBODIMENTS FOR CARRYING OUT THE INVENTION

[0109] The present invention will be further illustrated below with reference to the specific examples, but these examples are not to make any disadvantage limitation to the invention. This invention has been described in detail herein, and the embodiments for carrying out the invention are disclosed. It would be obvious for those skilled in the art can to make various changes and modifications to the embodiments for carrying out the present invention without departing from the spirit and scope of the present invention.

Examples 1 and 2

[0110] ##STR00024## ##STR00025## ##STR00026## ##STR00027##

[0111] A wavy bond indicates that the bond may be upward or downward, and is not influenced by other groups (It has the same meaning hereinafter).

Step 1 (Synthesis of 1-3)

[0112] Compound 1-1 (10.0 g, 44.4 mmol) was dissolved in 55 mL tetrahydrofuran, LDA (24.4 mL, 0.0488 mol) was slowly added dropwise under −78° C., and the mixture was stirred for 1 h under −78° C. Keeping the temperature at −78° C., compound 1-2 was added into the reaction dropwise, and after the addition, the temperature was slowly raised to room temperature, and the reaction was stirred overnight under room temperature. The reaction mixture was poured into aqueous ammonium chloride solution (50 mL), and concentrated under reduced pressure to give a crude product. 50 mL of saturated aqueous sodium chloride solution was added, and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with water (100 mL×2), saturated NaCl solution (100 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=50:1) to give the product 1-3 as a yellow liquid, yield: 80%. (Solid was precipitated after cooled and placed.)

[0113] LC/MS: 198.0 (M-Boc+H.sup.+)

Step 2 (Synthesis of 1-4)

[0114] Compound 1-3 (1.5 g, 5.05 mmol) was dissolved in 15 mL methanol, and NaBH.sub.4 (192 mg, 5.05 mmol) was added. The reaction mixture was stirred under room temperature for 12 hours. 20 mL of water was added into the reaction mixture to quench, and the mixture was concentrated and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (100 mL×2), saturated NaCl solution (100 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under vacuum to give the product 1-4, which was used in next step without purification.

Step 3 (Synthesis of 1-5)

[0115] The crude compound 1-4 (1.4 g) was dissolved in 40 mL dichloromethane. Triethylamine (1.01 g, 10 mmol) and methanesulfonyl chloride (1.12 g, 9.86 mmol) were added under 0° C. After stirred for 30 minutes, the mixture was warmed to room temperature and stirred under room temperature for 10 hours. The reaction mixture was poured into water and extracted with dichloromethane (100 mL×3). The combined organic phase was washed with water (100 mL×2), saturated NaCl solution (100 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under vacuum to give the product 1-5, which was used in next step without purification.

Step 4 (Synthesis of .SUB.1-6.)

[0116] The crude compound 1-5 (about 600 mg) was dissolved in 10 mL DMF, and DBU (4 g, 16 mmol) was added. The mixture was heated to 100° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature. After adding 50 mL of water, the mixture was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with water (20 mL×2) and saturated NaCl solution (20 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=50:1) to give 280 mg of the product 1-6 (yellow liquid. Solid was precipitated after cooled and placed. The total yield of the three steps: 30%).

[0117] LC/MS: 182.0 (M-Boc+H.sup.+), 226.0 (M-56+H.sup.+), 304.0 (M+Na.sup.+)

[0118] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.75 (s, 1H), 4.34-4.32 (m, 1H), 4.10-4.02 (m, 2H), 2.96-2.90 (m, 1H), 2.08-2.02 (m, 2H), 1.97-1.91 (m, 2H), 1.63-1.55 (m, 2H), 1.45 (s, 9H), 1.42-1.28 (m, 3H).

Step 5 (Synthesis of 1-7)

[0119] Compound 1-6 (300 mg, 1.06 mmol) was dissolved in 20 mL methanol, and wet Pd(OH).sub.2 (50 mg, 5%) was added and stirred under hydrogen for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the product 1-7, which was used in next step without purification.

Step 6 (Synthesis of 1-8)

[0120] The compound 1-7 (300 mg, 1.06 mmol) was dissolved in 30 mL tetrahydrofuran. Under 0° C., LAH (80 mg, 2 mmol) was added in several batches with small amount for each batch. After addition, the ice bath was removed and mixture was warmed to room temperature, and the reaction was conducted under room temperature for 4 hours. Into the reaction mixture were successively added 0.08 mL water, 0.08 mL 15% aqueous sodium hydroxide and 0.24 mL water. A small amount of magnesium sulfate was added. The mixture was filtered after being stirred for 10 minutes, and the filtrate was dried under rotation to obtain the product 1-8, which was used in next step without purification.

[0121] LC/MS: 237.0 (M-Boc+H.sup.+), 337.1 (M+H.sup.+)

Step 7 (Synthesis of 1-10)

[0122] The compound 1-8 (280 mg, 1.16 mmol) was dissolved in 14 mL DMF. Under 0° C., NaH (139 mg, 3.48 mmol) was added in several batches with small amount for each batch. The mixture was stirred under the same temperature for 30 minutes, and the compound 1-9 was slowly added. After addition, the reaction was conducted under room temperature for 10 hours. The reaction mixture was poured into 30 mL water and 10 mL saturated NaCl solution was added. The mixture was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with water (10 mL×2), saturated NaCl solution (10 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=50:1) to give product 1-10 (150 mg, and the total yield of the three steps: 42%).

Step 8 (Synthesis of 1-11)

[0123] Compound 1-10 (300 mg) was separated by preparative HPLC to obtain the racemic product 1-11 (120 mg, 80%), while the racemate product 1-12 (100 mg, 67%) was obtained at the same time.

Step 9 (Synthesis of 1-13)

[0124] Compound 1-11 (120 mg) was dissolved in 4 mL of ethyl acetate, and hydrogenchloride in ethyl acetate solution (4 mL, 4M) was added dropwise under ice bath cooling. The mixture was stirred for 2 hours, concentrated under reduced pressure to give product 1-13 (hydrochloride form), and the product was used in the next step without purification.

Step 10 (Synthesis of 1-15)

[0125] Compound 1-13 (120 mg, 0.32 mmol), compound 1-14 (77 mg, 0.38 mmol), HATU (182 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol) were dissolved in 5 mL of DMF, and mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated NaCl solution (10 mL×2), and dried under rotation to give the product 1-15 (28 mg, white solid, yield: 16%).

[0126] .sup.1H NMR (400 MHz, MeOD) δ 8.01 (s, 1H), 7.93-7.88 (m, 2H), 7.75-7.73 (m, 1H), 7.52-7.45 (m, 2H), 7.41-7.36 (m, 1H), 6.86 (s, br, 0.5H), 6.4.sub.1-6.38 (m, 0.5H), 4.75-4.66 (m, 1H), 4.48-4.33 (m, 1H), 4.14-4.04 (m, 1H), 3.77-3.72 (m, 1H), 2.45-2.42 (m, 1H), 2.30-225 (m, 1H), 1.94 (s, 3H), 1.87-1.83 (m, 4H), 1.67-1.46 (m, 3H).

Step 11 (Synthesis of 1-16 and 2-1)

[0127] Racemic compound 1-15 (28 mg) was separated via SFC separation (separation method: Instrument Model: MG II preparative SFC; separation column: phenomenex Lux C2, 250×30 mm I.D.; mobile phase: A: CO.sub.2, B: ethanol (0.1% aqueous ammonia); density: B 40%; flow rate: 50 mL/min; back flow pressure: 100 bar; column temperature: 38° C.; UV detection wavelength: 220 nm) to give optically pure compound 1-16 (10 mg, white solid, yield: 71%) and the optically pure compound 2-1 (10 mg, white solid, yield: 71%). The absolute configuration of compound 1-16 was confirmed by single crystal X-ray spectra.

Examples 3 and 4

[0128] ##STR00028## ##STR00029##

Step 1 (Synthesis of 3-1)

[0129] Compound 1-12 (100 mg) was dissolved in 4 mL of ethyl acetate, and hydrogen chloride in ethyl acetate (4 mL, 4M) was added dropwise under ice bath cooling. The mixture was stirred for 2 hours, concentrated under reduced pressure to give the product 3-1 (hydrochloride form) which was used in next step without purification.

Step 2 (Synthesis of 3-2)

[0130] Compound 3-1 (100 mg, 0.26 mmol), compound 1-14 (58 mg, 0.28 mmol), HATU (150 mg, 0.39 mmol) and DIEA (124 mg, 0.96 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated NaCl solution (10 mL×2), dried, filtered and concentrated to give a crude product. The crude product was separated by preparative HPLC to obtain the compound 3-2 (30 mg, white solid, yield: 20%).

[0131] .sup.1H NMR (400 MHz, MeOD) δ=8.14 (br. s., 1H), 8.00-7.61 (m, 4H), 7.49 (br. s., 0.5H), 7.33 (dd, J=8.0, 17.8 Hz, 1H), 7.12 (br. s., 1H), 6.56 (br. s., 0.5H), 5.00-4.83 (m, 1H), 4.48 (br. s., 3H), 3.88-3.62 (m, 1H), 2.45-2.34 (m, 3H), 2.05-1.56 (m, 5H), 1.42-1.35 (m, 3H)

Step 3 (Synthesis of 3-3 and 4-1)

[0132] Racemic compound 3-2 (30 mg) was separated via SFC separation (separation method: Instrument Model: MG II preparative SFC; separation column: ChiralPak IC, 250×30 mm I.D.; mobile phase: A: CO.sub.2, B: ethanol (0.1% aqueous ammonia); density: B 50%; flow rate: 45 mL/min; back flow pressure: 100 bar; column temperature: 38° C.; detection wavelength: 220 nm) to give optically pure compound 3-3 (12 mg, white solid, yield: 80%) and optically pure compound 4-1 (12 mg, white solid, yield: 80%).

[0133] (3-3 and 4-1 were a pair of enantiomers, and the relative structures were hypothetical structures, and the absolute structure was yet unconfirmed).

Examples 5 and 6

[0134] ##STR00030## ##STR00031##

Step 1 (Synthesis of 5-2)

[0135] Compound 1-12 (120 mg, 0.32 mmol), compound 5-1 (77 mg, 0.38 mmol), HATU (182 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated NaCl solution (10 mL×2), dried with anhydrous Na.sub.2SO.sub.4, filtered, the crude product was purified with preparative HPLC to give product 5-2 (24 mg, white solid, yield: 14%).

[0136] .sup.1H NMR (400 MHz, METHANOL-d.sub.4)=8.83 (br. s., 2H), 8.17-8.01 (m, 2H), 7.49-7.33 (m, 3H), 6.86 (dd, J=3.5, 9.0 Hz, 1H), 6.41 (br. s., 1H), 4.63 (br. s., 1H), 4.43 (br. s., 1H), 4.11 (br. s, 1H), 3.79 (br. s., 1H), 2.52-2.48 (m, 2H), 2.35-2.11 (m, 1H), 2.01-1.95 (m, 3H), 1.90-1.67 (m, 3H), 1.63-1.43 (m, 1H), 1.29-1.20 (m, 2H)

Step 2 (Synthesis of 3-3 and 6-1)

[0137] Racemic compound 5-2 (24 mg) was separated via SFC separation (separation method: Instrument Model: MG II preparative SFC; separation column: ChiralPak IC, 250×30 mm I.D.; mobile phase: A: CO.sub.2, B: ethanol (0.1% aqueous ammonia); density: B 45%; flow rate: 40 mL/min; back flow pressure: 100 bar; column temperature: 38° C.; detection wavelength: 220 nm) to give optically pure compound 5-3 (8 mg, white solid) and compound 6-1 (8 mg, white solid). The total yield of two compounds was 67%.

Examples 7 and 8

[0138] ##STR00032## ##STR00033##

Step 1 (Synthesis of 7-1)

[0139] Compound 3-1 (100 mg, 0.26 mmol), compound 5-1 (58 mg, 0.28 mmol), HATU (150 mg, 0.39 mmol) and DIEA (124 mg, 0.96 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated NaCl solution (10 mL×2), dried, filtered and concentrated to give a crude product. The crude product was separated by preparative HPLC to obtain compound 7-1 (30 mg, white solid, yield: 20%).

[0140] .sup.1H NMR (400 MHz, MeOD) δ=8.78 (dd, J=4.9, 9.7 Hz, 2H), 8.17 (d, J=8.2 Hz, 0.5H), 8.11 (d, J=7.9 Hz, 0.5H), 8.01 (d, J=3.1 Hz, 0.5H), 7.75 (br. s., 0.5H), 7.57-7.50 (m, 0.5H), 7.43 (d, J=8.2 Hz, 0.5H), 7.38-7.31 (m, 2H), 7.26 (s, 0.4H), 7.13 (s, 0.6H), 6.86 (dd, J=3.5, 9.0 Hz, 0.5H), 6.36 (dd, J=3.5, 9.0 Hz, 0.5H), 4.77-4.72 (m, 0.5H), 4.21-4.11 (m, 1.5H), 3.78 (br. s., 1H), 2.52 (br. s., 1H), 2.46 (s, 1.5H), 2.35 (s, 1.5H), 2.09-1.95 (m, 2H), 1.91-1.37 (m, 7H)

Step 7 (Synthesis of 3-2 and 8-1)

[0141] Racemic compound 7-1 (30 mg) was separated via SFC separation (separation method: Instrument Model: MG II preparative SFC; separation column: ChiralPak AS, 250×30 mm I.D.; mobile phase: A: CO.sub.2, B: ethanol (0.1% aqueous ammonia); density: B 15%; flow rate: 60 mL/min; back flow pressure: 100 bar; column temperature: 38° C.; detection wavelength: 220 nm) to give optically pure compound 7-2 (12 mg, white solid, yield: 80%) and optically pure compound 8-1 (12 mg, white solid, yield: 80%).

[0142] (7-2 and 8-1 were a pair of enantiomers, and the relative structures were hypothetical structures, and the absolute structure was yet unconfirmed).

Example 9

[0143] ##STR00034## ##STR00035##

Step 1 (Synthesis of 9-1)

[0144] Racemic compound 1-11 (280 mg) was separated via SFC separation (separation method: Instrument Model: MG II preparative SFC (SFC-1); separation column: ChiralPak AS, 250×30 mm I.D.; mobile phase: A: CO.sub.2, B: ethanol (0.1% aqueous ammonia); density: B 25%; flow rate: 60 mL/min; back flow pressure: 100 bar; column temperature: 38° C.; detection wavelength: 220 nm) to give optically pure product 9-1 (100 mg, white solid, yield: 71%).

Step 2 (Synthesis of 9-2)

[0145] Compound 9-1 (120 mg) was dissolved in 4 mL of ethyl acetate, and hydrogen chloride in ethyl acetate (4 mL, 4M) was added dropwise under ice bath cooling. The mixture was stirred for 2 hours, concentrated under reduced pressure to give product 9-2 (hydrochloride form), which was used in next step without purification.

Step 3 (Synthesis of 9-4)

[0146] Compound 9-2 (120 mg, 0.32 mmol), compound 9-3 (77 mg, 0.38 mmol), HATU (182 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated NaCl solution (10 mL×2), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to obtain a crude product. The crude product was purified with preparative HPLC to give product 9-4 (22 mg, white solid, yield: 21%).

[0147] .sup.1H NMR (400 MHz, MeOD) δ=8.20-7.98 (m, 3H), 7.85-7.72 (m, 1H), 7.71-7.50 (m, 2H), 7.48-7.17 (m, 1H), 7.03-6.75 (m, 1H), 4.87-4.66 (m, 1H), 4.54-4.36 (m, 1H), 4.31-4.05 (m, 1H), 3.86-3.55 (m, 1H), 2.14 (br. s., 1H), 2.08-1.95 (m, 1H), 1.88 (td, J=7.2, 19.8 Hz, 2H), 1.77 (dd, J=11.3, 18.1 Hz, 2H), 1.68-1.54 (m, 1H), 1.53-1.32 (m, 2H)

Example 10

[0148] ##STR00036##

Step 1 (Synthesis of 10-2)

[0149] Compound 9-2 (120 mg, 0.32 mmol), compound 10-1 (77 mg, 0.38 mmol), HATU (182 mg, 0.48 mmol) and DIEA (124 mg, 0.96 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated NaCl solution (10 mL×2), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to obtain a crude product. The crude product was purified with preparative HPLC to give product 10-2 (41 mg, white solid, yield: 42%).

[0150] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.11-7.90 (m, 1H), 7.81-7.56 (m, 2H), 7.49-7.38 (m, 2H), 7.35 (d, J=8.8 Hz, 1H), 6.77 (br. s., 1H), 6.42 (d, J=6.0 Hz, 1H), 4.97 (br. s., 0.3H), 4.82 (br. s., 0.7H), 4.40 (br. s., 0.5H), 4.14 (br. s., 1H), 4.06 (br. s., 0.6H), 4.00 (d, J=10.3 Hz, 0.5H), 3.74 (br. s., 0.4H), 2.76 (br. s., 1H), 2.12 (br. s., 0.5H), 2.06-1.86 (m, 2.5H), 1.85-1.67 (m, 2H), 1.62 (br. s., 1H), 1.65-1.56 (m, 2H), 1.45 (br. s., 1H), 1.12 (br. s., 1H), 0.67 (d, J=6.3 Hz, 1H)

Example 11

[0151] ##STR00037##

[0152] Example 11 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 11-1:

##STR00038##

and the product 11-2 was obtained by preparative HPLC purification (24 mg, white solid, yield: 25%).

[0153] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.55 (br. s., 1H), 8.42 (br. s., 0.5H), 8.03-7.85 (m, 1H), 7.80-7.63 (m, 2H), 7.57 (d, J=7.5 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 1.5H), 7.23 (d, J=5.0 Hz, 1H), 6.84-6.63 (m, 1H), 4.50 (t, J=9.5 Hz, 1H), 4.32 (dd, J=5.8, 10.8 Hz, 1H), 3.89 (br. s., 2H), 2.40 (s, 3H), 2.20-1.93 (m, 4H), 1.84 (dt, J=7.3, 13.4 Hz, 1H), 1.72 (d, J=8.5 Hz, 2H), 1.52 (d, J=11.5 Hz, 1H), 1.48-1.35 (m, 1H)

Example 12

[0154] ##STR00039##

[0155] Example 12 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 12-1:

##STR00040##

and the product 12-2 was obtained by preparative HPLC purification (8 mg, white solid, yield: 9%).

[0156] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=7.96 (d, J=2.5 Hz, 1H), 7.57-7.43 (m, 2H), 7.42-7.30 (m, 3H), 7.30-7.23 (m, 2.5H), 7.20 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.26 (dd, J=3.5, 9.0 Hz, 0.5H), 4.94-4.71 (m, 1H), 4.09-3.97 (m, 1H), 3.96-3.79 (m, 1H), 3.61 (d, J=7.0 Hz, 1H), 2.40 (s, 1H), 1.99-1.89 (m, 2.5H), 1.86-1.59 (m, 2.5H), 1.57-1.24 (m, 4H), 1.23-1.09 (m, 1H), 0.99-0.87 (m, 1H)

Example 13

[0157] ##STR00041##

[0158] Example 13 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 13-1:

##STR00042##

and the product 13-2 was obtained by preparative HPLC purification (37 mg, white solid, yield: 32%).

[0159] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.64 (br. s., 2H), 8.13-7.85 (m, 1H), 7.85-7.53 (m, 2H), 7.40-7.33 (m, 1.5H), 7.40-7.29 (m, 0.5H), 7.24 (br. s., 1H), 7.17 (d, J=7.5 Hz, 1H), 6.76 (dd, J=3.5, 9.0 Hz, 0.5H), 6.27 (dd, J=3.5, 9.0 Hz, 0.5H), 4.95-4.74 (m, 1H), 4.12-3.87 (m, 2H), 3.64-3.44 (m, 1H), 2.44 (s, 1H), 2.11 (d, J=6.5 Hz, 1H), 2.07-1.88 (m, 2H), 1.88-1.72 (m, 2H), 1.72-1.63 (m, 1H), 1.62-1.42 (m, 3H), 1.41-1.29 (m, 1H), 1.29-0.98 (m, 1H)

Example 14

[0160] ##STR00043##

[0161] Example 14 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 14-1:

##STR00044##

and the product 14-2 was obtained by preparative HPLC purification (19 mg, pale yellow solid, yield: 20%).

[0162] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.04-7.90 (m, 1H), 7.89-7.63 (m, 2H), 7.34-7.26 (m, 1H), 7.23 (d, J=8.0 Hz, 1.5H), 7.15-6.93 (m, 1.5H), 6.80-6.76 (m, 0.5H), 6.32-6.30 (m, 0.5H), 4.99-4.90 (m, 1H), 4.49-4.35 (m, 1H), 4.19-4.03 (m, 1H) 3.87-3.68 (m, 1H), 2.01-1.86 (m, 6H), 1.70-1.38 (m, 2.5H), 1.36-1.05 (m, 0.5H)

Example 15

[0163] ##STR00045##

[0164] Example 15 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 15-1:

##STR00046##

and the product 15-2 was obtained by preparative HPLC purification (17 mg, pale yellow solid, yield: 18%).

[0165] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.01 (br. s., 1H), 7.94-7.70 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.42-7.23 (m, 2H), 6.77 (d, J=6.3 Hz, 1H), 6.59-6.24 (m, 1H), 4.99 (d, J=17.1 Hz, 1H), 4.52-4.32 (m, 1H), 4.25-4.04 (m, 1H), 3.92-3.44 (m, 1H), 2.53-2.10 (m, 1H), 2.09-1.76 (m, 4H), 1.68 (br. s., 1H), 1.61-1.38 (m, 2H), 1.37-0.62 (m, 1H)

Example 16

[0166] ##STR00047##

[0167] Example 16 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 16-1:

##STR00048##

and the product 16-2 was obtained by preparative HPLC purification (6.5 mg, white solid, yield: 1.5%).

[0168] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.30-7.72 (m, 2H), 7.71-7.52 (m, 1H), 7.52-7.37 (m, 1H), 7.35-7.14 (m, 3H), 6.78-6.38 (m, 1H), 4.94-4.66 (m, 1H), 4.53-4.21 (m, 1H), 4.08 (br. s., 1H), 3.83-3.58 (m, 1H), 2.53-2.40 (m, 0.5H), 1.90-1.82 (m, 1.5H), 1.81-1.45 (m, 5.5H), 1.27 (br. s., 0.5H), 1.0-0.91 (m, 1H)

Example 17

[0169] ##STR00049##

[0170] Example 17 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 17-1:

##STR00050##

and the product 17-2 was obtained by preparative HPLC purification (4.3 mg, white solid, yield: 3.5%).

[0171] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.76 (d, J=4.5 Hz, 1.5H), 8.39-8.12 (m, 1H), 7.96 (br. s., 1H), 7.34 (t, J=6.7 Hz, 0.5H), 7.30-7.26 (m, 1H), 7.19 (br. s., 1H), 7.16-6.84 (m, 2H), 6.74 (d, J=5.8 Hz, 0.5H), 6.29 (br. s., 0.5H), 5.08-4.83 (m, 1H), 4.48-4.15 (m, 1.5H), 4.14-4.04 (m, 0.5H), 3.89 (br. s., 0.5H), 3.78-3.63 (m, 0.5H), 2.27-2.06 (m, 2H), 2.03-1.93 (m, 1H), 1.92-1.81 (m, 1.5H), 1.79-1.59 (m, 2H), 1.57-1.41 (m, 1.5H), 1.25 (br. s., 1H)

Example 18

[0172] ##STR00051##

[0173] Example 18 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 18-1:

##STR00052##

and the product 18-2 was obtained by preparative HPLC purification (4.3 mg, white solid, yield: 9.5%).

[0174] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.94-8.74 (m, 1H), 8.65 (br. s., 1H), 8.39-8.26 (m, 1.5H), 7.70-7.42 (m, 0.5H), 7.36-7.25 (m, 1H), 7.14 (br. s., 1H), 6.92-6.8 (m, 0.5H), 6.79 (d, J=19.3 Hz, 1H), 5.98 (br. s., 0.5H), 5.15-4.97 (m, 1H), 4.70-4.38 (m, 1H), 4.26-4.07 (m, 1.6H), 3.80 (br. s., 0.4H), 2.52-2.32 (m, 1H), 2.29-2.18 (m, 2H), 2.11-1.92 (m, 1H), 1.91-1.81 (m, 2H), 1.62-1.35 (m, 3H)

Example 19

[0175] ##STR00053##

[0176] Example 19 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 19-1:

##STR00054##

and the product 19-2 was obtained by preparative HPLC purification (29 mg, white solid, yield: 7%).

[0177] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.28-7.90 (m, 1H), 7.85-7.69 (m, 1H), 7.64-7.47 (m, 1.5H), 7.46-7.38 (m, 1H), 7.36-7.28 (m, 1H), 7.25-7.21 (m, 1.5H), 6.76 (dd, J=3.3, 9.0 Hz, 0.5H), 6.36 (dd, J=3.4, 8.9 Hz, 0.5H), 4.85-4.69 (m, 1H), 4.57-4.20 (m, 1H), 4.06 (d, J=4.5 Hz, 1H), 3.77-3.57 (m, 1H), 2.24-1.99 (m, 1H), 1.97-1.78 (m, 2.5H), 1.76-1.52 (m, 4H), 1.46 (d, J=8.0 Hz, 1.5H)

Example 20

[0178] ##STR00055##

[0179] Example 20 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 20-1:

##STR00056##

and the product 20-2 was obtained by preparative HPLC purification (51 mg, white solid, yield: 55%).

[0180] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.08-7.93 (m, 1H), 7.87-7.60 (m, 2H), 7.56-7.42 (m, 1H), 7.34-7.24 (m, 2H), 7.22-7.16 (m, 1H), 6.79 (d, J=5.3 Hz, 0.4H), 6.42-6.27 (m, 1.6H), 4.97-4.73 (m, 1H), 4.50-3.91 (m, 2H), 3.77 (d, J=6.0 Hz, 0.6H), 3.58 (br. s., 0.4H), 2.43 (br. s., 1H), 2.26-2.03 (m, 1H), 2.00-1.88 (m, 3H), 1.85-1.65 (m, 3H), 1.59 (d, J=6.0 Hz, 2H), 1.51-1.37 (m, 2H)

Example 21

[0181] ##STR00057##

Step 1 (Synthesis of 21-2)

[0182] Compound 9-2 (50 mg, 0.18 mmol) was dissolved in 2 mL dichloromethane. Then triethylamine (56 mg, 0.55 mmol) and compound 21-1 (48 mg, 0.28 mmol) were added and the mixture was stirred under room temperature for 2 hours. The reaction mixture was spin dried to remove solvent so as to obtain a crude product. The crude product was purified by preparative HPLC to obtain product 21-2 (31 mg, yellow solid, yield: 9%).

[0183] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=7.96 (br. s., 1H), 7.50-7.18 (m, 3H), 7.16-6.94 (m, 2H), 6.78-6.19 (m, 1H), 5.14-4.80 (m, 1H), 4.69-4.23 (m, 1.5H), 4.20-3.86 (m, 1.5H), 2.39 (br. s., 1H), 2.28-2.09 (m, 3H), 2.09-1.92 (m, 3H), 1.85 (br. s., 1H), 1.75 (br. s., 1H), 1.64 (s, 1H), 1.52 (br. s., 1H), 1.44-1.08 (m, 1H)

Example 22

[0184] ##STR00058##

[0185] Compound 9-2 (50 mg, 0.18 mmol) was dissolved in 2 mL dichloromethane. Triethylamine (56 mg, 0.55 mmol) and compound 22-1 (53 mg, 0.28 mmol) were added. After stirred under room temperature for 2 hours, the reaction mixture was spin dried to remove the solvent so as to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 22-2 (60 mg, white solid, yield: 87%).

[0186] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=7.96 (d, J=2.8 Hz, 1H), 7.78-7.54 (m, 2H), 7.34-7.19 (m, 3H), 6.63 (dd, J=3.4, 8.9 Hz, 1H), 4.48-4.24 (m, 3H), 4.21-4.07 (m, 1H), 2.35 (s, 3H), 2.03 (d, J=6.0 Hz, 1H), 1.97-1.69 (m, 4H), 1.68-1.60 (m, 2.6H), 1.54-1.45 (m, 1.5H)

Example 23

[0187] ##STR00059## ##STR00060##

Step 23 (Synthesis of 1-1)

[0188] Compound 1-7 (48 g) was dissolved in 50 mL of ethyl acetate, and hydrogen chloride in ethyl acetate (150 mL, 4M) was added dropwise under ice bath cooling. The mixture was stirred for 2 hours, concentrated under reduced pressure to give product 23-1 (hydrochloride form), which was used in next step without purification.

Step 2 (Synthesis of 23-2)

[0189] Compound 23-1 (33 g, 150 mmol) was dissolved in 300 mL dichloromethane. TEA (62.7 mL, 450 mmol) and CbzCl (21.3 mL, 150 mmol) were added successively in a condition of ice-bath. After half an hour, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (300 mL×3). The combined organic phase was washed with water (100 mL×2), saturated NaCl solution (100 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=50:1) to give the product 23-2 (35 g, yellow liquid. Solid was precipitated after cooled and placed. Yield: 74%).

Step 3 (Synthesis of 23-3)

[0190] Compound 23-2 (35 g) was separated by preparative HPLC to obtain the product 23-3 (22 g, 62.8%).

Step 4 (Synthesis of 23-4)

[0191] Compound 23-3 (5 g, 15.75 mmol) was dissolved in 100 mL methanol, and wet Pd(OH).sub.2 (500 mg, 5%) was added. The mixture was stirred under hydrogen for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give the product 23-4 (2.7 g, 94%) (colorless oil), which was used in next step without purification.

Step 5 (Synthesis of 23-5)

[0192] Compound 23-4 (8 g, 43.7 mmol), compound 5-1 (11.2 g, 52.4 mmol), HATU (24.9 g, 65.6 mmol) and DIEA (16.9 g, 131.1 mmol) were dissolved in 200 mL of THF, and the mixture was stirred under room temperature for 16 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (100 mL×3). The organic phase was combined and washed with water (50 mL×2) and saturated NaCl solution (50 mL×2), dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified with column (petroleum ether:ethyl acetate=1:2) to give product 23-5 (13 g, white solid, yield: 78%).

Step 6 (Synthesis of 23-6)

[0193] Compound 23-5 (950 mg, 2.5 mmol) was solved in 25 mL THF, and LAH (100 mg, 2.5 mmol) was added in iced ethanol bath. The reaction mixture was stirred under the present temperature for 1 hour. 20 mL of anhydrous THF was added for dilution. 0.1 mL of water, 0.1 mL of 15% sodium hydroxide solution and 0.3 mL of water were added dropwise successively to quench the reaction. Then the mixture was dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to give product 23-6 (800 mg, yellow solid, yield: 96%), which was used directly in next step without purification.

Step 7 (Synthesis of 23-8)

[0194] Compound 23-6 (80 mg, 0.237 mmol) was solved in 5 mL DMF, and NaH (38 mg, 60%, 0.984 mmol) was added in a condition of iced bath. Compound 23-7 (46 mg, 0.474 mmol) was added into the reaction mixture after stirred under the present temperature for 0.5 hour. The reaction mixture was stirred under room temperature for 16 hour, poured into saline solution and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (10 mL×2), saturated NaCl solution (10 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure, and purified with preparation TLC plate to give the product 23-8 (23.24 mg, white solid, yield: 23.7%).

[0195] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.75 (br. s., 2H), 8.22-8.06 (m, 2H), 7.58-7.46 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.23-7.05 (m, 2H), 6.88-6.76 (m, 1H), 6.34 (br. s., 1H), 5.01 (d, J=6.5 Hz, 1H), 4.65-4.37 (m, 1H), 4.16 (d, J=6.3 Hz, 1H), 3.94-3.75 (m, 1H), 2.41 (s, 1H), 2.21 (d, J=7.0 Hz, 1H), 1.96-1.77 (m, 5H), 1.54-1.45 (m, 2H), 1.33-0.77 (m, 3H)

Example 24

[0196] ##STR00061##

Step 1 (Synthesis of 24-2)

[0197] Compound 23-6 (80 mg, 0.237 mmol) was solved in 5 mL DMF, and NaH (38 mg, 60%, 0.984 mmol) was added in a condition of iced bath. Compound 24-1 (53 mg, 0.474 mmol) was added into the reaction mixture after it was stirred under the present temperature for 0.5 hour. The reaction mixture was stirred under room temperature for 16 hour, poured into saline solution and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (10 mL×2), saturated NaCl solution (10 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to provide a crude product, which was further purified with preparation TLC plate to give the product 24-2 (17.6 mg, white solid, yield: 19%).

[0198] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.75 (br. s., 2H), 8.20-8.07 (m, 1H), 7.98-7.88 (m, 1H), 7.41-7.28 (m, 1H), 7.23-7.08 (m, 3H), 6.71-6.25 (m, 1H), 5.01 (d, J=6.3 Hz, 1H), 4.64-4.30 (m, 1H), 4.12 (d, J=6.8 Hz, 1H), 3.92-3.75 (m, 1H), 2.41 (s, 1.5H), 2.29-2.16 (m, 4H), 2.01-1.75 (m, 6H), 1.56-1.44 (m, 1.5H), 1.30-1.21 (m, 1.5H), 0.98 (d, J=6.8 Hz, 0.5H)

Example 25

[0199] ##STR00062##

Step 1 (Synthesis of 25-2)

[0200] Example 25 followed the synthetic route of example 24, wherein the reagent 24-1 was replaced with 25-1:

##STR00063##

and the product 25-2 was obtained by TLC plate purification (33.72 mg, white solid, yield: 22%).

[0201] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.74 (br. s., 2H), 8.16 (dd, J=7.7, 18.2 Hz, 1H), 7.89 (br. s., 1H), 7.37-7.25 (m, 2H), 7.24-7.12 (m, 2H), 5.01 (br. s., 1H), 4.84-4.36 (m, 1H), 4.21 (br. s., 1H), 3.80 (d, J=19.8 Hz, 1H), 2.42 (br. s., 2H), 2.09 (br. s., 2H), 1.86-1.8 (m, 3H), 1.68-1.60 (m, 1H), 1.60-1.43 (m, 2H), 1.35-1.13 (m, 2H),

Example 26

[0202] ##STR00064## ##STR00065##

Step 26 (Synthesis of 26-1)

[0203] Compound 1-7 (4.0 g, 14.13 mmol) was dissolved in 30 mL tetrahydrofuran, and LDA (14.4 mL, 28.26 mmol) was slowly added dropwise under 0° C. The mixture was stirred at 0° C. for 1 h.

[0204] While the temperature was kept at 0° C., compound NFSI (5.3 g, 16.96 mmol) was added into the reaction. After the addition was completed, the temperature was slowly raised to room temperature, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into aqueous ammonium chloride solution (30 mL), and concentrated under reduced pressure. The crude product was added into 20 mL of saturated aqueous NaCl solution, and extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with water (40 mL×2), saturated NaCl solution (40 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=60:1-20:1) to give the product 26-1 (1.5 g, yellow oily liquid, yield: 40%).

[0205] LC/MS: 245.9 (M-56+H.sup.+), 323.9 (M+Na.sup.+)

Step 2 (Synthesis of 26-2)

[0206] The compound 26-1 (1.8 g, 6.0 mmol) was dissolved in 30 mL tetrahydrofuran. Under 0° C., LAH (500 mg, 13.15 mmol) was added in several batches with small amount for each batch. After addition was completed, the mixture was warmed to room temperature, and the reaction was conducted under room temperature overnight. 0.5 mL water, 0.5 mL 15% aqueous sodium hydroxide and 1.5 mL water were successively added into the reaction mixture. A small amount of magnesium sulfate was added. The mixture was filtered after being stirred for 10 minutes, and the filtrate was dried under rotation to obtain product 26-2, which was used in next step without purification.

Step 3 (Synthesis of 26-3)

[0207] The compound 26-2 (1.5 g, 5.88 mmol) was dissolved in 20 mL DMF. Under 0° C., NaH (800 mg, 20.0 mmol) was added in several batches with small amount for each batch. The mixture was stirred under the same temperature for 30 minutes, and the compound 1-9 (676 mg, 5.88 mmol) was added. After the addition, the reaction was conducted under room temperature for 10 hours. The reaction mixture was poured into 30 mL water. 10 mL saturated NaCl solution was added. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL×2), saturated NaCl solution (30 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=50:1) to give product 26-3 (500 mg. Yield of three steps: 25%).

[0208] LC/MS: 254.9 (M-56+H.sup.+), 254.9 (M-Boc+H.sup.+), 354.9 (M+H.sup.+)

Step 4 (Synthesis of 26-4)

[0209] Compound 26-3 (150 mg) was dissolved in 4 mL of ethyl acetate, and hydrogen chloride in ethyl acetate (4 mL, 4M) was added dropwise under ice bath cooling. The mixture was stirred for 2 hours, concentrated under reduced pressure to give product 26-4 (hydrochloride form), which was used in next step without purification.

Step 5 (Synthesis of 26-5)

[0210] Compound 26-4 (120 mg, 0.37 mmol), compound 5-1 (94 mg, 0.38 mmol), HATU (209 mg, 0.55 mmol) and DIEA (143 mg, 0.96 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under room temperature for 3 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and saturated NaCl solution (10 mL×2), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to obtain a crude product, which was purified with preparative HPLC to give product 26-5 (14 mg, yield: 7.8%).

[0211] .sup.1H NMR (400 MHz, METHANOL-d4)=8.91-8.78 (m, 2H), 8.21-8.00 (m, 2H), 7.59-7.40 (m, 2H), 7.38-7.17 (m, 2H), 6.92 (dd, J=3.8, 9.3 Hz, 1H), 5.17-5.01 (m, 1H), 4.81-4.58 (m, 2H), 4.34 (br. s., 1H), 2.64-2.36 (m, 3H), 2.29-2.09 (m, 2H), 2.01-1.67 (m, 6H)

Example 27

[0212] ##STR00066##

Step 1 (Synthesis of 27-1)

[0213] Compound 23-5 (190 mg) was dissolved in 10 mL THF, and 10 mL of 0.48% LiOH aqueous solution was added. The mixture was heated at reflux for 3 hours. The diluted hydrochloric acid was added dropwise until weak acidity. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to give product 27-1 (160 mg, 94%), which was used in next step directly without purification.

Step 2 (Synthesis of 27-3)

[0214] Compound 27-1 (105.4 mg, 0.3 mmol), compound 23-2 (65.5 mg, 0.6 mmol), HATU (171 mg, 0.45 mmol) and DIEA (0.157 mL, 0.9 mmol) were dissolved in 5 mL of THF, and the mixture was stirred under room temperature for 16 hours. The reaction mixture was poured into aqueous saline and extracted with ethyl acetate (10 mL×3). The organic phase was combined and washed with water (5 mL×2) and saturated NaCl solution (5 mL×2), dried with anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure and purified with preparation TLC plate to give 100 mg of product 27-3 (100 mg, faint yellow solid).

[0215] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=10.63 (br. s., 0.5H), 9.23 (br. s., 1H), 8.76 (br. s., 0.5H), 8.38 (br. s., 1H), 8.20 (br. s., 1H), 7.35 (d, J=8.0 Hz, 1.5H), 7.14-6.92 (m, 5H), 6.76-6.54 (m, 1.5H), 5.36-5.22 (m, 1H), 3.99 (br. s., 0.5H), 3.83 (br. s., 0.5H), 2.80 (s, 5H), 2.46-2.42 (m, 3H), 2.23 (d, J=7.5 Hz, 1H), 2.11-1.96 (m, 3H)

Example 28

[0216] ##STR00067##

Step 28 (Synthesis of 28-1)

[0217] Compound 27-3 (88 mg, 0.2 mmol) and triphenylphosphine (52.4 mg, 0.2 mmol) were dissolved in 25 mL of THF. Under nitrogen protection, 2 mL DIAD (40.4 mg, 0.2 mmol) in THF was added by syringe. The reaction mixture was heated at reflux for 3 hour, poured into saline solution and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with water (10 mL×2), saturated NaCl solution (10 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated to obtain a crude product which was purified with preparation TLC plate to give product 28-1 (11.7 mg, white solid, yield: 13.37%).

[0218] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=10.51 (br. s., 0.4H), 10.03 (br. s., 0.1H), 9.15 (s, 1H), 8.74 (br. s., 1H), 8.39 (br. s., 1H), 8.26-8.10 (m, 1H), 7.41-7.30 (m, 1.5H), 7.05 (br. s., 1.5H), 6.92 (d, J=8.5 Hz, 1.5H), 6.74 (br. s., 1H), 5.24 (br. s., 1H), 4.99-4.81 (m, 2H), 4.01 (br. s., 0.6H), 3.78 (br. s., 0.4H), 2.78 (br. s., 1H), 2.43 (br. s., 4H), 2.25 (br. s., 1H), 2.11-1.93 (m, 3H), 1.81 (br. s., 1H)

Example 29

[0219] ##STR00068## ##STR00069##

Step 29 (Synthesis of 29-1)

[0220] Compound 23-5 (5 g) was separated via SFC separation (separation method: Instrument Model: MG II preparative SFC (SFC-1); separation column: ChiralPak OD, 250×30 mm I.D.; mobile phase: A: CO.sub.2, B: ethanol (0.1% aqueous ammonia); density: B 30%; flow rate: 55 mL/min; back flow pressure: 100 bar; column temperature: 38° C.; detection wavelength: 220 nm) to give a chirally pure product 29-1 (2 g, white solid, yield: 80%).

Step 2 (Synthesis of 29-2)

[0221] Compound 29-1 (1.3 g, 3.426 mmol) was solved in 25 mL THF, and LAH (100 mg, 2.5 mmol) was added slowly under iced ethanol bath. The reaction mixture was stirred under the present temperature for 1 hour. 20 mL of anhydrous THF was added for dilution. 0.1 mL of water, 0.1 mL of 15% sodium hydroxide solution and 0.3 mL of water were added dropwise successively to quench the reaction. The mixture was then dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure to give product 29-2 (1.1 g, yellow solid, yield: 96%), which was used directly in next step without purification.

Step 3 (Synthesis of 29-3)

[0222] Compound 29-2 (200 mg, 0.6 mmol) was dissolved in 10 mL DCM, and triethylamine (152 mg, 1.5 mmol) and MsCl (103 mg, 0.9 mmol) were added successively. The reaction mixture was stirred under room temperature for 2 hours, poured into saline solution and extracted with dichloromethane (10 mL×3). The combined organic phase was washed with water (10 mL×2), saturated NaCl solution (10 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under vacuum to give the product 29-3 (244 mg, yield: 98%), which was used in next step without purification.

Step 4 (Synthesis of 29-5)

[0223] Compound 29-3 (98 mg, 0.237 mmol) and compound 29-4 (53 mg, 0.474 mmol) were dissolved in 5 mL DMF, and cesium carbonate (196 mg, 0.6 mmol) was added under room temperature. The reaction mixture was stirred under 80° C. for 16 hour, poured into saline solution and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (10 mL×2), saturated NaCl solution (10 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure, and purified with preparative HPLC to give product 29-5 (5.45 mg, white solid, yield: 5.3%).

[0224] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.76 (d, J=4.3 Hz, 1H), 8.70 (br. s., 1H), 8.16 (d, J=8.0 Hz, 0.5H), 8.10 (d, J=8.0 Hz, 0.5H), 7.31 (d, J=8.0 Hz, 0.5H), 7.17 (d, J=7.3 Hz, 1.5H), 7.10 (br. s., 1H), 6.98-6.88 (m, 3H), 6.57 (br. s., 1H), 5.00 (d, J=7.3 Hz, 0.6H), 4.92 (br. s., 0.4H), 4.26 (br. s., 0.6H), 4.04 (br. s., 0.4H), 3.84 (br. s., 1.5H), 3.66 (dd, J=6.0, 8.5 Hz, 0.5H), 2.41 (s, 2H), 2.17 (br. s., 0.5H), 1.98-1.73 (m, 7H), 1.52 (d, J=8.5 Hz, 1.5H), 1.25 (br. s., 1H)

Example 30

[0225] ##STR00070##

Step 30 (Synthesis of 30-2)

[0226] Compound 29-3 (98 mg, 0.237 mmol) and compound 30-1 (63 mg, 0.474 mmol) were dissolved in 5 mL DMF, and cesium carbonate (196 mg, 0.6 mmol) was added under room temperature. The reaction mixture was stirred under 80° C. for 16 hour, poured into saline solution and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with water (10 mL×2), saturated NaCl solution (10 mL×2) successively, and dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under reduced pressure, and purified with preparative HPLC to give product 30-2 (19.63 mg, white solid, yield: 18.4%).

[0227] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.75 (d, J=3.8 Hz, 1H), 8.70 (br. s., 1H), 8.17 (d, J=8.0 Hz, 0.6H), 8.12 (d, J=7.8 Hz, 0.4H), 7.31 (d, J=7.8 Hz, 0.5H), 7.21 (d, J=8.0 Hz, 0.5H), 7.18-7.05 (m, 2.5H), 6.91-6.82 (m, 1H), 6.79 (br. s., 1.5H), 5.01 (d, J=6.5 Hz, 0.5H), 4.92 (br. s., 0.5H), 4.32 (br. s., 0.6H), 4.12 (br. s., 0.4H), 4.03-3.68 (m, 2H), 2.41 (s, 2H), 2.21 (br. s., 1H), 2.02 (d, J=11.5 Hz, 2H), 1.94-1.78 (m, 4H), 1.61-1.48 (m, 2H), 1.25 (br. s., 1H)

Example 31

[0228] ##STR00071##

[0229] Example 31 followed the synthetic route of example 30, wherein the reagent 30-1 was replaced with 31-1:

##STR00072##

and the product 31-2 was obtained by preparative HPLC purification (5.79 mg, white solid, yield: 5.9%).

[0230] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.84-8.61 (m, 2H), 8.47-8.26 (m, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.12-8.06 (m, 0.5H), 8.02 (br. s., 0.5H), 7.37 (dd, J=1.5, 8.5 Hz, 0.5H), 7.33-7.27 (m, 1.5H), 7.22-7.04 (m, 3H), 5.02 (d, J=6.5 Hz, 1H), 4.40 (br. s., 0.5H), 4.17-4.06 (m, 0.5H), 3.92 (br. s., 1H), 3.80 (br. s., 0.5H), 3.74 (dd, J=5.5, 8.5 Hz, 0.5H), 2.41 (s, 1.5H), 2.26-2.21 (m, 0.5H), 1.99-1.73 (m, 6H), 1.67 (br. s., 1.5H), 1.51 (d, J=9.5 Hz, 1.5H), 0.98-0.79 (m, 1H)

Example 32

[0231] ##STR00073##

[0232] Example 31 followed the synthetic route of example 30, wherein the reagent 30-1 was replaced with 32-1:

##STR00074##

and the product 32-2 was obtained by preparative HPLC purification (7.32 mg, white solid, yield: 7.46%).

[0233] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.75 (d, J=4.5 Hz, 2H), 8.26 (d, J=6.8 Hz, 1H), 7.87 (br. s., 2H), 7.36 (d, J=8.0 Hz, 1H), 7.20 (br. s., 2H), 6.60 (br. s., 2H), 4.75 (d, J=5.5 Hz, 1H), 4.29 (br. s., 1H), 3.90 (br. s., 2H), 2.45 (s, 3.5H), 2.07 (br. s., 3.5H), 1.77 (br. s., 1H), 1.63 (br. s., 2H), 1.52 (d, J=12.8 Hz, 1H), 1.34 (br. s., 1H)

Example 33

[0234] ##STR00075##

[0235] Example 33 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 33-1:

##STR00076##

and the product 33-2 was obtained by preparative HPLC purification (25 mg, pale yellow solid, yield: 29%).

[0236] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.87-8.68 (m, 1H), 8.68-8.48 (m, 1H), 8.30-7.89 (m, 2H), 7.58-7.40 (m, 1H), 7.34 (s, 1H), 7.33-7.22 (m, 2H), 7.18 (d, J=7.8 Hz, 1H), 6.77 (dd, J=3.0, 8.8 Hz, 0.4H), 6.30 (dd, J=3.1, 8.9 Hz, 0.6H), 4.95-4.71 (m, 1H), 4.07-3.92 (m, 1H), 3.71-3.49 (m, 1H), 3.38 (br. s., 1H), 2.44 (s, 1H), 2.29-2.04 (m, 1H), 2.04-1.93 (m, 2H), 1.93-1.70 (m, 2H), 1.66-1.52 (m, 1H), 1.59-1.20 (m, 5H)

Example 34

[0237] ##STR00077##

[0238] Example 34 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 34-1:

##STR00078##

and the product 34-2 was obtained by preparative HPLC purification (30 mg, pale yellow solid, yield: 34.5%).

[0239] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=9.31-9.12 (m, 1H), 9.06-8.74 (m, 2H), 8.07-7.88 (m, 1H), 7.43-7.10 (m, 4H), 6.78 (dd, J=3.4, 8.9 Hz, 0.4H), 6.28 (dd, J=3.4, 8.9 Hz, 0.6H), 4.98-4.73 (m, 1H), 4.41 (br. s., 1H), 4.13-3.85 (m, 1H), 3.69-3.44 (m, 1H), 2.45 (s, 1H), 2.33-2.06 (m, 1H), 2.04-1.93 (m, 3H), 1.93-1.73 (m, 2H), 1.68 (br. s., 1H), 1.60-1.51 (m, 1H), 1.50-1.23 (m, 3H)

Example 35

[0240] ##STR00079##

[0241] Example 35 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 35-1:

##STR00080##

and the product 35-2 was obtained by preparative HPLC purification (4.47 mg, white solid, yield: 4.6%).

[0242] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.80 (br. s., 2H), 8.52-8.25 (m, 1H), 7.86-7.63 (m, 2H), 7.31 (t, J=8.2 Hz, 1H), 7.26-7.18 (m, 2H), 6.75 (dd, J=3.5, 9.0 Hz, 0.5H), 6.26 (br. s., 0.5H), 5.02 (br. s., 1H), 4.65-4.38 (m, 1H), 4.28-3.98 (m, 1H), 3.78 (br. s., 1H), 2.27-2.10 (m, 1H), 2.06-1.79 (m, 3H), 1.59-1.56 (m, 4H), 1.25 (br. s., 1H)

Example 36

[0243] ##STR00081##

[0244] Example 36 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 36-1:

##STR00082##

and the product 36-2 was obtained by preparative HPLC purification (25.32 mg, white solid, yield: 34.4%).

[0245] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.06-7.79 (m, 1H), 7.38-7.27 (m, 1H), 7.12-7.02 (m, 1H), 6.95-6.77 (m, 2H), 6.29 (br. s., 1H), 5.09-4.93 (m, 1H), 4.54 (dd, J=7.8, 10.5 Hz, 0.5H), 4.34 (dd, J=7.7, 10.4 Hz, 0.5H), 4.22-4.14 (m, 0.5H), 4.06 (br. s., 1H), 3.73 (br. s., 0.5H), 2.44-2.19 (m, 3H), 2.19-2.05 (m, 3H), 2.04-1.87 (m, 3H), 1.87-1.60 (m, 3H), 1.60-0.90 (m, 3H)

Example 37

[0246] ##STR00083##

[0247] Example 37 followed the synthetic route of example 10, wherein the reagent 10-1 was replaced with 37-1:

##STR00084##

and the product 37-2 was obtained by preparative HPLC purification (29.63 mg, beige solid, yield: 33.9%).

[0248] .sup.1H NMR (400 MHz, CHCl.sub.3-d)=8.30-7.93 (m, 1H), 7.92-7.78 (m, 1H), 7.77-7.54 (m, 1H), 7.46-6.95 (m, 4H), 6.79 (dd, J=3.5, 9.0 Hz, 0.5H), 6.33 (d, J=6.3 Hz, 0.5H), 5.11-4.76 (m, 1H), 4.69-4.24 (m, 1H), 4.16-3.97 (m, 1H), 3.89-3.55 (m, 1H), 2.42 (s, 1H), 2.27-1.94 (m, 3H), 1.92-1.70 (m, 3H), 1.63 (br. s., 1H), 1.56-1.39 (m, 2H), 1.27-0.80 (m, 2H)

Experimental Example 1: In Vitro Test of OX1/2R

[0249] Experimental Purpose:

[0250] The inhibitive effect of a compound on OX1 and OX2 GPCR receptor was evaluated by detecting calcium signal change in cells with FLIPR, and IC.sub.50 value of compound was used as an indication.

[0251] Experimental Materials: [0252] Cell line: HEK293-OX1 and OX2 stable cell strain [0253] HEK293-OX1 cell culture media (DMEM, Invitrogen#11960-044, 10% serum Gibco#10099141, L-Glutamine 1×, Gibco#25030, sodium pyruvate 1×, Gibco #11360, Geneticin 300 μg/ml, Gibco #10131). [0254] HEK293-OX2 cell culture media (DMEM, Invitrogen#11960-044, 10% serum Gibco#10099141, L-Glutamine 1×, Gibco#25030, sodium pyruvate 1×, Gibco #11360, Geneticin 300 μg/ml, Gibco #10131, Blasticin 2 μg/ml, Invitrogen # R21001). [0255] Pancreatic enzyme (Invitrogen, #25200-072) [0256] DPBS (Hyclone, #SH30028.01B) [0257] Fluo-4 AM, Invitrogen# F14202 [0258] F-127, Invitrogen # P3000MP [0259] Probenecid, Sigma # P8761 [0260] 384-well cell plate, Greiner #781946 [0261] 384-well compound plate, Greiner #781280 [0262] CO.sub.2 incubator, Thermo#371 [0263] Centrifuge, Eppendorf #5810R [0264] Vi-cell cytometry, Beckman Coulter [0265] POD 810 Plate Assembler Automatic microplate pretreatment system [0266] Labcyte FLIPR, Molecular Device.

[0267] Experimental Procedures and Methods:

[0268] a) cell inoculation (HEK293-OX1 and HEK293-OX2 cells) [0269] 1) The medium trypsin, and DPBS were preheated at 37° C. under water bath. Culture medium of cells was sucked and cells were washed with 10 mL DPBS. [0270] 2) The preheated trypsin was added into the culture bottle which was rotated so that trypsin uniformly covered the bottle. It was placed in an incubator (37° C., 5% CO.sub.2) to digest for 1-2 minutes; [0271] 3) Each T150 was suspended with 10-15 mL of culture medium, and centrifuged at 800 rpm for 5 minutes. Cells were resuspended with 10 mL medium, and 1 mL of the cell re-suspension was sucked out and counted with Vi-cell cytometry. [0272] 4) The OX1 cells were diluted with culture medium to 5×10.sup.5 cells/mL, and OX2 cells were diluted to 4×10.sup.5 cells/mL. The diluted cells were added into 384 plate (Greiner. 781946) with multichannel pipettes (50 μL/hole, OX1 cells: 25000 cells/hole; and OX2 cells: 20000 cells/hole). The cell plate was placed in an incubator (37° C., 5% CO.sub.2) overnight.

[0273] b) loading of the compound: [0274] 1) DMSO was used to dilute the compound into 20 mM by using 3-fold dilution. 8 gradients in duplicate wells were used. Echo liquid handler was used to add the compound into a compound plate. Then 20 μL buffer was added to ensure that the final DMSO concentration was 0.1%.

[0275] c) FLIPR Experiment: [0276] 1) The cell culture medium in 384-well plate was washed away with a vacuum pump. 30 μL fluorescent dye Fluo4AM was added. The cell was incubated at 37° C., 5% CO.sub.2 in an incubator for 1 hr and then re-equilibrated under room temperature for 10 minutes. [0277] 2) EC50 Test: Orexin A was diluted manually on ice by using 3-fold diluted. 8 gradients in duplicate wells were used. Then the DMSO plate was prepared and the DMSO concentration was 0.5%. The cell plate, Orexin A plate, and DMSO plate were placed into FLIPR respectively, and the fluorescence values were read. [0278] 3) EC70 value was calculated based on EC50 value of Orexin A. 5×EC70 solution was prepared and added into a 384-well compound plate with multichannel pipettes. The plate was placed on ice for preservation. [0279] 4) In the FLIPR, the compound plate, 5×EC70 plate, cell plate and FLIPR tips were placed respectively. The program was run and the fluorescence values were read.

[0280] d) Data Analysis: Prism5.0 was used to analysis the data, and the IC.sub.50 value of the compound was calculated.

The experimental results are shown in table 1:

TABLE-US-00001 TABLE 1 IC.sub.50 experimental results detected in FLIPR Test sample (title compound) hOX1R (nM) hOX2R (nM) MK6096 36 29 Example 1 (1-16) 10 24 Example 2 (2-1) 2296 2508 Example 3 (3-3) 2072 1425 Example 4 (4-1) 217 195 Example 5 (5-3) 20 36 Example 6 (6-1) 2552 4189 Example 7 (7-3) 1270 291 Example 8 (8-1) 4255 4609 Example 9 (9-4) 24 15 Example 10 (10-2) 29 73 Example 11 (11-2) 321 363 Example 12 (12-2) 219 206 Example 13 (13-2) 47 663 Example 14 (14-2) 16 20 Example 15 (15-2) 37 55 Example 16 (16-2) 56 440 Example 17 (17-2) 43 47 Example 18 (18-2) 127 904 Example 19 (19-2) 41 372 Example 20 (20-2) 7 26 Example 21 (21-2) 567 741 Example 22 (22-2) 2418 1371 Example 23 (23-8) 45 97 Example 24 (24-2) 56 87 Example 25 (25-2) 113 124 Example 26 (26-5) 48 37 Example 27 (27-3) 3000 3000 Example 28 (28-1) 34 23 Example 29 (29-5) 68 121 Example 30 (30-2) 489 262 Example 31 (31-2) 305 221 Example 32 (32-2) 7 6 Example 33 (33-2) 10 24 Example 34 (34-2) 2296 2508 Example 35 (35-2) 2072 1425 Example 36 (36-2) 217 195 Example 37 (37-2) 20 36

[0281] Conclusion: It can be seen from Table 1 that the exemplary compounds of invention significantly inhibit OX1 and OX2 GPCR receptors, and some of the compounds have more excellent activity when compared with the positive control. It has also found that for some exemplary compounds, the different spatial configuration may greatly impact the inhibitive effects on OX1 and OX2 GPCR receptors.