Use and pharmaceutical composition of phenylisoxazolyl methylene-naphthalene-ether derivatives

Abstract

Provided are a method of treating or preventing infection with hepatitis B virus in a human or animal, comprising administering to the human or animal in need thereof a therapeutically effective amount of a phenylisoxazolyl methylene-naphthalene-ether derivative having a structure of formula (I); use of a phenylisoxazolyl methylene-naphthalene-ether derivative having a structure of formula (I) in the preparation of a pharmaceutical composition for anti-hepatitis B vims and a pharmaceutical composition for anti-hepatitis B virus.

1 . A method of treating or preventing infection with hepatitis B virus in a human or animal, comprising administering to the human or animal in need thereof a therapeutically effective amount of a phenylisoxazolyl methylene-naphthalene-ether derivative having a structure of formula (I), or a pharmaceutically acceptable salt, ester or stereoisomer thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2  and R 3  are independently selected from H, halogen, unsubstituted or halogen substituted C 1-6  alkyl and unsubstituted or halogen substituted C 1-6  alkoxy, provided that at least one of R 1 , R 2  and R 3  is not hydrogen, R 0  is selected from unsubstituted or halogen substituted C 1-6  alkyl, C 3-6  cycloalkyl and C 4-7  alkylcycloalkyl; 
 X 1  and X 2  are independently selected from H and halogen; 
 moiety —O—Z attaches to the naphthalene ring, wherein Z is a residue selected from 5-10 membered aryl or 5-10 membered heteroaryl optionally having one or more hetero atoms selected from N, O and S, wherein the 5-10 membered aryl or 5-10 membered heteroaryl is substituted by R 4  and is optionally further substituted by R 5 ; and 
 wherein R4 is selected from —COOH, —CH 2 COOH, —NHSO 2 CF 3 , —SO 2 NH—C 1-6  alkyl, —SO 3 H, —CONHSO 2 —C 1-6  alkyl, —CONHSO 2 —C 3-6  cycloalkyl, —CONHSO 2 -5-10 membered aryl and —CONHSO2-5-10 membered aryl substituted by C 1-6  alkyl at the aryl, and wherein R 5  is selected from H, C 1-6  alkyl, halogen, C 1-6  haloalkyl, —O—(C 1-6  alkyl) and —NH—(C 1-6  alkyl). 
 
       
     
     
         2 . The method according to  claim 1 , wherein R 1 , R 2  and R 3  are independently selected from H, halogen and C 1-3  perfluoroalkoxy, and R 0  is selected from isopropyl or cyclopropyl;
 wherein Z is a phenyl which is substituted by R 4  and is optionally substituted by R 5 ; or Z is a 5-10 membered heteroaryl having one or more hetero atoms selected from N, O and S, which is substituted by R 4  and is optionally substituted by R 5 ; and   wherein the halogen is fluoro or chloro.   
     
     
         3 . The method according to  claim 2 , wherein R 1 , R 2  and R 3  are independently selected from H, Cl, F and —O—CF 3 ; and
 wherein Z is a 5-6 membered heteroaryl having one or more hetero atoms selected from N, O and S, which is substituted by R 4  and is optionally substituted by R 5 , wherein R 4  is selected from —COOH, —CH 2 COOH, —CONHSO 2 —C 1-6  alkyl and —CONHSO 2 —C 3-6  cycloalkyl, R 5  is selected from H, C 1-3  alkyl and halogen. 
 
     
     
         4 . The method according to  claim 3 , wherein Z is pyridyl; R 4  is —COOH; and R 5  is H or halogen. 
     
     
         5 . The method according to  claim 1 , wherein the phenylisoxazolyl methylene-naphthalene-ether derivative is of one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         49 . The method according to  claim 4 , wherein the phenylisoxazolyl methylene-naphthalene-ether derivative is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 1 , wherein the method comprises administering the phenylisoxazolylmethylene-naphthalene-ether derivative having the structure of formula (I), or a pharmaceutically acceptable salt, ester or stereoisomer thereof in combination with one or more other anti-HBV agents. 
     
     
         8 . The method of  claim 7 , wherein the other anti-HBV agents are selected from HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hepatitis b surface antigen (HBsAg) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, fatty acid synthase inhibitors, HBV antibodies, CCR2 chemokine antagonists, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, PD-1 inhibitors, PD-L1 inhibitors, KDM inhibitors, and HBV replication inhibitors. 
     
     
         9 . The method of  claim 8 , wherein the HBV DNA polymerase inhibitor is entecavir or tenofovir,
 the PD-1 inhibitor is one or more selected from nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, cemiplimab, camrelizumab, sintilimab, tislelizumab (BGB-A317), BCD-100, JNJ-63723283, Zimberelimab (GLS-010, WBP-3055), Balstilimab (AGEN2034) and dostarlimab (TSR-042);   the PD-L1 inhibitors is one or more selected from atezolizumab (RG-7446), avelumab, BGB-A333, BMS-936559 (MDX-1105), durvalumab, CX-072, GX-P2, KN035 (ASC022), GS-4224 and INCB086550;   the antisense oligonucleotide is Ionis-HBVRx or Ionis-HBV-LRx   the short interfering RNA is JNJ-3989, or Vir-2218, or DCR-HBVS   the fatty acid synthase inhibitor is TVB-2640 and/or TVB-3567;   the interferon is Pegasys; and   the capsid inhibitor is one or more selected from ABI-H0731, ABI-H2158, ABI-H3733, CB-HBV-001, JNJ-6379, JNJ-0440, QL-007, RG-7907 and RO7049389.   
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A pharmaceutical composition for anti-hepatitis B virus, comprising a therapeutically effective amount of a phenylisoxazolyl methylene-naphthalene-ether derivative having a structure of formula (I), or a pharmaceutically acceptable salt, ester or stereoisomer thereof and one or more other anti-HBV agents, and a pharmaceutically acceptable auxiliary material, 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2  and R 3  are independently selected from H, halogen, unsubstituted or halogen substituted C 1-6  alkyl and unsubstituted or halogen substituted C 1-6  alkoxy, provided that at least one of R 1 , R 2  and R 3  is not hydrogen, R 0  is selected from unsubstituted or halogen substituted C 1-6  alkyl, C 3-6  cycloalkyl and C 4-7  alkylcycloalkyl; 
 X 1  and X2 are independently selected from H and halogen; 
 moiety —O—Z attaches to the naphthalene ring, wherein Z is a residue selected from 5-10 membered aryl or 5-10 membered heteroaryl optionally having one or more hetero atoms selected from N, O and S, wherein the 5-10 membered aryl or 5-10 membered heteroaryl is substituted by R 4  and is optionally further substituted by R 5 ; and 
 wherein R 4  is selected from —COOH, —CH 2 COOH, —NHSO 2 CF 3 , —SO 2 NH—C 1-6  alkyl, —SO 3 H, —CONHSO 2 —C 1-6  alkyl, —CONHSO 2 —C 3-6  cycloalkyl, —CONHSO 2 -5-10 membered aryl and —CONHSO 2 -5-10 membered aryl substituted by C 1-6  alkyl at the aryl, and wherein R 5  is selected from H, C 1-6  alkyl, halogen, C 1-6  haloalkyl, —O—(C 1-6  alkyl) and —NH—C 1-4  alkyl). 
 
       
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein R 1 , R 2  and R 3  are independently selected from H, halogen and C 1-3  perfluoroalkoxy, and R 0  is selected from isopropyl or cyclopropyl;
 wherein Z is a phenyl which is substituted by R 4  and is optionally substituted by R 5 ; or Z is a 5-10 membered heteroaryl having one or more hetero atoms selected from N, O and S, which is substituted by R 4  and is optionally substituted by R 5 ; and   wherein the halogen is fluoro or chloro.   
     
     
         18 . The pharmaceutical composition according to claim  17 , wherein R 1 , R 2  and R 3  are independently selected from H, Cl, F and —O—CF 3 ; and
 wherein Z is a 5-6 membered heteroaryl having one or more hetero atoms selected from N, O and S, which is substituted by R 4  and is optionally substituted by R 5 , wherein R is selected from —COOH, —CH 2 COOH, —CONHSO 2 —C 1-6  alkyl and —CONHSO 2 —C 3-6  cycloalkyl, R 5  is selected from H, C 1-3  alkyl and halogen. 
 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein Z is pyridyl; R 4  is —COOH; and R 5  is H or halogen. 
     
     
         20 . The pharmaceutical composition according to  claim 16 , wherein the phenylisoxazolyl methylene-naphthalene-ether derivative is of one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . The pharmaceutical composition according to  claim 16 , wherein the phenylisoxazolyl methylene-naphthalene-ether derivative is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The pharmaceutical composition according to  claim 16 , wherein the pharmaceutical composition comprises one or more other anti-HBV agents and the phenylisoxazolylmethylene-naphthalene-ether derivative having the structure of formula (I), or a pharmaceutically acceptable salt, ester or stereoisomer thereof. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the other anti-HBV agents are selected from HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hepatitis b surface antigen (HBsAg) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, fatty acid synthesis inhibitors, HBV antibodies, CCR2 chemokine antagonists, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, PD-1 inhibitors, PD-L1 inhibitors, KDM inhibitors, and HBV replication inhibitors. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the HBV DNA polymerase inhibitor is entecavir or tenofovir,
 the PD-1 inhibitor is one or more selected from nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, cemiplimab, camrelizumab, sintilimab, tislelizumab (BGB-A317), BCD-100, JNJ-63723283, Zimberelimab (GLS-010, WBP-3055), Balstilimab (AGEN2034) and dostarlimab (TSR-042);   the PD-L1 inhibitors is one or more selected from atezolizumab (RG-7446), avelumab, BGB-A333, BMS-936559 (MDX-1105), durvalumab, CX-072, GX-P2, KN035 (ASC022), GS-4224 and INCB086550;   the antisense oligonucleotide is Ionis-HBVRx or Ionis-HBV-LRx;   the short interfering RNA is JNJ-3989, Vir-2218, or DCR-HBVS;   the fatty acid synthase inhibitor is TVB-2640 and/or TVB-3567;   the interferon is Pegasys; and   the capsid inhibitor is one or more selected from ABI-H0731, ABI-H2158, ABI-H3733, CB-HBV-001, JNJ-6379, JNJ-0440, QL-007, RG-7907 and RO7049389.