Pyrazolo-heteroaryl derivative, preparation method and medical use thereof

Abstract

Disclosed are a pyrazolo-heteroaryl derivative, a preparation method and medical use thereof. In particular, this invention relates to a new pyrazolo-heteroaryl derivative as shown in the general formula (I), a preparation method thereof and a pharmaceutical composition containing the derivative and the use thereof as a therapeutic agent, in particular as a TLR7 agonist, wherein each substituent in the general formula (I) is defined in the description.

What is claimed is: 
     
         1 . A method for treating an infection caused by a virus, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents or excipients, and a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, 
         wherein: 
         ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         G is CH or N; 
         X 1  is alkylene or S(O) m , wherein the alkylene is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl; 
         L 1  is selected from the group consisting of —NR 4 —, —O—, —S—, —C(O)—, —S(O) m —, —N(R 4 )C(O)—, —C(O)N(R 4 )—, —N(R 4 )S(O) 2 —, —S(O) 2 N(R 4 )— and a covalent bond; 
         R 1  is selected from the group consisting of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 ; 
         each R 2  is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 ; 
         L 2  is alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 ; 
         R 3  is selected from the group consisting of haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 , wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 8 , —S(O) m R 8 , —NR 9 R 10  and —C(O)NR 9 R 10 ; 
         R 4  is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 5  is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 6  and R 7  are identical or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 8 , —S(O) m R 8  and —C(O)NR 9 R 10 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         or, R 6  and R 7  together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl optionally contains one or two identical or different heteroatoms selected from the group consisting of N, O and S in addition to the nitrogen atom, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 8  is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         R 9  and R 10  are identical or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
         n is 0, 1, 2, 3 or 4; 
         m is 0, 1 or 2; 
         said cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring; 
         said heterocyclyl refers to a 3 to 20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group wherein 1 to 4 atoms are heteroatoms selected from the group consisting of N, O, S(O) and S(O) 2 , polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring; 
         said heteroaryl refers to a 5 to 14 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of O, S and N; and 
         wherein the virus is selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral disarrhea virus, Zika virus, HIV, HBV, HCV, HPV, RSV, SARS and influenza virus. 
       
     
     
         2 . The method according to  claim 1 , wherein R 3  is heterocyclyl, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
     
     
         3 . The method according to  claim 1 , wherein R 3  is —NR 6 R 7 , and R 6  and R 7  together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl optionally contains one or two identical or different heteroatoms selected from the group consisting of N, O and S in addition to the nitrogen atom, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
     
     
         4 . The method according to  claim 1 , wherein the ring A is phenyl. 
     
     
         5 . The method according to  claim 1 , wherein X 1  is alkylene. 
     
     
         6 . The method according to  claim 1 , wherein G is N. 
     
     
         7 . The method according to  claim 1 , wherein the compound is a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
 wherein: 
 s is 0, 1 or 2. 
 
     
     
         8 . The method according to  claim 1 , wherein L 1  is selected from the group consisting of —O—, —NR 4 —, —C(O)— and —C(O)N(R 4 )—, and R 4  is hydrogen or alkyl. 
     
     
         9 . The method according to  claim 1 , wherein R 1  is alkyl optionally substituted by one or more alkoxy. 
     
     
         10 . The method according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A method for treating or preventing melanoma, non-small cell lung carcinoma, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis or hepatic fibrosis, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents or excipients, and a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
 wherein: 
 ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 G is CH or N; 
 X 1  is alkylene or S(O) m , wherein the alkylene is optionally substituted by one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl; 
 L 1  is selected from the group consisting of —NR 4 —, —O—, —S—, —C(O)—, —S(O) m —, —N(R 4 )C(O)—, —C(O)N(R 4 )—, —N(R 4 )S(O) 2 —, —S(O) 2 N(R 4 )— and a covalent bond; 
 R 1  is selected from the group consisting of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 ; 
 each R 2  is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 ; 
 L 2  is alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 ; 
 R 3  is selected from the group consisting of haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —C(O)R 5 , —S(O) m R 5 , —NR 6 R 7  and —C(O)NR 6 R 7 , wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 8 , —S(O) m R 8 , —NR 9 R 1 ° and —C(O)NR 9 R 10 ; 
 R 4  is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 R 5  is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 R 6  and R 7  are identical or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 8 , —S(O) m R 8  and —C(O)NR 9 R 10 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 or, R 6  and R 7  together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl optionally contains one or two identical or different heteroatoms selected from the group consisting of N, O and S in addition to the nitrogen atom, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 R 8  is selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 R 9  and R 10  are identical or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 n is 0, 1, 2, 3 or 4; 
 m is 0, 1 or 2; 
 said cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring; 
 said heterocyclyl refers to a 3 to 20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group wherein 1 to 4 atoms are heteroatoms selected from the group consisting of N, O, S(O) and S(O) 2 , polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring; and 
 said heteroaryl refers to a 5 to 14 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of O, S and N. 
 
     
     
         12 . The method according to  claim 11 , wherein R 3  is heterocyclyl, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
     
     
         13 . The method according to  claim 11 , wherein R 3  is —NR 6 R 7 , and R 6  and R 7  together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl optionally contains one or two identical or different heteroatoms selected from the group consisting of N, O and S in addition to the nitrogen atom, and the heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. 
     
     
         14 . The method according to  claim 11 , wherein the ring A is phenyl. 
     
     
         15 . The method according to  claim 11 , wherein X 1  is alkylene. 
     
     
         16 . The method according to  claim 11 , wherein G is N. 
     
     
         17 . The method according to  claim 11 , wherein the compound is a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a tautomer, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof,
 wherein: 
 s is 0, 1 or 2. 
 
     
     
         18 . The method according to  claim 11 , wherein L 1  is selected from the group consisting of —O—, —NR 4 —, —C(O)— and —C(O)N(R 4 )—, and R 4  is hydrogen or alkyl. 
     
     
         19 . The method according to  claim 11 , wherein R 1  is alkyl optionally substituted by one or more alkoxy. 
     
     
         20 . The method according to  claim 11 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.